WO2013114173A1 - Nouveau procédé de préparation de sitagliptine - Google Patents

Nouveau procédé de préparation de sitagliptine Download PDF

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Publication number
WO2013114173A1
WO2013114173A1 PCT/IB2013/000099 IB2013000099W WO2013114173A1 WO 2013114173 A1 WO2013114173 A1 WO 2013114173A1 IB 2013000099 W IB2013000099 W IB 2013000099W WO 2013114173 A1 WO2013114173 A1 WO 2013114173A1
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WO
WIPO (PCT)
Prior art keywords
formula
solvents
sitagliptin
process according
amino
Prior art date
Application number
PCT/IB2013/000099
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English (en)
Inventor
Sambhu Prasad Sarma Mallela
Shrikant Hanumantappa HAVALE
Nagabhushana Rao BODDEPALLI
Nagarjuna GUNJI
Bhavani Sankar MOKKAPATI
Original Assignee
Smilax Laboratories Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Smilax Laboratories Limited filed Critical Smilax Laboratories Limited
Publication of WO2013114173A1 publication Critical patent/WO2013114173A1/fr

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    • 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
    • C07C227/30—Preparation of optical isomers
    • C07C227/34—Preparation of optical isomers by separation of optical isomers
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention is directed to a process for the preparation of enantiomerically enriched ⁇ -amino acid derivatives which are important chiral building blocks and intermediates in pharmaceuticals. More specifically, the invention pertains to a novel process for practically convenient and economically producing enantiomerically enriched ⁇ -amino acid derivatives that are useful for the synthesis of amide inhibitors of dipeptidyl peptidase IV like Sitagliptin, which have been used to treat type 2 diabetes.
  • Sitagliptin is 3(R)-amino-l(3-(trifluoromethyl)-5,6,7,8-tetrahydro-(l,2,4)triazolo(4,3- a)pyrazin-7-yl)-4-(2,4,5-trifluorophenyl)butan-l-one of Formula I and its pharmaceutically acceptable salts has the f llowing chemical structure
  • Sitagliptin phosphate is a glucagons-like peptide 1 metabolism modulator, hypoglycemic agent and dipeptidyl peptidase IV inhibitor.
  • Sitagliptin phosphate is currently marketed in the United States under the trade name JANUVIATM in its monohydrate form. JANUVIATM is indicated to improve glycemic control in patients with type 2 diabetes mellitus.
  • Sitagliptin phosphate is described in PCT publication No WO 2005/003135. Sitagliptin can be obtained by the condensation of the two key intermediates.
  • the first intermediate is (3R)-amino-4-(2,4,5-trifluorophenyl)butanoic acid (Synthon
  • the second intermediate is 3-(trifluoromethyl)-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3- a]pyrazine hydrochloride (Synthon 2) having the following formula
  • PCT publication No WO 2003/004498 discloses a method of introducing a chiral amine group using a chiral pyrazine derivative and to prepare sitagliptin by Arndt- Eistert Homologation using t-butyloxycarbonylamino-4-(2,4,5-trifluorophenyl)- butyric acid.
  • Boc is tert-butoxycarbonyl
  • TEA is trimethyl amine
  • HOBt is 1-hydroxybenzotriazole
  • EDC is N-ethyl-N'-(3-dimethylaminopropyl)carcodiimide
  • DIPEA is N,N-diisopropylethylamine.
  • PCT publication NO WO 2004/087650 refers to the synthesis of sitagliptin via the stereoselective reduction of methyl 4-(2,4,5-trifluorophenyl)-3-oxobutanoate to produce the sitagliptin intermediate (S ⁇ methyl 4-(2,4,5-trifluorophenyl)-3- hydroxybutanoate.
  • the said stereoselective reduction is performed by hydrogenation with H 2 and (S)BINAP-RuCl 2 catalyst in presence of hydrochloric acid followed by inversion of stereochemical centre, achieved by Mitsunobu cyclization of (35)-N- benzyloxy-3-hydroxy-4-(2,4,5-trifluorophenyl)butyramide.
  • the process is illustrated in the below scheme:
  • BINAP is 2,2'-bis(diphenylphosphino)-l,l '-binaphthyl
  • EDC is N-ethyl-N 3-dimethylaminopropyl)carbodiimide
  • Bn is benzyl
  • DIAD is diisopropyl azodicarboxylate
  • ACN is acetonitrile
  • PCT publication No WO 2004/085378 refers to the synthesis of Sitagliptin intermediate (3R)-[protected-amino]4-(2,4,5-trifluorophenyl)butanoic acid via stereoselective hydrogenation of a prochiral enamine, 3-Amino-l(3-trifluoromethyl- 5,6-dihydro-8Htl,2,4]triazole[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 2005/097733 discloses the preparation of sitagliptin by enantioselective hydrogenation of (2Z)-4-oxo-4-[3(trifluoromethyl),5,6- dihydri[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-l-(2,4,5-trifluorophenyl)but-2-en- 2amine in the presence of rhodium metal precursor complexed with a chiral mono or biphosphine ligand.
  • DMAP 4-(dimethylamino)pyridine
  • DMAc is N.N-Dimethylacetamide.
  • WO 2006/081 151 describes the asymmetric hydrogenation which is carried out in presence of ammonium salt and a transition metal precursor complexed with a chiral ferrocenyl diphosphine ligand.
  • WO 2009/084024 discloses process for the preparation of Sitagliptin and its pharmaceutically acceptable salts by resolving the amine with a resolving agent.
  • the resolving agent is dibenzyl-L- tartaric acid.
