Patent ID: 8067640
Filing Date: 2011-11-29
Classification: C07B,C07C,C07D,C12P

Abstract:
1. A process for the preparation of escitalopram having the formula or a pharmaceutically acceptable salt thereof, comprising (i) preparing the S-enantiomer of a diol having the formula (IIs) or a salt thereof; wherein R is cyano or a group which may be converted to a cyano group, the dotted line represents a double or a single bond, Z is a dimethylaminomethyl group or a group which may be converted to a dimethylaminomethyl group and Hal is a halogen or (ii) preparing the S-enantiomer of an acylated diol having the formula (IVs) or a salt thereof; wherein R, Z, the dotted line and Hal are as defined above, W is O or S, and R wherein the diol of formula (IIs) and/or the acylated diol of formula (IVs) is prepared by a method comprising: (a) subjecting a racemic diol of formula (II) wherein R is cyano or a group which may be converted to a cyano group, Z is —CH to selective enzymatic acylation using an acylating agent having the formula or an isocyanate having the formula R R R R to form a mixture of (1) the S-enantiomer of the diol of formula (II) and the R-enantiomer of the compound of formula (IV) or (2) the R-enantiomer of the diol of formula (II) and the S enantiomer of the compound of formula (IV) wherein R, Hal, the dotted line and Z are as defined above; wherein W is O or S, and R (b) subjecting a racemic compound of formula (IV) wherein R, Z, W, Hal, the dotted line and R wherein R, Hal, the dotted line and Z are as defined above, and the opposite enantiomer of a compound of formula (IV); and (c) isolating, in either order, (1) the S-enantiomer of the diol of formula (II) and the R-enantiomer of the compound of formula (IV) or a salt thereof or (2) the R-enantiomer of the diol of formula (II) and the S-enantiomer of the compound of formula (IV) or a salt thereof; (iii) optionally subjecting the diol of formula (IIs) or the acylated diol of formula (IVs) to one or more reactions, in any order, selected from (a) conversion of the group R to a cyano group, (b) conversion of the group Z to a dimethylaminomethyl group, (c) reduction of a double bond represented by the dotted line to a single bond and (d) conversion of the group Hal to a fluoro group; (iv) effecting ring closure under basic conditions of the diol of formula (IIs) or the acylated diol of formula (IVs), or a labile ester derivative thereof, to form a compound of formula (V) (v) subjecting the compound of formula (V) to, in any order: (a) conversion of the group R to a cyano group, if R is not cyano, (b) conversion of the group Z to a dimethylaminomethyl group, if Z is not dimethylaminomethyl, (c) reduction to a single bond, if the dotted line represents a double bond, and (d) conversion of Hal to a fluoro group, if Hal is not fluoro; and (vi) isolating escitalopram or a pharmaceutically acceptable salt thereof.