Eco-friendly, industrial process for synthesis of (S)-3-(aminomethyl)-5-methylhexanoic acid [pregabalin]

In the present work pregabalin has been synthesized by four novel routes, which have been broadly categorized into two approaches. In the first strategy, it has been synthesized through a hemiaminal intermediate. In the second approach, (RS)-ethyl-3-cyano-5-methylhexanoate, a key intermediate, has b...

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Bibliographic Details
Published inIndian journal of chemistry. Sect. B. Organic chemistry, including medicinal chemistry Vol. 51; no. 10; pp. 1470 - 1488
Main Authors Roy, Bhairab Nath, Singh, Girij Pal, Lathi, Piyush Suresh, Agrawal, Manoj Kunjabihari, Mitra, Rangan, Pise, Vijay Sadashiv
Format Journal Article
LanguageEnglish
Published NEW DELHI COUNCIL SCIENTIFIC & INDUSTRIAL RES 01.10.2012
Subjects
Chemistry
Chemistry, Organic
Physical Sciences
Science & Technology
REDUCTION
cinchonidine
lipase
GREEN CHEMISTRY
ESTERS
SUSTAINABILITY
Pregabalin
cyano mono ester
resolution
EFFICIENCY
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Summary:In the present work pregabalin has been synthesized by four novel routes, which have been broadly categorized into two approaches. In the first strategy, it has been synthesized through a hemiaminal intermediate. In the second approach, (RS)-ethyl-3-cyano-5-methylhexanoate, a key intermediate, has been synthesized through novel and cost effective routes, followed by either lipase catalyzed kinetic resolution to optically pure (S)-ethyl-3-cyano-5-methylhexanoate (> 99% ee, 85% yield) or resolution via diastereomeric salt formation with cinchonidine to obtain optically pure (S)-3-cyano-5-methyl-hexanoic acid (> 99% cc, 85% yield), which has been subsequently converted to pregabalin (> 99% ee). In addition, for improvement of atom economy as well as cost effectiveness, an efficient process for complete racemization of (R)-3-cyano-5-methyl-hexanoic acid has been developed.
ISSN:0376-4699