WO2015162506A1 - Procédé de préparation de sitagliptine et nouveaux intermédiaires - Google Patents

Procédé de préparation de sitagliptine et nouveaux intermédiaires Download PDF

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Publication number
WO2015162506A1
WO2015162506A1 PCT/IB2015/052020 IB2015052020W WO2015162506A1 WO 2015162506 A1 WO2015162506 A1 WO 2015162506A1 IB 2015052020 W IB2015052020 W IB 2015052020W WO 2015162506 A1 WO2015162506 A1 WO 2015162506A1
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WIPO (PCT)
Prior art keywords
formula
acid
compound
sitagliptin
trifluoromethyl
Prior art date
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PCT/IB2015/052020
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English (en)
Inventor
Veera Reddy Arava
Udaya Bhaskara Rao Siripalli
Lakshmi Narasimhulu GORENTLA
Venkateswarlu Jasti
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Suven Life Sciences Limited
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Publication of WO2015162506A1 publication Critical patent/WO2015162506A1/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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to an improved process for the preparation of ⁇ -amino acid derivatives. More particularly, the present invention relates to an improved process for the preparation of Sitagliptin of formula lor its pharmaceutically acceptable salts.
  • the present invention also relates to novel intermediates used in the preparation of Sitagliptin.
  • Sitagliptin is an oral antihyperglycemic agent of the dipeptidyl peptidase-IV (DPP-IV) inhibitor class. Inhibition of DPP-IV, an enzyme that inactivates both glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1), represents a recent approaches to the treatment and prevention of type-2 diabetes, also known as non-insulin dependent diabetes mellitus (NIDDM). Sitagliptin also has an effect on appetite as it slows down gastric motility and induces a feeling of satiety. This reduction of appetite can help patients to lose weight which is also a useful effect in patients with diabetes.
  • DPP-IV dipeptidyl peptidase-IV
  • NIDDM non-insulin dependent diabetes mellitus
  • Sitagliptin is chemically designated as (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 and is marketed in the form of dihydrogen phosphate monohydrate under the trade name Januvia®.
  • the empirical formula of Sitagliptin dihydrogen phosphate monohydrate is Ci 6 H 15 F 6 N 5 O.H 3 PO t.H 2 O and it has the following chemical structure:
  • Sitagliptin was first described and claimed in U.S. Pat. No. 6,699,871. This patent describes a class of beta-amino tetrahydrotriazolo[4,3-a]pyrazines, which are inhibitors of DPP-IV.
  • the patent also describes a specific method for producing Sitagliptin or a salt thereof which involves coupling of intermediate compounds, namely (3R)-3-[N-(tert- butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid of formula 2 with 3- trifluoromethyl-5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3-a]pyrazine hydrochloride of formula 3 to afford Boc-protected Sitagliptin of formula 4, which was deprotected using methanolic hydrochloride to obtain Sitagliptin hydrochloride of formula lb.
  • the process is shown in scheme-I given below:
  • the process involves synthesis of diketone compound of formula 8 by condensation of Mel drum's adduct of formula 7 and 3- trifluoromethyl-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3-a]pyrazine hydrochloride of formula 3.
  • the intermediate compound of formula 8 was further treated with (S)-phenylglycine amide in isopropanol and acetic acid to obtain enamide of formula 9, which was further converted to compound of formula 10 by asymmetric hydrogenation at 90 psi and 22°C for 24 hours in the presence of Pt0 2 as catalyst.
  • the intermediate compound of formula 10 was converted into Sitagliptin free base of formula 1 by a debenzylation reaction carried out at 40 psi at 50°C in the presence of 20% palladium hydroxide on carbon.
  • the process is shown in the scheme-II given below:
  • Ph is a phenyl group
  • Scheme-II PCT. Pub. Nos. WO 2011/025932 and WO 2011/060213 discloses process for the preparation of Sitagliptin or its salts, which involves reacting 2,4,5 -trifluorophenyl acetic acid of formula 5 with 2,2-dimethyl-l,3-dioxane-4,6-dione (Meldrum's acid) of formula 6 in the presence of a suitable base in an organic solvent to afford compound of formula 7, which is further reacted with 3-trifluoromethyl-5,6,7,8-tetrahydro[l,2,4]triazolo[4,3-a]pyrazine hydrochloride of formula 3 in the presence of diisopropylethylamine to afford intermediate compound of formula 8.
  • Ph is a phenyl and R is Q-C 4 alkyl group.
  • the present invention provides an improved process for the preparation of Sitagliptin of Formula 1
  • M is H, sodium or potassium
  • R 1 is a substituent on the phenyl group and is selected from hydroxy, halo, alkyl, alkoxy and the like, m is an integer in the range of 1 to 3 and R is Ci-C 6 alkyl group;
  • R and m are as defined above and,
