WO2009064476A1 - Préparation d'un intermédiaire de sitagliptine - Google Patents

Préparation d'un intermédiaire de sitagliptine Download PDF

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WO2009064476A1
WO2009064476A1 PCT/US2008/012813 US2008012813W WO2009064476A1 WO 2009064476 A1 WO2009064476 A1 WO 2009064476A1 US 2008012813 W US2008012813 W US 2008012813W WO 2009064476 A1 WO2009064476 A1 WO 2009064476A1
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Prior art keywords
trifluorophenyl
process according
alkyl ester
amino
acid
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PCT/US2008/012813
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English (en)
Inventor
Nurit Perlman
Marina Etinger
Valerie Niddam-Hildesheim
Mili Abramov
Gennady Nisnevich
Boris Fedotev
Lev Yudovich
Elena Goldat
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Teva Pharmaceutical Industries Ltd.
Teva Pharmaceuticals Usa, Inc.
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Publication of WO2009064476A1 publication Critical patent/WO2009064476A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
    • C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • 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 invention encompasses a process for the preparation of a Sitagliptin intermediate.
  • Sitagliptin, (3i?)-3-amino-l-[9-(trifluoromethyl)-l,4,7,8- tetrazabicyclo[4.3.0]nona-6,8-dien-4-yl]-4-(2,4,5- trifluorophenyl)butan-l-one, has the following chemical structure:
  • Sitagliptin is currently marketed in its phosphate salt in the United States under the tradename JANUVIATM in its monohydrate form. JANUVIATM is indicated to improve glycemic control in patients with type 2 diabetes mellitus.
  • Sitagliptin phosphate is a glucagon-like peptide 1 metabolism modulator, hypoglycemic agent, and dipeptidyl peptidase IV inhibitor. Sitagliptin phosphate is described in PCT Publication No. WO 2005/003135.
  • Sitagliptin can be obtained by condensation of 2 key intermediates. The first intermediate is (3R)-amino-4-(2,4,5-trifluorophenyl)butanoic acid ("Synthon I"). Synthon I has the following formula:
  • PCT Publication No. WO 2004/085378 refers to the synthesis of Sitagliptin intermediate (3R)-[protected-amino]-4-(2,4,5-trifiuorophenyl)butanoic acid via stereoselective hydrogenation of a prochiral enamine, 3-Amino-l-(3-trifluoromethyl-5,6- dihydro-8H-[l,2,4]triazolo[4,3-a]purazin-7-yl)-4-(2,4,5-trifluorophenyl)but-2-en-l-one, using Rhodium complex with (R,S)-tert-butyl-Josipos ligand.
  • PCT Publication No. WO 2004/087650 refers to the synthesis of Sitagliptin intermediate (3R)-[protected-amino]-4- (2,4,5-trifluorophenyl)butanoic acid via chiral reduction of 3-Oxo-4-(2,4,5- trifluorophenyl)-butyric acid with Ru-(S)-BINAP complex, followed by inversion of stereochemical center, achieved by Mitsunobu cyclization of (3S)-N-Benzoyloxy-3- hydroxy-4-(2,4,5-trifluorophenyl)butyramide.
  • U.S. Patent No. 6,699,871 refers to the synthesis of the Sitagliptin intermediate (3R)-[protected-amino]-4-(2,4,5-trifluorophenyl)butanoic acid by using diazomethane, which is a very dangerous and explosive reagent, and can not be used in industrial scale. Additionally, (S)-2,5-dihydro-2-isopropyl-3,6-dimethoxypyrazine is used as the starting material and leads to high costs.
  • the present invention provides intermediate compounds in the synthesis of Sitagliptin: 3-amino-4-(2,4,5-trifluorophenyl)but-2-enoic acid alkyl ester, and amino protected-3-amino-4-(2,4,5-trifluorophenyl)but-2-enoic acid alkyl ester, and the stereoselective reduction of these compound to give Synthon I, or the amino-protected Synthon I, which are key intermediates in the preparation of Sitagliptin.
  • alkyl refers to C 1 -C 6 hydrocarbons.
  • the Ci-C 6 hydrocarbon is methyl or ethyl.
  • the term optically pure refers to a sample of an optically active compound, comprising at least 90% percent of the predominant enantiomer.
  • room temperature refers to a temperature of about 20°C to about 35°C, more preferably about 25 0 C to about 35°C, more preferably about 25°C to about 30 0 C, and most preferably about 25°C.
