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Synfacts 2014; 10(5): 0453
DOI: 10.1055/s-0033-1341077
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of a TRPV1 Antagonist

Contributor(s):
Philip Kocienski
Bellizzi ME, Bhatia AV, Cullen SC, Gandarilla J, Kruger AW, * Welch DS. * AbbVie Inc., North Chicago, USA
Asymmetric Synthesis of a TRPV1 Antagonist via tert-Butanesulfinamide-Directed Reductive Amination with a Chromanone.

Org. Process Res. Dev. 2014;
18: 303-309
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Publication History

Publication Date:
17 April 2014 (online)

 
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Key words

TRPV1 antagonist - diastereoselective reductive amination - chromanone synthesis - sulfinyl ketimine

Significance

The target molecule is an antagonist of transient receptor potential vanilloid-1 (TRPV1) that is of interest for the treatment of nociceptive pain. The multikilogram-scale synthesis depicted delivered 2.6 kg of the active pharmaceutical ingredient with high enantiopurity (>99.9% ee). The synthesis features the auxiliary-directed diastereoselective imine reduction G → H.


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Comment

An optimization study of the one-pot imine reduction step (G → H) revealed that high ­diastereoselectivity depended on the use of 3.0 equivalents of Ti(OEt)4 in the imine formation step (E → G) and the presence of a single equivalent of EtOH generated in the formation of the sulfinyl imine G.


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