Racemization pregabalin

The P-cyanodiester 4 was prepared by condensation of isovaleraldehyde with diethyl malonate followed by the addihon of potassium cyanide. The cyanodiester 4 was hydrolyzed and decarboxylated to give the P-cyano acid 5. Reduction with Raney nickel gave racemic pregabalin (6), which was resolved with (S)-mandelic acid. The diastereomeric salt was split with wet TH F under neutral conditions to give pregabalin, which was recrystallized from isopropanol (IPA) to give the final Active Pharmaceutical Ingredient (API). 

Recently, another interesting application of nitrilases has been demonstrated for the synthesis of pregabalin-the API of the neurophatic pain drug Lyrica. In this approach, the key step is the resolution of racemic isobutylsuccinonitrile (Scheme 10.8) [18], the process takes place with total regio- and stereoselectivity, and the (S)-acid is obtained and the (R)-substrate can be recycled under basic conditions. To improve the biocatalytic step, directed evolution was applied using the electronic polymerase chain reaction and in the first round of evolution a single C236S mutation led to a mutant with 3-fold increase in activity [19]. 

Many of the synthetic routes derived for pregabalin (2) before 2003 have relied on classical chiral resolution of either an intermediate or the final racemic 3-isobutyl GABA (43). In 2003, Jacobsen and co-workers published their work on a novel enantio-selective synthesis of pregabalin (2) (Sammis and Jacobsen, 2003). The Harvard group was able to promote conjugate addition of hydrogen cyanide into the unsaturated imide... 

To address both the green chemistry and cost issues, a novel biocatalytic process was recently developed involving a lipolase-catalyzed resolution of a CNDE to produce the desired (S)-mono acid enantiomer, which was subsequently converted to pregabalin upon decarboxylation, hydrolysis, and hydrogenation (Scheme 8.11) [60]. The enzymatic step has an excellent volumetric activity of >500 gl-1 per day. Since the undesired R-enantiomer could be readily racemized to CNDE, the yield of... 

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