WO2011114246A1 - Process for the preparation of malic acid salt of sunitinib - Google Patents
Process for the preparation of malic acid salt of sunitinib Download PDFInfo
- Publication number
- WO2011114246A1 WO2011114246A1 PCT/IB2011/050820 IB2011050820W WO2011114246A1 WO 2011114246 A1 WO2011114246 A1 WO 2011114246A1 IB 2011050820 W IB2011050820 W IB 2011050820W WO 2011114246 A1 WO2011114246 A1 WO 2011114246A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- malic acid
- sunitinib
- process according
- acid salt
- preparation
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
-
- 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 of preparation of malic acid salt of sunitinib.
- Sunitinib is chemically described as N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro- l,2-dihydro-2-oxo-3H-indol-3-ylidine)methyl]-2,4-dimethyl-lH-pyrrole-3-carboxamide as represented by Formula I.
- Sunitinib is an oral multi-kinase inhibitor and useful for the treatment of gastrointestinal stromal tumor and advanced renal cell carcinoma. Sunitinib is
- L-malate salt which is described chemically as butanedioic acid, hydroxy-, (2S)-, compound with N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-l,2- dihydro-2-oxo-3H-indol-3-ylidine)methyl]-2,4-dimethyl-lH-pyrrole-3-carboxamide (1:1).
- U.S. Patent No. 7,125,905 describes a process for the preparation of sunitinib base wherein the process involves heating a mixture of N-[2-(diethylamino)ethyl]-5-formyl-2,4- dimethyl-lH-pyrrole-3-carboxamide of Formula II and 5-fluoro-l,3-dihydro-2H-indol-2- one of Formula III in the presence of ethanol and pyrrolidine at 78°C for 3 hours. The mixture is cooled to room temperature and sunitinib is collected as a base by vacuum filtration.
- WO 2009/067686 describes processes for preparing crystalline forms of racemic sunitinib malate, sunitinib hemi-L-malate and compositions containing sunitinib base and L- or racemic malic acid from sunitinib base.
- WO 2009/150523 describes processes for the preparation of L-malic acid salt of sunitinib, wherein the process involves preparation of L-malic acid salt of N-[2- (diethylamino)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3-carboxamide of Formula II and reacting the salt with 5-fluoro-l,3-dihydro-2H-indol-2-one of Formula III to obtain L- malic acid salt of sunitinib with 75.1% yield.
- the present inventors have developed a simple and efficient process for the preparation of malic acid salt of sunitinib.
- the present process does not require the isolation of sunitinib base from the reaction mixture and it can be directly converted into malic acid salt of sunitinib.
- the present process also avoids the preparation and isolation of malic acid salt of N-[2-(diethylamino)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3- carboxamide of Formula II.
- the malic acid salt of sunitinib can be obtained by the present process with a yield of about 80% or above directly from the reaction mixture.
- the present process minimizes the steps involved in the preparation of sunitinib while it is efficient to obtain malic acid salt of sunitinib with higher yield.
- malic acid salt of sunitinib includes a combination of sunitinib and L- malic acid in any ratio between about 1 :0.5 and about 1 : 1.5.
- a process for the preparation of malic acid salt of sunitinib comprises: a) reacting N- [2-(diethylamino)ethyl] -5-formyl-2,4-dimethyl- lH-pyrrole-3- carboxamide of Formula II with 5-fluoro-l,3-dihydro-2H-indol-2-one of Formula III in the presence of a solvent to obtain sunitinib base; and b) treating the reaction mixture obtained in step a) with malic acid to obtain malic acid salt of sunitinib.
- N- [2-(diethylamino)ethyl] -5-formyl-2,4-dimethyl- lH-pyrrole-3-carboxamide of Formula II may be prepared according to the method described in, for example, U.S.
- N-[2-(diethylamino)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3- carboxamide of Formula II is reacted with 5-fluoro-l,3-dihydro-2H-indol-2-one of Formula III in a solvent to obtain sunitinib base.
- the reaction may be carried out, for example, by mixing N-[2-(diethylamino)ethyl]-5-formyl-2,4-dimethyl-lH-pyrrole-3- carboxamide of Formula II with the solvent, followed by the addition of 5-fluoro-l,3- dihydro-2H-indol-2-one of Formula III.
- the solvent may be water, an organic solvent or a mixture thereof.
- the organic solvent may be an alkanol, for example, n-propanol, methanol, ethanol, isopropanol or n-butanol, an ester, for example, n-butyl acetate, isopropyl acetate, methyl acetate or ethyl acetate, a nitrile, for example, acetonitrile, an aromatic hydrocarbon, for example, toluene, a cyclic ether, for example, tetrahydrofuran, or a ketone, for example, acetone, or a mixture thereof.
- the reaction mixture may also contain a base.
- the base may be an organic amine, for example, pyrrolidine.
- the reaction may be carried out at a temperature of about the boiling point of the solvent. For example, the reaction may be carried out at about 75°C to about 80°C when ethanol is used as a solvent.
- the reaction may be carried out for about 10 minutes to about 10 hours, for example, about 1 hour to about 5 hours.
- Sunitinib base so obtained need not be isolated from the reaction mixture in any form, solid or oil.
- the reaction mixture comprising sunitinib base is treated with malic acid to form the malic acid salt of sunitinib.
- the malic acid may be L-malic acid, D-malic acid, or a mixture thereof.
- malic acid salt of sunitinib may be carried out in the same reaction mixture - for example, at substantially the same reaction conditions in which sunitnib base is formed.
