WO2018163190A1 - An improved process for the preparation of varenicline and salt thereof - Google Patents

An improved process for the preparation of varenicline and salt thereof Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
varenicline
salt
solvent
Prior art date
Application number
PCT/IN2017/050602
Other languages
French (fr)
Inventor
Vikas Bansal
Rohit CHAKRAVARTY
Anand Kumar Singh
Sujay Biswas
Dharam Vir
Original Assignee
Jubilant Generics Limited (Formerly A Division Of Jubilant Lifesciences 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 Jubilant Generics Limited (Formerly A Division Of Jubilant Lifesciences Limited) filed Critical Jubilant Generics Limited (Formerly A Division Of Jubilant Lifesciences Limited)
Publication of WO2018163190A1 publication Critical patent/WO2018163190A1/en

Links

Classifications

    • 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.

Abstract

of the Invention 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 2,7preparation of l-(4,5-dinitro-10-aza-tricyclo[6.3.1.0 ]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoroethanone of Formula 4 using ethyl trifluoroacetate and further converted to varenicline and salt thereof.

Description

An improved process for the preparation of Varenicline and salt thereof
Field of the Invention
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[6.3.1.02'7]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.
Background of the Invention
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[10.3.1.02'n.04'9]-hexadeca-2(ll),3,5,7,9-pentaene) and has an empirical formula of C13H13N3 and a molecular weight of 211.27 and shown in Formula 1:
COO
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 CHANTIX™ in the U.S. and CHAMPIX™ 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[6.3.1.02'7]dodeca-2(7),3,5-trien-10-yl)-2,2,2- trifluoroethanone of Formula 5, which was further treated with glyoxal sodium bisulfite addition compound to provide l-(5,8,14-triazatetracyclo[10.3.1.02'u.04'9]hexadeca- 2(l l),3,5,9-pentaene)-2,2,2-trifluoro-ethanone of Formula 6. It was further treated with sodium carbonate to obtain varenicline free base and finally converted to its hydrochloride salt of Formula 7 as per scheme 1:
Scheme 1
Figure imgf000004_0001
Formula 2 Formula 3 Formula 4
Figure imgf000004_0002
Formula 7 Formula 1
This process involves the use of hazardous and expensive reagents such as trifluoro acetic anhydride and trifluoromethane sulfonic acid, which are also not easy to handle on large scale production. Furthermore, trifluoromethane sulfonic acid is not environment friendly. Therefore this process is not efficient, very expensive and difficult to be used on industrial scale.
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:
Figure imgf000004_0003
Formula 5A Formula 6A 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 sulfuric acid to provide N- protected dinitroazotricyclo compound of Formula 4A and hydrogenating using a hydrogenation catalyst in the presence of a hydrogen source (formate salt) to provide the N- protected diaminoazatricyclo compound of Formula 5 A' as per scheme 3:
Scheme 3
Figure imgf000005_0001
Formula e Formula 9 Formula 10
Figure imgf000005_0002
Formula 2A
Figure imgf000005_0003
Formula 5A' Formula 4A Formula 3A
Wherein 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. Object of the invention
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[6.3.1.02'7]dodeca-2(7),3,5-trien- 10-yl)-2,2,2-trifluoroethanone by using ethyl trifluoroacetate.
Further, 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. Summary of the invention
In accordance with principal embodiment, the present invention provides a process for the preparation of 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;
Figure imgf000006_0001
Formula 2 by treating with a suitable N-protected reagent in the presence of a suitable solvent, base, optionally using catalyst, to provide compound of Formula 3A;
Figure imgf000007_0001
Formula 3A
Wherein R is nitrogen protecting group selected from CF3CO-, CH3CO-, 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;
Figure imgf000007_0002
Formula 4A c) reducing the compound of Formula 4A using suitable reducing agent and solvent to provide N-protected diaminoazatricyclo compound of Formula 5A';
Figure imgf000007_0003
Formula 5A' cyclizing compound of Formula 5 A' using a suitable cyclizing agent in the presence of suitable solvent and base to provide N-protected varenicline of Formula 11 ;
Figure imgf000007_0004
Formula 11 e) deprotecting compound of Formula 11 using the suitable reagent and solvent to obtain varenicline, and; converting varenicline into salt thereof. In accordance with one embodiment, the present invention provides a process for the preparation of varenicline and salt thereof, comprising the steps of:
2 7
a) N-protection of (10-aza-tricyclo[6.3.1.0 ' ] dodeca-2(7),3,5-triene or salt thereof of Formula 2 by treating with a suitable N-protected reagent in presence of a suitable solvent, base, optionally in the presence of catalyst, to provide compound of Formula 3; b) nitrating compound of Formula 3 using suitable nitrating agent in the presence of suitable solvent to provide compound of Formula 4; c) reducing the compound of Formula 4 using suitable reducing agent and solvent to provide compound of Formula 5; d) cyclizing compound of Formula 5 using a suitable cyclizing agent in the presence of suitable solvent and base to provide of Formula 6; e) deprotecting compound of Formula 6 using the suitable reagent and solvent to obtain varenicline, and; f) converting varenicline into salt thereof.
