Chemo-enzymatic approach to the synthesis of the antithrombotic clopidogrel

The (S)-2-chlorophenylglycine moiety is well recognized in the structure of (S)-clopidogrel, a known antithrombotic drug. We prepared an enantiomerically pure chiral building block via an enzyme-catalyzed resolution of (RS)-N-Boc-2-chlorophenylglycine methylester. The best results were obtained by means of an immobilized subtilisin, the cross-linked enzyme aggregate (Alcalase-CLEA®). The high enantiomeric excess of the synthon obtained remained the same over the course of clopidogrel synthesis; the simplicity of the process makes this pathway suitable for large-scale preparation.

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N-Boc-(S)-2-chlorophenylglycineC13H16ClNO4>98% Ee (by HPLC)[α]D20=+101 (c 1, CH3OH)Source of chirality: enzymatic hydrolysisAbsolute configuration: (S)

N-Boc-(S)-2-chlorophenylglycine methyl esterC14H18ClNO4>98% Ee (by HPLC)[α]D20=+119.3 (c 1, CHCl3)Source of chirality: N-Boc-(S)-2-chlorophenylglycineAbsolute configuration: (S)

(S)-2-Chlorophenylglycine methyl esterC9H10ClNO2>98% Ee (by HPLC)[α]D20=+123 (c 1, CH3OH)Source of chirality: N-Boc-(S)-2-chlorophenylglycineAbsolute configuration: (S)

(S)-α-(2-Chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetic acid methyl ester (clopidogrel)C16H16ClNO2S>98% Ee (by HPLC)[α]D20=+45 (c 1, CH3OH)Source of chirality: (S)-2-chlorophenylglycine methyl esterAbsolute configuration: (S)

(S)-α-(2-Chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetic acid methyl ester hydrogen sulfate (clopidogrel hydrogen sulfate)C16H16ClNO2S·H2SO4>98% Ee (by HPLC)[α]D20=+54.8 (c 1, CH3OH)Source of chirality: (S)-2-chlorophenylglycine methyl esterAbsolute configuration: (S)