DK161770B - METHOD OF ANALOGUE FOR THE PREPARATION OF CYCLOBUTYLAMINE DERIVATIVES OR PHARMACEUTICAL ACCEPTABLE SALTS THEREOF - Google Patents

METHOD OF ANALOGUE FOR THE PREPARATION OF CYCLOBUTYLAMINE DERIVATIVES OR PHARMACEUTICAL ACCEPTABLE SALTS THEREOF Download PDF

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DK161770B
DK161770B DK146482A DK146482A DK161770B DK 161770 B DK161770 B DK 161770B DK 146482 A DK146482 A DK 146482A DK 146482 A DK146482 A DK 146482A DK 161770 B DK161770 B DK 161770B
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cyclobutyl
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James Edward Jeffery
Antonin Kozlik
Eric Charles Wilmshurst
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Boots Co Plc
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    • C07D295/073Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

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Description

DK 161770 BDK 161770 B

Den foreliggende opfindelse angår en analogifremgangsmåde til fremstilling af hidtil ukendte cyklobutylaminderi-vater eller farmaceutisk acceptable salte deraf, hvilke forbindelser har den i krav 11 s indledning viste almene formel 1 o o λ R *7 ft 5 I, hvor R , , R , R4, R , R , R , R° og n har de samme steds angivne betydninger; forbindelserne har terapeutisk virkning, navnlig men ikke udelukkende som antidepressanter. Fremgangsmåden ifølge opfindelsen er ejendommelig ved det i krav 1's kendetegnende del angivne, 10 I formlerne i nærværende beskrivelse betegner symbolet 15 en 1,1-disubstitueret cyklobutangruppe med formlen #—C-CH0 I I 2 CH2-CH2 20 og -CR^R^(CR^R^)nNR^R^ en gruppe med formlen ?VA ^r3 25 IW- ^ n I de foretrukne forbindelser med formel I hvor n = 0 er R^ en ligekædet eller forgrenet alkylgruppe med 1-4 kul- stofatomer, en cykloalkylgruppe med 3-7 kulstofatomer, en cykloalkylmetylgruppe hvor cykloalkyIringen indeholder 3-6 g kulstofatomer eller en gruppe med formlen II hvor R og/el-ler R·*"0 er H, fluor eller metoxy og hvor R^ er H eller metyl. Eksempler på særlig foretrukne forbindelser med formel I 2^ er dem hvor, når n = 0 og R = H, R er metyl, ætyl, propyl, isopropyl, butyl, s-butyl, isobutyl, cyklopropyl, cyklobutyl, cyklopentyl, cyklohexyl, cyklopropylmetyl, cyklobutylmetyl, 2 !The present invention relates to an analogous process for the preparation of novel cyclobutylamine derivatives or pharmaceutically acceptable salts thereof, the compounds of which have the general formula 1 oo λ R * 7 ft 5 I shown in claim 11, wherein R 1, R R, R, R, R ° and n have the same meanings stated; the compounds have therapeutic effect, especially but not exclusively as antidepressants. The process of the invention is characterized by the characterizing part of claim 1, in the formulas of this specification, the symbol 15 represents a 1,1-disubstituted cyclobutane group of the formula # -C-CHO II 2 CH 2 -CH 2 20 and -CR 2 R 2 ( A group of the formula? VA ^ r3 25 IW- ^ n In the preferred compounds of formula I wherein n = 0, R 1 is a straight or branched alkyl group of 1-4 carbon atoms, a a cycloalkyl group having 3-7 carbon atoms, a cycloalkylmethyl group wherein the cycloalkyl ring contains 3-6 g of carbon atoms or a group of formula II wherein R and / or R R is O, H, fluorine or methoxy and where R R is H or methyl. Examples of particularly preferred compounds of formula I 2 are those wherein when n = 0 and R = H, R is methyl, ethyl, propyl, isopropyl, butyl, s-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl , cyclobutylmethyl, 2!

DK 161770 BDK 161770 B

cyklopentylmetyl, cyklohexylmetyl eller fenyl.cyclopentylmethyl, cyclohexylmethyl or phenyl.

I de foretrukne forbindelser med formel I hvor n = 1 1 2 er R =-H eller metyl og R = Η. I særlig foretrukne forbindel- 1 2 ser med formel I hvor n = 1 er både R og R hydrogen.In the preferred compounds of formula I wherein n = 1 1 2 is R = -H or methyl and R = Η. In particularly preferred compounds of formula I wherein n = 1, both R and R are hydrogen.

3 5 I foretrukne forbindelser med formel I er R og/eller R4 hydrogen, metyl, ætyl eller formyl eller, såfremt R1 og 4 R sammen med det nitrogenatom hvortil de er bundet danner en heterocyklisk ring, indeholder de foretrukne forbindelser med formel I en heterocyklisk gruppe indeholdende ét nitroso genatom og 4 eller 5 kulstofatomer (fx pyrrolidinyl eller piperidino), der eventuelt er substitueret med en eller flere alkylgrupper, fx metyl (fx pyrrolidinyl substitueret med to metylgrupper), en heterocyklisk gruppe indeholdende et andet nitrogenatom som eventuelt er alkyleret (fx 4-metylpi-]_5 perazinyl) eller en heterocyklisk gruppe indeholdende en eller flere dobbeltbindinger (fx 1,2,3,6-tetrahydropyridinyl).In preferred compounds of formula I, R and / or R 4 are hydrogen, methyl, ethyl or formyl or, if R 1 and 4 R together with the nitrogen atom to which they are attached form a heterocyclic ring, the preferred compounds of formula I contain a heterocyclic group containing one nitroso genome and 4 or 5 carbon atoms (e.g., pyrrolidinyl or piperidino) optionally substituted by one or more alkyl groups, e.g., methyl (e.g., pyrrolidinyl substituted by two methyl groups), a heterocyclic group containing another nitrogen atom optionally alkylated ( (for example, 4-methylpiperazinyl) or a heterocyclic group containing one or more double bonds (e.g. 1,2,3,6-tetrahydropyridinyl).

I ganske særligt foretrukne forbindelser med formlen I er R3 og/eller R4 H, metyl, ætyl eller formyl.In particularly preferred compounds of formula I, R 3 and / or R 4 are H, methyl, ethyl or formyl.

5 I foretrukne forbindelser med formel I er R og/eller g 20 R hydrogen, fluor, klor, brom, jod, trifluormetyl, metyl, 5 6 metoxy eller fenyl, eller danner R og R sammen med det kulstofatom hvortil de er knyttet en anden benzenring der eventuelt kan være halogensubstitueret.In preferred compounds of formula I, R and / or g are R hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, methyl, methoxy or phenyl, or form R and R together with the carbon atom to which they are attached. benzene ring which may optionally be halogen substituted.

En første gruppe foretrukne forbindelser er sådanne 25 med den almene formel III ; ,_. CR1R2(CR2R3) nr3r4 R?^ryj_ R4 30 1 ft hvor R -R og n har de foran angivne betydninger. I foretrukne 6 forbindelser med formel III er R og R , der kan være ens eller forskellige, hydrogen, fluor, klor, brom, jod, trifluormetyl, metyl, metoxy eller fenyl, eller tilsammen og sam- 35 men med det kulstofatom hvortil de er knyttet en anden ben- ............A first group of preferred compounds are those of the general formula III; , _. CR1R2 (CR2R3) nr3r4 R? ^ Ryj_ R4 30 1 ft where R -R and n have the meanings given above. In preferred 6 compounds of formula III, R and R which may be the same or different are hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, methyl, methoxy or phenyl, or together and together with the carbon atom to which they are linked another leg- ............

2 5 3 I særligt foretrukne forbindelser med formlen III er R og/el- 4 zenring som eventuelt kan være substitueret med et kloratom.In particularly preferred compounds of formula III, R and / or 4-zene ring are optionally substituted with a chlorine atom.

DK 161770 BDK 161770 B

3 g ler R hydrogen, fluor, klor, jod, trifluormetyl, metyl eller fenyl.3 g of clay R are hydrogen, fluorine, chlorine, iodine, trifluoromethyl, methyl or phenyl.

En anden klasse foretrukne forbindelser er sådanne med den almene formel IV 5 R5 ._. CR1R2(CR7R8) NR3R4 _ R6Another class of preferred compounds are those of the general formula IV R 5. CR1R2 (CR7R8) NR3R4 _ R6

10 R10 R

18 5 hvor R -R og n har de angivne betydninger og R specielt kan være H, fluor, klor, brom, jod, trifluormetyl, metyl,Wherein R -R and n have the indicated meanings and R in particular may be H, fluorine, chlorine, bromine, iodine, trifluoromethyl, methyl,

CC

metoxy eller fenyl, og hvor R er fluor eller metyl. I sær- 5 ligt foretrukne forbindelser med formel IV er R hydrogen 15 eller klor.methoxy or phenyl, and wherein R is fluorine or methyl. In particularly preferred compounds of formula IV, R is hydrogen or chlorine.

I foretrukne forbindelser med formel I, hvor n = 1 7 8 er R hydrogen, metyl eller ætyl og R hydrogen, og i særligt foretrukne sådanne forbindelser med formel I er R7 hy- g drogen eller ætyl og R hydrogen.In preferred compounds of formula I wherein n = 1,7 8 is R hydrogen, methyl or ethyl and R hydrogen, and in particularly preferred such compounds of formula I, R 7 is the drug or ethyl and R hydrogen.

20 Forbindelser med den almene formel I kan eksistere som salte med farmaceutisk acceptable syrer. Eksempler på sådanne salte er hydroklorider, maleater, acetater, citrater, fumarater, tartrater, succinater og salte med sure aminosyrer såsom asparaginsyre og glutaminsyre.Compounds of general formula I may exist as salts with pharmaceutically acceptable acids. Examples of such salts are hydrochlorides, maleates, acetates, citrates, fumarates, tartrates, succinates and salts with acidic amino acids such as aspartic acid and glutamic acid.

25 Forbindelser med den almene formel I som indeholder et eller flere asymmetriske kulstofatomer kan eksistere i o 1 2 forskellige optisk aktive former. Når R og R er forskellige eller R og R er forskellige, indeholder forbindelserne med formlen I et chiralcentrum. Sådanne forbindelser eksiste- 30 rer i to enantiomere former og den foreliggende opfindelse tager sigte på fremstilling både af de enantiomere former og blandinger deraf. Når både R og R er forskellige og 7 8 R og R er forskellige indeholder forbindelserne med formlen I to chiralcentre og forbindelsen eksisterer i fire dia-35 stereoisomere former. Opfindelsen tager sigte på fremstilling af alle disse diastereoisomere former og blandinger deraf.Compounds of general formula I which contain one or more asymmetric carbon atoms may exist in a variety of optically active forms. When R and R are different or R and R are different, the compounds of formula I contain a chiral center. Such compounds exist in two enantiomeric forms and the present invention is directed to the preparation of both the enantiomeric forms and mixtures thereof. When both R and R are different and 7 8 R and R are different, the compounds of formula I contain two chiral centers and the compound exists in four diastereoisomeric forms. The invention is directed to the preparation of all these diastereoisomeric forms and mixtures thereof.

DK 161770BDK 161770B

44

De omhandlede forbindelser kan oparbejdes til farmaceutiske præparater der indeholder en terapeutisk effektiv mængde forbindelse I sammen med et farmaceutisk acceptabelt fortyndingsmiddel eller bærestof.The present compounds can be worked up into pharmaceutical compositions containing a therapeutically effective amount of compound I together with a pharmaceutically acceptable diluent or carrier.

5 Til terapeutisk anvendelse kan den virksomme forbindel se indgives oralt, rektalt, parenteralt eller lokalt og fortrinsvis oralt. Således kan farmaceutiske præparater af de omhandlede forbindelser have en hvilken som helst kendt farmaceutisk form til oral, rektal, parenteral eller lokal admini-10 stration. Farmaceutisk acceptable bærere som egner sig til sådanne præparater er velkendte. Præparaterne kan indeholde 0,1-90 vægt% af det virksomme stof. Disse præap-rater fremstilles i almindelighed i dosisenhedsform.For therapeutic use, the active compound may be administered orally, rectally, parenterally or locally and preferably orally. Thus, pharmaceutical compositions of the subject compounds can be of any known pharmaceutical form for oral, rectal, parenteral or local administration. Pharmaceutically acceptable carriers suitable for such compositions are well known. The compositions may contain 0.1-90% by weight of the active substance. These preparations are generally prepared in dosage unit form.

Fortrinsvis fremstilles der præparater til oral ind-P5 gift i kendte farmaceutiske former såsom tabletter, kapsler, saft eller vandige eller olieagtige suspensioner.Preferably, preparations for oral in-P5 venom are made in known pharmaceutical forms such as tablets, capsules, juice or aqueous or oily suspensions.

De farmaceutiske præparater indeholdende en terapeutisk effektiv mængde af en forbindelse med formlen I kan bruges til behandling af depressioner hos pattedyr og mennesker.The pharmaceutical compositions containing a therapeutically effective amount of a compound of formula I can be used to treat depression in mammals and humans.

2q Ved en sådan behandling indgives en forbindelse med formlen I om dagen i en mængde i området 1-1000 mg, fortrinsvis 5-500 mg.In such a treatment, a compound of formula I per day is administered in an amount in the range of 1-1000 mg, preferably 5-500 mg.

Den reduktive amidering i henhold til reaktion a) af ketoner V eller ketoner eller aldehyder VI kan fx 25 ske med formamid og myresyre eller ammoniumformiat og myresyre, hvorved der dannes en forbindelse med formel I hvor R4 er CHO og R1 er H; eller med formamider med formlen 3 3 HCONHR , hvor R er en alkyl- eller cykloalkylgruppe som de- 3 fineret og myresyre; eller aminer med formlen R NEL·, hvor 3 . ^ ' R er en alkyl- eller cykloalkylgruppe som defineret og myresyre.For example, the reductive amidation according to reaction a) of ketones V or ketones or aldehydes VI may take place with formamide and formic acid or ammonium formate and formic acid, thereby forming a compound of formula I wherein R4 is CHO and R1 is H; or with formamides of the formula HCIHR 3 wherein R is an alkyl or cycloalkyl group as defined and formic acid; or amines of formula R NEL ·, wherein 3. R 'is an alkyl or cycloalkyl group as defined and formic acid.

Forbindelser med formel I, hvor R4 er CHO, kan fremstilles ved formylering af forbindelser med formel I hvor R4 er H, fx ved omsætning med metylformiat.Compounds of formula I wherein R 4 is CHO may be prepared by formylating compounds of formula I wherein R 4 is H, for example by reaction with methyl formate.

. 3. 3

Forbindelser med formel I hvor R er forskellig fra 35 4 H og R er CHO, kan fremstilles ved omsætning af forbindelser 4 med formlen I, hvor R er H og R er CHO, med en forbindelse 3 5Compounds of formula I wherein R is different from 35 4 H and R is CHO may be prepared by reacting compounds 4 of formula I wherein R is H and R is CHO, with a compound 35

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den almene formel R X, hvor X er en fraspaltelig gruppe såsom et halogenatom, i nærværelse af en base.the general formula R X, wherein X is a leaving group such as a halogen atom, in the presence of a base.

Forbindelser med formlen I kan fremstilles ved reduktiv aminering af ketoner med formlen V eller af ketoner eller 5 aldehyder med formlen VI. Eksempler på reduktive amineringsprocesser er anført i det følgende: a) Til fremstilling af forbindelser med formlen I hvor 3 4 R og R er H, omsætning af ketonen eller aldehydet med et ammoniumsalt, fx ammoniumacetat, og et reduktionsraiddel såsom 10 natriumcyanborhydrid, b) til fremstilling af forbindelser med formlen I hvor 3 4 R er alkyl og R er H, ved omsætning af ketonen eller aldehy- 3 det med en amin med formlen R NI^ og et reduktionsmiddel såsom natriumcyanborhydrid, 15 c) til fremstilling af forbindelser med formlen I hvor 3 4 3 4 hverken R eller R er hydrogen, eller hvor R og R sammen med nitrogenatomet danner en heterocyklisk ring, ved omsætning 3 4 af ketonen eller aldehydet med en amm med formlen HNR R og enten myresyre eller et reduktionsmiddel såsom natriumbor-20 hydrid, og d) til fremstilling af forbindelser med formlen I hvor 3 / 4 R og/eller R er hydrogen eller en alkyl- eller cykloalkyl- 1 4 gruppe, eller hvor R og R sammen med nitrogenatomet danner en heterocyklisk ring, katalytisk hydrogenering ved forhøjet 25 temperatur og tryk af en blanding af ketonen eller aldehydet 3 4 og en amin med den almene formel HNR R .Compounds of formula I can be prepared by reductive amination of ketones of formula V or of ketones or aldehydes of formula VI. Examples of reductive amination processes are listed below: a) For the preparation of compounds of formula I wherein R 4 and R are H, reacting the ketone or aldehyde with an ammonium salt, eg ammonium acetate, and a reducing agent such as sodium cyanoborohydride, b) to preparing compounds of formula I wherein R 4 is alkyl and R is H, by reacting the ketone or aldehyde with an amine of formula R N 1 4 and a reducing agent such as sodium cyanoborohydride, c) to prepare compounds of formula I wherein 3 4 3 4 is neither R nor R is hydrogen, or wherein R and R together with the nitrogen atom form a heterocyclic ring, by reacting 3 4 of the ketone or aldehyde with a breast of the formula HNR R and either formic acid or a reducing agent such as sodium boron and d) for the preparation of compounds of formula I wherein 3/4 R and / or R is hydrogen or an alkyl or cycloalkyl group or where R and R together with the nitrogen atom form a hetero cyclic ring, catalytic hydrogenation at elevated temperature and pressure of a mixture of the ketone or aldehyde 34 and an amine of the general formula HNR R.

Forbindelser med formlen I, hvor både R^ og R^ er en alkylgruppe, kan fremstilles ved omsætning af en keton med formlen V eller en keton eller et aldehyd med formlen 3 4 30 VI med et dialkylformamid med formlen HCONR R , fx i nærværelse af myresyre.Compounds of formula I wherein both R 1 and R 2 are an alkyl group can be prepared by reacting a ketone of formula V or a ketone or an aldehyde of formula 3 4 30 VI with a dialkylformamide of formula HCONR R, for example in the presence of formic acid.

Egnede reduktionsmidler til reduktion af en forbindelse med formel VII i henhold til reaktion c) er bl.a. na-triumborhydrid, natriumcyanborhydrid, litiumaluminiumhydrid og 35 boran-dimetylsulfid-kompleks.Suitable reducing agents for reducing a compound of formula VII according to reaction c) are in particular: sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride and borane dimethyl sulfide complex.

I de i krav 1 under c (ii) og c (iv) nævnte reaktioner er Y fortrinsvis MgBr afledet af et Grignard-reagens,In the reactions mentioned in claims 1 under c (ii) and c (iv), Y is preferably MgBr derived from a Grignard reagent,

OK 161770 BOK 161770 B

6 eller Li afledet af en organolitiumforbindelse.6 or Li derived from an organolithium compound.

. 3 4. 3 4

Forbindelser med formel I hvor R og R er hydrogen kan i henhold til reaktion d> fremstilles ved en dekarboxy-lativ omlejring, fx ved hjælp af jodosobenzen-bistrifluor-5 acetat eller ved en Hofman-reaktion med anvendelse af brom i alkalisk opløsning, af amider med formel XI til frembringelse af aminer med formlen I hvor n er 0 eller 1.Compounds of formula I wherein R and R are hydrogen may, according to reaction d>, be prepared by a decarboxylative rearrangement, e.g., by iodosobenzene bistrifluoroacetate or by a Hofman reaction using bromine in alkaline solution, of amides of formula XI to produce amines of formula I wherein n is 0 or 1.

44

Forbindelser med formel I hvor R er hydrogen kan i henhold til reaktion e) fremstilles ved hydrolyse af forbin- 4 10 delser med formlen I hvor R er CHO, fx ved sur hydrolyse.Compounds of formula I wherein R is hydrogen can, according to reaction e), be prepared by hydrolysis of compounds of formula I wherein R is CHO, for example by acid hydrolysis.

44

Forbindelser med formlen I hvor R er metyl kan i henhold til reaktion f) fremstilles ved reduktion af for- 4 bmdelser med formel I hvor R er CHO, fx med litiumalumi-niumhydrid eller med natrium-bis- (2-metoxyætoxy) -aluminium-15 hydrid.Compounds of formula I wherein R is methyl can, according to reaction f), be prepared by reducing compounds of formula I wherein R is CHO, for example with lithium aluminum hydride or with sodium bis- (2-methoxyethoxy) aluminum. Hydride.

Forbindelser med formlen I hvor R3 og/eller R4 er forskellig fra H kan i henhold til reaktion g) fremstilles ud fra forbindelser med formlen I hvor R3 og/eller R4 er hydrogen ved i og for sig kendte metoder til omdannelse af 20 primære aminer til sekundære eller tertiære aminer eller til omdannelse af sekundære til tertiære aminer. I det følgende gives nogle eksempler på egnede processer: a) Alkylering af primære aminer med formel I til dannelse af sekundære aminer med formel I, fx ved en proces som 25 omfatter trinnene beskyttelse af den primære amin med en beskyttelsesgruppe såsom trifluoracetyl, alkylering med et alkylhalogenid og fjernelse af beskyttelsesgruppen fx ved hydrolyse; b) _ alkylering af primære aminer med formel I, fx med 30 et alkylhalogenid til dannelse af en tertiær amin med formel 3 4 I hvor R og R er ens; c) alkylering af sekundære aminer med formel I, fx med et alkylhalogenid til dannelse af tertiære aminer med formelCompounds of formula I wherein R 3 and / or R 4 are different from H may, according to reaction g), be prepared from compounds of formula I wherein R 3 and / or R 4 are hydrogen by methods known per se to convert 20 primary amines to secondary or tertiary amines or for the conversion of secondary to tertiary amines. The following are some examples of suitable processes: a) Alkylation of primary amines of formula I to form secondary amines of formula I, for example, by a process comprising the steps of protecting the primary amine with a protecting group such as trifluoroacetyl, alkylation with a alkyl halide and removal of the protecting group, for example, by hydrolysis; b) - alkylation of primary amines of formula I, for example with an alkyl halide to form a tertiary amine of formula 344 wherein R and R are the same; c) alkylation of secondary amines of formula I, e.g., with an alkyl halide to form tertiary amines of formula

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7 3 4 I hvor R og R kan være forskellige; d) omsætning af primære aminer med formel I med natrium- borhydrid og eddikesyre til dannelse af sekundære aminer 3 4 med formel I hvor R er ætyl og R er hydrogen; 5 e) omsætning af primære aminer med formel I med formalde hyd og myresyre til dannelse af tertiære aminer med formel o 3 4 I hvor bade R og R er metyl; f) omsætning af sekundære aminer med formel I, hvor 4 R er hydrogen, med formaldehyd og myresyre til dannelse 4 10 af tertiære aminer med formel I hvor R er metyl; g) formylering af primære aminer med formel I, fx ved omsætning af metylformiat, og reduktion af det resulterende formamid, fx med litiumaluminiumhydrid til dannelse af sekun- 3 4 dære aminer med formel I hvor R er metyl og R er hydrogen; 15 h) formylering af sekundære aminer med formel I, fx ved omsætning med metylformiat, og reduktion af det resulterende formamid, fx med litiumaluminiumhydrid, til dannelse af 4 en tertiær amin med formel I hvor R er metyl; i) acylering af primære aminer med formel I, fx ved 12 20 omsætning med et acylklond med formlen R COC1 eller et 12 12 anhydrid med formlen (R CO)20, hvor R er en alkyl-, alkenyl- eller alkynylgruppe, og reduktion af det resulterende amid fx med litiumaluminiumhydrid til dannelse af en sekundær 3 12 4 amin med formel I hvor R er -Cl^R og R er hydrogen; 25 j) acylering af sekundære aminer med formel I hvor R4 12 er H, fx ved omsætning med et acylklond med formlen R COC1 12 12 eller et anhydrid med formlen (R CO)20, hvor R er en alkyl-, alkenyl- eller alkynylgruppe, og reduktion af det resulterende amid med fx litiumaluminiumhydrid til dannelse af en ter- 4 12 30 tiær amin hvor R er CH2R ; k) omsætning af en primær amin med formlen I med et alde- 13 13 hyd med formlen R CHO, hvor R er en alkyl-, alkenyl- 14 15 eller alkynylgruppe, eller en keton med formlen R COR , 14 15 hvor R og R kan være ens eller forskellige og hver er 14 157 3 4 In which R and R may be different; d) reacting primary amines of formula I with sodium borohydride and acetic acid to form secondary amines 34 of formula I wherein R is ethyl and R is hydrogen; E) reacting primary amines of formula I with formaldehyde and formic acid to form tertiary amines of formula o in which both R and R are methyl; f) reacting secondary amines of formula I wherein 4 R is hydrogen with formaldehyde and formic acid to give 4 tertiary amines of formula I wherein R is methyl; g) formylation of primary amines of formula I, for example by reaction of methyl formate, and reduction of the resultant formamide, for example with lithium aluminum hydride to form secondary amines of formula I wherein R is methyl and R is hydrogen; H) formylation of secondary amines of formula I, for example by reaction with methyl formate, and reduction of the resulting formamide, eg with lithium aluminum hydride, to give 4 a tertiary amine of formula I wherein R is methyl; i) acylating primary amines of formula I, for example, by reacting with an acyl clone of formula R COC1 or a 12 12 anhydride of formula (R CO) 20 wherein R is an alkyl, alkenyl or alkynyl group, and reduction of the resulting amide, for example, with lithium aluminum hydride to form a secondary amine of formula I wherein R is -Cl 2 R and R is hydrogen; J) acylation of secondary amines of formula I wherein R 4 12 is H, for example by reaction with an acyl clone of formula R COC 12 12 or an anhydride of formula (R CO) 20 wherein R is an alkyl, alkenyl or alkynyl group and reducing the resulting amide with, for example, lithium aluminum hydride to form a tertiary amine wherein R is CH 2 R; k) reacting a primary amine of formula I with an aldehyde of formula R CHO wherein R is an alkyl, alkenyl 14 or alkynyl group, or a ketone of formula R COR, 14 15 wherein R and R can be the same or different and each is 14 15

35 en alkyl-, alkenyl- eller alkynylgruppe eller R og RAn alkyl, alkenyl or alkynyl group or R and R

sammen med det kulstofatom hvortil de er knyttet danner en alicyklisk ring, og reduktion af den resulterende imin ellertogether with the carbon atom to which they are attached form an alicyclic ring, and reduction of the resulting imine or

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8 13 14 enamin med fx natnumcyanborhydrid eller, hvis R , R eller R·*"^ ikke er alkenyl eller alkynyl, ved katalytisk hydrogene-ring til dannelse af en sekundær amin med formlen I hvor R^ er henholdsvis R^CH-- og R^-CH-;Is not alkenyl or alkynyl, by catalytic hydrogenation to form a secondary amine of formula I wherein R 2 is R 2 CH 2 and R 2, respectively. R ^ -CH-;

5 l1S5 lS

1) ved omsætning af en primær amin med formel I med en ikke-geminalt disubstitueret alkan indeholdende 2 eller 3 kulstofatomer mellem de kulstofatomer som bærer substituen- terne, der fx kan være halogen og fortrinsvis brom, eller 10 p-toluensulfonyloxy, til dannelse af en forbindelse med for- 3 4 mel I hvor R og R sammen med det nitrogenatom hvortil de er knyttet danner en heterocyklisk ring der ikke indeholder andre heteroatomer end nitrogenatomet.1) by reacting a primary amine of formula I with a non-geminally disubstituted alkane containing 2 or 3 carbon atoms between the carbon atoms bearing the substituents which may be, for example, halogen and preferably bromine, or 10 p-toluenesulfonyloxy to form a compound of formula I wherein R and R together with the nitrogen atom to which they are attached form a heterocyclic ring containing no heteroatoms other than the nitrogen atom.

Ketonerne med formel V kan fremstilles ved hydrolyse 15 af iminer med formlen XVIThe ketones of formula V can be prepared by hydrolysis of imines of formula XVI

R^\-- CR1=NYR 1 - CR 1 = NY

\-- XVI\ - XVI

r6-- 20r6-- 20

hvor Y er en metalholdig rest afledet af en organometallisk reagens. Iminerne med formlen XVI kan fremstilles ved omsætning af nævnte organometalreagens med en cyanforbindelse med formlen XVIIwherein Y is a metal-containing residue derived from an organometallic reagent. The imines of formula XVI can be prepared by reacting said organometallic reagent with a cyan compound of formula XVII

2525

rIzt-^ CNrIzt- ^ CN

^ - XVII^ - XVII

— 2Q Egnede organometalreagenser er bl.a. Grignard-reagenser med formlen R^MgX hvor X er Cl, Br eller I (Y = MgX) og organo-litiumforbindelser med formlen R^Li (Y = Li).- 2Q Suitable organometallic reagents include Grignard reagents of formula R ^ MgX where X is Cl, Br or I (Y = MgX) and organolithium compounds of formula R ^ Li (Y = Li).

Ketonerne med formel VI kan fremstilles ved hydrolyse af iminer med formlen XVIIIThe ketones of formula VI can be prepared by hydrolysis of imines of formula XVIII

3535

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99

d5 __. CR1R2CR7=NYd5 __. CR1R2CR7 = NY

^ \__ XVIII^ \ __ XVIII

R6 -R6 -

5 hvor Y er en metalholdig rest afledet af et organometalreagens. Iminerne med formel XVIII kan fremstilles ved omsætning af organometalreagenset med cyanforbindelser med formlen XIX5 where Y is a metal-containing residue derived from an organometallic reagent. The imines of formula XVIII can be prepared by reacting the organometal reagent with cyan compounds of formula XIX

10 5 ___ CR1R2CN10 5 ___ CR1R2CN

ψΛ I XIXψΛ In XIX

R6 -R6 -

Egnede organometalreagenser er bl.a. Grignard-reagenser med 15 formlen R7MgX hvor X er Cl, Br eller I (Y = MgX) og organo-litiumforbindelser med formlen R^Li (Y = Li).Suitable organometallic reagents include Grignard reagents of formula R7MgX where X is Cl, Br or I (Y = MgX) and organolithium compounds of formula R ^ Li (Y = Li).

