Patent ID: 8487122
Filing Date: 2013-07-16
Classification: A61P,C07D

Abstract:
1. A process for the preparation of the compound Nebivolol in the form of racemic mixture of the two enantiomers [2S[2R[R[R]]]]α,α′-[imino-bis (methylene)]bis[6-fluoro-chroman-2-methanol] and [2R[2S[S[S]]]]α,α′-[imino-bis (methylene)]bis[6-fluoro-chroman-2-methanol], having the following formulas comprising the following steps: a. reacting a mixture of the four isomers SR, RS, RR and SS of the epoxide of formula (1)  with an amine R—NH b. reacting the amines 2 and 3, in mixture, with the pair of epoxides 4 and 5, in mixture, to obtain a mixture of four compounds (6, 7, 8 and 9); c. separating the compounds 6 and 8 (RSSS+SRRR), in mixture, from 7 and 9 by fractional crystallization, by a first solvent selected from the group consisting of ethanol, isopropanol, butanol, tert-butanol, and 2-methyl-2-butanol, and subsequently by a mixture of a polar aprotic solvent selected from the group consisting of methyl acetate, ethyl acetate, isopropyl acetate, acetone, methyl ethyl ketone, acetonitrile, and isopropyl ether, with an apolar solvent selected from the group consisting of pentane, hexane, cyclohexane, methylcyclohexane, heptane, benzene, and toluene; and d. removing the protecting group R, and optionally subsequently forming the hydrochloride salt, to obtain the final product Nebivolol or Nebivolol hydrochloride.