WO2017141202A1 - Complexe d'inhibiteur sglt2 et son procédé de préparation - Google Patents
Complexe d'inhibiteur sglt2 et son procédé de préparation Download PDFInfo
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- WO2017141202A1 WO2017141202A1 PCT/IB2017/050904 IB2017050904W WO2017141202A1 WO 2017141202 A1 WO2017141202 A1 WO 2017141202A1 IB 2017050904 W IB2017050904 W IB 2017050904W WO 2017141202 A1 WO2017141202 A1 WO 2017141202A1
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- Prior art keywords
- empagliflozin
- crystalline form
- complex
- proline
- crystalline
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- ONIBWKKTOPOVIA-BYPYZUCNSA-N OC([C@H]1NCCC1)=O Chemical compound OC([C@H]1NCCC1)=O ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 1
- XHHIKCIFLOKKAC-GLJLYWAVSA-N OC[C@H](C[C@@H](C1O)O)O[C@H]1c(cc1)cc(Cc(cc2)ccc2O)c1Cl Chemical compound OC[C@H](C[C@@H](C1O)O)O[C@H]1c(cc1)cc(Cc(cc2)ccc2O)c1Cl XHHIKCIFLOKKAC-GLJLYWAVSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
Definitions
- the present invention relates to a complex of Empagliflozin with amino acids and process for preparation thereof. More specifically, the present invention provides crystalline forms of a complex of Empagliflozin with L-Proline, specifically crystalline Form-A of Empagliflozin L-Proline complex and process for preparation thereof. The present invention further relates to a method of preparing pure crystalline Empagliflozin via the complex of Empagliflozin with L-Proline, specifically the crystalline Form-A of Empagliflozin L-Proline complex.
- Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a new class of diabetic medications indicated only for the treatment of type 2 diabetes. In conjunction with exercise and a healthy diet, they can improve glycemic control.
- One of the classes of compound useful for inhibiting SGLT2 includes C-glucoside derivatives such as those described in U.S. Pat. No. 6,414,126, US20040138439, US20050209166, US20050233988, WO2005085237, U.S. Pat. No. 7,094,763, US20060009400, US20060019948, US20060035841, US20060122126, US20060234953, WO2006108842, US20070049537 and WO2007136116.
- U.S. Pat. No. 6,774,112 discloses preparation of amino acid complexes of amorphous C- aryl glucosides formed from both the D- or L-enantiomers of natural amino acids which are useful for the treatment of type II diabetes.
- Empagliflozin a C-aryl glucoside derivative, is an orally-active inhibitor of the sodium- glucose co-transporter 2 (SGLT2). It is chemically chemically described as D-Glucitol, 1, 5-anhydro-l-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3furanyl] oxy] phenyl] methyl] phenyl]- , (IS) and structurally represented by formula (I) as given below.
- Empagliflozin has been approved as JardianceTM, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Furthermore it has been indicated to reduce the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and established cardiovascular disease.
- U.S. Patent No. 7,579,449 discloses Empagliflozin and process for its preparation.
- U.S. Patent No. 7,772,191 discloses a process for preparation of Empagliflozin.
- the processes disclosed in US'449 and US' 191 either involves chromatographic purification or purification involving chemical transformation i.e. protection followed by deprotection in the final or penultimate step to obtain chemically and/or stereoisomerically pure final compound.
- It is yet another object of the present invention to provide pharmaceutical composition comprising an effective amount of the pure crystalline Empagliflozin and crystalline Form-A of Empagliflozin L-Proline complex.
- Figure- 1 The PXRD diffractogram of crystalline Form-A of Empagliflozin L-Proline
- Figure-2 The DSC thermogram of crystalline Form-A of Empagliflozin L-Proline
- Figure-3 The Infra-Red (IR) spectrum of crystalline Form-A of Empagliflozin L-Proline
- Figure-4 1 H NMR of crystalline Form-A of Empagliflozin L-proline complex
- Figure-5 The PXRD diffractogram of crystalline Empagliflozin Tryptophan Complex
- Figure-6 The PXRD diffractogram of crystalline Empagliflozin L-hydroxyproline Complex
- the present invention relates to a complex of Empagliflozin with amino acid.
