NO813067L - PROCEDURE FOR THE PREPARATION OF APOVINCAMIN ACID ESTERS - Google Patents
PROCEDURE FOR THE PREPARATION OF APOVINCAMIN ACID ESTERSInfo
- Publication number
- NO813067L NO813067L NO813067A NO813067A NO813067L NO 813067 L NO813067 L NO 813067L NO 813067 A NO813067 A NO 813067A NO 813067 A NO813067 A NO 813067A NO 813067 L NO813067 L NO 813067L
- Authority
- NO
- Norway
- Prior art keywords
- acid
- reaction
- general formula
- toluene
- organic solvent
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 33
- 239000002253 acid Substances 0.000 title claims description 32
- 150000002148 esters Chemical class 0.000 title claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 57
- 238000006243 chemical reaction Methods 0.000 claims description 11
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 3
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 3
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- 150000004292 cyclic ethers Chemical class 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 150000001875 compounds Chemical class 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- 235000019441 ethanol Nutrition 0.000 description 9
- 125000004494 ethyl ester group Chemical group 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000000203 mixture Substances 0.000 description 7
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- RXPRRQLKFXBCSJ-GIVPXCGWSA-N vincamine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C[C@](O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-GIVPXCGWSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 150000007513 acids Chemical class 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 4
- 239000000908 ammonium hydroxide Substances 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- RXPRRQLKFXBCSJ-UHFFFAOYSA-N dl-Vincamin Natural products C1=CC=C2C(CCN3CCC4)=C5C3C4(CC)CC(O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-UHFFFAOYSA-N 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 3
- 229960002726 vincamine Drugs 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- OZDNDGXASTWERN-CTNGQTDRSA-N Apovincamine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C=C(C(=O)OC)N5C2=C1 OZDNDGXASTWERN-CTNGQTDRSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 229950006936 apovincamine Drugs 0.000 description 2
- OZDNDGXASTWERN-UHFFFAOYSA-N apovincamine Natural products C1=CC=C2C(CCN3CCC4)=C5C3C4(CC)C=C(C(=O)OC)N5C2=C1 OZDNDGXASTWERN-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 238000010533 azeotropic distillation Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000005260 corrosion Methods 0.000 description 2
- 230000007797 corrosion Effects 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- -1 methylenemalonic acid diesters Chemical class 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 238000007086 side reaction Methods 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- IDVYOLJGJUDVNL-UHFFFAOYSA-N 1,2,3,4,6,7-hexahydroindolo[3,2-a]quinolizine Chemical class C1=CC=C2C3=C4CCCCN4CCC3=NC2=C1 IDVYOLJGJUDVNL-UHFFFAOYSA-N 0.000 description 1
- LDMOEFOXLIZJOW-UHFFFAOYSA-N 1-dodecanesulfonic acid Chemical compound CCCCCCCCCCCCS(O)(=O)=O LDMOEFOXLIZJOW-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- DDNCQMVWWZOMLN-IRLDBZIGSA-N Vinpocetine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C=C(C(=O)OCC)N5C2=C1 DDNCQMVWWZOMLN-IRLDBZIGSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- ZFCQLDAGNBFMJQ-QUCCMNQESA-N apovincaminic acid Chemical class C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C=C(C(O)=O)N5C2=C1 ZFCQLDAGNBFMJQ-QUCCMNQESA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000007040 multi-step synthesis reaction Methods 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 1
- 239000012414 tert-butyl nitrite Substances 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D461/00—Heterocyclic compounds containing indolo [3,2,1-d,e] pyrido [3,2,1,j] [1,5]-naphthyridine ring systems, e.g. vincamine
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
Foreliggende oppfinnelse angår en ny fremgangsmåte for fremstilling av apovincaminsyreestere. Nærmere bestemt angår oppfinnelsen en fremgangsmåte for fremstilling av racemiske eller optisk aktive apovincaminsyreestere av generell formel I The present invention relates to a new process for the production of apovincamic acid esters. More specifically, the invention relates to a process for the production of racemic or optically active apovincamic acid esters of general formula I
12 hvori R og R uavhengig betegner alkyl med fra 1-6 carbonatomer. Ifølge oppfinnelsen fremstilles apovincaminsyré-estrene av generell formel I ved omsetning av et hydroxy-amino-E-homo-eburnan av generell formel II 12 in which R and R independently denote alkyl with from 1-6 carbon atoms. According to the invention, the apovincaminic acid esters of general formula I are prepared by reacting a hydroxy-amino-E-homo-eburnane of general formula II
hvori R 1 og R 2 er som ovenfor angitt, eller et syreaddisjonssalt derav, med en organisk sulfonsyre i et aprotisk organisk løsningsmiddel. wherein R 1 and R 2 are as above, or an acid addition salt thereof, with an organic sulphonic acid in an aprotic organic solvent.