  • the present invention also provides novel intermediate of formula 14
  • R is a substituent on the phenyl group and is selected from hydroxy, halo, alkyl, alkoxy and the like, m is an integer in the range of 1 to 3 and R is Ci-C 6 alkyl group.
  • the present invention also provides novel intermediate of formula 15 or its salts
  • R is a substituent on the phenyl group and is selected from hydroxy, halo, alkyl, alkoxy and the like, m is an integer in the range of 1 to 3 and R is Ci-C 6 alkyl group.
  • the main embodiment of the present invention provides an improved process for the preparation of Sitagliptin or its pharmaceutically acceptable salts of Formula 1, which involves asymmetric synthesis using substituted phenyl alkyl amine derivatives.
  • the present invention provides an improved process for the preparation of Sitagliptin of Formula 1
  • M is H, sodium or potassium
  • R 1 is a substituent on the phenyl group and is selected from hydroxy, halo, alkyl, alkoxy and the like, m is an integer in the range of 1 to 3 and R is Ci-C 6 alkyl group; in a solvent in the presence of an acid to afford enamide of formula 14,
  • R 1 and m are as defined above and,
  • the salts of compound of formula 3a are selected from HCl, HBr, HI and the like.
  • reaction in step (i) is carried out in a suitable solvent in the presence of a base at temperature less than about 120°, less than about 100°, less than about 80°, less than about 60° C, or any other suitable temperature for about 10 minutes to lOhours, or longer.
  • suitable solvent used in step (i) is selected from esters such as methyl acetate, ethyl acetate, n-propyl acetate and isopropyl acetate; nitriles such as acetonitrile; halogenated hydrocarbons such as dichloromethane, ethylene dichloride and chloroform; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, and cyclohexane; ethers such as diethyl ether, diisopropyl ether, methylbutyl ether, tetrahydrofuran, dimethoxyethane and 1,4-dioxane; aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO) and dimethylacetamide; and or mixtures thereof.
  • esters such as methyl acetate, ethyl acetate, n
  • Suitable bases used in step (i) according to the present invention is selected from organic bases such as triethylamine, diisopropyl amine, diisopropylethylamine, pyridine, dimethylamino pyridine (DMAP), diethylamino pyridine (DEAP), N- methyl morpholine, N- methyl pyrrolidone, DBU and sodium/potassium tert-butoxide, sodium methoxide and inorganic bases like sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate or mixtures thereof.
  • organic bases such as triethylamine, diisopropyl amine, diisopropylethylamine, pyridine, dimethylamino pyridine (DMAP), diethylamino pyridine (DEAP), N- methyl morpholine, N- methyl pyrrolidone, DBU and sodium/potassium tert-butoxide, sodium methoxide and inorganic bases
  • the reaction in step (ii) is carried out in a suitable solvent in the presence of an acid.
  • suitable solvents are selected from hydrocarbons such as toluene, xylene, n-hexane, n-heptane, and cyclohexane; alcohols such as methanol, ethanol, isopropyl alcohol, and n-butanol; halogenated hydrocarbons such as dichloromethane, ethylene dichloride, and chloroform; esters such as ethyl acetate, n-propyl acetate, and isopropyl acetate; ethers such as ethyl ether, isopropyl ether, methylbutyl ether, tetrahydrofuran, dimethoxyethane and 1,4- dioxane and or mixtures thereof.
  • Suitable acids used in step (ii) according to the present invention are selected from organic acids such as formic acid, acetic acid, propionic
  • the reduction in step (iii) is carried out in a suitable solvent selected from ethers such as diethyl ether, diisopropyl ether, methylbutyl ether, tetrahydrofuran, dimethoxyethane and 1,4-dioxane; alcohols, such as methanol, ethanol, isopropyl alcohol and n-butanol; halogenated hydrocarbons such as dichloromethane, ethylene dichloride, and chloroform; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, and cyclohexane; aprotic polar solvents such as ⁇ , ⁇ -dimethylformamide (DMF), dimethylsulfoxide (DMSO), and dimethylacetamide (DMA); and or mixtures thereof.
  • ethers such as diethyl ether, diisopropyl ether, methylbutyl ether, tetra
  • Suitable reducing agent used in step (iii) according to the present invention is selected from borohydride such as sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, lithium borohydride, zinc borohydride and the like.
  • Suitable acid used in step (iii) according to the present invention is selected from organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid and the like.
  • the compound of formula 15 is optionally purified by salt formation to enhance the purity.
  • Suitable acids that can be employed for purification of compound of formula 15 are selected from hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid or its derivatives, malic acid, maleic acid, mandelic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, benzenesulphonic acid and camphoric acidand the like.
