WO2013065066A1 - Procédés de préparation de 4-oxo-4-[3-(trifluorométhyl)-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8h)-yl]-1-(2,4,5-trifluorophényl)- butan-2-amine - Google Patents

Procédés de préparation de 4-oxo-4-[3-(trifluorométhyl)-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8h)-yl]-1-(2,4,5-trifluorophényl)- butan-2-amine Download PDF

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WO2013065066A1
WO2013065066A1 PCT/IN2012/000299 IN2012000299W WO2013065066A1 WO 2013065066 A1 WO2013065066 A1 WO 2013065066A1 IN 2012000299 W IN2012000299 W IN 2012000299W WO 2013065066 A1 WO2013065066 A1 WO 2013065066A1
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formula
compound
ammonium
group
butan
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PCT/IN2012/000299
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English (en)
Inventor
Bipin Pandey
Mayank Ghanshyambhai Dave
Himanshu M. Kothari
Bhavin Shriprasad Shukla
Sanjeev Kumar Mendiratta
Rupal Joshi
Umang Trivedi
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Cadila Healthcare Limited
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Publication of WO2013065066A1 publication Critical patent/WO2013065066A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to synthesis of 4-oxo-4-[3-(trifluoromethyl)-5,6- dihydro [ l ,2,4]-triazolo![4,3-a]pyrazin-7(8H)-yl]-l -(2,4,5-trifluorophenyl)butan-2- amine of Formula (I) or its salts either in its racemic (R/S) form or any of its optically active (S) or (R) forms or enantiorheric excess mixture of any of the forms by novel processes.
  • the invention further relates to certain novel intermediates useful in the preparation of compound of Formula (1) and processes for their preparation.
  • the invention also relates to pharmaceutical compositions that include the compound of Formula (1), prepared according to the processes disclosed herein.
  • the compound of Formula (I) either in its racemic (R/S) form or any of its optically active (S) or (R) forms or enantiomeric excess mixture of any of the forms is an industrially useful compound having the chemical name 4-oxo-4-[3- (trifluoromethyl)-5,6-dihydro [l ,2,4]*triazolo[4,3-a]pyrazin-7(8H)-yl]-l -(2,4,5- trifluoiOphenyi butan-2-amine and the following structure.
  • beta-amino tetrahydrotriazolo[4,3-a]pyrazines including (2R)-4-oxo-4-[3-(trifluoromethyl)-5, 6-dihydro [ l ,2,4]-triazolo[4,3- a]pyrazin-7(8H)-yl]-l -(2,4,5-trifluorophenyl)butan-2-amine (sitagliptin), are disclosed in U.S. patent No. 6,699,871 , which are inhibitors of DPP-IV. Disclosed therein are compounds, whose general formula is,
  • (2R)-4-oxo-4-[3-(trifluoromethyl)-5, 6-dihydro [1 ,2,4]-triazolo[4,3-a]pyrazin-7(8H)- yl]-l -(2,4,5-trifiuorophenyl)butan-2 -amine can be synthesized by method disclosed in the above specification, depicted by following scheme
  • WO 2004085661 describes another process for preparation of chiral beta amino acid derivatives including compound of Formula (I) in its (R) form.
  • S-phenylglycine amide (S-PGA) as a chiral auxiliary is used to get pure Z-enamines from diketone.
  • a metal catalyst like Pt0 2 is used, which is expensive and high pressure is required.
  • > 90% e.e is reported for the reduced amine.
  • PCT Publication No. WO 2004085378 and WO 2006081 151 describe a process of preparation of chiral beta amino acid derivatives which includes compound of Formula (I) in its (R) form.
  • the product is prepared by an enantioselective reduction via transition metal catalyzed asymmetric hydrogenation at high pressure, of a prochiral enamine.
  • hydrogenation of enamine is carried out to get final product using special catalysts such as R,S t-butyl Josiphos, as given below (IV) , and another special catalyst is used in PCT Publication No. WO 2006081 151 as given below (V), *
  • PCT Publication No. WO 2005097733 describes a process of preparation of compound of Formula (I) in its (R) form by asymmetric hydrogenation using Rhodium metal precursor complexes with chiral mono or bisphosphine ligand.
  • Such mono and bis phosphine ligand disclosed are de icted below:
  • PCT Publication o WO2009084024 discloses process for the preparation of compound of Formula (I) and its pharmaceutically acceptable salts by resolving the amine with a suitable resolving agent. Additionally, the same document also describes resolution of a racemic (50:50 mixture of R & S) amine with a chirally pure resolving agent which gives dibenzolyl-L-tartaric acid diastereomer of Formula (I) having ratio of (R) and (S) isomers 50: 50 (racemic mixture). Of course, by subsequent solvent treatments the desired diastereomer is obtained by repeated recrystallization to get a chiral purity 85-90 %. (Example- 5a, 5b and 5c)
  • PCT Publication No. WO2009085990 discloses process for the preparation of compound of Formula (1) and its pharmaceutically acceptable salts, wherein the resolution was carried out with of di-p-tolyl-L-tartaric acid.
  • Process as disclosed in WO2009085990 involves the use of sodium cyanoborohydride with methanolic HCI (Example 4) during reduction step which may lead to generation of HCN gas.
  • HCI methanolic HCI
  • PCT Publication No. WO2010032264 discloses the compound 3-hydroxy-l -(3- (trifluoromethyl)-5,6-dihydro-[ l ,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5- trifluorophenyl) butan- 1 -one (IV).
  • WO2010032264 only provides the racemic form of 3-hydroxy- l - (3-(trifluoromethyl)-5,6-dihydro-[ 1 ,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5- trifluorophenyl) butan- 1 -one (Formula IV).
  • 2805/MU /2010 provides two enantiomers of 3-hydroxy- l -(3- (trifluoromethyl)-5.6-dihydro-[ 1 ,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5- trifluorophenyl) butan- 1 -one of opposite chirality of the following Formula,
  • WO2010122578 disclosed process for the preparation of formula (I) in optically active (R) form.
  • the process involves the steps wherein all the intermediates are obtained in (R) configuration from (R)-isomer of starting material with retention throughout all the steps.
  • Such a reaction proposition is difficult to follow.
  • Reagents for Organic Synthesis Vol.5, p-728-729, John Wiley & sons by-Fieser & Fieser.
  • WO201 1049344 and WO201 102640 discloses processes for the preparation of compound of formula (I) by using chemical method.
  • EP2397141 discloses process for the preparation of 3-hydroxy- l -(3- (trif1uoromethyl)-5,6-dihydro-[ l ,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5- trifluorophenyl) butan- 1 -one of formula (IV) and also compound of formula (I) comprising, (i) the (S)-epihalohydrin reacts with l -metalo-2,4,5-trifluorobenzene to form halohydrin (ii) a conversion of halohydrin into cyanohydrin by reaction with cyanide anion (iii) hydrolysis of cyanohydrin leading to carboxylic derivatives (iv) which on amidation process with amines provides compound of formula (IV), which is further converted to formula (I).
  • the enzymatic reduction processes in which the enzyme acts as a reduction catalyst are environmentally advantageous compared to the process as described in the EP2397141 .
