WO2022009036A1 - Synthèse de favipiravir - Google Patents

Synthèse de favipiravir Download PDF

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Publication number
WO2022009036A1
WO2022009036A1 PCT/IB2021/055912 IB2021055912W WO2022009036A1 WO 2022009036 A1 WO2022009036 A1 WO 2022009036A1 IB 2021055912 W IB2021055912 W IB 2021055912W WO 2022009036 A1 WO2022009036 A1 WO 2022009036A1
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WO
WIPO (PCT)
Prior art keywords
carbonitrile
hydroxypyrazine
fluoro
favipiravir
ammonia salt
Prior art date
Application number
PCT/IB2021/055912
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English (en)
Inventor
Srinivas Reddy Desi Reddy
Madhava Reddy VEDURURI
Original Assignee
Optimus Drugs (P) Ltd
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 Optimus Drugs (P) Ltd filed Critical Optimus Drugs (P) Ltd
Priority to KR1020217024015A priority Critical patent/KR20230034848A/ko
Publication of WO2022009036A1 publication Critical patent/WO2022009036A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having 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
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to a novel 6-Fluoro-3-hydroxypyrazine-2-carbonitrile ammonia salt and to an improved and commercially viable process for preparation of Favipiravir using 6-fluoro-3-hydroxypyrazine-2-carbonitrile ammonia salt.
  • Favipiravir (T-705; 6-fluoro-3-hydroxypyrazine-2-methan amide), is new RNA polymerase (RdRp). Favipiravir is effective against type-A influenza virus (including bird flu and influenza A H1N1 infection). Moreover, it is possible to suppress the transcription of other viruses, such as Arena vims, yellow fever virus, west Nile vims, Bunya vims and hand-foot-mouth disease virus etc. with Favipiravir. It has also been reported that it can be effective for treatment of COVID-19. Its stmctural formula is as follows:
  • Favipiravir is reported in US 6787544 by Toyama chemical.
  • the synthetic process for Favipiravir is reported in US ‘544, which comprises, reacting methyl 6-bromo-3-amino-2- pyrazine carboxylate of formula (2) with methanol in presence of H 2 SO 4 / NaNC> 2 to obtain methyl 6-bromo-3-methoxy- 2-pyrazinecarboxylate (3).
  • the compound of formula (3) converts into methyl 6-amino-3-methoxy-2-pyrazinecarboxylate (4) in presence of (S)-(-)- 2,2'-bis (di phenylphosphino)- 1,1 '-binaphthyl / benzophenone-imine and Pd 2 (dba) 3 to obtain 6-amino-3-methoxy-2-pyrazinecarboxamide (5).
  • the compound of formula (5) is reacted with pyridine hydrofluoride in presence of NaNC / water and chloroform to obtain 6-fluoro-3-methoxy-2- pyrazine carboxamide (6).
  • the compound of formula (6) converts into Favipiravir (1) in presence of Nal and TMSC1.
  • US 8586741 of Nippon soda discloses a process for the preparation of Favipiravir, which comprises reacting 6-bromo-3-hydroxypyrazine-2-carboxamide (10) with POCI3 in presence of DIPEA / toluene and monochlorobenzene to obtain 3,6-dichloropyrazine-2- carbonitrile (11).
  • the compound of formula (11) is reacted with KF in presence of TBAB / toluene and DMSO to obtain 3,6-difluoropyrazine-2-carbonitrile (12).
  • the compound of formula (12) converts into 6-fluoro-3-hydroxypyrazine-2-carbonitrile (13) in presence of CfpCOONa / DMSO and toluene.
  • the compound of formula (13) converts into pure Favipiravir (I) in presence of cone. H2SO4, NaOH and water.
  • the present invention provides as result of extensive studies, process for the preparation of Favipiravir (I) using 6-fluoro-3-hydroxypyrazine-2- carbonitrile ammonia salt.
  • the improved process involves direct conversion of 6-bromo-3- hydroxypyrazine-2-carboxamide compound of formula (10) to 6-fluoro-3- hydroxypyrazine-2-carbonitrile (13), without isolation of compound of formula (12), which is further converted into Favipiravir (I).
  • the process for the preparation of Favipiravir (I) is carried out in less span of time; hence, the number of required operations are reduced.
  • the advantage of the present invention w.r.t environmental variables, such as humidity, moisture content is eliminate from the manufacturing process.
  • the present invention relates to novel 6-Fluoro-3-hydroxypyrazine-2-carbonitrile ammonia salt and an improved and industrially advantageous process of Favipiravir using 6-fluoro- 3-hydroxypyrazine-2-carbonitrile ammonia salt.