  • the present invention encompasses a process for the preparation of a Sitagliptin key intermediate, 3-amino-4-(2,4,5-trifluorophenyl)butanoic acid, alkyl ester via enamine reduction. This synthesis gives high stereoselectivity. [0015] In one embodiment, the present invention encompasses a process for preparing 3-amino-4-(2,4,5-trifluorophenyl)butanoic acid, alkyl ester ("Synthon I"-alkyl ester), comprising reducing 3-amino-4-(2,4,5-trifluorophenyl)but-2-enoic acid alkyl ester of the following formula:
  • R is C 1 -C 6 alkyl (such as methyl, ethyl, iso-propyl and tert-butyl), C 6 -Ci 2 sryh C 7 - Ci 2 arylalkyl, or C 7 -Ci 2 alkylaryl, in the presence of hydrogen source and a chiral catalyst to obtain Synthon I-alkyl ester.
  • the reduction is stereoselective.
  • the reduction reaction is carried out in the presence of an organic solvent. An acid may also be added to the reaction mixture.
  • the process for preparing 3-amino-4-(2,4,5-trifluorophenyl)butanoic acid, alkyl ester comprises combining 3-amino-4-(2,4,5-trifiuorophenyl) but-2- enoic acid alkyl ester with a chiral catalyst, and a hydrogen source, and optionally an acid, and in the presence of a solvent such as CpC 6 alcohol, or a C 1 -C 6 fluorinated alkylalcohol.
  • the molar ratio of the 3-amino-4-(2,4,5-trifluorophenyl) but-2-enoic acid alkyl ester and the chiral catalyst is from about 0.001% to about 5%.
  • 3-amino-4-(2,4,5-trifiuorophenyl)but-2-enoic acid alkyl ester used in the above process can be prepared using any method known in the art, for example, according to the reaction disclosed in Tetrahedron: Asymmetry 17 (2006), 205-209, and depicted in the following scheme:
  • the chiral catalyst is a complex Ru-BINAP.
  • the complex is formed from a mixture of a first metal complex and a chiral ligand.
  • the complexes are [Ru(COD)Cb] n - preferably X is F, Cl, or Br, more preferably X is Cl or Br, and most preferably, X is Cl.
  • the chiral ligand is (R or S)- 2,2'-bis(diphenylphosphino)-l,l'- binaphthyl (BINAP), or derivatives thereof. More preferably, the ligand is (R)-2,2 - bis(diphenylphosphino)- 1 , 1 '-binaphthyl or (S)-2,2'-bis(diphenylphosphino)- 1,1'- binaphthyl, and most preferably. Most preferably, the ligand is (R)-2,2'- bis(diphenylphosphino)-l,l'-binaphthyl.
  • the solvent for the reaction is selected from the group consisting of Ci-C 6 alcohols, and C]-C 6 fluorinated alkyl alcohols; more preferably, the solvent is a C 1 - C 6 alcohol, or a Cj-C 6 fluorinated alkyl alcohol selected from the group consisting of: methanol, ethanol, isopropyl alcohol, and trifluoroethanol; preferably, ethanol or trifiuoroethanol.
  • the acid is an organic acid. More preferably, the organic acid is selected from the group consisting of: acetic acid, chloroacetic acid, propionic acid, and methanesulfonic acid. Most preferably, the organic acid is acetic acid. However, where the alcohol is a fluorinated Ci-C 6 alkyl alcohol, such as trifluoroethanol, no acid is needed.
  • the reaction is carried out at about 5 to 7 bar of hydrogen pressure. More preferably, the pressure is about 5.5 to 6.5 bar.
  • the reaction mixture is maintained at a temperature of greater than 50°C to about 140°C, preferably about 60 0 C to about 100°C (e.g.
  • the reaction mixture may be maintained at a temperature of about 80°C.
  • the reaction mixture is preferably maintained at this temperature for about 10 to 80 hours, preferably about 15 hours to about 60 hours, and more preferably about 15 hours to about 45 hours. Good results and high yields have been obtained maintaining the reaction fixture for a period of about 24 to about 45 hours.
  • the reaction mixture is preferably maintained at a temperature of about 60 0 C to about 100°C (e.g. about 60 0 C to 80°C), and most preferably about 80 0 C.
  • the mixture is maintained at this temperature for a period of about 10 to about 25 hours (e.g., about 10 to about 15 hours), more preferably.12 to about 24 hours, and most preferably about 15-18 hours.
  • the 3-amino-4-(2,4,5-trifluorophenyl)butanoic acid, alkyl ester (“Synthon I"- alkyl ester) can be purified and recovered using any method known to those skilled in the art, for example, by extracting, washing, drying and evaporating.