  • the use of the enzymes is also typically lower in cost than the process as in EP2397141.
  • Enzymes can have a unique stereo selective property of producing only one enantiomer of compound of formula (IV) with good chiral purity and therefore no need to do chiral chromatography.
  • the use of compound of formula (IV) prepared by enzymatic route, as a starting material for the preparation of formula (I) is also advantagous because the purity of starting material plays an important role in the preparation of formula (I), in high yield and better purity.
  • the present process overcomes the problem of the prior art.
  • a process for the preparation of compound Formula (I) either in its racemic (R/S) form or any of its optically active (S) or (R) forms or enantiomeric excess mixture of any of the forms includes: a) reacting 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l ,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl]-l - (2,4,5-trifluorophenyl)butan-2-one of formula (V) or its metal ion salt
  • the compound of Formula (IV) is directly converted to the compound of Formula (II) with inversion of configuration, by using suitable amine equivalent ⁇ optionally with suitable additives in suitable solvents.
  • the product so obtained may be further or additionally purified by suitable salt formation, diastereomeric salt formation or by purification using suitable solvents or other techniques known to obtain desired purity levels.
  • the process may include further formulating the product so obtained into a finished dosage form.
  • the term "reflux temperature” refers to the boiling point of the solvent.
  • the term “compound of Formula (I)” refers to 4- ⁇ oxo-4-[3- (trifluoromethy l)-5,6-dihydro[ 1 ,2,4]-triazolo[4,3-a]pyrazin-7(8H)-yI]- 1 -(2,4,5- trifluorophenyl)butan-2-amine in racemic (R/S) form or any of its optically active (S) or (R) forms or their enantiomerically excess mixture.
  • the term “THF” refers to tetrahydrofuran
  • the term “DCM” refers to dichloro methane
  • the term “DMF” refers to dimethyl formamide
  • the term “DIPE” refers to di-isopropyl ether
  • the term “MTBE” refers to methyl t-butyl ether
  • the term “DMSO” refers to dimethyl sulfoxide
  • the term “DMA” refers to dimethylacetamide
  • I PA refers to isopropyl alcohol
  • the term TEA refers to Triethylamine
  • the term LDA refers to Lithium diisopropylamide
  • the term HMDS refers to Potasssium hexamethyldisilazane
  • the term DABCO refers to 1 ,4- diazabicyclo[2,2,2]octane
  • the term HM PA refers to Hexamethylphosphoramide
  • the term D1AD
  • the term Lindlar catalyst refers to 5.0 % Palladium on calcium carbonate (poisoned with lead),
  • DMAP refers to Dimethylamino pyridine
  • Co- factors include, for example, nicotinamide co-factors such as nicotinamide adenine dinucleotide ("NAD"), reduced nicotinamide adenine dinucleotide ("NADH”), nicotinamide adenine dinucleotide phosphate (“NADP+”), reduced nicotinamide adenine dinucleotide phosphate (“NADPH”).
  • NAD nicotinamide co-factors
  • NAD nicotinamide adenine dinucleotide
  • NADH reduced nicotinamide adenine dinucleotide
  • NADP+ nicotinamide adenine dinucleotide phosphate
  • NADPH reduced nicotinamide aden
  • the inventors have developed a process for the preparation of compound of Formula (I) either in its racemic (R/S) form or any of its optically active (S) or (R) forms or enantiomeric excess mixture of any of the forms.
  • the process includes:
  • the compound of Formula (IV) is directly converted to the compound of Formula (II) with inversion of configuration, by using suitable amine equivalent, optionally with suitable additives in suitable solvents.
  • the compound of Formula (III) may be directly converted to the compound of Formula (I) with inversion of configuration, by using suitable amine equivalent.
  • the process is further exemplified below:
  • reaction of compound of Formula (V) or its suitable metal ion salts with suitable enzyme to give compound of Formula (IV) in racemic (R/S) form or any of its optically active (S) or (R) forms or their enantiomerically excess mixtures can be carried out using suitable polypeptides.
  • the metal ion salt of compound of formula (V) is selected from Na, , Li, Mg, Ca, Zn, Cu and like.
  • polypeptide having desired enzymatic activity and variants thereof can be isolated from suitable bacteria, yeast or fungi.
  • suitable polypeptides having enzymatic activities are selected from oxidoreductases.
  • suitable enzymes are selected from aldo-keto reductases.
  • suitable enzymes are
  • NAD(P) + dependent reductase is selected from the Saccharomyces species.
  • NAD(P) + dependent reductase is selected (derived) from Saccharomyces cerevisiae and having Genebank id:- NP 012630.1.
  • NAD(P) + dependent alcohol dehydrogenase is selected (derived) from Saccharomyces' cerevisiae and having Genebank id:- NP_013953.1 , NP_014763.1 , NP_01 1972.1 , NP_014068 and NP 01 1330..
  • reaction of compound of Formula (IV) with suitable reagent to give 1 compound of Formula (III) having a suitable leaving group 'R' as defined earlier, with retention of configuration may be carried out using a suitable reagents, suitable base and suitable solvents.
  • Suitable reagents which can be used in step (b) may include one or more of suitable acid chlorides such as acetyl chloride, benzoyl chlorides and substituted benzoyl chloride such as p-nitrobenzoyl chloride and the like; anhydrides such as acetic anhydride, trifluoroacetic anhydride, triflic anhydride and the like; sulfonyl chlorides such as , 2,2,2-trifluoroethanesulfonyI chloride, benzenesulfonyl chloride, substituted benzenesulfonyl chlorides such as p-toluenesulfonyl chloride, p-nitro benzenesulfonyl chlorides and the like; acid chloro phosphates such as diethyl chloro phosphate and the like.
  • suitable acid chlorides such as acetyl chloride, benzoyl chlorides and substituted benzoyl chloride such as p-
  • the compound of Formula (III), wherein when 'R' represents a caboxylate leaving group such as -OCOCH3, -OCOCF 3 , -OC(0)OEt, - OCOPh, substituted -OCOPh etc. was prepared with retention of configuration from the compound of formula (I V) by reacting with suitable acid chlorides such as acetyl chloride, benzoyl chlorides and substituted benzoyl chloride such as p-nitrobenzoyl chloride and the like; anhydrides such as acetic anhydride, trifluoroacetic anhydride, triflic anhydride and the like in suitable solvents in the presence of a base.
  • suitable acid chlorides such as acetyl chloride, benzoyl chlorides and substituted benzoyl chloride such as p-nitrobenzoyl chloride and the like
  • anhydrides such as acetic anhydride, trifluoroacetic anhydride, triflic anhydride and the like in suitable solvents in the presence
  • the compound of Formula (I II), wherein * R' represents suitable sulfonate leaving group such as -OSO2CF3, -OSO2CH2CF3, -OS0 2 Ph, substituted -OS0 2 Ph, etc. was prepared with retention of configuration from the compound of formula (IV) by reacting with suitable sulfonyl chlorides such as methanesulfonyl chloride, 2,2,2-trifluoroethanesulfonyl chloride, benzenesulfonyl chloride and substituted benzenesulfonyl chlorides such as p-toluenesulfonyl chloride, p-nitro benzenesulfonyl chlorides and the like, in suitable solvents in presence of a base.