1 2 1 2
I definisjonen for R og R anvendes uttrykket "alkyl med fra 1-6 carbonatomer" for å angi rettkjedede eller forgrenede alkylgrupper med 1-6 carbonatomer, f.eks. methyl, ethyl, n-propyl, isopropyl, n-butyl, sek.-butyl etc. In the definition for R and R, the expression "alkyl with from 1-6 carbon atoms" is used to denote straight-chain or branched alkyl groups with 1-6 carbon atoms, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl etc.
Det er velkjent at apovincaminsyreestrene av gene-reil formel I hvori R 1 og R 2er som ovenfor definert, ut- viser verdifulle farmakologiske egenskaper, og i særdeles-het er (+.)-apovincaminsyreethylesteren er glimrende vaso-dilator. It is well known that the apovincamic acid esters of general formula I in which R 1 and R 2 are as defined above, exhibit valuable pharmacological properties, and in particular the (+.)-apovincamic acid ethyl ester is an excellent vaso-dilator.
Ifølge ungarsk patentskrift 163 143 har disse forbindelser vært fremstilt ved at det farmasøytisk aktive vincamin er blitt underkastet hydrolyse, og at den erholdte vincaminsyre er blitt omdannet til en tilsvarende ester. According to Hungarian patent document 163 143, these compounds have been prepared by subjecting the pharmaceutically active vincamine to hydrolysis, and the resulting vincamic acid being converted into a corresponding ester.
Fra den fremstilte vincaminsyreester har de tilsvarende apovincaminsyreestere blitt fremstilt ved å spalte av vann. Ifølge et annet alternativ ble vincamin først omdannet til apovincamin ved avsplitting av vann, hvorpå apovincamin ble hydrolysert og den erholdte apovincaminsyre omdannet til den ønskede ester. From the produced vincamic acid ester, the corresponding apovincamic acid esters have been produced by splitting off water. According to another alternative, vincamine was first converted to apovincamine by splitting off water, after which apovincamine was hydrolysed and the resulting apovincamic acid converted to the desired ester.
En ulempe ved denne prosess er at vincamin først må fremstilles ved en flertrinnssyntese og fra denne forbindelse kan de tilsvarende apovincaminsyreestere bare erholdes med et utbytte på maksimalt 60 %. A disadvantage of this process is that vincamine must first be prepared by a multi-step synthesis and from this compound the corresponding apovincamic acid esters can only be obtained with a yield of a maximum of 60%.
Ifølge en annen fremgangsmåte beskrevet i publi-sert japansk patentsøknad 53-061757 er forbindelser av gene-reil formel I hvor R 1 og R 2 er som tidligere definert, blitt fremstilt ved omsetning av det tilsvarende 14-oxo-15-hydroxy-imino-3a,17a-E-homo-eburnan med den tilsvarende alkohol i nærvær av en syre. According to another method described in published Japanese patent application 53-061757, compounds of general formula I where R 1 and R 2 are as previously defined have been prepared by reaction of the corresponding 14-oxo-15-hydroxy-imino- 3a,17a-E-homo-eburnane with the corresponding alcohol in the presence of an acid.
Den mest betydelige ulempe ved denne prosess består i det faktum at ved den anvendte reaksjonstemperatur, som overskrider 100 til 104° C, erholdes også en stor mengde ether svarende til den anvendte alkohol. Hvis for eksempel ethylalkohol anvendes som en alkohol i reaksjonen, dannes store mengder diethylether også på grunn av nærvær av den dehydratiserte syre. Dannelsen av ether er særlig ufordel-aktig innen de prosesser som anvendes industrielt da nærvæ-ret av dette fører til øket fare for brand og eksplosjon, og følgelig til ekstreme sikkerhetskrav. The most significant disadvantage of this process consists in the fact that at the used reaction temperature, which exceeds 100 to 104° C, a large amount of ether corresponding to the alcohol used is also obtained. If, for example, ethyl alcohol is used as an alcohol in the reaction, large amounts of diethyl ether are also formed due to the presence of the dehydrated acid. The formation of ether is particularly disadvantageous within the processes used industrially, as the presence of this leads to an increased risk of fire and explosion, and consequently to extreme safety requirements.