  • the obtained 3-amino-4-(2,4,5-trifluorophenyl)butanoic acid, alkyl ester (“Synthon F'-alkyl ester) is optically pure.
  • the ratio between the two enantiomers is preferably about 60% to about 100%, more preferably about 80% to about 100%, more preferably about 90% to about 100%, most preferably about 95% to about 99.8% (for example, the ration is 95.4:4.6 to about 99.5:0.5).
  • the predominant enantiomer is the (3R) enantiomer of Synthon I-alkyl ester.
  • the chemical purity of 3-amino-4-(2,4,5-trifluorophenyl)butanoic acid, alkyl ester according to HPLC is more that about 90%, preferably about 90% to about 100%, and most preferably about 90% to about 94% (preferably about 91.1 % to 93.14 %) .
  • this process for preparing 3-amino-4-(2,4,5- trifluorophenyl)butanoic acid, alkyl ester comprises combining 3-amino-4-(2,4,5-trifluorophenyl)but-2-enoic acid alkyl ester, a chiral organic acid, a reducing reagent and an organic solvent, and maintaining the reaction mixture for a sufficient period of time to obtain 3-amino-4-(2,4,5-trifluorophenyl)butanoic acid, alkyl ester.
  • the mixture is maintained for about 4 to about 24 hours.
  • the molar ratio of 3-amino-4-(2,4,5-trifluorophenyl)but-2-enoic acid alkyl ester, organic acid, and reducing reagent is from about 0.25 to about 0.4.
  • about 5 to about 40 ml of organic solvent is used per gram of 3-amino-4-(2,4,5-trifluorophenyl)but-2-enoic acid alkyl ester.
  • the organic acid is optically pure.
  • the organic acid is (R or S)-mandelic acid.
  • the reducing reagent is a borohydride or hydride reducing reagent selected from the group consisting of sodium borohydride, sodium cyanoborohydride, lithium borohydride, and lithium aluminum hydride. More preferably, the reducing reagent is sodium borohydride.
  • the organic solvent is an ether, such as a C 4 to C 8 alkyl ether or a C 4 to C 8 cyclic ether. Most preferably the organic solvent is tetrahydrofuran.
  • the mixture is stirred at a temperature of about -5 0 C to about 30 0 C, more preferably at about room temperature, i.e., about 25°C for about 8 to about 24 hours.
  • the mixture is The mixture is stirred at this temperature range preferably for a period of about 30 minutes to about 20 hours, more preferably about 30 minutes to about 12 hours. More preferably the mixture is stirred at this temperature range for a period of about 1 to about 12 hours, and most preferably for about 12 hours.
  • the obtained 3-amino-4-(2,4,5-trifluorophenyl)butanoic acid, alkyl ester may be recovered and purified using any method known in the art, for example, by filtration.
  • the obtained 3-amino-4-(2,4,5-trifluorophenyl)butanoic acid, alkyl ester is optically pure.
  • the predominant enantiomer is the (3R) enantiomer of Synthon I-alkyl ester.
  • the enantiomers ratio of the obtained 3-amino-4-(2,4,5- trifluorophenyl)butanoic acid, alkyl ester is 92.2:7.8.
  • the present invention encompasses a process for preparing Sitagliptin or salts thereof, comprising obtaining 3-amino-4-(2,4,5- trifluorophenyl)butanoic acid, alkyl ester by any of the methods described above, and further converting it to Sitagliptin or salts thereof.
  • the present invention encompasses 3-amino-protected-
  • R' is BOC.
  • the present invention encompasses a process for preparing 3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)but-2-enoic acid alkyl ester comprising converting the carbonyl group of 3-oxo-4-(2,4,5-trifluorophenyl)butanoic acid alkyl ester into a protected enamine functional group, according to the reaction.
  • R' is BOC.
  • the invention encompasses a process for preparing 3- tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)but-2-enoic acid alkyl ester comprising reacting 3-oxo-4-(2,4,5-trifluorophenyl)butanoic acid alkyl ester with tert butyl carbamate.
  • the reaction is carried out in the presence of a catalytic amount (0.01-0.1 equivalents) of organic acid.
  • the reaction is carried out in the presence of an organic solvent.
  • the process for preparing 3-tert-butoxycarbonylamino-4- (2,4,5-trifluorophenyl)but-2-enoic acid alkyl ester comprises combining tert-butyl carbamate with 3-oxo-4-(2,4,5-trifluorophenyl)butanoic acid alkyl ester, a catalytic amount (0.06 equivalents) of organic acid and an organic solvent (8 ml/gr).
