WO2020089828A1 - Procédé amélioré pour la préparation de sitagliptine et de ses intermédiaires - Google Patents

Procédé amélioré pour la préparation de sitagliptine et de ses intermédiaires Download PDF

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Publication number
WO2020089828A1
WO2020089828A1 PCT/IB2019/059349 IB2019059349W WO2020089828A1 WO 2020089828 A1 WO2020089828 A1 WO 2020089828A1 IB 2019059349 W IB2019059349 W IB 2019059349W WO 2020089828 A1 WO2020089828 A1 WO 2020089828A1
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Prior art keywords
formula
intermediate compound
compound
acid
substituted
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PCT/IB2019/059349
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English (en)
Inventor
Satyanarayana Janagani
Venkateshwar Kumar Thaduri
Venugopala Rao BANDI
Ravisankar VAMARAJU
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Stereokem Pvt. Ltd.
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Publication of WO2020089828A1 publication Critical patent/WO2020089828A1/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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/16—Preparation of optical isomers
    • C07C231/18—Preparation of optical isomers by stereospecific synthesis
    • 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
    • C07C269/04—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 from amines with formation of carbamate groups
    • 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
    • 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 relates to a process for the preparation of novel intermediates useful for the preparation of Sitagliptin or its pharmaceutically acceptable salts.
  • the present invention relates to an efficient process for the preparation of Sitagliptin intermediates.
  • the present invention relates to an improved process for the preparation of Sitagliptin or its pharmaceutically acceptable salts.
  • 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-l), 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. Sitagliptin which exists as its phosphate salt is chemically described as 7-[(3R)-
  • 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 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:
  • the second intermediate is 3-(trifluoromethyl)-5,6,7,8-tetrahydro [l,2,4]triazolo[4,3-a]pyrazine (“Synthon II”), having the following formula:
  • Sitagliptin was first described and claimed in US 6,699,871 and describes the preparation of Sitagliptin hydrochloride salt, while US 7,326,708 claims the phosphate salt of Sitagliptin or a hydrate thereof.
  • the key step in the synthesis of Sitagliptin is the condensation of synthon I and synthon II. This being a peptide bond formation, according to the prior art, standard peptide coupling conditions and reagents are used.
  • WO2004/085661 discloses the preparation of Sitagliptin using S-phenylglycine amide as a chiral auxiliary.
  • WO2004/085378, WO2005/097733, and WO2006/081151 disclose the preparation of Sitagliptin which involves an enantioselective reduction of the intermediate chiral enamine in the presence of specific catalysts.
  • WO2009/085990 discloses the preparation of Sitagliptin using various chiral auxiliaries, such as chiral resolving agents.
  • compound of Formula lla or its enantiomer of Formula lib are condensed with compound of Formula III or its salt thereof, to form a compound of Formula IVa, or its enantiomer of Formula IVb respectively.
  • This is followed by hydrogenolysis of compound of Formula IVa or its enantiomer of a compound of Formula IVb to the give corresponding compound of Formula la or compound of Formula lb.
  • the compounds of Formula la or lb are further converted to Sitagliptin or pharmaceutically acceptable salts. While these methods are useful for preparing Sitagliptin, alternative methods of the preparation, particularly for manufacturing scale production, are desirable. Hence, there still exists a need for an efficient and economical synthesis of Sitagliptin or its pharmaceutically acceptable salts, which provides highly pure final product with high yield.
  • the main objective of the present invention is to provide a process for preparation of novel intermediates of Sitagliptin or its pharmaceutically acceptable salts.
  • Another objective of the present invention is to provide novel intermediates of Sitagliptin or its pharmaceutically acceptable salts.
  • Yet another objective of the present invention is to provide a feasible and commercially viable process for preparation Sitagliptin or its pharmaceutically acceptable salts employing the novel intermediates.
  • the present invention provides an improved process for the preparation of intermediate compound of Formula (IV)
  • R H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl; wherein the process comprises the steps of:
  • the present invention provides process for the preparation of intermediate compound of Formula (III)
  • the present invention provides the compound of Formula (P)
  • R H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl.
  • the present invention provides the compound of Formula
  • R H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl; and Ph is substituted or unsubstituted.
  • the present invention provides an improved process for the preparation of compound of Formula (IV) which comprises reduction of the compound of Formula (III) with various reducing agents.
  • the present invention provides an improved process for the preparation of compound of Formula (VI)
