WO2020217190A1 - Procédé de purification de roxadustat - Google Patents

Procédé de purification de roxadustat Download PDF

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Publication number
WO2020217190A1
WO2020217190A1 PCT/IB2020/053820 IB2020053820W WO2020217190A1 WO 2020217190 A1 WO2020217190 A1 WO 2020217190A1 IB 2020053820 W IB2020053820 W IB 2020053820W WO 2020217190 A1 WO2020217190 A1 WO 2020217190A1
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WIPO (PCT)
Prior art keywords
roxadustat
solution
crystalline
water
optionally
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PCT/IB2020/053820
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English (en)
Inventor
Prasoon SRIVASTAVA
Arjun Kumar Tummala
Venkata Krishna Rao Badarla
Mohammad AASEEF
Amarnath Reddy Lekkala
Srinivasulu Rangineni
Venkatarajesh CHEBOLU
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Dr. Reddy’S Laboratories Limited
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Publication of WO2020217190A1 publication Critical patent/WO2020217190A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • the present invention provides a process for the preparation of crystalline Roxadustat Form-d and pharmaceutical composition thereof.
  • the present invention also provides a purification process of Roxadustat.
  • the present invention also provides a process for the preparation of Roxadustat Form A and its purification.
  • the present invention also provides a process for the preparation of co-crystal of Roxadustat with L-proline.
  • Roxadustat (I) or FG-4592 is chemically known as [(4-Hydroxy- l-methyl-7- phenoxy-isoquinoline-3-carbonyl)-amino] -acetic acid. It is an oral small molecule inhibitor of Hypoxia-Inducible Factor-prolyl hydroxylases, or HIF-PHs, in Phase 3 clinical development for treating and preventing disorders associated with HIF, including anemia in chronic kidney disease or CKD, ischemia, and hypoxia.
  • HIF-PHs Hypoxia-Inducible Factor-prolyl hydroxylases
  • the US patent number 8883823 B2 discloses crystalline Forms of Roxadustat and their processes for the preparation.
  • the crystalline forms are designated as Form A, Form B (hemihydrate), Form C (hexafluropropan-2-ol solvate) and Form D (DMSO: Water solvate). It further discloses various salts of Roxadustat and amorphous form Roxadustat.
  • the US patent number 9206134 B2 discloses various crystalline Forms of Roxadustat and their processes for the preparation.
  • the crystalline forms are designated as Form I, Form II, Form III, Form IV, Form V, Form VI and Form VII.
  • W02019/030711A1 discloses various crystalline forms of Roxadustat and their processes for the preparation.
  • the crystalline forms are designated as Form g, Form d, Form RLP (L-proline co-crystal), Form RNM (nicotinamide co-crystal) and Form RU (Urea co-crystal).
  • API Active pharmaceutical ingredients
  • pharmaceutical compositions can be prepared in amorphous form, crystalline forms, solvate or hydrate and salt form.
  • This variation in solid forms may be significant and may result in differences in pharmaceutical products with respect to solubility, bioavailability, stability and other properties.
  • variation of the crystalline state of Roxadustat is one way in which physical properties of the Roxadustat can be modulated. It has now been found that new solid state form i.e., co crystals of Roxadustat can be obtained which may modify the properties of Roxadustat as compared to traditional solid forms such as salts, polymorphs, hydrates, solvates etc.
  • the present invention provides a process for purification of crystalline Roxadustat comprising;
  • step b) optionally, filtering the solution of step a);
  • the present invention provides a process for preparation of crystalline Roxadustat form-d, comprising; a) dissolving Roxadustat in formic acid;
  • step b) optionally, filtering the solution of step a);
  • step g) humidifying material obtained from step f) by using fluidized bed drier.
  • the present invention provides a process for preparation of crystalline Roxadustat form-d, comprising;
  • step b) optionally, filtering the solution of step a);
  • step (f) humidifying material obtained from step (f) using fluidized bed drier.
  • the present invention provides a process for the preparation of crystalline Roxadustat Form A comprising, contacting Roxadustat with formic acid to get crystalline Roxadustat Form A.
  • the present invention provides a process for the preparation of co-crystals of Roxadustat (crystalline form RLP), comprising:
  • the present invention provides a process for purification of crystalline Roxadustat comprising;
  • step b) optionally, filtering the solution of step a);
  • Step a) involves the solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and/or to clarify the solution.
  • Hydroflow flux-calcined diatomaceous earth
  • Suitable polar aprotic solvent may be used in step a) include, but are not limited to dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide (DMA), N-methylpyrrolidine (NMP), hexamethylphosphoramide (HMPA) or mixtures thereof.
  • DMF dimethylformamide
  • DMSO dimethylsulfoxide
  • DMA dimethylacetamide
  • NMP N-methylpyrrolidine
  • HMPA hexamethylphosphoramide
  • the solution obtained in step (b) may be filtered to remove any insoluble particles.
  • the insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques.
  • the solution may be filtered by passing thorough paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or hyflow.
  • the filtration apparatus may need to be preheated to avoid premature crystallization.