  • the molar ratio of tert-butyl carbamate, 3-oxo-4-(2,4,5-trifluorophenyl)butanoic acid alkyl ester, and organic acid is from about 10 to about 100.
  • the organic solvent is used in an amount of from about 5 to about 20 ml per gram of 3-oxo-4-(2,4,5- trifluorophenyl)butanoic acid alkyl ester.
  • Tert-butyl carbamate used in the above process can be prepared using any method known in the art, for examples according to the procedure disclosed in Tetrahedron: Asymmetry, 12 (2001), 2989 and in Organic Synthesis, 48 (1968), 32.
  • the organic acid is selected from the group consisting of p- toluenesulfonic acid, methansulfonic acid, and trifluoroacetic acid. More preferably, the organic acid is p-toluenesulfonic acid.
  • the organic solvent is a C 6 -Cj 2 aromatic solvent, such as benzene, toluene, or chlorobenzene, or a halogenated Ci-C 6 alkane, such as methylene chloride; preferably the solvent is methylene chloride.
  • water removal is carried out during the reaction.
  • water removal may be carried out by the addition of a drying agent, or by azeotropic distillation.
  • a drying agent is introduced to the reaction mixture.
  • the drying agent may be selected from any drying agent known to the skilled in the art.
  • the drying agent is a molecular sieve, more preferably, MS-4A (Molecular Sieves-4A).
  • the water may be removed from the reaction mixture by azeotropic distillation.
  • 3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)but-2-enoic acid alkyl ester is further recovered and purified by any method known in the art, for example, by evaporation and purification using HPLC techniques and/or crystallization.
  • the present invention encompasses a process for preparing Sitagliptin or salts thereof, comprising obtaining 3-tert-butoxycarbonylamino-4- (2,4,5-trifluorophenyl) but-2-enoic acid alkyl ester as described above, and further converting it to Sitagliptin or salts thereof.
  • the present invention encompasses a process for preparing the amino-protected group, 3-amino-protected-4-(2,4,5-trifluorophenyl) butanoic acid alkyl ester comprising reducing 3-amino-protected-4-(2,4,5-trifluorophenyl) but-2-enoic acid alkyl ester, in the presence of hydrogen and a chiral catalyst.
  • the reduction is stereoselective.
  • the reduction is carried out by a process as defined in any embodiment of the present invention.
  • the reaction is conducted in the presence of a solvent such as Ci-C 6 alcohol or a fluorinated Ci -6 alkyl alcohol.
  • Preferred metal complexes, chiral ligands, solvents and conditions are as described in any of the above embodiments for the reduction of 3-amino-4-(2,4,5-trifluorophenyl) but-2-enoic acid alkyl ester.
  • the process for preparing the amino-protected group "Synthon I", 3-tert- butoxycarbonylamino-4-(2,4,5-trifluorophenyl)butanoic acid alkyl ester comprises combining 3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)but-2-enoic acid alkyl ester with a chiral catalyst, a hydrogen source and a Ci-C 6 alcohol.
  • the molar ratio of 3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)but-2-enoic acid alkyl ester, a metal complex, and a chiral ligand is from about 5% to about 0.01%.
  • about 3 ml to about 10 ml of the Ci-C 6 alcohol is used per gram of 3-tert-butoxycarbonylamino-4- (2,4,5-trifluorophenyl)but-2-enoic acid alkyl ester.
  • the chiral catalyst is a complex Ru-BINAP.
  • the complex is formed from a mixture of a first metal complex and a chiral ligand.
  • the chiral ligand is (R or S)- 2,2'-bis(diphenylphosphino)- 1,1 '-binaphthyl or (R or S)- 2,2'-bis(diphenylphosphino)-l,l'-binaphthyl.
  • the ligand is (R)-2,2'- bis(diphenylphosphino)- 1 , 1 '-binaphthyl or (S)-2,2'-bis(diphenylphosphino)- 1,1'- binaphthyl.
  • the ligand is (R)-2,2'-bis(diphenylphosphino)- 1,1 '-binaphthyl.
  • the solvent is a Ci-C 6 alcohol or a fluorinated Ci-C 6 alcohol, and is more preferably a Ci-C 4 alcohol or a fluorinated Ci-C 4 alcohol, and is most preferably selected from the group consisting of: methanol, ethanol, isopropyl alcohol, and trifluoroethanol. More preferably, the alcohol is trifluoroethanol.
  • the reaction is carried out in the presence of an organic acid.
  • the organic acid is selected from the group consisting of: acetic acid, chloroacetic acid, propionic acid, and methanesulfonic acid.