  • the said patent describes that the chiral purity obtained is only 85-90 % that too after repeated recrystallizations.
  • WO 2009/085990 discloses process for the preparation of Sitagliptin by using phenylalkyl amine as a chiral handle for crystallization of diastereomeric mixture as shown below:
  • WO 2009/064476 discloses a process for intermediate compounds in the synthesis of Sitagliptin, 3-amino-4-(2,4,5-trifluorophenyl)but-2-enoic acid alkyl ester and the stereoselective reduction of these compound to give (3R)-amino-4- (2,4,5trifluorophenyl)butanoic acid of the following formula:
  • the WO 2009/064476 discloses a process for preparing the above intermediate from corresponding imine ester of followin formula:
  • PCT publication No WO 2010/131025 discloses a process for the preparation of enantiomerically enriched ⁇ -amino acid derivatives such as ⁇ -amino esters useful for the synthesis of enantiomerically enriched biologically active molecules such as sitagliptin.
  • the process utilizes the resolution of the racemate with mandelic acid which is shown below:
  • US 2011/0130587 Al discloses a process for preparing single enantiomers of ⁇ - amino phenylbutyric acid derivatives and pharmaceutically acceptable salts thereof, which affords the desired compounds having special optical configuration.
  • the process comprises a step of chemical synthesis and a step of resolving the optical isomers of ⁇ -amino phenylbutyric acid derivatives with a resolving agent.
  • R-P-amino phenylbutyric acid derivatives (II) have high optical purity, and the total yield of the accumulative resolution of the leavo and the dextro isomer is up to above 70%.
  • Resolving agents used in the above reaction are dibenzoyl-D-tartaric acid, dibenzoyl- L-tartaric acid, di-p-toluoyl-D-tartaric acid, di-p-toluoyl-L-tartaric acid.
  • PCT publication No 2010/122578 also discloses a process for the preparation of Sitagliptin and intermediates which is shown below:
  • US 2011/0213149 Al discloses the synthesis of ⁇ -amino acid derivatives of formula (I) and its salts by a novel process.
  • the process comprises the reduction of a protected or unprotected prochiral ⁇ -amino acrylic acid or derivative there of, by using borane containing reducing agents at atmospheric pressure.
  • the resulting racemic ⁇ -amino compound is resolved to a pure stereoisomer of formula (I), specifically to (2R)-4- oxo-4-[3-Ctrifluoromethyl)-5,6-dihydrol[l,2,4]triazolo[4,3-alpyrazin-7(8H)-yl]-l- (2,4,4-trifluorophenyl)butan-2 -amine.
  • Tetrahedron Asymmetry 17(2006), 205-209 describes asymmetric hydrogenation enamines to the preparation of ⁇ -amino acid pharmacophore.
  • the prior-art teaches a variety of asymmetric synthesis to prepare enantiomerically enriched ⁇ -amino acids and their derivatives in the preparation of Sitagliptin.
  • the prior-art also illustrates the importance of ⁇ -amino acid derivatives as key intermediates for the synthesis of sitagliptin.
  • the prior-art suffers from various disadvantages with respect to commercial production. These above mentioned asymmetric synthesis provide products with low purity. Hence, a further purification is needed to control the stereo-selectivity and improve optical purity.
  • Optical resolution is a particularly convenient technique for the commercial production of chiral molecules as the technique eliminates the economic problems associated with asymmetric synthesis.
  • the resolution of racemic ⁇ - amino acids or derivatives to obtain enantiomerically enriched ⁇ -amino acids or derivatives and their subsequent conversion into enantiomerically enriched sitagliptin free base and its dihydrogen phosphate salt is not widely reported in the prior-art.
  • the present inventors have developed a method of resolution of racemic ⁇ -amino acid derivatives, in particular ⁇ -amino esters, to obtain enantiomerically pure sitagliptin and salts thereof.
  • the main object of the present invention is to provide a novel process for the preparation of compound of Formula I and its pharmaceutically acceptable salts.
  • Another main objective of the invention is to provide an improved process for effectively resolving a mixture of (R) and (S) isomers ⁇ -amino acid in any proportion, to obtain either of the isomer in an enantiomeric purity of at least 99 %.
  • Another object of the present invention is to prepare an enantiomerically enriched ⁇ - amino acid derivative of Formula II and its salts.
  • Another object of the present invention is further conversion of Formula II to Sitagliptin.
  • the present invention relates to a novel process for the preparation of ⁇ -amino acid intermediates of Formula Ila and its enantiomers lib.
  • Ar denotes phenyl and substituted phenyl
  • Ri - R 2 is aryl, alkyl, O-alkyl, O-phenyl, O-arylalkyl to give Sitagliptin of Formula I.
  • the present invention comprises a process for the preparation of sitagliptin free base and its salts with chiral acids by a simple, reliable, convenient and commercially acceptable process as detailed below.
  • the present invention provides a simple, convenient process for the preparation of compound of Formula Ila or lib.
