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WO2018109781A1 - Procédé de préparation de firocoxib - Google Patents

Procédé de préparation de firocoxib Download PDF

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Publication number
WO2018109781A1
WO2018109781A1 PCT/IN2017/050572 IN2017050572W WO2018109781A1 WO 2018109781 A1 WO2018109781 A1 WO 2018109781A1 IN 2017050572 W IN2017050572 W IN 2017050572W WO 2018109781 A1 WO2018109781 A1 WO 2018109781A1
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WO
WIPO (PCT)
Prior art keywords
formula
firocoxib
phenyl
methyl
cyclopropylmethoxy
Prior art date
Application number
PCT/IN2017/050572
Other languages
English (en)
Inventor
Suresh Ramasamy
Ponnuchamy SINGANAN
Hariprasad BARVE
Krishna BETTADAPURA GUNDAPPA
Anil Ganpatrao Holkar
Original Assignee
Sequent Scientific Limited
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Sequent Scientific Limited filed Critical Sequent Scientific Limited
Publication of WO2018109781A1 publication Critical patent/WO2018109781A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
    • C07D307/60—Two oxygen atoms, e.g. succinic anhydride

Definitions

  • the present invention provides an improved process for the preparation of Firocoxib of Formula I. Further, the present invention also relates to process for the preparation of crystalline polymorphic form B of Firocoxib.
  • Firocoxib is a coxib-class of non-steroidal anti -inflammatory drug approved as veterinary medicine for the treatment of equine osteoarthritis, chronic pain and inflammation caused by the clinical surgery.
  • COX-2 is a subtype of cyclooxygenase, responsible for prostaglandin synthesis, regulation of pain, inflammation and fever. Selective inhibition of COX-2 can effectively relieve osteoarthritis pain.
  • Firocoxib is highly effective than other non-steroidal antiinflammatory drugs because of highly selective inhibition of COX-2, upon oral administration it is rapidly absorbed.
  • Firocoxib have chemical name 3- (cyclopropylmethoxy)-5,5-dimethyl-4-[4-(methylsulfonyl)phenyl]-(5H)-furan-2- one as represented by Formula I.
  • US6677373B2 describes a process for preparation of crystalline polymorph B of Firocoxib.
  • Polymorph B of Firocoxib was prepared from polymorph A, either by conversion of polymorph A to polymorph B or by recrystallization of Form A in methylcyclohexane and tetrahydrofuran mixture along with seeding with polymorph B.
  • US6787342B2 provided veterinary paste formulation of Firocoxib polymorph B.
  • the examples used polymorph A for the preparation of polymorph B along with seeding.
  • CN104803956A describes a process for preparation of Firocoxib using phase transfer catalysts as shown in below reaction scheme B.
  • Hazardous solvents such as chloroform, chlorobenzene and pyridine were used that are not preferred industrially.
  • CN105859664A provides a process for the preparation of Firocoxib as shown in below synthetic scheme C.
  • the reaction steps take very long duration for completion.
  • the drawback is the use of solvent like chloroform, which is hazardous to health and environmentally unfriendly, also recovery or recycle of solvent is very difficult.
  • the present inventors have developed a cost effective simple process for the preparation of crystalline polymorphic Form B of Firocoxib, without the necessity for seeding with polymorphic Form B of Firocoxib, with better purity, better yield, easy handling in bulk and avoided formation of unwanted impurities.
  • the principal aspect of the present invention is to provide a process for the preparation of Firocoxib of formula I, which comprises: a) condensing thioanisole of formula VII with isobutyryl chloride of formula VIII in presence of aluminum chloride and solvent to obtain 2-methyl-l-[4- (m ethyl sulfanyl) phenyl]propan-l-one of formula VI; b) brominating 2-methyl-l-[4-(methylsulfanyl)phenyl]propan-l-one of formula VI with liquid bromine in presence of solvent or mixture thereof to give 2-bromo- 2-methyl-l-[4-(methylsulfanyl)phenyl]propan-l-one of formula V; c) oxidizing 2-bromo-2-methyl-l-[4-(methylsulfanyl)phenyl]propan-l-one of formula V with oxidizing agent to give 2-bromo-2-methyl-l-[4- (methylsulfonyl)phen
  • Firocoxib of formula I which comprises the steps of:
  • a process for preparing polymorphic form B of Firocoxib from cyclisation reaction of 2-methyl-l-[4-(methylsulfonyl)phenyl]- l-oxopropan-2-yl (cyclopropylmethoxy)acetate is carried out using DBU, acetonitrile and isopropyl trifluoroacetate followed by adjusting pH to 3.5 to 4.5 with dilute hydrochloric acid.
  • the present invention provides a process for preparing crystalline Polymorphic Form B of Firocoxib, which comprises:
  • a process for the preparation of (cyclopropylmethoxy)acetic acid by the reaction of cyclopropylmethanol with haloacetic acid or salts thereof comprising bromoacetic acid, chloroacetic acid, sodium chloroacetate, potassium chloroacetate preferably bromoacetic acid using potassium ie/t-butoxide.
