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WO2010095024A2 - Procédé amélioré de préparation de célécoxib - Google Patents

Procédé amélioré de préparation de célécoxib Download PDF

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Publication number
WO2010095024A2
WO2010095024A2 PCT/IB2010/000325 IB2010000325W WO2010095024A2 WO 2010095024 A2 WO2010095024 A2 WO 2010095024A2 IB 2010000325 W IB2010000325 W IB 2010000325W WO 2010095024 A2 WO2010095024 A2 WO 2010095024A2
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WIPO (PCT)
Prior art keywords
celecoxib
acid
formula
toluene
methylphenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2010/000325
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English (en)
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WO2010095024A3 (fr
Inventor
V Raghava Reddy Ambati
Srinivas Garaga
Sambhu Prasad Sarma Mallela
Sivakumaran Meenakshisunderam
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Aurobindo Pharma Ltd
Original Assignee
Aurobindo Pharma Ltd
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Filing date
Publication date
Application filed by Aurobindo Pharma Ltd filed Critical Aurobindo Pharma Ltd
Publication of WO2010095024A2 publication Critical patent/WO2010095024A2/fr
Publication of WO2010095024A3 publication Critical patent/WO2010095024A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

  • the present invention relates to an improved process for the preparation of 4-[5-(4- methylphenyl)-3-(trifluoromethyl)-l H-pyrazol-l -yl]benzenesulfonamide of Formula
  • Selective inhibitors of cyclooxygenase-2 have demonstrated effective antiinflammatory activity with reduced gastrointestinal side effects, as compared to other antiinflammatory agents, e.g., NSAIDs, which inhibit both the constitutive form of cyclooxygenase (COX-I ), and the inducible form of the enzyme (COX-2).
  • Particularly effective structural classes of selective COX-2 inhibitors are the 1 ,5-diarylpyrazoles.
  • Cisoxib 4-[5-(4-Methylphenyl)-3-(trifluoromethyl)- l H-pyrazol-l -yl]benzenesulfonamide (Celecoxib) is a 1 ,5-diarylpyrazole compound, which has been approved by the US Food and Drug Administration for the treatment of rheumatoid arthritis and osteoarthritis.
  • Celecoxib is the active ingredient used in the Celebrex, which is marketed by Pharmacia Corporation. G. D. Searle & Co., has disclosed Celecoxib and its pharmaceutically acceptable salts in US 5,466,823.
  • US 6, 150,534 discloses a process for the preparation of Celecoxib, which comprises, condensing l-(4-methylphenyl)-4,4,4-trifluorobutane-l ,3-dione (IV) with 4- sulphonamido-phenylhydrazine in presence of an amide solvent at controlled temperature to produce amide solvate of Celecoxib, which is further desolvated by recrystallization from isopropanol and water.
  • US 5,892,053 discloses a process for the preparation of Celecoxib by condensing 4- methylacetophenone (II) with 1-ethyltrifluoro acetate (III) to produce l-(4- methylphenyl)-4,4,4-trifluoiObutane-l ,3-dione (IV), which is further reacted with 4- hydrazinophenylsulfonamide (V) in presence of aqueous mixture of alcohol and acid to produce Celecoxib.
  • US 2008/0234491 Al discloses the condensation of l-(4-methylphenyl)-4,4,4- trifluorobutane-l,3-dione (IV) with 4-hydrazinophenylsulfonamide (V) or its acid addition salts in the presence of a solvent medium comprising an alkyl ester, water or mixtures thereof to produce Celecoxib. Further, crystallization of crude Celecoxib is carried out in toluene alone.
  • the instant invention describes a process, which produces Celecoxib with regioisomer (VI) to less than 2.5% by HPLC analysis.
  • the instant invention also describes a purification process using specific solvent mixture, which results in pure crystalline Celecoxib Form III, having regioisomer (VI) less than 0.1 % by HPLC analysis.
  • the main objective of the present invention is to provide a simple and effective process for the preparation of Celecoxib with high purity and good yields on a commercial scale.
  • the present application provides an improved process for the preparation of 4-[5-(4- methyIphenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl]benzenesulfonamide (Celecoxib) of Formula I,
  • the present invention also provides a process for the purification of 4-[5-(4-methylphenyl)-3-(trifluoiOmethyl)- 1 H-pyrazol- 1 - yl]benzenesulfonamide (Celecoxib) of Formula I, comprises:
  • step (ii) optionally, filtering the solution of step (i);
  • l-(4-Methylphenyl)-4,4,4-trifluorobutane-l,3-dione (IV) is condensed with 4- hydrazinophenylsulfonamide (V) or its acid addition salt in a solvent selected from water, inert organic solvent to produce 4-[5-(4-methylphenyl)-3-(trifluoiOmethyl)-lH- pyrazol-l-yl]benzenesulfonamide (Celecoxib) of Formula I.
  • the acid addition salts of compound of the formula IV includes, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, oxalate, mesylate, methane sulfonate, and tartrate, preferably, hydrochloride salt.
