A Simplified Process for the Manufacture of Imagabalin Hydrochloride (PD-0332334), an α2δ-Ligand for the Treatment of Generalised Anxiety Disorder

Abstract

The development of a highly efficient two-step process for the manufacture of the α2δ-ligand imagabalin hydrochloride 1 is described in 50% overall yield from (R)-3-methylhexanoic acid 2. Key aspects of this route include the development of a one-pot process for the synthesis of β-enamine ester 7 and its subsequent diastereoselective hydrogenation with a Ru-(S)-BINAP catalyst. The use of a combination of TFA, ammonium trifluoroacetate, and relatively low pressures in the asymmetric hydrogenation are novel conditions reported for this type of transformation. The simplified process described realised a 4-fold reduction in cost of goods compared with the previously described enabling route.

Practical, Catalytic Enantioselective Hydrogenation to Synthesize N-Unprotected β-Amino Esters

“…Furthermore, even more ambitiously, we wished to develop a direct reductive amination of β-keto esters (Scheme ). Similar to our strategy, several direct syntheses of unprotected β-amino acids using asymmetric hydrogenation have been reported. ,, For example, Merck and Solvias that reported the Rh–Josiphos complexes catalyze the asymmetric hydrogenation of unprotected β-enamine esters and amides with excellent enantioselectivity, which is an important breakthrough…”

“…This direct reductive amination is not only applicable to a wide range of substrates through the appropriate choice of the ammonium salt but can also be easily scaled up. Asymmetric hydrogenation of unprotected β-enamine esters and direct reductive amination reactions are becoming a new standard for β-amino acid synthesis. ,, …”

Transaminases and their Applications

“…Imagabalin is a candidate for the treatment of anxiety disorder. Up to now the synthesis of imagabalin has been based on chemical catalysis: however, the high costs make this process inadequate for industrial applications [125,126]. With these combined engineering techniques, eight mutations were detected, of which five clearly provided more space and interaction with the substrate.…”

Industry Perspectives on Process Analytical Technology: Tools and Applications in API Development

“…Common tools that are routinely used in manufacturing include thermocouples and pressure sensors. Spectroscopic tools (e.g., near-infrared, − mid-infrared, − Raman, − UV − and NMR) − are utilized for increased analytical specificity (ability to monitor for the presence or disappearance of functional groups during the synthesis). By monitoring these specific functional groups, qualitative trending or quantitative assessment of the reaction component(s) levels is achieved.…”