Ketonerne med formel V kan fremstilles ved omsætning af karboxylsyrederivater såsom amider eller syrehalogenider med et organometalreagens, fx ved omsætning af et syreklorid 20 med formlen XXThe ketones of formula V can be prepared by reacting carboxylic acid derivatives such as amides or acid halides with an organometal reagent, for example by reacting an acid chloride 20 of formula XX

5 -- C0C1 25 R65 - COC1 R6

med et Grignard-reagens med formlen R1MgX hvor X er Cl, Br eller I ved lav temperatur, eller ved omsætning af en karb-oxylsyre med formlen XXIwith a Grignard reagent of formula R1MgX wherein X is Cl, Br or I at low temperature, or by reaction of a carboxylic acid of formula XXI

30 R5 , COOHR 5, COOH

fy±_ R6 _ '-' med et organometalreagens som fx en organolitiumforbindelse •5C 1 med formlen R Li.with an organometallic reagent such as an organolithium compound • 5C1 of formula R Li.

1010

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Ketoner med formel VI kan fremstilles ved omsætning af karboxylsyrederivater såsom amider eller syrehalogenider med et organometalreagens, fx ved omsætning af et syreklorid 7 med formlen XII med et Grignard-reagens med formlen R MgX 5 hvor X er Cl,. Br eller I ved lav temperatur, eller ved omsæt- . ning af en karboxylsyre med formlen XIV med et organometal- 7 reagens, fx en organolitiumforbindelse med formlen R Li.Ketones of formula VI can be prepared by reacting carboxylic acid derivatives such as amides or acid halides with an organometallic reagent, for example by reacting an acid chloride 7 of formula XII with a Grignard reagent of formula R MgX 5 where X is Cl,. Br or I at low temperature, or at conversion. yielding a carboxylic acid of formula XIV with an organometallic reagent, for example an organolithium compound of formula R Li.

Ketoner med formel V hvor R^ er alkyl (fx metyl) og ketoner med formlen VI hvor R er alkyl (fx metyl) kan 10 fremstilles ved omsætning af en diazoalkan (fx diazometan) med aldehyder med formlerne henholdsvis XXII og VI:Ketones of formula V wherein R 1 is alkyl (e.g. methyl) and ketones of formula VI wherein R is alkyl (e.g. methyl) can be prepared by reacting a diazoalkane (e.g. diazomethane) with aldehydes of formulas XXII and VI, respectively:

R^ ,-, CHOR 2, -, CHO

„ £H=i„£ H = i

RR

Aldehyder med formel . VI kan fremstilles ved velkendte metoder. Nogle egnede eksempler er anført i det følgende: a) Reduktion af cyanforbindelser med formel XIX med 20 fx di-t-butylaluminiumhydrid eller diisobutylaluminiumhydrid; b) reduktion af karboxylsyrederivater som fx i) reduktion af forbindelser med formlen VII hvor Z er CR^R2CONR2R^ og R2 og R^ er forskellige fra hydrogen, fx ved hjælp .af litiumdiætoxyaluminohydrid; 25 ii) reduktion af amider dannet ved omsætning af ætylenimin med et syreklorid med formlen XII· e cr1r2coci 30 ^y<~J xiifAldehydes of formula. VI can be prepared by well known methods. Some suitable examples are set forth below: a) Reduction of Cyan Compounds of Formula XIX by 20, for example, di-t-butylaluminum hydride or diisobutylaluminum hydride; b) reduction of carboxylic acid derivatives such as i) reduction of compounds of formula VII wherein Z is CR 2 R 2 CON 2 R 2 and R 2 and R 2 are different from hydrogen, for example by means of lithium diethoxyoxyaluminohydride; Ii) reduction of amides formed by reaction of ethylenimine with an acid chloride of formula XII · e cr1r2coci 30 ^ y <~ J xiif

JlV — '* fx ved hjælp af litiumaluminiumhydrid som reduktionsmiddel; iii) reduktion af syreklorider med formel XII, fx med litium-tr i-t-butoxyaluminohydr id; 35 c) omsætning af alkoholer (dannet ved reduktion af karb- oxylsyrer med formlen XIV) 11 UK Ί bV/'/Ub 5 cr1r2cooh > ,£>hJlV - '* eg using lithium aluminum hydride as reducing agent; iii) reduction of acid chlorides of formula XII, eg with lithium-tr i-t-butoxyaluminohydride; C) Reaction of alcohols (formed by reduction of carboxylic acids of formula XIV) 11 UK Ί bV / '/ Ub 5 cr1r2cooh>, £> h

RR

med fx kromtrioxyd-pyridin-kompleks i diklormetan under vandfri betingelser.with, for example, chromium trioxide-pyridine complex in dichloromethane under anhydrous conditions.

10 Forbindelser med formel VII hvor Z er en gruppe med formlen -CR^=NOH eller -CR^R2CR^=N0H eller ætere eller estere deraf kan fremstilles ved omsætning af hydroxylamin eller en æter eller ester deraf med henholdsvis ketoner med formlen V og ketoner eller aldehyder med formlen VI.Compounds of Formula VII wherein Z is a group of formula -CR 2 = NOH or -CR 2 R 2CR 2 = NOH or ethers or esters thereof may be prepared by reaction of hydroxylamine or an ether or ester thereof with ketones of formula V and ketones, respectively. or aldehydes of formula VI.

15 Forbindelser med formel VII hvor Z er en gruppe med formlen -CR^=NR^ eller -CR^R2CR^=NR^ kan fremstilles ved 3 omsætning af aminer med formlen NE^R med ketoner med formlen V og ketoner eller aldehyder med formlen VI.Compounds of formula VII wherein Z is a group of formula -CR 2 = NR 2 or -CR 2 R 2CR 2 = NR 3 can be prepared by reacting amines of formula NE 1 R with ketones of formula V and ketones or aldehydes of formula WE.

Fremstilling af forbindelser med formel VII hvor 1 127 20 z er en gruppe med formlen -CR =NY eller -CR R CR =NY er beskrevet foran med hensyn til forbindelser med formlen henholdsvis XVI og XVIII.Preparation of compounds of formula VII wherein 1 127 20 z is a group of formula -CR = NY or -CR R CR = NY is described above with respect to compounds of formula XVI and XVIII, respectively.

Fremstilling af forbindelser med formel VII hvor 1 2 Z er en gruppe med formlen -CR R CN vil blive beskrevet senere 25 med hensyn til cyanforbindelser med formel XIX.Preparation of Compounds of Formula VII wherein 1 2 Z is a group of formula -CR R CN will be described later on with respect to cyano compounds of formula XIX.

Forbindelser med formel VII hvor z er en gruppe med 12 3 4 formlen -CR R CONR R kan fremstilles ved omsætning af syrederivater såsom estere eller syrehalogenider (fx syreklorider 3 4 med formel XII) med aminer med formlen HNR R . Forbindelser 2 3Q med formel VII hvor Z er CR R CONH2 kan fremstilles ud fra cyanforbindelser med formlen XIX fx ved hydratisering, med vandige syrer eller ved omsætning med hydrogenperoxyd i nærværelse af en base.Compounds of formula VII wherein z is a group of formula -CR R CONR R can be prepared by reacting acid derivatives such as esters or acid halides (e.g., acid chlorides 3 of formula XII) with amines of formula HNR R. Compounds 2 3Q of formula VII wherein Z is CR R CONH 2 can be prepared from cyan compounds of formula XIX for example by hydration, with aqueous acids or by reaction with hydrogen peroxide in the presence of a base.

22

Amider med formel XI, hvor n = 0 kan fremstilles ved 35 omsætning af ammoniak med karboxylsyrederivater, fx syreklorider med formel XII, eller de kan fremstilles ud fra cyanforbindelser med formel XIX fx ved hydratisering med vandig 12Amides of Formula XI, where n = 0 can be prepared by reacting ammonia with carboxylic acid derivatives, e.g., acid chlorides of formula XII, or they can be prepared from cyan compounds of formula XIX, e.g., by hydration with aqueous 12

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syre eller ved omsætning med hydrogenperoxyd i nærværelse af en base.acid or by reaction with hydrogen peroxide in the presence of a base.

Amider med formel XI hvor n = 1 kan fremstilles ved omsætning af ammoniak med karboxylsyrederivater, fx syre-5 klorider med formel XIII, eller de kan fremstilles ud fra cyanforbindelser med formlen XXIII fx ved hydratisering med vandig syre eller ved omsætning med hydrogenperoxyd i nærværelse af en base: r;* ,—. cr1r2cr7r8cnAmides of formula XI wherein n = 1 can be prepared by reacting ammonia with carboxylic acid derivatives, e.g., acid chlorides of formula XIII, or they can be prepared from cyan compounds of formula XXIII, e.g., by hydration with aqueous acid or by reaction with hydrogen peroxide in the presence of a base: r; *, -. cr1r2cr7r8cn

10 TI10 TI

i! Ί-- XXIIIin! Ί-- XXIII

— 1 2- 1 2

Amider med formel XI hvor R og R er hydrogen kan 15 fremstilles ud fra syreklorider med formel XX eller XII ved omsætning med diazometan til dannelse af en diazoketon, der omlejres i nærværelse af ammoniak og en katalysator som fx sølv, hvorved der dannes det ønskede amid.Amides of formula XI wherein R and R are hydrogen can be prepared from acid chlorides of formula XX or XII by reaction with diazomethane to form a diazoketone which is rearranged in the presence of ammonia and a catalyst such as silver to form the desired amide .

Karboxylsyrer med formlerne XIV og XXI kan fremstil-20 les ved hydrolyse, fx basisk hydrolyse, af cyanforbindelser med formlerne XIX og XVII. Karboxylsyrer med formel XIV kan fremstilles ved omsætning af amider med formel X med salpetersyrling. Karboxylsyrer med formel XXI kan fremstilles ved omsætning af salpetersyrling med amider dannet ved omsætning 25 af ammoniak med karboxylsyrederivater som fx syreklorider med formel XX, eller ved omsætning af en cyanforbindelse med formel XVII med hydrogenperoxyd i nærværelse af en base.Carboxylic acids of formulas XIV and XXI can be prepared by hydrolysis, e.g., basic hydrolysis, of cyan compounds of formulas XIX and XVII. Carboxylic acids of formula XIV can be prepared by reacting amides of formula X with nitric acid. Carboxylic acids of formula XXI can be prepared by reacting nitric acid with amides formed by reaction of ammonia with carboxylic acid derivatives such as acid chlorides of formula XX, or by reacting a cyan compound of formula XVII with hydrogen peroxide in the presence of a base.

1 21 2

Karboxylsyrer med formel XIV hvor R og R er hydrogen kan fremstilles ud fra syreklorider med formel XX ved 30 omsætning med diazometan til dannelse af diazoketoner som omlejres i nærværelse af vand og en katalysator såsom sølv til dannelse af den ønskede syre.Carboxylic acids of formula XIV wherein R and R are hydrogen can be prepared from acid chlorides of formula XX by reaction with diazomethane to form diazoketones which are rearranged in the presence of water and a catalyst such as silver to form the desired acid.

Cyanforbindelser med formel XVII kan fremstilles ved omsætning af cyanforbindelser med formlen XXIV 35 i-t I \ i υ i / / v_< u-> 13 med en 1,3-disubstitueret propan såsom 1,3-dibrompropan og 5 en base såsom natriumhydrid.Cyan compounds of formula XVII can be prepared by reacting cyan compounds of formula XXIV 35 i-t I \ i υ i / v_ <u-> 13 with a 1,3-disubstituted propane such as 1,3-dibromopropane and a base such as sodium hydride.

1 21 2

Cyanforbindelser med formlen XIX hvor R og R er hydrogen kan fremstilles ud fra cyanforbindelser med formlen XVII fx ved følgende reaktioner: a) hydrolyse af cyangruppen til dannelse af en karboxyl-10 syre med formel XXI; b) reduktion af karboxylsyren med fx litiumaluminiumhy-drid eller boran-dimetylsulfid-kompleks til dannelse af den tilsvarende alkohol; c) udskiftning af hydroxygruppen i alkoholen med en fra-15 spaltelig gruppe som fx en p-toluensulfonyloxygruppe; og d) udskiftning af den fraspaltelige gruppe med en cyangruppe.Cyan compounds of formula XIX wherein R and R are hydrogen can be prepared from cyan compounds of formula XVII, for example by the following reactions: a) hydrolysis of the cyano group to form a carboxylic acid of formula XXI; b) reducing the carboxylic acid with, for example, lithium aluminum hydride or borane-dimethyl sulfide complex to form the corresponding alcohol; c) replacing the hydroxy group in the alcohol with a leaving group such as a p-toluenesulfonyloxy group; and d) replacing the leaving group with a cyano group.

På lignende måde kan cyanforbindelser med formel XXIII fremstilles ud fra cyanforbindelser med formel XIX.Similarly, cyan compounds of formula XXIII can be prepared from cyan compounds of formula XIX.

1 2 20 Cyanforbindelser med formlen XIX hvor R og/eller R er forskellig fra hydrogen kan fremstilles ud fra de tilsvarende 1 2 cyanforbindelser med formlen XIX hvor R og/eller R er hydrogen, fx ved alkylering med et alkylhalogenid i nærværelse af en base såsom litiumdiisopropylamid.Cyan compounds of formula XIX wherein R and / or R are different from hydrogen may be prepared from the corresponding 1 2 cyano compounds of formula XIX wherein R and / or R are hydrogen, for example, by alkylation with an alkyl halide in the presence of a base such as lithium diisopropylamide.

25 Cyanforbindelser med formel XIX hvor R = H kan også fremstilles ved omsætning af en keton med formel V eller et aldehyd med formel XII med et reagens til indførelse af en cyangruppe såsom p-toluensulfonylmetylisocyanid. På lignende måde kan cyanforbindelsen med formel XIII fremstil-30 les ud fra aldehyder eller ketoner med formel VI.Cyan compounds of formula XIX wherein R = H can also be prepared by reacting a ketone of formula V or an aldehyde of formula XII with a reagent to introduce a cyano group such as p-toluenesulfonylmethyl isocyanide. Similarly, the cyan compound of formula XIII can be prepared from aldehydes or ketones of formula VI.

Syreklorider med formel XX kan fremstilles ved '^omsætning af karboxylsyrer med formel XXI med fx trinylklo-rid.Acid chlorides of formula XX can be prepared by reacting carboxylic acids of formula XXI with, for example, trinyl chloride.

Aldehyder med formel XXII kan fremstilles ved velkend-35 te fremgangsmåder. De følgende anføres som eksempler på egnede metoder: 14Aldehydes of formula XXII can be prepared by well known methods. The following are given as examples of suitable methods: 14

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a) reduktion af cyanforbindelser med formlen XVII med fx di-t-butylaluminiumhydrid eller diisobutylaluminiumhydrid; b) reduktion af karboxylsyrederivater, fx i) reduktion af tertiære amider dannet ved omsætning 5 af sekundære aminer med syreklorid med formlen XX, fx når den sekundære amin er en dialkylamin under anvendelse af li-tiumdiætoxyaluminiumhydrid som reduktionsmiddel, eller når den sekundære amin er ætylenimin under anvendelse af litium-aluminiumhydrid som reduktionsmiddel; ii) reduktion af syreklorider med formel XX, fx med litium-tri-t-butoxyaluminohydrid; c) oxydation af alkoholer (fremstillet ved reduktion af karboxylsyrer med formel XXI) med fx kromtrioxyd-pyridin- kompleks i diklormetan under vandfri betingelser.a) reducing cyano compounds of formula XVII with, for example, di-t-butyl aluminum hydride or diisobutyl aluminum hydride; b) reduction of carboxylic acid derivatives, eg i) reduction of tertiary amides formed by reaction of secondary amines with acid chloride of formula XX, eg when the secondary amine is a dialkylamine using lithium diethoxy aluminum hydride as reducing agent or when the secondary amine is ethylene amine using lithium aluminum hydride as reducing agent; ii) reduction of acid chlorides of formula XX, eg with lithium tri-t-butoxyaluminohydride; c) oxidation of alcohols (prepared by reduction of carboxylic acids of formula XXI) with, for example, chromium trioxide-pyridine complex in dichloromethane under anhydrous conditions.

15. Ketoner med formel V (undtagen sådanne hvor og15. Ketones of Formula V (except those where and

6 X6 X

R er hydrogen og R er metyl eller ætyl), ketoner med formel VI og aldehyder med formel VI (undtagen sådanne hvor R^, 2 5 6R is hydrogen and R is methyl or ethyl), ketones of formula VI and aldehydes of formula VI (except those where R

R , R og R er hydrogen), forbindelserne med formel VII IR, R and R are hydrogen), the compounds of formula VII I

o X 5 6 (undtagen sådanne hvor Z = CR -NY og R og R er hydrogen 20 og R^ er metyl og ætyl), iminerne med formel XVI (undtagen sådanne 5 6 1 hvor R og R er hydrogen og R er metyl eller ætyl) og XVIII,o X 5 6 (except those where Z = CR -NY and R and R are hydrogen 20 and R 1 is methyl and ethyl), the imines of formula XVI (except such 5 6 1 where R and R are hydrogen and R is methyl or ethyl) and XVIII,

amider med formel X og XI, karboxylsyrer med formel XIVamides of formula X and XI, carboxylic acids of formula XIV

o X 2 5 6 (undtagen sådanne hvor R , R , R og R er hydrogen), 25 cyanforbindelser med formel XIX og XXIII og syreklorider med formel XII (undtagen sådanne hvor Rx, R2, R~* og R^ er hydrogen) og XIII der er beskrevet i nærværende beskrivelse som mellemprodukter, er hidtil ukendte forbindelser. Nogle af cyanforbindelserne med formel XVII og XXIV er hidtil ukend- 30 te forbindelser.o X 2 5 6 (except those where R, R, R and R are hydrogen), cyano compounds of formula XIX and XXIII and acid chlorides of formula XII (except those where Rx, R2, R ~ * and R ^ are hydrogen) and XIII described herein as intermediates are novel compounds. Some of the cyan compounds of formulas XVII and XXIV are novel compounds.

Fra GB patentskrift nr. 973887 kendes fenylcykloal-kanmetylaminer som angives at have centralanaleptiske egenskaber og har den almene formel 35GB Patent No. 973887 discloses phenylcycloal-kanmethylamines which are stated to have central analgesic properties and have the general formula 35

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15 pa .Rd \_C-ch9_n \ JW7\ VRe' 5 ch9 chrc \2/ CH2 hvor Ra og Rd hver er hydrogen, hydroxy, metyl eller met- 10 oxy eller tilsammen metylendioxy, R er hydrogen eller β d.15 pa. Rd \ _C-ch9_n \ JW7 \ VRe '5 ch9 chrc \ 2 / CH2 wherein Ra and Rd are each hydrogen, hydroxy, methyl or methoxy or together methylenedioxy, R is hydrogen or β d.

alkyl og R og R hver betegner hydrogen, en mættet eller umættet alifatisk _^kulbrintegruppe eller en cykloalkylgruppe, eller tilsammen og med N-atomet en mættet ring som kan være afbrudt af et yderligere heteroatom.alkyl and R and R each represent hydrogen, a saturated or unsaturated aliphatic hydrocarbon group or a cycloalkyl group, or together and with the N atom a saturated ring which may be interrupted by a further heteroatom.

15 En række af disse forbindelser er afprøvet ved den senere i nærværende beskrivelse beskrevne reser-pin-reverseringstest. Resultaterne fremgår af nedenstående tabel I, der viser at ingen af forbindelserne ved en dosis på 30 mg/kg gav en procentuel reversering på 50% 20 eller derover. Det betyder at ED^-g er over 30 mg/kg. Det' var ikke muligt at beregne en værdi for ED^g fordi virkningen ikke indtrådte i mange tilfælde der kunne dosisrelateres. Man ville vente at den procentuelle reversering ville være større når der blev indgivet en dosis på 25 60 mg/kg end når der blev indgivet en dosis på 30 mg/kg.A number of these compounds have been tested by the reser pin reversal test described later in this specification. The results are shown in Table I below, which shows that none of the compounds at a dose of 30 mg / kg resulted in a 50% or greater reversal of 50%. This means that ED 2 -g is above 30 mg / kg. It was not possible to calculate a value for ED 2g because the effect did not occur in many cases that could be dose related. It would be expected that the percent reversal would be greater when a dose of 25 60 mg / kg was administered than when a dose of 30 mg / kg was administered.

Dette kunne ikke verificeres på grund af forbindelsers toxicitet ved den højere dosis, hvilket især ses for forbindelsen C, hvor 2 af de 10 forsøgsdyr døde under forsøget.This could not be verified due to the toxicity of the compounds at the higher dose, as seen especially for compound C, where 2 of the 10 test animals died during the trial.

30 På baggrund af disse forsøgsresultater kan man ik ke vente at de fra GB 973887 kendte forbindelser har an-tidepressiv virkning hos mennesker. Alle de i henhold til omstående eksempler fremstillede forbindelser har, som det ses senere i beskrivelsen, en ED,, g værdi på 30 mg/kg el-35 ler derunder og mange af dem på 10 mg/kg eller derunder, hvilket viser at de har antidepressiv virkning hos mennesker.30 Based on these experimental results, it is not to be expected that the compounds known from GB 973887 have anti-depressant effect in humans. All of the compounds prepared by the following examples, as will be seen later in the specification, have an ED, g value of 30 mg / kg or less and many of them of 10 mg / kg or less, showing that they has antidepressant effect in humans.

1616

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Tabel I CH2NRdRe.HXTable I CH2NRdRe.HX

5 R1^ -15 R1 ^ -1

Ra Rd NRdRe X dosis, % reverse- gns.Ra Rd NRdRe X dose,% reverse gns.

- ____mg/kg ring__ A H OMe NH2 Cl 30 25,8,5 13 10 60 1,0 1 B H OMe Cl 10 2 2- ____ mg / kg ring__ A H OMe NH 2 Cl 30 25.8.5 13 10 60 1.0 1 B H OMe Cl 10 2 2

NN

30 46,41,37,24 37 60 27,15 21 15 Λ- C H OH ' Cl 30 22,15,17 18 60 1 D Η H NH2 Cl 30 9,1 1 ,-7 4 20 60 12,22 17 E OMe OMe NH2 Cl 30 3,3,6 4 60 6,12 9 25 F OMe OMe NPr2 Cl 30 2,11 7 60 28,11 20 G OH OH NH2 Br 30 4,4 4 60 -3,2 -1 30 H OH OH NPr2 Br 30 6,-1 3 60 0,3 2 3530 46,41,37,24 37 60 27,15 21 15 Λ- CH OH 'Cl 30 22,15,17 18 60 1 D Η H NH 2 Cl 30 9,1 1, -7 4 20 60 12,22 17 E OMe OMe NH2 Cl 30 3.3.6 4 60 6.12 9 25 F OMe OMe NPr2 Cl 30 2.11 7 60 28.11 20 G OH OH NH2 Br 30 4.4 4 60 -3.2 -1 30 H OH OH NPr2 Br 30 6, -1 3 60 0.3 2 35

Toxiske virkninger set, så 2 af 10 dyr døde.Toxic effects seen, leaving 2 out of 10 animals dead.

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1717

Fra Israel J.Chem 5(5), 223-229 (1967, i det følgende kaldt afhandling I, jfr. Chemical Abstracts bind 68, 19170 j, kendes der 1-fenylcykloalkylaminderivater. Der siges intet om at de har farmakologisk virkning, men der-5 imod at de skal afprøves for farmakologisk virkning; af hvilke art anføres ikke. Man kan således ikke herfra slutte noget om de ved den foreliggende fremgangsmåde fremstillede forbindelsers antidepressive virkning.From Israel J. Chem 5 (5), 223-229 (1967, hereinafter referred to as Dissertation I, cf. Chemical Abstracts Vol. 68, 19170 j), 1-phenylcycloalkylamine derivatives are known to have no pharmacological effect, but on the contrary, they must be tested for pharmacological action, of which nature is not stated, and thus no conclusion can be drawn from the antidepressant effect of the compounds of the present process.

Nævnte afhandling er fulgt op med to senere, den 10 ene i J.Med.Chem. J_2, 473-477, 1969 (i det følgende kaldt afhandling II), den anden i Israel Journal of Chemistry 13, nr. 1, 125-136, 1975 (i det følgende kaldt afhandling III).That thesis was followed up by two later, the 10th one in J.Med.Chem. J_2, 473-477, 1969 (hereinafter referred to as Dissertation II), the second in the Israel Journal of Chemistry 13, No. 1, 125-136, 1975 (hereinafter referred to as Dissertation III).

Hvad angår afhandling II er det vanskeligt at for-15 stå hvilken type forbindelser den beskriver, da tabellerne ikke er forsynet med nogen formel til hvilken kolonnernes overskrifter kan henføres. Man har imidlertid sluttet at formlerne for forbindelserne i de to tabeller må være henholdvis 20As for dissertation II, it is difficult to understand the type of compounds it describes, since the tables are not provided with any formula to which the headings of the columns can be attributed. However, it has been concluded that the formulas for the compounds in the two tables must be 20 respectively

Ar^NR'R" Ar \ NR'R" 0 „ 6Ar ^ NR'R "Ar \ NR'R" 0 "6

Tabel 1 Tabel 2 25 altså cyklohexyl- og cyklopentylderivater, der ikke er nær beslægtede med de foreliggende forbindelser eller med forbindelsen II (n=3) i afhandling I.Thus, cyclohexyl and cyclopentyl derivatives which are not closely related to the present compounds or to the compound II (n = 3) in thesis I.

Afhandling III angår fenylcyclidinanaloger med formlenThesis III relates to phenylcyclidine analogues of the formula

30 Ar NR RAr NR NR

((Οί,)η' 2 n hvor n kan være 3 (forbindelserne nr. 3 og 4). Disse for-35 bindeiser er klart forskellige fra de ved fremgangsmåden ifølge opfindelsen fremstillede (cyklobutylringen er forbundet direkte med aminogruppen), og forbindelserne nr.(Οί,) η '2 n where n can be 3 (Compounds Nos. 3 and 4.) These compounds are clearly different from those prepared by the process of the invention (the cyclobutyl ring is directly linked to the amino group) and Compounds Nos. .

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18 34 og 35 er inaktive ved de i afhandling III rapporterede farmakologiske prøver.18 34 and 35 are inactive in the pharmacological tests reported in Thesis III.

De fra den anførte litteratur kendte forbindelse giver således ikke anledning til at formode at de ved 5 fremgangsmåden ifølge opfindelsen fremstillede forbin delser har antidepressiv virkning.Thus, the compound known from the literature cited does not give rise to the presumption that the compounds prepared by the process according to the invention have antidepressant effect.

Den terapeutiske virkning af forbindelserne med formlen I er bestemt ved bedømmelse af forbindelsernes evne til at reversere de hypothermiske virkninger af reserpin på følgen-]_q de måde. Hanmus af stammen Charles River CD1 med en vægt mellem 18 og 30 g opdeltes i grupper på 5 og forsynedes med føde og vand ad libitum. Efter 5 timer blev alle musenes legemstemperatur taget oralt og musene fik intraperitoneale injektioner af reserpin (5 mg/kg) i opløsning i deioniseret vand indehol-^5 dende askorbinsyre (50 mg/ml). Den injicerede væskemænde var 10 ml/kg legemsvægt. 9 Timer efter forsøgets begyndelse blev dyrene afskåret fra føde mens vand stadig var til rådighed ad libitum. 24 Timer efter forsøgets begyndelse blev musenes temperatur atter taget og dyrene fik testforbindelsen suspen-20 deret i en 0,25%s opløsning af hydroxyætylcellulose (der for handles under det i Danmark ikke indregistrerede varemærke "Cellosize QP 15000") i deioniseret vand i et dosisrumfang på 10 ml/kg legemsvægt. 3 Timer senere blev alle dyrenes temperatur taget på ny. Den procentuelle reversering af den af 25 reserpin inducerede nedgang i legemsvægten beregnes derefter efter formlen (temp, efter 27 timer - temp, efter 24 timer) . 100 (temp, efter 5 timer - temp, efter 24 timer) 30The therapeutic effect of the compounds of formula I is determined by assessing the ability of the compounds to reverse the hypothermic effects of reserpine in the following manner. Male mice of the Charles River CD1 strain weighing between 18 and 30 g were divided into groups of 5 and provided with food and water ad libitum. After 5 hours, all mice body temperatures were taken orally and the mice received intraperitoneal injections of reserpine (5 mg / kg) in solution in deionized water containing ascorbic acid (50 mg / ml). The amount of fluid injected was 10 ml / kg body weight. 9 Hours after the start of the experiment, the animals were cut off from food while water was still available ad libitum. Twenty-four hours after the start of the experiment, the mice temperature was again taken and the animals were suspended in a 0.25% solution of hydroxyethyl ethyl cellulose (which is traded under the trademark "Cellosize QP 15000" not registered in Denmark) in a deionized water. dose volume of 10 ml / kg body weight. Three hours later, all animals' temperature was resumed. The percent reversal of the 25 reserpine-induced decrease in body weight is then calculated according to the formula (temp, after 27 hours - temp, after 24 hours). 100 (temp, after 5 hours - temp, after 24 hours) 30

Gennemsnitsværdien for hver gruppe på 5 mus blev bestemt ved flere forskellige dosisstørrelser for at tillade beregning af en værdi for den gennemsnitlige dosis, der bevirker en reversering på 50% (ED^q). Alle de forbindelser der er slutpro-35 dukter af de senere i beskrivelsen anførte eksempler giver værdier for ED,-0 på 30 mg/kg eller derunder. Det er klart for sagkyndige at denne test angiver forbindelser med antide- 19The average value for each group of 5 mice was determined at several different dose sizes to allow calculation of a value for the average dose causing a 50% reversal (ED ED q). All of the compounds which are final products of the examples set forth later in the specification give values for ED, -0 of 30 mg / kg or less. It is clear to the experts that this test indicates compounds with antide- 19

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pressiv virkning hos mennesker.depressive effect in humans.

I tabel II er der anført forbindelser med formlen I som gav en værdi for ED5Q ved ovennævnte prøve på 10 mg/kg eller derunder.Table II lists compounds of formula I which gave a value for ED5Q of the above test of 10 mg / kg or less.

