WO2014097152A1 - Procédé de préparation du pazopanib ou de ses sels - Google Patents
Procédé de préparation du pazopanib ou de ses sels Download PDFInfo
- Publication number
- WO2014097152A1 WO2014097152A1 PCT/IB2013/061048 IB2013061048W WO2014097152A1 WO 2014097152 A1 WO2014097152 A1 WO 2014097152A1 IB 2013061048 W IB2013061048 W IB 2013061048W WO 2014097152 A1 WO2014097152 A1 WO 2014097152A1
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- WIPO (PCT)
- Prior art keywords
- formula
- compound
- process according
- pazopanib
- salts
- Prior art date
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Classifications
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- 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
- C07D403/12—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 chain containing hetero atoms as chain links
Definitions
- the present invention provides a process for the preparation of pazopanib of Formula la or salts, and intermediates thereof.
- Pazopanib is a tyrosine kinase inhibitor of Formula la.
- Pazopanib is marketed as the hydrochloride salt, with the chemical name 5-[[4- [(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2- methylbenzenesulfonamide monohydrochloride, having the structure as depicted in Formula I:
- U.S. Patent No. 7,105,530 provides a process for the preparation of a hydrochloride salt of a compound of Formula II
- PCT Publication No. WO 2007/064752 provides a process for the preparation of a compound of Formula II comprising reducing 2,3-dimethyl-6-nitro-2H-indazole with 10% Palladium-carbon (50% wet) in the presence of methanol, followed by the addition of ammonium formate at a rate that ensures the reaction temperature is maintained at or between 25°C and 30°C. It also discloses the preparation of a compound of Formula III comprising heating the compound of Formula II with sodium bicarbonate in presence of tetrahydrofuran and ethanol at or between 75°C and 80°C followed by cooling to 20°C to
- the present invention provides a process for the preparation of a compound of Formula II which offers recycling of the Raney nickel catalyst used in the process, and an easy filtration work-up procedure. Further, the present invention offers selective reduction under mild conditions that is economical to use at an industrial scale.
- the present invention also provides a process for the preparation of compound of Formula III which avoids the use of two or more solvents, and additionally, also circumvents heating and cooling procedures during the reaction.
- the aforesaid advantages yield a compound of Formula III with a lesser amount of N-(4-chloropyrimidin-2-yl)-2,3- dimethyl-2H-indazol-6-amine (CPDMI) impurity.
- CPDMI N-(4-chloropyrimidin-2-yl)-2,3- dimethyl-2H-indazol-6-amine
- the compounds of Formula II and Formula III prepared by the present invention yield a compound of Formula la or its salts in comparable yield and suitable purity required for medicinal preparations.
- a first aspect of the present invention provides a process for the preparation of pazopanib of Formula la or its salts
- a second aspect of the present invention provides a process for the preparation of pazopanib of Formula la or its salts
- the term "about”, as used herein, refers to ⁇ 5% variation in the values mentioned herein.
- the 2,3-dimethyl-6-nitro-2H-indazole may be prepared by processes known in the prior art, for example, the process known in PCT Publication No. WO 2007/064752, or may be prepared by the process provided herein.
- the Raney nickel used in the reaction is in the form of a fine grained solid.
- Step i) is carried out in the presence of an organic solvent and hydrogen gas.
- the organic solvent may be an alcoholic solvent.
- the alcoholic solvents include methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, sec-butanol, or mixtures thereof.
- the compound of Formula II may be isolated from the reaction mixture or may be carried as such on to step ii) without isolation.
- the compound of Formula II may be isolated from reaction mixture by any method known in the art.
- the catalyst Raney nickel is recovered back and recycled.
- the compound of Formula II may be further treated with suitable solvents, or mixtures thereof.
- the treatment of compound of Formula II with solvents may include preparing a suspension, stirring, or slurrying.
- the solvents to be used include halogenated solvents, aliphatic hydrocarbon solvents, or mixtures thereof.
- halogenated solvents include dichloromethane, dichloroethane, chloroform, and carbon tetrachloride.
- aliphatic hydrocarbons include n-pentane, n-hexane, n- heptane, and n-octane.
- Step ii) is carried out in the presence of an organic solvent and a base.
- organic solvents include alcoholic solvents like methanol, ethanol, n-propanol, iso- propanol, n-butanol, iso-butanol, sec-butanol, or mixtures thereof.
- the base may be selected from organic or inorganic bases.