- the amino acid is selected from the group consisting of L-proline, L-hydroxyproline, L- phenylalanine, L-aspartamine, L-arginine, Tryptophan and the like.
- the present invention relates to a complex of Empagliflozin with L-Proline. More specifically, the invention provides a crystalline Form-A of Empagliflozin L-Proline complex of formula (II).
- the crystalline form A of Empagliflozin L-Proline complex of the present invention is characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and infra-red spectroscopy.
- the crystalline Form-A of Empagliflozin L-Proline complex of the present invention is characterized by powder X-ray diffraction (PXRD) diffractogram substantially as illustrated by Figure- 1.
- the crystalline Form-A of Empagliflozin L-proline complex is characterized by X-ray diffraction peaks at 2 ⁇ values of 4.32, 6.24, 8.62, 11.77, 12.94, 14.12, 15.17, 15.64, 16.26, 16.90, 17.27, 18.06, 18.23, 18.78, 19.14, 19.58, 19.82, 20.19, 21.63, 22.30, 23.06, 24.74, 24.87 and 30.57 (2 ⁇ ⁇ 0.2) degree.
- the crystalline Form-A of Empagliflozin L-proline complex is further characterized by PXRD pattern having characteristic X-ray diffraction peaks at 2 ⁇ values of 4.32, 6.24, 8.62, 11.77, 12.94, 14.12, 15.17, 15.64, 18.06, 18.78, 19.58, 21.63, 22.30 and 24.74 (2 ⁇ ⁇ 0.2) degree.
- the crystalline Form-A of Empagliflozin L-proline complex is further characterized by PXRD pattern having characteristic X-ray diffraction peaks at 2 ⁇ values of 4.32, 6.24, 8.62, 11.77, 12.94, 14.12, 15.17, 15.64, 18.06, 18.78, 19.58 and 21.63 (2 ⁇ ⁇ 0.2) degree.
- the crystalline Form-A of Empagliflozin L-proline complex is characterized by a differential scanning calorimetry thermogram having endothermic onsets at 47.57°C, 60.83°C and 155.54 °C ⁇ 3°C.
- the crystalline Form-A of Empagliflozin L-proline complex is further characterized by a differential scanning calorimetry thermogram substantially as illustrated by Figure-2.
- the crystalline Form-A of Empagliflozin L-proline complex is further characterized by infra-red spectrum substantially as illustrated by Figure-3.
- the crystalline Form-A of Empagliflozin L-proline complex of the present invention is prepared by reacting Empagliflozin with L-proline in a suitable solvent.
- the present inventors have also found that isolation of crystalline Form-A of Empagliflozin L-proline complex of formula (II) is also possible by reacting Empagliflozin of formula (V) in situ with L-proline as per the reaction sequence depicted in the following Scheme-1.
- the present invention provides a process for the preparation of the crystalline Form-A of Empagliflozin L-Proline complex comprising:
- step (b) contacting Empagliflozin in a solvent B and the mixture of step (a); (c) heating the reaction mass of step (b);
- step (d) cooling the reaction mass of step (c) to obtain crystalline Form-A of Empagliflozin L- proline complex
- the solvent A and solvent B is selected from the group consisting of alcohol, ketone, chlorinated hydrocarbon, ester, nitrile, water and a combination thereof in a suitable proportion.
- the preferred alcohol is methanol, ethanol, propanol, isopropanol, butanol, 2- butanol, 1-pentanol and the like
- the preferred ketone is acetone and methyl ethyl ketone and the like
- the preferred chlorinated hydrocarbon is dichloromethane and the like
- the preferred ester is ethyl acetate, isopropyl acetate and the like
- the preferred nitrile is acetonitrile and the like.