En ytterligere ulempe ved denne prosess er at den generelt sterkt aggressive konsentrerte svovelsyre anvendes for dehydrering, og bireaksjoner finner derfor sted, som nedsetter utbyttet og forverrer kvaliteten på sluttproduktet. A further disadvantage of this process is that the generally highly aggressive concentrated sulfuric acid is used for dehydration, and side reactions therefore take place, which reduce the yield and worsen the quality of the final product.
Det er nå funnet at hvis man som utgangsmateriale anvender en forbindelse som allerede har estergruppen svarende til den•ønskede apovincaminsyreester av generell formel I, kan nærvær av alkohol elimineres, og følgelig finnert ingen etherdannelse sted. For dette formål kan forbindel-1 2 It has now been found that if one uses as starting material a compound which already has the ester group corresponding to the desired apovincamic acid ester of general formula I, the presence of alcohol can be eliminated, and consequently no ether formation takes place. For this purpose, connection-1 2
ser av generell formel II, hvori R og R har de ovenfor angitte betydninger, med hell anvendes. species of general formula II, in which R and R have the meanings given above, are successfully used.
Utgangsforbindelser av generell formel II fremstilles etter en fremgangsmåte beskrevet i ungarsk patent-søknad RI-713 fra de tilsvarende hexahydroindolo-kinoli-ziniumforbindelser med methylenmalonsyrediestere. Ved fremgangsmåten ifølge oppfinnelsen kan forbindelsene av generell formel II anvendes som sådanne, eller i form av deres syreaddisjonssalter med uorganiske eller organiske syrer, fortrinnsvis som deres hydroklorid. Starting compounds of general formula II are prepared according to a method described in Hungarian patent application RI-713 from the corresponding hexahydroindolo-quinolizinium compounds with methylenemalonic acid diesters. In the method according to the invention, the compounds of general formula II can be used as such, or in the form of their acid addition salts with inorganic or organic acids, preferably as their hydrochloride.
Det er ennvidere funnet at hvis konsentrert svovelsyre erstattes med de mindre korrosivé organiske.sulfonsyrer, f .eks. alifatiske eller aromatiske sulfonsyrer, kan faren for korrosjon på det anvendte anlegg ytterligere reduseres. It has further been found that if concentrated sulfuric acid is replaced by the less corrosive organic sulphonic acids, e.g. aliphatic or aromatic sulphonic acids, the risk of corrosion on the plant used can be further reduced.
Anvendelse av organiske sulfonsyrer i stedet for konsentrert svovelsyre nedsetter også bireaksjonene grunnet korrosjon, og således bedres ikke bare utbyttet men også kvaliteten av sluttproduktet. Den kvalitative forbedring er av særlig betydning, da forbindelsene av generell formel I fremstilt ved foreliggende fremgangsmåte, er beregnet for farmasøytisk.bruk. The use of organic sulphonic acids instead of concentrated sulfuric acid also reduces the side reactions due to corrosion, and thus improves not only the yield but also the quality of the final product. The qualitative improvement is of particular importance, as the compounds of general formula I produced by the present method are intended for pharmaceutical use.
Som alifatiske sulfonsyrer kan anvendes sulfonsyre inneholdende en alifatisk carbonkjede med 1 til 12 carbonatomer, f.eks. methansulfonsyre, ethansulfonsyre, dodecylsulfonsyre, etc. Aromatiske sulfonsyrer innbefatter fulonsyrer inneholdende én eller flere aromatiske ringer som kan være substituert med én eller flere identiske eller forskjellige substituenter, f.eks. benzensulfonsyre, p-toluensulf onsyre , a-naf thylsulf onsyre , (3-naf thylsulf onsyre etc. For 1 mol av en forbindelse av generell formel II anvendes fortrinnsvis 2 til 3 mol sulfonsyre. As aliphatic sulphonic acids, sulphonic acid containing an aliphatic carbon chain with 1 to 12 carbon atoms can be used, e.g. methanesulfonic acid, ethanesulfonic acid, dodecylsulfonic acid, etc. Aromatic sulfonic acids include fulonic acids containing one or more aromatic rings which may be substituted with one or more identical or different substituents, e.g. benzenesulfonic acid, p-toluenesulfonic acid, α-naphthylsulfonic acid, (3-naphthylsulfonic acid etc. For 1 mol of a compound of general formula II, preferably 2 to 3 mol of sulfonic acid is used.