  • Suitable anti-solvent may be used in step c) include, but are not limited to methanol, ethanol, 1 -propanol, 2-propanol (isopropyl alcohol), 1 -butanol, 2-butanol, pentanol or mixtures thereof.
  • Step c) involves adding anti-solvent to the solution obtained instep b), or adding the solution obtained in step b) to the anti-solvent, wherein the solution ismade in step b) with only polar aprotic solvent. After adding anti-solvent, the reaction mass may be maintained from 15 minutes to 24 hours.
  • the reaction mass may be maintained further at temperature lower than the dissolution temperatures such as for example below about 10° C. to about 25°C, for a period of time as required for complete isolation of the product.
  • the exact cooling temperature and time required for complete crystallization can be readily determined by a person skilled in the art and will also depend on parameters such as concentration and temperature of the solution or slurry.
  • step d) can be effected, if desired, by any suitable separation methods such as precipitation, filtration, centrifugation, extraction, acid-base treatment, by scraping, orby shaking the container conventional isolation and refining means such as concentration, concentration under reduced pressure or by a combination of these procedures.
  • suitable separation methods such as precipitation, filtration, centrifugation, extraction, acid-base treatment, by scraping, orby shaking the container conventional isolation and refining means such as concentration, concentration under reduced pressure or by a combination of these procedures.
  • the temperature at which the above steps may be carried out in between about 8 °C and about 100 °C, preferably at about 10°C and about 80°C.
  • Roxadustat may be either in a crystalline Roxadustat form A or amorphous Roxadustat or an alternate crystalline form of Roxadustat known in the art.
  • drying can be carried out at reduced pressures. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer, atmospheric drying and the like.
  • the present invention provides a process for preparation of crystalline Roxadustat form-d, comprising; a) dissolving Roxadustat in formic acid;
  • step b) optionally, filtering the solution of step a);
  • step g) humidifying material obtained from step f) by using fluidized bed drier.
  • Step a) involves the solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and/or to clarify the solution.
  • Hydroflow flux-calcined diatomaceous earth
  • the solution obtained in step (a) may be filtered to remove any insoluble particles.
  • the insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques.
  • the solution may be filtered by passing thorough paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or hyflow.
  • the filtration apparatus may need to be preheated to avoid premature crystallization.
  • step (c) seeding the crystalline Roxadustat form-d crystal to the solution obtained step b).
  • Step d) involves adding DM water to the mixture obtained instep c), or adding the solution obtained in step b) to the DM water, wherein the solution ismade in step b) with only formic acid. After adding DM water, the reaction mass may be maintained from 15 minutes to 24 hours.
  • Step e) involves isolation of crystalline Roxadustat from the mixture.
  • step (f) material isolated in step (e) can be slurried in water for 15 minutes to 50 hours and filtered to separate the solid from the mixture suitably by filtration, centrifugation, decantation, or any other suitable techniques.
  • material obtained in step (f) can be humidified in fluidized bed drier by controlling the humidity of inlet air. Humidity may vary from 10%RH to 95%RH.
  • step e) can be effected, if desired, by any suitable separation methods such as precipitation, filtration, centrifugation, extraction, acid-base treatment, by scraping, orby shaking the container, conventional isolation and refining means such as concentration, concentration under reduced pressure or by a combination of these procedures.
  • suitable separation methods such as precipitation, filtration, centrifugation, extraction, acid-base treatment, by scraping, orby shaking the container, conventional isolation and refining means such as concentration, concentration under reduced pressure or by a combination of these procedures.
  • the temperature at which the above steps may be carried out in between about 8 °C and about 100 °C, preferably at about 10°C and about 80°C.
  • Drying can be carried out at reduced pressures. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer, atmospheric drying and the like.
  • the present invention provides a process for preparation of crystalline Roxadustat form-d, comprising;
  • step b) optionally, filtering the solution of step a);
  • step (f) humidifying material obtained from step (f) using fluidized bed drier.
  • Step a) involves the solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow), or any other suitable material to remove color and/or to clarify the solution.
  • the solution obtained in step (b) may be filtered to remove any insoluble particles.
  • the insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques.
  • the solution may be filtered by passing thorough paper, glass fiber, or other membrane material, or a bed of a clarifying agent such as celite or hyflow.
  • the filtration apparatus may need to be preheated to avoid premature crystallization.
  • Step d) involves adding DM water to the solution obtained instep b), or adding the solution obtained in step b) to the DM water, wherein the solution is made in step b) with only formic acid. After adding DM water, the reaction mass may be maintained from 15 minutes to 24 hours.
