Acetic Anhydride → 5-Amino-5-oxopentanoic acid

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Reaction Steps

Several processes were reported for the synthesis of (S)-Pregabalin. One such process is illustrated in drugs of the future, 24 (8), 862-870 (1999), represented as scheme-1. In which 3-isobutylglutaric acid, compound 2, is converted into the corresponding anhydride, compound 3, by treatment with refluxing acetic anhydride. The reaction of the anhydride with NH4OH produces the glutaric acid mono-amide, compound 4, which is resolved with (R)-1-phenylethylamine, yielding the (R)-phenyl ethylamine salt of (R)-3-(carbamoylmethyl)-5-methylhexanoic acid, compound 5. Combining the salt with an acid liberates the (R)-enantiomer, compound 6. Finally, a Hoffmann's degradation with Br2/NaOH provides (S)-Pregabalin. A disadvantage of this method is that, it requires separating the two enantiomer thereby resulting in the loss of half of the product, such that the process cost is high.

Provenance & Evidence