Process for preparing varenicline, varenicline intermediates, and pharmaceutically acceptable salts thereof

Abstract

Provided herein is an improved, convenient, commercially viable and environmentally friendly process for the preparation of varenicline or a pharmaceutically acceptable salt thereof comprising reacting 1-(4 ,5-diamino-10-aza-tricyclo[6.3.1.0 2.7 ]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone with chloroacetaldehyde in the presence of an oxygen source. Provided further herein is an improved and industrially advantageous process for the preparation of 1-(4,5-diamino-10-aza-tricyclo[6.3.1.0 2.7 ]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone.

1 . A process for the preparation of varenicline of formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; comprising: 
         a) reacting a protected diaminoazatricyclo compound of formula III: 
       
       
         
           
           
               
               
           
         
         wherein ‘R’ represents a nitrogen protecting group, with haloacetaldehyde compound of formula IV: 
       
       
         
           
           
               
               
           
         
         wherein ‘Y’ represents a halogen atom selected from the group consisting of F, Cl, Br and I; optionally in the presence of oxygen source, to provide a protected triazatetracyclo compound of formula II: 
       
       
         
           
           
               
               
           
         
         wherein R is as defined in formula III; and 
         b) deprotecting the compound of formula II to provide pure varenicline of formula I, and optionally converting the varenicline obtained into a pharmaceutically acceptable salt thereof 
       
     
     
         2 . The process of  claim 1 , wherein the reaction in step-(a) is carried out in the presence of a solvent selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, n-propanol, tert-butanol, n-butanol, methylene chloride, ethyl dichloride, chloroform, carbon tetrachloride, acetone, methyl isobutyl ketone, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, acetonitrile, propionitrile, ethyl acetate, isopropyl acetate, and mixtures thereof; and wherein the oxygen source employed in step-(a) is selected from the group consisting of lead monoxide, manganese dioxide, mercuric iodide and ceric ammonium nitrate. 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . The process of  claim 1 , wherein the condensation reaction in step-(a) is carried out at a temperature of about 0° C. to the reflux temperature of the solvent used wherein the varenicline of formula I obtained in step-(b) is isolated from a solvent by cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum drying, spray drying, freeze drying, or a combination thereof, and wherein the solvent used for isolation is selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, t-butanol, acetone, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, monoglyme, diglyme, and mixtures thereof; and wherein the pharmaceutically acceptable salt of varenicline is a hydrochloride salt, a hydrobromide salt, a sulfate salt, a phosphate salt, a tartrate salt, a fumarate salt, a maleate salt, an oxalate salt, an acetate, a propionate salt, a succinate salt, a citrate salt, or a mandelate salt. 
     
     
         6 . The process of  claim 5 , wherein the reaction is carried out at the reflux temperature of the solvent used for about 2 hours to about 10 hours. 
     
     
         7 . The process of  claim 1 , wherein the nitrogen protecting group ‘R’ in the compounds of formulae II and III is selected from the group consisting of acetyl, trifluoroacetyl, trichloro acetyl, pyrrolidinylmethyl, cumyl, benzhydryl, trityl, benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxy carbonyl (Fmoc), benzyloxymethyl (BOM), pivaloyloxymethyl (POM), trichloroethxoycarbonyl (Troc), 1-adamantyloxycarbonyl (Adoc), allyl, allyloxycarbonyl, trimethylsilyl, tert.-butyldimethylsilyl, triethylsilyl (TES), triisopropylsilyl, trimethylsilylethoxymethyl (SEM), t-butoxycarbonyl (BOC), t-butyl, 1-methyl-1,1-dimethylbenzyl, pyrridinyl and pivaloyl; and wherein the halogen atom ‘Y’ in the compound of formula IV is Cl. 
     
     
         8 . The process of  claim 7 , wherein the nitrogen protecting group ‘R’ is trifluoroacetyl or t-butoxycarbonyl. 
     
