Waser M, * Moher ED et al.. * DSM Fine Chemicals Austria Nfg GmbH & Co KG, Linz, Austria
and Eli Lilly and Company, Indianapolis, USA
Process Development for a Key Synthetic Intermediate of LY2140023, a Clinical Candidate
for the Treatment of Schizophrenia.
Org. Process Res. Dev. 2011;
15: 1266-1274
Key words
LY2140023 - mGlu2/3 receptor agonist - cyclopropanation - Bucherer–Bergs reaction
Significance
LY2140023 is a conformationally restricted glutamic acid analogue that is an mGlu2/3
receptor agonist. It entered phase II
clinical trials for the treatment of schizophrenia. The following synthesis was used
to deliver over one metric ton of the key intermediate K.
Comment
Whilst the later steps are described on large scale, the earlier steps, especially
the critical carbene insertion reaction leading to cyclopropane B, is reported on a small scale. A large-scale (206 mol) hydroboration of B using
BH3·THF complex is described.
