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

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; in the presence of an oxygen source selected from the group consisting of lead monoxide, manganese dioxide, mercuric iodide and ceric ammonium nitrate, to provide a protected triazatetracyclo compound of formula II:

wherein R is as defined in formula III;

b) deprotecting the compound of formula II, and

c) 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.

3. 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.

4. The process of claim 3 , wherein the reaction is carried out at the reflux temperature of the solvent used for about 2 hours to about 10 hours.

5. 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, trichloroacetyl, pyrrolidinylmethyl, cumyl, benzhydryl, trityl, benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxy carbonyl (Fmoc), benzyloxymethyl (BOM), pivaloyloxymethyl (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; and wherein the halogen atom ‘Y’ in the compound of formula IV is Cl.

6. The process of claim 5 , wherein the nitrogen protecting group ‘R’ is trifluoroacetyl or t-butoxycarbonyl.

7. The process of claim 1 , 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.

8. The process of claim 1 , 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.