  • suitable sulfonyl chlorides such as methanesulfonyl chloride, 2,2,2-trifluoroethanesulfonyl chloride, benzenesulfonyl chloride
  • the compound of Formula (I II), wherein ; R' represents suitable phosphate leaving group such as -OP(0)(OEt) 2 was prepared with retention of configuration from the compound of formula (IV) by reacting with suitable chloro phosphates such as diethyl chloro phosphate in suitable solvents in the presence of a base with or without suitable additives.
  • Suitable solvents which can be used at step-(b), when 'R' represents a caboxylate, sulfonate and phosphate may include one or more of ethers such as diethyl ether, 1 ,4- dioxane, dimethoxy ethane, DIPE, MTBE, THF; chlorinated solvents such as chloroform, dichloromethane, dichloroethane; nitriles such acetonitrile; hydrocarbons such as hexane, heptane, cyclohexane, toluene, xylene, chlorobenzene; aprotic polar solvents such as DMF, DMA; N-methyl pyrrolidone, pyridine and the like or their suitable mixtures.
  • ethers such as diethyl ether, 1 ,4- dioxane, dimethoxy ethane, DIPE, MTBE, THF
  • chlorinated solvents such as
  • Suitable bases which can be , used at step-(b), when 'R' represents a caboxylate, sulfonate and phosphate may be selected from C(i -5) alkyl amines, i-sj substituted alkyl amines such as triethyl amine (TEA), diisopropyl amine, diisopropylethyl amine, heterocyclic saturated or unsaturated amines, preferably morpholine, piperidine, pyrollidine, DBU, DBN, l ,4-diazabicyclo[2,2,2]octane, dimethylamino pyridine and pyridine; hydrides such as NaH; n-BuLi, LDA and XHMDS and the like or mixtures thereof.
  • TAA triethyl amine
  • DBU diisopropyl amine
  • diisopropylethyl amine diisopropylethyl amine
  • the reaction mixture in step (b) is maintained at - 10 to 70 °C.
  • the temperature is at - 10 to 50 °C.
  • the reaction of step-(b) may be carried out in an inert atmosphere such as N 2 , He or Ar.
  • the duration of the reaction may be from 1 to 24 hrs, more specifically 2 to 8 hrs.
  • the compound of Formula (III) was prepared with retention of configuration, wherein 'R' represents the oxyphosphonium ion leaving group [e.g. -0 " P + Ph 3 ], which is generated in situ using phosphines with azodicarboxylates or azoamides, from the compound of Formula (IV) in suitable solvents (Mitsunobu reaction).
  • 'R' represents the oxyphosphonium ion leaving group [e.g. -0 " P + Ph 3 ]
  • phosphines with azodicarboxylates or azoamides from the compound of Formula (IV) in suitable solvents (Mitsunobu reaction).
  • An oxyphosphonium ion leaving group can be generated in situ by reacting suitable phosphines such as, trialkylphosphine such as tributylphosphine, tri-t- butylphosphine, trihexylphosphine, trioctylphosphine, cyanomethlenetri-n- butylphosphorane; cycloalkylphosphine such as tricyclohexylphosphine, i dicyclohexylphenylphosphine, or arylphosphine such as triphenylphosphine, dicyclohexy!phenylphosphine, diethylphenylphosphine, 4-
  • suitable phosphines such as, trialkylphosphine such as tributylphosphine, tri-t- butylphosphine, trihexylphosphine, trioctylphosphine, cyanomethlenetri-
  • azodicarboxylates such as diethylazodicarboxylate, diisopropyl azodicarboxylate, dimethyl azodicarboxylate, dibenzyl azodicarboxylate, bis(2,2,2-trichloroethyl)azodicarboxylate or with azoamides such as 1 , 1 '- (azodicarbonyl)dipiperidine, ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethylazodicarboxamide (Mitsunobu reaction) by techniques known in the art.
  • azodicarboxylates such as diethylazodicarboxylate, diisopropyl azodicarboxylate, dimethyl azodicarboxylate, dibenzyl azodicarboxylate, bis(2,2,2-trichloroethyl)azodicarboxylate or with azoamides such as 1 , 1 '- (azodicarbonyl)dipiperidine, ⁇ , ⁇ , ⁇ '
  • Suitable solvents which can be used in Mitsunobu reaction of step-(b) may include one or more of ethers such as diethyl ether, 1 ,4-dioxane, dimethoxy ethane, diethoxy ethane, DIPE, MTBE, THF, 2-methyl tetrahydrofuran or their suitable mixtures.
  • ethers such as diethyl ether, 1 ,4-dioxane, dimethoxy ethane, diethoxy ethane, DIPE, MTBE, THF, 2-methyl tetrahydrofuran or their suitable mixtures.
  • the reaction mixture in step (b) is maintained at -10 to 50 °C.
  • the temperature is at - 10 to 30 °C.
  • the reaction of step-(b) may be carried out in an inert atmosphere such as N 2 , He or Ar.
  • the duration of the reaction may be from 1 to 24 hrs, more specificall 2 to 8 hrs.
  • the compound of Formula (III), wherein 'R' represents a leaving group as defined earlier, can be isolated or it may be generated in situ.
  • Suitable amine equivalent which can be used in step-(d) may include -N 3 (azide), cyclic imides, araalkyamine, sulfonamide and the like.
  • is -N 3 can be obtained by reacting the compound of formula (III) with suitable azidating agents like, HN 3 , Na 3 , LiN 3 , Zn(N 3 ):, Cu(N 3 ) , Tetrabutylammonium azide etc. in suitable solvents.
  • suitable azidating agents like, HN 3 , Na 3 , LiN 3 , Zn(N 3 ):, Cu(N 3 ) , Tetrabutylammonium azide etc.
  • is -N 3 may include one or more of ethers such as 1 ,4-dioxane, dimethoxy ethane, THF; esters such as ethyl acetate, n-butyl acetate and isopropyl acetate; chlorinated solvents such as chloroform, dichloromethane, dichloroethane; hydrocarbons such as hexane, heptane, cyclohexane, toluene, xylene, chlorobenzene; aprotic polar solvents such as DMF, DMA, DMSO; N- methyl pyrrolidone, pyridine, HMPA and the like, water or their suitable mixtures.
  • ethers such as 1 ,4-dioxane, dimethoxy ethane, THF
  • esters such as ethyl acetate, n-buty
  • the compound of Formula (II) where Ri is suitable cyclic imide can be obtained by reacting the compound 1 of Formula (HI) with cyclic imides like phthalimide, succinimide etc. in suitable solvents.
  • the compound of Formula (II) where Ri is an aralkylamine can be obtained by reacting the compound of Formula (III) with araalkylamine like benzylamine, p-methoxybenzylamine, a-methylphenethylamine, tritylamine, etc. in suitable solvents.
