An efficient synthesis of (S)-3-aminomethyl-5-methylhexanoic acid (Pregabalin) via quinine-mediated desymmetrization of cyclic anhydride

A highly enantioselective synthesis of (S)-3-aminomethyl-5-methylhexanoic acid 1 (Pregabalin) is reported. The key step of the synthesis is a quinine-mediated ring opening of 3-isobutylglutaric anhydride with cinnamyl alcohol. A Curtius rearrangement and subsequent deprotection provides 1 in high yield and excellent enantiomeric excess.

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(R)-3-Isobutyl-pentanedioic acid mono-(3-phenyl-allyl) esterC18H24O4Ee = 97%[α]D25=-0.53 (neat)Source of chirality: asymmetric synthesisAbsolute configuration: (R)

(S)-5-Methyl-3-[(3-phenyl-allyloxycarbonilamino)-methyl]-hexanoic acid 3-phenyl-allyl esterC27H33NO4Ee = 97%[α]D25=-4.3 (c 20, EtOH)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

(S)-3-(Benzyloxycarbonylamino-methyl)-5-methyl-hexanoic acid 3-phenyl-allyl esterC25H31NO4Ee = 97%[α]D25=-4.2 (c 20, EtOH)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

(S)-3-(Benzyloxycarbonylamino-methyl)-5-methyl-hexanoic acidC16H23NO4Ee = 97%[α]D25=-4.4 (c 25, EtOH)Source of chirality: asymmetric synthesisAbsolute configuration: (S)

(S)-3-Aminomethyl-5-methyl-hexanoic acidC8H17NO2Ee = 99.7%[α]D25=+10.8 (c 1.1, H2O)Source of chirality: asymmetric synthesisAbsolute configuration: (S)