  • the (cyclopropylmethoxy)acetic acid thus prepared using potassium ie/t-butoxide was used further in the preparation of Firocoxib.
  • the invention relates to the preparation of crystalline 2- methyl- 1 -[4-(methylsulfonyl)phenyl]- 1 -oxopropan-2-yl
  • Firocoxib of formula I which comprises the steps of:
  • Figure 1 shows PXRD pattern of 2-methyl-l-[4-(methylsulfonyl)phenyl]-l-oxopropan-2- yl (cyclopropylmethoxy)acetate (Compound of formula II).
  • Figure 2 shows DSC of 2-methyl-l-[4-(methylsulfonyl)phenyl]-l-oxopropan-2-yl
  • Figure 3 shows Infrared (IR) spectrum of 2-methyl-l-[4-(methylsulfonyl)phenyl]-l- oxopropan-2-yl (cyclopropylmethoxy)acetate (Compound of formula II).
  • FIG. 4 shows TGA of 2-methyl-l-[4-(methylsulfonyl)phenyl]-l-oxopropan-2-yl
  • step a) the condensation of thioanisole of formula VII with isobutyryl chloride of formula VIII in step a) is carried out in presence of aluminum chloride (Lewis acid) in chlorinated solvent preferably dichloromethane (MDC) to obtain 2-methyl-l-[4-(methylsulfanyl)phenyl]propan- 1-one of formula VI.
  • Al chloride Lewis acid
  • MDC dichloromethane
  • bromination of 2-methyl-l-[4- (methylsulfanyl)phenyl]propan-l-one of formula VI in step b) is carried out using bromine solution in presence of solvent selected from cyclohexane, ethyl acetate, dichloromethane or mixture thereof preferably cyclohexane and ethyl acetate mixture to give 2-bromo-2-methyl-l-[4-(methylsulfanyl)phenyl]propan-l-one of formula V.
  • oxidation of 2-bromo-2-methyl-l-[4- (methylsulfanyl)phenyl]propan-l-one of formula V in step c) is carried out using oxidizing agent selected from hydrogen peroxide or peracetic acid preferably hydrogen peroxide, at the temperature range 30 to 50 °C, preferably at 40 to 45 °C to give 2-bromo-2-methyl-l-[4-(methylsulfonyl)phenyl]propan-l-one of formula III.
  • oxidizing agent selected from hydrogen peroxide or peracetic acid preferably hydrogen peroxide
  • condensation of cyclopropylmethanol of formula IX with bromoacetic acid of formula X in step d) is carried out in presence of a base preferably potassium tertiary butoxide and a solvent selected from tetrahydrofuran (THF) or dimethylformamide (DMF) or acetonitrile preferably tetrahydrofuran at a temperature 20 to 70 °C preferably 30 to 35 °C to give (cyclopropylmethoxy)acetic acid of formula IV.
  • a base preferably potassium tertiary butoxide
  • potassium ie/t-butoxide used was about 2 to 2.5 mole equivalent to cyclopropylmethanol. Preferably 2.2 equivalent was used. Potassium ie/t-butoxide and cyclopropylmethanol were used in the mole ratio of 2: 1 to 2.5: 1. Preferred mole ratio of potassium ie/t-butoxide : cyclopropylmethanol is 2.2: 1.
  • condensation of 2-bromo-2-methyl-l-[4- (methylsulfonyl)phenyl]propan-l-one of formula III with (cyclopropylmethoxy)acetic acid of formula IV in step e) is carried out using a solvent selected from methanol or ethanol or isopropanol preferably methanol and base preferably ⁇ , ⁇ -diisopropylethylamine (DIPEA) to give 2-methyl-l-[4- (methylsulfonyl)phenyl]- 1 -oxopropan-2-yl (cyclopropylmethoxy)acetate of formula II.
  • DIPEA ⁇ , ⁇ -diisopropylethylamine
  • 2-methyl-l-[4-(methylsulfonyl)phenyl]-l- oxopropan-2-yl (cyclopropylmethoxy)acetate of formula II is obtained in step e) is in crystalline form.
  • the cyclization of 2-methyl-l-[4- (methylsulfonyl)phenyl]- 1 -oxopropan-2-yl (cyclopropylmethoxy)acetate of formula II in step f) is carried out using isopropyl trifluoroacetate in presence of a base preferably l,8-diazabicycloundec-7-ene (DBU) and solvent selected from acetonitrile or dimethylformamide (DMF) preferably acetonitrile, to obtain Firocoxib of formula I.
  • a base preferably l,8-diazabicycloundec-7-ene (DBU)
  • solvent selected from acetonitrile or dimethylformamide (DMF) preferably acetonitrile preferably acetonitrile
  • polymorphic B of Firocoxib was prepared directly from cyclisation reaction of 2-methyl-l-[4-(methylsulfonyl)phenyl]-l- oxopropan-2-yl (cyclopropylmethoxy)acetate.
  • the cyclisation process is carried out using DBU, acetonitrile and isopropyl trifluoroacetate.
  • polymorphic B of Firocoxib was prepared from cyclisation reaction of 2-methyl-l-[4-(methylsulfonyl)phenyl]-l-oxopropan- 2-yl (cyclopropylmethoxy)acetate.
  • the cyclisation process is carried out using DBU, acetonitrile and isopropyl trifluoroacetate followed by adjusting pH to 3 to 5 with dilute hydrochloric acid.
  • polymorphic B of Firocoxib was prepared from cyclisation reaction of 2-methyl-l-[4-(methylsulfonyl)phenyl]-l-oxopropan- 2-yl (cyclopropylmethoxy)acetate.
  • the cyclisation process is carried out using DBU, acetonitrile and isopropyl trifluoroacetate followed by adjusting pH to 3.5 to 4.5 with dilute hydrochloric acid.
  • the process for the preparation of polymorph B does not proceed via using polymorph A.
  • Form B was isolated after completion of the reaction.
  • the use of polymorph A as starting compound in the preparation of polymorph B as described in prior art is avoided in the instant invention.