Som løsningsmiddel anvendes aprotiske organiske løsningsmidler slik som eventuelt halogenerte aromatiske hydrocarboner, f.eks. benzen, toluen, xylen, klorbenzen, eller cykliske ethere, f.eks. dioxan. As a solvent, aprotic organic solvents are used such as optionally halogenated aromatic hydrocarbons, e.g. benzene, toluene, xylene, chlorobenzene, or cyclic ethers, e.g. dioxane.
Reaksjonen utføres ved en temperatur' på fra 80 til 150° C, fortrinnsvis 100 til 120° C. Reaksjonstiden er en funksjon av temperaturen. The reaction is carried out at a temperature of from 80 to 150° C, preferably 100 to 120° C. The reaction time is a function of the temperature.
Reaksjonen utføres fortrinnvis under vannfri betingelser . The reaction is preferably carried out under anhydrous conditions.
Ved den nye fremgangsmåte ifølge oppfinnelsen kan racemiske og optisk aktive forbindelser av generell formel I fremstilles ut fra racemisk og optisk aktive forbindelser av generell formel II. By the new process according to the invention, racemic and optically active compounds of general formula I can be prepared from racemic and optically active compounds of general formula II.
En hovedfordel ved foreliggende fremgangsmåte i forhold til de kjente metoder består i det faktum at apovincaminsyreestrene av generell formel I ved denne fremgangsmåte kan fremstilles ut fra lett tilgjengelige forbindelser, med lite korrosive reaktanter som er lett å håndtere, og i et forbedret utbytte og i høy renhet. Fremgangsmåten er lett å utføre i industriell målestokk og medfører ikke sik-kerhetsproblemer . A main advantage of the present process compared to the known methods consists in the fact that the apovincamic acid esters of general formula I can be prepared by this process from readily available compounds, with little corrosive reactants that are easy to handle, and in an improved yield and in high purity. The procedure is easy to carry out on an industrial scale and does not cause safety problems.
Ifølge den mest foretrukne utførelsesform av fremgangsmåten kokes en forbindelse av generell formel II eller et syreaddisjonssalt, fortrinnsvis hydroklorid derav, med tørr p-toluensulfonsyre i toluen i 1 til 2 timer. According to the most preferred embodiment of the method, a compound of general formula II or an acid addition salt, preferably its hydrochloride, is boiled with dry p-toluenesulfonic acid in toluene for 1 to 2 hours.
De etterfølgende eksempler illustrerer oppfinnelsen . The following examples illustrate the invention.
Eksempel 1Example 1
70 g' (0,1 mol) (-)-la-(carbomethoxyethyl)-la-ethyl-1,2,3,4,6,7,12,12b-octahydro-indol[2,3a]kinolizin-D-dibenzoyltartarat ble suspendert i 300 ml toluen. Til sus-pensjonen ble tilsatt 70 ml konsentrert vandig ammonium-hydroxydløsning og reaksjonsblandingen ble omrørt ved romtemperatur i 10 minutter. Toluenfasen ble fraskilt fra den vandige fase, og ble tørket ved azeotrop destillasjon, hvorpå volumet av blandingen ble øket til 300 ml toluen. Til toluenløsningen ble tilsatt 36 ml (31 g) tert.-butylnitritt og 25 g natrium-tert.-butylat, og blandingen ble omrørt i nitrogenatmosfære ved 30° C i 25 minutter. Til reaksjonsblandingen ble tilsatt 300 ml ethanol og blandingen ble omrørt ved 60° C i 1 time. pil ble justert til 2 med 36 %-ig vandig saltsyreløsning ved romtemperatur, blandingen ble avkjølt til 0° C og det utfelte materiale ble.filtrert fra ved denne temperatur og vasket med to 100 ml<1>s porsjoner vann. Det erholdte produkt ble lufttørket og ble deretter behandlet med 150 ml av en 10 %-ig vandig ammoniumhydroxyd-løsning. Produktet ble filtrert fra, vasket med tre 50 ml's porsjoner av vann og tørket. 