  • the compound of Formula (II) where Ri is sulfonamide can be obtained by reacting the compound of Formula (I II) with suitable sulfonamides like p-toluene sulfonamide, sulfamic acid, N-(t-butoxycarbonyl)-p-toluenesulfonamide etc. in suitable solvents.
  • suitable sulfonamides like p-toluene sulfonamide, sulfamic acid, N-(t-butoxycarbonyl)-p-toluenesulfonamide etc. in suitable solvents.
  • is cyclic imide, aralkylamine, sulfonamide may be selected from ethers such as diethyl ether, 1 ,4-dioxane, dimethoxy ethane, THF; chlorinated solvents such as chloroform, dichloromethane, dichloroethane; nitriles such as acetonitrile; hydrocarbons such as hexane, heptane, cyclohexane, toluene, xylene, chlorobenzene; aprotic polar solvents such as DMF, DMA, DMSO; N-methyl pyrrolidone, HMPA, pyridine and the like, water or their suitable mixtures.
  • ethers such as diethyl ether, 1 ,4-dioxane, dimethoxy ethane, THF
  • chlorinated solvents such as chloroform, dichloromethane, dichlor
  • suitable additives may be added in step (d) to enhance the conversion.
  • Such additives may be selected from those known in the art, such as suitable phase transfer catalysts like, trialkyl ammonium halides, tetraalkyl ammonium halides, trialkyl ammonium acetates, tetraalkyl ammonium acetates, trialkyl ammonium hydroxides, tetraalkyl ammonium trialkyl ammonium sulfates, tetraalkyl ammonium sulfates, trialkyl ammonium tetrafluoroborate, tetraalkyl ammonium tetrafuloroborate, trialkyl phosphonium halides, tetraalkyl phosphonium halides, tetrapenyl phosphonium halides , pyridinium halides, Aliquat , Adogen, crown ethers, silicon analouges of crown ethers, PEG, TDA- 1
  • the reaction mixture in step (d) is maintained at - 10 to 100 °C.
  • the temperature is at - 10 to 30 °C,
  • the reaction of step-(d) may be carried out in an inert atmosphere such as N 2 , He or Ar.
  • the duration of the reaction may be from 1 to 48 hrs, more specifically 2 to 24 hrs.
  • the compound of formula (I) can be obtained from the compound of formula (II) either by reduction and/or deprotection or employing suitable chemistry as discussed herein under. i
  • the compoound of Formula (I) is prepared with retention of configuration by reduction of the compound of Formula (II) when Ri is -N 3 .
  • the reduction of compound of formula (II) when R ⁇ is -N 3 may be carried out using suitable reagents and suitable solvents.
  • the suitable reagent may be selected from precious metal catalyst like, Pd/H 2 , Pt/H 2 , Pd/Al 2 0 3 , Pd-CaC0 3 , Pd(QH) 2 , PdO, Pt0 2 , Pd-C/HCOOH, Pd-C/HCOONH 4 , Pd(OH) 2 -C/ 2 H 4 , Pd-C/NaBH 4 : Lindlar catalyst; Metal catalyst like, Mg, Ca, Zn, Zn- HCI, Zn-CH 3 COOH, SnCI 2 .
  • Suitable solvents which can be used at step-(e) may include one or more of alcohols such as methanol, ethanol, isopropanol, butanol, 1 ,2-dimethoxy ethanol, 2- methoxy ethanol, 2-ethoxy ethanol and ethylene glycol; ethers such as diethyl ether, 1 ,4-dioxane, dimethoxy ethane, DIPE, MTBE, THF and the like, water or their suitable mixtures.
  • alcohols such as methanol, ethanol, isopropanol, butanol, 1 ,2-dimethoxy ethanol, 2- methoxy ethanol, 2-ethoxy ethanol and ethylene glycol
  • ethers such as diethyl ether, 1 ,4-dioxane, dimethoxy ethane, DIPE, MTBE, THF and the like, water or their suitable mixtures.
  • the reaction mixture in step (e) is maintained at 0 to 80 °C.
  • the temperature is at 20 to 40 °C.
  • reaction of step-(e) ' " may be carried out in an inert atmosphere such as N 2 , He or Ar.
  • the duration of the reaction may be from 1 to 48 hrs, more specifically 5 to 24 hrs.
  • Deprotection of the protected compound of Formula (II.) when Ri is cyclic imido group, araalkyamino group, carbamate group, hydroxy I amino group, alkenyiamino group, sulfonamido group etc. as defined earlier, may be carried out by standard techniques reported in the literature provides the compound of formula (I).(See for e.g. Protection and Deprotection of amines in Text book -Title: Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, By-T. W. Grene and Peter G. M. Wuts).
  • Suitable amine equivalent used may be selected from cyclic imides, araalkyamine, etc.
  • is cyclic imides can be obtained by reacting the compound of formula (IV) with cyclic imides via oxyphosphonium ion formation which is generated in situ using suitable phosphines with azodicarboxylates or azoamides (Mitsunobu reaction).
  • the cyclic imides like phthalimide, succinimide can be used.
  • the compound of formula (II) where Ri is aralkylamine can be obtained by reacting the compound of formula (IV) with suitable aralkylamines via oxyphosphonium ion formation which is generated in situ using suitable phosphines with azodicarboxylates or azoamides (Mitsunobu reaction).
  • suitable aralkylamines like benzylamine, p-methoxybenzylamine, a-methylphenethylamine, tritylamine, etc can be used.
  • the compound of Formula (II) where Ri is sulfonamide can be obtained by reacting the compound of Formula (III) with suitable sulfonamides like p-toluene sulfonamide, sulfamic acid, N-(t-butoxycarbonyl)-p-toluenesulfonamide etc. in suitable solvents.
  • An oxyphosphonium ion leaving group can be generated in situ by reacting trialkylphosphine such as tributylphosphine, tri-t-butylphosphine, trihexylphosphine, trioctylphosphine, cyanomethlenetri-n-butylphosphorane; cycloalkylphosphines such as tricyclohexylphosphine, dicyclohexylphenylphosphine, or arylphosphine such as triphenylphosphine, dicyclohexylphenylphosphine, diethylphenylphosphine, 4- (dimethylamino)phenyldiphenylphosphine, diphenyl-2-pyridylphosphine, isopropyldiphenylphosphine; with azodicarboxylates such as diethylazodicarboxylate, diisopropyl azodica
  • Suitable solvents which can be used in Mitsunobu reaction of step-(f) may include one or more of ethers such as diethyl ether, 1 ,4-dioxane, dimethoxy ethane, diethoxy ethane, D1PE, MTBE, THF, 2-methyl tetrahydrofuran or their suitable mixtures.
  • ethers such as diethyl ether, 1 ,4-dioxane, dimethoxy ethane, diethoxy ethane, D1PE, MTBE, THF, 2-methyl tetrahydrofuran or their suitable mixtures.
  • the reaction mixture in step (f) is maintained at -10 to 50 °C.
  • the temperature is at -10 to 30 °C.
  • the reaction of step-(f) may be carried out in an inert atmosphere such as N 2 , He or Ar.
  • the duration of the reaction may be from 1 to 24 hrs, more specifically 2 to 8 hrs.
