Development of a practical and large scale synthesis of a Statin Intermediate via Horner-Wittig olefination

ORGN 13

Bin Zheng, bin.zheng@bms.com, Melissa Marchetti, Jason Zhu, Xinhua Qian, David Kacsur, Otute Akiti, Joydeep Kant, and David Kronenthal. Process Research and Development, Bristol-Myers Squibb Pharmaceutical Research Institute, 1 Squibb Drive, P.O. Box 191, New Brunswick, NJ 08903-0191
In our research and development program for the preparation of a potent HMG-CoA inhibitor, we carried out extensive studies of the olefination of Kaneka aldehyde (2) to prepare the trans-olefin, 3. While the classic Wittig reaction provided this intermediate with poor trans/cis selectivity, the Horner-Wadsworth-Emmons modification resulted in better stereoselectivity albeit in low yield. The Horner-Wittig reaction of diphenyl phosphine oxide 1 afforded exclusively the desired trans-olefin in good yield. Subsequent understanding of the effects of solvent, base, additives and temperature led to a process that was demonstrated on 21 kg scale. The desired intermediate was obtained in 75% yield with excellent quality. Reaction kinetics, mechanism and the study of impurity formation will be described as well.

 

Combinatorial, Parallel, and Process Chemistry
8:00 AM-11:40 AM, Sunday, August 19, 2007 BCEC -- 253 A/B/C, Oral

Division of Organic Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007