  • the conversion of compound of formula 15 or its salt to Sitagliptin of formula 1 in step (v) is carried out by hydrogenation using a hydrogen donor in a solvent at temperature less than about 120°, less than about 100°, less than about 80°, less than about 60°C, or any other suitable temperature for about 10 minutes to 2 hours or longer.
  • Suitable hydrogen donors are selected from formic acid or salt thereof, acetic acid, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, trifluoroacetic acid and methanesulphonic acid and the like.
  • the hydrogenation is carried out in suitable solvents used selected from ethers such as diethyl ether, diisopropyl ether, methylbutyl ether, tetrahydrofuran, dimethoxyethane, anisole, diphenyl ether and 1,4-dioxane; alcohols, such as methanol, ethanol, isopropyl alcohol and n- butanol; halogenated hydrocarbons such as dichloromethane, ethylene dichloride, and chloroform; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, and cyclohexane; aprotic polar solvents such as ⁇ , ⁇ -dimethylfornnannide (DMF), dimethylsulfoxide (DMSO), and dimethylacetamide (DMA); and or mixtures thereof.
  • suitable solvents used selected from ethers such as diethyl ether, diisopropyl ether
  • Sitagliptin free base of formula 1 is converted to its pharmaceutically acceptable salts such as phosphate, hydrochloride.
  • the salt formation may be carried out in a suitable solvent selected from alcohols such as methanol, ethanol, isopropyl alcohol, and n-butanol; esters such as ethyl acetate, n-propyl acetate, and isopropyl acetate; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, and cyclohexane; ethers such as 1,4-dioxane and tetrahydrofuran; and water or mixtures thereof.
  • a suitable solvent selected from alcohols such as methanol, ethanol, isopropyl alcohol, and n-butanol; esters such as ethyl acetate, n-propyl acetate, and isopropyl acetate; hydrocarbons such as toluene, xylene, n-hexane, n-heptane, and cyclohexane
  • the present invention provides an improved process for the preparation of Sitagliptin or a pharmaceutically acceptable salt of Formula 1, which comprises:
  • M is H, sodium or potassium
  • the present invention provides an improved process for the preparation of Sitagliptin or a pharmaceutically acceptable salt of Formula 1, which comprises:
  • M is H, sodium or potassium
  • the present invention also provides novel intermediate of formula 14
  • R is a substituent on the phenyl group and is selected from hydroxy, halo, alkyl, alkoxy and the like, m is an integer in the range of 1 to 3 and R is Ci-C 6 alkyl group.
  • the present invention also provides novel intermediate of formula 15 or its salts
  • R is a substituent on the phenyl group and is selected from hydroxy, halo, alkyl, alkoxy and the like, m is an integer in the range of 1 to 3 and R is Ci-C 6 alkyl group.
  • the preferred compounds of formula 15 and formula 14 of the present invention include: 7-[l-oxo-(3R)-(R-l-(4-methoxyphenyl)ethylamino)-4-(2,4,5-trifluorophenyl)-butyl)-3- trifluoromethyl-5,6,7,8-tetrahydro-l,2,4-triazolo[4,3-a]pyrazine;
  • the process of the present invention involves use of less expensive reagents unlike the use of the expensive transition metal catalysts in the prior art.
  • the process of the present invention involves simple procedures for deprotection of p- methoxy benzyl group at penultimate step.
  • Example- 1 describes the nature of the invention and are given only for the purpose of illustrating the present invention in more detail and are not limited and relate to solutions which have been particularly effective on a bench scale.
  • Example- 1 describes the nature of the invention and are given only for the purpose of illustrating the present invention in more detail and are not limited and relate to solutions which have been particularly effective on a bench scale.
  • Dimethoxyethane (1.5 ltr) was cooled to -40°C, sodium borohydride (31.55 g) was added and stirred for about 5 min.
  • Methanesulfonic acid (205.7 g) was added drop wise to the reaction mixture over a period of 30 minutes under constant stirring.
  • DM water (750 ml) and n-hexane (300 ml) were added and stirred the reaction mass for about 10 min.
  • Aqueous layer was separated from organic layer and adjusted the pH of the aqueous layer to 10 with 1: 1 aq. NaOH solution and extracted the compound in to ethyl acetate (750 ml x 2).
  • the solvent was distilled off completely under vacuum to get 109g of title compound.
  • Sitagliptin free base obtained in step (v) 50g was dissolved in ethanol (225ml) and purified water (60ml) at 25-30°C. Heated the reaction mass to a temperature of 50°C and stirred for about 10 min. o-phosphoric acid (85% soln, 1.05 equivalents) was added to the reaction mixture at the same temperature and stirred for about 10 min. The reaction mass was heated again to a temperature of 75°C and stirred for about 10 min. Cooled the temperature of the reaction mass to 65°C, seed sample was added and stirred the reaction mass at this temperature for about 1 hour. Slowly cooled the temperature of the reaction mass to 25-30°C, ethanol (750ml) was added to the reaction mixture and stirred for about 18 hours at this temperature.