  • suitable additives can be selected from phase transfer catalysts like, trialkyi ammonium halides, tetraalkyl ammonium halides, trialkyi ammonium acetates, tetraalkyl ammonium acetates, trialkyi ammonium hydroxides, tetraalkyl ammonium hydroxides, trialkyi ammonium sulfates, tetraalkyl ammonium sulfates, trialkyi ammonium tetrafluoroborate, tetraalkyl ammonium tetrafuloroborate, trialkyi phosphonium halides, tetraalkyl phosphonium halides, tetraphenyl phosphonium halides, pyridinium halides, aliquat, adogen, crown ethers, silicon analouges of crown ethers, PEG, TDA- 1 etc.
  • phase transfer catalysts like, trialkyi ammonium halides, t
  • the compound of Formula (111) can be converted directly to compound of Formula (I) with inversion of configuration using ammonia or suitable ammonium salts in suitable solvents and optionally in the presence of suitable additives and under pressure.
  • Suitable ammonium salt which can be used at step-(f) may include one or more of ammonium acetate, ammonium carbonate, ammonium hydroxide, ammonium formate, ammonium lactate, ammonium citrate dibasic, ammonium carbamate, ammonium benzoate.
  • Suitable solvents which can be used at step-(g) may include one Or more of alcohols such as methanol, ethanol, isopropanol, butanol, 1 ,2-dimethoxy ethanol, 2-methoxy ethanol, 2-ethoxy ethanol and ethylene glycol; ethers such as diethyl ether, 1 ,4-dioxane, dimethoxy ethane, DIPE, MTBE, THF and the like, water or their suitable mixtures.
  • alcohols such as methanol, ethanol, isopropanol, butanol, 1 ,2-dimethoxy ethanol, 2-methoxy ethanol, 2-ethoxy ethanol and ethylene glycol
  • ethers such as diethyl ether, 1 ,4-dioxane, dimethoxy ethane, DIPE, MTBE, THF and the like, water or their suitable mixtures.
  • the reaction mixture in step (g) is maintained at 0 to 80 °C.
  • the temperature is at 20 to 40 °C.
  • the reaction of step-(g) may be carried out in an inert atmosphere such as N 2 , He or Ar.
  • the duration of the reaction may be from 1 to 48 hrs, more specifically 5 to 24 hrs.
  • suitable additives may be added to enhance the conversion.
  • Such additives may be selected from those known in the art, such as suitable phase transfer catalysts like, trialkyl ammonium halides, tetraalky I ammonium halides, trialkyl ammonium acetates, tetraalky!
  • ammonium acetates trialkyl ammonium hydroxides, tetraalkyl ammonium hydroxides, trialkyl ammonium sulfates, tetraalkyl ammonium sulfates, trialkyl ammonium tetrafluoroborate, tetraalkyl ammonium tetrafuloroborate, trialkyl phosphonium halides, tetraalkyl phosphonium halides, tetrapenyl phosphonium halides , pyridinium halides, Aliquat , Adogen, crown ethers, silicon analouges of crown ethers, PEG, TDA-1 etc.
  • the product so obtained may be further or additionally purified by suitable salt formation, diastereomeric salt formation or by purification using suitable solvents to obtain desired purity levels.
  • the compound of Formula (I) thus obtained is converted to its corresponding acid addition salts by reacting with corresponding acids in suitable solvents.
  • the suitable solvents used for salt preparation may be selected from alcohols such as methanol, ethanol, isopropanol, butanol, 1 ,2-dimethoxy ethanol, 2-methoxy ethanol, 2- ethoxy ethanol.
  • ethylene glycol and the like hydrocarbons such as hexane, cyclohexane, toluene, chloro benzene and like; esters such as ethyl acetate, isopropyl acetate & the like; nitriles such as acetonitrile & the like; ethers such as, DIPE, 1 ,4- dioxane,THF & the like; ketones such as acetone, MIBK and like; aprotic polar solvents such as DMf, DMSO, DMA & the like; water and suitable mixtures of one or more of the solvents described above.
  • alcohols such as methanol, ethanol, isopropanol, butanol
  • the suitable acid used may be selected from phosphoric acid, HCI, benzenesulfonic acid, p-toliienesulfonic acid, 10-camphorsulfonic acid, tartaric acid, dodecylsulfuric acid, citric acid, maleic acid, fumaric acid and the like.
  • Suitable chiral acids used for the diastereomeric salt formation may be selected from tartaric acid, di-p-toluoyl tartaric acid, dibenzoyltartaric acid, o-nitrobenzoyl tartaric acid, lactic acid, 10-camphorsulfonic acid, 8-camphorsulfonic acid, malic acid, N-acetyl glutamic acid, mandelic acid, o-acetylmandelic acid, o-methylmandelic acid, thiazolidine-4-carboxylic acid, a-methoxyphenylacetic acid, a-methoxy-a- trifluoromethylphenylacetic acid, 2-pyrrrolidone-5-carboxylic acid and the like.
  • the chiral acid used for resolution may be selected from tartaric acid and dibenzoyltartaric acid.
  • the suitable solvents used used for the diastereomeric salt formation may be selected from suitable alcohols like methanol, ethanol, isopropanol, butanol, 1 ,2- dimethoxy ethanol, 2-methoxy ethanol, 2-ethoxy ethanol, isoamyl alcohol and ethylene glycol; esters like ethyl acetate and isopropyl acetate; chlorinated solvents like chloroform and dichloromethane; nitriles like acetonitrile; hydrocarbons like toluene, xylene and chlorobenzene; ketones like acetone, methyl ethyl ketone; ethers like diethyl ether, 1 ,4-dioxane, DIPE, MTBE, THF; aprotic polar solvents such as DMF, DMSO, DMA; water and their suitable mixtures.
  • suitable alcohols like methanol, ethanol, isopropanol, butanol, 1
  • Suitable diastereomeric salt obtained above may be further converted to its pure base by employing standard techniques in the art.
  • the compound of Formula (1) and its salt thus obtained is purified by using suitable solvents.
  • the suitable solvents used for the purification may be selected from alcohols like , methanol, ethanol, isopropanol, butanol, 1 ,2-dimethoxy ethanol, 2-methoxy ethanol, 2-ethoxy ethanol.
  • ethylene glycol and the like esters like ethyl acetate, isopropyl acetate & the like; chlorinated solvents like chloroform, dichloromethane & the like; nitriles like acetonitrile & the like; hydrocarbons like toluene, xylene, chlorobenzene & the like; ketones like acetone & the like; ethers like diethyl ether, 1 ,4- dioxane, DIPE, MTBE, THF & the like; aprotic polar solvents such as DMF, DMSO, DMA & the like; water and suitable mixtures of one Or more of the solvents described above.
  • the pure compound of Formula (I) thus obtained is converted to its pharmaceutically acceptable salts such as acetate, benzenesulfonate, benzoate, camphorsulfonate, citrate, ethanesulfonate, fumarate, gluconate, glutamate, HBr, HCI, isethionate, lactate, maleate.
  • pharmaceutically acceptable salts such as acetate, benzenesulfonate, benzoate, camphorsulfonate, citrate, ethanesulfonate, fumarate, gluconate, glutamate, HBr, HCI, isethionate, lactate, maleate.