  • the organic acid is acetic acid.
  • the reaction is carried out at a hydrogen pressure of about 3 bar to about 8 bar, more preferably about 4 bar to about 7 bar, and most preferably about 5 to 7 bar, particularly at about 5 bar.
  • the reaction mixture is maintained at about 40 0 C to about 100 0 C, more preferably about 60 0 C to about 100 0 C, and most preferably about 60 0 C to about 80 0 C for about 10 to 80 hours, preferably about 20 hours to about 60 hours, and more preferably about 30 hours, to about 50 hours.
  • the reaction is carried out at about 5 bar at 80 0 C for about 40 hours.
  • the protected 3-arnino-4-(2,4,5-trifluorophenyl)butanoic acid, alkyl ester can be purified and recovered using any method known to the skilled in the art, for example, by extracting, washing, drying and evaporating.
  • the obtained protected-3-amino-4-(2,4,5-trifluorophenyl)butanoic acid, alkyl ester is optically pure.
  • the predominant enantiomer is the (3R) enantiomer of protected-Synthon I-alkyl ester.
  • the present invention encompasses a process for preparing Sitagliptin or salts thereof, comprising obtaining 3-tert-butoxycarbonylamino-4- (2,4,5-trifluorophenyl)butanoic acid alkyl ester by any of the methods described above, and further converting it to Sitagliptin or salts thereof.
  • Sitagliptin can be prepared by other processes, such as coupling 3-protected- amino-4-(2,4,5-trifluorophenyl)butanoic acid with 3-(trifluoromethyl)-5,6,7,8- tetrahydro[l,2,4]triazolo[4,3- ⁇ ]pyrazine hydrochloride to obtain (R)-3-protected-amino-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; and then removing the amino protected group to obtain Sitagliptin.
  • 4-(3-(trifluoromethyl)-5,6-dihydro-[ 1 ,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl)-l-(2,4,5-trifluorophenyl)-4-oxobutan-2-yl-carbamate is optically pure.
  • the obtained coupling product is (R)-4-(3-(trifluoromethyl)-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-l-(2,4,5-trifluorophenyl)-4-oxobutan-2-yl- carbamate.
  • the 3-tert-butoxycarbonylamino-4-(2,4,5-trifluorophenyl)butanoic acid is cooled to a temperature of about -10 0 C to about 25°C, more preferably about 0 0 C in the presence of a first organic solvent; followed by the addition of Dicyclohexylcarbodiimide in a second organic solvent; introducing 3-(trifluoromethyl)- 5,6,7,8-tetrahydro[l,2,4]triazolo[4,3- ⁇ ]pyrazine hydrochloride, an organic base, and a catalyst to the reaction mixture; and recovering 4-(3-(trifluoromethyl)-5,6-dihydro- [l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-l-(2,4,5-trifluorophenyl)-4-oxobutan-2-yl- carbamate.
  • the first and the second organic solvents are selected from the group consisting of aprotic solvent, such as dimethylformamide, tetrahydrofuran, and dichloromethane.
  • Dimethylformamide is preferred.
  • a solution of Dicyclohexylcarbodiimide and Dimethylformamide is added drop-wise.
  • the catalyst is 4-Dimethylaminopyridine ("DMAP").
  • Suitable organic bases for this reaction are alkyl amines, preferably C 1 -C 6 trialkyl amines, more preferably triethylamine, diisopropyl ethyl amine, and N methyl morpholine.
  • the deprotection of the amine protecting group is carried out by introducing a solution of concentrated hydrochloric acid into a solution of tert-butyl-4-(3- (trifluoromethyl)-5,6-dihydro-[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-l-(2,4,5- trifluorophenyl)-4-oxobutan-2-yl-carbamate and an organic solvent selected from a group consisting OfC 1 -Co alcohols, most preferably, the organic solvent is iso-propanol; heating the reaction mixture at about 40 0 C for a sufficient period of time.
  • the reaction mixture is heated at about 25°C to about reflux, preferably to about 40 0 C for about 1 hour to about 24 hours, preferably an hour to about 5 hours, and more preferably about 2 hours; basifying the reaction mixture with an inorganic base, such as alkali bicarbonate, alkali carbonates, or alkali hydroxides, for example, sodium hydroxide; and recovering Sitagliptin.
  • an inorganic base such as alkali bicarbonate, alkali carbonates, or alkali hydroxides, for example, sodium hydroxide
  • Sitagliptin may be recovered from the reaction mixture using any known method, such as evaporation, extraction, and filtration.