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  • Health & Medical Sciences (AREA)
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  • Organic Chemistry (AREA)
  • Diabetes (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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Abstract

La présente invention concerne un procédé amélioré de préparation de dérivés d'acides β-aminés. La présente invention concerne plus particulièrement un procédé amélioré de préparation de Sitagliptine ou de ses sels pharmaceutiquement acceptables de formule 1. La présente invention concerne en outre de nouveaux intermédiaires utilisés dans la préparation de Sitagliptine.
PCT/IB2015/052020 2014-04-21 2015-03-19 Procédé de préparation de sitagliptine et nouveaux intermédiaires WO2015162506A1 (fr)

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IN4736CH2013 2014-04-21

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3524605A1 (fr) * 2018-02-13 2019-08-14 F.I.S.- Fabbrica Italiana Sintetici S.p.A. Nouveau procédé efficace pour la préparation de sitagliptine
CN115260200A (zh) * 2022-08-30 2022-11-01 宿迁阿尔法科技有限公司 一种西他列汀中间体的制备方法

Citations (7)

* 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
WO2011025932A2 (fr) 2009-08-28 2011-03-03 Dr. Reddy's Laboratories Ltd. Préparation de la sitagliptine et de ses sels
WO2011060213A2 (fr) 2009-11-12 2011-05-19 Dr. Reddy's Laboratories Ltd. Préparation de la sitagliptine et de ses sels
WO2012148246A2 (fr) * 2011-04-29 2012-11-01 Daewoong Pharmaceutical Co., Ltd. Procédé de préparation de sitagliptine
WO2013065066A1 (fr) * 2011-11-02 2013-05-10 Cadila Healthcare Limited 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
CN103319487A (zh) * 2013-01-10 2013-09-25 药源药物化学（上海）有限公司 西格列汀的制备方法及其中间体

Patent Citations (7)

* 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
WO2011025932A2 (fr) 2009-08-28 2011-03-03 Dr. Reddy's Laboratories Ltd. Préparation de la sitagliptine et de ses sels
WO2011060213A2 (fr) 2009-11-12 2011-05-19 Dr. Reddy's Laboratories Ltd. Préparation de la sitagliptine et de ses sels
WO2012148246A2 (fr) * 2011-04-29 2012-11-01 Daewoong Pharmaceutical Co., Ltd. Procédé de préparation de sitagliptine
WO2013065066A1 (fr) * 2011-11-02 2013-05-10 Cadila Healthcare Limited 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
CN103319487A (zh) * 2013-01-10 2013-09-25 药源药物化学（上海）有限公司 西格列汀的制备方法及其中间体

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3524605A1 (fr) * 2018-02-13 2019-08-14 F.I.S.- Fabbrica Italiana Sintetici S.p.A. Nouveau procédé efficace pour la préparation de sitagliptine
WO2019158285A1 (fr) * 2018-02-13 2019-08-22 F.I.S. - Fabbrica Italiana Sintetici S.P.A. Nouveau procédé efficace pour la préparation de sitagliptine
CN111712500A (zh) * 2018-02-13 2020-09-25 意大利合成制造有限公司 制备西他列汀的新的有效方法
US11174266B2 (en) 2018-02-13 2021-11-16 F.I.S.—Fabbrica Italiana Sintetici S.p.A. Efficient process for the preparation of sitagliptin
CN111712500B (zh) * 2018-02-13 2023-07-11 意大利合成制造有限公司 制备西他列汀的有效方法
CN115260200A (zh) * 2022-08-30 2022-11-01 宿迁阿尔法科技有限公司 一种西他列汀中间体的制备方法
CN115260200B (zh) * 2022-08-30 2024-03-26 宿迁阿尔法科技有限公司 一种西他列汀中间体的制备方法

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