5 Tabel IITable II

1-[1-(3,4-diklorfenyl)-cyklobutyl]-ætylamin-hydroklorid, N-metyl-1-[1-(3,4-diklorfenyl)-cyklobutyl]-ætylamin-hydroklorid, 10 N,N-dimetyl-1-[1-(3,4-diklorfenyl)-cyklobutyl]-ætylamin-hydroklorid, l-[1-(4-jodfenyl)-cyklobutyl]-ætylamin-hydroklorid, N-metyl-1-[1-(4-j odfenyl)-cyklobutyl]-ætylamin-hydroklorid, N,N-dimetyl-1-[1-(4-jodfenyl)-cyklobutyl]-ætylamin-hydroklorid, 15 N-metyl-1-[1-(2-naftyl)-cyklobutyl]-ætylamin-hydroklorid, N,N-dimetyl-1-[1-(4-klor-3-trifluormetylfenyl)-cyklobutyl]-ætylamin-hydroklorid, 1-[1-(4-klorfenyl)-cyklobutyl]-butylamin-hydroklorid, N-metyl-1-[1-(4-klorfenyl)-cyklobutyl]-butylamin-hydroklorid, 20 N,N-dimetyl-1-[1-(4-klorfenyl)-cyklobutyl]-butylamin-hydroklorid, 1-[1-(3,4-diklorfenyl)-cyklobutyl]-butylamin-hydroklorid, N-metyl-1-[1-(3,4-diklorfenyl)-cyklobutyl]-butylamin-hydroklorid, 25 N,N-dimetyl-1-[1-(3,4-diklorfenyl)-cyklobutyl]-butylamin-hydroklorid, 1-[1-(4-bifenylyl)-cyklobutyl]-butylamin-hydroklorid, N,N-dimetyl-1-[1-(4-bifenylyl)-cyklobutyl]-butylamin-hydroklorid, 30 1-[1-(4-klor-3-fluorfenyl)-cyklobutyl]-butylamin-hydroklorid, N-formyl-1-[1-(4-klor-3-fluorfenyl)-cyklobutyl]-butylamin, l-[1-(3-klor-4-metylfenyl)-cyklobutyl]-butylamin-hydroklorid, N-formyl-l~[1-fenylcyklobutyl]-butylamin, 1-[1-(3-trifluormetylfenyl)-cyklobutyl]-butylamin-hydroklorid, 35 1-[1-(naft-2-yl)-cyklobutyl]-butylamin-hydroklorid, 1-[1-(6-klornaft-2-yl)-cyklobutyl]-butylamin,1- [1- (3,4-Dichlorophenyl) -cyclobutyl] -ethylamine hydrochloride, N-methyl-1- [1- (3,4-dichlorophenyl) -cyclobutyl] -ethylamine hydrochloride, N, N-dimethyl -1- [1- (3,4-dichlorophenyl) cyclobutyl] ethylamine hydrochloride, 1- [1- (4-iodophenyl) cyclobutyl] ethylamine hydrochloride, N-methyl-1- [1- (4 N-Dimethyl-1- [1- (4-iodophenyl) -cyclobutyl] -ethylamine hydrochloride, N-methyl-1- [1- (2-naphthyl) -hydroxyphenyl) -cyclobutyl] -ethylamine hydrochloride ) -cyclobutyl] -ethylamine hydrochloride, N, N-dimethyl-1- [1- (4-chloro-3-trifluoromethylphenyl) -cyclobutyl] -ethylamine hydrochloride, 1- [1- (4-chlorophenyl) -cyclobutyl] -butylamine hydrochloride, N-methyl-1- [1- (4-chlorophenyl) -cyclobutyl] -butylamine hydrochloride, N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -butylamine hydrochloride, 1- [1- (3,4-dichlorophenyl) -cyclobutyl] -butylamine hydrochloride, N-methyl-1- [1- (3,4-dichlorophenyl) -cyclobutyl] -butylamine hydrochloride, N, N -dimethyl-1- [1- (3,4-dichlorophenyl) -cyclobutyl] -butylamine hydrochloride, 1- [1- (4-biphenylyl) -cyclobutyl] -butylamine hydrochloride, N, N-dimethyl-1- [ 1- (4-biphenylyl) cyclobutyl] - butylamine hydrochloride, 1- [1- (4-chloro-3-fluorophenyl) -cyclobutyl] -butylamine hydrochloride, N-formyl-1- [1- (4-chloro-3-fluorophenyl) -cyclobutyl] -butylamine , 1- [1- (3-Chloro-4-methylphenyl) -cyclobutyl] -butylamine hydrochloride, N-formyl-1- [1-phenylcyclobutyl] -butylamine, 1- [1- (3-trifluoromethylphenyl) -cyclobutyl] -butylamine hydrochloride, 1- [1- (naphth-2-yl) -cyclobutyl] -butylamine hydrochloride, 1- [1- (6-chloro-naphth-2-yl) -cyclobutyl] -butylamine,

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20 N-metyl-1-[1-(4-klorfenyl)-cyklobutyl]-2-metylpropylamin-hydro-klorid, 1-[1-(4-klorfenyl)-cyklobutyl]-pentylamin-hydroklorid, N-metyl-1-[1-(4-klorfenyl)-cyklobutyl]-pentylamin-hydroklorid, 5 N,N-dimetyl-1-[1-fenylcyklobutyl]-3-metylbutylamin-hydroklorid, 1-[1-(4-klorfenyl)-cyklobutyl]-3-metylbutylamin-hydroklorid, N-metyl-1-[1-(4-klorfenyl)-cyklobutyl]-3-metylbutylamin-hydroklorid, N,N-dimetyl-1-[1-(4-klorfenyl)-cyklobutyl]-3-metylbutylamin-10 hydroklorid, N-formyl-1-[1-(4-klorfenyl)-cyklobutyl]-3-metylbutylamin, N,N-dimetyl-1-[1-(3,4-diklorfenyl)-cyklobutyl]-3-metylbutylamin-hydroklorid, N-metyl-1-[1-(naft-2-yl)-cyklobutyl]-3-metylbutylamin-hydro-15 klorid, N-metyl-1-[1-(3,4-dimetylfenyl)-cyklobutyl]-3-metylbutulamin-hydroklorid, [1-(4-klorfenyl)-cyklobutyl]-(cyklopropyl)-metylamin-hydroklo-rid, 20 N-metyl-[1-(4-klorfenyl)-cyklobutyl]-(cyklopentyl)-metylamin-hydroklorid, [1-(4-klorfenyl)-cyklobutyl]-(cyklohexyl)-metylamin-hydroklo-rid, N-metyl-[1-(4-klorfeny1)-cyklobutyl]-(cyklohexyl)-metylamin-25 hydroklorid, [1-(3,4-diklorfenyl)-cyklobutyl]-(cyklohexyl)-metylamin-hydro-klorid, N-metyl-[1-(3,4-diklorfenyl)-cyklobutyl]-(cyklohexyl)-metyl-amin-hydroklorid, 30 [1"(4-klorfenyl)-cyklobutyl]-(cyklohexyl)-metylamin-hydroklo- rid, l-[1-(4-klorfenyl)-cyklobutyl]-2-cyklopropylætylamin-hydroklo-rid, N,N-dimetyl-1-[1-(4-klorfenyl)-cyklobutyl]-2-cyklohexylætyl-35 amin-hydroklorid, a-[1-(4-klorfenyl)-cyklobutyl]-benzylamin-hydroklorid,N-methyl-1- [1- (4-chlorophenyl) -cyclobutyl] -2-methylpropylamine hydrochloride, 1- [1- (4-chlorophenyl) -cyclobutyl] -pentylamine hydrochloride, N-methyl-1 - [1- (4-chlorophenyl) -cyclobutyl] -pentylamine hydrochloride, 5 N, N-dimethyl-1- [1-phenylcyclobutyl] -3-methylbutylamine hydrochloride, 1- [1- (4-chlorophenyl) -cyclobutyl ] -3-methylbutylamine hydrochloride, N-methyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine hydrochloride, N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl ] -3-methylbutylamine hydrochloride, N-formyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine, N, N-dimethyl-1- [1- (3,4-dichlorophenyl) - cyclobutyl] -3-methylbutylamine hydrochloride, N-methyl-1- [1- (naphth-2-yl) -cyclobutyl] -3-methylbutylamine hydrochloride, N-methyl-1- [1- (3, 4-Dimethylphenyl) cyclobutyl] -3-methylbutulamine hydrochloride, [1- (4-chlorophenyl) cyclobutyl] - (cyclopropyl) methylamine hydrochloride, N-methyl- [1- (4-chlorophenyl) cyclobutyl] - (cyclopentyl) methylamine hydrochloride, [1- (4-chlorophenyl) cyclobutyl] - (cyclohexyl) methylamine hydrochloride, N-methyl- [1- (4-chlorophenyl) cyclobutyl] - ( cyclohex yl) methylamine hydrochloride, [1- (3,4-dichlorophenyl) cyclobutyl] - (cyclohexyl) methylamine hydrochloride, N-methyl- [1- (3,4-dichlorophenyl) cyclobutyl] - (cyclohexyl) methylamine hydrochloride, [1 "(4-chlorophenyl) cyclobutyl] - (cyclohexyl) methylamine hydrochloride, 1- [1- (4-chlorophenyl) cyclobutyl] -2-cyclopropylethylamine hydrochloride, N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -2-cyclohexylethyl-amine hydrochloride, α- [1- (4-chlorophenyl) cyclobutyl] benzylamine hydrochloride,

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21 N-metyl-α- [1-(4-klorfenyl)-cyklobutyl]-benzylamin-hydroklorid, 1-[1-(4-klor-2-fluorfenyl)-cyklobutyl]-butylamin, N,N-dimetyl-1-[1-(4-klor-2-fluorfenyl)-cyklobutyl]-butylamin-hydroklorid, 5 1- ([ 1- (3,4-diklorfenyl)-cyklobutyl]-metyl}-propylamin-hydro- klorid, N,N-dimetyl-1-£[1-(3,4-diklorfenyl)-cyklobutyl]-metyl}-propyl-amin-hydroklorid, N,N-dimetyl-2-[1-(4-jodfenyl)-cyklobutyl]-ætylamin-hydroklo-rid, N-ætyl-1-[1-(3,4-diklorfenyl)-cyklobutyl]-ætylamin-hydroklo-rid, N,N-diætyl-l-[1-(3,4-diklorfenyl)-cyklobutyl]-ætylamin-hydro-klorid.21 N-methyl-α- [1- (4-chlorophenyl) -cyclobutyl] -benzylamine hydrochloride, 1- [1- (4-chloro-2-fluorophenyl) -cyclobutyl] -butylamine, N, N-dimethyl-1 - [1- (4-chloro-2-fluorophenyl) -cyclobutyl] -butylamine hydrochloride, 1- ([1- (3,4-dichlorophenyl) -cyclobutyl] -methyl} -propylamine-hydrochloride, N, N-dimethyl-1- [[1- (3,4-dichlorophenyl) -cyclobutyl] -methyl} -propyl-amine hydrochloride, N, N-dimethyl-2- [1- (4-iodophenyl) -cyclobutyl] - ethylamine hydrochloride, N-ethyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] -ethylamine hydrochloride, N, N-diethyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] -ætylamin-hydro-chloride.

1515

Fremgangsmåden ifølge opfindelsen vil i det følgende blive belyst ved nogle eksempler. Alle forbindelserne blev karakteriseret ved konventionel analyseteknik og gav tilfredsstillende elementæranalyse.The method according to the invention will now be illustrated by some examples. All the compounds were characterized by conventional analytical technique and provided satisfactory elemental analysis.

2020

Eksempel 1Example 1

En opløsning af 25 g 3,4-diklorbenzylcyanid og 15 ml 1,3-dibrompropan i 150 ml tørt dimetylsulfoxyd sattes dråbevis 25 under nitrogen til en omrørt blanding af 7,5 g natriumhydrid dispergeret i 7,5 g mineralsk olie og 200 ml dimetylsulfoxyd ved en temperatur i området 30-35°C. Blandingen omrørtes ved stuetemperatur i 2 timer hvorpå der dråbevis tilsattes 8 ml propan-2-on og derefter 110 ml vand. Blandingen filtreredes 2Q gennem diatoméjord, forhandlet under navnet "Celite" ® , og den faste remanens vaskedes med æter. Æterlaget fraskiltes, vaskedes med vand, tørredes og inddampedes. 1-(3,4-Diklorfenyl)-1-cyklobutankarbonitril (kp. 108-120°C/0,15 mm Hg) isoleredes ved destillation. Denne metode er en modifikation af den der 35 er beskrevet af Butler og Pollatz (J. Org. Chem., Vol. 36 nr. 9, 1971, side 1308).A solution of 25 g of 3,4-dichlorobenzyl cyanide and 15 ml of 1,3-dibromopropane in 150 ml of dry dimethyl sulfoxide was added dropwise under nitrogen to a stirred mixture of 7.5 g of sodium hydride dispersed in 7.5 g of mineral oil and 200 ml of dimethyl sulfoxide. at a temperature in the range of 30-35 ° C. The mixture was stirred at room temperature for 2 hours, then 8 ml of propan-2-one was added dropwise and then 110 ml of water. The mixture was filtered 2Q through diatomaceous earth, marketed under the name "Celite" ®, and the solid residue was washed with ether. The ether layer was separated, washed with water, dried and evaporated. 1- (3,4-Dichlorophenyl) -1-cyclobutanecarbonitrile (bp 108-120 ° C / 0.15 mm Hg) was isolated by distillation. This method is a modification of that described by Butler and Pollatz (J. Org. Chem., Vol. 36, No. 9, 1971, p. 1308).

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22 21,7 g af den på den ovenfor beskrevne måde fremstillede 1-(3,4-diklorfenyl)-1-cyklobutankarbonitril opløstes i 50 ml tør æter og opløsningen sattes under nitrogen til produktet af omsætning af gasformigt metylbromid med 3,9 g magnium-5 spåner i 150 ml tør æter. Blandingen omrørtes ved stuetemperatur i 2 timer og derefter under tilbagesvaling i 2 timer.21.7 g of the 1- (3,4-dichlorophenyl) -1-cyclobutanecarbonitrile prepared in the manner described above were dissolved in 50 ml of dry ether and the solution was added under nitrogen to the product of reaction of gaseous methyl bromide with 3.9 g of magnesium -5 chips in 150 ml dry ether. The mixture was stirred at room temperature for 2 hours and then under reflux for 2 hours.

Der tilsattes knust is og derpå 100 ml koncentreret saltsyre og blandingen opvarmedes under tilbagesvaling i 2 timer. Æterlaget fraskiltes, vaskedes med vand og vandigt natriumbikarbo-10 nat, tørredes og inddampedes. 1-Acety1-1-(3,4-diklorfenyl)-cyklobutan (kp. 108-110uC/0,2 mm Hg) isoleredes ved destillation.Crushed ice was added then 100 ml of concentrated hydrochloric acid and the mixture was heated under reflux for 2 hours. The ether layer was separated, washed with water and aqueous sodium bicarbonate, dried and evaporated. 1-Acetyl-1- (3,4-dichlorophenyl) -cyclobutane (b.p. 108-110uC / 0.2 mm Hg) was isolated by distillation.

9,1 g l-acetyl-l-(3,4-diklorfenyl)-cyklobutan, fremstillet som beskrevet ovenfor, 6,5 ml formamid og 3 ml 98%s myre-15 syre opvarmedes til 180°C i 16 timer hvorved der vandtes N-formyl-l-[l-(3,4-diklorfenyl)-cyklobutyl]-ætylamin. Der til-sattes 20 ml koncentreret saltsyre og blandingen opvarmedes I9.1 g of 1-acetyl-1- (3,4-dichlorophenyl) cyclobutane prepared as described above, 6.5 ml of formamide and 3 ml of 98% formic acid were heated to 180 ° C for 16 hours, N-Formyl-1- [1- (3,4-dichlorophenyl) -cyclobutyl] -ethylamine was obtained. 20 ml of concentrated hydrochloric acid was added and the mixture heated

under tilbagesvaling i 3 timer. Derefter afkøledes opløsningen og vaskedes med æter og der tilsattes natriumhydroxydopløsning.under reflux for 3 hours. Then, the solution was cooled and washed with ether and sodium hydroxide solution was added.

20 Produktet ekstraheredes med æter og æterekstrakten vaskedes med vand, tørredes og inddampedes. l-[l-(3,4-Diklorfenyl)-cyklobutyl]-ætylamin (kp. 112-118°C/0,2 mm Hg) isoleredes ved destillation. Aminen opløstes i propan-2-on og koncentreret saltsyre og opløsningen inddampedes til tørhed, hvorved 25 der vandtes l-[1-(3,4-diklorfenyl)-cyklobutyl]-ætylamin-hydro-klorid med smp. 185-195°C. (Formel I, n = 0; R3, = Me; R2 = R3 = R4 = H; R5 = 4-Cl; R6 = 3-Cl).The product was extracted with ether and the ether extract washed with water, dried and evaporated. 1- [1- (3,4-Dichlorophenyl) -cyclobutyl] -ethylamine (bp 112-118 ° C / 0.2 mm Hg) was isolated by distillation. The amine was dissolved in propan-2-one and concentrated hydrochloric acid and the solution evaporated to dryness to give 1- [1- (3,4-dichlorophenyl) cyclobutyl] ethylamine hydrochloride, m.p. 185-195 ° C. (Formula I, n = 0; R3, = Me; R2 = R3 = R4 = H; R5 = 4-Cl; R6 = 3-Cl).

Eksempel la 30Example la 30

Den ovenfor beskrevne fremstilling af N-formyl-l-[1-(3,4-diklorfenyl)-cyklobutyl]-ætylamin med smp. 124-125°C (eksempel la, formel I: n = 0; R1 = Me; R2 = H; R3 = H; R4 = CHO; R3 = 4-C1 og R3 = 3-C1) blev gentaget og produktet isoleredes ved afkøling af reaktionsblandingen og opsamling af 3 5 det faste produkt ved filtrering. Formamidet blev derefter hydrolyseret med koncentreret saltsyre i industrielt metyle-The above-described preparation of N-formyl-1- [1- (3,4-dichlorophenyl) -cyclobutyl] -ethylamine, m.p. 124-125 ° C (Example 1a, Formula I: n = 0; R1 = Me; R2 = H; R3 = H; R4 = CHO; R3 = 4-C1 and R3 = 3-C1) were repeated and the product isolated by cooling the reaction mixture and collecting the solid product by filtration. The formamide was then hydrolyzed with concentrated hydrochloric acid in industrial methylene.

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23 ret ætanol, og der vandtes hydrokloridsaltet af l-[1-(3,4-diklorfenyl)-cyklobutyl]-ætylamin.23 of ethanol and the hydrochloride salt of 1- [1- (3,4-dichlorophenyl) -cyclobutyl] -ethylamine was obtained.

På lignende måde som beskrevet i eksempel la blev følgende forbindelser fremstillet. Betingelserne for hydrolysen 5 af formamiderne, der isoleredes ved passende metoder, er anført i fodnoter.In the same manner as described in Example 1a, the following compounds were prepared. The conditions for the hydrolysis 5 of the formamides isolated by appropriate methods are set out in footnotes.

__. CHR1NH0,HC1 - l£H=i__. CHR1NH0, HCl - l £ H = i

Eksempel R R6 kp. (fri base) HCl-saltets Note smp.Example R R6 kp. (free base) HCl salt Note m.p.

15 1 (b) metyl Cl H 107°C/1,2 mm Hg A1 (b) methyl Cl H 107 ° C / 1.2 mm Hg A

1 (c) n-butyl Cl H 138-139°C B1 (c) n-butyl Cl H 138-139 ° C B

1 (d) metyl I H 205-207°C C1 (d) methyl I H 205-207 ° C

1 (e) metyl Cl CP3 216-217°C D1 (e) methyl Cl CP3 216-217 ° C D

2q A. Vandig saltsyre/industriel metyleret ætanol.2q A. Aqueous hydrochloric acid / industrial methylated ethanol.

B. 1-Valeryl-l-(4-klorfenyl)-cyklobutan fremstilledes i tetrahy-drofuran; hydrolyse udførtes med koncentreret HCL/industri-el metyleret ætanol.B. 1-Valeryl-1- (4-chlorophenyl) cyclobutane was prepared in tetrahydrofuran; hydrolysis was performed with concentrated HCl / industrial or methylated ethanol.

C. Koncentreret HCl/diætylenglykoldimetylæter (på lignende 2^ måde som beskrevet nedenfor i eksempel 12).C. Concentrated HCl / diethylene glycol dimethyl ether (similarly as described below in Example 12).

D. Koncentreret HCl/industriel metyleret ætanol.D. Concentrated HCl / industrial methylated ethanol.

Eksempel 2 4,04 g af produktet fra eksempel 1, 0,5 ml vand og 30 3,6 ml 98%s myresyre blandedes under afkøling. Der tilsattes 3,8 ml 37-40%s vandig formaldehyd og opløsningen ovparmedes til 85-95°C i 5 timer. Derefter inddampedes opløsningen til tørhed og remanensen syrnedes med koncentreret saltsyre og vandet fjernedes ved gentagen tilsætning af propan-2-ol efter-fulgt af inddampning i vakuum. Der isoleredes krystaller af N,N-dimetyl-1-[1-(3,4-diklorfenyl)-cyklobutyl]-ætylamin-hydro- 24Example 2 4.04 g of the product of Example 1, 0.5 ml of water and 3.6 ml of 98% formic acid were mixed with cooling. 3.8 ml of 37-40% aqueous formaldehyde was added and the solution was heated to 85-95 ° C for 5 hours. The solution was then evaporated to dryness and the residue was acidified with concentrated hydrochloric acid and the water removed by repeated addition of propan-2-ol followed by evaporation in vacuo. Crystals of N, N-dimethyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] ethylamine hydrochloride were isolated.

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klorid med smp. 211-213°C. (Formel I: n = 0; R3" = Me; R2 = H; R3 = R4 = Me; R5 = 4-C1; R6 = 3-C1).chloride, m.p. 211-213 ° C. (Formula I: n = 0; R3 = Me; R2 = H; R3 = R4 = Me; R5 = 4-C1; R6 = 3-C1).

På lignende måde omdannedes forbindelserne ifølge eksempel 1(b) og 1(d) til de nedenfor anførte forbindelser.Similarly, the compounds of Examples 1 (b) and 1 (d) were converted to the compounds listed below.

5 ,_. CHR1NMe^,HCl Π r6>>— .......5, _. CHR1NMe ^, HCl Π r6 >> - .......

10 15 610 15 6

Eksempel Udgangs- R R R HCl-saltets Fri bases kp., _materiale_smp., °C °C/mm· Hg_ 2 (a) 1 (b) metyl Cl H 98-100/0,5 2 (b) 1 (d) metyl I H 260-261Example Starting RRR HCl salt Free base bp., Material_mp., ° C ° C / mm · Hg_ 2 (a) 1 (b) methyl ClH 98-100 / 0.5 2 (b) 1 (d) methyl IH 260-261

Eksempel 3 på lignende måde som beskrevet foran i eksemplerne 1 og 2 fremstilledes N,N-dimetyl-l-[l-(4-bifenylyl)-cyklobu-tyl]-ætylamin-hydroklorid med smp. 196-197°C. (Formel I, n = 20 0; R1 = Me; R2 = H; R3 = R4 = Me; R5 = 4-fenyl og R6 = H) .Example 3 In a similar manner as described above in Examples 1 and 2, N, N-dimethyl-1- [1- (4-biphenylyl) -cyclobutyl] -ethylamine hydrochloride was prepared, m.p. 196-197 ° C. (Formula I, n = 20 O; R1 = Me; R2 = H; R3 = R4 = Me; R5 = 4-phenyl and R6 = H).

Eksempel 4 15 g l-acetyl-l-(3,4-diklorfenyl)-cyklobutan, fremstillet som beskrevet i eksempel 1, 47,5 ml N-metylformamid, 10,3 25 ml 98%s myresyre og 1,5 ml 25%s vandig opløsning af metylamin sammenblandedes og opvarmedes under omrøring ved 170-180°C i 8 timer. Blandingen afkøledes og ekstraheredes med æter. Æterekstrakten vaskedes, tørredes og inddampedes til en lysegul olie som opvarmedes under tilbagesvaling med 50 ml koncentre-30 ret saltsyre i 2 timer. Der tilsattes 50 ml industrielt mety-leret ætanol (IMS) og blandingen opvarmedes under tilbagesvaling i 16 timer. Derefter afkøledes blandingen til 0°C og det hvide bundfald opsamledes ved filtrering, vaskedes med acetone og tørredes. Produktet, N-metyl-l-[1-(3,4-diklorfenyl)-35 cyklobutyl]-ætylamin-hydroklorid havde smp. 254-256°C (formel______ 25Example 4 15 g of 1-acetyl-1- (3,4-dichlorophenyl) cyclobutane prepared as described in Example 1, 47.5 ml of N-methylformamide, 10.3 25 ml of 98% formic acid and 1.5 ml % aqueous methylamine solution was mixed and heated with stirring at 170-180 ° C for 8 hours. The mixture was cooled and extracted with ether. The ether extract was washed, dried and evaporated to a pale yellow oil which was refluxed with 50 ml of concentrated hydrochloric acid for 2 hours. 50 ml of industrially methylated ethanol (IMS) was added and the mixture was heated under reflux for 16 hours. Then the mixture was cooled to 0 ° C and the white precipitate collected by filtration, washed with acetone and dried. The product, N-methyl-1- [1- (3,4-dichlorophenyl) -cyclobutyl] -ethylamine hydrochloride had m.p. 254-256 ° C (Formula 25)

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I: n = 0; R1 = Me; R2 = H; R3 = Me; R^ = H; R5 = 4-C1 og R6 = 3-Cl).I: n = 0; R1 = Me; R2 = H; R3 = Me; = H; R5 = 4-C1 and R6 = 3-Cl).

På lignende måde fremstilledes følgende forbindelser med formel I: 5 1 .-. CHR NHMe ,HC1 1 c c 10 Eksempel R R R aminens kp. HCl-saltets Note _______ smp._Similarly, the following compounds of formula I were prepared: CHR NHMe, HCl 1 c c Example R R R amine bp. Note of HCl salt _______ m.p.

4 (a) Me Cl H 98-100°C/0,15mm Hg 240-241°C4 (a) Me Cl H 98-100 ° C / 0.15mm Hg 240-241 ° C

4 (b) Me H Cl 260-272°C4 (b) Me H Cl 260-272 ° C

4 (c) Me Br H 96-98°C/0,1 mm Hg4 (c) Me Br H 96-98 ° C / 0.1 mm Hg

4 (d) Me H Br 251-255°C4 (d) Me H Br 251-255 ° C

15 4 (e) Me CF3 H 219-221°C4 (e) Me CF3 H 219-221 ° C

4 (f) Me H CF3 225-228°C4 (f) Me H CF3 225-228 ° C

4 (g) Me -(CH=CH)2- 254-257°C4 (g) Me - (CH = CH) 2- 254-257 ° C

4 (h) Me Cl CF3 198-200°C4 (h) Me Cl CF3 198-200 ° C

4 (i) Et Cl H 238-240°C4 (i) Et Cl H 238-240 ° C

20 4 (j) Pr Cl H 228-229°C A4 (j) Pr Cl H 228-229 ° C A

4 (k) Bu Cl H 152-153°C A4 (k) Bu Cl H 152-153 ° C A

4 (1) Me I H 242-243°C4 (1) Me I H 242-243 ° C

Note A: Den som udgangsmateriale anvendte keton fremstilledes 25 i tetrahydrofuran som reaktions-opløsningsmiddel i stedet for æter.Note A: The ketone used as starting material was prepared in tetrahydrofuran as a reaction solvent instead of ether.

30 35 2630 35 26

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Eksempel 5Example 5

En blanding af 50 ml 70%s vandig ætylamin og 100 ml j vand blandedes gradvis med en blanding af 50 ml 98%s myresyre og 100 ml vand til frembringelse af en neutral opløsning·, 5 der inddampedes ved 100°C/100 ml Hg indtil der var opsamlet 180 ml vand. Remanensen opvarmedes til 140°C og der tilsattes 10,4 g l-acetyl-l-(4-klorfenyl)-cyklobutan (fremstillet på lignende måde som beskrevet i eksempel 1 for l-acetyl-l-(3,4-diklorfenyl)-cyklobutan) og 10 ml 98%s myresyre. Blandingen 10 opvarmedes på et oliebad til temperaturen 180-200°C i 16 timer. Blandingen destilleredes indtil der var opnået en indre temperatur på 170°C, og denne temperatur opretholdtes i 2 timer.A mixture of 50 ml of 70% aqueous ethylamine and 100 ml of water was gradually mixed with a mixture of 50 ml of 98% formic acid and 100 ml of water to give a neutral solution, evaporated at 100 ° C / 100 ml of Hg. until 180 ml of water was collected. The residue was heated to 140 ° C and 10.4 g of 1-acetyl-1- (4-chlorophenyl) cyclobutane (prepared in the same manner as described in Example 1 for 1-acetyl-1- (3,4-dichlorophenyl)) was added. -cyclobutane) and 10 ml of 98% formic acid. The mixture 10 was heated on an oil bath to the temperature 180-200 ° C for 16 hours. The mixture was distilled until an internal temperature of 170 ° C was obtained and this temperature was maintained for 2 hours.

Alt flygtigt materiale fjernedes ved destillation ved 160°C/ 20 mm Hg og remanensen opvarmedes under tilbagesvaling med 15 15 ml koncentreret saltsyre og 15 ml IMS i 3 timer. Den indu strielt metylerede ætanol afdampedes på en roterende vaporator og remanensen vaskedes med æter. Den vandige fase bragtes til pH 12 med natriumhydroxyd og ekstraheredes med æter. Æterekstrakten tørredes og efter inddampning gav den en remanens 20 som behandledes med vandig saltsyre til frembringelse af N-ætyl-l-[1-(4-klorfenyl)-cyklobutyl]-ætylamin-hydroklorid med srnp. 203-205°C. (Formel I: n = 0? R"4 = Me; R^ = H; R^ =All volatiles were removed by distillation at 160 ° C / 20 mm Hg and the residue was heated under reflux with 15 ml of concentrated hydrochloric acid and 15 ml of IMS for 3 hours. The industrially methylated ethanol was evaporated on a rotary vaporizer and the residue was washed with ether. The aqueous phase was brought to pH 12 with sodium hydroxide and extracted with ether. The ether extract was dried and, after evaporation, gave a residue 20 which was treated with aqueous hydrochloric acid to give N-ethyl-1- [1- (4-chlorophenyl) cyclobutyl] ethylamine hydrochloride with srnp. 203-205 ° C. (Formula I: n = 0? R "4 = Me; R ^ = H; R ^ =

Et; R4 = H; R5 = 4-Cl; R6 =H).One; R 4 = H; R5 = 4-Cl; R6 = H).