- the preferred solvent A is selected from the group consisting of alcohol, such as methanol, ethanol, propanol, isopropanol, butanol, 2-butanol, 1-pentanol and the like.
- the preferred alcohol is isopropanol.
- the preferred solvent B is selected from the group consisting of alcohol, such as methanol, ethanol, propanol, isopropanol, butanol, 2-butanol, 1-pentanol and the like and chlorinated hydrocarbon, such as dichloromethane and a combination thereof.
- the preferred solvent B is dichloromethane, isopropanol or a combination thereof.
- step (c) the reaction mass of step (b) is heated to about 30 °C to about 90 °C, preferably to about 50 °C to about 80 °C, more preferably to about 30 °C to about 40 °C.
- step (d) the reaction mass of step (c) is cooled to about -5 °C to 15 °C, more preferably to about 0 °C to 10 °C to obtain the crystalline Form A of Empagliflozin L-Proline complex.
- step (e) the crystalline Form A of Empagliflozin L-Proline complex is isolated by techniques known in the art such as decantation, filtration by gravity or suction or centrifugation.
- step (f) the crystalline Form A of Empagliflozin L-Proline complex is dried at a suitable temperature and pressure for a suitable time.
- the suitable temperature for drying is about 30 °C to about 70°C, preferably is about 40 °C to about 50°C, and more preferably is not more than 45 °C.
- the molar ratio of L- Proline used for complex formation ranges from about 1.0 to 20.0 equivalents of L-Proline, preferably about 2 to 15 equivalents, more preferably about 1.5 to 9 equivalents of L-Proline relative to Empagliflozin of step (b).
- a pure crystalline Empagliflozin is obtained from the crystalline Form A of Empagliflozin L-proline complex of formula (II) of the present invention.
- the preparation of pure crystalline Empagliflozin from the crystalline Form-A of Empagliflozin L-Proline complex comprises of adding a mixture of water and a water immiscible organic solvent to the crystalline Form-A of Empagliflozin L-proline complex and stirring at temperature of about 30 °C to about 80 °C, more preferably at about 30 °C to about 50 °C.
- said process for the preparation of pure crystalline Empagliflozin from the crystalline Form-A of Empagliflozin L-Proline complex of formula (II) comprises:
- step (b) heating the mixture of step (a) to obtain a reaction mass
- step (c) separating the layers of the reaction mass of step (b) to obtain an organic layer
- step (e) optionally seeding the organic layer of step (c);
- step (f) isolating the pure crystalline Empagliflozin.
- crystalline Form-A of Empagliflozin L-proline complex is mixed with water and a water immiscible organic solvent selected from the group consisting of chlorinated hydrocarbon and ester.
- the preferred chlorinated hydrocarbon is dichloromethane and the preferred ester is ethyl acetate and isopropyl acetate or mixtures thereof, wherein the volume of organic solvent used is 5 to 20 times, preferably 10 to 15 times of the crystalline Form-A of Empagliflozin L-proline complex.
- the preferred water immiscible organic solvent of step (a) is ethyl acetate wherein the ratio of ethylacetate to water is in the range of 3: 1, preferably the ratio is 2: 1 (volume/volume).
- step (b) the reaction mass of step (a) is heated to about 40 °C to about 80 °C, preferably to about 55 °C to about 60 °C, more preferably to about 45 °C to about 50 °C.
- the reaction mass of step (b) is separated at 45 °C to about 50 °C to obtain an organic layer.
- the organic layer of step (c) is micron filtered to make it clear and free of unwanted particles.
- the organic layer of step (c) is cooled to about -5 °C to about 30 °C, more preferably the solution is cooled to about 0 °C to about 5 °C to obtain pure crystalline Empagliflozin.
- the pure crystalline Empagliflozin is isolated by techniques known in the art such as decantation, filtration by gravity or suction or centrifugation.
- the isolated pure crystalline Empagliflozin is dried at a suitable temperature and pressure for a suitable time.