  • the present invention provides 6-fluoro-3-hydroxypyrazine-2-carbonitrile ammonia salt.
  • the present invention provides a process for the preparation of Favipiravir, comprising the steps of; a) 6-bromo-3-hydroxypyrazine-2-carboxamide is reacted with chlorinating agent in presence of organic base to obtain 3,6-dichloropyrazine-2-carbonitrile, b) 3,6-dichloropyrazine-2-carbonitrile is reacted with fluorinating agent in presence of phase transfer catalyst (PTC) to obtain in-situ 3,6-difluoropyrazine-2-carbonitrile, further its treated with inorganic base and isolated in presence of ammonia to give 6-fluoro-3-hydroxypyrazine-2-carbonitrile ammonia salt, and c) 6-fluoro-3-hydroxypyrazine-2-carbonitrile ammonia salt is hydrolyzed and oxidized to obtain Favipiravir (1).
  • PTC phase transfer catalyst
  • the present invention provides purification process for the preparation of Favipiravir having 99.97% having HPLC purity.
  • the present invention relates to 6-Fluoro-3-hydroxypyrazine-2-carbonitrile ammonia salt and to an improved and industrially advantageous process of Favipiravir using 6-fluoro-3- hydroxypyrazine-2-carbonitrile ammonia salt.
  • the present invention provides a process for the preparation of Favipiravir, comprising the steps of; a) 6-bromo-3-hydroxypyrazine-2-carboxamide is reacted with chlorinating agent in presence of organic base to obtain in-situ 3,6-dichloropyrazine-2-carbonitrile b) 3,6-dichloropyrazine-2-carbonitrile is reacted with fluorinating agent in presence of phase transfer catalyst (PTC) to obtain ⁇ h-situ 3,6-difluoropyrazine-2-carbonitrile, further its treated with inorganic base and isolated in presence of ammonia to give 6-fluoro-3-hydroxypyrazine-2-carbonitrile ammonia salt, and c) 6-fluoro-3-hydroxypyrazine-2-carbonitrile ammonia salt is hydrolyzed and oxidized to obtain Favipiravir (1).
  • PTC phase transfer catalyst
  • 6-bromo-3-hydroxypyrazine-2-carboxamide is added into round bottom flask (RBF), followed by slow addition of POCI 3 and then cooled to below 10°C, DIPEA is added into reaction mixture at same temperature.
  • the reaction mass is heated to 80-85°C, stirred for 1 hour at same temperature and then heated at 95- 100°C and stirred for 6-8 hrs.
  • the reaction mass was cooled to 25-30°C, quenched with cold water, extracted the material into toluene, washed the toluene layer with sodium bicarbonate solution and sodium chloride solution. The resultant toluene layer was distilled under vacuum and kept aside as part- A solution.
  • RBF is taken separately and KF, tetrabutylammonium bromide, DMSO and toluene are added to it.
  • the reaction mixture is heated to 125°C and toluene is distilled out at atmosphere pressure at below 150°C.
  • the reaction mixture is cooled to 55-60°C, and above DMSO solution of part-A is now slowly added and the reaction mass is stirred for 10-12 hrs.
  • the reaction mixture was cooled to 25-30°C, and purified water and sodium acetate are added.
  • the reaction mass is heated to 55-60°C and stirred for 3-4 hrs.
  • the reaction mass was cooled to 25-30°C, and added purified water, adjusted pH to 2-3 by dil.HCl solution, added ethyl acetate and stirred for 10 min to separate the layers.
  • the obtained ethyl acetate layer was washed with purified water, sodium chloride solution and adjusted the pH 8-9 by using ammonia gas at 25-30°C.
  • the resultant ethyl acetate layer was allowed to cool at 0-5°C, stirred for 60 min, the obtained precipitated material was filtered and dried at 45-50°C for 8 hrs to get 6-fluoro-3-hydroxypyrazine-2-carbonitrile ammonia salt.
  • reaction is carried out at 50-70°C stir for 2-5 hrs, adjusted the pH to 2-5 by using dil. HC1, preferably 55-60°C stirred for 3-4 hrs, adjusted pH to 2-3, to obtain Favipiravir (1).
  • the chlorinating agent is selected from phosphorus pentachloride, phosphoryl chloride, phosphorus oxychloride, thionyl chloride, aluminium chloride, methyl sulfonyl chloride, acetyl chloride, chlorine gas, phosgene, diphosgene, triphosgene, sodium hypochlorite, cyanuric chloride and N-chloro succinimide.
  • the fluorinating agent is selected from hydrofluoric acid, potassium fluoride, fluorine gas, sodium fluoride, xenon fluoride, lithium fluoride and silver fluoride.