  • Solvent A Acetonitril
  • Solvent B 10 mM KH2PO4 (1.36 g) and 10 niM (0.4 g) NaOH in
  • the reaction was stirred for 2 hours, then, 65 mL of DCC solution was added drop-wise, and after another 1 hour of stirring in an ice bath, the last 65 mL of DCC solution was added drop- wise.
  • the reaction was stirred at room temperature over night.
  • the mixture was filtrated by vacuum filtration and washed with DMF 2X50 mL.
  • the solvent was evaporated and EtOAc was added (1400 mL), the organic phase washed with 90 mL of 5% citric acid, 60 mL of 10% citric acid, and 100 mL of saturated NaHCO 3 , dried over Na 2 SO 4 and evaporated to yield a beige solid.
  • the product was dissolved in IPA (300 mL) by heating to reflux.

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Abstract

L'invention concerne des composés intermédiaires, l'ester alkylique de l'acide 3-amino-4-(2,4,5-trifluorophényl)but-2-énoïque et l'ester alkylique de l'acide 3-amino-4-(2,4,5-trifluorophényl)but-2-énoïque dont le groupe amino est protégé, dans la synthèse de Sitagliptine. L'invention concerne également la réduction stéréosélective de ces composés pour donner le synthon I ou le synthon I dont le groupe amino est protégé.
PCT/US2008/012813 2007-11-13 2008-11-13 Préparation d'un intermédiaire de sitagliptine WO2009064476A1 (fr)

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US303307P 2007-11-13 2007-11-13
US61/003,033 2007-11-13
US355307P 2007-11-16 2007-11-16
US61/003,553 2007-11-16
US6865308P 2008-03-06 2008-03-06
US61/068,653 2008-03-06
US7285408P 2008-04-02 2008-04-02
US61/072,854 2008-04-02
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Cited By (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010131025A1 (fr) * 2009-05-11 2010-11-18 Generics [Uk] Limited Synthèse de la sitagliptine
WO2011127794A1 (fr) * 2010-04-12 2011-10-20 上海源力生物技术有限公司 Dérivés cycliques chiraux d'acide bêta-aminoarylbutyrique, leurs procédés de préparation et procédés pour la préparation de dérivés chiraux d'acide bêta-aminoarylbutyrique par leur intermédiaire
EP2392575A1 (fr) 2010-06-04 2011-12-07 LEK Pharmaceuticals d.d. Nouvelle approche synthétique pour composés à substitution ß-aminobutyryle
WO2011151443A1 (fr) 2010-06-04 2011-12-08 Lek Pharmaceuticals D.D. Nouvelle approche synthétique de ss-aminobutyryles substitués
EP2397141A1 (fr) 2010-06-16 2011-12-21 LEK Pharmaceuticals d.d. Procédé pour la synthèse d'acides aminés beta et leurs dérivés
EP2423178A1 (fr) * 2010-07-28 2012-02-29 Chemo Ibérica, S.A. Procédé de production de sitagliptine
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CN102485718A (zh) * 2010-12-03 2012-06-06 浙江海翔药业股份有限公司 西他列汀的中间体及其制备方法
US8278486B2 (en) 2008-12-31 2012-10-02 Chiral Quest, Inc. Process and intermediates for the preparation of N-acylated-4-aryl beta-amino acid derivatives
EP2508506A1 (fr) 2011-04-08 2012-10-10 LEK Pharmaceuticals d.d. Préparation d'intermédiaires de la sitagliptine
EP2527320A1 (fr) 2011-05-27 2012-11-28 LEK Pharmaceuticals d.d. Préparation d'intermédiaires de la sitagliptine
CN102838603A (zh) * 2011-06-24 2012-12-26 上海医药工业研究院 一种西他列汀的中间体化合物的制备方法
WO2013013833A1 (fr) 2011-07-27 2013-01-31 Farma Grs, D.O.O. Procédé pour la préparation de sitagliptine et ses sels pharmaceutiquement acceptables
