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WO2018163190A1 - Procédé amélioré pour la préparation de varénicline et son sel - Google Patents

Procédé amélioré pour la préparation de varénicline et son sel Download PDF

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Publication number
WO2018163190A1
WO2018163190A1 PCT/IN2017/050602 IN2017050602W WO2018163190A1 WO 2018163190 A1 WO2018163190 A1 WO 2018163190A1 IN 2017050602 W IN2017050602 W IN 2017050602W WO 2018163190 A1 WO2018163190 A1 WO 2018163190A1
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Prior art keywords
formula
compound
varenicline
salt
solvent
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Ceased
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PCT/IN2017/050602
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English (en)
Inventor
Vikas Bansal
Rohit CHAKRAVARTY
Anand Kumar Singh
Sujay Biswas
Dharam Vir
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Jubilant Generics Ltd
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Jubilant Generics Ltd
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Publication of WO2018163190A1 publication Critical patent/WO2018163190A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems

Definitions

  • the present invention relates to an improved process for the preparation of varenicline and salt thereof.
  • the present invention also provides a process for the preparation of l-(4,5-dinitro-10-aza-tricyclo[6.3.1.0 2 ' 7 ]dodeca-2(7),3,5-trien-10-yl)-2,2,2- trifluoroethanone of Formula 4 using ethyl trifluoro acetate and further converted to varenicline and salt thereof.
  • Varenicline is the chemically known as 7,8,9, 10-tetrahydro-6,10-methano-6H- pyrazino[2,3-h][3]benzazepine (which is also known as 5,8,14- triazatetracyclo[10.3.1.0 2 ' n .0 4 ' 9 ]-hexadeca-2(ll),3,5,7,9-pentaene) and has an empirical formula of C 13 H 13 N 3 and a molecular weight of 211.27 and shown in Formula 1:
  • Varenicline as a nicotinic receptor partial agonist, reduces both cravings and the pleasurable affects of cigarettes and other tobacco products, and through these mechanisms it assists some patients with quitting smoking. Being known to be useful in modulating cholinergic function, it is indicated for the treatment of smoking cessation. Varenicline is present in the form of a salt with L-tartaric acid, i.e., varenicline tartrate, in products marketed as CHANTIXTM in the U.S. and CHAMPIXTM in Europe and Canada. US 6410550B 1 disclosed the process for the preparation of Varenicline base or a pharmaceutically acceptable salt thereof.
  • the process for the preparation of varenicline base and its hydrochloride salt involves treating (10-aza-tricyclo[6.3.1.0 2 ' 7 ]dodeca-2(7),3,5-triene hydrochloride salt of Formula 2 with trifluoroacetic anhydride and pyridine to obtain 1-(10- aza-tricyclo[6.3.1.0 2 ' 7 ]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone of Formula 3, followed by reacting with trifluoromethanesulfonic acid and nitric acid to obtain l-(4,5- dinitro-10-aza-tricyclo[6.3.1.0 2 ' 7 ]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoroethanone of Formula 4, further hydrogenating using Pd(OH) 2 under hydrogen gas in methanol to obtain l-(4,5-diamino-10-aza-tricyclo[6.3.1.0 2 ' 7 ]d
  • US6890927B2 discloses varenicline L-tartrate salt and its various polymorphic forms such as A, B and C; and the process for the preparation thereof.
  • US2008/0275051A1 discloses a process for the preparation of varenicline free base by cyclizing nitrogen protected compound of Formula 8 using aq. glyoxal in a protic solvent, further removing the nitrogen protection to obtain varenicline as per scheme 2:
  • Varenicline US8314235B2 discloses a process for the preparation of protected diaminoazotricyclo compound of Formula 5A' by oxidizing l,2,3,4-tetrahydro-l,4-methanonaphthalene-2,3-diol of Formula 8 in the presence of an oxidizing agent in a solvent to provide indane-1,3- dicarbaldehyde of Formula 9, further reacting with benzyl amine in the presence of a reducing agent to provide 10-benzyl-10-aza-tricyclo[6.3.1.0 27 ]-dodeca-2(7),3,5-triene of Formula 10, followed by hydrogenating using a hydrogenation catalyst in the presence of a hydrogen source, to provide 10-aza-tricyclo[6.3.1.0 27 ]-dodeca-2(7),3,5-triene of Formula 2A, then protecting with a nitrogen protecting group to provide N-protected compound of Formula 3A after that nitrating using mixture of nitric and
  • R is nitrogen protecting group
  • the present invention involves the use of ethyl trifluoroacetate for the preparation of varenicline and salts thereof, which is less expensive as compare to ethyl trifluoroacetic anhydride and other similar reagents known in the art.
