ASP3627
(1) is a potent Janus kinase inhibitor discovered
and developed by Astellas Pharma Inc. Here, we report the development
of a practical and scalable method for manufacturing ASP3627 featuring
a six-reaction telescoping process consisting of DIBAL reduction,
hydrolysis, Wittig reaction, cyclization, and a two-step sequence
to remove the SEM group. In addition, a simple palladium removal procedure
using l-cysteine is described. This method was used to successfully
perform the first multikilogram synthesis of ASP3627, producing 30
kg with high purity in excellent overall yield.
Several pyrrolidine- and piperidine-based organocatalysts were evaluated for the asymmetric Michael addition of thiols to β-nitrostyrenes. We found a structure–activity relationship between the catalyst and a higher catalytic activity for 1,3-bis[(3R,4S)-1-benzyl-4-phenylpyrrolidin-3-yl]urea.
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