  • the suitable inert organic solvents for the above reaction include but are not limited to ketone solvents, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, n-butanone, and tertiary-butyl ketone; nitrile solvents, such as acetonitrile.
  • halogenated solvents such as dichloromethane, ethylene dichloride, and chloroform
  • esters such as ethyl acetate, n-propylacetate, isopropyl acetate, and tertiary-butyl acetate
  • aprotic polar solvents such as N,N- dimethylformamide, dimethylsulfoxide, and N,N-dimethylacetamide
  • ethers such as diisopropyl ether, tetrahydrofuran and 1,4-dioxane
  • hydrocarbon solvents such as cyclohexane, toluene and xylene; and mixtures thereof.
  • the preferred solvent is water.
  • the reaction may be performed at a temperature ranging from about 25°C to about reflux temperature of the solvent or mixture of solvents used for the reaction.
  • the above reaction is conducted in presence of an acid selected from aqueous hydrochloric acid, aqueous sulfuric acid, p-toluene sulfonic acid, trifluoroacetic acid, and acetic acid to maintain the pH of the reaction mixture is below 7. More preferably, aqueous HCl is added.
  • Crude Celecoxib (I) produced may be isolated by precipitation of compound from the reaction mixture, which may be performed by cooling the reaction mixture, followed by addition of an organic solvent selected from alcohols such as methanol, ethanol, isopropanol or aromatic hydrocarbons such as toluene, xylene, ethyl benzene and mixtures thereof solvents.
  • an organic solvent selected from alcohols such as methanol, ethanol, isopropanol or aromatic hydrocarbons such as toluene, xylene, ethyl benzene and mixtures thereof solvents.
  • the preferred solvent is mixture of methanol and toluene.
  • the present invention further provides a process for the purification Celecoxib (I).
  • the process comprises dissolving crude Celecoxib in a solvent mixture, precipitating Celecoxib Form III by cooling the solution to about 0-5°C, and isolating crystalline Celecoxib Form III.
  • the crude Celecoxib is dissolved in a solution at a temperature from about 4O 0 C to about the boiling temperature of the solvent.
  • the Celecoxib Form III is isolated by filtration.
  • the solution is treated with carbon, followed by filtration to remove insoluble material.
  • the step of cooling the reaction is performed by cooling the solution to a temperature from about - 1O 0 C to 25°C temperature.
  • the solvent mixture is selected from the group consisting of alcohol: toluene such as methanol: toluene, ethanol: toluene, isopropanol: toluene, n-butanol: toluene, t-butanol: toluene.
  • the ratio of alcohol to toluene may range from about 2.5:97.5 (v/v) to about 8:92 (v/v), preferably 5:95 (v/v).
  • the reaction mass was cooled to 70-75 C and a mixture of toluene (600 ml) and methanol (10 ml) was added to the reaction mass. After 1 hr stirring at 70-75 0 C, the reaction mass was cooled to 20-25 0 C, the product was filtered and ⁇ vashed with toluene (100 ml) followed by DM water (200 ml). The product obtained was dried at 55-60 0 C under reduced pressure to produce 1 15 g of Celecoxib crude. Chromatographic purity: 99%(by PTPLC, by area normalization)
  • Celecoxib crude (50 g) was dissolved in a mixture of toluene (300 ml) and methanol (20 ml) at 55-60 0 C. Carbon (2 g) was added and stirred for 15 min, the resulting solution was filtered through hyflo and washed with toluene (50 ml). The combined filtrate was stirred at 50-55 0 C for 1 hr, further the reaction mass was cooled and stirred another 1 hr at 0-5 0 C. The product was filtered and washed with chilled toluene (50 ml). The product was dried at 55-6O 0 C under reduced pressure to obtain 40 g of Form III Celecoxib. Chromatographic purity: 99.8% (by HPLC, by area normalization) Example 2:
  • Celecoxib crude (50 g) was dissolved in a mixture of toluene (250 ml) and ethanol (25 ml) at 60-65 0 C. Carbon (2 g) was added and stirred for 15 min, the resulting solution was filtered through hyflo and washed with toluene (50 ml). The combined filtrate was stirred at 50-55 0 C for 1 hr, further the reaction mass was cooled and stirred another 1 hr at 0-5 0 C. The product was filtered and washed with chilled toluene (50 ml). The product was dried at 55-6O 0 C under reduced pressure to obtain 41 g of Form III Celecoxib. Chromatographic purity: 99.8%(by HPLC, by area normalization)
  • Celecoxib crude (50 g) was dissolved in a mixture of toluene (250 ml) and isopropanol (25 ml) at 60-65 0 C. Carbon (2 g) was added and stirred for 15 min, the resulting solution was filtered through hyflo and washed with toluene (50 ml). The combined filtrate was stirred at 50-55 0 C for 1 hr, further the reaction mass was cooled and stirred another 1 hr at 0-5 0 C. The product was filtered and washed with chilled toluene (50 ml). The product was dried at 55-6O 0 C under reduced pressure to obtain 41 g of Form III Celecoxib. Chromatographic purity: 99,8% (by HPLC, by area normalization)

