ZD-3638

The asym. sulfoxidation of an aryl Et sulfide in high enantioselectivity was required as part of a manufacturing route to a candidate drug (ZD3638) within AstraZeneca Pharmaceuticals.The initial discovery process provided small quantities of the required material to satisfy early toxicol. work.The optimization of this sulfoxidation process was required to improve enantioselectivity and therefore yield, and also to improve robustness for manufacturing routinely.Previous studies had indicated that asym. sulfoxidation of an aryl Et sulfide proceeded with moderate enantioselectivity.Initially, Sharpless conditions which are used for the oxidation of allylic alcs. were employed to effect sulfoxidation in 60% ee; this system was then studied extensively to provide new conditions in 80% ee.Finally, the use of factorial exptl. design to explore key parameters in the catalyst formation for these conditions was then studied.This showed the equivalent of the titanium (IV) isopropoxide (0.95 equiv) and (-)-D-diethyl-D-tartrate (1.45 equiv) to be essential factors in controlling enantioselectivity; this has resulted in a viable process with 92% ee in solution, which is improved to greater than 99% ee in the subsequent work-up.