  • Many other patent publications have also been disclosed so far, which describe the process for the preparation of varenicline and salt thereof. Still there is a need to develop a simple, cost effective, high yielding, environment friendly and easy to implement on industrial scale process for the preparation of varenicline and salt thereof.
  • the principal object of the present invention is to provide a process for the preparation of varenicline and salt thereof which alleviates one or more drawbacks of prior art processes.
  • One object of the present invention is to provide an improved, efficient, safe and convenient process for preparation of varenicline and salt thereof.
  • Another object of the present invention is to provide a process for preparation of 1- (4,5-dinitro- 10-aza-tricyclo[6.3.1.0 2 ' 7 ]dodeca-2(7),3,5-trien- 10-yl)-2,2,2-trifluoroethanone by using ethyl trifluoroacetate.
  • yet another object of the present invention is to provide a process for the preparation varenicline and salt thereof comprising the steps of N-protection of (10-aza- tricyclo[6.3.1.0 2 ' 7 ] dodeca-2(7),3,5-triene or salt thereof of Formula 2 by treating with ethyl trifluoroacetate in the presence of methanol with or without using organic base such as di- isopropyl ethylamine or triethyl amine or pyridine and catalyst, to provide compound of Formula 3, further converting compound of Formula 3 into varenicline and salt thereof.
  • the present invention provides a process for the preparation of varenicline and salt thereof, comprising the steps of:
  • R is nitrogen protecting group selected from CF 3 CO-, CH 3 CO-, alkyl or aryl chloroformates b) nitrating compound of Formula 3A using suitable nitrating agent in the presence of suitable solvent to provide N-protected dinitroazotricyclo compound of Formula 4A;
  • the present invention provides a process for the preparation of varenicline and salt thereof, comprising the steps of:
  • the present invention provides a process for the preparation of varenicline tartrate, comprising the steps of: a) N-protection of (10-aza-tricyclo[6.3.1.0 2 ' 7 ] dodeca-2(7),3,5-triene or salt thereof of Formula 2 by treating with ethyl trifluoroacetate in the presence of methanol using di-isopropyl ethylamine, optionally using catalyst, to provide compound of Formula 3; b) nitrating compound of Formula 3 using nitrating mixture of nitric acid and sulfuric acid in the presence of dichloromethane as solvent to provide compound of Formula 4; c) reducing the compound of Formula 4 using Raney Ni, and hydrogen gas in the presence of methanol as solvent to provide compound of Formula 5; d) cyclizing compound of Formula 5 using aq.
  • varenicline tartrate glyoxal solution and triethyl amine to provide of Formula 6; e) deprotecting compound of Formula 6 using aq. sodium hydroxide solution to obtain varenicline, and; f) converting varenicline into its tartrate salt using tartaric acid and methanol as solvent to provide varenicline tartrate.
  • the present invention provides a process
  • the present invention provides a process for the preparation varenicline and salt thereof, comprising the steps of: a) N-protection of (10-aza-tricyclo[6.3.1.0 2 ' 7 ] dodeca-2(7),3,5-triene or salt thereof of Formula 2 by treating with ethyl trifluoroacetate in the presence of methanol, with or without using organic base such as di-isopropyl ethylamine or triethyl amine or pyridine and catalyst, to provide compound of Formula 3, and; b) converting compound of Formula 3 into varenicline and salt thereof.
  • Fig.2. X-ray powder diffraction (XRPD) pattern of varenicline tartrate obtained from according to example 6 Detail description of the invention
  • the present invention provides an efficient and industrially advantageous process for the preparation of varenicline and salt thereof.
