Recent advances in the preparation of active pharmaceutical ingredient (S)-Pregabalin

*Corresponding author
1. Centre for Synthesis and Chemical Biology (CSCB), Royal College of Surgeons in Ireland (RCSI), 123 St Stephen’s Green, Dublin 2, Ireland
2. Centre for Synthesis and Chemical Biology (CSCB), University College Dublin, Science Centre South, Belfield, Dublin 4, Ireland
3. IC-CNR, Via Giovanni Amendola,122, 70126, Bari, Italy


In recent times, several efforts have been devoted to develop new synthetic methodologies to access active the pharmaceutical ingredient (S)-Pregabalin. Marketed as (LyricaTM), (S)-Pregabalin is indicated for the treatment of epilepsy, neuropatic pain and anxiety. As presented in this short review, the methodologies available to prepare (S)-Pregabalin can be classified by the method employed to install the desired absolute stereochemistry, namely: (a) preparation of Pregabalin as a racemate and its resolution; (b) enantioselective syntheses; (c) processes involving a biocatalytic step. This review provides an overview of the state of the art on the synthetic methodology available to prepare this blockbuster API.


In recent times, several efforts have been devoted to the development of new synthetic methodologies to access the active pharmaceutical ingredient (S)-3-aminomethyl-5-methyl-hexanoic acid, commonly known as (S)- Pregabalin 1 (Figure 1). (S)- Pregabalin 1 is marketed as (LyricaTM) and indicated as a treatment for epylepsy. Pregabalin is approved in US and Europe for adjunctive therapy of partial seizures in adults, and also has been approved for the treatment of pain from diabetic neuropathy or post-herpetic neuralgia in adults. Recently, it has been approved for treatment of anxiety disorders in Europe. Pregabalin is structurally related to the antiepileptic drug gabapentin and the site of action of both drugs is similar, the a2d2 protein, an auxiliary subunit of voltage-gated calcium channels (1). Beginning with old style approaches that provided (S)- Pregabalin 1 as a racemate, chemists have since developed

more efficient technologies based on contemporary concepts such as biocatalysis, organocatalysis and flow chemistry. Hence, the methodologies available ...