Patent ID: 7560575
Filing Date: 2009-07-14
Classification: C07D

Abstract:
1. A process for preparing racemic [2S*[R*[R*[R*]]]] and [2R*[S*[S*[S*]]]]-(+)α,α′-[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) as a diastereomerically pure compound comprising at least 95% of RS/SR configuration or RR/SS configuration, wherein PG is hydrogen or an amine protecting group, wherein the amine protecting group is at least one of an allyl group or an aryl-C 1 alkyl group; (b) providing a racemic compound of formula (V) wherein LG is a member selected from the group consisting of chloro, bromo, iodo, alkylsulfonyloxy and arylsufonyloxy; (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 and optionally in the presence of a catalyst 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, wherein the compound of formula (IX) and the compound of formula (IX′) are mixtures of diastereomers; (d) separating diastereomers of the compound of formula (IX) or the compound of formula (IX′) by fractional crystallization to obtain substantially pure diastereomers of formula (IX) or formula (IX′) having at least 50% of a RSS/SRR or RRS/SSR configuration; (e) reducing substantially pure diastereomers of formula (IX) or formula (IX′) having a RSS/SRR or RRS/SSR configuration to give a compound of formula (X) as a RSSS/SRRR diastereomeric mixture having a ratio of a RSSS/SRRR diastereomeric configuration to a SRSR or RRSS diastereomeric configuration, wherein said ratio is at least 1; (f) deprotecting the compound of formula (X), provided that PG is not H and if PG is H then omitting said deprotecting, 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*]]]]-(±).α,α′-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol]or pharmaceutically acceptable salts thereof.