MEDI 573

Practical asymmetric synthesis of a potent PDE4 inhibitor via stereoselective enolate alkylation of a chiral aryl-heteroaryl secondary tosylate

Cheng-yi Chen, cheng_chen@merck.com¹, Paul D. O'Shea², Weirong Chen¹, Philippe Dagneau², Lisa F. Frey, lisa_frey@merck.com¹, Edward J. J. Grabowski¹, Karen M Marcantonio, karen_marcantonio@merck.com¹, Robert A. Reamer¹, Lushi Tan, lushi_tan@merck.com¹, Richard D. Tillyer¹, Amelie Roy², Xin Wang, Xin_Wang@merck.com², and Dalian Zhao, dalian_zhao@merck.com¹. (1) Department of Process Research, Merck Research Laboratories, P. O. Box 2000, Rahway, NJ 07065, (2) Merck Frosst Centre for Therapeutic Research, P.O. Box 1005, Pointe-Claire-Dorval, QC H9R 4P8, Canada

A practical, chromatography-free catalytic asymmetric synthesis of a potent and selective PDE4 inhibitor is described. Catalytic asymmetric hydrogenation of thiazole ketone afforded the corresponding alcohol in excellent enantioselectivity. Activation of the alcohol via formation of the corresponding p-toluenesulfonate followed by an unprecedented displacement with the lithium enolate of ethyl-3-pyridyl acetate N-oxide generated the required chiral trisubstituted methane. The displacement reaction proceeded with inversion of configuration and without loss of optical purity. Conversion of esters to the PDE4 inhibitor was accomplished via a one-pot deprotection, saponification and decarboxylation sequence in excellent overall yield.

From Bench to Pilot Plant: Sponsored by Teledyne Isco, Inc
9:00 AM-12:00 PM, Thursday, 17 March 2005 Convention Center -- Room 6C, Oral

Division of Medicinal Chemistry

The 229th ACS National Meeting, in San Diego, CA, March 13-17, 2005