- the malic acid salt of sunitinib may be isolated by filtration, solvent removal, evaporation, solvent precipitation, layer separation, decantation, centrifugation, or a combination thereof.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13/634,737 US20160185760A1 (en) | 2010-03-18 | 2011-02-25 | Process for the preparation of malic acid salt of sunitinib |
EP11712676.3A EP2547674A1 (en) | 2010-03-18 | 2011-02-25 | Process for the preparation of malic acid salt of sunitinib |
AU2011228765A AU2011228765A1 (en) | 2010-03-18 | 2011-02-25 | Process for the preparation of malic acid salt of sunitinib |
CA2793359A CA2793359A1 (en) | 2010-03-18 | 2011-02-25 | Process for the preparation of malic acid salt of sunitinib |
ZA2012/07547A ZA201207547B (en) | 2010-03-18 | 2012-10-08 | Process for the preparation of malic acid salt of sunitinib |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN635/DEL/2010 | 2010-03-18 | ||
IN635DE2010 | 2010-03-18 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2011114246A1 true WO2011114246A1 (en) | 2011-09-22 |
Family
ID=43983774
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2011/050820 WO2011114246A1 (en) | 2010-03-18 | 2011-02-25 | Process for the preparation of malic acid salt of sunitinib |
Country Status (6)
Country | Link |
---|---|
US (1) | US20160185760A1 (en) |
EP (1) | EP2547674A1 (en) |
AU (1) | AU2011228765A1 (en) |
CA (1) | CA2793359A1 (en) |
WO (1) | WO2011114246A1 (en) |
ZA (1) | ZA201207547B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RU2774382C1 (en) * | 2021-03-19 | 2022-06-20 | Общество с ограниченной ответственностью «АксельФарм» | Method for producing an amorphous form of n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-1,2-dihydro-2-oxo-3h-indole-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrol-3-carboxamide malate, product and application thereof for treating oncological and immunological diseases |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20030069298A1 (en) | 2001-08-15 | 2003-04-10 | Pharmacia & Upjohn Company | Crystals including a malic acid salt of a 3-pyrrole substituted 2-indolinone, and compositions thereof |
US7125905B2 (en) | 2000-02-15 | 2006-10-24 | Agouron Pharmaceuticals, Inc. | Pyrrole substituted 2-indolinone protein kinase inhibitors |
WO2009067686A2 (en) | 2007-11-21 | 2009-05-28 | Teva Pharmaceutical Industries Ltd. | Sunitinib hemi-l-malate, polymorphs and preparation thereof, polymorphs of racemic sunitinib malate, compositins containing sunitinib base and malic acid and preparation thereof |
WO2009150523A1 (en) | 2008-06-13 | 2009-12-17 | Medichem, S.A. | Process for preparing a 3-pyrrole substituted 2-indolinone malate salt |
WO2009157011A1 (en) * | 2008-06-23 | 2009-12-30 | Natco Pharma Limited | Process for the preparation of high purity sunitinib and its pharmaceutically acceptable salt |
WO2010055082A2 (en) * | 2008-11-13 | 2010-05-20 | Lek Pharmaceuticals D.D. | New crystal form of sunitinib malate |
-
2011
- 2011-02-25 AU AU2011228765A patent/AU2011228765A1/en not_active Abandoned
- 2011-02-25 EP EP11712676.3A patent/EP2547674A1/en not_active Withdrawn
- 2011-02-25 US US13/634,737 patent/US20160185760A1/en not_active Abandoned
- 2011-02-25 WO PCT/IB2011/050820 patent/WO2011114246A1/en active Application Filing
- 2011-02-25 CA CA2793359A patent/CA2793359A1/en not_active Abandoned
-
2012
- 2012-10-08 ZA ZA2012/07547A patent/ZA201207547B/en unknown
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7125905B2 (en) | 2000-02-15 | 2006-10-24 | Agouron Pharmaceuticals, Inc. | Pyrrole substituted 2-indolinone protein kinase inhibitors |
US20030069298A1 (en) | 2001-08-15 | 2003-04-10 | Pharmacia & Upjohn Company | Crystals including a malic acid salt of a 3-pyrrole substituted 2-indolinone, and compositions thereof |
US20070191458A1 (en) | 2001-08-15 | 2007-08-16 | Pharmacia & Upjohn Company | Crystals Including a Malic Acid Salt of a 3-Pyrrole Substituted 2-Indolinone, and Compositions Thereof |
WO2009067686A2 (en) | 2007-11-21 | 2009-05-28 | Teva Pharmaceutical Industries Ltd. | Sunitinib hemi-l-malate, polymorphs and preparation thereof, polymorphs of racemic sunitinib malate, compositins containing sunitinib base and malic acid and preparation thereof |
WO2009150523A1 (en) | 2008-06-13 | 2009-12-17 | Medichem, S.A. | Process for preparing a 3-pyrrole substituted 2-indolinone malate salt |
WO2009157011A1 (en) * | 2008-06-23 | 2009-12-30 | Natco Pharma Limited | Process for the preparation of high purity sunitinib and its pharmaceutically acceptable salt |
WO2010055082A2 (en) * | 2008-11-13 | 2010-05-20 | Lek Pharmaceuticals D.D. | New crystal form of sunitinib malate |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
RU2774382C1 (en) * | 2021-03-19 | 2022-06-20 | Общество с ограниченной ответственностью «АксельФарм» | Method for producing an amorphous form of n-[2-(diethylamino)ethyl]-5-[(z)-(5-fluoro-1,2-dihydro-2-oxo-3h-indole-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrol-3-carboxamide malate, product and application thereof for treating oncological and immunological diseases |
Also Published As
Publication number | Publication date |
---|---|
CA2793359A1 (en) | 2011-09-22 |
US20160185760A1 (en) | 2016-06-30 |
ZA201207547B (en) | 2013-06-26 |
AU2011228765A1 (en) | 2012-10-11 |
EP2547674A1 (en) | 2013-01-23 |
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