Pregabalin Enzymatic Synthesis of Ethyl S -3-Cyano-5-Methylhexanoate

13 PREGABALIN ENZYMATIC SYNTHESIS OF ETHYL (S)-3-CYANO-5-METHYLHEXANOATE 

Several routes were examined in detail [68,69]. The first-generation manufacturing resolution process and asymmetric hydrogenation process were potentially elegant manufacturing processes, but they were surpassed in terms of cosf-effecfiveness and environmental performance by an enzymatic route [70]. 

Under optimized conditions, the enzymatic process was tested for robustness in multiple runs at a 10 kg scale. Three pilot runs at a 900kg (16001 reactor) scale as well as manufacturing trials at 3.5f (80001 reactor) demonstrated the consistently high performance of fhis enzymatic reaction. A heat-promoted decarboxylation of (S)-36 efficienfly generafed ethyl ester (S)-38, a known precursor of pregabalin 1 [70]. 

Pregabalin enzymatic synthesis of ethyl (S)-3-cyano-5-methyl-hexanoate. 

Three synthetic approaches, suitable for the large-scale manufacture of the (x25-ligand, (3S,5] )-3-(aminomethyl)-5-methyloctanoic acid 44, have been developed [67, 77, 78]. The selected seven-step manufacturing process was optimized and used to prepare 20 kg of API. From this process it was concluded that the medicinal chemistry route, although suitable for the preparation of material to support early toxicological and clinical studies, would not be a suitable long-term manufacturing process 

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