Process development in the synthesis of the AGE intermediate MDL 28,726

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 tricycli c acid, which has three chiral centers, was developed beginning with 3,4-di hydro-2H-pyran. A key step in the synthesis features an enzyme-catalyzed re solution of the lithium salt of the N-trifluoroacetamide of (R,S)-6-hydroxy norleucine. All of the steps were optimized and completed in reactor equipm ent using environmentally acceptable processes. Process development of this route is described.