25 30 __________ 3525 30 __________ 35

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2727

Eksempel 6 15 g l-(4-klorfenyl)-l-cyklobutankarbonitril, fremstillet på lignende måde som l-(3,4-diklorfenyl)-cyklobutankarbo-nitril i eksempel 1, i 50 ml tør æter sattes til produktet 5 af reaktionen mellem 3,18 g magniumspåner og 15,99 g propyl-bromid i 50 ml tør æter. Æteren erstattedes med tetrahydrofu-ran og blandingen opvarmedes under omrøring ~og tilbagesvaling i 18 timer. Blandingen afkøledes og der tilsattes is og derpå 52 ml koncentreret saltsyre. Den resulterende blanding omrørtes 10 under tilbagesvaling i 10 timer og ekstraheredes med æter. Æterekstrakten gav en remanens hvorfra der destilleredes 1-butyryl-1-(4-klorfenyl)-cyklobutan med smp. 106-108°C/0,3 mm Hg.Example 6 15 g of 1- (4-chlorophenyl) -1-cyclobutanecarbonitrile, prepared in a similar manner to 1- (3,4-dichlorophenyl) cyclobutanecarbonitrile in Example 1, in 50 ml of dry ether was added to the product 5 of the reaction between 3.18 g of magnesium chips and 15.99 g of propyl bromide in 50 ml of dry ether. The ether was replaced with tetrahydrofuran and the mixture heated under stirring and reflux for 18 hours. The mixture was cooled and ice and 52 ml of concentrated hydrochloric acid were added. The resulting mixture was stirred under reflux for 10 hours and extracted with ether. The ether extract gave a residue from which 1-butyryl-1- (4-chlorophenyl) cyclobutane was distilled with m.p. 106-108 ° C / 0.3 mm Hg.

En blanding af 21 g af den på den ovenfor beskrevne måde fremstillede keton og 6 ml 98%s myresyre sattes i løbet 15 af en periode på 1 1/2 time til 15 ml formamid ved 160°C.A mixture of 21 g of the ketone prepared in the manner described above and 6 ml of 98% formic acid was added to 15 ml of formamide at 160 ° C over a period of 1 1/2 hours.

Efter fuldførelse af tilsætningen hævedes temperatur til 180-185°C og holdtes her i 5 timer. Blandingen afkøledes og ekstraheredes med kloroform til frembringelse af en tyk gummi, der ved opvarmning med petroleumsæter (kp. 60-80°C) gav et farve-20 løst fast stof som omkrystalliseredes fra petroleumsæter (kp. 60-80°C) til frembringelse af N-formyl-l-[l-(4-klorfenyl)-cyklobutyl]-butylamin med smp. 97,5-98°C (formel I: n = 0; R1= propyl; R2 = R3 = H; R4 =CHO; R5 = 4-C1; R6 = H).Upon completion of the addition, the temperature was raised to 180-185 ° C and kept here for 5 hours. The mixture was cooled and extracted with chloroform to give a thick gum which upon heating with petroleum ether (bp 60-80 ° C) afforded a colorless dissolved solid which was recrystallized from petroleum ether (bp 60-80 ° C) to produce of N-formyl-1- [1- (4-chlorophenyl) -cyclobutyl] -butylamine, m.p. 97.5-98 ° C (formula I: n = 0; R1 = propyl; R2 = R3 = H; R4 = CHO; R5 = 4-C1; R6 = H).

25 Eksempel 7Example 7

En opløsning af 35,2 g l-(3,4-diklorfenyl)-l-cyklobutan-karbonitril, fremstillet som beskrevet i eksempel 1, i 100 ml æter sattes til en opløsning af propylmagniumbromid frem-stillet ved omsætning af 32 g propylbromid med 6,36 g magniumspåner i 100 ml æter. Æteren udskiftedes med tørt toluen og blandingen opvarmedes under tilbagesvaling i 1 time. Der tilsattes 200 ml æter og derpå 120 ml koncentreret saltsyre og blandingen opvarmedes med tilbagesvaling i 1 time. Reaktions-^ blandingen ekstraheredes med æter og efter vask og tørring gav ekstrakten en remanens hvorfra der destilleredes 1-butyryl-l-(3,4-diklorfenyl)-cyklobutan med smp. 120-128°C/0,25 mm Hg.A solution of 35.2 g of 1- (3,4-dichlorophenyl) -1-cyclobutane carbonitrile, prepared as described in Example 1, in 100 ml of ether was added to a solution of propyl magnesium bromide prepared by reaction of 32 g of propyl bromide with 6.36 g of magnesium chips in 100 ml ether. The ether was replaced with dry toluene and the mixture heated under reflux for 1 hour. 200 ml of ether were added and then 120 ml of concentrated hydrochloric acid and the mixture was heated at reflux for 1 hour. The reaction mixture was extracted with ether and after washing and drying the extract gave a residue from which 1-butyryl-1- (3,4-dichlorophenyl) cyclobutane was distilled with m.p. 120-128 ° C / 0.25 mm Hg.

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28 37.0 g af den på den ovenfor beskrevne måde fremstillede keton og 9 ml 98%s myresyre sattes til 23,5 ml formamid ved 170°C og temperaturen holdtes på 175-180°C i 5 timer.28 37.0 g of the ketone prepared in the manner described above and 9 ml of 98% formic acid were added to 23.5 ml of formamide at 170 ° C and the temperature maintained at 175-180 ° C for 5 hours.

Der tilsattes en yderligere portion på 4,5 ml myresyre og 5 blandingen holdtes på 175-180°C i endnu 15 timer. Blandingen ekstraheredes med æter som efter afdampning gav en tyk olie der krystalliseredes fra petroleumsæter (kp. 60-80°C) til frembringelse af N-formyl-l-[l-(3,4-diklorfenyl)-cyklobutyl]-butylamin med smp. 103-105°C (formel I: n = 0; = propyl; 10 R2 = R3 = H; R4 = CHO; R5 = 4-C1 og R6 = 3-C1).An additional portion of 4.5 ml of formic acid was added and the mixture maintained at 175-180 ° C for another 15 hours. The mixture was extracted with ether which after evaporation afforded a thick oil which crystallized from petroleum ether (bp 60-80 ° C) to give N-formyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] -butylamine, m.p. . 103-105 ° C (formula I: n = 0; = propyl; R2 = R3 = H; R4 = CHO; R5 = 4-C1 and R6 = 3-C1).

På lignende måde som netop beskrevet fremstilledes følgende forbindelser:In the same manner as just described, the following compounds were prepared:

_____ CHR1NHCHO_____ CHR1NHCHO

Eksempel R^ R3 R^ smp. (°C) 20 7 (a) isobutyl Cl H 110-112 7 (b) propyl Cl F 115-116 7 (c) fenyl Cl H 94-96 7 (d) propyl Η H 98-102 25 Eksempel 8 4.0 g af produktet fra eksempel 7 i 25 ml tørt tetrahy-drofuran sattes hurtigt til en omrørt blanding af 1,4 g liti-umaluminiumhydrid i 25 ml tørt tetrahydrofuran under nitrogen.Example R 2 R 3 R 3 m.p. (° C) 20 7 (a) Isobutyl Cl H 110-112 7 (b) Propyl Cl F 115-116 7 (c) Phenyl Cl H 94-96 7 (d) Propyl Η H 98-102 Example 8 4.0 g of the product of Example 7 in 25 ml of dry tetrahydrofuran was rapidly added to a stirred mixture of 1.4 g of lithium aluminum hydride in 25 ml of dry tetrahydrofuran under nitrogen.

^ Blandingen opvarmedes under tilbagesvaling i 5 timer og afkøledes derefter. Der tilsattes 15 ml vand og derpå 3 ml 10%s natriumhydroxydppløsning, og blandingen filtreredes gennem diatoméjord ("Celite" ® ). Produktet ekstraheredes over i æter og tilbageekstraheredes med 5N saltsyre hvorpå det vandige lag gjordes basisk og ekstraheredes med æter. ffiterekstrak- 35 ten gav en olie som opløstes i 5 ml propan-2-ol og der tilsattes saltsyre til pH 2. Inddampning af den resulterende opløsning gav et hvidt fast stof som opsamledes, vaskedes med acetone og tørredes. Produktet var N-metyl-l-[l-(3,4-diklorfenyl)-The mixture was heated under reflux for 5 hours and then cooled. 15 ml of water and then 3 ml of 10% sodium hydroxide solution were added and the mixture was filtered through diatomaceous earth ("Celite" ®). The product was extracted into ether and back extracted with 5N hydrochloric acid, then the aqueous layer was basified and extracted with ether. The phytite extract gave an oil which was dissolved in 5 ml of propan-2-ol and hydrochloric acid was added to pH 2. Evaporation of the resulting solution gave a white solid which was collected, washed with acetone and dried. The product was N-methyl-1- [1- (3,4-dichlorophenyl) -

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29 cyklobutyl]-butylamin-hydroklorid og havde smp. 234-235°C (formel I: n = 0; R^ = propyl; R^ = R^ = H; R^ = Me; R5 = 4-Cl og R6 = 3-C1).29 cyclobutyl] -butylamine hydrochloride and had m.p. 234-235 ° C (formula I: n = 0; R R = propyl; R ^ = R R = H; R ^ = Me; R R = 4-Cl and R R = 3-C1).

På lignende måde fremstilledes følgende forbindelser: 5 ,_. CHR^NHMe,HCl »5 ΓΛ | - 1°Similarly, the following compounds were prepared: 5. CHR ^ NHMe, HCl »5 ΓΛ | - 1 °

Eksempel Rx R3 R° Smp. (°C) 8 (a) fenyl Cl H 275-278 8 (b) propyl Cl H 223-228 15 Eksempel 9 10 g af produktet fra eksempel 7 i opløsning i 50 ml æter sattes til 40 ml 70%s toluenopløsning af natrium-bis-(2-metoxyætoxy)-aluminiumhydrid der forhandles under det i 2Q Danmark ikke indregistrerede varemærke "Red-al", ved en temperatur i området 25-30°C. Blandingen omrørtes ved denne temperatur i 4 timer. Der tilsattes dråbevis og under afkøling 25 ml vand og blandingen filtreredes gennem diatoméjord ("Ce-lite" ® ). Der tilsattes vandigt NaOH og udførtes ekstrakti- on med æter. Æterekstrakten vaskedes med vand og tilbageekstra-heredes med 5N saltsyre. Der viste sig i grænselaget et hvidt fast stof med smp. 232-235°C, og det opsamledes. Der sattes base til den vandige fase og ekstraheredes endnu en gang med æter. Inddampning af æterekstrakten gav en olie som opløstes i 5 ml propan-2-ol og der tilsattes koncentreret saltsyre til pH 2. Inddampning til tørhed gav et hvidt fast stof med smp. 233-236°C. De hvide faste stoffer forenedes og omkrystalliseredes fra propan-2-ol, hvorved der vandtes N-metyl-l-[1-(3,4-diklorfeny1)-cyklobutyl]-butylamin-hydroklorid med smp. 236-237°C (formel I: n = 0; R^ = propyl; R^ = R^ = H; 4 5 6 R = Me; R = 4-C1 og R = 3-C1.Example Rx R3 R ° Mp. (° C) 8 (a) phenyl Cl H 275-278 8 (b) propyl Cl H 223-228 Example 9 10 g of the product of Example 7 in solution in 50 ml ether was added to 40 ml 70% sodium toluene solution -bis- (2-methoxyethoxy) aluminum hydride traded under the trademark "Red-al" not registered in 2Q Denmark, at a temperature in the range 25-30 ° C. The mixture was stirred at this temperature for 4 hours. 25 ml of water was added dropwise and, under cooling, and the mixture was filtered through diatomaceous earth ("Ce-lite" ®). Aqueous NaOH was added and extracted with ether. The ether extract was washed with water and back-extracted with 5N hydrochloric acid. A white solid with m.p. 232-235 ° C and it was collected. Base was added to the aqueous phase and extracted again with ether. Evaporation of the ether extract gave an oil which was dissolved in 5 ml of propan-2-ol and concentrated hydrochloric acid was added to pH 2. Evaporation to dryness gave a white solid, m.p. 233-236 ° C. The white solids were combined and recrystallized from propan-2-ol to give N-methyl-1- [1- (3,4-dichlorophenyl) cyclobutyl] -butylamine hydrochloride, m.p. 236-237 ° C (Formula I: n = 0; R = = propyl; R ^ = R = = H; 4,5 6 R = Me; R = 4-C1 and R = 3-C1.

På lignende måde som ovenfor beskrevet fremstilledes følgende forbindelser. Hvor formyl-udgangsmaterialet var uop-In the same way as described above, the following compounds were prepared. Where the formyl starting material was unopened

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30 løseligt i æter sattes der en opløsning af reduktionsmidlet til en omrørt suspension af formylforbindelsen. Efterhånden j som størrelsen af gruppen stiger bliver hydrokloridsaltene af de ønskede forbindelser mindre opløselige i den vandige i 5 fase og mere opløselige i den organiske fase, så at passende modifikationer er nødvendige i isolationsprocessen, som det vil være klart for de sagkyndige.After dissolving in ether, a solution of the reducing agent was added to a stirred suspension of the formyl compound. As the size of the group increases, the hydrochloride salts of the desired compounds become less soluble in the aqueous phase and more soluble in the organic phase, so that appropriate modifications are needed in the isolation process as will be apparent to those skilled in the art.

........ CHR1 2 3 4NHMe, HC1 “ *5-Ofi........ CHR1 2 3 4NHMe, HC1 “* 5-Ofi

Eksempel R^ R^ Smp. (°C) 9 (a) isopropyl Cl H 275-259 15 9 (b) s-butyl Cl H 209-212 9 (c) isobutyl Cl H 225-233 9 (d) cyklopentyl Cl H 252-256 9 (e) n-hexyl Cl H 117-118 9 (f) 4-metoxyfeny1 Cl H 264-266 9 (g) 3-metoxyfenyl Cl H 254-255 9 (h) 2-metoxyfenyl Cl H 149-153Example R (° C) 9 (a) isopropyl Cl H 275-259 9 (b) s-Butyl Cl H 209-212 9 (c) Isobutyl Cl H 225-233 9 (d) Cyclopentyl Cl H 252-256 9 (e) (f) 4-methoxyphenyl Cl H 264-266 9 (g) 3-methoxyphenyl Cl H 254-255 9 (h) 2-methoxyphenyl Cl H 149-153

9 (i) cyklohexyl Cl H 170-172 I9 (i) cyclohexyl Cl H 170-172 I

9 (j) isobutyl -(CH = CH)^ 256-259 9 (k) cyklohexyl Cl Cl 223-224 25 9 (i) isobutyl Me Me (1) 9 (m) propyl OMe H 173-175 9 (n) metyl fenyl H 116-1189 (j) isobutyl - (CH = CH) + 256-259 9 (k) cyclohexyl Cl Cl 223-224 25 9 (i) isobutyl Me Me (1) 9 (m) propyl OMe H 173-175 9 (n) methyl phenyl H 116-118

Kogepuhkt over 150°C/1,0 mm Hg for den fri base.Boiling point above 150 ° C / 1.0 mm Hg for the free base.

2 3° 32 3 ° 3

Eksempel 10 4 4 g af produktet fra eksempel 7, 25 ml diætylenglykol- 5 dimetylæter, 10 ml vand og 10 ml koncentreret saltsyre sammen-35 blandedes og opvarmedes under tilbagesvaling i 9 timer. Opløsningen vaskedes med æter og der tilsattes vandigt NaOH før der foretoges ekstraktion med æter. Æterekstrakten vaskedes med saltlage og gav ved inddampnning en olie. 3,19 g af olienExample 10 4 4 g of the product of Example 7, 25 ml of diethylene glycol dimethyl ether, 10 ml of water and 10 ml of concentrated hydrochloric acid were mixed and heated under reflux for 9 hours. The solution was washed with ether and aqueous NaOH was added before extraction with ether. The ether extract was washed with brine and evaporated to give an oil. 3.19 g of the oil

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31 opløstes i en blanding af 4 ml propan-2-ol og 20 ml æter og der tilsattes 1,5 ml koncentreret saltsyre. Opløsningsmidlet afdampedes i vakuum. Gentagen opløsning i industriel metyleret ætanol og inddampning i vakuum gav en gummi som størknede 5 ved opvarmning i vakuum. Produktet omkrystalliseredes fra petroleumsæter (kp. 100-120°C) og havde smp. 201-203°C. Produktet var 1-[1-(3,4-diklorfenyl)-cyklobutyl]-butylamin-hydro-klorid (formel I: n = 0; R^ = propyl; = H; = 4-Cl og R6 = 3-Cl).31 was dissolved in a mixture of 4 ml of propan-2-ol and 20 ml of ether and 1.5 ml of concentrated hydrochloric acid was added. The solvent was evaporated in vacuo. Repeated solution in industrial methylated ethanol and evaporation in vacuo gave a gum which solidified on heating in vacuo. The product was recrystallized from petroleum ether (b.p. 100-120 ° C) and had m.p. 201-203 ° C. The product was 1- [1- (3,4-dichlorophenyl) -cyclobutyl] -butylamine hydrochloride (Formula I: n = 0; R 2 = propyl; = H; = 4-Cl and R 6 = 3-Cl) .

10 På lignende måde som netop beskrevet fremstilledes følgende forbindelser. Efterhånden som størrelsen af gruppen R^ stiger bliver de ønskede forbindelsers hydrokloridsalte mindre opløselige i den vandige fase og mere opløselige i den organiske fase, således at der behøves passende modifika-15 tioner af isolationsprocessen, hvilke modifikationer vil være åbenbare for de sagkyndige.In the same manner as just described, the following compounds were prepared. As the size of the R group increases, the hydrochloride salts of the desired compounds become less soluble in the aqueous phase and more soluble in the organic phase, so that appropriate modifications of the isolation process are needed, which modifications will be apparent to those skilled in the art.

-- απΑϊΗ,,ΗΟΙ R6^ -- απΑϊΗ ,, ΗΟΙ R6 ^ -

Eksempel R1 R5 R6 Smp. (°C) 10 (a) isopropyl Cl H 200-202 10 (b) s-butyl Cl H 178-179 25 10 (c) isobutyl Cl H 163-165 10 (d) cyklopentyl Cl H 185-210 10 (e) fenyl Cl H 271-276 10 (f) 4-metoxyfenyl Cl H 214-219 10 (g) cyklohexyl Cl H 206-210 10 (h) isobutyl Η H 210-212 10 (i) cyklopropyl Cl H 204-206 10 (j) propyl Ph H 235-236 10 (k) propyl Me Cl 214-217 10 (1) propyl -(CH = CH)2~ 157-159 10 (m) cykloheptyl Cl H 156-162 10 (n) cyklohexyl Cl Cl 215 10 (p) metyl Cl F 215-217Example R1 R5 R6 m.p. (° C) 10 (a) isopropyl Cl H 200-202 (b) s-Butyl Cl H 178-179 (c) Isobutyl Cl H 163-165 (d) Cyclopentyl Cl H 185-210 10 (e) (f) 4-methoxyphenyl Cl H 214-219 10 (g) cyclohexyl Cl H 206-210 10 (h) isobutyl Η H 210-212 10 (i) cyclopropyl Cl H 204-206 10 (j) propyl Ph H 235-236 (k) propyl Me Cl 214-217 (1) propyl - (CH = CH) 2 ~ 157-159 (m) cycloheptyl Cl H 156-162 10 (n) cyclohexyl Cl Cl 215 10 (p) methyl Cl F 215-217

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32 10 (q) propyl OMe H 178-179 10 (r) propyl Cl F 186-188 10 (s) propyl Cl H 174-175 10 (t) cyklohexylmetyl Cl H 148-150 5 10 (u) butényl Cl H 184-185 , 10 (v) propyl -CH=CH-CC1-CH- (a) 10 (w) propyl H CF^ 126-128 10 (x) 4-fluorfenyl Cl H 279 10 (y) (b) metyl -C—C-CH=CH- 248-26232 (q) propyl OMe H 178-179 10 (r) propyl Cl F 186-188 10 (s) propyl Cl H 174-175 10 (t) cyclohexylmethyl Cl H 148-150 5 (u) butenyl Cl H 184 -185, 10 (v) propyl -CH = CH-CC1-CH- (a) 10 (w) propyl H CF ^ 126-128 (x) 4-fluorophenyl Cl H 279 10 (y) (b) methyl - C-C-CH = CH-248-262

10 CH CH10 CH CH

\ //\ //

CH-CHCH-CH

(a) Kogepunkt af den fri base 168°C/0,05 mm Hg.(a) Boiling point of the free base 168 ° C / 0.05 mm Hg.

(b) Diætylenglykoldimetylæter erstattet med ætylenglykoldime- . r tylæter.(b) Diethylene glycol dimethyl ether replaced by ethylene glycol dimethyl. r tyleat.

Ib På lignende måde som beskrevet ovenfor fremstilledes l-[l-(4-klor-2-fluorfenyl)-cyklobutyl]-butylamin med kp. 99°C/ 0,05 mm Hg (formel I: n = 0; R^ = propyl; R2 = R2 = R4 = H; R^ = 4-C1; R^ = 2-F), l-[1-(2-fluorfenyl)-cyklobutyl]-butyl- ZU τ : amin-hydroklorid med smp. 175-177°C (formel I: n = 0; Rx = propyl; R2 = R3 = R4 = R5 = H; R6 = 2-F) og l-[1-(4-klor-2-1b In a similar manner as described above, 1- [1- (4-chloro-2-fluorophenyl) -cyclobutyl] -butylamine was prepared with b.p. 99 ° C / 0.05 mm Hg (Formula I: n = 0; R 2 = propyl; R 2 = R 2 = R 4 = H; R 2 = 4-C 1; R 2 = 2-F), 1- [1- (2-fluorophenyl) -cyclobutyl] -butyl-ZU τ: amine hydrochloride, m.p. 175-177 ° C (formula I: n = 0; Rx = propyl; R2 = R3 = R4 = R5 = H; R6 = 2-F) and 1- [1- (4-chloro-2-

metyl)-cyklobutyl]-butylamin-hydroklorid med smp. 188-190°Cmethyl) cyclobutyl] -butylamine hydrochloride, m.p. 188-190 ° C

(formel I:n=0;R^= propyl; R2 = R2 = R4 = H; R2 - 4-C1; R6 = 2-Me) som eksempel 10 (z), 10 (aa) og 10 (bb)* 25(Formula I: n = 0; R 1 = propyl; R 2 = R 2 = R 4 = H; R 2 - 4-C 1; R 6 = 2-Me) as Examples 10 (z), 10 (aa) and 10 (bb) * 25

Eksempel 11 3,3 g af produktet ifølge eksempel 10(c) i form af den fri base, 2,99 g myresyre og 1 ml vand blandedes under afkøling. Der tilsattes 3,93 ml 37-40%s vandigt formaldehyd 0* ' 0 og blandingen opvarmedes i 18 timer ved en temperatur pa 85- ' -Example 11 3.3 g of the product of Example 10 (c) in the form of the free base, 2.99 g of formic acid and 1 ml of water were mixed with cooling. 3.93 ml of 37-40% aqueous formaldehyde 0 * 0 was added and the mixture was heated for 18 hours at a temperature of 85 ° C.

.. N.. N

95°C. Der tilsattes overskud af fortyndet saltsyre og opløsningen inddampedes til tørhed. Remanensen gjordes basisk med 5N natriumhydroxydopløsning og produktet ekstraheredes med æter. Afdampning af æteren gav en lysegul olie som opløstes i en blanding af 4 ml propan-2-ol og 20 ml æter, og der tilsattes dråbevis 2 ml koncentreret saltsyre. Opløsningen inddam-95 ° C. Excess dilute hydrochloric acid was added and the solution evaporated to dryness. The residue was basified with 5N sodium hydroxide solution and the product extracted with ether. Evaporation of the ether gave a pale yellow oil which was dissolved in a mixture of 4 ml of propan-2-ol and 20 ml of ether, and 2 ml of concentrated hydrochloric acid was added dropwise. The solution evaporates

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33 pedes og remanensen opløstes gentagne gange i ætanol og inddampedes i vakuum til frembringelse af en gummi der triturere-des med petroleumsæter (kp. 60-80°C) til frembringelse af et gult fast stof som omkrystalliseredes fra acetone. Produk-5 tet var N,N-dimetyl-l-[l-(4-klorfenyl)-cyklobutyl]-3-metylbu-tylamin-hydroklorid med smp. 195-197°C (formel I: n = 0; R"*" = isobutyl; R2 = H; R3 = R4 = Me; R5 = 4-C1; R6 = H).33 pedes and the residue was dissolved repeatedly in ethanol and evaporated in vacuo to give a gum triturated with petroleum ether (bp 60-80 ° C) to give a yellow solid which was recrystallized from acetone. The product was N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutylamine hydrochloride, m.p. 195-197 ° C (formula I: n = 0; R "+" = isobutyl; R2 = H; R3 = R4 = Me; R5 = 4-C1; R6 = H).

På lignende måde som beskrevet ovenfor fremstilledes følgende forbindelser med formel I: 10 CHR-'-NMe^HCl --Pfi R6"^ - 15In a similar manner as described above, the following compounds of formula I were prepared: 10 CHR-1-NMe 2 HCl - Pfi R 6

Eksempel Udgangs- R^ R^ R^ Smp.(°C) materiale 11 (a) 10 (h) isobutyl Η H 195-198 11 (b) 10 (j) propyl Ph H 194-196 20 11 (c) 10 (n) cyklohexyl Cl Cl 227-228 11 (d) 10 (q) propyl OMe H 187-188 11 (e) 10 (s) propyl Cl H 194-196 11 (f) 10 (t) cyklohexyl- Cl H 194-196 metyl 11 (g) 10 (u) bute- Cl H 165-167 25 nyl 11 (h) 10 (v) propyl -CH=CH-CC1=CH- (a) 11 (i) - isobutyl Cl Cl 225-226 11 (j) 10 (x) 4-fluorfenyl Cl H 234 11 (k) - propyl isopropyl Η 211-213 30 (a) Den fri bases kogepunkt under 250°C/0,05 mm Hg.Example Initial R ^ R ^ R ^ Mp (° C) material 11 (a) 10 (h) isobutyl Η H 195-198 11 (b) 10 (j) propyl Ph H 194-196 20 11 (c) 10 (n) cyclohexyl Cl Cl 227-228 11 (d) 10 (q) propyl OMe H 187-188 11 (e) 10 (s) propyl Cl H 194-196 11 (f) 10 (t) cyclohexyl Cl H 194 -196 methyl 11 (g) 10 (u) butane Cl H 165-167 nyl 11 (h) 10 (v) propyl -CH = CH-CC1 = CH- (a) 11 (i) - isobutyl Cl Cl 225 -226 11 (j) 10 (x) 4-fluorophenyl Cl H 234 11 (k) - propyl isopropyl Η 211-213 30 (a) The free base boiling point below 250 ° C / 0.05 mm Hg.

Eksempel 11 (1) 35 På lignende måde som beskrevet ovenfor fremstilledes N,N-dimety1-1-[1-(4-klor-2-fluorfenyl)-cyklobuty1]-butylamin-hydroklorid med smp. 183°C (formel I: n = 0; R3" = propyl; R2 = H; R3 = R4 = Me; R5 = 4-C1; R6 = 2-F).Example 11 (1) In a similar manner as described above, N, N-dimethyl-1- [1- (4-chloro-2-fluorophenyl) -cyclobutyl] -butylamine hydrochloride was prepared, m.p. 183 ° C (formula I: n = 0; R3 "= propyl; R2 = H; R3 = R4 = Me; R5 = 4-C1; R6 = 2-F).

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3434

Eksempel 12 8,3 g af produktet fra eksempel 7, 50 ml dimetylengly-kol-dimetylæter, 20 ml vand og 20 ml koncentreret saltsyre blandedes og opvarmedes under tilbagesvaling i 16 timer. Blan-5 dingen udhældtes i vand, der tilsattes vandigt NaOH og produk- ! tet ekstraheredes med æter. Inddampning gav en mørk olie.Example 12 8.3 g of the product of Example 7, 50 ml of dimethylene glycol dimethyl ether, 20 ml of water and 20 ml of concentrated hydrochloric acid were mixed and heated under reflux for 16 hours. The mixture was poured into water, which was added aqueous NaOH and the product. extracted with ether. Evaporation gave a dark oil.

En prøve på 7,9 g af denne olie, 0,7 ml vand og 6,5 ml myresyre blandedes og der tilsattes 6,5 ml formaldehyd. Blandingen opvarmedes under tilbagesvaling i 3 timer og derefter 10 tilsattes der 10 ml koncentreret saltsyre og 10 ml propan- 2-ol. Inddampning til tørhed gav N,N-dimetyl-l-[l-(3,4-diklor-A sample of 7.9 g of this oil, 0.7 ml of water and 6.5 ml of formic acid was mixed and 6.5 ml of formaldehyde was added. The mixture was heated under reflux for 3 hours and then 10 ml of concentrated hydrochloric acid and 10 ml of propan-2-ol were added. Evaporation to dryness gave N, N-dimethyl-1- [1- (3,4-dichloroacetic acid)

fenyl)-cyklobutyl]-butylamin-hydroklorid med smp. 195-196°Cphenyl) -cyclobutyl] -butylamine hydrochloride, m.p. 195-196 ° C

1 2 som et hvidt fast stof (formel I: n = 0; R = propyl; R = H; R3 = R4 = Me; R5 = 4-C1; R6 = 3-C1).1 2 as a white solid (formula I: n = 0; R = propyl; R = H; R3 = R4 = Me; R5 = 4-C1; R6 = 3-C1).

15 I15 I

Eksempel 13 ! 37,6 g l-(4-klorfenyl)-l-cyklobutankarbonitril, fremstillet på lignende måde som beskrevet for 1-(3,4-diklorfenyl)-2Q 1-cyklobutankarbonitril i eksempel 1, sattes til en opløsning af 32,4 g kaliumhydroxyd i 370 ml diætylenglykol og blandingen opvarmedes under tilbagesvaling i 3 1/2 time. Reaktionsblandingen udhældtes i en blanding af is og vand og den resulterende opløsning vaskedes med æter. Det vandige lag sattes til en blanding af 100 ml koncentreret saltsyre og is og det 25 resulterende bundfald af l-(4-klorfenyl)-l-cyklobutankarboxyl-syre (smp. 86-88°C) opsamledes, vaskedes med vand og tørredes.Example 13! 37.6 g of 1- (4-chlorophenyl) -1-cyclobutanecarbonitrile prepared in a similar manner as described for 1- (3,4-dichlorophenyl) -2Q1-cyclobutanecarbonitrile in Example 1 were added to a solution of 32.4 g. potassium hydroxide in 370 ml of diethylene glycol and the mixture heated under reflux for 3 1/2 hours. The reaction mixture was poured into a mixture of ice and water and the resulting solution washed with ether. The aqueous layer was added to a mixture of 100 ml of concentrated hydrochloric acid and ice and the resulting precipitate of 1- (4-chlorophenyl) -1-cyclobutanecarboxylic acid (mp 86-88 ° C) was collected, washed with water and dried.