  • R 1 is as defined above
  • R 1 is as defined above, and
  • R 1 is as defined above, wherein the process comprises the steps of:
  • R 1 represents alkyl and Hal represents halogen, in presence of base and solvent to give carbamate compound of Formula (VII).
  • the present invention provides use of intermediate compounds of Formula (II), Formula (III), Formula (VII) and Formula (VIII) in the preparation of Sitagliptin or its pharmaceutically acceptable salts.
  • the present invention provides an improved process for the preparation of Sitagliptin or its pharmaceutically acceptable salts.
  • the present invention provides an improved process for the preparation of intermediate compound of Formula (IV) starting from compounds of Formula (I).
  • the present invention also provides novel intermediate compounds of Formula (II) and Formula (III).
  • These intermediate compounds of Formula (II) and Formula (III) are used in the preparation of Sitagliptin or its pharmaceutically acceptable salts.
  • the present invention also provides process for the preparation of novel intermediate compound of Formula (II) and Formula (III).
  • the present invention also provides an improved process for the preparation of novel intermediate compound of Formula (IV), Formula (V), Formula (VI), Formula (VII) and Formula (VIII).
  • Formula (VII) and Formula (VIII) are used in the preparation of Sitagliptin or its pharmaceutically acceptable salts.
  • the compound of Formula (I) is converted to compound of Formula (II) by treating with an amine derivative R-NH 2 in an organic solvent. After completion of the reaction, the organic solvent was distilled off and the obtained solid was washed with an appropriate solvent.
  • the obtained novel intermediate compound of Formula (II) is further converted to compound of Formula (III).
  • the obtained compound of Formula (II) is treated with substrate (R)-Phenylethylamine in presence of an organic acid in an organic solvent. After completion of the reaction, solvent was distilled off completely under vacuum to obtain compound of Formula (III).
  • Formula (III) may be isolated or not. Any of the above reactions may be carried out in- situ to obtain Sitagliptin or its pharmaceutically acceptable salts.
  • the above compounds may be isolated as salts or free bases. If the above compounds are isolated as salts, they are converted to their free bases first and used for further reactions.
  • the intermediate compound of Formula (III) is reduced to intermediate compound of Formula (IV) using a reducing agent in an organic solvent.
  • the reduction is carried out in the presence of an acid.
  • the hydrogenolysis of compound of Formula (IV) is converted in to compound of Formula (V) using metal catalysts with hydrogen pressure in the range of 8-12 kg/cm 2 followed by hydrolysis and protection of amine group to give compound of Formula (VI).
  • the hydrogenolysis is carried out in an alcohol solvent using a catalyst followed by hydrolysis and protection of amine group to give compound of Formula (VI).
  • This hydrogenolysis is carried out in presence of an acid and subsequent protection of the amine group which is carried out in situ.
  • the appropriate amine protecting group are selected from acetyl, di-tert-butyl dicarbonate, benzoyl tert- butyloxycarbonyl (BOC), carbobenzyloxy, -methoxybenzyl carbonyl, 9- fluorenylmethyloxycarbonyl, benzyl group, 3,4-dimethoxybenzyl, -methoxyphenyl etc. more preferably di-tert-butyl dicarbonate.
  • the amine protection reaction is carried out in ether solvents. After completion of the reaction, solvent was removed and the crude product was washed with an appropriate solvent followed by pH adjustment with HC1. The organic layer and aqueous layer was washed with an organic solvent. The combined organic layer was again washed with water and distilled off completely under vacuum. The obtained crude was washed with an appropriate solvent and the obtained solid was filtered to give compound of Formula (VI).
  • the compound of Formula (VI) is further converted to carbamate compound of Formula (VII) using appropriate reactive acid derivatives, wherein the conversion may be optionally carried in-situ which in turn is condensed with Synton II to give compound of Formula (VIII).
  • reactive acid derivatives means halides like branched aliphatic carboxylic acid halides, such as e.g. 2-ethylbutyryl chloride, cyclohexanecarboxylic acid chloride, 2,2-dimethyl-propionyl chloride, pivaloyl chloride and isovaleroyl chloride and more preferably, acid derivatives are pivaloyl chloride, isovaleroyl chloride and ethyl chloroformate.
  • the intermediate compound of Formula (IV) is further converted to Sitagliptin or its pharmaceutically acceptable salts in a number of steps.
  • the conversion of compound of Formula (VI) to compound of Formula (VIII) is carried out using any conventional bases.
  • the conversion of compound (VI) to compound of Formula (VIII) is carried out in suitable solvent.
  • obtained compound of Formula (VII) is coupled with Synthon II to obtain intermediate compound of Formula (VIII), wherein the carbamate and coupling process may be optionally carried out in-situ.
  • the compound of Formula (VII) along with reactive acid halide is dissolved in suitable solvent and in a suitable base; then Synthon II is added portion wise.
  • the reaction mixture is stirred for 4 hrs and after completion of the reaction, solvent is distilled off under vacuum and the obtained solid was dried to give compound of Formula (VIII) directly.