  • the present invention provides a process for the preparation of varenicline and salt thereof, comprising the steps of:
  • R is nitrogen protecting group selected from CF 3 CO-, CH 3 CO-, alkyl or aryl chloroformates b) nitrating compound of Formula 3A using suitable nitrating agent in the presence of suitable solvent to provide N-protected dinitroazotricyclo compound of Formula 4A;
  • First step involves N-protection of (10-aza-tricyclo[6.3.1.0 2 ' 7 ] dodeca-2(7),3,5-triene or salt thereof of Formula 2 by treating with the suitable N-protecting reagent in the presence of suitable solvent, base and with or without using catalyst to provide N-protected intermediate of Formula 3 A.
  • the suitable N-protecting reagent used for preparation of compound of formula 3A may be selected from alkyl trifluoroacetate, trifluoroacetic anhydride, trifluoroacetic acid, trifluoroacetyl chloride, alkyl or aryl chloroformates; wherein alkyl is Ci-C 6 branched or straight chain such as methyl chloroformate, ethyl chloroformate, n-propyl chloroformate, isopropyl chloroformate, isobutyl chloroformate; aryl is substituted or unsubstituted phenyl such as benzyl chloroformate, phenyl chloroformate and the like thereof.
  • the N-protected intermediate of Formula 3A may be without isolation or after isolation treated with nitrating mixture in presence of suitable solvent to provide ⁇ -protected dinitroazotricyclo compound of Formula 4A.
  • varenicline free base into its salt by treating with suitable source of acid known using suitable solvent by any method known in the art.
  • the present invention provides a process for the preparation of varenicline and salt thereof, comprising the steps of:
  • First step involves N-protection of (10-aza-tricyclo[6.3.1.0 2 ' 7 ] dodeca-2(7),3,5-triene or salt thereof of Formula 2 by treating with a suitable N-protecting reagent in the presence of suitable solvent, base and with or without using catalyst to provide compound of Formula 3.
  • reaction may be carried out at temperature of 10 to 60°C for few minutes to few hours or till completion of reaction.
  • reaction is conducted at a temperature of 0 to 30°C, more preferably reaction is conducted at a temperature of 5 to 25°C and it takes 1 to 4 hours for completion of the reaction.
  • compound of Formula 3 may be without isolation or after isolation used for next step.
  • Next step involves nitration of compound of Formula 3 using suitable nitrating agent in the presence of suitable solvent to provide compound of Formula 4.
  • this step may be carried out at a temperature of -10°C to room temperature for few minutes to few hours or till completion of reaction.
  • nitration is conducted at a temperature of -5 to 20°C, more preferably nitration is conducted at a temperature of 0 to 5°C for 1 to 4 hours.
  • next step involves reducing compound of Formula 4 by treating with a suitable reducing agent in presence of suitable solvent to provide a compound of Formula 5.
  • reducing step may be carried out at a temperature of 15°C to room temperature for a few minutes to few hours, preferably at a temperature of 20 to 30°C for 3 to 10 hours, more preferably at room temperature for 4 to 8 hours.
  • Next step involves cyclizing the compound of Formula 5 using suitable cyclizing agent in the presence of suitable solvent and base to provide compound of Formula 6.
  • suitable cyclizing agent in the presence of suitable solvent and base to provide compound of Formula 6.
  • cyclization may be carried out at a temperature of 0°C to room temperature for a few minutes to few hours, preferably at a temperature of 20 to 30°C for 1 to 5 hours, more preferably at room temperature for 1 to 3 hours.
  • compound of Formula 6 without isolation or after isolation is used for next step.
  • deprotection of compound of Formula 6 is carried out using the suitable deprotecting reagent and solvent to obtain varenicline.
  • deprotection may be carried out at a temperature of 0°C to room temperature for a few minutes to few hours, preferably at a temperature of 20 to 30°C for 1 to 10 hours, more preferably at room temperature for 2 to 5 hours.
  • varenicline free base into its salt by treating with suitable source of acid in a suitable solvent by the method known in the art.
  • reaction completion is monitored by suitable techniques known in the art such as thin layer chromatography (TLC), high performance liquid chromatography (HPLC), ultra- performance liquid chromatography (UPLC), gas chromatography (GC) and like thereof.
  • TLC thin layer chromatography
  • HPLC high performance liquid chromatography
  • UPLC ultra- performance liquid chromatography
  • GC gas chromatography
  • Suitable solvent used for N-protection in step a) includes but not limited to organic solvents selected from the group comprising of water, sulfoxides, amides, alcohols, nitriles, chloro solvents, ketones, ethers, aromatic hydrocarbons, esters and the like or mixture thereof.