20 g (-)-14-ethoxycarbonyl-14-hydroxyamino-3cc, 16a-eburnan ble erholdt med smeltepunkt 172 - 173° C. Utbytte: 52 %. 70 g' (0.1 mol) (-)-1α-(carbomethoxyethyl)-1α-ethyl-1,2,3,4,6,7,12,12b-octahydro-indole[2,3a]quinolizine-D -dibenzoyl tartarate was suspended in 300 ml of toluene. To the suspension was added 70 ml of concentrated aqueous ammonium hydroxide solution and the reaction mixture was stirred at room temperature for 10 minutes. The toluene phase was separated from the aqueous phase, and was dried by azeotropic distillation, after which the volume of the mixture was increased to 300 ml of toluene. To the toluene solution were added 36 ml (31 g) of tert-butyl nitrite and 25 g of sodium tert-butylate, and the mixture was stirred in a nitrogen atmosphere at 30° C. for 25 minutes. 300 ml of ethanol was added to the reaction mixture and the mixture was stirred at 60° C. for 1 hour. pil was adjusted to 2 with 36% aqueous hydrochloric acid solution at room temperature, the mixture was cooled to 0° C. and the precipitated material was filtered off at this temperature and washed with two 100 ml<1>s portions of water. The product obtained was air-dried and then treated with 150 ml of a 10% aqueous ammonium hydroxide solution. The product was filtered off, washed with three 50 ml portions of water and dried. 20 g of (-)-14-ethoxycarbonyl-14-hydroxyamino-3cc, 16a-eburnane was obtained with melting point 172 - 173° C. Yield: 52%.
[ a]* ° = -144,1° (c = 1, kloroform).[α]*° = -144.1° (c = 1, chloroform).
Eksempel 2Example 2
19 g (0,05 mol) (-)-14-ethoxycarbonyl-14-hydroxy-amino-3a,16a-eburnan fremstilt i eksempel 1 og 19,8 g 19 g (0.05 mol) (-)-14-ethoxycarbonyl-14-hydroxy-amino-3α,16α-eburnane prepared in Example 1 and 19.8 g
(0,125 mol) tørr p-toluensulfonsyre ble kokt i 350 ml tørr toluen i 1,5 timer. Reaksjonsblandingen ble avkjølt til 20° C, hvorpå 200 ml vann ble tilsatt og pH på blandingen ble justert til 9 med ca. 20 ml konsentrert ammoniumhhdroxyd-løsning. Den organiske fase ble fraskilt og den vandige fase ble ekstrahert med 50 ml toluen. Toluenfasen ble kombinert, tørket over vannfri natriumsulfat, filtrert og filtratet ble avfarvet med 1 g aktivert carbon og filtrert. Filtratet ble fordampet til tørrhet i vakuum, fordampnings-residuet ble løst i 20 ml ethanol, ble kokt i 1 minutt og krystalliser5 etter avkjøling til 0° C. 16,6 g (+)-apovincaminsyreethylester ble erholdt med smeltepunkt 144 - 146° C. Utbytte: 95 %. (0.125 mol) of dry p-toluenesulfonic acid was boiled in 350 ml of dry toluene for 1.5 hours. The reaction mixture was cooled to 20° C, after which 200 ml of water was added and the pH of the mixture was adjusted to 9 with approx. 20 ml of concentrated ammonium hydroxide solution. The organic phase was separated and the aqueous phase was extracted with 50 ml of toluene. The toluene phase was combined, dried over anhydrous sodium sulfate, filtered and the filtrate was decolorized with 1 g of activated carbon and filtered. The filtrate was evaporated to dryness in vacuo, the evaporation residue was dissolved in 20 ml of ethanol, was boiled for 1 minute and crystallized after cooling to 0° C. 16.6 g (+)-apovincinamic acid ethyl ester was obtained with melting point 144 - 146° C .Yield: 95%.
[ct]p° = +(144 , 1 - 145,1)° (c = 1, kloroform).[ct]p° = +(144 , 1 - 145.1)° (c = 1, chloroform).
Renhet: 99,8 - 100,1 % (i iseddik, i nærvær av indikator, under anvendelse av perklorsyre for titrering). Purity: 99.8 - 100.1% (in glacial acetic acid, in the presence of indicator, using perchloric acid for titration).