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé amélioré de préparation du composé 4-[5-(4- méthylphényl)-3 -(trifluorométhyl)- 1 H-pyrazol-1-y l]benzènesulfonamide représenté par la formule (I), par la condensation du composé l-(4-méthylphényl)-4,4,4-trifluorobutane-l,3-dione (IV), formule IV, avec le composé 4-hydrazinophénylsulfonamide (V) ou son sel d'addition acide, formule V, dans un solvant aqueux et en présence d'acide. L'invention concerne aussi un procédé de purification de Célécoxib dans un mélange de solvants.
PCT/IB2010/000325 2009-02-20 2010-02-18 Procédé amélioré de préparation de célécoxib Ceased WO2010095024A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN378/CHE/2009 2009-02-20
IN378CH2009 2009-02-20

Publications (2)

Publication Number Publication Date
WO2010095024A2 true WO2010095024A2 (fr) 2010-08-26
WO2010095024A3 WO2010095024A3 (fr) 2010-12-02

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103102306A (zh) * 2013-02-06 2013-05-15 河南东泰制药有限公司 一种塞来昔布的制备方法
CN103724268A (zh) * 2012-10-15 2014-04-16 成都国弘医药有限公司 一种塞来昔布的制备方法
CN103923011A (zh) * 2014-05-04 2014-07-16 苏州天马精细化学品股份有限公司 一种塞来西布的合成方法
CN108558759A (zh) * 2018-04-26 2018-09-21 齐鲁天和惠世制药有限公司 一锅法制备塞来昔布的方法
CN110143923A (zh) * 2018-07-18 2019-08-20 四川国为制药有限公司 一种安全性更高的药物组合物
CN110698404A (zh) * 2019-11-26 2020-01-17 安徽恒星制药有限公司 一种高纯度塞来昔布的制备方法
WO2020157771A1 (fr) 2019-02-01 2020-08-06 Council Of Scientific And Industrial Research Micro-système de traitement total à flux continu pour la préparation du célécoxib et d'analogues de celui-ci
CN116023329A (zh) * 2022-12-20 2023-04-28 常州制药厂有限公司 一种非甾体抗炎药塞来昔布的合成工艺

