Process Development in the Synthesis of the ACE Intermediate MDL 28,726

Abstract

MDL 28,726 is a key intermediate in the synthesis of the ACE inhibitors MDL 27,210A and MDL 100,240. An efficient nine-step synthesis of this tricyclic acid, which has three chiral centers, was developed beginning with 3,4-dihydro-2H-pyran. A key step in the synthesis features an enzyme-catalyzed resolution of the lithium salt of the N-trifluoroacetamide of (R,S)-6-hydroxynorleucine. All of the steps were optimized and completed in reactor equipment using environmentally acceptable processes. Process development of this route is described.

Using Continuous Processes to Increase Production

“…ID pipe with two 90° bends to increase turbulence. The 61% isolated yield of 39 was only slightly better than the batch yield of 55%, but continuous operations afforded better control of the processing . The latter is a good example of HTST processing.…”

The Swern Oxidation: Development of a High-Temperature Semicontinuous Process

“…Consequently, the order of reagent addition was preserved, but cryogenic conditions (<−50 °C) were employed for the balance of the campaign, affording the ketone 4 in an average yield of 67% . A subsequent request for the production of the tricyclic acid 8 (Scheme ) prompted a renewed investigation into the Swern oxidation.…”