A Simplified Process for the Manufacture of Imagabalin Hydrochloride (PD-0332334), an alpha 2 delta-Ligand for the Treatment of Generalised Anxiety Disorder

The development of a highly efficient two-step process for the manufacture of the alpha 2 delta-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 beta-enami...

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Published inOrganic process research & development Vol. 15; no. 6; pp. 1358 - 1364
Main Authors Birch, Melissa, Challenger, Stephen, Crochard, Jean-Philippe, Fradet, David, Jackman, Hayley, Luan, Amy, Madigan, Evelyn, Mathew, Jinu S., McDowall, Neil, Meldrum, Kevin, Gordon, Charles M., Peach, Philip, Yeo, Stephen
Format Journal Article
LanguageEnglish
Published WASHINGTON Amer Chemical Soc 01.11.2011
Subjects
Chemistry
Chemistry, Applied
Chemistry, Organic
Physical Sciences
Science & Technology
ACID
ESTERS
ENAMINES
ASYMMETRIC HYDROGENATION
CHLORIDE
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Summary:The development of a highly efficient two-step process for the manufacture of the alpha 2 delta-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 beta-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.
ISSN:1083-6160
DOI:10.1021/op2002326