     
         9 . (canceled) 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . A process for the preparation of a protected diaminoazatricyclo compound of formula III: 
       
         
           
           
               
               
           
         
         wherein ‘R’ represents a nitrogen protecting group, comprising: 
         a) oxidizing 1,2,3,4-tetrahydro-1,4-methanonaphthalene-2,3-diol of formula X: 
       
       
         
           
           
               
               
           
         
         in the presence of an oxidizing agent in a solvent, optionally in the presence of a phase transfer catalyst, to provide indane-1,3-dicarbaldehyde of formula IX: 
       
       
         
           
           
               
               
           
         
         b) reacting the compound of formula IX with benzyl amine in the presence of a reducing agent, optionally in the presence of a Lewis acid, in a solvent to provide 10-benzyl-10-aza-tricyclo[6.3.1.0 2.7 ]-dodeca-2(7),3,5-triene of formula VIII: 
       
       
         
           
           
               
               
           
         
         c) hydrogenating the compound of formula VIII using a hydrogenation catalyst in the presence of a hydrogen source in a solvent to provide 10-aza-tricyclo[6.3.1.0 2.7 ]-dodeca-2(7),3,5-triene of formula VII: 
       
       
         
           
           
               
               
           
         
         or an acid addition salt thereof, wherein the hydrogen source is a formate salt; 
         d) protecting the compound of formula VII with a nitrogen protecting group ‘R’ to provide a protected compound of formula VI: 
       
       
         
           
           
               
               
           
         
         
           wherein ‘R’ represents a nitrogen protecting group; 
         
         e) nitrating the compound of formula VI in the presence of a mixture of nitric acid and sulfuric acid in a solvent, to provide a dinitro compound of formula V: 
       
       
         
           
           
               
               
           
         
         
           wherein R is as defined in formula VI; and 
         
         f) hydrogenating the compound of formula V using a hydrogenation catalyst in the presence of a hydrogen source in a solvent to provide the protected diaminoazatricyclo compound of formula III, wherein the hydrogen source is a formate salt. 
       
     
     
         14 . The process of  claim 13 , wherein the nitrogen protecting group ‘R’ in the compounds of formulae III, V and VI is selected from the group consisting of acetyl, trifluoroacetyl, trichloroacetyl, pyrrolidinylmethyl, cumyl, benzhydryl, trityl, benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxy carbonyl (Fmoc), benzyloxymethyl (BOM), pivaloylo xymethyl (POM), trichloroethxoycarbonyl (Troc), 1 -adamantylo xycarbonyl (Adoc), allyl, allyloxycarbonyl, trimethylsilyl, tert.-butyldimethylsilyl, triethylsilyl (TES), triisopropylsilyl, trimethylsilylethoxymethyl (SEM), t-butoxycarbonyl (BOC), t-butyl, 1-methyl-1,1-dimethylbenzyl, pyrridinyl and pivaloyl. 
     
     
         15 . The process of  claim 14 , wherein the nitrogen protecting group ‘R’ is trifluoroacetyl. 
     
     
         16 . The process of  claim 13 , wherein the solvent used in step-(a) is selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, n-propanol, tert-butanol, n-butanol, amyl alcohol, hexanol, acetone, methyl isobutyl ketone, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, monoglyme, diglyme, acetonitrile, ethyl acetate, isopropyl acetate, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, methylene chloride, ethyl dichloride, chloroform, carbon tetrachloride, and mixtures thereof; wherein the solvent used in steps-(b) and (e) is, each independently, selected from the group consisting of tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, monoglyme, diglyme, acetonitrile, ethyl acetate, isopropyl acetate, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, methylene chloride, ethyl dichloride, chloroform, carbon tetrachloride, and mixtures thereof; and wherein the solvent used in steps-(c) and (f) is, each independently, selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, n-propanol, tert-butanol, n-butanol, amyl alcohol, hexanol, acetone, methyl isobutyl ketone, tetrahydrofuran, acetonitrile, ethyl acetate, isopropyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and mixtures thereof. 
     