Eksempel 3Example 3
Fra en løsning av 47,5 g (0,25 mol) p-toluensulfonsyrehydrat i 400 ml toluen ble vann eliminert ved azeotrop destillasjon. Deretter ble 42 g (0,1 mol) (-)-14-ethoxycarbonyl-14-hydroxyamino-3a,16a-eburnan-hydroklorid tilsatt til den tørre blanding, som deretter ble kokt under tilbakeløpskjøling i 2 timer under omrøring. Reaksjonsblandingen ble avkjølt til +10° C, 100 ml vann, 30 ml From a solution of 47.5 g (0.25 mol) of p-toluenesulfonic acid hydrate in 400 ml of toluene, water was eliminated by azeotropic distillation. Then 42 g (0.1 mol) (-)-14-ethoxycarbonyl-14-hydroxyamino-3α,16α-eburnane hydrochloride was added to the dry mixture, which was then refluxed for 2 hours with stirring. The reaction mixture was cooled to +10° C., 100 ml water, 30 ml
25 %-ig ammoniumhydroxydløsning og 2 g celite ble tilsatt,A 25% ammonium hydroxide solution and 2 g of celite were added,
og reaksjonsblandingen ble omrørt ved +10° C i 5 minutter, hvorpå den ble filtrert. Den vandige fase og toluenfasen i filtratet ble separert, den vandige fase ble ekstrahert med 50 ml toluen og toluenfasen ble kombinert. De' kombinerte toluenfaser ble vasket med 50 ml vann, tørket på 20 g vann-, fritt natriumsulfat og filtrert. Filtratet ble fordampet til tørrhet i vakuum, og til fordampningsresten ble tilsatt 40 ml ethanol, løsningen ble kokt i 1 minutt og ble deretter avkjølt til 0° C. Blandingen fikk stå ved 0° C i 1 time, and the reaction mixture was stirred at +10°C for 5 minutes, after which it was filtered. The aqueous phase and the toluene phase in the filtrate were separated, the aqueous phase was extracted with 50 ml of toluene and the toluene phase was combined. The combined toluene phases were washed with 50 ml of water, dried over 20 g of water, free sodium sulfate and filtered. The filtrate was evaporated to dryness in vacuo, and to the evaporation residue 40 ml of ethanol was added, the solution was boiled for 1 minute and then cooled to 0° C. The mixture was allowed to stand at 0° C for 1 hour,
det utfelte produkt ble filtrert fra, vasket med to 20 ml's porsjoner ethanol ved 0° C og ble tørket. 30 g (86 %) (+)-apovincaminsyreethylester ble erholdt med sm.p. 114 - 146° C. the precipitated product was filtered off, washed with two 20 ml portions of ethanol at 0° C. and dried. 30 g (86%) of (+)-apovincinamic acid ethyl ester was obtained with m.p. 114 - 146° C.
[a]^° = +(141 til 146)° (c = 1, klorforom)[a]^° = +(141 to 146)° (c = 1, chloroform)
Analyse for C22H25N2°2 (molekYlvekt: 350 44)=Analysis for C22H25N2°2 (molecular weight: 350 44)=
Beregnet: C 75,33 % H 7,45 % N 7,99 %Calculated: C 75.33% H 7.45% N 7.99%
Funnet : C 75,31 % H 7,42 % N 7,90 % Found : C 75.31% H 7.42% N 7.90%
Eksempel 4Example 4
Ved å følge den prosedyre som er beskrevet i eksempel 3, men å starte fra 38 g (0,1 mol) (-)-14-ethoxy-carbonyl-14-hydroxyamino-3a,16a-eburnan, ble 31,5 g (90 %) By following the procedure described in Example 3, but starting from 38 g (0.1 mol) (-)-14-ethoxy-carbonyl-14-hydroxyamino-3a,16a-eburnane, 31.5 g ( 90%)
(+)-apovincaminsyreethylester erholdt, med sm.p. 144 - 146° C. (+)-apovincinamic acid ethyl ester obtained, with m.p. 144 - 146° C.
[a]^° = +(141 til 146)° (c - 1, kloroform). [a]^° = +(141 to 146)° (c - 1, chloroform).
Eksempel 5Example 5
Ved å følge den prosedyre som er beskrevet i eksempel 3, men anvende 400 ml benzen i stedet for 400 ml toluen som løsningsmiddel og utføre reaksjonen i løpet av 12 timer, ble 23,4 g (67,0 %) (+)-apovincaminsyreethylester erholdt, med sm.p. 141 - 145° C. By following the procedure described in Example 3, but using 400 ml of benzene instead of 400 ml of toluene as the solvent and carrying out the reaction within 12 hours, 23.4 g (67.0%) of (+)-apovincaminic acid ethyl ester was obtained, with sm.p. 141 - 145° C.