  • recrystallization of Firocoxib of formula I is carried out by treating Firocoxib of formula I using a solvent selected from ethanol or methanol preferably methanol at the temperature range 40 to 70 °C preferably at 50 to 55 °C. Further, the reaction mass was treated with activated carbon, followed by filtration and finally the Firocoxib polymorph B obtained was filtered and dried to get Firocoxib of formula I.
  • the Firocoxib obtained was highly pure with the purity of 99.9%.
  • the crystalline compound of formula II is used in the preparation of Firocoxib of compound of formula I.
  • PXRD powder X-ray diffraction
  • crystalline 2-methyl-l-[4-(methylsulfonyl)phenyl]-l- oxopropan-2-yl (cyclopropylmethoxy)acetate or compound of formula II exhibits characteristic 2 ⁇ ° PXRD peaks ( ⁇ 0.2) at 7.37, 11.27, 19.39, 22.15, 37.32, and
  • 29.66 Preferably, 7.37, 19.39, and 29.66. Most preferably, 7.37 and 19.39.
  • the present invention provides a process for preparing crystalline polymorphic Form B of Firocoxib, which comprises:
  • the present invention provides a process for preparing crystalline polymorphic Form B of Firocoxib, which comprises:
  • the present invention provides a process for preparing crystalline polymorphic Form B of Firocoxib, which comprises:
  • the present invention provides a process for preparing polymorph B of Firocoxib, which comprises:
  • the present invention provides a process for preparing polymorph B of Firocoxib, which comprises: a) treating Firocoxib in methanol;
  • Firocoxib is micronized, where necessary, to desired particle size range using appropriate micronization techniques known in the prior art.
  • 'crystalline polymorphic form B' or 'polymorph B' or 'Form B' refers to Firocoxib crystalline polymorph B as characterized with the melting point around 120 °C.
  • the process of the present invention is advantageous over prior art, some of them are stated below:
  • Polymorphic Form B is obtained without the need of going via polymorph A.
  • the process of the present invention provides preparation of polymorph Form B of Firocoxib without the necessity of seeding with polymorph B.
  • the process of the present invention is very user friendly avoids the lengthy workup and in turn minimizes the generation of hazardous effluent.
  • Step b) and step c) reactions were carried out using same solvent system, cyclohexane and ethyl acetate mixture.
  • US6677373B2 indicates that polymorph B of Firocoxib possesses better flow characteristics and therefore easy to handle than polymorph A.
  • the examples 1-4 provided in US6677373B2 use Firocoxib polymorph A in the preparation of polymorph B.
  • Inventors of the instant invention arrived at preparing Firocoxib polymorph B directly from the reaction, avoiding using polymorph A. Therefore the process of the instant invention is simple with the ease of handling polymorph B and easy for scale up.
  • Example-3a Preparation of 2-methyl-l-[4-(methylsulfonyl)phenyl]-l- oxopropan-2-yl (cyclopropylmethoxy)acetate
  • Example-3b Preparation of 2-methyl-l-[4-(methylsulfonyl)phenyl]-l- oxopropan-2- yl (cyclopropylmethoxy)acetate
  • Firocoxib (100 g) and methanol (500 mL) were added into a flask at 25 to 35 °C and reaction mass was refluxed to get clear solution.
  • Firocoxib Form B was seeded at 50 to 55 °C. After cooling, the solid obtained was filtered and washed with cold methanol (100 mL). The solid was dried under vacuum. The recrystallization is optional to further improve the purity. Yield: 95 g; 95%. Purity: 99.8%.
  • Example-5a Recrystallisation of Firocoxib
  • Firocoxib (100 g) and methanol (1500 mL) were added into a flask at 25 to 35°C and reaction mass was heated to 50 to 55 °C to get clear solution. Carbon was added, stirred for 30 minutes. The solution was filtered through hyflow bed and washed with hot methanol (100 mL). The filtrate was concentrated by distilling out methanol. Seeding material of Form B was added at 50 to 55 °C. The reaction mass was cooled to 25 to 30 °C, stirred for one hour and further cooled to 0 to 5°C and further stirred for one hour. The solid obtained was filtered and washed with cold methanol (100 mL). The solid was dried under vacuum. Solids was isolated. The results on the polymorphic form were confirmed by powder X-Ray diffraction and DSC to be crystalline polymorphic Form B of Firocoxib. Yield: 94 g; 94%. Purity: 99.9%.
  • Firocoxib (100 g) and methanol (1500 mL) were added into a flask at 25 to 35°C and reaction mass was heated to 50 to 55 °C to get clear solution. Carbon was added, stirred for 30 minutes. The solution was filtered through hyflow bed and washed with hot methanol (100 mL). The filtrate was concentrated by distilling out methanol. The reaction mass was cooled to 25 to 30 °C, stirred for one hour, cooled to 0 to 5 °C and further stirred for one hour. The solid obtained was filtered and washed with cold methanol (100 mL). The solid was dried under vacuum and isolated. The results on the polymorphic form were confirmed by powder X-Ray diffraction to be crystalline polymorphic Form B of Firocoxib. Yield: 92 g; 92%. Purity: 99.9%.