In accordance with another embodiment, 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. 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.
In accordance with yet another embodiment, the present invention provides a process
2 7
for the preparation of l-(4,5-dinitro-10-aza-tricyclo[6.3.1.0 ' ]dodeca-2(7),3,5-trien-10-yl)- 2,2,2-trifluoroethanone of Formula 4, 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.
In accordance with further yet another embodiment, 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.
Detail description of the drawings: Fig.l. X-ray powder diffraction (XRPD) pattern of varenicline free base obtained according to example 5
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.
In accordance with principal embodiment, the present invention provides a process for the preparation of 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;
Figure imgf000010_0001
Formula 2 by treating with a suitable N-protected reagent in presence of a suitable solvent, base, optionally using catalyst, to provide compound of Formula 3A;
Figure imgf000010_0002
Formula 3A
Wherein R is nitrogen protecting group selected from CF3CO-, CH3CO-, 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;
Figure imgf000010_0003
Formula 4A c) reducing the compound of Formula 4A using suitable reducing agent and solvent to provide of N-protected diaminoazatricyclo compound of Formula 5A';
Figure imgf000011_0001
Formula 5Α' cyclizing compound of Formula 5 A' using a suitable cyclizing agent in the presence of suitable solvent and base to provide N-protected varenicline of Formula 11 ;
Figure imgf000011_0002
Formula 11 e) deprotecting compound of Formula 11 using the suitable reagent and solvent to obtain varenicline, and; f) converting varenicline into salt thereof.
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-C6 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.
After completion of reaction, 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 Ν-protected dinitroazotricyclo compound of Formula 4A.
Further, reducing the compound of Formula 4A by using a suitable reducing agent in the presence of a suitable solvent to provide N-protected diaminoazatricyclo compound of Formula 5A'. Next step involves cyclizing the compound of Formula 5 A' using suitable cyclizing agent in the presence of suitable solvent and base to provide N-protected varenicline of Formula 11.
Further deprotecting N-protected varenicline of Formula 11 using the suitable reagent and solvent to obtain varenicline.
Finally converting varenicline free base into its salt by treating with suitable source of acid known using suitable solvent by any method known in the art.
In accordance with one embodiment, the present invention provides a process for the preparation of 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;
Figure imgf000012_0001
Formula 2 by treating with a suitable N-protected reagent in the presence of a suitable solvent, base, optionally in the presence of catalyst, to provide compound of Formula 3;
Figure imgf000012_0002
Formula 3 b) nitrating compound of Formula 3 using suitable nitrating agent in the presence of suitable solvent to provide compound of Formula 4;
Figure imgf000012_0003
Formula 4 c) reducing the compound of Formula 4 using suitable reducing agent and solvent to provide compound of Formula 5;
Figure imgf000013_0001
Formula 5 cyclizing compound of Formula 5 using a suitable cyclizing agent in the presence of suitable solvent and base to provide of Formula 6;
Figure imgf000013_0002
Formula 6 e) deprotecting compound of Formula 6 using the suitable reagent and solvent to obtain varenicline, and; f) converting varenicline into salt thereof.
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. Generally reaction may be carried out at temperature of 10 to 60°C for few minutes to few hours or till completion of reaction. Preferably 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. After completion of 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. Generally, 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. Preferably 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.
Further, 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. Generally 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.
After completion of reaction, compound of Formula 5 without isolation or after isolation is used for next step. 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. Generally 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. After the cyclization, compound of Formula 6 without isolation or after isolation is used for next step.
Further, deprotection of compound of Formula 6 is carried out using the suitable deprotecting reagent and solvent to obtain varenicline. Generally 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.
Finally converting varenicline free base into its salt by treating with suitable source of acid in a suitable solvent by the method known in the art.
The 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.
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. Preferably, selected from dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), Ν,Ν-dimethylacetamide (DMAC), 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.
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 - C4 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. 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, KN03/H2S04, NaN03/H2S04, CH3COOH/HN03, (CH3CO)20/HN03; 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.