En opløsning af 10,5 g af den på den ovenfor beskrevne måde fremstillede syre i 150 ml tetrahydrofuran sattes dråbe-^ vis under nitrogen til en omrørt suspension af 2 g litiumalu-miniumhydrid i 150 ml tetrahydrofuran. Blandingen opvarmedes under tilbagesvaling i 2 timer og der tilsattes vand. Blandingen filtreredes gennem diatoméjord ("Celite" ® ), og produktet ekstraheredes med æter. Efter vask med vand og tørring afdampe-^ des æteren og der fremkom en remanens som omkrystalliseredes fra petroleumsæter (kp. 60-80°C).Produktet var l-[1-(4-klor-fenyl)-cyklobutyl]-metylalkohol med smp. 60-62°C.A solution of 10.5 g of the acid prepared in the manner described above in 150 ml of tetrahydrofuran was added dropwise under nitrogen to a stirred suspension of 2 g of lithium aluminum hydride in 150 ml of tetrahydrofuran. The mixture was heated under reflux for 2 hours and water was added. The mixture was filtered through diatomaceous earth ("Celite" ®) and the product extracted with ether. After washing with water and drying, the ether was evaporated and a residue was obtained which was recrystallized from petroleum ether (b.p. 60-80 ° C). The product was 1- [1- (4-chloro-phenyl) -cyclobutyl] -methyl alcohol with mp. 60-62 ° C.

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En opløsning af 60 g af den på den ovenfor beskrevne måde fremstillede alkohol i 52 ml pyridin sattes dråbevis til en opløsning af 60 g p-toluensulfonylklorid i 100 ml pyridin, afkølet i is. Temperaturen fik lov at stige til stuetem-5 peratur og blive der i 18 timer. l-[1-(4-klorfenyl)-cyklobutyl]-metyl-p-toluensulfonat med smp. 99-100°C udfældedes ved udhæld-ning af reaktionsblandingen i en blanding af is og koncentreret saltsyre (200 ml). En opløsning af 97 g af sulfonatforbin-delsen, fremstillet på den ovenfor beskrevne måde, og 16,6 10 g natriumcyanid i 370 ml dimetylsulfoxyd opvarmedes på et dampbad i 18 timer. Blandingen udhældtes i vand og ekstrahere-des med æter. Efter vask og tørring afdampedes æteren og efterlod en fast remanens af 2-[l-(4-klorfenyl)-cyklobutyl]-aceto-nitril med smp. 63-65°C.A solution of 60 g of the alcohol prepared in the manner described above in 52 ml of pyridine was added dropwise to a solution of 60 g of p-toluenesulfonyl chloride in 100 ml of pyridine, cooled in ice. The temperature was allowed to rise to room temperature and stayed there for 18 hours. 1- [1- (4-chlorophenyl) -cyclobutyl] -methyl-p-toluenesulfonate, m.p. 99-100 ° C was precipitated by pouring the reaction mixture into a mixture of ice and concentrated hydrochloric acid (200 ml). A solution of 97 g of the sulfonate compound prepared in the manner described above and 16.6 10 g of sodium cyanide in 370 ml of dimethyl sulfoxide were heated on a steam bath for 18 hours. The mixture was poured into water and extracted with ether. After washing and drying, the ether was evaporated leaving a solid residue of 2- [1- (4-chlorophenyl) cyclobutyl] acetonitrile with m.p. 63-65 ° C.

15 En opløsning af 16,5 g diisopropylamin i 50 ml tørt tetrahydrofuran omrørtes under nitrogen ved en temperatur på 0°C og der tilsattes dråbevis en 1,6M opløsning af n-butyl-litium i 100 ml hexan. Reaktionsblandingen omrørtes i 30 minutter og afkøledes derefter til -78°C. Der tilsattes dråbevis 20 en opløsning af 9,5 g (2-[l-(4-klorfenyl)-cyklobutyl]-acetoni-tril, fremstillet på den ovenfor beskrevne måde, i 25 ml tørt tetrahydrofuran. Blandingens temperatur fik lov at stige til 0°C og blandingen omrørtes i 10 minutter før der tilsattes en opløsning af 10 ml metyljodid i 10 ml tetrahydrofuran.A solution of 16.5 g of diisopropylamine in 50 ml of dry tetrahydrofuran was stirred under nitrogen at a temperature of 0 ° C and a 1.6M solution of n-butyl lithium in 100 ml of hexane was added dropwise. The reaction mixture was stirred for 30 minutes and then cooled to -78 ° C. A solution of 9.5 g of (2- [1- (4-chlorophenyl) -cyclobutyl] -acetonitrile), prepared in the manner described above, was added dropwise in 25 ml of dry tetrahydrofuran dropwise. 0 ° C and the mixture was stirred for 10 minutes before adding a solution of 10 ml of methyl iodide in 10 ml of tetrahydrofuran.

25 Der tilsattes 75 ml tetrahydrofuran for at give en homogen opløsning og yderligere tilsattes der en opløsning af 4 ml metyljodid i 10 ml tetrahydrofuran. Blandingen omrørtes ved omgivelsernes temperatur i 2 timer og der tilsattes derefter 50 ml vand. Den vandige fase vaskedes med æter og æteren fore-30 nedes med reaktionsblandingens organiske fase. De forenede organiske faser vaskedes tre gange med 5N saltsyre og tre gange med vand, tørredes og inddampedes til frembringelse af en olie som størknede og omkrystalliseredes fra IMS til frembringelse af 2-[l-(4-klorfenyl)-cyklobutyl]-2-metylpropio-35 nitril med smp. 73-75°C.25 ml of tetrahydrofuran was added to give a homogeneous solution and further a solution of 4 ml of methyl iodide in 10 ml of tetrahydrofuran was added. The mixture was stirred at ambient temperature for 2 hours and then 50 ml of water was added. The aqueous phase is washed with ether and the ether is added with the organic phase of the reaction mixture. The combined organic phases were washed three times with 5N hydrochloric acid and three times with water, dried and evaporated to give an oil which solidified and recrystallized from IMS to give 2- [1- (4-chlorophenyl) cyclobutyl] -2-methylpropio -35 nitrile with m.p. 73-75 ° C.

4 g af den på den ovenfor beskrevne måde fremstillede nitril opvarmédes under tilbagesvaling med 8 g kaliumhydroxyd i 40 ml diætylenglykol i 24 timer. Reaktionsblandingen afkøle-4 g of the nitrile prepared in the manner described above was heated under reflux with 8 g of potassium hydroxide in 40 ml of diethylene glycol for 24 hours. The reaction mixture cools.

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36 des og sattes til 50 ml vand og den vandige fase vaskedes to gange med æter. Den vandige fase syrnedes med 5N saltsyre og ekstraheredes med 3 portioner æter. De forenede æterekstrakter vaskedes med vand, tørredes og inddampedes og gav et hvidt 5 fast stof som omkrystalliseredes fra petroleumsæter (kp. 60- 80°C), hvorved der vandtes 2-[l-(4-klorfenyl)-cyklobutyl]-2-metylpropionsyre med smp. 95-110°C.36 dec and added to 50 ml of water and the aqueous phase washed twice with ether. The aqueous phase was acidified with 5N hydrochloric acid and extracted with 3 portions of ether. The combined ether extracts were washed with water, dried and evaporated to give a white solid which was recrystallized from petroleum ether (bp 60-80 ° C) to give 2- [1- (4-chlorophenyl) cyclobutyl] -2- methylpropionic acid, m.p. 95-110 ° C.

Der sattes 10 ml oxalylklorid til 2 g af den på den ovenfor beskrevne måde fremstillede syre, og efter at den 10 oprindelige brusning var ophørt opvarmedes blandingen under tilbagesvaling i 1 time. Overskydende oxalylklorid fjernedes ved destillation og den tilbageværende olie sattes til 75 ml koncentreret ammoniakvand. Der dannedes sig et olieagtigt fast stof som ekstraheredes med ætylacetat. Ekstrakten vaske- j 15 des med vand, tørredes og inddampedes til frembringelse af ! 2-[l-(4-klorfenyl)-cyklobutyl]-2-metylpropionamid. j 1,34 g af det på denne måde fremstillede amid opløstes j i i en blanding af 8 ml acetonitril og 8 ml vand, og der tilsat- j tes 3,4 g jodosobenzen-bistrifluoracetat hvorpå blandingen 20 omrørtes ved stuetemperatur i 5 1/2 time. Der tilsattes 75 ml vand og 8 ml koncentreret saltsyre og blandingen ekstraheredes med æter. Æterekstrakten vaskedes med 5N saltsyre og den vandige fase gjordes basisk og ekstraheredes med yderligere portioner æter,der tørredes og inddampedes til frembringelse 25 af en olie. Olien opløstes i petroleumsæter (kp. 80-100°C) og der førtes tør hydrogenkloridgas gennem opløsningen. 1-[1-(4-Klorfenyl)-cyklobutyl]-1-metylætylamin-hydroklorid med smp. 257-259°C opsamledes ved filtrering (formel I: n = 0; R1 = R2 = Me; R3 = R4 = H; R5 = 4-C1; R6 = H).10 ml of oxalyl chloride was added to 2 g of the acid prepared in the manner described above, and after the initial effervescence had ceased, the mixture was heated under reflux for 1 hour. Excess oxalyl chloride was removed by distillation and the residual oil was added to 75 ml of concentrated ammonia water. An oily solid formed which was extracted with ethyl acetate. The extract was washed with water, dried and evaporated to give! 2- [L- (4-chlorophenyl) cyclobutyl] -2-metylpropionamid. 1.34 g of the amide thus prepared was dissolved in a mixture of 8 ml of acetonitrile and 8 ml of water, and 3.4 g of iodosobenzene-bistrifluoroacetate was added and the mixture was stirred at room temperature for 5 1/2 hours. . 75 ml of water and 8 ml of concentrated hydrochloric acid were added and the mixture was extracted with ether. The ether extract was washed with 5N hydrochloric acid and the aqueous phase was basified and extracted with additional portions of ether which were dried and evaporated to give an oil. The oil was dissolved in petroleum ether (bp 80-100 ° C) and dry hydrogen chloride gas was passed through the solution. 1- [1- (4-Chlorophenyl) -cyclobutyl] -1-methylethylamine hydrochloride, m.p. 257-259 ° C were collected by filtration (formula I: n = 0; R1 = R2 = Me; R3 = R4 = H; R5 = 4-C1; R6 = H).

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Eksempel 14 3,4 g af produktet fra eksempel 4(h) blandedes med 0,72 g vandfrit natriumformiat, 10 ml 98%s myresyre og 5 ml 37-40%s vandig formaldehydopløsning, og blandingen opvarmedes 35 o o til en temperatur på 85-95 C i 16 timer. Blandingen fortyndedes med 50 ml vand og gjordes basisk til pH 10 med vandig natriumhydroxydopløsning. Den basiske vandige opløsning ekstra-Example 14 3.4 g of the product of Example 4 (h) was mixed with 0.72 g of anhydrous sodium formate, 10 ml of 98% formic acid and 5 ml of 37-40% aqueous formaldehyde solution, and the mixture was heated to a temperature of 85 -95 C for 16 hours. The mixture was diluted with 50 ml of water and basified to pH 10 with aqueous sodium hydroxide solution. The basic aqueous solution is extra-

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37 heredes med æter, vaskedes med vand og tørredes med magniumsulfat. Der bobledes tørt hydrogenklorid gennem æterekstrakten til frembringelse af et hvidt bundfald af N,N-dimetyl-1-[1-(4-klor-3-trifluormetylfenyl)-cyklobutyl]-ætylamin-hydro-5 klorid med smp. 246-247°C (formel I: n = 0; = R2 = R^ = Me; R2 = H; R5 = 4-Cl og R6 = 3-CF3).37 was cured with ether, washed with water and dried with magnesium sulfate. Dry hydrogen chloride was bubbled through the ether extract to give a white precipitate of N, N-dimethyl-1- [1- (4-chloro-3-trifluoromethylphenyl) cyclobutyl] ethylamine hydrochloride, m.p. 246-247 ° C (Formula I: n = 0; = R2 = R4 = Me; R2 = H; R5 = 4-Cl and R6 = 3-CF3).

Eksempel 15Example 15

Fremstilling af salte af forbindelsen med formlen I belyses ved følgende eksempler, hvor ækvimolære mængder af basen og syren blev optaget i et opløsningsmiddel. Saltet vandtes derefter fra opløsningen på konventionel måde.Preparation of salts of the compound of formula I is illustrated by the following examples in which equimolar amounts of the base and acid were taken up in a solvent. The salt was then extracted from the solution in a conventional manner.

Opløsnings- Smp. af saltetSolution Mp. of the salt

Eksempel Base Syre middel (°C) 15 . .....................— - 15 (a) 10 (s) citron- vandig acetone 158-160 15 (b) 10 (s) malein- æter 155-157 15 (c) 10 (s) rav- æter 152-155 15 (d) 2 L(+)vin- IMS 150-153 20 15 (e) Note (a) citron- æter/metanol 163-164 (sønder deling) (a) Basen var 1-[l-(3,4-dimetylfenyl)-cyklobutylJ-3-metylbutyl-amin, fremstillet på lignende måde som beskrevet i eksempel 10.Example Base Acid Agent (° C) 15. ...................... - 15 (a) 10 (s) lemon aqueous acetone 158-160 15 (b) 10 (s) maleic ether 155 -157 15 (c) 10 (s) amber 152-155 15 (d) 2 L (+) wine- IMS 150-153 20 15 (e) Note (a) lemon-ether / methanol 163-164 (probes) (a) The base was 1- [1- (3,4-dimethylphenyl) -cyclobutyl] -3-methylbutylamine, prepared in a similar manner as described in Example 10.

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Eksempel 16Example 16

En opløsning af 15,7 g brombenzen i 50 ml æter sattes dråbevis under afkøling til 2,4 g magniumspåner under en atmos-30 fære af nitrogen. Der tilsattes en opløsning af 19,1 g l-(4-klorfenyl)-cyklobutankarbonitril, fremstillet på lignende måde som beskrevet i eksempel 1 for l-(3,4-diklorfenyl)-cyklobutankarbonitril, i 50 ml æter og æteren udskiftedes med 130 ml tørt toluen. Reaktionsblandingen opvarmedes på et dampbad 35 il time. Der tilsattes en prøve på 20 ml af den resulterende opløsning til en opløsning af 1 g natriumborhydrid i 60 ml diætylenglykoldimetylaster, og blandingen omrørtes i 1 1/2 time. Der tilsattes langsomt 60 ml vand og det vandige lag DK 161770 B ! j 38 j ekstraheredes med toluen. Toluenekstrakterne vaskedes med vand, tørredes og inddampedes og gav en remanens som opløstes i 50 ml metanol. Der tilsattes 5 ml 6N saltsyre og opløsningen filtreredes og inddampedes. Triturering med tør acetone gav 5 a-[1-(4-klorfenyl)-cyklobutyl]-benzylamin-hydroklorid med smp. 277-279°C (formel I: n = 0; R1 = Ph; R2 = R3 = R4 = H; R5 = 4-Cl; R6 = H).A solution of 15.7 g of bromobenzene in 50 ml of ether was added dropwise while cooling to 2.4 g of magnesium chips under an atmosphere of nitrogen. A solution of 19.1 g of 1- (4-chlorophenyl) -cyclobutanecarbonitrile, prepared in a similar manner as described in Example 1 for 1- (3,4-dichlorophenyl) -cyclobutanecarbonitrile, was added in 50 ml of ether and the ether was replaced by 130 ml. ml of dry toluene. The reaction mixture was heated on a steam bath for 35 hours. A sample of 20 ml of the resulting solution was added to a solution of 1 g of sodium borohydride in 60 ml of diethylene glycol dimethyl ester and the mixture was stirred for 1 1/2 hours. 60 ml of water were slowly added and the aqueous layer DK 161770 B! j 38 j was extracted with toluene. The toluene extracts were washed with water, dried and evaporated to give a residue which was dissolved in 50 ml of methanol. 5 ml of 6N hydrochloric acid was added and the solution filtered and evaporated. Dry acetone trituration gave 5? - [1- (4-chlorophenyl) cyclobutyl] benzylamine hydrochloride, m.p. 277-279 ° C (formula I: n = 0; R1 = Ph; R2 = R3 = R4 = H; R5 = 4-Cl; R6 = H).

Eksempel 17 10 : 62-ml metylformiat sattes dråbevis til 85,5 ml isopro-pylamin under omrøring med en hastighed som sikrede opretholdelse af forsigtig tilbagesvalingsbetingelser. Omrøringen fortsattes i 2 timer efter tilsætningen. Metanolen afdestille- ! redes ved 100°C og der vandtes N-isopropylformamid med kp. ! 108-109°C/25 mm Hg) ved destillation.Example 17 10: 62 ml of methyl formate was added dropwise to 85.5 ml of isopropylamine with stirring at a rate which ensured the maintenance of gentle reflux conditions. Stirring was continued for 2 hours after addition. The methanol is distilled off! was prepared at 100 ° C and N-isopropylformamide was obtained with b.p. ! 108-109 ° C / 25 mm Hg) by distillation.

Der sattes 10,4 g 1-acetyl-l-(4-klorfenyl)-cyklobutan, fremstillet på lignende måde som beskrevet i eksempel 1 for 1-acetyl-l-(3,4-diklorfenyl)-cyklobutan, og 5 ml 98%s myresyre j til 43,5 g N-isopropylformamid, og blandingen opvarmedes til «U ^ 18Q°C i 4 timer. Overskydende udgangsmateriale afdestilleredes under nedsat tryk (20 mm Hg) og efterlod en viskos remanens som opvarmedes under tilbagesvaling med 30 ml koncentreret saltsyre i 6 timer. Reaktionsblandingen vaskedes med æter indtil der var vundet en farveløs opløsning. Den vandige fase 25 gjordes basisk, ekstraheredes med æter, tørredes og inddampedes til en olie som opløstes i 5N saltsyre. Ved inddampning vandtes der en gul olie som tritureredes med petroleumsæter (kp. 62-68°C) til dannelse af N-isopropyl-l-[1-(4-klorfenyl)-cyklobu-tyl]-ætylamin-hydroklorid med smp. 170-174°C (formel I: n = 0; R1 = Me; R2 = R4 = H; R3 = isopropyl; R5 = 4-C1; R6 = H).10.4 g of 1-acetyl-1- (4-chlorophenyl) cyclobutane prepared in the same manner as described in Example 1 for 1-acetyl-1- (3,4-dichlorophenyl) cyclobutane were added and 5 ml of 98 % formic acid j to 43.5 g of N-isopropylformamide, and the mixture was heated to U U18 ° C for 4 hours. Excess starting material was distilled off under reduced pressure (20 mm Hg) leaving a viscous residue which was heated under reflux with 30 ml of concentrated hydrochloric acid for 6 hours. The reaction mixture was washed with ether until a colorless solution was obtained. The aqueous phase was made basic, extracted with ether, dried and evaporated to an oil which was dissolved in 5N hydrochloric acid. Evaporation gave a yellow oil which was triturated with petroleum ether (b.p. 62-68 ° C) to give N-isopropyl-1- [1- (4-chlorophenyl) -cyclobutyl] -ethylamine hydrochloride, m.p. 170-174 ° C (formula I: n = 0; R1 = Me; R2 = R4 = H; R3 = isopropyl; R5 = 4-C1; R6 = H).

Eksempel 18 7,0 g 1-acetyl-l-(3,4-diklorfenyl)-cyklobutan, fremsti1-35 iet som beskrevet i eksempel 1, sattes langsomt til en blanding af 25 ml pyrrolidin og 15 ml 98%s myresyre opvarmet til 130-135°C i 5 timer. Blandingen omrørtes og opvarmedes til 39Example 18 7.0 g of 1-acetyl-1- (3,4-dichlorophenyl) cyclobutane, prepared as described in Example 1, was slowly added to a mixture of 25 ml of pyrrolidine and 15 ml of 98% formic acid heated to 130-135 ° C for 5 hours. The mixture was stirred and heated to 39

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160-165°C i 16 timer. Efter afkøling udhældtes blandingen i 200 ml 5N saltsyre. Opløsningen vaskedes med æter, gjordes basisk med vandig natriumhydroxydopløsning og ekstraheredes med æter. Æterekstrakten vaskedes med vand og tørredes og 5 der førtes hydrogenkloridgas ind i ekstrakten, som derpå inddampedes til tørhed. Remanensen tritureredes med tør æter og gav et fast stof som omkrystalliseredes fra propan-2-ol og gav N-l-[1-(3,4-diklorfenyl)-cyklobutyl]-ætylpyrrolidin- hydroklorid med smp. 233-235°C (formel I: n = 0; R"^ = Me; R2 = 3 4 , 10 H; R plus R danner sammen med det tilknyttede nitrogenatom 5 6 en pyrrolidinring; R = 4-C1; R = 3-C1).160-165 ° C for 16 hours. After cooling, the mixture was poured into 200 ml of 5N hydrochloric acid. The solution was washed with ether, basified with aqueous sodium hydroxide solution and extracted with ether. The ether extract was washed with water and dried and hydrogen chloride gas was introduced into the extract which was then evaporated to dryness. The residue was triturated with dry ether to give a solid which was recrystallized from propan-2-ol to give N-1- [1- (3,4-dichlorophenyl) cyclobutyl] -ethylpyrrolidine hydrochloride, m.p. 233-235 ° C (Formula I: n = 0; R "= Me; R 2 = 3 4, 10 H; R plus R together with the associated nitrogen atom 5 6 forms a pyrrolidine ring; R = 4-C1; R = 3 -C 1).

Eksempel 19 10,5 g 1-(4-klorfenyl)-1-cyklobutankarboxylsyre, frem-15 stillet som beskrevet i eksempel 13, opvarmedes under tilbagesvaling med 20 ml tionylklorid i 2 1/2 time. Overskydende tionylklorid afdampedes og syrekloridet af ovennævnte syre destilleredes (kp. 82-96°C/0,2 mm Hg).Example 19 10.5 g of 1- (4-chlorophenyl) -1-cyclobutanecarboxylic acid, prepared as described in Example 13, was heated under reflux with 20 ml of thionyl chloride for 2 1/2 hours. Excess thionyl chloride was evaporated and the acid chloride of the above acid distilled (bp 82-96 ° C / 0.2 mm Hg).

En opløsning af 23,0 g af syrekloridet i 100 ml tørt tetrahydrofuran sattes langsomt til reaktionsproduktet af 3,0 g magniumspåner og 12,0 g ætylbromid i tørt tetrahydrofuran ved en temperatur på -70 til -60°C. Temperaturen holdtes på -60°C i 1 time og fik derefter lov til at stige til 0°C.A solution of 23.0 g of the acid chloride in 100 ml of dry tetrahydrofuran was slowly added to the reaction product of 3.0 g of magnesium shavings and 12.0 g of ethyl bromide in dry tetrahydrofuran at a temperature of -70 to -60 ° C. The temperature was kept at -60 ° C for 1 hour and then allowed to rise to 0 ° C.

2^. Der tilsattes 50 ml vand efterfulgt af 150 ml 5N saltsyre under afkøling. Reaktionsblandingen ekstraheredes med æter, vaskedes med vand og natriumbikarbonatopløsning og tørredes. Opløsningsmidlet fjernedes ved afdampning og 1-propionyl-l-(4-klorfenyl)-cyklobutan vandtes ved destillation og havde kp. 96-104°C/0,25 mm Hg.2 ^. 50 ml of water was added followed by 150 ml of 5N hydrochloric acid under cooling. The reaction mixture was extracted with ether, washed with water and sodium bicarbonate solution and dried. The solvent was removed by evaporation and 1-propionyl-1- (4-chlorophenyl) cyclobutane was obtained by distillation and had b.p. 96-104 ° C / 0.25 mm Hg.

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Den i henhold til det foranstående fremstillede keton omdannedes til N,N-dimetyl-l-[1-(4-klorfenyl)-cyklobutylpropyl- amin-hydroklorid med smp. 213-215°C på lignende måde som den der er beskrevet i eksempel 12 (formel I: n=0;R^=Et; R2 = H; R3 = R4 = Me; R5 = 4-C1; R6 = H).The ketone prepared according to the foregoing was converted to N, N-dimethyl-1- [1- (4-chlorophenyl) cyclobutylpropylamine hydrochloride, m.p. 213-215 ° C in a similar manner to that described in Example 12 (formula I: n = 0; R 2 = Et; R 2 = H; R 3 = R 4 = Me; R 5 = 4-C 1; R 6 = H).

Eksempel 20 61 g l-acetyl-l-(4-klorfenyl)-cyklobutan, fremstillet 35 i 40Example 20 61 g of 1-acetyl-1- (4-chlorophenyl) cyclobutane, prepared in 40

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på lignende måde som beskrevet i eksempel 1 for 1-acetyl-l-(3,4-diklorfenyl)-cyklobutan, 0,75 g platinoxyd, 60 g 33%s opløsning af metylamin i ætanol og 30 ml ætanol indfyldtes i en autoklav. Autoklaven fyldtes med hydrogen og holdtes på 5 ca. 60 C og et tryk pa 20 bar i 10 timer. Reaktionsblandingen filtreredes gennem trækul og de faste stoffer vaskedes med absolut alkohol. Opløsningsmidlerne fjernedes ved afdampning og en prøve på 10 g af remanensen rystedes med 50 ml 2M saltsyre og 50 ml æter. Det vandige lag gjordes basisk og ekstra-10 heredes med æter. Æterekstrakten gav ved inddampning en væske som destilleredes ved 109°C/0,3 mm Hg til frembringelse af N-metyl-l-[1-(4-klorfenyl)-cyklobutyl]-ætylamin (formel I: n = 0; R1 = R3 = Me; R2 = R4 = H; R5 = 4-C1; R6 = H).in a similar manner as described in Example 1 for 1-acetyl-1- (3,4-dichlorophenyl) cyclobutane, 0.75 g of platinum oxide, 60 g of 33% solution of methylamine in ethanol and 30 ml of ethanol were charged into an autoclave. The autoclave was filled with hydrogen and held at approx. 60 C and a pressure of 20 bar for 10 hours. The reaction mixture was filtered through charcoal and the solids washed with absolute alcohol. The solvents were removed by evaporation and a 10 g sample of the residue was shaken with 50 ml of 2M hydrochloric acid and 50 ml of ether. The aqueous layer was made basic and extracted with ether. The ether extract gave by evaporation a liquid distilled at 109 ° C / 0.3 mm Hg to give N-methyl-1- [1- (4-chlorophenyl) cyclobutyl] ethylamine (Formula I: n = 0; R1 = R3 = Me; R2 = R4 = H; R5 = 4-C1; R6 = H).

15 Eksempel 21 iExample 21 i

2,0 g natriumborhydrid sattes til en opløsning af 1,5 I2.0 g of sodium borohydride was added to a solution of 1.5 l

i g 1-[l-(3,4-diklorfenyl)-cyklobutyl]-ætylamin (fremstillet ! i ved behandling af produktet fra eksempel 1 med vandigt natrium-2g hydroxyd) i 30 ml iseddikesyre. Blandingen opvarmedes til j 95-100°C i 16 timer og afkøledes derefter. Der tilsatttes vandig natriumhydroxydopløsning og reaktionsblandingen ekstra- i heredes med æter. Æterekstrakten rystedes med 5N saltsyre og det vandige lag vaskedes med æter, gjordes basisk og ekstra-heredes med æter. Der førtes hydrogenkloridgas ind i æterekstrakten, der inddampedes til tørhed. Triturering med acetone gav N-ætyl-1-[1-(3,4-diklorfenylj-cyklobutyl]-ætylamin-hydroklorid med smp. 211-212°C (formel I: n = 0; R^ = Me; R2 = r4 = H; R3 - Et; R5 = 4-Cl; R6 = 3-C1).in g of 1- [1- (3,4-dichlorophenyl) -cyclobutyl] -ethylamine (prepared by treating the product of Example 1 with aqueous sodium-2g hydroxide) in 30 ml of glacial acetic acid. The mixture was heated to 95-100 ° C for 16 hours and then cooled. Aqueous sodium hydroxide solution was added and the reaction mixture was extracted with ether. The ether extract was shaken with 5N hydrochloric acid and the aqueous layer was washed with ether, basified and extracted with ether. Hydrogen chloride gas was introduced into the ether extract which evaporated to dryness. Trituration with acetone gave N-ethyl-1- [1- (3,4-dichlorophenyl] -cyclobutyl] -ethylamine hydrochloride, mp 211-212 ° C (formula I: n = 0; R 2 = Me; R 2 = r 4 = H; R3 - Et; R5 = 4-Cl; R6 = 3-C1).

3030

Eksempel 22Example 22

En blanding af 0,5 g N-ætyl-1-[1—(3,4-diklorfenyl)-cyklobutyl]-ætylamin (fremstillet ved behandling af produktet fra eksempel 21 med vandigt natriumhydroxyd) og 1 ml eddikesyre-35 anhydrid opvarmedes til 40-45°C i 30 minutter. Reaktionsblandingen gjordes basisk og eksrraheredes med æter. Æterekstrakten vaskedes, tørredes og inddampedes til N-acetyl-N-ætyl-l-[1-(3,4-diklorfenyl)-cyklobutyl]-ætylamin som en olie.A mixture of 0.5 g of N-ethyl-1- [1- (3,4-dichlorophenyl) -cyclobutyl] -ethylamine (prepared by treating the product of Example 21 with aqueous sodium hydroxide) and 1 ml of acetic anhydride was heated to 40-45 ° C for 30 minutes. The reaction mixture was made basic and extracted with ether. The ether extract was washed, dried and evaporated to N-acetyl-N-ethyl-1- [1- (3,4-dichlorophenyl) -cyclobutyl] -ethylamine as an oil.

