Process for the preparation of nebivolol

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:
• a1. reacting a mixture of the four isomers SR, RS, RR and SS of the epoxide of formula (1)
• with an amine RR3NH, wherein R and R3 are benzyl groups, possibly each independently mono- or disubstituted with a group selected from the group consisting of:
• halogen, nitro, a C1-C4 alkyl chain, CF3, CHF2, and an OR2 group, where R2 is a hydrogen or C1-C4 alkyl, in a solvent represented by a sterically hindered alcohol selected from the group consisting of iPrOH, sec-BuOH, tert-BuOH, isoamyl, 2-methyl-2-butanol and 2-methyl-2-pentanol, used alone or in mixture with an apolar solvent selected from the group consisting of petroleum ether, pentane, hexane, cyclohexane, methylcyclohexane, heptane, benzene, and toluene, to obtain a mixture of the four compounds 12, 13, 4 and 5, from which the pair 12/13 is separated from the pair 4/5;
• a2. eliminating the group R3 to obtain a mixture of compound 2/3;
• 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.