Patent ID: 6344563
Filing Date: 2002-02-05
Classification: A61P,C07D

Abstract:
A process for preparing a substantially pure mesylate salt of Formula (1.0.1): comprising: (a) reacting a tetrahydro-4-(3-bromo-phenyl)-2H-pyran-4-nitrile of Formula (3.2.0): and a 4-fluorothiophenol of Formula (4.0.0): in a solvent selected from the group consisting of iso-propyl alcohol, sec-butyl alcohol, iso-pentyl alcohol, 2-heptanol, and an aqueous mixture of any one thereof; in the presence of a strong base selected from the group consisting of sodium hydroxide NaOH; and potassium hydroxide, KOH; and further in the presence of a transition metal catalyst comprising a member independently selected from the group consisting of palladium metal complexes; followed by heating the resulting reaction mixture; whereby there is produced a compound of Formula (2.0.0); (b) reacting said compound of Formula (2.0.0) and a compound of Formula (1.3.10): in an aprotic solvent; in the presence of a strong base in solid form selected from the group consisting of sodium hydroxide, NaOH; and potassium hydroxide, KOH; or additionally in the presence of a catalytic amount of cesium carbonate, Cs2CO3, or of a phase transfer catalyst; followed by (c) heating said reaction mixture under a nitrogen atmosphere, whereby there is produced a compound of Formula (1.0.0): followed by (d1) forming a concentrated methanol solution of said compound of Formula (1.0.0) contained in the resulting heated reaction mixture; wherein the resulting heated, concentrated methanol solution additionally contains methanesulfonic acid, MeSO3H, which is added before, during, or after formation of said methanol solution; filtering said heated, concentrated methanol solution while still in a heated condition, and thereafter concentrating the resulting filtrate solution; inducing crystallization of said compound of Formula (1.0.0) from said filtrate solution by displacing residual methanol in said filtrate solution with ethyl acetate; and thereafter recovering said substantially pure mesylate salt of Formula (1.0.1) in crystalline or followed by (d2) forming a concentrated methanol solution of said compound of Formula (1.0.0) contained in the resulting heated reaction mixture; filtering said heated, concentrated methanol solution while still in a heated condition, and thereafter concentrating the resulting filtrate solution; treating said filtrate solution with methanesulfonic acid, MeSO3H; inducing crystallization of said compound of Formula (1.0.0) from said filtrate solution by displacing residual methanol in said filtrate solution with ethyl acetate; and thereafter recovering said substantially pure mesylate salt of Formula (1.0.1) in crystalline form.