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4141

Denne olie opløstes i 10 ml tetrahydrofuran og der tilsattes dråbevis 0,5 ml boran-dimetylsulfid-kompleks. Reaktionsblandingen omrørtes ved stuetemperatur i 2 timer og opvarmedes derefter til 35-40°C i 30 minutter. Efter afkøling 5 gjordes reaktionsblandingen basisk og ekstraheredes med aster. Der førtes hydrogengas ind i den tørredes æterekstrakt, der inddampedes til tørhed. Triturering med æter gav N,N-diætyl-l-[1-(3,4-diklorfenyl)-cyklobutyl]-ætylamin-hydroklorid med smp. 199-201°C (formel I: n = 0; R1 = Me; R2 = H; R^ = R^ = 10 Et; R5 = 4-Cl; R6 = 3-C1).This oil was dissolved in 10 ml of tetrahydrofuran and 0.5 ml of borane-dimethyl sulfide complex was added dropwise. The reaction mixture was stirred at room temperature for 2 hours and then heated to 35-40 ° C for 30 minutes. After cooling 5, the reaction mixture was basified and extracted with aster. Hydrogen gas was introduced into the dried ether extract which evaporated to dryness. Trituration with ether gave N, N-diethyl-1- [1- (3,4-dichlorophenyl) -cyclobutyl] -ethylamine hydrochloride, m.p. 199-201 ° C (formula I: n = 0; R1 = Me; R2 = H; R4 = R4 = 10 Et; R5 = 4-Cl; R6 = 3-C1).

Eksempel 23Example 23

En blanding af 2,2 g 1-acetyl-l-(3,4-diklorfenyl)-cyklo- butan (fremstillet som beskrevet i eksempel 1), 7 g ammonium-15 acetat, 0,4 g natriumcyanborhydrid og 28 ml metanol omrørtes ved stuetemperatur i 4 dage. Reaktionsblandingen udhældtes i en blanding af is og vand og den resulterende blanding ekstraheredes med æter. Æterekstrakten vaskedes med vand og tør-redes og æteren fjernedes og efterlod 1-[1-(3,4-diklorfenyl)-cyklobutyl)-ætylamin som en olie der identificeredes ved stan-dardanalyseteknik som forbindelsen ifølge eksempel 1 i form af den frie base.A mixture of 2.2 g of 1-acetyl-1- (3,4-dichlorophenyl) cyclobutane (prepared as described in Example 1), 7 g of ammonium acetate, 0.4 g of sodium cyanoborohydride and 28 ml of methanol was stirred. at room temperature for 4 days. The reaction mixture was poured into a mixture of ice and water and the resulting mixture extracted with ether. The ether extract was washed with water and dried and the ether removed, leaving 1- [1- (3,4-dichlorophenyl) -cyclobutyl) -ethylamine as an oil identified by standard analysis technique as the compound of Example 1 in the form of the free base .

Eksempel 24 λ 3 ___________Example 24 λ 3 ___________

En blanding af 4,86 g 1-acetyl-l-(3,4-diklorfenyl)-cyklobutan, fremstillet som beskrevet i eksempel 1, 1,6 g hydroxylamin-hydroklorid, 3,3 g natriumacetat-trihydrat, 15 ml industriel metyleret ætanol og 2 ml vand opvarmedes under o η , υ tilbagesvaling i 20 timer. Den afkølede reaktionsblanding udhældtes i vand og den olie der udskilte sig afkøledes til frembrin gelse af et fast stof som omkrystalliseredes fra industriel metyleret ætanol og gav 1-acetyl-l-(3,4-diklorfenyl)-cyklobutan-oxim med smp. 120-121°C.A mixture of 4.86 g of 1-acetyl-1- (3,4-dichlorophenyl) cyclobutane prepared as described in Example 1, 1.6 g of hydroxylamine hydrochloride, 3.3 g of sodium acetate trihydrate, 15 ml of industrial methylated ethanol and 2 ml of water were heated under 0 η, υ reflux for 20 hours. The cooled reaction mixture was poured into water and the oil which separated cooled to give a solid which was recrystallized from industrial methylated ethanol to give 1-acetyl-1- (3,4-dichlorophenyl) cyclobutane oxime, m.p. 120-121 ° C.

En opløsning af 4,0 g af den som ovenfor beskrevet fremstillede oxim i 50 ml æter sattes langsomt til en omrørt suspension af 0,9 g litiumaluminiumhydrid i 50 ml æter under nitrogen. Blandingen opvarmedes under tilbagesvaling i 1 timeA solution of 4.0 g of the oxime prepared as described above in 50 ml of ether was slowly added to a stirred suspension of 0.9 g of lithium aluminum hydride in 50 ml of ether under nitrogen. The mixture was heated at reflux for 1 hour

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42 og efter afkøling tilsattes der vand og derpå 27 ml af en 20%s vandig opløsning af Rochelle's salt (kaliumnatriumtartrat-tetrahydrat) og 6 ml af en 10%s vandig opløsning af natrium-hydroxyd. Reaktionsblandingen omrørtes i 1 time og ekstrahere- i 5 des derefter kontinuerligt med æter gennem 18 timer. Æterekstrakten tørredes og æteren fjernedes og efterlod et fast stof hvorfra l-[l-(3,4-diklorfenyl)-cyklobutyl]-ætylamin fraskiltes ved højtryks-væskekromatografi. Produktet identificeredes ved standardanalyseteknik som forbindelsen ifølge eksempel ]_g li form af den frie base.After cooling, water and then 27 ml of a 20% aqueous solution of Rochelle's salt (potassium sodium tartrate tetrahydrate) and 6 ml of a 10% aqueous solution of sodium hydroxide were added. The reaction mixture was stirred for 1 hour and then extracted continuously with ether for 18 hours. The ether extract was dried and the ether removed, leaving a solid from which 1- [1- (3,4-dichlorophenyl) -cyclobutyl] -ethylamine was separated by high-pressure liquid chromatography. The product was identified by standard analysis technique as the compound of Example 1 in the form of the free base.

Eksempel 25 200 ml af en 1M opløsning af diisobutylaluminiumhydrid i hexan sattes under nitrogen til en opløsning af 31,4 g 1-Example 25 200 ml of a 1M solution of diisobutyl aluminum hydride in hexane was added under nitrogen to a solution of 31.4 g of 1-

fenyl-l-cyklobutankarbonitril i 100 ml æter ved en temperatur Iphenyl-1-cyclobutanecarbonitrile in 100 ml ether at a temperature I

under -30°C. Temperaturen holdtes under 0°C i 30 minutter og der tilsattes 200 ml 5N saltsyre ved en temperatur på -10°C. Reaktionsblandingen vaskedes med petroleumsæter (kp.below -30 ° C. The temperature was kept below 0 ° C for 30 minutes and 200 ml of 5N hydrochloric acid was added at a temperature of -10 ° C. The reaction mixture was washed with petroleum ether (b.p.

60-80°C) og opvarmedes derpå til 40°C. Reaktionsbalndingen ekstraheredes med petroleumsæter (samme kogepunktområde) og ekstrakten tørredes og inddampedes til frembringelse af 1- fenyl-l-cyklobutan-karbaldehyd som en olie.60-80 ° C) and then heated to 40 ° C. The reaction mixture was extracted with petroleum ether (same boiling range) and the extract dried and evaporated to give 1- phenyl-1-cyclobutane-carbaldehyde as an oil.

Der bobledes metylamin gennem en opløsning af 9,4 g af det på den ovenfor beskrevne måde fremstillede aldehyd 25 i 100 ml toluen mens reaktionsblandingens temperatur holdes under 0°C. Der sattes 20 g magniumsulfat, der var blevet tørret over en flamme og derefter afkølet under nitrogen, til reaktionsblandingen som henstod i 16 timer ved stuetemperatur før den filtreredes. Toluenet fjernedes derefter ved afdamp-30 nxng og remanensen opløstes i 50 ml æter. Denne opløsning sattes til en opløsning af propyllitium, fremstillet ved langsom tilsætning af overskud af propylbromid (12,8 g) til en suspension af 1,26 g litium i 50 ml æter. Den resulterende blanding henstod i 16 timer ved stuetemperatur. Spor af uom-35 sat litium fjernedes ved filtrering og filteret vaskedes med æter, vand og derpå 5N saltsyre. Filtratet og vaskevæskerne opvarmedes på et dampbad i 1 time. Efter afkøling vaskedes reaktionsblandingen med æter og det vandige lag gjordes basiskMethylamine was bubbled through a solution of 9.4 g of the aldehyde 25 prepared in the manner described above in 100 ml of toluene while maintaining the temperature of the reaction mixture below 0 ° C. 20 g of magnesium sulfate, which had been dried over a flame and then cooled under nitrogen, was added to the reaction mixture which was left for 16 hours at room temperature before being filtered. The toluene was then removed by evaporation and the residue dissolved in ether (50 ml). This solution was added to a solution of propyllithium prepared by slowly adding excess propyl bromide (12.8 g) to a suspension of 1.26 g of lithium in 50 ml of ether. The resulting mixture was left at room temperature for 16 hours. Traces of unreacted lithium were removed by filtration and the filter washed with ether, water and then 5N hydrochloric acid. The filtrate and washings were heated in a steam bath for 1 hour. After cooling, the reaction mixture was washed with ether and the aqueous layer was basified

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43 ved hjælp af en vandig natriumhydroxydopløsning. Reaktionsblandingen ekstraheredes med æter og ekstrakten tørredes og æteren fjernedes til frembringelse af en remanens hvorfra N-metyl-l-[l-fenylcyklobutyl)-butylamin med kp. 80-86°C/0,l mm Hg 5 destilleredes.43 using an aqueous sodium hydroxide solution. The reaction mixture was extracted with ether and the extract dried and the ether removed to give a residue from which N-methyl-1- [1-phenylcyclobutyl) -butylamine with b.p. 80-86 ° C / 0.1 mm Hg was distilled.

2,3 g af den på den ovenfor beskrevne måde fremstillede amin opløstes i 40 ml æter og der førtes hydrogenkloridgas gennem opløsningen for at udfælde N-metyl-1-(1-fenylcyklobutyl)-butylamin-hydroklorid med smp. 196-197°C (formel I: n = 0; Rx = 10 propyl; R2 = R4 = R5 = R6 = H; R3 = Me).2.3 g of the amine prepared in the manner described above was dissolved in 40 ml of ether and hydrogen chloride gas was passed through the solution to precipitate N-methyl-1- (1-phenylcyclobutyl) -butylamine hydrochloride with m.p. 196-197 ° C (formula I: n = 0; Rx = propyl; R2 = R4 = R5 = R6 = H; R3 = Me).

Eksempel 26Example 26

En opløsning af 8,0 g 1-(3-klor-5-metylfenyl)-1-cyklobutan-^ karbonitril i 40 ml æter sattes til en opløsning af propylmag-niumbromid (fremstillet ved reaktion af 6,7 g 1-brompropan og 1,3 g magnium) i 80 ml æter, og blandingen opvarmedes under tilbagesvaling i 2 1/2 time. 2/3 af æteren afdampedes og efter afkøling tilsattes der derpå en opløsning af 3,5 g natriumbor-2Q hydrid i 150 ml ætanol. Blandingen holdtes på 50°C i 1 time og der tilsattes 50 ml vand og derpå 50 ml 5N saltsyre. Æterlaget fraskiltes, tørredes og inddampedes og gav et fast stof som omkrystalliseredes fra propan-2-ol til frembringelse af 1-[1-(3-klor-5-metylfenyl)-cyklobutyl]-butylamin-hydroklorid 25 med smp. 145-146°C.A solution of 8.0 g of 1- (3-chloro-5-methylphenyl) -1-cyclobutane-carbonitrile in 40 ml of ether was added to a solution of propylmagnonium bromide (prepared by reaction of 6.7 g of 1-bromopropane and 1.3 g of magnesium) in 80 ml of ether and the mixture was heated under reflux for 2 1/2 hours. 2/3 of the ether was evaporated and after cooling a solution of 3.5 g of sodium boro-2Q hydride in 150 ml of ethanol was then added. The mixture was kept at 50 ° C for 1 hour and 50 ml of water and then 50 ml of 5N hydrochloric acid were added. The ether layer was separated, dried and evaporated to give a solid which was recrystallized from propan-2-ol to give 1- [1- (3-chloro-5-methylphenyl) -cyclobutyl] -butylamine hydrochloride, m.p. 145-146 ° C.

Det på den ovenfor beskrevne måde fremstillede hydroklo-ridsalt rystedes med æter og 5N natriumhydroxydopløsning og æterlaget inddampedes til frembringelse af den primære amin, der omdannedes til N,N-dimetyl-l-[ l-(3-klor-5-metylfenyl)-cyklobu-2Q tyl]-butylamin-hydroklorid med smp. 148°C på lignende måde som beskrevet i eksempel 2 (formel I: n = 0; R3- = propyl; R2 = H; R3 = R4 = Me; R5 = 3-C1; R6 = 5-Me).The hydrochloride salt prepared in the manner described above was shaken with ether and 5N sodium hydroxide solution and the ether layer was evaporated to give the primary amine converted to N, N-dimethyl-1- [1- (3-chloro-5-methylphenyl) - cyclobut-2-methyl-butylamine hydrochloride, m.p. 148 ° C in a similar manner as described in Example 2 (formula I: n = 0; R3- = propyl; R2 = H; R3 = R4 = Me; R5 = 3-C1; R6 = 5-Me).

Eksempel 27 35 37,6 g 1-(4-klorfenyl)-1-cyklobutankarbonitril (fremstillet på lignende måde som l-(3,4-diklorfenyl)-l-cyklobutan-karbonitril beskrevet i eksempel 1) sattes til en opløsning af 32,4 g kaliumhydroxyd i 370 ml diætylenglykol, og blandin- 44 ' -Example 27 37.6 g of 1- (4-chlorophenyl) -1-cyclobutanecarbonitrile (prepared in a similar manner to 1- (3,4-dichlorophenyl) -1-cyclobutane carbonitrile described in Example 1) were added to a solution of 32 4 g of potassium hydroxide in 370 ml of diethylene glycol, and mix 44 '-

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>>

gen opvarmedes under tilbagesvaling i 3 1/2 time. Reaktionsblandingen udhældtes i en blanding af is og vand og den resulterende opløsning vaskedes med æter. Det vandige lag sat- Ithe gene was heated at reflux for 3 1/2 hours. The reaction mixture was poured into a mixture of ice and water and the resulting solution washed with ether. The aqueous layer sat- I

tes til en blanding af 100 ml koncentreret saltsyre og is 1 5 og det resulterende bundfald af l-(4-klorfenyl)-l-cyklobutan-karboxylsyre med smp. 86-88°C opsamledes, vaskedes med vand og tørredes. En opløsning af 10,5 g af den på den ovenfor beskrevne måde fremstillede syre i 150 ml tetrahydrofuran sattes dråbevis under nitrogen til en omrørt suspension af 10 2 g litiumaluminiumhydrid i 150 ml tetrahydrofuran. Blandingen omrørtes under tilbagesvaling i 2 timer og der tilsattes i S) i vand. Blandingen filtreredes gennem diatoméjord ("Celite" w ) og produktet ekstraheredes med æter. Efter vask med vand og tørring afdampedes æteren og gav en remanens som omkrystalli-15 seredes fra petroleumsæter (kp. 60-80°C). Produktet var ΙΕ 1- (4 -klor feny 1) -cyklobutyl] -metylalkohol med smp. 60-62°C. jto a mixture of 100 ml of concentrated hydrochloric acid and ice and the resulting precipitate of 1- (4-chlorophenyl) -1-cyclobutane-carboxylic acid, m.p. 86-88 ° C were collected, washed with water and dried. A solution of 10.5 g of the acid prepared in the above described manner in 150 ml of tetrahydrofuran was added dropwise under nitrogen to a stirred suspension of 10 2 g of lithium aluminum hydride in 150 ml of tetrahydrofuran. The mixture was stirred under reflux for 2 hours and added in S) in water. The mixture was filtered through diatomaceous earth ("Celite" w) and the product extracted with ether. After washing with water and drying, the ether was evaporated to give a residue which was recrystallized from petroleum ether (bp 60-80 ° C). The product was ΙΕ 1- (4-chloro-phenyl-1-cyclobutyl] -methyl alcohol, m.p. 60-62 ° C. j

En opløsning af 60 g af den på den ovenfor beskrevne måde fremstillede alkohol i 52 ml pyridin sattes dråbevis til en opløsning af 60 g p-toluensulfonylklorid i 100 ml pyri-20 din afkølet i is. Temperaturen fik lov til at stige til stuetemperatur og forblive der i 18 timer. Der udfældede 1-[1- j (4-klorfenyl)-cyklobutyl]-metyl-p-toluensulfonat med smp. j o i 99-100 C ved udhældnmg af reaktionsblandingen i en blanding af is og koncentreret saltsyre (200 ml). i ! 25 En opløsning af 97 g af sulfonatforbindelsen fremstil let som ovenfor og 16,6 g natriumcyanid i 370 ml dimetylsulf-oxyd opvarmedes på et dampbad i 18 timer. Blandingen udhældtes i vand og ekstraheredes med æter. Efter vask og tørring afdampedes æteren og efterlod en fast remanens af 2-[l-(4-klorfe-30 nyl)-cyklobutyl]-acetonitril med smp. 63-65°C.A solution of 60 g of the alcohol prepared in the manner described above in 52 ml of pyridine was added dropwise to a solution of 60 g of p-toluenesulfonyl chloride in 100 ml of pyridine cooled in ice. The temperature was allowed to rise to room temperature and remain there for 18 hours. 1- [1- [(4-chlorophenyl) -cyclobutyl] -methyl-p-toluenesulfonate precipitated with m.p. at 99-100 ° C by pouring the reaction mixture into a mixture of ice and concentrated hydrochloric acid (200 ml). i! A solution of 97 g of the sulfonate compound was readily prepared as above and 16.6 g of sodium cyanide in 370 ml of dimethyl sulfoxide were heated on a steam bath for 18 hours. The mixture was poured into water and extracted with ether. After washing and drying, the ether was evaporated leaving a solid residue of 2- [1- (4-chlorophenyl) cyclobutyl] acetonitrile, m.p. 63-65 ° C.

20 g af den således fremstillede acetonitril opløstes 1 120 ml æter og opløsningen sattes dråbevis under nitrogen til en omrørt suspension af 5,84 g litiumaluminiumhydrid i 80 ml æter. Blandingen omrørtes ved omgivelsernes temperatur 35 il 1/2 time og derefter under tilbagesvaling i yderligere 2 timer. Der tilsattes vand dråbevis og den resulterende blanding filtreredes gennem diatoméjord. Remanensen vaskedes med æter. Filtratet ekstraheredes med æter og de forenede æter-20 g of the acetonitrile thus prepared were dissolved in 120 ml of ether and the solution was added dropwise under nitrogen to a stirred suspension of 5.84 g of lithium aluminum hydride in 80 ml of ether. The mixture was stirred at ambient temperature for 35 1/2 hours and then refluxed for another 2 hours. Water was added dropwise and the resulting mixture was filtered through diatomaceous earth. The residue was washed with ether. The filtrate was extracted with ether and the combined ether.

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45 ekstrakter vaskedes med vand og ekstraheredes med 5N saltsyre.45 extracts were washed with water and extracted with 5N hydrochloric acid.

Den sure opløsning vaskedes med æter og der tilsattes vandigt NaOH. Produktet ekstraheredes med æter og ekstrakten vaskedes med vand, tørredes og inddampedes og gav en remanens der ved 5 destillation gav 2-[1-(4-klorfenyl)-cyklobutyl]-ætylamin med kp. 119-121°C/1,5 mm Hg.The acidic solution was washed with ether and aqueous NaOH was added. The product was extracted with ether and the extract was washed with water, dried and evaporated to give a residue which gave, by distillation, 2- [1- (4-chlorophenyl) cyclobutyl] ethylamine with b.p. 119-121 ° C / 1.5 mm Hg.

6,9 g af den således fremstillede ætylamin, 6,6 ml 98%s myresyre, 0,9 g vand og 9 ml 37-40%s vandig formaldehydopløsning opvarmedes på et dampbad i 18 timer. Blandingen 10 afkøledes og der tilsattes overskud af koncentreret saltsyre.6.9 g of the ethylamine thus prepared, 6.6 ml of 98% s formic acid, 0.9 g of water and 9 ml of 37-40% s aqueous formaldehyde solution were heated in a steam bath for 18 hours. The mixture was cooled and excess concentrated hydrochloric acid was added.

Ved inddampning til tørhed vandtes der en gul fast remanens.Evaporation to dryness gave a yellow solid residue.

Det faste stof fordeltes med diklormetan og 5N natriumhydroxyd-opløsning, og det vandige ekstraheredes med en yderligere portion diklormetan. Deklormetanfaserne forenedes, vaskedes 15 med vand, tørredes og inddampedes og gav en fast remanens som opløstes i 15 ml propan-2-ol hvorpå der tilsattes koncentreret saltsyre til pH 2. Blandingen inddampedes til tørhed og remanensen omkrystalliseredes fra ætylacetat og gav farveløse krystaller af N,N-dimetyl-2-[l-(4-klorfenyl)-cyklobutyl]-20 ætylamin-hydroklorid med smp. 220-222°C (formel I: n = 1; R3, = R2 = R6 = R7 = R8 = H; R3 = R4 = Me? R5 = 4-C1) .The solid was partitioned with dichloromethane and 5N sodium hydroxide solution and the aqueous extracted with a further portion of dichloromethane. The dichloromethane phases were combined, washed with water, dried and evaporated to give a solid residue which was dissolved in 15 ml of propan-2-ol, then concentrated hydrochloric acid was added to pH 2. The mixture was evaporated to dryness and the residue was recrystallized from ethyl acetate to give colorless crystals of N N-dimethyl-2- [1- (4-chlorophenyl) -cyclobutyl] -20-ethylamine hydrochloride, m.p. 220-222 ° C (formula I: n = 1; R3, = R2 = R6 = R7 = R8 = H; R3 = R4 = Me? R5 = 4-C1).

På lignende måde som netop beskrevet fremstilledes følgende forbindelser: 25 ,-. CH~CH0NMe0,HC1 »s ΓΛ i 2 2 R6 30 Eksempel R5 R8 Smp. af HCl-saltet (°C) 27 (a) Cl Cl 218-220 27 (b) I H 263-265 27 (c) -CH=CH-CH=CH- 234-236 27 (d) På lignende måde fremstilledes N,N-dimetyl-2-[1-(4-klor-2-fluorfenyl)-cyklobutyl]-ætylamin-hydroklorid med smp. 232-233°C under sønderdeling.In the same manner as just described, the following compounds were prepared: 25, -. CH ~ CH0NMe0, HCl »s ΓΛ i 2 2 R6 Example R5 R8 m.p. of the HCl salt (° C) 27 (a) Cl Cl 218-220 27 (b) 1H 263-265 27 (c) -CH = CH-CH = CH-234-236 27 (d) Similarly, N N-Dimethyl-2- [1- (4-chloro-2-fluorophenyl) -cyclobutyl] -ethylamine hydrochloride, m.p. 232-233 ° C with decomposition.

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Eksempel 28 12 g 2-[l-(4-klorfenyl)-cyklobutyl]-ætylamin, fremstillet som beskrevet i eksempel 27, 12,4 g 1,4-dibrombutan og 14,3 g vandfrit natriumkarbonat blandedes i 100 ml xylen og ' 5 blandingen opvarmedes under tilbagesvaling og omrøring i 16 timer. Blandingen afkøledes og filtreredes og xylenet fjernedes ved afdampning og gav en remanens som ved destillation førte til N-2-[l-(4-klorfenyl)-cyklobutyl]-ætylpyrrolidin med kp. 148-150°C/1,5 mm Hg (formel I: n = 1; = R2 = R^ = 7 8 3 4 10 R = R = H; R plus R plus nitrogenatomet en pyrrolidin-ring; R5 = 4-C1).Example 28 12 g of 2- [1- (4-chlorophenyl) -cyclobutyl] -ethylamine, prepared as described in Example 27, 12.4 g of 1,4-dibromobutane and 14.3 g of anhydrous sodium carbonate were mixed in 100 ml of xylene and The mixture was heated under reflux and stirring for 16 hours. The mixture was cooled and filtered and the xylene removed by evaporation to give a residue which, by distillation, gave N-2- [1- (4-chlorophenyl) cyclobutyl] ethylpyrrolidine with b.p. 148-150 ° C / 1.5 mm Hg (Formula I: n = 1; = R2 = R 2 = 7 8 3 4 10 R = R = H; R plus R plus the nitrogen atom and pyrrolidine ring; R5 = 4- C1).

På lignende måde fremstilledes følgende forbindelser, der isoleredes som deres hydrokloridsalte:Similarly, the following compounds were prepared which were isolated as their hydrochloride salts:

/N/ N

rlT\P 2 vJ L—IrlT \ P 2 vJ L — I

Eksempel R5 R6 Smp. af HCl-saltet (°C) 20 -— 28 (a) Cl Cl 213 28 (b) -CH=CH-CH=CH- 232-233Example R5 R6 m.p. of the HCl salt (° C) 20 - 28 (a) Cl Cl 213 28 (b) -CH = CH-CH = CH-232-233

Eksempel 29 ^ En opløsning af 30 g 2-[l-(4-klorfenyl)-cyklobutyl]- acetonitril, fremstillet som beskrevet i eksempel 27, i 100 ml æter sattes til reaktionproduktet af metylbromidgas og 5,95 g magniumspåner i 80 ml æter. Blandingen opvarmedes under tilbagesvaling i 4 timer. Der tilsattes is og derpå 105 ml o η koncentreret saltsyre og blandingen opvarmedes under tilbagesvaling indtil alt det faste materiale var opløst. Det vandige lag vaskedes med æter og den til vasken brugte æter forenedes med æterfasen af reaktionsblandingen. De forenede æterekstrakter vaskedes med vand, tørredes og inddampedes og gav en rema-3·* nens der destilleredes to gange til frembringelse af 1-[1-(4-klorfenyl)-cyklobutyl]-propan-2-cn med kp. 133-136°C/2,5 mm Hg.Example 29 A solution of 30 g of 2- [1- (4-chlorophenyl) cyclobutyl] acetonitrile, prepared as described in Example 27, in 100 ml of ether was added to the reaction product of methyl bromide gas and 5.95 g of magnesium chips in 80 ml of ether . The mixture was heated at reflux for 4 hours. Ice was added and then 105 ml o of concentrated hydrochloric acid and the mixture was heated under reflux until all the solid was dissolved. The aqueous layer was washed with ether and the ether used for the wash was combined with the ether phase of the reaction mixture. The combined ether extracts were washed with water, dried and evaporated to give a rema-3 · 4 which was distilled twice to give 1- [1- (4-chlorophenyl) cyclobutyl] -propan-2-cn with b.p. 133-136 ° C / 2.5 mm Hg.

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47 5,4 g af den således fremstillede keton blandedes med 18 ml N-metylformamid, 4 ml 98%s myresyre og 0,6 ml 25%s vandig metylamin, og blandingen opvarmedes under tilbagesvaling i 16 timer. Blandingen udhældtes i vand og ekstraheredes med 5 diklormetan. Ekstrakten vaskedes, tørredes og inddampedes og gav en remanens der opvarmedes under tilbagesvaling med 10 ml koncentreret saltsyre i 6 timer. Blandingen inddampedes til tørhed og remanensen tørredes ved gentagen tilsætning og vakuumafdampning af en blanding af IMS og toluen. Den faste 10 remanens omkrystalliseredes fra propan-2-ol og gav N-metyl-2-[1-(4-klorfenyl)-cyklobutyl]-1-metylætylamin-hydroklorid med smp. 193-194°C (formel I: n = 1; R^ = R2 = R4 = R^ = R8 = H; R3 = R7 = Me; R5 = 4-C1).47 5.4 g of the ketone thus prepared were mixed with 18 ml of N-methylformamide, 4 ml of 98% s formic acid and 0.6 ml of 25% s aqueous methylamine and the mixture was heated under reflux for 16 hours. The mixture was poured into water and extracted with dichloromethane. The extract was washed, dried and evaporated to give a residue which was heated under reflux with 10 ml of concentrated hydrochloric acid for 6 hours. The mixture was evaporated to dryness and the residue dried by repeated addition and vacuum evaporation of a mixture of IMS and toluene. The solid residue was recrystallized from propan-2-ol to give N-methyl-2- [1- (4-chlorophenyl) cyclobutyl] -1-methylethylamine hydrochloride, m.p. 193-194 ° C (formula I: n = 1; R3 = R2 = R4 = R4 = R8 = H; R3 = R7 = Me; R5 = 4-C1).

15 Eksempel 30Example 30

En blanding af 15 g l-[l-(4-klorfenyl)-cyklobutyl]-pro-pan-2-on, fremstillet som beskrevet i eksempel 29, og 4 ml 98%s myresyre sattes dråbevis til 12 ml formamid ved 160°C. Temperaturen hævedes til 180°C og holdtes på denne temperaturA mixture of 15 g of 1- [1- (4-chlorophenyl) -cyclobutyl] -propan-2-one, prepared as described in Example 29, and 4 ml of 98% formic acid were added dropwise to 12 ml of formamide at 160 ° C. The temperature was raised to 180 ° C and maintained at this temperature

u Vu V

i 10 timer. Blandingen afkøledes, fortyndedes med vand og ekstraheredes med diklormetan. Ekstrakten vaskedes, tørredes og inddampedes til en gul olie der hydrolyseredes med koncentreret saltsyre under tilbagesvaling. Den resulterende vandige opløsning efter fortynding med vand vaskedes med æter, der 25 tilsattes vandigt NaOH og den vandige opløsning ekstraheredes med æter. Ekstrakten vaskedes, tørredes og inddampedes og gav en remanens som ved destillation gav 2-[1-(4-klorfenyl)-cyklobutyl]-1-metylætylamin med kp. 105-107°C/0,7 mm Hg.for 10 hours. The mixture was cooled, diluted with water and extracted with dichloromethane. The extract was washed, dried and evaporated to a yellow oil which was hydrolyzed with concentrated hydrochloric acid under reflux. The resulting aqueous solution after dilution with water was washed with ether, aqueous NaOH was added and the aqueous solution extracted with ether. The extract was washed, dried and evaporated to give a residue which gave, by distillation, 2- [1- (4-chlorophenyl) cyclobutyl] -1-methylethylamine with b.p. 105-107 ° C / 0.7 mm Hg.