  • DMSO dimethyl sulfoxide
  • DMF N,N-dimethylformamide
  • DMAC ⁇ , ⁇ -dimethylacetamide
  • methanol ethanol, n-propanol, isopropanol, n- butanol, acetonitrile, butyronitrile, acrylonitrile, dichloromethane, dichloroethane, chloroform, chlorobenzene, acetone, propanone, butanone, methyl isobutyl ketone, diethyl ether, methyl tert-butyl ether (MTBE), diisopropyl ether, tetrahydrofuran (THF), dioxane, toluene, xylene, ethyl acetate, propyl acetate, butyl acetate and the like or mixture thereof, more preferably solvent used is methanol.
  • solvent used is methanol.
  • the suitable N-protecting reagent used for the preparation of compound of Formula 3 may be selected from alkyl trifluoroacetate, trifluoroacetic anhydride, trifluoroacetic acid, trifluoroacetyl chloride wherein alkyl is Ci - C 4 straight or branched chain preferably N- protecting reagent used is ethyl trifluoroacetate.
  • the base used for N-protection in step a) may be selected from inorganic or organic base, wherein inorganic base is selected from alkali or alkaline earth metal hydroxides, carbonates, bicarbonates selected from such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, magnesium bicarbonate, cesium bicarbonate, or sodium with liquid ammonia, sodamide or the like and mixture thereof.
  • inorganic base is selected from alkali or alkaline earth metal hydroxides, carbonates, bicarbonates selected from such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, magnesium bicarbonate, cesium bicarbonate, or
  • Organic base is selected from diisopropyl ethyl amine, triethyl amine, tributyl amine, N-methyl morpholine, pyridine, 1 ,8-diazabicyclo[5.4.0] undec-7-ene (DBU), and (l,4-diazabicyclo[2.2.2]octane) (DABCO) or like thereof; preferably base used is diisopropyl ethyl amine.
  • the catalyst used for N-protection in step a) may be selected from DMAP, potassium iodide, sodium iodide and like thereof.
  • the suitable nitrating agent used for nitration in step b) may be selected from the mixture of nitric and sulfuric acid, KN0 3 /H 2 S0 4 , NaN0 3 /H 2 S0 4 , CH 3 COOH/HN0 3 , (CH 3 CO) 2 0/HN0 3 ; preferably the nitration is conducted by using the mixture of nitric and sulfuric acid.
  • Solvent used during nitration in step b) may be selected from but not limited to organic solvents selected from halogenated hydrocarbons such as dichloromethane (DCM), chloroform, dichloroethane, chlorobenzene and the like thereof; ketone such as acetone, propanone, butanone, methyl isobutyl ketone and the like thereof; hydrocarbons are selected from aliphatic hydrocarbons or aromatic hydrocarbons, aliphatic hydrocarbons are selected from the group comprising of alkanes or cycloalkanes such as pentane, hexane, heptane, octane, nitromethane, cyclohexane, cyclopentane and the like thereof, aromatic hydrocarbons such as toluene, xylene and the like or mixture thereof, preferably solvent used is dichloromethane.
  • halogenated hydrocarbons such as dichloromethane (DCM), chloroform, dichlor
  • the reducing agent used in step c) may be selected from group comprising of Raney Ni, Pd(OH) 2 , Pd/C and the like in the presence of hydrogen gas, preferably reducing agent used is Raney/Ni.
  • reduction can be carried out by transfer hydrogenation using formate salt as hydrogen source or by using reagents such as sodium borohydride, lithium aluminium hydride.
  • the suitable solvent for reduction in step c) may be selected from group comprising of water, alcohols, halogenated hydrocarbons, ethers, amides, hydrocarbons and the like or mixture thereof; alcohols are selected from such as methanol, ethanol, n-propanol, isopropanol, n-butanol and the like thereof; halogenated hydrocarbons are selected from dichloromethane (DCM), chloroform, dichloroethane, chlorobenzene and the like thereof; ethers are selected from diethyl ether, methyl ie/ -butyl ether (MTBE), diisopropyl ether, tetrahydrofuran (THF), methyl THF, dioxane and the like thereof; amides are selected from N,N-dimethylformamide (DMF), N,N- dimethylacetamide (DMAC), N-methylformamide, N-methylpyrrolidone and the like thereof; aliphatic hydrocarbons
  • the suitable cyclizing agent for used cyclization in step d) may be selected from glyoxal, glyoxal sodium bisulfite addition compound hydrate, 2, 3-dihydroxy-l,4-dioxane and like thereof, preferably cyclizing agent used is glyoxal.