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. Alternatively, 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 are selected from the group comprising of alkanes or cycloalkanes such as pentane, hexane, heptane, octane, cyclohexane, cyclopentane and the like; aromatic hydrocarbons are selected from the group comprising of toluene, xylene and the like or mixture thereof; preferably, solvent used is methanol.
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. 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. Preferably, 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.
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, ethyl acetate, propyl acetate, butyl acetate and the like or mixture thereof. Preferably, solvents used are water and methanol.
In accordance with another embodiment, 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;
Figure imgf000017_0001
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;
Figure imgf000018_0001
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;
Figure imgf000018_0002
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;
Figure imgf000018_0003
Formula 5 d) cyclizing compound of Formula 5 using aq. glyoxal solution and triethyl amine to provide compound of Formula 6;
Figure imgf000018_0004
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. In accordance with yet another embodiment, the present invention provides a process
2 7
for the preparation of l-(4,5-dinitro-10-aza-tricyclo[6.3.1.0 ' ]dodeca-2(7),3,5-trien-10-yl)- 2,2,2-trifluoroethanone of Formula 4, 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;
Figure imgf000019_0001
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;
Figure imgf000019_0002
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
Figure imgf000019_0003
Formula 4
In accordance with further yet another embodiment, 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.
Accordingly, 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 μιη, the 50th volume percentile particle size D(0.5) is less than about 75 μιη, or the 90th volume percentile particle size D(0.9) is less than about 150 μιη, 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. The following 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. Although the following examples illustrate the present invention in more detail but the examples are not intended in any way to limit the scope of the present invention. It will thus be readily apparent to the one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modifications and variation of the concepts herein disclosed may be resorted to by those skilled in the art and that such modifications and variations are considered to be falling within the scope of the invention.
Example 1:
Preparation of l-(10-aza- tricyclo[6.3.1.02'7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro- ethanone
To the mixture of 10-aza-tricyclo[6.3.1.0 2 ' 7 ]dodeca-2(7),3,5-triene hydrochloride (75g) in methanol (225 ml) at 10 to 15°C DIPEA (140 ml) was added slowly and stirred at same temperature for 30 minutes, followed by addition of ethyl trifluoroacetate (59 ml). The resulting reaction mixture was maintained at the same temperature for 2 to 3 hour. After completion of the reaction, the reaction mixture was concentrated and dichloromethane (375 ml) was added. The resulting solution was washed with IN HCl (375 ml) to obtain the title compound.
Example 2
Preparation of l-(4,5-dinitro-10-aza- tricyclo[6.3.1.02'7]dodeca-2(7),3,5-trien-10-yl)- 2,2,2-trifluoroethanone
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[6.3.1.02'7]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. Further, the 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). Example 3
Preparation of l-(4,5-diamino-10-aza- tricyclo[6.3.1.02'7]dodeca-2(7),3,5-trien-10-yl)- 2,2,2-trifluoroethanone
2 7
To the mixture of l-(4,5-dinitro-10-aza-tricyclo[6.3.1.0 ' ]dodeca-2(7),3,5-trien-10- yl)-2,2,2-trifluoroethanone (75 g) in methanol (375 ml) in an autoclave vessel Raney nickel (15% w/w) (11.2 g) was added at 25 to 30°C and mixture was stirred under hydrogen pressure (7-8 Kg/cm ) for about 10 to 12 hours at same temperature. After completion of the reaction, the reaction mixture was filtered to remove the catalyst and the washed with methanol (225 ml) to obtain the title compound.
Example 4
Preparation of l-(5,8,14-triazatetracyclo[10.3.1.02 11.04'9]hexadeca-2(ll),3,5,9- pentaene)-2,2,2-trifluoro-ethanone
To the filtrate obtained from example 3 was added DM water (150 ml) and triethylamine (1.6 g) at room temperature. The reaction mixture was cooled 10 to 15°C and 40% aqueous solution of glyoxal (26.2 ml in 26.3 ml water) was added slowly at the same temperature. Further, temperature of the reaction mixture was raised to 25 to 30°C and stirred for 1 hour to obtain the title compound.
Example 5
Preparation of varenicline free base
To the 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. To this solution neutral alumina (7.5 g) and activated carbon (3.75 g) was added and stirred for 15 min at 60 to 65°C. Filtered the reaction mixture, filtrate was concentrated to the minimum volume and filtered the solid to yield varenicline free base (HPLC Purity 99.5%, Yield 87.0%).
Example 6
Preparation of varenicline tartrate
The solution of L-(+)-tartaric acid (29.3 g) and methanol (225 ml) was cooled to 10 to 15°C and a solution of varenicline free base (40 g in methanol 487 ml) was added slowly at the same temperature. Further, the temperature of reaction mixture was raised to 25 to 30°C and stirred for 10 hour. The reaction mixture was filtered to obtain the title compound as off-white solid (54.5 g).