  • the obtained compound of Formula (VIII) is hydrolyzed to give Sitagliptin or its pharmaceutically acceptable salts.
  • the hydrolysis is carried out by adding appropriate acid.
  • the reaction mixture was stirred for 2 hrs and water was added.
  • the reaction mixture was cooled and pH adjusted to 11-12.
  • the reaction mixture was extracted with appropriate solvent and dried to give Sitagliptin.
  • Compound of Formula (I) can be prepared by any known methods in the art.
  • alkyl group as used herein is a straight or branched, substituted or unsubstituted alkyl.
  • the substituents on alkyl group are selected from C C 6 alkyl, halogen such as chloro, bromo, fluoro, iodo; nitro, hydroxyl, 6 to 10 member aryl ring such as phenyl, napthyl.
  • aryl group as used herein is substituted or unsubstituted selected from phenyl, naphthyl, anthryl, phenanthryl or biphenyl.
  • the substituents on aryl group are selected from halogen such as chloro, bromo, fluoro, iodo; nitro, hydroxyl, cyano, amino.
  • heteroaryl group as used herein is substituted or unsubstituted2,3-dihydroindene, indene, indoline, 3H-indole, lH-indole, 2H-isoindole, indolizine, lH-indazole, benzimidazole, 7-azaindole, 4-azaindole, 5- azaindole, 6-azaindole, 7-azaindazole, pyrazolo[l,5-a] pyrimidine, purine, benzofuran, isobenzofuran, benzo[c]thiophene, benzo[b] thiophene, 1 ,2-benzisoxazole, 2,1- benzisoxazole, l,2-benzisothiazole, 2,l-benzisothiazole, benzoxazole, benzthiazole, benzo[c][l,2,5]thiadiazole
  • the substituents on heteroaryl group are selected from halogen such as chloro, bromo, fluoro, iodo, nitro, hydroxyl, (C C 6 ) alkyl group, which may further be substituted, alkoxyalkyl, 6 to 10 member aryl ring such as phenyl, napthyl.
  • solvent used in the present invention are selected from "alcohol solvents” such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like or "hydrocarbon solvents” such as benzene, toluene, xylene, heptane, hexane and cyclohexane and the like or "ketone solvents” such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like or "esters solvents” such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, and the like or "nitrile solvents” such as acetonitrile,
  • base used in the present invention is selected from either inorganic base like ammonium hydroxide; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate and lithium carbonate; alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof or silicon- based amides, such as sodium and potassium bis(trimethylsilyl)amide, lithium hexamethyldisilazide, sodium hexamethyldisilazide and potassium hexamethyldisilazide or organic bases such as LDA (lithium diisoprop ylamide), aniline, triethylamine, triethanolaminetributylamine, N-alkyl morpholines, N-
  • DBU l,5-diazabicyclo[4.3.0]non-5-ene
  • DBN l,4-diazabicyclo[2.2.2]-octane
  • salts refers to salts which are known to be non-toxic and are commonly used in the pharmaceutical literature.
  • Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and the like.
  • Such salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene- 2-benzoate, bromide, isobutyrate, phenylbutyrate, beta-hydroxybutyrate, chloride, cinnamate, citrate, formate, fumarate, glycolate, heptanoate, lactate, maleate, hydroxymaleate, malonate, mesylate, nitrate, oxalate, phthalate, phosphate, monohydro genphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, propionate, phenylpropionate, salicylate, succinate, sulfate, bisulfate, pyrosulfate, sulfite, bisulfite,
  • Reducing agent as used herein is and not limited to NaHg, ZnHg, ZnCl 2 , MgCl 2 , diborane, lithium borohydride, sodium borohydride, potassium borohydride, cesium borohydride iron sulfate, tin chloride, dithionates, DIBAL-H, phosphonic acid, hypophosphite, phosphite, tetrakis ⁇ 3,5-trifluoromethyl ⁇ phenyl borate and l,4-Dithio- D-threitol.
  • Acid used in hydrogenation herein is and not limited to inorganic acid such as hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid and perchloric acid, poly phosphoric acid, cone.
  • H 2 SO 4 organic acid selected from formic acid, acetic acid, propionic acid, citric acid and oxalic acid.
  • the present invention is to provide an improved process for the preparation of intermediate compound of Formula (IV)
  • R H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl; wherein the process comprises the steps of:
  • the present invention is to provide an improved process for the preparation of compound of Formula (VI)
  • reaction mixture was further cooled to -45 °C and sodium borohydride (17.5 g, 0.46 mol) added portion wise in 1 hr. Subsequently, the reaction temperature was allowed to reach to room temperature and quenched with 1000 ml of water slowly at below 20 °C. The pH of the reaction mixture was adjusted to 9 with 50% lye solution at below 20 °C. The organic layer was separated and washed with another 300 ml of water. The organic layer was distilled off completely and cooled to room temperature. Then Di isopropyl ether (300 ml) was added to the residue and stirred for 1 hr. The obtained solid was filtered and washed with diisopropyl ether again to obtain title compound (140 g, 80%).
  • the pH of the reaction mixture was adjusted to 2-3 with hydrochloric acid at 0-5 °C.
  • the organic layer was separated and aq. layer was washed with another 100 ml of ethyl acetate. Combined organic layers were washed with water (100 ml) and distilled off completely under vacuum. n-Hexane (150 ml) was added to the crude product and stirred for 30 min at room temperature. The obtained solid was filtered to obtain the title compound (23 g, 88%).