  • the organic base is selected from trimethylamine, diethylamine, triethylamine, diisopropylamine, diisopropylethylamine, aniline, N,N-dimethylaniline, pyridine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 5- diazabi cyclo[4.3.0]non-5-ene (DBN).
  • DBU diazabicyclo[5.4.0]undec-7-ene
  • DBN 5- diazabi cyclo[4.3.0]non-5-ene
  • the suitable inorganic base is selected from, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate and potassium carbonate, sodium acetate, and potassium acetate.
  • the phase transfer catalyst is selected from, tetrabutyl ammonium bromide, tetraoctylammonium bromide, tetrabutyl ammonium chloride, tetrabutylamine iodide, polyethylene glycol dimethyl ether, polyethylene glycol diethyl ether, 18 crown 6, 15 crown 5, or cyclodextrin.
  • the oxidizing agent is selected from, hydrogen peroxide (H2O2), urea-hydrogen peroxide (UHP), trifluoroacetic acid (TFA) - sulfuric acid (H2SO4), acetic acid- sulfuric acid and FFC ⁇ FeSC (Fenton's reagent).
  • the reaction is carried out in the presence of solvents such as ethanol, methanol, isopropanol, toluene, dimethyl sulfoxide (DMSO), dimethyl formamide (DMF), ethyl acetate, isopropyl acetate, n-butyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone, methylene dichloride, diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane and acetonitrile.
  • solvents such as ethanol, methanol, isopropanol, toluene, dimethyl sulfoxide (DMSO), dimethyl formamide (DMF), ethyl acetate, isopropyl acetate, n-butyl acetate, acetone, methyl ethyl
  • the present invention also provides novel 6-fluoro-3-hydroxypyrazine- 2-carbonitrile ammonia salt.
  • the present invention provides purification process for the preparation of Favipiravir which comprises purifying the Favipiravir (1) with mixture of acetone and dimethyl formamide to obtain pure Favipiravir (1).
  • the present invention provides purification process for the preparation of Favipiravir having 99.97% having HPLC purity.
  • Example-1 6-fluoro-3-Hydroxypyrazine-2-carbonitrile ammonia salt.
  • Part-B Preparation of 6-fluoro-3-hydroxypyrazine-2-carbonitrile ammonia salt.
  • reaction mass was heated to 125°C, and distilled out toluene at atmosphere pressure at below 150°C.
  • the reaction mixture was cooled to 55-60°C, now slowly added above DMSO solution of part-A and stir the reaction mass for 10-12 hrs.
  • the reaction mixture was cool to 25-30°C, added 400 ml of purified water and 90 gm of sodium acetate.
  • the reaction mass was heated to 55-60°C and stir for 3-4 hrs.
  • the reaction mass was cooled to 25-30°C, added 1000 ml of purified water, adjusted pH to 2-3 by dil.HCl solution, added 500 ml of ethyl acetate and stirred for 10 min to separate the layers.
  • the obtained ethyl acetate layer was washed with purified water, 5% sodium chloride solution and adjusted the pH to 8-9 by using ammonia gas at 25-30°C.
  • the resultant ethyl acetate layer was allowed to cool at 0-5°C, stir for 60 min, the obtained precipitated material was filtered and dried at 45- 50°C for 8 hrs to get title compound.
  • the obtained material was filtered and dried, the afford material was charged into 1200 ml of acetone and heat it to 40-45°C, followed by 10 gm of activated charcoal and stir for 30 min at same temperature.
  • the obtain reaction mass was filter through hyflo bed, wash with 100 ml of acetone, take filtrate into RBF, distilled out acetone at below 40°C under vacuum until remain 200 ml acetone present in the RBF, cool the reaction mass to 0-5°C, stir for 60 min.
  • the resultant material was filtered and dried at 45-50°C for 8 hrs to get desired compound.
  • the obtain material was filtered and dried, the afford material was charged into 1200 ml of acetone and heat it to 40-45°C, followed by 10 gm of activated charcoal and stir for 30 min at same temperature.
  • the obtain reaction mass was filter through hyflo bed, wash with 100 ml of acetone, 100 ml of dimethylformamide into RBF take filtrate into RBF, distilled out acetone at below 40°C under vacuum until remain 200 ml acetone present in the RBF, cool the reaction mass to 0-5°C and stir for 60 min.
  • the resultant material was filtered and dried at 45-50°C for 8 hrs to get desired compound.