2,65 g af den i henhold til den foranstående vundne amin opløstes i 15 ml propan-2-ol og der tilsattes dråbevis koncentreret saltsyre til pH var 2. Der tilsattes 110 ml æter og opsamledes farveløse krystaller af 2-[1-(4-klorfenyl)-cyklobutyl] -1-metylætylamin-hydroklorid med smp. 184-185°C (formel 35 I: n = 1; R1 = R2 = R3 = R4 = R6 = R8 = H; R5 = 4-C1; R7 = Me).2.65 g of the amine obtained according to the foregoing was dissolved in 15 ml of propan-2-ol and dropwise concentrated hydrochloric acid was added to the pH was 2. 110 ml of ether was added and colorless crystals of 2- [1- (4) were added. -chlorophenyl) -cyclobutyl] -1-methylethylamine hydrochloride, m.p. 184-185 ° C (formula I: n = 1; R1 = R2 = R3 = R4 = R6 = R8 = H; R5 = 4-C1; R7 = Me).

Eksempel 31 3,94 g 2-[1-(4-klorfenyl)-cyklobutyl]-1-metylætylamin,Example 31 3.94 g of 2- [1- (4-chlorophenyl) cyclobutyl] -1-methylethylamine,

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48 fremstillet som beskrevet i eksempel 30, 3,82 g 1,4-dibrombu-tan, 4,4 g vandfrit natriumkarbonat og 30 ml xylen blandedes og opvarmedes under tilbagesvaling i 16 timer. Blandingen afkøledes, filtreredes og inddampedes og gav en remanens som 5 destilleredes to gange og så havde kp. 130-132°C/0,5 mm Hg. Destillationsproduktet opløstes i 5 ml propan-2-ol og der tilsattes 70 ml æter og koncentreret saltsyre til pH 2. Opløsningen inddampedes i vakuum og remanensen omkrystalliseredes fra ætylacetat og gav N-if2-[l-(4-klorfenyl)-cyklobutyl]-Ι-ΙΟ metylj-ætylpyrrolidin-hydroklorid med smp. 151-152°C (formel I: n = 1; R^" = R^ = R8 = R8 = H; R8 plus R^ plus nitrogenato- 5 7 met danner en pyrrolidinnng; R = 4-Cl; R = Me).48 prepared as described in Example 30, 3.82 g of 1,4-dibromobutane, 4.4 g of anhydrous sodium carbonate and 30 ml of xylene were mixed and heated under reflux for 16 hours. The mixture was cooled, filtered and evaporated to give a residue which was distilled twice and then had b.p. 130-132 ° C / 0.5 mm Hg. The distillation product was dissolved in 5 ml of propan-2-ol and 70 ml of ether and concentrated hydrochloric acid were added to pH 2. The solution was evaporated in vacuo and the residue was recrystallized from ethyl acetate to give N-if 2 - [1- (4-chlorophenyl) cyclobutyl] - Ι-ΙΟ methyljethylpyrrolidine hydrochloride, m.p. 151-152 ° C (formula I: n = 1; R R = R = = R R = R8 = H; R8 plus R ^ plus nitrogen atom with 7 and pyrrolidation; R = 4-Cl; R = Me) .

Eksempel 32 15 25 g 1-[1-(4-klorfenyl)-cyklobutyl]-propan-2-on, fremstillet som beskrevet i eksempel 29, og 10 ml 98%s myresyre sattes til 22 ml formamid ved 160°C. Temperaturen hævedes til 175°C og holdtes på denne temperatur i 16 timer. Blandin-gen afkøledes og ekstraheredes med diklormetan. Ekstrakten vaskedes med vand og inddampedes til en gummi der krystalliseredes fra petroleumsæter (kp. 40-60°C) og gav N-formyl-2-[1-(4-klorfenyl)-cyklobutyl]-1-metylætylamin med smp. 71-73°C.Example 32 25 g of 1- [1- (4-chlorophenyl) cyclobutyl] propan-2-one, prepared as described in Example 29, and 10 ml of 98% formic acid were added to 22 ml of formamide at 160 ° C. The temperature was raised to 175 ° C and kept at this temperature for 16 hours. The mixture was cooled and extracted with dichloromethane. The extract was washed with water and evaporated to a gum which crystallized from petroleum ether (bp 40-60 ° C) to give N-formyl-2- [1- (4-chlorophenyl) cyclobutyl] -1-methylethylamine, m.p. 71-73 ° C.

11,06 g N-formyl-2-[1-(4-klorfenyl)-cyklobutyl]-1-metylætylamin, fremstillet som beskrevet ovenfor, opvarmedes under tilbagesvaling i 6 timer med en blanding af 34 ml koncentreret saltsyre, 34 ml vand og 40 ml diætylenglykoldimetylæter. Blandingen afkøledes, vaskedes med æter og gjordes basisk med vandigt natriumhydroxyd. Den basegjorte opløsning ekstrahere-2Q des med æter, vaskedes med vand, tørredes, inddampedes og destilleredes og gav 2-[l-(4-klorfenyl)-cyklobutyl]-l-metyl-ætylamin med kp. 119-121°C/0,8 mm Hg. 2,65 g af aminen opløstes i 15 ml propan-2-ol og der tilsattes koncentreret saltsyre til pH 2. Der tilsattes 110 ml æter og opsamledes krystal-ler af 2-[l-(4-klorfenyl)-cyklobutyl]-l-metylætylamin-hydroklo-rid med smp. 184-185°C (formel I: n = 1; R^" = R^ = R8 = R^ = R6 = R8 = H; R5 = 4-Cl; R7 = Me).11.06 g of N-formyl-2- [1- (4-chlorophenyl) cyclobutyl] -1-methylethylamine, prepared as described above, were refluxed for 6 hours with a mixture of 34 ml of concentrated hydrochloric acid, 34 ml of water and 40 ml of diethylene glycol dimethyl ether. The mixture was cooled, washed with ether and basified with aqueous sodium hydroxide. The base solution was extracted-2Q with ether, washed with water, dried, evaporated and distilled to give 2- [1- (4-chlorophenyl) cyclobutyl] -1-methyl-ethylamine with b.p. 119-121 ° C / 0.8 mm Hg. 2.65 g of the amine was dissolved in 15 ml of propan-2-ol and concentrated hydrochloric acid was added to pH 2. 110 ml of ether was added and crystals of 2- [1- (4-chlorophenyl) cyclobutyl] -1 were added. -methylethylamine hydrochloride, m.p. 184-185 ° C (formula I: n = 1; R R = R = = R R = R R = R6 = R8 = H; R5 = 4-Cl; R7 = Me).

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Eksempel 33 1,8 g 2-[l-(4-klorfenyl)-cyklobutyl]-l-metylætylamin, fremstillet som beskrevet i eksempel 32, blandedes med 4,5 ml myresyre. Der tilsattes 6 ml 37-40%s vandig formaldehyd-5 opløsning og blandingen opvarmedes først til 45-50°C i 30 minutter og derpå under tilbagesvaling i 2 timer. Blandingen afkøledes, gjordes basisk med vandigt natriumhydroxyd og ekstraheredes med æter hvorpå æterekstrakten vaskedes med vand og ekstraheredes med 5N saltsyre. Den sure ekstrakt vaskedes med æter, gjordes 10 basisk med vandigt natriumhydroxyd og ekstraheredes med æter.Example 33 1.8 g of 2- [1- (4-chlorophenyl) cyclobutyl] -1-methylethylamine, prepared as described in Example 32, were mixed with 4.5 ml of formic acid. 6 ml of 37-40% aqueous formaldehyde solution was added and the mixture was first heated to 45-50 ° C for 30 minutes and then refluxed for 2 hours. The mixture was cooled, basified with aqueous sodium hydroxide and extracted with ether, then the ether extract was washed with water and extracted with 5N hydrochloric acid. The acidic extract was washed with ether, basified with aqueous sodium hydroxide and extracted with ether.

Der førtes hydrogenkloridgas gennem æterekstrakten og der dannedes et hvidt fast stof. Det faste stof opsamledes og omkrystalliseredes fra ætylacetat, hvorved der fremkom N,N-dimetyl-2-[1-(4-klorfeny1)-cyklobutyl]-1-metylætylamin-hydro-15 klorid med smp. 108-110°C (formel I: n = 1; = R2 = R8 = R8 = H; R3 = R4 = R7 = Me; R5 = 4-C1).Hydrogen chloride gas was passed through the ether extract and a white solid formed. The solid was collected and recrystallized from ethyl acetate to give N, N-dimethyl-2- [1- (4-chlorophenyl) cyclobutyl] -1-methylethylamine hydrochloride, m.p. 108-110 ° C (formula I: n = 1; = R2 = R8 = R8 = H; R3 = R4 = R7 = Me; R5 = 4-C1).

Eksempel 34 35 ml af en 70%s opløsning af natrium-bis-(2-metoxy- α v ætoxy)-aluminiumhydrid i toluen ("Red-al") sattes dråbevis til en opløsning af 5 g N-formyl-2-[l-(4-klorfenyl)-cyklobutyl]-1-metylætylamin, fremstillet som beskrevet i eksempel 32, i 110 ml tør æter under afkøling til opretholdelse af en tem-2^ peratur på under 10°C. Temperaturen fik lov til at stige til ca. 25°C og derefter opvarmedes blandingen under tilbagesvaling i 2 timer. Reaktionsblandingen udhældtes i en blanding af knust is og koncentreret saltsyre. Den resulterende blanding vaskedes med æter, gjordes basisk med vandigt natriumhydroxyd 2Q og ekstraheredes med æter. Æterekstrakten vaskedes med saltlage, tørredes og inddampedes og gav en væske som opløstes i petroleumsæter (kp. 40-60°C). Der bobledes hydrogenkloridgas gennem opløsningen for at udfælde et fast stof der omkrystalliseredes fra propan-2-ol og gav N-metyl-2-[l-(4-klorfenyl)-25 cyklobutyl]-1-metylætylamin-hydroklorid (formel I: n = 1; R^ = R2 = R3 = R6 = R8 = H; R4 = R7 = Me; R5 = 4-C1) med smp. 192-194°C.Example 34 35 ml of a 70% solution of sodium bis- (2-methoxy-α-ethyloxy) aluminum hydride in toluene ("Red-al") was added dropwise to a solution of 5 g of N-formyl-2- [ 1- (4-Chlorophenyl) -cyclobutyl] -1-methylethylamine, prepared as described in Example 32, in 110 ml of dry ether under cooling to maintain a temperature below 10 ° C. The temperature was allowed to rise to approx. 25 ° C and then the mixture was heated under reflux for 2 hours. The reaction mixture was poured into a mixture of crushed ice and concentrated hydrochloric acid. The resulting mixture was washed with ether, basified with aqueous sodium hydroxide 2Q and extracted with ether. The ether extract was washed with brine, dried and evaporated to give a liquid which was dissolved in petroleum ether (bp 40-60 ° C). Hydrogen chloride gas was bubbled through the solution to precipitate a solid which was recrystallized from propan-2-ol to give N-methyl-2- [1- (4-chlorophenyl) -cyclobutyl] -1-methylethylamine hydrochloride (Formula I: n = 1; R ^ = R2 = R3 = R6 = R8 = H; R4 = R7 = Me; R5 = 4-C1) with m.p. 192-194 ° C.

Eksempel 35 50Example 35 50

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En opløsning i 80 ml æter af 23 g 2-[l-(3,4-diklorfe-nyl)-cyklobutyl]-acetonitril (fremstillet på lignende måde som beskrevet i eksempel 27 for 2-[l-(4-klorfenyl)-cyklobutyl]- ’ 5 acetonitril) sattes til produktet af reaktionen mellem 3,53 g magniumspåner og 10,8 ml ætylbromid i 80 ml tør æter under omrøring og opvarmning på et dampbad. Æteren fjernedes og erstattedes med toluen og blandingen opvarmedes under tilbagesvaling i 1 time. Der tilsattes vand og blandingen sattes 10 til en blanding af is og koncentreret saltsyre. Blandingen opvarmedes på et dampbad i 1 time og filtreredes gennem diatoméjord ("Celite"® ). Filtratet ekstraheredes med diklorme-tan og ekstrakten vaskedes med vand og natriumbikarbonatop-løsning og tørredes. Opløsningsmidlet fjernedes ved afdampning 15 og remanensen destilleredes og gav 1-[l-(3,4-diklorfenyl)-cyklobutyl]-butan-2-on med kp. 149-150°C/l,.l mm Hg.A solution in 80 ml of ether of 23 g of 2- [1- (3,4-dichlorophenyl) -cyclobutyl] -acetonitrile (prepared in a similar manner as described in Example 27 for 2- [1- (4-chlorophenyl) - cyclobutyl] -5 'acetonitrile) was added to the product of the reaction between 3.53 g of magnesium chips and 10.8 ml of ethyl bromide in 80 ml of dry ether with stirring and heating on a steam bath. The ether was removed and replaced with toluene and the mixture heated under reflux for 1 hour. Water was added and the mixture was added to a mixture of ice and concentrated hydrochloric acid. The mixture was heated on a steam bath for 1 hour and filtered through diatomaceous earth ("Celite" ®). The filtrate was extracted with dichloromethane and the extract was washed with water and sodium bicarbonate solution and dried. The solvent was removed by evaporation and the residue was distilled to give 1- [1- (3,4-dichlorophenyl) -cyclobutyl] -butan-2-one with b.p. 149-150 ° C / l, .1 mm Hg.

Den således fremstillede keton omdannedes til 1-£[1-(3,4-diklorfenyl)-cyklobutyl]-metyl} -propylamin-hydroklorid med smp. 225-2260C på lignende måde som beskrevet i eksempel 20 32 (formel I: n = 1; R1» R2 = R3 = R4 = H; R5 = 4-C1; R6 = 3-Cl; R7 = Et; R8 = H).The ketone thus prepared was converted to 1- [1- (3,4-dichlorophenyl) cyclobutyl] methyl} propylamine hydrochloride, m.p. 225-2260C in the same manner as described in Example 20 32 (formula I: n = 1; R1 »R2 = R3 = R4 = H; R5 = 4-C1; R6 = 3-Cl; R7 = Et; R8 = H) .

På lignende måde som beskrevet ovenfor fremstilledes 2-[1-(3,4-diklorfenyl)-cyklobutyl]-1-metylætylamin-hydroklo- 1 2 rid med smp. 179°C (eksempel 35a, formel I: n = 1; R1 = R = 25 R3 = R4 = H; R5 = 4-C1; R6 = 3-C1; R7 = Me; R8 = H).In a similar manner as described above, 2- [1- (3,4-dichlorophenyl) cyclobutyl] -1-methylethylamine hydrochloride was prepared with m.p. 179 ° C (Example 35a, Formula I: n = 1; R1 = R = 25 R3 = R4 = H; R5 = 4-C1; R6 = 3-C1; R7 = Me; R8 = H).

Eksempel 36 På lignende måde som beskrevet i eksempel 33 omdannedes 2Q forbindelser fremstillet på lignende måde som beskrevet i eksempel 35 til de.tilsvarende Ν,Ν-dimetylforbindelser.Example 36 In a similar manner as described in Example 33, 2Q compounds prepared in a similar manner as described in Example 35 were converted to the corresponding Ν, Ν-dimethyl compounds.

__. CH„CHR7NMe0,HCl__. CH "CHR7NMe0, HCl

RiJllL 2 35 R6"^ * ’RIllll 2 35 R6

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Eksempel Udgangs- R7 Smp., (°C) materiale 36 (a) 35 Cl Cl Et 177-178 36 (b) 35 (a) Cl Cl Me 204-205 5Example Starting R7 Mp, (° C) Material 36 (a) 35 Cl Cl Et 177-178 36 (b) 35 (a) Cl Cl Me 204-205 5

Eksempel 37 På lignende måde som beskrevet i eksempel 34 omdannedes N-formylforbindelser, fremstillet som beskrevet i eksem-pel 32 ud fra ketoner fremstillet i eksempel 35, til de tilsvarende N-metylforbindelser.Example 37 In a similar manner as described in Example 34, N-formyl compounds prepared as described in Example 32 from ketones prepared in Example 35 were converted to the corresponding N-methyl compounds.

,-. CH0CHR7NHMe,HCl 15 r6^~ I-1-. CHOCHR7NHMe, HCl 15 r6 ^ ~ I-1

Eksempel r5 r® r7 Smp., (°C) 37 (a) Cl H Et 170-172 2Q 37 (b) Cl Cl Et 193-194Example r5 r® r7 Mp, (° C) 37 (a) Cl H Et 170-172 2Q 37 (b) Cl Cl Et 193-194

Eksempel 38Example 38

En blanding af 10,1 g 2-[1-(4-klorfenyl)-cyklobutyl]-A mixture of 10.1 g of 2- [1- (4-chlorophenyl) cyclobutyl] -

acetonitril, fremstillet som beskrevet i eksempel 27, 8,1 9 Sacetonitrile, prepared as described in Example 27, 8.1 9 S

g kaliumhydroxyd og 92 ml diætylenglykol opvarmedes under tilbagesvaling i 3 1/2 time. Blandingen udhældtes i en blanding af is og vand og den resulterende opløsning vaskedes tre gange med æter og sattes til blanding af is og koncentreret saltsyre. Ved afkøling udskilte der sig et fast produkt som omkrystalliseredes fra petroleumsæter (kp. 62-68°C) under anvendelse af trækul. Det omkrystalliserede produkt var 2-[l-(4-klorfenyl)-cyklobutyl]-eddikesyre med smp. 83-84°C.g of potassium hydroxide and 92 ml of diethylene glycol were refluxed for 3 1/2 hours. The mixture was poured into a mixture of ice and water and the resulting solution was washed three times with ether and added to ice and concentrated hydrochloric acid. On cooling, a solid product separated out which was recrystallized from petroleum ether (bp 62-68 ° C) using charcoal. The recrystallized product was 2- [1- (4-chlorophenyl) -cyclobutyl] -acetic acid, m.p. 83-84 ° C.

5 g af den således fremstillede syre sattes til 20 ml tionylklorid og opvarmedes under tilbagesvaling i 1 time.5 g of the acid thus prepared was added to 20 ml of thionyl chloride and heated under reflux for 1 hour.

Derpå fjernedes overskydende tionylklorid og remanensen udhældtes i en opløsning af 3,8 g piperidin i 20 ml æter. Blandingen omrørtes i 30 minutter og derefter sattes vand for at opløse piperidin-hydrokloridet. Æterlaget fraskiltes og - 52 . ! UK TbT/'/U-b i det vandige lag vaskedes med æter. De forenede æterfaser vaskedes med vand, tørredes og inddampedes og gav en brun olie j som rensedes ved destillation (kp. 168°C/1 mm Hg) og omkrystallisation fra petroleumsæter (kp. 40-60°C). Det faste pro-5 dukt var N-2-[l-(4-klorfenyl)-cyklobutyl]-acetylpiperidin med smp. 66-67°C. iThen, excess thionyl chloride was removed and the residue was poured into a solution of 3.8 g of piperidine in 20 ml of ether. The mixture was stirred for 30 minutes and then water was added to dissolve the piperidine hydrochloride. The ether layer was separated and - 52. ! UK TbT / '/ U-b in the aqueous layer was washed with ether. The combined ether phases were washed with water, dried and evaporated to give a brown oil which was purified by distillation (bp 168 ° C / 1 mm Hg) and recrystallization from petroleum ether (bp 40-60 ° C). The solid product was N-2- [1- (4-chlorophenyl) -cyclobutyl] -acetylpiperidine, m.p. 66-67 ° C. in

En opløsning af 2,7 g af den således fremstillede for- jA solution of 2.7 g of the thus-prepared yeast

bindelse i 20 ml æter sattes dråbevis til en omrørt blanding Icompound in 20 ml ether was added dropwise to a stirred mixture I

af 0,7 g litiumaluminiumhydrid og æter under nitrogenatmosfære.of 0.7 g of lithium aluminum hydride and ether under a nitrogen atmosphere.

10 Omrøringen fortsattes i 1 time ved stuetemperatur og derefter ! under opvarmning under tilbagesvaling i 2 timer. Efter afkøling i is blev overskud af litiumaluminiumhydrid nedbrudt ved til- j i sætning af vand. Blandingen filtreredes gennem diatoméjord ("Celite"® ). Filtratets vandige del vaskedes med en portion 15 æter og denne portion forenedes med de æterportioner der var i blevet anvendt til vask af den faste remanens. De forenede æterportioner vaskedes med vand, tørredes og inddampedes.Stirring was continued for 1 hour at room temperature and then! under reflux for 2 hours. After cooling in ice, excess lithium aluminum hydride was degraded by addition of water. The mixture was filtered through diatomaceous earth ("Celite" ®). The aqueous portion of the filtrate was washed with a portion of 15 ether and this portion was combined with the ether portions used to wash the solid residue. The combined ether portions were washed with water, dried and evaporated.

Remanensen rensedes ved destillation. Produktet var W-2-[l-(4-klorfenyl)-cyklobutyl]-ætylpiperidin med kp. 152-156°C/1,5 20 mm Hg (formel Is n = 1; R1= R2 = R6 = R7 = R8 = H; R3 plus i 4 5 i R plus nitrogenatomet danner en piperidinring; R = 4-C1). j På lignende måde som beskrevet ovenfor fremstilledes i følgende forbindelser og isoleredes som deres hydrokloridsalte ved at tør hydrogenkloridgas bobledes gennem en opløsning 25 af basen i petroleumsæter (kp. 62-68°C).The residue was purified by distillation. The product was W-2- [1- (4-chlorophenyl) -cyclobutyl] -ethyl piperidine with b.p. 152-156 ° C / 1.5 20 mm Hg (formula Is n = 1; R1 = R2 = R6 = R7 = R8 = H; R3 plus in 45 in R plus nitrogen atom forms a piperidine ring; R = 4-C1) . In a similar manner as described above, the following compounds were prepared and isolated as their hydrochloride salts by bubbling dry hydrogen chloride gas through a solution 25 of the base in petroleum ether (bp 62-68 ° C).

OCH0CH0NR3R4,HC1 —li - 30 R6OCHOCHONR3R4, HCl - li - R6

Eksempel R5 R6 NR3R4 Smp., (°C)Example R5 R6 NR3R4 Mp. (° C)

Me 38 (a) Cl H -lf] 167-169Me 38 (a) Cl H -lf] 167-169

VV

35 Me 38 (b) Cl H -N* VN -Me 281-283 (sønder- \—/ deling)35 Me 38 (b) Cl H -N * VN -Me 281-283 (shredder / split)

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53 38 (c) Cl H -O 246-24853 38 (c) Cl H -O 246-248

Eksempel 39 5 En blanding af 9 g natriumhydrid, 9 g mineralsk olie og 150 ml tørt dimetylformamid omrørtes under nitrogen ved 0°C. I løbet af 20 minutter tilsattes der en opløsning af 24,6 g p-toluensulfonylmetylisocyanid (forhandlet under det i Danmark ikke indregistrerede handelsnavn TosMIC) i 50 ml 10 dimetylformamid. Derpå sattes der 18 g absolut alkohol til blandingen ved 0°C i løbet af 1 time. Der tilsattes 24 g 1-acetyl-1-(4-klorfenyl)-cyklobutan (fremstillet på lignende måde som beskrevet i eksempel 1 for l-acetyl-l-(3,4-diklorfe-nyl)-cyklobutan)opløst i 20 ml dimetylformamid, og blandingen 15 omrørtes i 16 timer i løbet af hvilken periode temperaturen steg til omgivelsernes. Blandingen blev viskos og der tilsattes 25 ml petroleumsæter (kp. 80-100°C). Blandingen udhældtes i vand og pH reguleredes til 6 ved tilsætning af 5N saltsyre.Example 39 A mixture of 9 g of sodium hydride, 9 g of mineral oil and 150 ml of dry dimethylformamide was stirred under nitrogen at 0 ° C. Within 20 minutes, a solution of 24.6 g of p-toluenesulfonylmethyl isocyanide (traded under the trade name TosMIC not registered in Denmark) was added in 50 ml of 10 dimethylformamide. Then, 18 g of absolute alcohol was added to the mixture at 0 ° C over 1 hour. 24 g of 1-acetyl-1- (4-chlorophenyl) cyclobutane (prepared in a similar manner as described in Example 1 for 1-acetyl-1- (3,4-dichlorophenyl) cyclobutane) dissolved in 20 ml was added. dimethylformamide and the mixture was stirred for 16 hours during which time the temperature rose to ambient. The mixture was viscous and 25 ml of petroleum ether (bp 80-100 ° C) was added. The mixture was poured into water and the pH was adjusted to 6 by the addition of 5N hydrochloric acid.

Den resulterende blanding ekstraheredes med æter og æterekstrak-20 ten vaskedes med vand, tørredes og inddampedes partielt. Der udskilte sig et brunt fast stof og det fjernedes ved filtrering hvorpå filtratet inddampedes og 2-[1-(4-klorfenyl)-cyklo-butyl]-propionitril med kp. 128-136°C/0,6 mm Hg opsamledes ved destillation.The resulting mixture was extracted with ether and the ether extract was washed with water, dried and partially evaporated. A brown solid separated and was removed by filtration and the filtrate was evaporated and 2- [1- (4-chlorophenyl) -cyclobutyl] -propionitrile with b.p. 128-136 ° C / 0.6 mm Hg was collected by distillation.

25 En opløsning af 3,5 g af den på den ovenfor beskrevne måde fremstillede propionitril i 20 ml tør æter sattes dråbevis til en omrørt blanding af 0,9 g litiumaluminiumhydrid i 20 ml tør æter ved en temperatur i området 15-20°C. Blandingen omrørtes ved omgivelsernes temperatur i 2 timer og deref-30 ter under opvarmning og tilbagesvaling i yderligere 3 timer.A solution of 3.5 g of the propionitrile prepared in the manner described above in 20 ml of dry ether was added dropwise to a stirred mixture of 0.9 g of lithium aluminum hydride in 20 ml of dry ether at a temperature in the range 15-20 ° C. The mixture was stirred at ambient temperature for 2 hours and then heated and refluxed for an additional 3 hours.

Der tilsattes 20 ml 5N natriumhydroxydopløsning og 50 ml vand og blandingen filtreredes gennem diatoméjord ("Celite" ® ). Filtermediet vaskedes med æter og vaskevæskerne forenedes med reaktionsblandingens æter. De forenedes ekstrakter ekstra-35 heredes med 5N saltsyre. Der dannede sig et fast stof i kontaktfladen og det opsamledes ved filtrering, vaskedes med acetone og tørredes. Det faste stof var 2-[1-(4-klorfenyl)-cyklobutyl]-propylamin-hydroklorid med smp. 210-230°C.20 ml of 5N sodium hydroxide solution and 50 ml of water were added and the mixture was filtered through diatomaceous earth ("Celite" ®). The filter medium was washed with ether and the washings were combined with the ether of the reaction mixture. The combined extracts were extracted with 5N hydrochloric acid. A solid formed in the contact surface and it was collected by filtration, washed with acetone and dried. The solid was 2- [1- (4-chlorophenyl) -cyclobutyl] -propylamine hydrochloride, m.p. 210-230 ° C.

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54 1,0 g af det som ovenfor beskrevet fremstillede hydro-kloridsalt opløstes i vand, der tilsattes 5N vandig natrium-hydroxydopløsning og opløsningen ekstraheredes med æter. Æterekstrakten tørredes og inddampedes og gav en olie der opvarme-5 des under tilbagesvaling i 6 timer med 0,82 g 1,4-dibrombutan, 0,96 g vandfrit natriumkarbonat og 6,5 ml xylen. Blandingen afkøledes, filtreredes gennem diatoméjord ("Celite" ® ) og inddampedes til tørhed. Remanensen opløstes i 10 ml propan-2-ol og der tilsattes 5 ml koncentreret saltsyre. Blandingen 10 inddampedes til tørhed og remanensen opsamledes, vaskedes med æter og tørredes. Produktet var N-2-[l-(4-klorfenyl)-cyklo-butyl]-propylpyrrolidin-hydroklorid med smp. 238-248°C (formel I: n = 1; R1 = Me? R2 = R6 = R7 = R8 = H? R3 plus R4 plus ni- 5 trogenatomet danner en pyrrolidinrmg; R = 4-C1).54 g of the hydrochloride salt prepared as described above was dissolved in water, to which 5N aqueous sodium hydroxide solution was added and the solution extracted with ether. The ether extract was dried and evaporated to give an oil which was refluxed for 6 hours with 0.82 g of 1,4-dibromobutane, 0.96 g of anhydrous sodium carbonate and 6.5 ml of xylene. The mixture was cooled, filtered through diatomaceous earth ("Celite" ®) and evaporated to dryness. The residue was dissolved in 10 ml of propan-2-ol and 5 ml of concentrated hydrochloric acid was added. The mixture 10 was evaporated to dryness and the residue collected, washed with ether and dried. The product was N-2- [1- (4-chlorophenyl) -cyclobutyl] -propylpyrrolidine hydrochloride, m.p. 238-248 ° C (Formula I: n = 1; R1 = Me? R2 = R6 = R7 = R8 = H? R3 plus R4 plus the nitrogen atom forms a pyrrolidine ring; R = 4-C1).

1515

Eksempel 40Example 40

En opløsning af 70 g l-(3,4-diklorfenyl)-l-cyklobutan- karbonitril, fremstillet på lignende måde som beskrevet i 2Q eksempel 1, i 200 ml industriel metyleret ætanol blandedes med en opløsning af 3,7 g natriumhydroxyd i 5 ml vand og der tilsattes dråbevis 30%s hydrogenperoxydopløsning. Blandingen opvarmedes til 50°C i 1 time og omrørtes derefter med 0,5 g 10%s palladium på kul i 1 time. Blandingen filtreredes og inddampedes til tørhed og gav l-(3,4-diklorfenyl)-l-cyklobutan-25 karboxamid.A solution of 70 g of 1- (3,4-dichlorophenyl) -1-cyclobutanecarbonitrile, prepared in a similar manner as described in Example 1Q, in 200 ml of industrial methylated ethanol, was mixed with a solution of 3.7 g of sodium hydroxide in 5 ml. ml of water and 30% hydrogen peroxide solution was added dropwise. The mixture was heated to 50 ° C for 1 hour and then stirred with 0.5 g of 10% palladium on charcoal for 1 hour. The mixture was filtered and evaporated to dryness to give 1- (3,4-dichlorophenyl) -1-cyclobutane-carboxamide.