CN103172539A (zh) * 2011-12-23 2013-06-26 上海阳帆医药科技有限公司 糖尿病新药西格列汀中间体氨基苯丁酸衍生物的制备方法
EP2615080A1 (fr) 2012-01-12 2013-07-17 LEK Pharmaceuticals d.d. Préparation d'ingrédients pharmaceutiques actifs de type acide aminés ß purs optiquement et intermédiaires associés
CN103232455A (zh) * 2013-05-14 2013-08-07 聊城九州和谷生物科技有限公司 一种西他列汀的工业化生产方法
WO2013128000A1 (fr) 2012-03-02 2013-09-06 Moehs Iberica S.L. Nouvelle forme cristalline de sulfate de sitagliptine
EP2674432A1 (fr) 2012-06-14 2013-12-18 LEK Pharmaceuticals d.d. Nouvelle voie de synthèse pour la préparation de composés à substitution ß-aminobutyryle 5,6,7,8-tétrahydro[1,4]diazolo[4,3-alpha]pyrazines-7-yl
WO2014023930A1 (fr) 2012-08-08 2014-02-13 Cipla Limited Procédé pour la préparation de sitagliptine et composés intermédiaires
TWI453182B (zh) * 2009-06-26 2014-09-21 Jiangsu Hengrui Medicine Co Ｒ－β－胺基苯丁酸衍生物的製備方法
CN104447374A (zh) * 2013-09-17 2015-03-25 深圳翰宇药业股份有限公司 一种西他列汀及其中间体的制备方法
WO2015145333A1 (fr) 2014-03-26 2015-10-01 Sun Pharmaceutical Industries Limited Procédé de préparation de sitagliptine et son intermédiaire
CN105061434A (zh) * 2015-07-30 2015-11-18 新发药业有限公司 一种低成本的西他列汀磷酸盐的制备方法
WO2015189862A1 (fr) * 2014-06-10 2015-12-17 Council Of Scientific & Industrial Research Amines chirales, procédé pour leur préparation et leur utilisation
CN105315286A (zh) * 2014-07-30 2016-02-10 连云港润众制药有限公司 西格列汀的制备
KR20160146124A (ko) 2015-06-11 2016-12-21 동방에프티엘(주) 시타글립틴의 개선된 제조방법
KR20160148371A (ko) 2015-06-16 2016-12-26 경동제약 주식회사 Dpp-iv 억제제의 제조를 위한 신규 중간체, 이의 제조방법 및 이를 이용한 dpp-iv 억제제의 제조방법
CN106458853A (zh) * 2014-10-11 2017-02-22 浙江华海药业股份有限公司 一种不对称还原法制备西他列汀中间体的方法
CN109928888A (zh) * 2017-12-19 2019-06-25 浙江瑞博制药有限公司 一种西格列汀中间体的制备方法
KR20210057603A (ko) 2019-11-12 2021-05-21 제이투에이치바이오텍 (주) 시타글립틴의 제조방법
CN113121540A (zh) * 2020-01-15 2021-07-16 鲁南制药集团股份有限公司 一种西格列汀游离碱的合成方法
WO2021227641A1 (fr) 2020-05-11 2021-11-18 浙江医药股份有限公司新昌制药厂 PROCÉDÉ DE PRÉPARATION D'UN DÉRIVÉ DE 4-ARYL-β-AMINOACIDE CHIRAL
CN114644568A (zh) * 2020-12-21 2022-06-21 浙江医药股份有限公司新昌制药厂 西格列汀中间体的纯化方法
US11459549B2 (en) 2018-05-10 2022-10-04 China Fortune Way Company Method for biocatalytic synthesis of Sitagliptin and intermediate thereof
KR20220145631A (ko) 2021-04-22 2022-10-31 주식회사 메디켐코리아 시타글립틴 인산염의 개선된 제조방법
CN116891838A (zh) * 2023-09-11 2023-10-17 瑞博(苏州)制药有限公司 烯还原酶突变体、其组合物、生物材料及应用

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US8278486B2 (en) 2008-12-31 2012-10-02 Chiral Quest, Inc. Process and intermediates for the preparation of N-acylated-4-aryl beta-amino acid derivatives
AU2010247193B2 (en) * 2009-05-11 2016-05-19 Generics [Uk] Limited Sitagliptin synthesis
CN102574856B (zh) * 2009-05-11 2016-09-21 基因里克斯(英国)有限公司 西他列汀的合成
US8846916B2 (en) 2009-05-11 2014-09-30 Generics [Uk] Limited Sitagliptin synthesis
WO2010131025A1 (fr) * 2009-05-11 2010-11-18 Generics [Uk] Limited Synthèse de la sitagliptine
CN102574856A (zh) * 2009-05-11 2012-07-11 基因里克斯(英国)有限公司 西他列汀的合成
TWI453182B (zh) * 2009-06-26 2014-09-21 Jiangsu Hengrui Medicine Co Ｒ－β－胺基苯丁酸衍生物的製備方法
WO2011127794A1 (fr) * 2010-04-12 2011-10-20 上海源力生物技术有限公司 Dérivés cycliques chiraux d'acide bêta-aminoarylbutyrique, leurs procédés de préparation et procédés pour la préparation de dérivés chiraux d'acide bêta-aminoarylbutyrique par leur intermédiaire
CN102471294A (zh) * 2010-04-12 2012-05-23 上海源力生物技术有限公司 手性环状β-氨基芳基丁酸衍生物、其制备方法及通过其制备手性β-氨基芳基丁酸衍生物的方法