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5466823A (en) 1993-11-30 1995-11-14 G.D. Searle & Co. Substituted pyrazolyl benzenesulfonamides
US5892053A (en) 1995-05-25 1999-04-06 G. D. Searle & Co. Process for preparing 3-haloalkyl-1H-pyrazoles
US6150534A (en) 1999-01-14 2000-11-21 Merck Frosst Canada & Co. Synthesis of 4-[5-substituted or unsubstituted phenyl)-3-substituted-1H-pyrazol-1-yl]benzenesulfonamides
US6579988B2 (en) 2001-09-18 2003-06-17 Onconova Therapeutics, Inc. Processes for the preparation of 1,5-diarylpyrazoles
US20070004924A1 (en) 2002-05-24 2007-01-04 Pharmacia Corporation Synthesis of diaryl pyrazoles
US20080234491A1 (en) 2007-03-19 2008-09-25 Raghupathi Reddy Anumula Process for preparation of celecoxib

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5466823A (en) 1993-11-30 1995-11-14 G.D. Searle & Co. Substituted pyrazolyl benzenesulfonamides
US5892053A (en) 1995-05-25 1999-04-06 G. D. Searle & Co. Process for preparing 3-haloalkyl-1H-pyrazoles
US6150534A (en) 1999-01-14 2000-11-21 Merck Frosst Canada & Co. Synthesis of 4-[5-substituted or unsubstituted phenyl)-3-substituted-1H-pyrazol-1-yl]benzenesulfonamides
US6579988B2 (en) 2001-09-18 2003-06-17 Onconova Therapeutics, Inc. Processes for the preparation of 1,5-diarylpyrazoles
US20070004924A1 (en) 2002-05-24 2007-01-04 Pharmacia Corporation Synthesis of diaryl pyrazoles
US20080234491A1 (en) 2007-03-19 2008-09-25 Raghupathi Reddy Anumula Process for preparation of celecoxib

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103724268A (zh) * 2012-10-15 2014-04-16 成都国弘医药有限公司 一种塞来昔布的制备方法
CN103724268B (zh) * 2012-10-15 2016-02-03 成都国弘医药有限公司 一种塞来昔布的制备方法
CN103102306A (zh) * 2013-02-06 2013-05-15 河南东泰制药有限公司 一种塞来昔布的制备方法
CN103923011A (zh) * 2014-05-04 2014-07-16 苏州天马精细化学品股份有限公司 一种塞来西布的合成方法
CN108558759A (zh) * 2018-04-26 2018-09-21 齐鲁天和惠世制药有限公司 一锅法制备塞来昔布的方法
CN110143923A (zh) * 2018-07-18 2019-08-20 四川国为制药有限公司 一种安全性更高的药物组合物
WO2020157771A1 (fr) 2019-02-01 2020-08-06 Council Of Scientific And Industrial Research Micro-système de traitement total à flux continu pour la préparation du célécoxib et d'analogues de celui-ci
US11802112B2 (en) 2019-02-01 2023-10-31 Council Of Scientific & Industrial Research Continuous flow micro-total process system for preparation of celecoxib and analogs thereof
CN110698404A (zh) * 2019-11-26 2020-01-17 安徽恒星制药有限公司 一种高纯度塞来昔布的制备方法
CN116023329A (zh) * 2022-12-20 2023-04-28 常州制药厂有限公司 一种非甾体抗炎药塞来昔布的合成工艺

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