  • the base used for cyclization in step d) may be selected from inorganic or organic base, wherein inorganic base is selected from alkali or alkaline earth metal hydroxides, carbonates, bicarbonates selected from such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, magnesium bicarbonate, cesium bicarbonate and the like or mixture thereof; organic base is selected from diisopropyl ethyl amine, triethyl amine, tributyl amine, N-methyl morpholine, pyridine, DBU and DABCO or like thereof; preferably base used is triethyl amine.
  • inorganic base is selected from alkali or alkaline earth metal hydroxides, carbonates, bicarbonates selected from such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydrox
  • the suitable solvent used for cyclization in step d) may be selected from group comprising of water, nitriles, alcohols, amides, sulfoxides such as acetonitrile, butyronitrile, acrylonitrile, methanol, ethanol, n-propanol, isopropanol, n-butanol, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-methylformamide, dimethyl sulfoxide (DMSO) and the like or mixture thereof.
  • solvents used are water and methanol.
  • the suitable reagent used for deprotection in step e) may be selected from inorganic base or organic base, wherein inorganic base is selected from alkali or alkaline earth metal hydroxides, carbonates, bicarbonates selected from such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, magnesium bicarbonate, cesium bicarbonate and the like and or mixture thereof; organic base is selected from diisopropyl ethyl amine, triethyl amine, tributyl amine, N-methyl morpholine, pyridine, DBU and DABCO or like thereof, preferably, suitable reagent used is sodium hydroxide.
  • inorganic base is selected from alkali or alkaline earth metal hydroxides, carbonates, bicarbonates selected from such as sodium hydroxide, potassium hydroxide, calcium
  • the suitable solvent for deprotection in step e) may be selected from group comprising of water, alcohols, amides, nitriles, ethers, esters and the like or mixture thereof; alcohols are selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol and the like; amides are selected from the group comprising of N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-methylformamide, N-methylpyrrolidone, nitriles such as acetonitrile, propionitrile, butyronitrile, acrylonitrile; ethers are selected from the group comprising of diethyl ether, methyl tert-butyl ether (MTBE), diisopropyl ether, tetrahydrofuran (THF), methyl THF, dioxane; esters such as methyl acetate, eth
  • the present invention provides a process for the preparation of varenicline tartrate, comprising the steps of: a) N-protection of (10-aza-tricyclo[6.3.1.0 2 ' 7 ] dodeca-2(7),3,5-triene or salt thereof of Formula 2;
  • the present invention provides a process
  • the present invention provides a process for the preparation varenicline and salt thereof, comprising the steps of: a) N-protection of 10-aza-tricyclo[6.3.1.0 2 ' 7 ] dodeca-2(7),3,5-triene or salt thereof of Formula 2 by treating with ethyl trifluoroacetate in the presence of methanol, with or without using organic base such as di-isopropyl ethylamine or triethyl amine or pyridine and catalyst, to provide compound of Formula 3, and; b) converting compound of Formula 3 into varenicline and salt thereof.
  • the process is simple, economic with high throughput, operationally efficient, reproducible and environment friendly.
  • varenicline tartrate obtained according to the instant invention possess the relative particle size distribution, wherein the 10th volume percentile particle size D(0.1) is less than about 15 ⁇ , the 50th volume percentile particle size D(0.5) is less than about 75 ⁇ , or the 90th volume percentile particle size D(0.9) is less than about 150 ⁇ , or any combination thereof.
  • CHANTIX is supplied for oral administration in two strengths: a 0.5 mg capsular biconvex, white to off-white, film-coated tablet debossed with "Pfizer” on one side and “CHX 0.5" on the other side and a 1 mg capsular biconvex, light blue film-coated tablet debossed with "Pfizer” on one side and "CHX 1.0" on the other side.