     
         17 . The process of  claim 16 , wherein the solvent used in step-(a) is a mixture of water and methylene chloride; wherein the solvent used in steps-(b) and (e) is, each independently, selected from the group consisting of methylene chloride, toluene, and mixtures thereof; and wherein the solvent used in steps-(c) and (f) is methanol. 
     
     
         18 . The process of  claim 13 , wherein the oxidizing agent used in step-(a) is selected from the group consisting of sodium periodate, sodium chlorate, sodium hypochlorite, collins reagent, barium permanganate, 2,2,6,6-tetramethylpiperidinyloxy (TEMPO), iodine/K 2 CO 3 , N-chlorosuccinimide/dimethylsulfide and ceric ammonium nitrate; wherein the oxidation in step-(a) is carried out in the presence of a phase transfer catalyst, wherein the phase transfer catalyst is selected from the group consisting of tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutyl ammonium fluoride, tetrabutylammonium iodide, tetrabutylammonium hydroxide, tetrabutylammonium hydrogen sulfate, tributylmethylammonium chloride, tributylbenzyl ammonium chloride, tetrapentylammonium chloride, tetrapentylammonium bromide, tetrahexylammonium chloride, benzyldimethyloctylammonium chloride, methyltrihexyl ammonium chloride, benzylmethyloctadecanylammonium chloride, methyltridecanyl ammonium chloride, benzyltripropylammonium chloride, benzyltriethylammonium chloride, phenyltriethylammonium chloride, tetraethylammonium chloride, tetramethyl ammonium chloride, tetrabutylphosphonium chloride and 1-dodecanylpyridinium chloride; wherein the reducing agent used in step-(b) is selected from the group consisting of sodium borohydride, sodium cyanoborohydride, lithium aluminium hydride, diisobutyl aluminium hydride, borane and its derivatives; wherein the Lewis acid used in step-(b) is selected from the group consisting of aluminium chloride, calcium chloride, boron triflouride and zinc chloride;
 wherein the hydrogenation catalyst used in steps-(c) and (f) is, each independently, selected from the group consisting of platinum plate, platinum sponge, platinum black, colloidal platinum, platinum oxide, platinum wire, palladium sponge, palladium black, palladium oxide, palladium on carbon, palladium hydroxide on carbon, colloidal palladium, palladium on barium sulfate, palladium on barium carbonate, reduced nickel, nickel oxide and Raney nickel; and wherein the formate salt used in steps-(c) and (f) is, each independently, selected from the group consisting of ammonium formate, sodium formate and potassium formate.   
     
     
         19 . The process of  claim 13 , wherein the reaction in step-(a) is carried out at a temperature of about 0° C. to about 40° C. for at least 30 minutes; wherein the reaction in steps-(c) and (0 is carried out at a temperature of about 0° C. to the reflux temperature of the solvent used and wherein the reaction in step-(e) is carried out at a temperature of about 0° C. to about 30° C. for about 3 hours to about 20 hours. 
     
     
         20 . (canceled) 
     
     
         21 . The process of claim  2018 , wherein the phase transfer catalyst used in step-(a) is benzyltriethylammonium chloride or tetrabutylammonium bromide; wherein the reducing agent used in step-(b) is sodium cyanoborohydride; wherein the Lewis acid used in step-(b) is aluminium chloride; and wherein the hydrogenation catalyst used in steps-(c) and (f) is palladium hydroxide. 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . (canceled) 
     
     
         25 . (canceled) 
     
     
         26 . (canceled) 
     
     
         27 . (canceled) 
     
     
         28 . (canceled) 
     
     
         29 . (canceled) 
     
     
         30 . (canceled) 
     
     
         31 . (canceled) 
     
     
         32 . The process of  claim 19 , wherein the reaction in steps-(c) and (f) is carried out at the reflux temperature of the solvent used for about 30 minutes to about 5 hours. 
     
     
         33 . (canceled) 
     
     
         34 . (canceled)