  • UV absorption photometer Wave length 210 mil Column temp. : 25 °C Flow, rate: 1 .0 mL/min. Injection Vol.: 10 ⁇ L
  • the inventors have developed a process for the preparation of compound of Formula (1) or its salts either in its racemic (R/S) form or any of its optically active (S) or (R) forms or enantiomeric excess mixture of any of the forms.
  • the process includes: (i) reacting 3-hydi xy-l -(3-(trifluoromethyl)-5,6-dihydro-[l ,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl) butan- l -one of Formula (IV) either in its racemic ( S) form or any of its optically active (S) or (R) forms or enantiomeric excess mixture of any of the forms with a p-toluenesulfonyl chloride or p-nitro benzenesulfonyi chloride to obtain compound of Formula (i ll) wherein 'R'represents p-
  • Suitable solvents which can be used at step-(i), when * R' represents p- toluenesulfonyl chloride or p-nitro benzenesulfonyi chloride may include one or more of chlorinated solvents such as chloroform, dichloromethane, dichloroethane; nitriles such acetonitrile; hydrocarbons such as hexane, heptane, cyclohexane, toluene, xylene, chlorobenzene; aprotic polar solvents such as DMF, DMA; N-methyl pyrrolidone, pyridine and the like or their suitable mixtures.
  • chlorinated solvents such as chloroform, dichloromethane, dichloroethane
  • nitriles such acetonitrile
  • hydrocarbons such as hexane, heptane, cyclohexane, toluene, xylene, chloro
  • chloride or p-nitro benzenesulfonyi chloride may be selected from heterocyclic saturated or unsaturated amines, preferably morpholine, piperidine, pyrollidine, DBU, DBN, l ,4-diazabicyclo[2,2,2]octane, dimethylamino pyridine and pyridine; hydrides such as K HMDS and the like or mixtures thereof.
  • Suitable azides which can be used at step-(iii), for preparation of compounds of formula (II) may be selected from HN 3 , NaN 3 , L1N3, Zn(N 3 ) 2 , Cu(N 3 ) 2 , Tetrabutylammonium azide etc.;
  • Suitable additives may be added in step (iii) to enhance the conversion.
  • Such additives may be selected from those known in the art, such as suitable phase transfer catalysts like, trialkyl ammonium halides, tetraalkyl ammonium halides, trialkyl ammonium acetates, tetraalkyl ammonium acetates, trialkyl ammonium hydroxides, tetraalkyl ammonium hydroxides, trialkyl ammonium sulfates, tetraalkyl ammonium sulfates, trialkyl ammonium tetrafkioroborate, tetraalkyl ammonium tetrafuloroborate, trialkyl phosphonium halides.
  • tetraalkyl phosphonium halides tetrapenyl phosphonium halides , pyridinium halides, Aliquat , Adogen, crown ethers, silicon analouges of crown ethers, PEG, TDA- 1 etc.
  • Suitable solvents which can be used in step-(iii), where i is -N 3 may include one or more of ethers such as 1 ,4-dioxane, dimethoxy ethane, THF; esters such as ethyl acetate, n-butyl acetate and isopropyl acetate; chlorinated solvents such as chloroform, dichloromethane, dichloroethane; hydrocarbons such as hexane, heptane, cyclohexane, toluene, xylene, chlorobenzene; aprotic polar solvents such as DMF, DMA, DMSO; N- methyl pyrrolidone, pyridine, HMPA and the like, water or their suitable mixtures.
  • ethers such as 1 ,4-dioxane, dimethoxy ethane, THF
  • esters such as ethyl acetate, n-
  • the suitable reducing reagent can be used inn step-(iv) may be selected from precious metal catalyst like.
  • LiBH 3 NMe 2 NaBH 4 /Phase Transfer Catalyst, NaBH - exchange resin, NaBH 4 / iCI 2 .6H 2 0, NaBH 4 /Ni(OAc 2 ), NaBH 4 /l ,3-propanedithiol; sulfur compounds like HS(CH 2 ) 3 SH/Et 3 N, PhSH;
  • Suitable solvents which can be used at step-(iv) may include one or more of alcohols such as methanol, ethanol, isopropanol, butanol, 1 ,2-dimethoxy ethanol, 2- methoxy ethanol, 2-ethoxy ethanol and ethylene glycol; ethers such as diethyl ether, 1 ,4-dioxane, dimethoxy ethane, DIPE, MTBE, THF and the like, water or their suitable mixtures.
  • alcohols such as methanol, ethanol, isopropanol, butanol, 1 ,2-dimethoxy ethanol, 2- methoxy ethanol, 2-ethoxy ethanol and ethylene glycol
  • ethers such as diethyl ether, 1 ,4-dioxane, dimethoxy ethane, DIPE, MTBE, THF and the like, water or their suitable mixtures.
  • mula (HI) haloalkyl carboxylate group such as -OCOCF3; aryl carboxylate group such as -OCOPh, substituted -GCOPh; alkoxy carboxylate group such as -OC(0)OCH 2 CH 3 ; alkyl sulfonates group such as -OSO2CH2CH3; -haloalkyl sulfonate group such as, - OSO2CF3, -OSO2CH2CF ; aryl sulfonates group such as -OSChPh, substituted - OS0 Ph such as
  • alkoxy phosphates group such as -OP(0)(OEt)2; an oxyphosphonium ion leaving group such as -0 " P + (X);, where "X * may be alkyl groups, aryl groups, cycloalkyl groups.
  • ' represent cyclic imido group, aralkylamino group, sulfonamido group.
  • 'RT represents araalkyamino group such as -NHCH 2 (4-OCH3Ph), -NHCH(CH 3 )Ph, -NHCH(Ph) 3 ;
  • Glucose 6.28 gm (0.0349 moles) and ⁇ -Nicotinamide adenine dinucleotide phosphate disodium salt ( l Omg) was dissolved in 100 ml of water.
  • Glucose Dehydrogenase lyophilized powder prepared as per example 4 of 2805/ UM/2010 (pET27bZBG 13.1 .1 , 12.5 gm) was added to the reaction mixture to get a suspension.
  • 50 gm cells prepared by the process as mentioned in the example no 6 of 2805/MU /2010 (pET27BZBG2.0.9) suspended in 50 ml water was added to the
  • reaction mixture and homogeneous preparation was incubated at 25-30 °C under stirring condition.
  • substrate i.e., sodium salt of 4-oxo-4-[3- (trifluoromethyl)-5,6-dihydro[ l ,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]- l -(2,4,5- trifluorophenyl)butan-2-one prepared as per process similar to WO2010/032264 was added in portions.
  • the product was further analyzed by HPLC analysis showing an HPLC purity of >90% of the corresponding alcohol, followed by chiral HPLC analysis (as described in example no 5 of 2805/MU /2010) showing an enantiomeric excess of >99% of single enantiomer.
  • Glucose (6.28 gm, 0.0349 moles) and ⁇ - Nicotinamide adenine dinucleotide phosphate disodium salt ( l Omg) was dissolved in 50 ml of water.