- the organic base is selected from the group comprising N,N-diisopropylethylamine, triethylamine, tri-isopropylamine, N,N-2- trimethyl-2-propanamine, N-methylmorpholine, 4-dimethylaminopyridine, 2,6-di-fert- butyl-4-dimethylaminopyridine, l,4-diazabicyclo[2.2.2]octane, 1,8- diazabicyclo[5.4.0]undec-7-ene, or mixtures thereof.
- the inorganic base is selected from the group comprising sodium carbonate, potassium carbonate, sodium hydride, sodium bicarbonate, potassium bicarbonate, or mixtures thereof.
- Step ii) is carried out at a temperature of about 45 °C or below, for example, at about 25°C to 30°C.
- the temperature of about 45°C or below is critical for controlling the formation of N-(4-chloropyrimidin-2-yl)-2,3-dimethyl-2H-indazol-6-amine impurity (4-CPDMI as disclosed in PCT Publication No. WO 201 1/069053) during step ii).
- the compound of Formula III is subjected to sequential treatment with water and an organic solvent.
- the treatment of the compound of Formula III with water and an organic solvent may include preparing a suspension, stirring, or slurrying.
- the organic solvent is selected from the group comprising ethyl acetate, n-propyl acetate, butyl acetate, or mixtures thereof.
- the compound of Formula III may be isolated from the reaction mixture or may be carried as such on to step iii) without isolation.
- the compound of Formula III may be isolated from the reaction mixture by any method known in the art.
- Step iii) may be carried out as per the embodiments described hereinafter, or by any other method known in the art.
- the salt of pazopanib is the hydrochloride salt of Formula I.
- the compound of Formula I prepared by the process of the present invention may be further converted to pazopanib hydrochloride thereof by any method known to a person skilled in the art.
- Trimethyloxonium tetrafluoroborate (125.2 g, 0.85 mol) was added to a stirred suspension of 3-methyl-6-nitro-indazole (100 g, 0.56 mol) in ethyl acetate (2000 mL) over a period of 4 hours in four equal lots at 1 hour time intervals.
- the reaction mixture was stirred at 25 °C to 30°C for 16 hours.
- the solvent was recovered under reduced pressure.
- a saturated sodium bicarbonate solution (3240 mL) was added to the mixture slowly, and the reaction mixture was extracted with 4: 1 mixture of dichloromethane:isopropyl alcohol (1080 mL x 5). The solvent was recovered under reduced pressure.
- Methyl fert-butyl ether (800 mL) was added to the residue, and the reaction mixture was stirred for 30 minutes at 45 °C to 50°C. The reaction mixture was cooled to 25 °C to 30°C and was stirred at this temperature for 30 minutes. The solid was filtered, washed with methyl tert- butyl ether (100 mL x 2), and dried in an air oven at 50°C for 12 hours to afford 2,3- dimethyl-6-nitro-2H-indazole as a yellow solid.
- Raney nickel 12.50 g was added to a suspension of 2,3-dimethyl-6-nitro-2H- indazole (50 g, 0.26 mol) in methanol (500 mL). The reaction mixture was stirred in an autoclave under hydrogen pressure of 3.5 kg/cm 2 - 4.0 kg/cm 2 at 25°C to 30°C for 5 hours. Further, the reaction mixture was filtered through a hyflo bed, and the catalyst was washed with methanol (100 mL x 2). The filtrates were combined, and the solvent was recovered completely.
- De-ionized water (850 mL) was added to the wet material to obtain a slurry, and the slurry was stirred at 25°C to 30°C for 30 minutes.
- the solid was filtered, then washed with de-ionized water (170 mL x 2).
- the wet material obtained was treated with ethyl acetate (340 mL) to obtain a slurry.
- the slurry was stirred at 35°C to 40°C for 30 minutes and then cooled to 0°C to 5°C.
- the slurry was further stirred at 0°C to 5°C for 30 minutes.
- the solid was collected by filtration, then washed with cold ethyl acetate (170 mL x 2).
- the solid was dried in an air oven at 50°C for 16 hours to afford N-(2-chloropyrimidin-4-yl)-2,3 -dimethyl -2H-indazol-6-amine as an off-
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
L'invention concerne un procédé de préparation du pazopanib de formule Ia ou de ses sels, et de ses intermédiaires.