Det således fremstillede karboxamid opløstes i 500 ml dioxan og der tilsattes dråbevis 100 ml koncentreret saltsyre og derpå en opløsning af 35 g natriumnitrit i 80 ml vand.The thus prepared carboxamide was dissolved in 500 ml of dioxane and 100 ml of concentrated hydrochloric acid were added dropwise and then a solution of 35 g of sodium nitrite in 80 ml of water.

^ Blandingen opvarmedes til 85-95°C i 16 timer og udhældtes derpå i vand. Blandingen ekstraheredes med æter og ekstrakten tilbageekstraheredes med vandigt kaliumkarbonat. Den basiske ekstrakt vaskedes med æter og syrnedes med koncentreret salt-‘ syre til frembringelse af l-(3,4-diklorfenyl)-l-cyklobutankarb-oxylsyre med smp. 120-121°C.The mixture was heated to 85-95 ° C for 16 hours and then poured into water. The mixture was extracted with ether and the extract was back extracted with aqueous potassium carbonate. The basic extract was washed with ether and acidified with concentrated hydrochloric acid to give 1- (3,4-dichlorophenyl) -1-cyclobutanecarboxylic acid, m.p. 120-121 ° C.

Den således fremstillede syre omdannedes til forbindelsen ifølge eksempel 27 (a) på lignende måde som beskrevet i eksempel 27, og til forbindelsen ifølge eksempel 28 (a) på lignende måde som beskrevet i eksempel 28.The acid thus prepared was converted to the compound of Example 27 (a) in a similar manner as described in Example 27, and to the compound of Example 28 (a) in a similar manner to that described in Example 28.

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Eksempel 41 55Example 41 55

En opløsning af 23 g 2-[l-(3,4-diklorfenyl)-cyklobutyl]-acetonitril (fremstillet på lignende måde som beskrevet i eksempel 27 for 2-[l-(4-klorfenyl)-cyklobutyl]-acetonitril) 5 i 50 ml tør æter sattes til en opløsning af ætylmagniumbromid, fremstillet ved dråbevis tilsætning af 15,83 g ætylbromid i 80 ml tør æter til en omrørt blanding af 3,53 g magniumspåner og 80 ml æter. Blandingen opvarmedes under tilbagesvaling i 30 minutter og omrørtes uden yderligere opvarmning i 16 10 timer og derpå under tilbagesvaling i endnu 2 timer. Der opsamledes 1-[1-(3,4-diklorfenyl)-cyklobutyl]-2-butaniminyl-magniumbromid ved filtrering, og en prøve på ca. 1 g af det faste stof sattes til en opløsning af 3 g natriumborhydrid i 30 ml diætylenglykoldimetylæter. Blandingen omrørtes ved 15 45°C i 90 minutter. Reaktionsblandingen ekstraheredes med 5N saltsyre. Den vandige fase gjordes basisk med vandig natri-umhydroxydopløsning og ekstraheredes med æter. Æterekstrakten tørredes og der førtes hydrogenkloridgas gennem ekstrakten til udfældning af l-{[1-(3,4-diklorfenyl)-cyklobutyl]-metyl)-20 propylamin-hydroklorid med smp. 223-224°C (formel I: n = 1; R1 = R2 = R3 = R4 = R8 = H; R5 = 4-C1; R6 = 3-C1; R7 = Et).A solution of 23 g of 2- [1- (3,4-dichlorophenyl) -cyclobutyl] -acetonitrile (prepared in a similar manner to Example 27 for 2- [1- (4-chlorophenyl) -cyclobutyl] -acetonitrile) in 50 ml of dry ether was added to a solution of ethyl magnesium bromide prepared by dropwise addition of 15.83 g of ethyl bromide in 80 ml of dry ether to a stirred mixture of 3.53 g of magnesium chips and 80 ml of ether. The mixture was heated under reflux for 30 minutes and stirred without further heating for 16 hours and then under reflux for another 2 hours. 1- [1- (3,4-Dichlorophenyl) -cyclobutyl] -2-butaniminyl-magnium bromide was collected by filtration, and a sample of ca. 1 g of the solid was added to a solution of 3 g of sodium borohydride in 30 ml of diethylene glycol dimethyl ether. The mixture was stirred at 45 ° C for 90 minutes. The reaction mixture was extracted with 5N hydrochloric acid. The aqueous phase was basified with aqueous sodium hydroxide solution and extracted with ether. The ether extract was dried and hydrogen chloride gas was passed through the extract to precipitate 1 - {[1- (3,4-dichlorophenyl) cyclobutyl] methyl) -propylamine hydrochloride, m.p. 223-224 ° C (formula I: n = 1; R1 = R2 = R3 = R4 = R8 = H; R5 = 4-C1; R6 = 3-C1; R7 = Et).

Eksempel 42 7 ml myresyre sattes dråbevis til 15 ml pyrrolidin ved en temperatur i området 135-140 C. Der tilsattes dråbevis 3 g l-[l-(3,4-diklorfenyl)-cyklobutyl]-butan-2-on, fremstillet som beskrevet i eksempel 35, og blandingen opvarmedes til 140°C i 1 time. Temperaturen hævedes til 185-190°C i 16 timer.Example 42 7 ml of formic acid was added dropwise to 15 ml of pyrrolidine at a temperature in the range 135-140 C. 3 g of 1- [1- (3,4-dichlorophenyl) -cyclobutyl] -butan-2-one were added dropwise as prepared. described in Example 35, and the mixture was heated to 140 ° C for 1 hour. The temperature was raised to 185-190 ° C for 16 hours.

^ Reaktionsblandingen afkøledes og udhældtes i 5N saltsyre.The reaction mixture was cooled and poured into 5N hydrochloric acid.

Opløsningen vaskedes med æter, gjordes basisk og ekstraheredes med æter. Æterekstrakten tørredes og der førtes hydrogenkloridgas ind i ekstrakten. Inddampning til tørhed gav et fast stof der tritureredes med tør æter og omkrystalliseredes ^ fra en blanding af petroleumsæter og propan-2-ol til frembringelse af N-l-£[1-(3,4-diklorfenyl)-cyklobutyl]-metyl}-propyl-pyrrolidin-hydroklorid med smp. 157-160°C (formel I: n = 1; R1 = R2 = R8 = H; R3 plus R4 plus nitrogenatomet danner en pyr- 56The solution was washed with ether, made basic and extracted with ether. The ether extract was dried and hydrogen chloride gas was introduced into the extract. Evaporation to dryness gave a solid which was triturated with dry ether and recrystallized from a mixture of petroleum ether and propan-2-ol to give N1- [1- (3,4-dichlorophenyl) cyclobutyl] methyl} propyl pyrrolidine hydrochloride, m.p. 157-160 ° C (Formula I: n = 1; R1 = R2 = R8 = H; R3 plus R4 plus the nitrogen atom forms a pyr

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rolidinring; R° = 4-C1; R° = 3-Cl; R7 = Et).rolidinring; R4 = 4-C1; R ° = 3-Cl; R7 = Et).

Eksempel 43 5 25 g 1—[1—(3,4-diklorfenyl)-cyklobutyl]-2-butaniminyl- magniumbromid, fremstillet som beskrevet i eksempel 41, opvarmedes til 90-95°C i 2 timer med en blanding af 20 ml koncentreret saltsyre og 30 ml vand. Reaktionsblandingen ekstrahé-redes med æter og æterekstrakten tørredes og inddampedes til 10 tørhed. Der destilleredes l-[l-(3,4-diklorfenyl)-cyklobutyl]-butan-2-on med kp. 122-124°C/0,1 mm Hg.Example 43 25 g of 1- [1- (3,4-dichlorophenyl) cyclobutyl] -2-butaniminyl magnesium bromide, prepared as described in Example 41, were heated to 90-95 ° C for 2 hours with a mixture of 20 ml concentrated hydrochloric acid and 30 ml of water. The reaction mixture was extracted with ether and the ether extract dried and evaporated to dryness. 1- [1- (3,4-Dichlorophenyl) -cyclobutyl] -butan-2-one was distilled off with b.p. 122-124 ° C / 0.1 mm Hg.

En blanding af 4,3 g 1-[l-(3,4-diklorfenyl)-cyklobutyl]-butan-2-on, fremstillet som beskrevet ovenfor, 2,65 g hydroxyl-aminsulfat, 4,0 g natriumacetat, 56 ml industriel metyleret 15 ætanol og 23 ml vand omrørtes ved omgivelsernes temperatur i 16 timer. Reaktionsblandingen ekstraheredes med æter. Æterekstrakten vaskedes med vand, tørredes og inddampedes og gav et fast stof der omkrystalliseredes fra petroleumsæter (kp. 80-100°C) til frembringelse af l-[l-(3,4-diklorfenyl)-cyklobu-20 tyl]-butan-2-on-oxim med smp. 106-110°C.A mixture of 4.3 g of 1- [1- (3,4-dichlorophenyl) -cyclobutyl] -butan-2-one, prepared as described above, 2.65 g of hydroxylamine sulfate, 4.0 g of sodium acetate, 56 ml industrial methylated 15 ethanol and 23 ml of water were stirred at ambient temperature for 16 hours. The reaction mixture was extracted with ether. The ether extract was washed with water, dried and evaporated to give a solid which was recrystallized from petroleum ether (bp 80-100 ° C) to give 1- [1- (3,4-dichlorophenyl) cyclobutyl] -butane] 2-on oxime with m.p. 106-110 ° C.

En opløsning af 2,33 ml trifluoreddikesyre i 5 ml tetra-hydrofuran sattes til en omrørt suspension af 1,13 g natrium-borhydrid i 30 ml tetrahydrofuran i løbet af en periode på 5 minutter. Der tilsattes dråbevis en opløsning af 1,7 g af 25 oximen fremstillet som beskrevet ovenfor i 25 ml tetrahydrofuran, og blandingen opvarmedes under tilbagesvaling i 6 timer. Blandingen afkøledes og der tilsattes 25 ml vand og derpå 25 ml 5N natriumhydroxydopløsning. Blandingen ekstraheredes med æter og ekstrakten vaskedes med vand, tørredes og inddampe-30 des og gav en remanens der opløstes i 25 ml petroleumsæter.A solution of 2.33 ml of trifluoroacetic acid in 5 ml of tetrahydrofuran was added to a stirred suspension of 1.13 g of sodium borohydride in 30 ml of tetrahydrofuran over a period of 5 minutes. A solution of 1.7 g of the 25 oxime prepared as described above in 25 ml of tetrahydrofuran was added dropwise and the mixture was heated under reflux for 6 hours. The mixture was cooled and 25 ml of water and then 25 ml of 5N sodium hydroxide solution were added. The mixture was extracted with ether and the extract was washed with water, dried and evaporated to give a residue which was dissolved in 25 ml of petroleum ether.

Der førtes tør hydrogenkloridgas gennem æteropløsningen til frembringelse af 1- {[ 1-(3,4-diklorfenyl)-cyklobutyl]-metyl} -propylamin-hydroklorid med smp. 222-224°C (formel I: n = 1; R1 = R2 = R3 = R4 = R8 = H; R5 = 4-C1; R6 = 3-Cl; R7 = Et).Dry hydrogen chloride gas was passed through the ether solution to give 1- {[1- (3,4-dichlorophenyl) -cyclobutyl] -methyl} -propylamine hydrochloride, m.p. 222-224 ° C (formula I: n = 1; R1 = R2 = R3 = R4 = R8 = H; R5 = 4-C1; R6 = 3-Cl; R7 = Et).

3535

Eksempel 44Example 44

En opløsning af 5,0 g 1-(1-(3,4-diklorfenyl)-cyklobutyl]-butan-2-on, fremstillet som beskrevet i eksempel 43, og 1,63A solution of 5.0 g of 1- (1- (3,4-dichlorophenyl) -cyclobutyl] -butan-2-one, prepared as described in Example 43, and 1.63

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57 g metoxyamin-hydroklorid i en blanding af 60 ml pyridin og 60 ml ætanol opvarmedes under tilbagesvaling i 72 timer. Reaktionsblandingen inddampedes til tørhed og der sattes en blanding af vand og æter til reamensen. Æterlaget vaskedes med 5 natriumbikarbonatopløsning og vand, tørredes og inddampedes og gav l-[1-(3,4-diklorfenyl)-cyklobutyl]-butan-2-on-oxim-O-metylæter.57 g of methoxyamine hydrochloride in a mixture of 60 ml of pyridine and 60 ml of ethanol were heated under reflux for 72 hours. The reaction mixture was evaporated to dryness and a mixture of water and ether was added to the residue. The ether layer was washed with 5 sodium bicarbonate solution and water, dried and evaporated to give 1- [1- (3,4-dichlorophenyl) cyclobutyl] -butan-2-one oxime-O-methyl ether.

15 g af den således fremstillede oximæter blev derpå reduceret til produktet ifølge eksempel 43 ved hjælp af 0,95 10 g natriumborhydrid på lignende måde som beskrevet i eksempel 43.15 g of the oxime ether thus produced was then reduced to the product of Example 43 by 0.95 10 g of sodium borohydride in a similar manner as described in Example 43.

Eksempel 45 __ 0,4 g natriumcyanborhydrid sattes til en opløsning 15 af 2,45 g l-[1-(3,4-diklorfenyl)-cyklobutyl]-butan-2-on, fremstillet som beskrevet i eksempel 42, og 7 g ammoniumacetat i 28 ml ætanol, og blandingen omrørtes ved stuetemperatur i 4 dage. Der tilsattes dråbevis og under afkøling 25 ml vand.Example 45 0.4 g of sodium cyanoborohydride was added to a solution of 2.45 g of 1- [1- (3,4-dichlorophenyl) cyclobutyl] -butan-2-one, prepared as described in Example 42, and 7 g ammonium acetate in 28 ml of ethanol and the mixture was stirred at room temperature for 4 days. 25 ml of water were added dropwise and with cooling.

Den vandige blanding ekstraheredes med æter og æterlaget va-The aqueous mixture was extracted with ether and the ether layer was

VV

skedes med vand og 50 ml 5N saltsyre. Forbindelsen ifølge eksempel 43 udfældedes som et hvidt fast stof.spoon with water and 50 ml of 5N hydrochloric acid. The compound of Example 43 precipitated as a white solid.

Eksempel 46 25 1,5 g 2-[1-(4-klorfenyl)-cyklobutyl]-eddikesyre, frem stillet som beskrevet i eksempel 38, opvarmedes under tilbagesvaling med tionylklorid. Overskydende tionylklorid fjernedes i vakuum og remanensen sattes dråbevis til en opløsning af 0,94 g cyklopropylamin i 10 ml æter hvorpå blandingen om-5® rørtes i 30 minutter. Der tilsattes vand og den vandige fase ekstraheredes med æter. Æterekstrakten tørredes og æteren fjernedes og gav 2-[1-(4-klorfenyl)-cyklobutyl]-N-cyklopropyl-acetamid.Example 46 1.5 g of 2- [1- (4-chlorophenyl) -cyclobutyl] -acetic acid, prepared as described in Example 38, was heated under reflux with thionyl chloride. Excess thionyl chloride was removed in vacuo and the residue was added dropwise to a solution of 0.94 g of cyclopropylamine in 10 ml of ether and the mixture was stirred for 5 minutes for 30 minutes. Water was added and the aqueous phase extracted with ether. The ether extract was dried and the ether removed to give 2- [1- (4-chlorophenyl) -cyclobutyl] -N-cyclopropyl-acetamide.

En opløsning af 1,45 g af det således fremstillede 55 amid i 15 ml æter sattes dråbevis til en omrørt suspension af 0,42 g litiumaluminiumhydrid i 7,5 ml æter under nitrogen. Blandingen omrørtes ved stuetemperatur i 1 time og opvarmedes derefter under tilbagesvaling i yderligere 2 timer. Efter 58A solution of 1.45 g of the thus obtained 55 amide in 15 ml of ether was added dropwise to a stirred suspension of 0.42 g of lithium aluminum hydride in 7.5 ml of ether under nitrogen. The mixture was stirred at room temperature for 1 hour and then refluxed for a further 2 hours. After 58

DK 161770 BDK 161770 B

afkøling tilsattes der 0,45 ml vand, derpå 0,45 ml 15%s na-triumhydroxydopløsning og så 1,35 ml vand, og blandingen om-rørtes i 15 minutter. Blandingen filtreredes og ekstraheredes med æter. Æterekstrakten rystedes med N-saltsyre og der danne-5 de sig et fast stof i det vandige lag. Det faste stof var , N-cyklopropyl-2-[1-(4-klorfenyl)-cyklobutyl]-ætylamin-hydro-klorid med smp. 166-170°C.After cooling, 0.45 ml of water was added, then 0.45 ml of 15% sodium hydroxide solution and then 1.35 ml of water, and the mixture was stirred for 15 minutes. The mixture was filtered and extracted with ether. The ether extract was shaken with N-hydrochloric acid and a solid formed in the aqueous layer. The solid was N-cyclopropyl-2- [1- (4-chlorophenyl) -cyclobutyl] -ethylamine hydrochloride, m.p. 166-170 ° C.

En blanding af 0,41 g af det således fremstillede hydro-kloridsalt, 0,1 g natriumformiat, 1 ml 98%s myresyre og 0,5 10 ml 37-40%s vandig formaldehydopløsning opvarmedes til 85-90°C i 18 timer. Reaktionsblandingen afkøledes og ekstraheredes med æter. Æterekstrakten vaskedes med vand, tørredes og filtreredes. Der førtes hydrogerikloridgas gennem filtratet, der derpå opvarmedes og gav et fast stof som var N-cyklopropyl-15 N-metyl-2-[l-(4-klorfenyl)-cyklobutyl]-ætylamin-hydroklorid med msp. 149-153°C (formel I: n = 1; R1 = R2 = R6 = R7 = R8 = H; R3 = cyklopropyl; R4 = Me; R5 = 4-C1).A mixture of 0.41 g of the hydrochloride salt thus prepared, 0.1 g of sodium formate, 1 ml of 98% s formic acid and 0.5 10 ml of 37-40% s aqueous formaldehyde solution was heated to 85-90 ° C for 18 hours. . The reaction mixture was cooled and extracted with ether. The ether extract was washed with water, dried and filtered. Hydrogen chloride gas was passed through the filtrate which was then heated to give a solid which was N-cyclopropyl-15 N-methyl-2- [1- (4-chlorophenyl) cyclobutyl] ethylamine hydrochloride with m.p. 149-153 ° C (formula I: n = 1; R1 = R2 = R6 = R7 = R8 = H; R3 = cyclopropyl; R4 = Me; R5 = 4-C1).

20 25 30 3520 25 30 35

Claims (2)

1. Analogifremgangsmåde til fremstilling af cyklobutyl-aminderivater med den almene formel I 5 R5 ___ CR1R2(CR7R8) NR1R2 3 ,£>b hvor n er 0 eller 1 og 10 hvor, såfremt n = 0, R1" er en ligekædet eller forgrenet alkyl-gruppe med 1-6 kulstofatomer, en cykloalkylgruppe med 3-7 kulstofatomer, en cykloalkylalkylgruppe hvis cykloalkyldel indeholder 3-6 kulstofatomer og alkyldelen 1-3 kulstofatomer, en alkenylgruppe med 2-6 kulstofatomer eller en gruppe med 15 formlen II ,-. R10 -GC, 20 9 10 hvor R og R , der er ens eller forskellige, hver betegner hydrogen, halogen eller en alkoxygruppe med 1-3 kulstofatomer, og hvor, såfremt n = 1, R1 er hydrogen eller en alkylgruppe med 1-3 kulstofatomer, 2 25. er hydrogen eller en alkylgruppe med 1-3 kulstofatomer, 4 R og R , der er ens eller forskellige, hver er hydrogen, en ligekædet eller forgrenet alkylgruppe med 1-4 kulstofatomer, 2 en alkenyl- eller alkynylgruppe med 3-6 kulstofatomer, en cykloalkylgruppe hvis ring indeholder 3-7 kulstofatomer, el- 30 ler en gruppe CHO, eller 3 4 hvor R og R tilsammen og sammen med nitrogenatomet danner en eventuelt substitueret heterocyklisk ring med 5 eller 6 atomer i ringen, der kan indeholde yderligere heteroatomer foruden nitrogenatomet, 3 6 35. og R , der er ens eller forskellige, hver er hydrogen, halogen, trifluormetyl, en alkylgruppe med 1-3 kulstofatomer, en alkoxy- eller alkyltiogruppe med 1-3 kulstofatomer eller 60 | DK 161770 B j C g en fenylgruppe, eller hvor R og R tilsammen og sammen med det kulstofatom hvortil de er bundet danner en yderligere benzenring der eventuelt kan være substitueret med et eller flere halogenatomer eller en alkyl- eller alkoxygruppe med 5 1-4 kulstofatomer, eller hvor substituenterne på den yderlige- i re benzenring sammen med de to kulstofatomer hvortil de er bundet danner endnu en benzenring, 7 8 og hvor R og R , der er ens eller forskellige hver er hydrogen eller en alkylgruppe med 1-3 kulstofatomer, 10 eller farmaceutisk acceptable salte deraf, kendetegnet ved at man a) reduktivt amiderer en keton med den almene formel V ,,5 --- COR1 i is · i R6 - I 2 i til dannelse af en forbindelse med formlen I hvor n = 0, R = H, R4 = CHO og R1, R^ og R^ har de ovenfor angivne betydnin-20 ger, eller en keton eller et aldehyd med den almene formel VI R5 ___ CR1R2COR7 I 25 , 4 til dannelse af en forbindelse med formlen I hvor n = 1, R = 8 1 2 5 6 7 CHO, R = H og R , R , R , R og R har de ovenfor angivne betydninger, eller b) reduktivt aminerer en keton med den almene formel V .An analogous process for the preparation of cyclobutylamine derivatives of the general formula I wherein R is 0 or 1 and 10 where, if n = 0, R1 "is a straight or branched alkyl a group of 1-6 carbon atoms, a cycloalkyl group of 3-7 carbon atoms, a cycloalkylalkyl group whose cycloalkyl moiety contains 3-6 carbon atoms and the alkyl moiety 1-3 carbon atoms, an alkenyl group of 2-6 carbon atoms or a group of formula II, - R10 -GC, 20 9 10 wherein R and R, being the same or different, each represent hydrogen, halogen or an alkoxy group having 1-3 carbon atoms and where, if n = 1, R1 is hydrogen or an alkyl group having 1-3 carbon atoms Is hydrogen or an alkyl group having 1-3 carbon atoms, 4 R and R being the same or different, each being hydrogen, a straight or branched alkyl group having 1-4 carbon atoms, 2 an alkenyl or alkynyl group having 3- 6 carbon atoms, a cycloalkyl group whose ring contains are 3-7 carbon atoms, or a group CHO, or 34 where R and R together and together with the nitrogen atom form an optionally substituted heterocyclic ring of 5 or 6 atoms in the ring which may contain additional heteroatoms besides the nitrogen atom, 35. and R are the same or different, each being hydrogen, halogen, trifluoromethyl, an alkyl group having 1-3 carbon atoms, an alkoxy or alkylthio group having 1-3 carbon atoms, or 60 | DK 161770 B j C g a phenyl group or where R and R together and together with the carbon atom to which they are attached form an additional benzene ring which may be optionally substituted with one or more halogen atoms or an alkyl or alkoxy group having from 5 to 4 carbon atoms. or wherein the substituents on the additional benzene ring together with the two carbon atoms to which they are attached form another benzene ring, 7 and wherein R and R which are the same or different each are hydrogen or an alkyl group having 1-3 carbon atoms, Or pharmaceutically acceptable salts thereof, characterized in that a) reductively amidates a ketone of the general formula V, 5 --- COR1 in ice · in R6 - I2 i to form a compound of formula I wherein n = 0 , R = H, R4 = CHO and R 1, R 2 and R 2 have the above meanings, or a ketone or an aldehyde of the general formula VI R 5 ___ CR 1 R 2 COR 7 I 25, 4 to form a compound of the formula In which n = 1, R = 8 1 2 5 6 7 CHO, R = H and R, R, R, R and R have the above meanings, or b) reductively amine a ketone of the general formula V. 2 30 til dannelse af en forbindelse med formlen I hvor n = 0, R = 15 6 H og R , R og R har de ovenfor angivne betydninger, eller-.en keton eller et aldehyd med den almene formel VI til dannelse af en forbin- o 12 5 6 delse med formlen I hvor n = 1, R = H og R , R , R , R og 7 R har de ovenfor angivne betydninger, eller 35 c) reducerer en forbindelse med den almene formel VII R5 --1 Z \-- VII DK 161770 B 61 hvor i) Z er en gruppe med formlen -CRUNCH eller en ester eller æter deraf til dannelse af en forbindelse med formlen I hvor n = 0 og R2, R3 og R4 er hydrogen, eller 5 ii) Z er en gruppe med formlen -CR1=NY, hvor Y er en metal holdig rest afledet af et organometalreagens til dannelse af en forbindelse med formlen I hvor n = 0 og hvor 2 3 4 R , R og R er hydrogen, eller 12 7 iii) Z er en gruppe med formlen -CR R CR =NOH eller en ester 10 eller æter deraf til dannelse af en forbindelse med 3 4 8 formlen I hvor n = 1 og R , R og R er hydrogen, eller 12 7 iv) Z er en gruppe med formlen -CR R CR =NY, hvor Y er en metalholdig rest afledet af et organometalreagens, til dannelse af en forbindelse med formlen I hvor n = 1 3 4 8 15 og R , R og R er hydrogen, eller v) Z er en gruppe med formlen -CR1R2CONR3R4 til dannelse 7 af en forbindelse med formlen I hvor n = 1 og R og g R er hydrogen, eller 1 2 vi) Z er en gruppe med formlen -CR R CN til dannelse af 3 4 20 en forbindelse med formlen I hvor n = 1 og R , R , 7 8 R og R er hydrogen, eller d) foretager dekarboxylativ omlejring af et amid med den almene formel XI 25. cr1h2(ce7r'’] conh n r6-A_/T_ 30 hvor R1, R2, R5, R6, R7, R8 og n har ha ovenfor angivne betyd-ninger, til dannelse af en amin med formel I hvor R =R =H, eller 4 e) hydrolyserer en forbindelse med formlen I, hvor R er CHO, til dannelse af en forbindelse med formlen I hvor R4 1K er hydrogen, eller DK 161770 B 62 f) reducerer en forbindelse med formlen I, hvor R4 er CHO, til dannelse af en forbindelse med formi en I hvor R4 er en metylgruppe, eller g) omdanner en forbindelse med den almene formel I, hvor 3 ^ ' 5. og/eller R er hydrogen, til dannelse af en forbindelse 3 λ med formlen I hvor R og/eller R er forskellige fra hydrogen, hvorpå man om ønsket omdanner den ved en hvilken som helst af fremgangsmåderne a)-f) vundne forbindelse til et farmaceutisk acceptabelt salt deraf. 10 2. Fremgangsmåde ifølge krav 1(c), kendetegnet ved at Y er MgBr eller Li. j ! 12 to form a compound of formula I wherein n = 0, R = 15 6 H and R, R and R have the meanings given above, or -one ketone or an aldehyde of the general formula VI to form a compound - compound of formula I wherein n = 1, R = H and R, R, R, R and 7 R have the above meanings, or c) reduces a compound of the general formula VII R5 - 1 Z i - VII DK 161770 B 61 wherein i) Z is a group of formula -CRUNCH or an ester or ether thereof to form a compound of formula I wherein n = 0 and R 2, R 3 and R 4 are hydrogen, or 5 ii Z is a group of formula -CR1 = NY, where Y is a metal-containing residue derived from an organometallic reagent to form a compound of formula I where n = 0 and where 2 3 4 R, R and R are hydrogen, or 12 7 iii) Z is a group of formula -CR R CR = NOH or an ester 10 or ether thereof to form a compound of formula 4 wherein n = 1 and R, R and R are hydrogen, or 12 7 iv ) Z e r is a group of formula -CR R CR = NY, where Y is a metal-containing residue derived from an organometallic reagent, to form a compound of formula I wherein n = 1 3 4 8 15 and R, R and R are hydrogen, or v ) Z is a group of formula -CR1R2CONR3R4 to form 7 a compound of formula I wherein n = 1 and R and g R are hydrogen, or 1 2 vi) Z is a group of formula -CR R CN to form 3 4 A compound of formula I wherein n = 1 and R, R, 7 8 R and R are hydrogen, or d) performs decarboxylative rearrangement of an amide of the general formula XI 25. cr1h2 (ce7r ''] conh n r6-A_ Wherein R 1, R 2, R 5, R 6, R 7, R 8 and n have the above meanings to form an amine of formula I wherein R = R = H, or 4 e) hydrolyzes a compound of formula I wherein R is CHO to form a compound of formula I wherein R4 is K, or DK f) reduces a compound of formula I wherein R4 is CHO to form a compound of formula I n in which R 4 is a methyl group, or g) converts a compound of general formula I wherein 3 5 and / or R is hydrogen to form a compound 3 λ of formula I wherein R and / or R different from hydrogen, and, if desired, converting the compound obtained by any one of the processes a) to f into a pharmaceutically acceptable salt thereof. Process according to claim 1 (c), characterized in that Y is MgBr or Li. j! 1
DK146482A 1981-04-06 1982-03-31 METHOD OF ANALOGUE FOR THE PREPARATION OF CYCLOBUTYLAMINE DERIVATIVES OR PHARMACEUTICAL ACCEPTABLE SALTS THEREOF DK161770C (en)

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YU6385A (en) 1985-08-31
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GEP19970661B (en) 1997-01-04
UA7589A1 (en) 1995-09-29
SE452611B (en) 1987-12-07
FI821197A0 (en) 1982-04-05
IT8248157A0 (en) 1982-04-02
PL240079A1 (en) 1983-09-12
MY8800048A (en) 1988-12-31
NL192201C (en) 1997-03-04
UA7838A1 (en) 1995-12-26
AU8221382A (en) 1982-10-14
GB2098602B (en) 1984-08-22
IN155773B (en) 1985-03-09
DK161770C (en) 1992-02-10
CA1248955A (en) 1989-01-17
GB2098602A (en) 1982-11-24
NO156785B (en) 1987-08-17
YU44253B (en) 1990-04-30
ES8406413A1 (en) 1984-08-01
ES519032A0 (en) 1984-03-01
NO821087L (en) 1982-10-07
SU1482522A3 (en) 1989-05-23
KE3753A (en) 1987-10-02
ES511152A0 (en) 1983-04-16
AU545595B2 (en) 1985-07-18
IT1235758B (en) 1992-09-28
ES8406414A1 (en) 1984-08-01

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