- the suitable temperature for drying is about 30 °C to about 70 °C, preferably is about 40 °C to about 50 °C, and more preferably is not more than 45 °C.
- the processes of the present invention are particularly useful as they represent an efficient process for the preparation of SGLT2 inhibitor, pure crystalline Empagliflozin.
- the methods of the present invention involve the reduction of an intermediate of formula (IV) to obtain Empagliflozin of formula (V) followed by complex formation with an amino acid, preferably L-Proline, wherein the complex is solid, typically crystalline, and is formed on large scale without intervening protection and deprotection steps.
- an amino acid preferably L-Proline
- the final product can be produced in higher yield and in the absence of solvent impurities e.g., pyridine that are difficult to remove with the known processes.
- the formation of the crystalline Empagliflozin L-proline complex of formula (II) is carried out without purification of the Empagliflozin intermediate compound of formula (V).
- pure crystalline Empagliflozin prepared according to the present invention are pure having a chemical purity greater than about 98.5%, or greater than about 99.0%, or greater than about 99.5 % by weight as determined using high performance liquid chromatography (HPLC).
- HPLC high performance liquid chromatography
- the pure crystalline Empagliflozin produced by a method of present invention are chemically pure Empagliflozin having purity greater than about 99.5% and contain no single impurity in amounts greater than about 0.15%, by HPLC.
- the pure crystalline Empagliflozin produced by the methods of present invention are chemically pure Empagliflozin having purity greater than about 99.8% and contain no single impurity in amounts greater than about 0.1% by HPLC.
- Empagliflozin used as the input material for the preparation of Empagliflozin L-proline complex is obtained by a process known to a person ordinary skilled in the art.
- the input material is prepared by practicing the chemistry disclosed in US'449 and US' 191 patents or by method illustrated in the present specification.
- the present invention provides a pharmaceutical composition comprising the crystalline Form A of Empagliflozin L-proline complex along with one or more pharmaceutically acceptable carriers, excipients, or diluents.
- the present invention provides a pharmaceutical composition comprising the pure crystalline Empagliflozin along with one or more pharmaceutically acceptable carriers, excipients, or diluents.
- the crystalline Form A of Empagliflozin L-proline complex and the pure crystalline Empagliflozin of the present invention can be used as SGLT2 inhibitor indicated for the treatment of type 2 diabetes mellitus.
- Such pharmaceutical composition can be prepared by the methods known in the literature.
- the present invention provides crystalline complexes of Empagliflozin with Tryptophan and L-hydroxyproline and processes for preparation thereof.
- the present invention provides a process for preparation of crystalline Empagliflozin Tryptophan complex comprising:
- step (b) contacting tryptophan to the mixture of step(a);
- step (c) heating the reaction mass of step(b) to about 50°C to about 60°C;
- step (d) cooling the reaction mass of step ( c) to about 20 °C to about 25 °C to obtain crystalline complex of Empagliflozin with Tryptophan;
- the present invention further provides a process for preparation of crystalline Empagliflozin L-hydroxyproline complex comprising:
- step (c) heating the reaction mass of step(b) to about 50°C to about 60°C;
- step (d) cooling the reaction mass of step ( c) to about 20 °C to about 25 °C to form crystalline complex of Empagliflozin with L-hydroxyproline;
- the crystalline complexes of Empagliflozin with tryptophan and L-hydroxyproline are useful intermediate for the preparation of pure crystalline Empagliflozin.
- the present invention provides a pharmaceutical composition
- a pharmaceutical composition comprising the crystalline complexes of Empagliflozin with tryptophan and L- hydroxyproline along with one or more pharmaceutically acceptable carriers, excipients, or diluents.
- the crystalline complexes of Empagliflozin with tryptophan and L-hydroxyproline of the present invention can be used as SGLT2 inhibitor indicated for the treatment of type 2 diabetes mellitus.
- Such pharmaceutical composition can be prepared by the methods known in the literature.
- the present invention is further illustrated with the following non-limiting examples.