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP13828826.1A EP2935250B1 (fr) | 2012-12-17 | 2013-12-17 | Procédé de préparation de pazopanib ou de sels de celui-ci |
ES13828826.1T ES2669425T3 (es) | 2012-12-17 | 2013-12-17 | Procedimiento para la preparación de pazopanib o sales del mismo |
US14/652,807 US9802923B2 (en) | 2012-12-17 | 2013-12-17 | Process for the preparation of pazopanib or salts thereof |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
INDE38972012 | 2012-12-17 | ||
IN3897/DEL/2012 | 2012-12-17 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2014097152A1 true WO2014097152A1 (fr) | 2014-06-26 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2013/061048 WO2014097152A1 (fr) | 2012-12-17 | 2013-12-17 | Procédé de préparation du pazopanib ou de ses sels |
Country Status (1)
Country | Link |
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WO (1) | WO2014097152A1 (fr) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107721989A (zh) * | 2017-11-14 | 2018-02-23 | 苏州东南药业股份有限公司 | 一种帕唑帕尼的制备方法及其中间体 |
US10730859B2 (en) | 2013-11-05 | 2020-08-04 | Laurus Labs Limited | Process for the preparation of pazopanib or a pharmaceutically acceptable salt thereof |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003106416A2 (fr) * | 2002-06-17 | 2003-12-24 | Smithkline Beecham Corporation | Processus chimique |
WO2005054212A2 (fr) * | 2003-12-05 | 2005-06-16 | Ciba Specialty Chemicals Holding Inc. | Dispositif electroluminescent |
US7105530B2 (en) | 2000-12-21 | 2006-09-12 | Smithkline Beecham Corporation | Pyrimidineamines as angiogenesis modulators |
WO2007064752A2 (fr) | 2005-11-29 | 2007-06-07 | Smithkline Beecham Corporation | Procede de traitement |
WO2011069053A1 (fr) | 2009-12-04 | 2011-06-09 | Teva Pharmaceutical Industries Ltd. | Procede de preparation de pazopanip hcl et formes cristallines de pazopanib hcl |
WO2012051659A1 (fr) * | 2010-10-20 | 2012-04-26 | Biota Scientific Management Pty Ltd | Inhibiteurs d'une polymérase virale |
-
2013
- 2013-12-17 WO PCT/IB2013/061048 patent/WO2014097152A1/fr active Application Filing
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7105530B2 (en) | 2000-12-21 | 2006-09-12 | Smithkline Beecham Corporation | Pyrimidineamines as angiogenesis modulators |
WO2003106416A2 (fr) * | 2002-06-17 | 2003-12-24 | Smithkline Beecham Corporation | Processus chimique |
WO2005054212A2 (fr) * | 2003-12-05 | 2005-06-16 | Ciba Specialty Chemicals Holding Inc. | Dispositif electroluminescent |
WO2007064752A2 (fr) | 2005-11-29 | 2007-06-07 | Smithkline Beecham Corporation | Procede de traitement |
WO2011069053A1 (fr) | 2009-12-04 | 2011-06-09 | Teva Pharmaceutical Industries Ltd. | Procede de preparation de pazopanip hcl et formes cristallines de pazopanib hcl |
WO2012051659A1 (fr) * | 2010-10-20 | 2012-04-26 | Biota Scientific Management Pty Ltd | Inhibiteurs d'une polymérase virale |
Non-Patent Citations (1)
Title |
---|
DAVIES R R: "Indazole derivatives: the synthesis of various amino- and hydroxy-indazoles and derived sulphonic acids", JOURNAL OF THE CHEMICAL SOCIETY, CHEMICAL SOCIETY, LETCHWORTH; GB, 1 January 1955 (1955-01-01), pages 2412 - 2423, XP009176650, ISSN: 0368-1769, DOI: 10.1039/JR9550002412 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10730859B2 (en) | 2013-11-05 | 2020-08-04 | Laurus Labs Limited | Process for the preparation of pazopanib or a pharmaceutically acceptable salt thereof |
US11299477B2 (en) | 2013-11-05 | 2022-04-12 | Laurus Labs Limited | Process for the preparation of Pazopanib or a pharmaceutically acceptable salt thereof |
US11427570B2 (en) | 2013-11-05 | 2022-08-30 | Laurus Labs Limited | Process for the preparation of pazopanib or a pharmaceutically acceptable salt thereof |
CN107721989A (zh) * | 2017-11-14 | 2018-02-23 | 苏州东南药业股份有限公司 | 一种帕唑帕尼的制备方法及其中间体 |
CN107721989B (zh) * | 2017-11-14 | 2019-06-14 | 苏州东南药业股份有限公司 | 一种帕唑帕尼的制备方法及其中间体 |
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