  • Step e) involves isolation of crystalline Roxadustat from the mixture.
  • step (f) material isolated in step (e) can be slurried in water for 15 minutes to 50 hours and filtered to separate the solid from the mixture suitably by filtration, centrifugation, decantation, or any other suitable techniques.
  • step (g) material obtained in step (f) can be humidified in fluidized bed drier by controlling the humidity of inlet air. Humidity may vary from 10%RH to 95% RH.
  • step e) can be effected, if desired, by any suitable separation methods such as precipitation, filtration, centrifugation, extraction, acid-base treatment, by scraping, orby shaking the container conventional isolation and refining means such as concentration, concentration under reduced pressure or by a combination of these procedures.
  • suitable separation methods such as precipitation, filtration, centrifugation, extraction, acid-base treatment, by scraping, orby shaking the container conventional isolation and refining means such as concentration, concentration under reduced pressure or by a combination of these procedures.
  • the temperature at which the above steps may be carried out in between about 8 °C and about 100 °C, preferably at about 10°C and about 80°C. Drying can be carried out at reduced pressures. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer, atmospheric drying and the like.
  • Roxadustat may be either in a crystalline or amorphous state or an alternate crystalline form of Roxadustat known in the art.
  • the present invention provides a process for the preparation of crystalline Roxadustat Form A comprising, contacting Roxadustat with formic acid to get crystalline Roxadustat Form A.
  • Contacting step means isolating the crystalline Roxadustat Form A.
  • the isolation of Roxadustat can be effected, by any suitable separation methods such as precipitation, washing, drying, filtration, centrifugation, extraction, acid-base treatment, by scraping, orby shaking the container, conventional isolation and refining means such as concentration, concentration under reduced pressure or by a combination of these procedures.
  • the temperature at which the above steps may be carried out in between about 8 °C and about 100 °C, preferably at about 10°C and about 80°C.
  • drying can be carried out at reduced pressures. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer, atmospheric drying and the like.
  • the present invention provides a process for the preparation of L-Proline co-crystal Form RLP of Roxadustat comprising:
  • Suitable ketone solvent may be used in step a) include, but are not limited to acetone, methyl ethyl ketone, diethyl ketone, methyl isobutyl ketone, C3-C6 ketones or mixtures thereof.
  • Suitable alcohol solvent may be used in step b) include, but are not limited to methanol, ethanol, 1 -propanol, 2-propanol (isopropyl alcohol), 1 -butanol, 2-butanol, pentanol or mixtures thereof.
  • the reaction mass may be maintained further at temperature lower than the dissolution temperatures such as for example below about 10°C to about 25°C, for a period of time as required for complete isolation of the product.
  • the exact cooling temperature and time required for complete crystallization can be readily determined by a person skilled in the art and will also depend on parameters such as concentration and temperature of the solution or slurry.
  • step d) can be effected, if desired, by any suitable separation methods such as precipitation, filtration, centrifugation, extraction, acid-base treatment, by scraping, orby shaking the container conventional isolation and refining means such as concentration, concentration under reduced pressure or by a combination of these procedures.
  • suitable separation methods such as precipitation, filtration, centrifugation, extraction, acid-base treatment, by scraping, orby shaking the container conventional isolation and refining means such as concentration, concentration under reduced pressure or by a combination of these procedures.
  • the temperature at which the above steps may be carried out in between about 8 °C and about 100 °C, preferably at about 10°C and about 80°C.
  • drying can be carried out at reduced pressures. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer, atmospheric drying and the like.
  • Roxadustat may be either in a crystalline or amorphous state or an alternate crystalline form of Roxadustat known in the art.
  • Example- 1 Purification of crystalline Roxadustat.
  • Roxadustat (5 g), DMSO (10 mL) were charged at 27°C and stirred for 5-10 minutes.
  • the reaction mixture was heated to 53°C and maintained for 5-10 minutes.
  • 2-Butanol (25 mL) was added to the reaction mixture at 53 °C and maintained for 30 minutes.
  • 2- Butanol (30 mL) was added to the reaction mixture at 53°C and maintained for 80 minutes.
  • 2-Butanol (45 mL) was added to the reaction mixture at 53°C.
  • the reaction mass was cooled to room temperature and maintained for 90 minutes.
  • the obtained solid was filtered and washed with 2-butanol (10 mL)and kept for drying in vacuum at 68°C to obtain the title compound.
  • Example-2 Purification of crystalline Roxadustat.
  • Roxadustat (10 g), DMF (20 mL) were charged at 27°C and stirred for 5-10 minutes.
  • the reaction mixture was heated to 61°C and maintained for 5-10 minutes.
  • 2-Butanol (100 mL) was slowly added to the reaction mixture at 62°C and maintained for 60 minutes.