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Abstract

La présente invention concerne un sel d'ammoniac de 6-fluoro-3-hydroxypyrazine-2-carbonitrile et un procédé amélioré et commercialement viable pour la préparation de favipiravir à l'aide d'un sel d'ammoniac de 6-fluoro-3-hydroxypyrazine-2-carbonitrile.
PCT/IB2021/055912 2020-07-06 2021-07-01 Synthèse de favipiravir WO2022009036A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
KR1020217024015A KR20230034848A (ko) 2020-07-06 2021-07-01 파비피라비르의 합성

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IN202041028704 2020-07-06
IN202041028704 2020-07-06

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WO2022009036A1 true WO2022009036A1 (fr) 2022-01-13

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1256588B1 (fr) * 2000-02-16 2005-02-02 Toyama Chemical Co., Ltd. Nouveaux derives de pyrazine ou leurs sels, compositions pharmaceutiques contenant ces derives ou leurs sels et intermediaires utilises dans leur preparation
US20100286394A1 (en) * 2007-09-27 2010-11-11 Toyama Chemical Co., Ltd. Organic amine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile and method for producing the same
JP2011006404A (ja) * 2009-05-27 2011-01-13 Toyama Chem Co Ltd ３，６−ジクロロ−２−ピラジンカルボニトリルの製造法
CN106866553A (zh) * 2017-03-28 2017-06-20 中南大学 一种法匹拉韦的合成方法
CN107226794A (zh) * 2017-07-17 2017-10-03 郑州大学 一种法匹拉韦的合成方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1256588B1 (fr) * 2000-02-16 2005-02-02 Toyama Chemical Co., Ltd. Nouveaux derives de pyrazine ou leurs sels, compositions pharmaceutiques contenant ces derives ou leurs sels et intermediaires utilises dans leur preparation
US20100286394A1 (en) * 2007-09-27 2010-11-11 Toyama Chemical Co., Ltd. Organic amine salt of 6-fluoro-3-hydroxy-2-pyrazinecarbonitrile and method for producing the same
JP2011006404A (ja) * 2009-05-27 2011-01-13 Toyama Chem Co Ltd ３，６−ジクロロ−２−ピラジンカルボニトリルの製造法
CN106866553A (zh) * 2017-03-28 2017-06-20 中南大学 一种法匹拉韦的合成方法
CN107226794A (zh) * 2017-07-17 2017-10-03 郑州大学 一种法匹拉韦的合成方法

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