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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 amélioré de préparation de firocoxib de formule I. La présente invention concerne également, un nouveau procédé de préparation de la forme B polymorphe cristalline du firocoxib de formule I.
PCT/IN2017/050572 2016-12-13 2017-12-06 Procédé de préparation de firocoxib WO2018109781A1 (fr)

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IN201621042452 2016-12-13

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109810031A (zh) * 2017-11-21 2019-05-28 乳源瑶族自治县东阳光生物科技有限公司 非罗考昔中间体的制备方法
CN110452199A (zh) * 2019-09-03 2019-11-15 山东鲁抗舍里乐药业有限公司 一种非罗考昔的制备方法
CN110452198A (zh) * 2019-09-03 2019-11-15 山东鲁抗舍里乐药业有限公司 一种非罗考昔的制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104803956A (zh) * 2015-03-06 2015-07-29 江苏天和制药有限公司 非罗考昔的一种合成方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104803956A (zh) * 2015-03-06 2015-07-29 江苏天和制药有限公司 非罗考昔的一种合成方法

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109810031A (zh) * 2017-11-21 2019-05-28 乳源瑶族自治县东阳光生物科技有限公司 非罗考昔中间体的制备方法
CN109810031B (zh) * 2017-11-21 2023-10-17 乳源瑶族自治县东阳光生物科技有限公司 非罗考昔中间体的制备方法
CN110452199A (zh) * 2019-09-03 2019-11-15 山东鲁抗舍里乐药业有限公司 一种非罗考昔的制备方法
CN110452198A (zh) * 2019-09-03 2019-11-15 山东鲁抗舍里乐药业有限公司 一种非罗考昔的制备方法

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