- Example-1 Preparation of crystalline Form A of Empagliflozin L-proline complex
- Example-3 Preparation of crystalline Form A of Empagliflozin L-proline complex
- the temperature was raised to 25 °C to 30 °C followed by addition of 200 mL of isopropyl alcohol. Thereafter the organic layer was separated. To the organic layer 79 gm of L-proline and 100 mL of isopropanol was added and stirred at 40 °C to 45 °C for 1 to 2 hrs. Thereafter the reaction mixture was cooled to 0°C to 10 °C, stirred for 1 to 2 hrs and filtered. The wet cake was slurry washed with isopropanol and dried under vacuum to afford 110 gm of crystalline Form A of Empagliflozin L-proline complex.
- Example-4 Preparation of pure crystalline Empagliflozin
- a mixture of 20 gm of crystalline Form A of Empagliflozin L-proline complex in 120 mL ethylacetate and 100 mL water was stirred at 25 °C to 50°C for 45 to 60 min. Thereafter the layers were separated and the aqueous layer was extracted with 25 mL ethylacetate. The combined organic layer was washed with 25 mL water and concentrated to afford 10.2 gm solid. The solid thus obtained was mixed with 70 mL ethylacetate and 10 mL water and was heated to 60°C to 70°C to obtain a clear solution. Thereafter the solution was cooled to 20°C to 30°C, followed by filtration and drying under vacuum to afford 9 gm of pure crystalline Empagliflozin.
- a mixture of 100 gm of crystalline Form A of Empagliflozin L-proline complex in 800 mL ethylacetate and 400 mL water was heated 45°C to 50°C for 30 to 45 min. Thereafter the reaction mixture was allowed to settle and the layers were separated. The organic layer was passed through micron filtered, the filtrate obtained was heated to 55°C to 60°C, stirred for 30 to 45 min. and cooled to 30°C to 40°C, optionally seeded with Empagliflozin and stirred for 45 to 60 min.
- the reaction mass was further cooled to 20°C to 25°C and stirred for 2 to 3 hrs. Thereafter, the reaction mass was further cooled to 0°C to 5°C, stirred for 1 to 2 hrs, filtered and dried under vacuum to afford 35 gm of pure crystalline Empagliflozin.
- Example-6 Preparation of crystalline Empagliflozin Tryptophan complex
- Example-7 Preparation of crystalline Empagliflozin L-hydroxyproline complex To 10.0 gm of Empagliflozin in 50 mL of isopropyl alcohol was added 4.5gm of L- hydroxyproline. The obtained slurry was heated to 50 °C to 55 °C and stirred for lhr. Thereafter the reaction mixture was cooled to 20 °C to 30 °C, filtered and dried under vacuum at 45 °C to yield 13.9 gm of crystalline Empagliflozin L-hydroxyproline complex.
Abstract
La présente invention concerne une forme cristalline A de complexe d'empagliflozine avec de la L-proline et son procédé de préparation. La présente invention concerne également un procédé de préparation d'empagliflozine cristalline pure par la formation dudit complexe.
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2018207111A1 (fr) * | 2017-05-09 | 2018-11-15 | Piramal Enterprises Limited | Procédé de préparation d'inhibiteurs de sglt2 et de ses intermédiaires |
WO2023217058A1 (fr) * | 2022-05-12 | 2023-11-16 | 浙江华海药业股份有限公司 | Procédé de préparation d'un composé contenant du glucopyranosyle |
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WO2018207111A1 (fr) * | 2017-05-09 | 2018-11-15 | Piramal Enterprises Limited | Procédé de préparation d'inhibiteurs de sglt2 et de ses intermédiaires |
US11312740B2 (en) | 2017-05-09 | 2022-04-26 | Piramal Pharma Limited | Process for the preparation of SGLT2 inhibitors and intermediates thereof |
WO2023217058A1 (fr) * | 2022-05-12 | 2023-11-16 | 浙江华海药业股份有限公司 | Procédé de préparation d'un composé contenant du glucopyranosyle |
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