  • the reaction mass was cooled to 35°C and maintained for 60 minutes.
  • the obtained solid was filtered and washed with 2-butanol (20 mL)and kept for drying in vacuum at 60°C to obtain the title compound.
  • Ethyl 4-hydroxy- l-methyl-7-phenoxyisoquinoline-3-carboxylate hydrochloride 50 g
  • dimethyl formamide 250 mL
  • glycine 15.63 g
  • DBU 63.5 g
  • the reaction mass was heated upto 65°C and maintained for 4-5 hours.
  • the reaction mass was cooled to 16°C.
  • DM- Water 250 mL
  • toluene 250 mL
  • Acetonitrile (30 mL) was added to the aqueous layer and stirred for 10 minutes.
  • Water (100 mL) and formic acid (45 mL) were slowly added to the reaction mass and stirred for 10 minutes.
  • the reaction mass was cooled to 18°C and maintained for 2 hours. Liltered the obtained solid and washed with water (250 mL) to give wet compound.
  • the obtained wet compound and acetonitrile (250 mL) were charged at 28°C and stirred for 90 minutes. Liltered the obtained solid and washed with acetonitrile (50 mL), and dried at 74°C for 4-5 hours to get the compound.
  • the obtained compound (20 g), DMF (90 mL) were charged at 26°C and stirred for 10 minutes to get the clear solution.
  • DM- water (10 mL) was added to the reaction mixture at 26°C and stirred for 10 minutes.
  • the reaction mass was heated upto 60°C and maintained for 5-8 hours.
  • the reaction mass was cooled to 30°C and stirred for 10 minutes.
  • DBU (8.6 mL), DM-water (90 mL) and toluene (100 mL) were charged at 31°C and stirred for 10 minutes. Layers were separated and the aqueous layer was washed with acetonitrile (40 mL).
  • the reaction mass pH was adjusted 3.0 to 4.2 by using formic acid.
  • DM-water (90 mL) was added to the reaction mass at 30°C and maintained for 3-4 hours. Liltered the obtained solid and washed with water (60 mL) and acetonitrile (30 mL) and kept for drying in vacuum at 63 °C to obtain the title compound.
  • Roxadustat (22 g), DMSO (38.5 mL) were charged at 27°C and stirred for 5-10 minutes.
  • the reaction mixture was heated to 60°C and maintained for 5-10 minutes.
  • DMSO (5.5 mL) was added to the reaction mixture to get the particle free reaction mass.
  • 2-Butanol (440 mL) was added to the reaction mass at 60°C and maintained for 30 minutes.
  • Water (44 mL) was added to the reaction mixture at 60°C and maintained for 120 minutes.
  • the reaction mass was cooled to room temperature and maintained for 3 hours.
  • the obtained solid was filtered and washed with 2-butanol (44 mL) and kept for drying in vacuum at 75° C to obtain the title compound.
  • Roxadustat(1000 g), Formic acid (5000 mL) were charged at 25°C and stirred for 15- 20 minutes. Filtered the solution to make it free of particles.
  • the reaction mixture was cooled to 10°C and maintained for 5-10 minutes.
  • Roxadustat Form-d (10 g) was added to the reaction mixture as a seeding at 10°C and maintained for 80 minutes.
  • DM water (11000 mL) was slowly added for a period of 2-3 hours to the reaction mixture at 10°C - 15 °C and maintained for 150 minutes.
  • the obtained solid was filtered and washed with DM water (2000 mL) and kept for drying 25°C - 30°C for 2 hours.
  • the obtained material and DM water (10000 mL) were charged at 0°C and slurried for 8 hours at 0°C. Filtered the solution and washed with DM water (2000 mL) and kept for drying at 25°C - 30°C for 5 hours.
  • the obtained material was kept at Fluidized Bed Dryer (Inlet air RH 70% - 80%) for 15 hours to get the title compound.
  • the desired product attributes were obtained within 6 hours of FBD processing.
  • Roxadustat(48 g), Formic acid (240 mL) were charged at 28°C and stirred for 5-10 minutes. Filtered the solution to make it free of particles.
  • the reaction mixture was cooled to 5°C and maintained for 5-10 minutes.
  • Roxadustat Form-g 500 mg was added to the reaction mixture as a seeding at 5°C and maintained for 45 minutes.
  • DM water 530 mL was slowly added for a period of 60 minutes to the reaction mixture at 0°C - 5°C and maintained for 60 minutes.
  • the obtained solid was filtered and washed with DM water (100 mL) and kept for drying 30°C for 2 hours.
  • the obtained material was kept at Fluidized Bed Dryer (Inlet air RH 30% - 40%) for 14 hours to get the title compound.
  • the desired product attributes were obtained within 4 hours of FBD processing.
  • Roxadustat(30 g), Formic acid (150 mL) were charged at 25°C and stirred for 5-10 minutes. Filtered the solution to make it free of particles.
  • the reaction mixture was cooled to 10°C and maintained for 5-10 minutes.
  • Roxadustat Form-g 300 mg was added to the reaction mixture as a seeding at 10°C and maintained for 60 minutes.
  • DM water (330 mL) was slowly added for a period of 70 minutes to the reaction mixture at 0°C - 5°C and maintained for 50 minutes.
  • the obtained solid was filtered and washed with DM water (60 mL) and kept for drying 30°C for 2 hours.
  • DM water (3X300 mL) was added to the obtained material at 5°C and slurried for 13 hours and kept at vacuum tray drier at 24°C for 2 hours to get the title compound.
  • Example-8 Preparation of co-crystal of Roxadustat with L-Proline.
  • Roxadustat (20 g), Acetone (300 mL) were charged at 21°C and stirred for 5-10 minutes.
  • the reaction mixture was heated to 46°C.
  • L-Proline (13.08 g) in methanol (118 mL) was added to the reaction mixture at 46°C and maintained for 12-14 hours.
  • the reaction mass was cooled to 3°C and stirred for 30 minutes. Filtered the obtained solid and kept for drying in vacuum at 25°C to obtain the title compound.

