Diastereomeric Resolution of Racemic o‐Chloromandelic Acid

Abstract

The separation of rac-o-chloromandelic acid 1 with enantiopure aryloxypropylamine via diastereomeric salt formation was investigated. (R)-o-chloromandelic acid (R)-1, a key intermediate for the antithrombotic agent clopidogrel, was obtained in 65% yield and 98% ee by Dutch resolution of rac-1 with (S)-2-hydroxyl-3-(p-chlorophenoxy) propylamine (S)-5 as resolving agent and (S)-2-hydroxyl-3-(o-nitrophenoxy) propylamine (S)-4 as nucleation inhibitor.

Dutch Resolution of a configurationally stable [5]helquat

“…55,56 The use of family of resolving agents for the racemate resolution effectively changes trial-anderror resolution method into an acceptable and almost routine practice. [55][56][57][58][59][60][61][62][63][64][65][66] The extremely high success rate, defined in terms of yield and enantiomeric excess in a first trial, is the most attractive feature of this method. Out of the 1000 tested racemate resolutions, 95% have been reported as successful.…”

“…Family resolution approach called Dutch Resolution was discovered by Ton Vries and reported in a seminal paper in 1998 . The use of family of resolving agents for the racemate resolution effectively changes trial‐and‐error resolution method into an acceptable and almost routine practice . The extremely high success rate, defined in terms of yield and enantiomeric excess in a first trial, is the most attractive feature of this method.…”

Efficient Preparation of (R)‐2‐chloromandelic Acid Via a Recycle Process of Resolution

“…20 These resolutions can be achieved via diastereomeric salts, which are always composed of the acid 1 and amine resolving agents. However, almost all amine resolving agents are toxic or expensive.…”

“…1,2 The preparation of (R)-1 has been investigated by the following general methods: 1) asymmetric synthesis via metal catalyst [3][4][5] or biocatalyst; 6,7 2) racemic resolution by chromatography; 8 3) enzymatic resolution; [9][10][11][12][13][14][15] and 4) diastereomeric salt resolution. [16][17][18][19][20] In methods (1-3), (R)-1 can be obtained in high optical purity. However, these methods are used mainly in the laboratory because of the high price of efficient chiral catalysts and the limitation of equipment.…”

“…Four kinds of resolving agents were used to resolve rac-1: N-benzyl-α-phenylethanamine, 16,17 alanine, 18 1-aryl-2-amino-1,3-propane-diol, 19 and aryloxypropylamine. 20 These resolutions can be achieved via diastereomeric salts, which are always composed of the acid 1 and amine resolving agents. However, almost all amine resolving agents are toxic or expensive.…”