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
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.
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.