Claims

Claims:
1. A process for the preparation of 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;
Figure imgf000023_0001
Formula 2 by treating with a suitable N-protected reagent in the presence of a suitable solvent, base, optionally using catalyst, to provide compound of Formula 3A;
Figure imgf000023_0002
Formula 3A
Wherein R is nitrogen protecting group selected from CF3CO-, CH3CO-, 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;
Figure imgf000023_0003
Formula 4A c) reducing the compound of Formula 4A using suitable reducing agent and solvent to provide N-protected diaminoazatricyclo compound of Formula 5A';
Figure imgf000023_0004
Formula 5A' d) cyclizing compound of Formula 5 A' using a suitable cyclizing agent in the presence of suitable solvent and base to provide N-protected varenicline of Formula 11 ;
Figure imgf000024_0001
Formula 11 e) deprotecting compound of Formula 11 using the suitable reagent and solvent to obtain varenicline, and; f) converting varenicline into salt thereof.
2. A process for the preparation of varenicline and salt thereof, comprising the steps of:
2 7
a) N-protection of (10-aza-tricyclo[6.3.1.0 ' ] dodeca-2(7),3,5-triene or salt thereof of Formula 2 by treating with a suitable N-protected reagent in presence of a suitable solvent, base, optionally in the presence of catalyst, to provide compound of Formula 3; b) nitrating compound of Formula 3 using suitable nitrating agent in the presence of suitable solvent to provide compound of Formula 4; c) reducing the compound of Formula 4 using suitable reducing agent and solvent to provide compound of Formula 5; d) cyclizing compound of Formula 5 using a suitable cyclizing agent in the presence of suitable solvent and base to provide of Formula 6; e) deprotecting compound of Formula 6 using the suitable reagent and solvent to obtain varenicline, and; f) converting varenicline into salt thereof.
3. The process according to claim 1 and 2, wherein in step a) N-protecting reagent used is selected from alkyl trifluoroacetate, trifluoroacetic anhydride, trifluoroacetic acid, trifluoroacetyl chloride; alkyl or aryl chloroformates; wherein alkyl is Ci-C6 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 and phenyl chlorofornate.
The process according to claim 1 and 2, wherein the solvent used is selected from the group comprising of water, sulfoxides, amides, alcohols, nitriles, chloro solvents, ketones, ethers, aliphatic or aromatic hydrocarbons, esters and mixture thereof such as dimethyl sulfoxide (DMSO), Ν,Ν-dimethylformamide (DMF), N- methylformamide, Ν,Ν-dimethylacetamide (DM AC), N-methylformamide, N- methylpyrrolidone, 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), methyl THF, dioxane, nitromethane, pentane, hexane, heptane, octane, cyclohexane, cyclopentane, toluene, xylene, benzene, ethyl acetate, propyl acetate, butyl acetate and mixture thereof;
The process according to claim 1 and 2, wherein base used is selected from inorganic or organic base, wherein inorganic base is selected from alkali or alkaline earth metal hydroxides, carbonates, bicarbonates 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 and mixture thereof; 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) and mixture thereof.
The process according to claim 1 and 2, wherein in step b) nitrating agent used is selected from mixture of nitric and sulfuric acid, KN03/H2S04, NaN03/H2S04, CH3COOH/HN03, (CH3CO)20/HN03; and in step c) reducing agent is selected from Raney Ni, Pd(OH)2, Pd/C in the presence of hydrogen gas or formate salt as a hydrogen source or by using reagents such as sodium borohydride, lithium aluminium hydride.
The process according to claim 1 and 2, wherein in step d) cyclizing agent used is selected from glyoxal, glyoxal sodium bisulfite addition compound hydrate and 2,3- dihydroxy-l,4-dioxane; and in step e) reagent used for deprotection is 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 mixture thereof; organic base is selected from diisopropyl ethyl amine, and triethyl amine.
8. 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 suitable 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. 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.
2 7
9. A process for the preparation of l-(4,5-dinitro-10-aza-tricyclo[6.3.1.0 ' ]dodeca- 2(7),3,5-trien-10-yl)-2,2,2-trifluoroethanone of Formula 4, 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.
10. 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 selected from 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.
PCT/IN2017/050602 2017-03-08 2017-12-19 An improved process for the preparation of varenicline and salt thereof WO2018163190A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201711008042 2017-03-08
IN201711008042 2017-03-08