  • Each 0.5 mg CHANTIX tablet contains 0.85 mg of varenicline tartrate equivalent to 0.5 mg of varenicline free base; each lmg CHANTIX tablet contains 1.71 mg of varenicline tartrate equivalent to 1 mg of varenicline free base.
  • microcrystalline cellulose microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, Opadry® White (for 0.5 mg), Opadry® Blue (for 1 mg), and Opadry® Clear.
  • inactive ingredients are included in the tablets: microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, Opadry® White (for 0.5 mg), Opadry® Blue (for 1 mg), and Opadry® Clear.
  • Fuming nitric acid 54 ml was added slowly in sulphuric acid (92 ml) at 0 to 5°C and stirred at same temperature for 2 to 3 hour.
  • the resulting mixture was slowly added into the solution of l-(10-aza-tricyclo[6.3.1.0 2 ' 7 ]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro- ethanone obtained from example 1 at 0 to 5 °C.
  • the reaction mixture was stirred at the same temperature for 1 hour followed by the stirring at room temperature for 3 hour. After completion of the reaction chilled DM water (375 ml) and dichloromethane (375 ml) was added slowly at the same temperature.
  • reaction mixture was stirred at room temperature for 30 minutes, separate the layers and the aqueous layer was extracted with dichloromethane (375 ml).
  • the organic layers were combined and washed with DM water (375 ml) which was further washed with 2.5% aq. sodium carbonate solution (375 ml).
  • the organic layer was concentrated under vacuum and toluene (937.5 ml) was added to the residue and heated to 80 to 85°C for 1 hour.
  • the reaction mixture was slowly cooled to room temperature and maintained under stirring for 3 to 4 hour. Filtered the solid and washed with toluene (150 ml) to obtain the title compound as an off white solid (93.5 g).
  • reaction mixture obtained from example 4 was added 20% aq. sodium hydroxide solution (13 g in 63.7 ml DM water) slowly at room temperature and stirred for 3 to 4 hour. After completion of the reaction, the reaction mixture was concentrated to remove methanol and toluene (375 ml) was added. Further the reaction mixture was heated to 60 to 65°C and stirred for 30 minutes. The organic layer was separated and aqueous layer was extracted with toluene 375 ml at 60 to 65°C. The combined organic layer was washed with 25% aqueous NaCl solution (150 ml) at 60 to 65°C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention concerne un procédé amélioré pour la préparation de varénicline et son sel. La présente invention concerne également un procédé de préparation de 1-(4,5-dinitro-10-aza-tricyclo[6.3.1.02,7] dodéca-2 (7),3,5-trién-10-yl)-2,2,2-trifluoroéthanone de formule 4 au moyen de trifluoroacétate d'éthyle qui est ensuite converti en varénicline et son sel.
PCT/IN2017/050602 2017-03-08 2017-12-19 Procédé amélioré pour la préparation de varénicline et son sel Ceased WO2018163190A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022035434A1 (fr) 2020-08-14 2022-02-17 Almatica Pharma Llc Co-cristal de varénicline et d'acide oxalique, composition pharmaceutique correspondante et méthodes d'utilisation correspondantes
CN115894488A (zh) * 2021-08-20 2023-04-04 威智医药有限公司 低亚硝胺杂质含量的酒石酸伐尼克兰原料药及其制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009065872A2 (fr) * 2007-11-20 2009-05-28 Medichem, S.A. Procédés améliorés pour la synthèse de l-tartrate de varénicline

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009065872A2 (fr) * 2007-11-20 2009-05-28 Medichem, S.A. Procédés améliorés pour la synthèse de l-tartrate de varénicline

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JOTHAM W. COE ET AL.: "Varenicline: An r4a2 Nicotinic Receptor Partial Agonist for Smoking Cessation", J. MED. CHEM., vol. 48, 23 April 2005 (2005-04-23), pages 3474 - 3477, XP055556824 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022035434A1 (fr) 2020-08-14 2022-02-17 Almatica Pharma Llc Co-cristal de varénicline et d'acide oxalique, composition pharmaceutique correspondante et méthodes d'utilisation correspondantes
CN115894488A (zh) * 2021-08-20 2023-04-04 威智医药有限公司 低亚硝胺杂质含量的酒石酸伐尼克兰原料药及其制备方法

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