Abstract

La présente invention concerne un procédé de préparation de nouveaux intermédiaires utiles pour la préparation de sitagliptine ou de ses sels pharmaceutiquement acceptables. La présente invention concerne un procédé efficace pour la préparation d'intermédiaires de sitagliptine. La présente invention concerne également un procédé amélioré pour la préparation de sitagliptine ou de ses sels pharmaceutiquement acceptables.
PCT/IB2019/059349 2018-11-01 2019-10-31 Procédé amélioré pour la préparation de sitagliptine et de ses intermédiaires WO2020089828A1 (fr)

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IN201841041324 2018-11-01

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111057061A (zh) * 2019-12-25 2020-04-24 台州保灵药业有限公司 一种叔丁氧羰基-西他列汀的制备方法
CN114195664A (zh) * 2021-12-30 2022-03-18 辰欣药业股份有限公司 一种磷酸西格列汀关键中间体的制备方法
WO2023175492A1 (fr) * 2022-03-14 2023-09-21 Hikal Limited Nouveaux intermédiaires et leur utilisation dans la fabrication de sitagliptine

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
RAM NAJAR KUSHWAHA ET AL.: "Discovery of 17 Gliptins in 17-Years of Research for the Treatment of Type 2 Diabetes: A Synthetic Overview", CHEMISTRY & BIOLOGY INTERFACE, vol. 4, no. 3, 14 June 2014 (2014-06-14), pages 137 - 162, ISSN: 2249-4820 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111057061A (zh) * 2019-12-25 2020-04-24 台州保灵药业有限公司 一种叔丁氧羰基-西他列汀的制备方法
CN114195664A (zh) * 2021-12-30 2022-03-18 辰欣药业股份有限公司 一种磷酸西格列汀关键中间体的制备方法
WO2023175492A1 (fr) * 2022-03-14 2023-09-21 Hikal Limited Nouveaux intermédiaires et leur utilisation dans la fabrication de sitagliptine

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