posted on 2015-04-17, 00:00authored byMichael E. Kopach, Perry C. Heath, Roger B. Scherer, Mark A. Pietz, Bret A. Astleford, Mary Kay McCauley, Utpal
K Singh, Sze Wing Wong, David M. Coppert, Mark S. Kerr, Peter G. Houghton, Gary
A. Rhodes, Gregg
A. Tharp
A convergent
synthesis of (S)-(4-benzylmorpholin-2-yl)(morpholino)methanone
methanesulfonate (1), a key regulatory starting material
for edivoxetine·HCl, was developed at Eli Lilly & Company.
This novel synthesis utilizes d-serine as the source of chirality,
which is preserved throughout the synthesis. Key features include
the development of a scalable diazotization process to produce (S)-epoxy acid 7, which was optimized to improve
the process safety profile. The final (S)-morpholino
acid intermediate 11 was converted to the title compound
using T3P with >99.9% purity in 75% yield. Life cycle analysis
of
the new route revealed a 69% reduction in global warming potential
(GWP) for solvent usage relative to the prior route of manufacture.