A process for preparation of racemic nebivolol

摘要

Disclosed is a process for preparing racemic [2S*[R*[R*[R*]]]] and [2R*[S*[S*[S*]]]]-(±)alpha,alpha'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] and pharmaceutically acceptable salts thereof, the process comprising: (a) providing a compound of formula (VIII), wherein PG is hydrogen or an amine protecting group; (b) providing a racemic compound of formula (V) wherein LG is a member selected from the group consisting of chIoro, bromo, iodo, alkylsulfonyloxy and arylsulfonyloxy; (c) N-alkylating the compound of formula (VIII) with the compound of formula (V), wherein said N-alkylating is carried out in an inert organic solvent in a presence of a base to give a compound of formula (IX), a compound of formula (IX') which is a cyclic semi-ketal form of the compound of formula (IX) or a mixture thereof; (d) separating diastereomers of the compound of formula (IX) or the compound of formula (IX') by fractional crystallization after salt formation or after derivatization to obtain substantially pure diastereomers of formula (IX) or formula (IX') separating diastereomers of the compound of formula (IX) or the compound of formula (IX') to obtain substantially pure diastereomers of formula (IX) or formula (IX') in a simultaneous epimerization-crystallization step, provided that said epimerizing is conducted in a presence of a base and an organic solvent and (2) crystallizing substantially pure diastereomers of formula (IX) or formula (IX'); separating the mixture by fractional crystallization to obtain substantially pure diastereomers of formula (IX) or formula (IX'); (e) reducing substantially pure diastereomers of formula (IX) or formula (IX') to give a compound of formula (X); (f) deprotecting the compound of formula (X, to obtain a compound of formula (I) or pharmaceutically acceptable salts thereof; and (g) removing a RSRS or RRSS diastereomeric configuration of the compound of formula (I) or pharmaceutically acceptable salts thereof if present by recrystallization or by a slurry to give racemic [2S*[R*[R*[R*]]]] and [2R*[S*[S*[S*]]]]·(±)a,a'-[iminobis (methylene)]bis[6-fluoro-3 ,4-dihydro-2H·1-benzopyran-2-methanol] or pharmaceutically acceptable salts thereof. Also disclosed are the meldrum's ester of 6-fluoro-chroman-2-carboxylic acid, the chloro and bromo acid halogens of 6-fluoro-chroman-2-carboxylic acid and bis-protected Nebivolol.