Patent ID: 6346624
Filing Date: 2002-02-12
Classification: A61P,C07D

Abstract:
A process for preparing a substantially pure mesylate salt of Formula (1.0.1): comprising:(a) preparing a compound of Formula (2.0.0): â€ƒcomprising: (1) establishing a reaction mixture consisting of (i) tetrahydro-4-(3-bromo-phenyl)-2H-pyran-4-nitrile of Formula (3.2.0): â€ƒand (ii) 4-fluorothiophenol of Formula (4.0.0): (iii) in a solvent selected from the group consisting of iso-propyl alcohol, sec-butyl alcohol, iso-pentyl alcohol, and 2-heptanol, optionally as an aqueous mixture thereof; (iv) in the presence of a strong base selected from the group consisting of sodium hydroxide, NaOH; and potassium hydroxide, KOH; â€ƒand further (v) in the presence of a transition metal catalyst comprising a member independently selected from the group consisting of palladium metal complexes; â€ƒfollowed by (2) heating said reaction mixture; whereby there is produced said compound of Formula (2.0.0); (b) establishing a reaction mixture consisting of said compound of Formula (2.0.0) and a compound of Formula (1.3.10): (1) in an aprotic solvent; (2) in the presence of cesium carbonate, CS2CO3; â€ƒfollowed by (c) heating said reaction mixture at reflux, under a nitrogen atmosphere; whereby there is produced a compound of Formula (1.0.0): â€ƒfollowed by (d) forming a concentrated methanol solution of said compound of Formula (1.0.0) to which there is then added methanesulfonic acid, MeSO3H; followed by further concentration and the addition of ethyl acetate ad seriatim until a crystalline product is isolated comprising substantially pure mesylate salt of Formula (1.0.1) â€ƒor, alternatively, followed by (e) forming a concentrated methanol solution of said compound of Formula (1.0.0) to which there is then added methanesulfonic acid, MeSO3H; followed by filtering of the mixture, preferably through activated carbon, after which there follows further concentration and the addition of ethyl acetate ad seriatim until a crystalline product is isolated comprising said substantially pure mesylate salt of Formula (1.0.1).