EP2392575A1 (fr) 2010-06-04 2011-12-07 LEK Pharmaceuticals d.d. Nouvelle approche synthétique pour composés à substitution ß-aminobutyryle
WO2011151443A1 (fr) 2010-06-04 2011-12-08 Lek Pharmaceuticals D.D. Nouvelle approche synthétique de ss-aminobutyryles substitués
EP2397141A1 (fr) 2010-06-16 2011-12-21 LEK Pharmaceuticals d.d. Procédé pour la synthèse d'acides aminés beta et leurs dérivés
EP2423178A1 (fr) * 2010-07-28 2012-02-29 Chemo Ibérica, S.A. Procédé de production de sitagliptine
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
CN102485718A (zh) * 2010-12-03 2012-06-06 浙江海翔药业股份有限公司 西他列汀的中间体及其制备方法
WO2012136383A2 (fr) 2011-04-08 2012-10-11 Lek Pharmaceuticals D.D. Préparation d'intermédiaires de sitagliptine
EP2508506A1 (fr) 2011-04-08 2012-10-10 LEK Pharmaceuticals d.d. Préparation d'intermédiaires de la sitagliptine
US9174930B2 (en) 2011-04-08 2015-11-03 Lek Pharmaceuticals D.D. Preparation of sitagliptin intermediates
EP2527320A1 (fr) 2011-05-27 2012-11-28 LEK Pharmaceuticals d.d. Préparation d'intermédiaires de la sitagliptine
WO2012163815A1 (fr) 2011-05-27 2012-12-06 Lek Pharmaceuticals D.D. Préparation d'intermédiaires de sitagliptine
CN102838603B (zh) * 2011-06-24 2015-05-13 上海医药工业研究院 一种西他列汀的中间体化合物的制备方法
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WO2013013833A1 (fr) 2011-07-27 2013-01-31 Farma Grs, D.O.O. Procédé pour la préparation de sitagliptine et ses sels pharmaceutiquement acceptables
CN102391142A (zh) * 2011-09-30 2012-03-28 山东铂源化学有限公司 一种3-(s)-氨基-4-(2,4,5-三氟苯基)-丁酸酯回收利用方法
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WO2013104774A1 (fr) 2012-01-12 2013-07-18 Lek Pharmaceuticals D.D. Préparation d'ingrédients pharmaceutiques actifs de type acide ss-aminé optiquement purs et leurs intermédiaires
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US9181260B2 (en) 2012-03-02 2015-11-10 Moehs Iberica, S.L. Crystalline form of sitagliptin sulfate
WO2013128000A1 (fr) 2012-03-02 2013-09-06 Moehs Iberica S.L. Nouvelle forme cristalline de sulfate de sitagliptine
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EP2674432A1 (fr) 2012-06-14 2013-12-18 LEK Pharmaceuticals d.d. Nouvelle voie de synthèse pour la préparation de composés à substitution ß-aminobutyryle 5,6,7,8-tétrahydro[1,4]diazolo[4,3-alpha]pyrazines-7-yl
WO2014023930A1 (fr) 2012-08-08 2014-02-13 Cipla Limited Procédé pour la préparation de sitagliptine et composés intermédiaires
US9233967B2 (en) 2012-08-08 2016-01-12 Cipla Limited Process for the preparation of sitagliptin and intermediate compounds
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WO2015145333A1 (fr) 2014-03-26 2015-10-01 Sun Pharmaceutical Industries Limited Procédé de préparation de sitagliptine et son intermédiaire
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US10189760B2 (en) 2014-10-11 2019-01-29 Zhejiang Huahai Pharmaceutical Co., Ltd. Method for preparing sitagliptin intermediate via asymmetrical reduction method
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CN105061434A (zh) * 2015-07-30 2015-11-18 新发药业有限公司 一种低成本的西他列汀磷酸盐的制备方法
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WO2021227641A1 (fr) 2020-05-11 2021-11-18 浙江医药股份有限公司新昌制药厂 PROCÉDÉ DE PRÉPARATION D'UN DÉRIVÉ DE 4-ARYL-β-AMINOACIDE CHIRAL
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