  • 50 gm cells prepared as mentioned in the above example no 7 of 2805/ UM/20 I 0 suspended in 500 ml water was subjected to cell lysis and clear cell free extract was added in the reaction mixture.
  • the homogeneous reaction preparation was incubated at 25-30 °C tinder stirring condition.- 10 gm (0.0233 1 moles) of Sodium salt of 4-oxo-4-[3-(triiluoi methyl)-5,6-dihydro[ l ,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]- l -(2,4,5-trifluorophenyl)biitan-2-one prepared as per process similar to WO2010/032264 was added in portions to the reaction mixture by maintaining pH of the reaction at 7.0 to 8.0 as has already been explained in example 9 above. The progress of the reaction was observed on TLC. During 25 to 30 hrs the starting material was almost disappeared and product spot was seen. Reaction mixture was extracted twice in equal volumes of Ethyl acetate and upon evaporating the solvent the desired product was obtained in 72% yield.
  • the enzymatically prepared alcohol product was analyzed by various classical tools i.e. Melting Point (m.p.). Specific Optical Rotation (SOR), Infra Red Spectroscopy (IR) and Nuclear Magnetic Resonance spectroscopy (N MR) and ES1-MS with the following results - m.p. ; 1 16- 120 V :
  • the product was further analyzed by HPLC and chiral HPLC analysis (as described in example 5 of 2805/MUM/2010), which showed 96. 1 % HPLC purity of corresponding alcohol and 99.7 % chiral purity of single enantiomer .
  • Reaction mixture was added into diluted aqueous HCI solution at -5 to 0 °C and it was stirred for 2 h at -5 to 0 °C to obtain solid compound. It was filtered and washed with water and aqueous saturated sodium bicarbonate solution. It was dried at 45-50 °C. (Wt.- I 2.7 g, % Y-92.1 , % Purity by HPLC-98.8 %, % Chiral purity-99.8 %).
  • Reaction mixture was added into diluted aqueous HCI solution at -5 to 0 °C and it was stirred for 2 h at -5 to 0 °C to obtain solid compound. It was filtered and washed with water and aqueous saturated sodium bicarbonate solution. It was dried at 45-50 °C. (Wt.-94.0 g, % Y-85.2, % Purity by HPLC-98.5%, % Chiral purity->99.5 %).
  • Reaction mixture was diluted with toluene (5.0 mL). It was transferred into a separating funnel. It was washed four times with water. The organic layer was collected. It was dried over anhydrous sodium sulfate. It was distilled out at reduced pressure to obtain the title compound (Wt.- 0.260 g, % Purity by HPLC- 87 %).
  • the reaction mixture was added into cold water and extracted with ethyl acetate.
  • the organic layer was washed with water and brine solution, it was dried over anhydrous sodium sulfate. It was distilled out at reduced pressure to obtain the title compound (Wt.-93 mg, % Purity by HPLC- 25.8 % and % of olefin impurity - 54.5 %).
  • reaction mixture was extracted with ethyl acetate.
  • the organic layer was washed with water and brine solution, it was dried over anhydrous sodium sulfate. It was distilled out at reduced pressure to obtain the title compound (Wt.- 0.446 g, % Purity by HPLC- 25.3 %).
  • the filtrate was collected and transferred into a 500 mL one neck round bottom flask.

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Abstract

Cette invention concerne la synthèse d'une 4-oxo-4-[3-(trifluorométhyl)- 5,6-dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluoro-phényl)butan-2-amine de Formule (I) soit sous sa forme racémique (R/S), soit sous l'une quelconque de ses formes (S) ou (R) optiquement actives ou d'un mélange à excédent énantiomère de l'une quelconque des formes, par de nouveaux procédés. Cette invention concerne en outre certains nouveaux intermédiaires utiles dans la préparation du composé de Formule (I) et des procédés de préparation desdits intermédiaires.
PCT/IN2012/000299 2011-11-02 2012-04-24 Procédés de préparation de 4-oxo-4-[3-(trifluorométhyl)-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8h)-yl]-1-(2,4,5-trifluorophényl)- butan-2-amine WO2013065066A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104130264A (zh) * 2014-08-14 2014-11-05 广东东阳光药业有限公司 一种异构体的转化方法
CN104387393A (zh) * 2014-10-31 2015-03-04 广东东阳光药业有限公司 制备西格列汀杂质
CN104893989A (zh) * 2015-05-29 2015-09-09 浙江工业大学 小孢根霉须状变种zjph1308及在制备西他列汀中间体中的应用
WO2015162506A1 (fr) * 2014-04-21 2015-10-29 Suven Life Sciences Limited Procédé de préparation de sitagliptine et nouveaux intermédiaires
CN106397444A (zh) * 2015-07-30 2017-02-15 四川科伦药物研究院有限公司 一种磷酸西格列汀类似物i的制备方法
CN106536523A (zh) * 2014-02-05 2017-03-22 斯特里奥肯公司 西他列汀的权宜合成

Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6699871B2 (en) 2001-07-06 2004-03-02 Merck & Co., Inc. Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
WO2004085661A2 (fr) 2003-03-24 2004-10-07 Merck & Co., Inc Procede de synthese de derives d'acides amines beta chiraux
WO2004085378A1 (fr) 2003-03-19 2004-10-07 Merck & Co. Inc. Procede pour preparer des derives d'acide amine beta chiraux par hydrogenation asymetrique
WO2004087650A2 (fr) 2003-03-27 2004-10-14 Merck & Co. Inc. Procede et intermediaires pour la preparation d'inhibiteurs d'amide d'acide beta-amino de dipeptidyle peptidase-iv
WO2005097733A1 (fr) 2004-04-05 2005-10-20 Merck & Co., Inc. Procede pour la preparation de derives d'acides amines beta a enrichissement enantiomerique
WO2006045598A1 (fr) * 2004-10-27 2006-05-04 Iep Gmbh Production d'alcools chiraux
WO2006081151A1 (fr) 2005-01-24 2006-08-03 Merck & Co., Inc. Procede de transformation en derives chiraux d'acides amines beta par l'hydrogenation asymetrique
WO2009084024A2 (fr) 2007-11-02 2009-07-09 Glenmark Generics Limited Procédé pour la préparation de r-sitagliptine et de ses sels pharmaceutiquement acceptables
WO2009085990A2 (fr) 2007-12-20 2009-07-09 Dr. Reddy's Laboratories Limited Procédés de préparation de sitagliptine et sels pharmaceutiquement acceptables de celle-ci