  • the present invention also provides a process for the preparation of enantiomerically enriched sitagliptin free base and sitagliptin dihydrogen phosphate using enantiomerically enriched ⁇ -amino acid derivative of Formula Ha or lib.
  • a preferred embodiment of the present invention involves a process of resolving racemic compound of Formula II with compound of Formula Ilia or Illb to obtain enantiomerically enriched ⁇ -amino acid derivative of Formula Ila or lib.
  • the enantiomerically enriched ⁇ -amino acid derivative obtained is converted into enatiomerically enriched sitagliptin of Formula I or its dihydrogen phophate salt.
  • the process comprises the steps of :
  • step (a) treating the racemic ⁇ -amino acid derivative of Formula II with a compound of Formula Ilia or Illb to obtain enantiomerically enriched ⁇ -amino acid salts and b) optionally crystalizing the enantiomerically enriched ⁇ -amino acid salt and c) dissolving or suspending the enantiomerically enriched ⁇ -amino acid salt obtained in step (a) or (b) in an organic solvent or water or a mixture thereof and adjusting the pH of the solution or suspension with a base to obtain an enantiomerically enriched ⁇ -amino acid derivative of Formula Ila or Formula lib
  • the compounds of Formula Ilia or Illb include but not limited to are N-acetyl-L- phenylalanine, (S)-l-2-pentamido-3-phenylpropanoic acid, (S)-l-(phenoxycarbonyl) pyrrolodine-2-carboxylic acid.
  • the obtained compounds were characterized by spectroscopic methods.
  • the resolution step can be performed in a alcoholic solvents, chlorosolvents, ketone solvents, hydrocarbon solvents, nitrile solvents, ester solvents, ether solvents, polar solvents, polar aprotic solvents and mixtures thereof
  • the chiral N-acetyl-D-Phenylalanine was recovered by acidifying the aqueous layer by cone. HC1 and then filtered and dried under vacuum.
  • the present invention also includes stereo-selective process for the preparation of sitagliptin for which process comprises the following.
  • step (b) isolating the salt formed from sitagliptin and chiral acid of formula Ilia or Illb. c) converting the salt from step (b) to sitagliptin phosphate of Formula I.
  • the racemic Sitagliptin and N-acetyl-D-phenylalanine in methanol was refluxed for about 30 minutes and allowed to cool to ambient temperature.
  • the reaction mixture was maintained at ambient temperature for about 15 hrs.
  • the resulting precipitate was collected by filtration, washed with methanol and dried to obtain Sitagliptin having a chiral purity of >99 % by HPLC.
  • the obtained sitaglitpin was subsequently converted to pharmaceutically acceptable ⁇ salts.
  • the resolution step of resolving racemic Sitagliptin can be performed in a alcoholic solvents, chlorosolvents, ketone solvents, hydrocarbon solvents, nitrile solvents, ester solvents, ether solvents, polar solvents, polar aprotic solvents and mixtures thereof
  • the optical purity of the optically active intermediate compounds was determined by chiral HPLC methods
  • the present invention has certain advantages over the prior-art methods like the use of n-acetyl-l-phenylalanine of Formula III, it is possible to resolve the enantiomers of Formula II with high yield.
  • prior-art processes are either with respect to the resolution agent for the separation of isomers or use entirely different agents for the optical resolution. There are no suggestions in the prior-art which might point the skilled person towards the use of compound of Formula III as the resolution agent.
  • the resolving agents employed in the present invention are recoverable in a quality fit for recycling as a resolving agent, thereby making the process economical
  • the Sitagliptin prepared by the process of the present invention are suitable for pharmaceutical composition
  • reaction mass was acidified with 30% aq.citric acid at pH 5.5-6.0.
  • the resulting solution was extracted with MDC (3x 100 ml).
  • the organic layer was washed with brine, dried over sodium sulphate and concentrated to give a thick residue. This thick mass was triturated with n-Hexane to give 1.8 gm of product.
  • Racemic Sitagliptin (3 gm, 0.0073moles) and N-acetyl-D-phenylalanine (1.53gm, 0.0073moles) in methanol (120 ml) were refluxed for 30 minutes, allowed to cool to 20 to 25° C and maintained at same temperature for 15hrs.
  • the resulting precipitate was collected by filtration, washed with methanol (10 ml) and dried at 50 to 55° C under vacuum.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Analytical Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de préparation de dérivés de β-aminoacides enrichis énantiomériquement qui sont des blocs de construction et des intermédiaires chiraux importants dans des produits pharmaceutiques. De manière plus spécifique, l'invention concerne un nouveau procédé de production pratique et économique de dérivés de β-aminoacides enrichis énantiomériquement, utiles pour la synthèse d'inhibiteurs de type amide de la dipeptidyle peptidase IV, analogues à la sitagliptine, qui ont été utilisés pour traiter le diabète de type 2.
PCT/IB2013/000099 2012-01-30 2013-01-28 Nouveau procédé de préparation de sitagliptine WO2013114173A1 (fr)

