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Synfacts 2013; 9(1): 0005
DOI: 10.1055/s-0032-1317723
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of a p38 Kinase Inhibitor

Contributor(s):
Philip Kocienski
Shi Z * et al. Bristol-Myers Squibb Co., New Brunswick and Princeton, USA
Development of a Practical Synthesis of a p38 Kinase Inhibitor via a Safe and Robust Amination.

Org. Process Res. Dev. 2012;
16: 1618-1625
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Further Information

Publication History

Publication Date:
17 December 2012 (online)

 
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Key words

p38 kinase inhibitors - amination - O-(4-nitrobenzoyl)hydroxylamine - pyrrolotriazines

Significance

The target pyrrolotriazine is a p38 kinase inhibitor that was a lead compound for the treatment of rheumatoid arthritis. The synthesis depicted features a safe and scalable N-amination of the pyrrole F using O-(4-nitrobenzoyl)hydroxylamine (G). The synthesis delivered 1.6 kg of active pharmaceutical ingredient (API) in 26% overall yield.


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Comment

Competing ester hydrolysis products generated in the condensation of E to the pyrrole F were minimized by adding ethyl trifluoroacetate as a water scavenger. A large-scale process for the synthesis of the crystalline O-4-(nitrobenzoyl)hydroxylamine (G) is described.


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