WO2010032264A2 (fr) 2008-08-27 2010-03-25 Cadila Healthcare Limited Procédé amélioré de préparation de (2r)-4-oxo-4-[3-(trifluorométhyl)-5,6-dihydro[1,2,4]-triazolo [4,3-a]pyrazin-7(8h)-yl]-1-(2,4,4-trifluorophényl)butan-2-amine et nouvelles impuretés présentes lors de sa préparation
WO2010122578A2 (fr) 2009-04-20 2010-10-28 Msn Laboratories Limited Procédé de préparation de la sitagliptine et de ses intermédiaires
WO2011002640A1 (fr) 2009-06-30 2011-01-06 The Procter & Gamble Company Compositions de blanchiment particulaires conditionnées
WO2011025932A2 (fr) * 2009-08-28 2011-03-03 Dr. Reddy's Laboratories Ltd. Préparation de la sitagliptine et de ses sels
WO2011049344A2 (fr) 2009-10-21 2011-04-28 Hanmi Holdings Co., Ltd. Procédé de préparation de sitagliptine et intermédiaires utilisés dans celui-ci
EP2397141A1 (fr) 2010-06-16 2011-12-21 LEK Pharmaceuticals d.d. Procédé pour la synthèse d'acides aminés beta et leurs dérivés
WO2012046254A2 (fr) * 2010-10-08 2012-04-12 Cadila Healthcare Limited Méthode de préparation d'un intermédiaire de sitagliptine par conversion enzymatique
WO2012072036A1 (fr) * 2010-12-03 2012-06-07 浙江海翔药业股份有限公司 Intermédiaires de sitagliptine et leur procédé de préparation

Patent Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6699871B2 (en) 2001-07-06 2004-03-02 Merck & Co., Inc. Beta-amino heterocyclic dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes
WO2004085378A1 (fr) 2003-03-19 2004-10-07 Merck & Co. Inc. Procede pour preparer des derives d'acide amine beta chiraux par hydrogenation asymetrique
WO2004085661A2 (fr) 2003-03-24 2004-10-07 Merck & Co., Inc Procede de synthese de derives d'acides amines beta chiraux
WO2004087650A2 (fr) 2003-03-27 2004-10-14 Merck & Co. Inc. Procede et intermediaires pour la preparation d'inhibiteurs d'amide d'acide beta-amino de dipeptidyle peptidase-iv
WO2005097733A1 (fr) 2004-04-05 2005-10-20 Merck & Co., Inc. Procede pour la preparation de derives d'acides amines beta a enrichissement enantiomerique
WO2006045598A1 (fr) * 2004-10-27 2006-05-04 Iep Gmbh Production d'alcools chiraux
WO2006081151A1 (fr) 2005-01-24 2006-08-03 Merck & Co., Inc. Procede de transformation en derives chiraux d'acides amines beta par l'hydrogenation asymetrique
WO2009084024A2 (fr) 2007-11-02 2009-07-09 Glenmark Generics Limited Procédé pour la préparation de r-sitagliptine et de ses sels pharmaceutiquement acceptables
WO2009085990A2 (fr) 2007-12-20 2009-07-09 Dr. Reddy's Laboratories Limited Procédés de préparation de sitagliptine et sels pharmaceutiquement acceptables de celle-ci
WO2010032264A2 (fr) 2008-08-27 2010-03-25 Cadila Healthcare Limited Procédé amélioré de préparation de (2r)-4-oxo-4-[3-(trifluorométhyl)-5,6-dihydro[1,2,4]-triazolo [4,3-a]pyrazin-7(8h)-yl]-1-(2,4,4-trifluorophényl)butan-2-amine et nouvelles impuretés présentes lors de sa préparation
WO2010122578A2 (fr) 2009-04-20 2010-10-28 Msn Laboratories Limited Procédé de préparation de la sitagliptine et de ses intermédiaires
WO2011002640A1 (fr) 2009-06-30 2011-01-06 The Procter & Gamble Company Compositions de blanchiment particulaires conditionnées
WO2011025932A2 (fr) * 2009-08-28 2011-03-03 Dr. Reddy's Laboratories Ltd. Préparation de la sitagliptine et de ses sels
WO2011049344A2 (fr) 2009-10-21 2011-04-28 Hanmi Holdings Co., Ltd. Procédé de préparation de sitagliptine et intermédiaires utilisés dans celui-ci
EP2397141A1 (fr) 2010-06-16 2011-12-21 LEK Pharmaceuticals d.d. Procédé pour la synthèse d'acides aminés beta et leurs dérivés
WO2012046254A2 (fr) * 2010-10-08 2012-04-12 Cadila Healthcare Limited Méthode de préparation d'un intermédiaire de sitagliptine par conversion enzymatique
WO2012072036A1 (fr) * 2010-12-03 2012-06-07 浙江海翔药业股份有限公司 Intermédiaires de sitagliptine et leur procédé de préparation

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
BARRY M. TROST; IAN FLEMING: "Comprehensive organic Synthesis", vol. 8, PERGAMON PRESS, pages: 383 - 386
BARRY M. TROST; LAN FLEMING: "Comprehensive organic Synthesis", vol. 8, PERGAMON PRESS, pages: 383 - 386
BECONI, MARIA G. ET AL: "Disposition of the dipeptidyl peptidase 4 inhibitor sitagliptin in rats and dogs", DRUG METABOLISM AND DISPOSITION, vol. 35, no. 4, 2007, pages 525 - 532, XP002686516, ISSN: 0090-9556, DOI: 10.1124/dmd.106.013110 *
FIESER; FIESER: "Reagents for Organic Synthesis", vol. 5, JOHN WILEY & SONS, pages: 728 - 729
JERRY MARCH: "Advanced organic chemistry, 4th Edition,", JOHN WILEY & SONS, pages: 294 - 297,346-
RICHARD C. LAROCK.: "Comprehensive organic transformations, 2nd Edition,", WILEY-VCH, pages: 815 - 819
RICHARD C. LAROCK: "Comprehensive organic transformations, 2nd Edition,", WILEY-VCH, pages: 815 - 819
RUSSIAN CHEM. REV, vol. 73, no. 6, 2004, pages 581 - 608
S.D. BURKE; R. L. DANHEISER: "Hanbook of reagents for organic synthesis-Oxidizing and Reducing agents", JOHN WILEY & SONS
S.D. BURKE; R. L. DANHEISER: "Hanbook of reagents for organic synthesis-Oxidizing and Reducing agents", vol. 6, JOHN WILEY & SONS
T.W. GRENE; PETER G. M. WUTS: "Protective Groups in Organic Synthesis, 3rd Edition,", JOHN WILEY & SONS
TETRAHEDRON ASSYMETRY, vol. 3, no. 12, 1992, pages 1475 - 1504

Cited By (6)

* Cited by examiner, † Cited by third party
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CN106536523A (zh) * 2014-02-05 2017-03-22 斯特里奥肯公司 西他列汀的权宜合成
WO2015162506A1 (fr) * 2014-04-21 2015-10-29 Suven Life Sciences Limited Procédé de préparation de sitagliptine et nouveaux intermédiaires
CN104130264A (zh) * 2014-08-14 2014-11-05 广东东阳光药业有限公司 一种异构体的转化方法
CN104387393A (zh) * 2014-10-31 2015-03-04 广东东阳光药业有限公司 制备西格列汀杂质
CN104893989A (zh) * 2015-05-29 2015-09-09 浙江工业大学 小孢根霉须状变种zjph1308及在制备西他列汀中间体中的应用
CN106397444A (zh) * 2015-07-30 2017-02-15 四川科伦药物研究院有限公司 一种磷酸西格列汀类似物i的制备方法

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