A process for the preparation of macrocyclic metalloprotease inhibitors

摘要

The present invention is directed to a process for the preparation of a compound of formula (X-a):or a pharmaceutically acceptable salt form thereof, wherein:R1 is selected from the group consisting of:C1-5 alkyl substituted with 0-5 R1a, -(CH2)r-C3-10 cycloalkyl substituted with 0-5 R1a, and -(CH2)r-aryl substituted with 0-5 R1a.Compounds of Formula (X-a) are macrocyclic molecules containing anti-succinate residues which inhibit metalloproteinases such as aggrecanase, and the production of tumor necrosis factor (TNF). The anti-succinates are formed by an Ireland Claisen rearrangement of a silyl ketene acetal which proceeds with high stereoselectivity.