Publications (1)

Publication Number Publication Date
WO2018163190A1 true WO2018163190A1 (en) 2018-09-13

Family

ID=63447595

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2017/050602 WO2018163190A1 (en) 2017-03-08 2017-12-19 An improved process for the preparation of varenicline and salt thereof

Country Status (1)

Country Link
WO (1) WO2018163190A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022035434A1 (en) 2020-08-14 2022-02-17 Almatica Pharma Llc Cocrystal of varenicline and oxalic acid, pharmaceutical composition thereof, and methods of use thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009065872A2 (en) * 2007-11-20 2009-05-28 Medichem, S.A. Improved processes for the synthesis of varenicline l-tartrate

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009065872A2 (en) * 2007-11-20 2009-05-28 Medichem, S.A. Improved processes for the synthesis of varenicline l-tartrate

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 (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022035434A1 (en) 2020-08-14 2022-02-17 Almatica Pharma Llc Cocrystal of varenicline and oxalic acid, pharmaceutical composition thereof, and methods of use thereof

Similar Documents

Publication Publication Date Title
US10266492B2 (en) Processes and intermediates in the preparation of C5aR antagonists
CN101119991B (en) Salt of proline derivative, solvate thereof, and production method thereof
AU2019287460B2 (en) Substituted heterocycle fused gamma-carbolines synthesis
ES2615487T3 (en) an effective method for the preparation of (S) -3 - [(1-dimethylamino) ethyl] -phenyl-N-ethyl-N-methyl-carbamate
TW200813046A (en) Process for the preparation of tiotropium bromide
TW201434851A (en) Process for the synthesis of E1 activating enzyme inhibitors
JP5546539B2 (en) Substances and methods for the stereoselective synthesis of variolamines
WO2009016653A1 (en) Stable polymorphic form of paliperidone and process for its preparation
CA3126096A1 (en) Methods for producing viloxazine salts and novel polymorphs thereof
WO2018163190A1 (en) An improved process for the preparation of varenicline and salt thereof
CN113227045B (en) Synthesis of substituted heterocycle fused gamma-carbolines
CA3150961A1 (en) Processes for the synthesis of valbenazine
WO2014081047A1 (en) Process for the preparation of (1s,4s,5s)-4-bromo-6-oxabicyclo[3.2.1] octan-7-one
US20190263815A1 (en) Processes for preparing tph1 inhibitors
JP2002167385A (en) MANUFACTURING METHOD OF 2-PHENYLIMIDAZO[1,2a]PYRIDINE-3- ACETAMIDES
CN113195450B (en) Synthesis of substituted heterocycle fused gamma-carbolines
US11434226B2 (en) Salt and polymorph of benzopyrimidinone compound and pharmaceutical composition and use thereof
FI81583C (en) FOERFARANDE FOER N-DEMETYLERING AV MORFINANALKALOIDER.
WO2010049500A2 (en) A process for the preparation of tadalafil.
EP2867206A2 (en) Saxagliptin salts
RU2795581C2 (en) Synthesis of substituted gamma-carbolines condensed with a heterocycle
CN109651286A (en) A kind of highly selective 4-(4- aminophenyl) morpholine -3- ketone synthetic method
WO2023205116A1 (en) Pyridine derivatives for treating psychiatric disorders
EP2152697A2 (en) Process for the preparation of alfuzosin and salts thereof
JP2012180282A (en) Method for producing lactam compound and production intermediate thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17900243

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17900243

Country of ref document: EP

Kind code of ref document: A1