[aPu - +(141 til 144)° (c = 1, kloroform).[aPu - +(141 to 144)° (c = 1, chloroform).
D D
Eksempel 6Example 6
Ved å følge den prosedyre som er beskrevet i eksempel 4, men anvende 400 ml xylen i stedet for 400 ml toluen som løsningsmiddel og utføre reaksjonen i løpet av 30 minutter ved en temperatur på 140° C, ble 30,5 g (87,3 %) By following the procedure described in Example 4, but using 400 ml of xylene instead of 400 ml of toluene as solvent and carrying out the reaction during 30 minutes at a temperature of 140° C, 30.5 g (87.3 %)
(+)-apovincaminsyreethylester erholdt, med smeltepunkt 144 - 146° C. (+)-apovincamic acid ethyl ester obtained, with melting point 144 - 146° C.
[a]^° = +(141 til 146)° (c = 1, kloroform).[a]^° = +(141 to 146)° (c = 1, chloroform).
Eksempel 7Example 7
Ved å følge den prosedyre som er beskrevet i eksempel 3, men anvende 400 ml klorbenzen i stedet for 400 ml toluen som løsningsmiddel, og utføre reaksjonen ved . 130° C i løpet av 40 minutter, ble 30,8 g (88 %) (+)-apovincaminsyreethylester erholdt. By following the procedure described in example 3, but using 400 ml of chlorobenzene instead of 400 ml of toluene as solvent, and carrying out the reaction at . 130° C. during 40 minutes, 30.8 g (88%) of (+)-apovincamic acid ethyl ester was obtained.
Eksempel 8Example 8
Ved. å følge den prosedyre som er beskrevet i eksempel 3, men anvende 43 g (0,25 mol) tørr p-toluensulfonsyre i stedet for 47,5 g (0,25 mol) p-toluensulfonsyrehydrat og 400 ml dioxan i stedet for 400 ml toluen, ble 18,0 g (51,5 %) (+)-apovincaminsyreethylester erholdt, med smeltepunkt 141 - 143° C. By. to follow the procedure described in Example 3, but use 43 g (0.25 mol) of dry p-toluenesulfonic acid instead of 47.5 g (0.25 mol) of p-toluenesulfonic acid hydrate and 400 ml of dioxane instead of 400 ml toluene, 18.0 g (51.5 %) of (+)-apovincamic acid ethyl ester was obtained, with a melting point of 141 - 143° C.
[a]^° = +(140 til 143)° (c - 1, kloroform).[a]^° = +(140 to 143)° (c - 1, chloroform).
Eksempel 9Example 9
Ved å følge den prosedyre som er beskrevet i eksempel 3, men erstatte 47,5 g (0,25 mol) p-toluensulfqn-syrehydrat med 27,5 g (0,25 mol) ethansulfonsyre, ble 30,0 g (86 %) (+)-apovincaminsyreethylester erholdt, med smeltepunkt 144 - 146° C. By following the procedure described in Example 3, but replacing 47.5 g (0.25 mol) of p-toluenesulfonic acid hydrate with 27.5 g (0.25 mol) of ethanesulfonic acid, 30.0 g (86% ) (+)-apovincamic acid ethyl ester obtained, with melting point 144 - 146° C.
[a]^° = +(141 - 146)° (c = 1, kloroform).[a]^° = +(141 - 146)° (c = 1, chloroform).
Eksempel 10Example 10
Ved å følge den prosedyre som er beskrevet i eksempel 3, men erstatte 48 g (0,25 mol) p-toluensulfonsyrehydrat med 39,5 g (0,25 mol) benzensulfonsyre, ble 30,5 g (87,5 %) (+)-apovincaminsyreethylester erholdt, med smeltepunkt 141 - 146° C. By following the procedure described in Example 3, but replacing 48 g (0.25 mol) of p-toluenesulfonic acid hydrate with 39.5 g (0.25 mol) of benzenesulfonic acid, 30.5 g (87.5%) ( +)-apovincamic acid ethyl ester obtained, with melting point 141 - 146° C.
[ct]^° = +(141 - 146)° (c = 1, kloroform). [ct]^° = +(141 - 146)° (c = 1, chloroform).
