Synthesis of Pregabalin

The first enantioselective synthesis of pregabalin (2) was developed by Yuen and co-workers at Pfizer using Evans chiral oxazolidinone chemistry (Yuen et al., 1994). 

Saponification followed by catalytic hydrogenation of the azidoester gave pregabalin (2) in 29% overall yield. With the use of trimethylsilyl iodide in this process, the cost of goods was still too high to be practical. 

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 

Kissel, Ramsden, and other researchers at Pfizer and Chirotech jointly published a novel chiral synthesis of pregabalin (2) in 2003 based on asymmetric hydrogenation (Burk et al., 2001, 2003). Their synthesis started with the condensation of isobutyralde-hyde with acrylonitrile under Baylis-Hillman conditions to give allylic alcohol 65. This alcohol was activated as the carbonate 66 and subjected to palladium-catalyzed car-bonylation conditions to give cyanoester 67. The ester 67 was hydrolyzed and converted to 

Karlsson, A., Fonnum, F., Malthe-Sorensson, D., and Storm-Mathisen, J. (1974). Biochem. Pharmacol, 23 3053-3061. 

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Scheme 10. Chemoenzymatic synthesis of pregabalin by overcoming product inhibition...

Scheme 13. Nitrilase-catalyzed synthesis of pregabalin by ePCR...

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]. 

Scheme 10.8 Synthesis of pregabalin using an evolved nitrilase.

Scheme 8.1 Initial synthesis of pregabalin in its chiral form.

An attractive feature of this two-step one-pot reaction is that it not only incorporates an innovative technique for site-isolation but also produces enantiomerically enriched useful intermediates. Indeed the Michael adducts that are produced represent precursors to y-amino acids, allowing access to y-amino butyric acid analogues. Pregabalin (145) is one such analogue that is approved for the treatment of both epilepsy and neuropathic pain. Following this one-pot synthetic strategy there is no need for nitroalkene isolation and byproduct formation can be avoided. Scheme 3.42 depicts the total synthesis of pregabalin. 

Bassas O, Huuskonen J, Rissanen K, Koskmen AMP (2009) A Simple Organocatalytic Enantioselective Synthesis of Pregabalin. Enr J Oig Chem 2009 1340... 

C.K. Winkler, D. Clay, S. Davies, P. O Neill, P. McDaid, S. Debaige,). Steflik, M. Karmilowicz, J.W. Wong, K. Faher, Chemoenzymatic asymmetric synthesis of pregabalin precursors via asymmetric bioreduction of (J-cyanoacrylate esters using ene-reductases, 1. Org. Chem. 78 (2013) 1525-1533. 

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