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

Abstract

La présente invention concerne un procédé de préparation de la forme cristalline delta de roxadustat et la composition pharmaceutique de celle-ci. La présente invention concerne également un procédé de purification de roxadustat. Un autre aspect de la présente invention concerne un procédé de préparation de la forme A de roxadustat et sa purification. La présente invention concerne également un procédé de préparation de co-cristal de roxadustat avec de la L-proline.
PCT/IB2020/053820 2019-04-26 2020-04-22 Procédé de purification de roxadustat WO2020217190A1 (fr)

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IN201941016662 2019-04-26

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113956200A (zh) * 2021-12-16 2022-01-21 南京威凯尔生物医药科技有限公司 一种粒径控制的罗沙司他原料药的结晶工艺

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014014835A2 (fr) * 2012-07-16 2014-01-23 Fibrogen, Inc. Formes cristallines d'un inhibiteur de la prolyl hydroxylase
WO2019030711A1 (fr) * 2017-08-11 2019-02-14 Dr. Reddy’S Laboratories Limited Polymorphes et co-cristaux de roxadustat

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014014835A2 (fr) * 2012-07-16 2014-01-23 Fibrogen, Inc. Formes cristallines d'un inhibiteur de la prolyl hydroxylase
WO2019030711A1 (fr) * 2017-08-11 2019-02-14 Dr. Reddy’S Laboratories Limited Polymorphes et co-cristaux de roxadustat

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CAIRA M R: "Crystalline polymorphism of organic compounds", TOPICS IN CURRENT CHEMISTRY, SPRINGE R, vol. 198, 1 January 1998 (1998-01-01), BERLIN, DE, pages 163 - 208, XP008166276, DOI: 10.1007/3-540-69178-2_5 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113956200A (zh) * 2021-12-16 2022-01-21 南京威凯尔生物医药科技有限公司 一种粒径控制的罗沙司他原料药的结晶工艺

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