Claims (9)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU802208A HU183207B (en) | 1980-09-10 | 1980-09-10 | Process for preparing apovincaminic acid esters |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO813067L true NO813067L (en) | 1982-03-11 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO813067A NO813067L (en) | 1980-09-10 | 1981-09-09 | PROCEDURE FOR THE PREPARATION OF APOVINCAMIN ACID ESTERS |
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| JP (1) | JPS5780384A (en) |
| AT (1) | AT382616B (en) |
| AU (1) | AU544436B2 (en) |
| BE (1) | BE890274A (en) |
| CA (1) | CA1162543A (en) |
| CH (1) | CH646167A5 (en) |
| DD (1) | DD201680A5 (en) |
| DE (1) | DE3135728C2 (en) |
| DK (1) | DK151020C (en) |
| ES (1) | ES505325A0 (en) |
| FI (1) | FI69628C (en) |
| FR (1) | FR2489824B1 (en) |
| GB (1) | GB2086886B (en) |
| GR (1) | GR75030B (en) |
| HU (1) | HU183207B (en) |
| IL (1) | IL63720A0 (en) |
| IT (1) | IT1146707B (en) |
| NL (1) | NL8104044A (en) |
| NO (1) | NO813067L (en) |
| NZ (1) | NZ198318A (en) |
| PT (1) | PT73644B (en) |
| SE (1) | SE443141B (en) |
| SU (1) | SU1114336A3 (en) |
| YU (1) | YU41987B (en) |
| ZA (1) | ZA816100B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2052449B1 (en) * | 1992-12-22 | 1995-02-16 | Covex Sa | NEW PROCEDURE FOR THE PREPARATION OF THE ETHYL APOVINCAMINATE. |
| EP1369344B1 (en) | 2001-03-15 | 2009-09-16 | Honda Access Corporation | Structure for mounting a saddle bag on a motorcycle |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| FR2389625B1 (en) * | 1977-05-06 | 1980-04-18 | Roussel Uclaf | |
| HU179292B (en) * | 1978-12-01 | 1982-09-28 | Richter Gedeon Vegyeszet | Process for preparing ester derivatives of apovincaminic acid |
| HU181495B (en) * | 1979-05-31 | 1983-07-28 | Richter Gedeon Vegyeszet | Process for producing hydroxy-imino-eburnane derivatives |
-
1980
- 1980-09-10 HU HU802208A patent/HU183207B/en not_active IP Right Cessation
-
1981
- 1981-08-31 AT AT0376081A patent/AT382616B/en not_active IP Right Cessation
- 1981-09-01 NL NL8104044A patent/NL8104044A/en not_active Application Discontinuation
- 1981-09-02 ZA ZA816100A patent/ZA816100B/en unknown
- 1981-09-02 IL IL63720A patent/IL63720A0/en not_active IP Right Cessation
- 1981-09-04 IT IT68172/81A patent/IT1146707B/en active
- 1981-09-07 DD DD81233097A patent/DD201680A5/en not_active IP Right Cessation
- 1981-09-08 SE SE8105338A patent/SE443141B/en not_active IP Right Cessation
- 1981-09-08 BE BE0/205907A patent/BE890274A/en not_active IP Right Cessation
- 1981-09-08 GR GR65987A patent/GR75030B/el unknown
- 1981-09-08 FI FI812785A patent/FI69628C/en not_active IP Right Cessation
- 1981-09-08 CH CH579581A patent/CH646167A5/en not_active IP Right Cessation
- 1981-09-08 DK DK396881A patent/DK151020C/en not_active IP Right Cessation
- 1981-09-09 JP JP56141112A patent/JPS5780384A/en active Granted
- 1981-09-09 NO NO813067A patent/NO813067L/en unknown
- 1981-09-09 NZ NZ198318A patent/NZ198318A/en unknown
- 1981-09-09 PT PT73644A patent/PT73644B/en not_active IP Right Cessation
- 1981-09-09 CA CA000385471A patent/CA1162543A/en not_active Expired
- 1981-09-09 FR FR8117112A patent/FR2489824B1/en not_active Expired
- 1981-09-09 GB GB8127201A patent/GB2086886B/en not_active Expired
- 1981-09-09 SU SU813333370A patent/SU1114336A3/en active
- 1981-09-09 ES ES505325A patent/ES505325A0/en active Granted
- 1981-09-09 AU AU75092/81A patent/AU544436B2/en not_active Ceased
- 1981-09-09 DE DE3135728A patent/DE3135728C2/en not_active Expired - Fee Related
- 1981-09-10 YU YU2181/81A patent/YU41987B/en unknown
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