Applications Claiming Priority (2)

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IN338CH2012 2012-01-30
IN338/CHE/2012 2012-01-30

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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
WO2015145333A1 (fr) 2014-03-26 2015-10-01 Sun Pharmaceutical Industries Limited Procédé de préparation de sitagliptine et son intermédiaire
WO2015189862A1 (fr) * 2014-06-10 2015-12-17 Council Of Scientific & Industrial Research Amines chirales, procédé pour leur préparation et leur utilisation
CN106892832A (zh) * 2017-03-14 2017-06-27 珠海联邦制药股份有限公司 一种西格列汀杂质及其制备方法
CN112209931A (zh) * 2019-07-10 2021-01-12 浙江昌海制药有限公司 一种提高西格列汀收率和纯度的工艺方法
WO2024121301A1 (fr) 2022-12-09 2024-06-13 Krka, D.D., Novo Mesto Procédé de préparation de sitagliptine

Citations (3)

* 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
CN101928289A (zh) * 2009-06-19 2010-12-29 北京海步国际医药科技发展有限公司 制备二肽基肽酶-iv抑制剂的方法
CN101959406A (zh) * 2008-03-04 2011-01-26 默沙东公司 二甲双胍和二肽基肽酶-ⅳ抑制剂的组合的药物组合物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101959406A (zh) * 2008-03-04 2011-01-26 默沙东公司 二甲双胍和二肽基肽酶-ⅳ抑制剂的组合的药物组合物
WO2010131025A1 (fr) * 2009-05-11 2010-11-18 Generics [Uk] Limited Synthèse de la sitagliptine
CN101928289A (zh) * 2009-06-19 2010-12-29 北京海步国际医药科技发展有限公司 制备二肽基肽酶-iv抑制剂的方法

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015145333A1 (fr) 2014-03-26 2015-10-01 Sun Pharmaceutical Industries Limited Procédé de préparation de sitagliptine et son intermédiaire
WO2015189862A1 (fr) * 2014-06-10 2015-12-17 Council Of Scientific & Industrial Research Amines chirales, procédé pour leur préparation et leur utilisation
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
CN106892832A (zh) * 2017-03-14 2017-06-27 珠海联邦制药股份有限公司 一种西格列汀杂质及其制备方法
CN112209931A (zh) * 2019-07-10 2021-01-12 浙江昌海制药有限公司 一种提高西格列汀收率和纯度的工艺方法
WO2024121301A1 (fr) 2022-12-09 2024-06-13 Krka, D.D., Novo Mesto Procédé de préparation de sitagliptine

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