Preparation of optically pure (3RS)-2-oxy-3-(2-thienyl)-propylamine compound, useful as drug intermediate for e.g. serotonin and norepinephrine uptake inhibitor duloxetine, by enantioselective Reformatsky type synthesis via new intermediate

摘要

Preparation of (3R)- or (3S)-2-oxy-3-(2-thienyl)-propylamines (I) involves: (i) reacting a 2-thiophene-carboxaldehyde (II) with a reactive halo compound (III) and zinc in presence of an enantiomerically pure chiral auxiliary having at least two amino groups; (ii) adding water, acid or base or an alkylating, arylating, esterifying or silylating reagent; (iii) adding an amine (IV); and (iv) reducing product. Preparation of (3R)- or (3S)-2-oxy-3-(2-thienyl)-propylamines of formula (I) involves: (i) reacting a 2-thiophene-carboxaldehyde of formula (II) with a reactive halo compound of formula Hal-CR3R4-Y (III) and zinc in presence of an enantiomerically pure chiral auxiliary having at least two amino groups (provided that the protons present have a pKa of more than 20; (ii) adding water, acid or base or an alkylating, arylating, esterifying or silylating reagent; (iii) if Y is COOR1 or COOSi(Rs)3 adding an amine of formula NHR1R2 (IV); and (iv) reducing the product. R1, R2 = H or 1-30C hydrocarbyl ; R3 - R7 = halo or as defined for R1; Rx = H or 1-30C hydrocarbyl; W = H, alkyl, aryl, acyl or silyl; Y = CN or COZ; Z = OR1, OSi(Rs)3 or NR1R2; Rs = 1-30C hydrocarbyl; Hal = Cl, Br or I. The OW group in (I) is in alpha- or beta-configuration. 1-30C Hydrocarbyl either: (a) is optionally substituted by halo or CN; or (b) has one or more non-adjacent CH2 units replaced by O, CO, COO, OCO, OCOO, S or NRx; and/or (c) has one or more CH units replaced by N or P. Independent claims are included for the following new intermediates: (1) (3R)- or (3S)-2-oxy-3-(2-thienyl)-propionic acid amides, esters, silyl esters or nitriles of formula (V) (including mixtures of the (3R)- and (3S)-isomers in the case of amides) and (2) enantiomerically pure (3S)-3-hydroxy-3-(2-thienyl)-propionate esters of formula (VII). Q = CONR1R2, COOR1, COOSi(Rs)3 or CN; Ra = optionally halo- or cyano-substituted 2-30C hydrocarbyl; W' = H, alkyl, aryl, acyl, silyl or CORa. The OW group in (V) is in either the alpha- or beta-configuration, or may also be a mixture if Q = CONR1R2. When W is alkyl, aryl, silyl or CORa then Q is COOR1; and when R5 - R7 is H then Q is CN.