Organic Process Research & Development 2010, 14, 1147–1152
Process Development for a Large Scale Stereoselective Synthesis of (Z)-(1-Bromobut-1-ene-1,2-diyl)dibenzene, a Key Intermediate of a Selective Estrogen Receptor Modulator Reginald O. Cann,* Robert E. Waltermire, Jihchin Chung,† Matthew Oberholzer,‡ Jiri Kasparec,§ Yun K. Ye, and Robert Wethman Chemical Process Research and DeVelopment, Pharmaceutical DeVelopment R & D, Bristol-Myers Squibb Company, One Squibb DriVe, New Brunswick, New Jersey 08903-0191, U.S.A.
Abstract: Two efficient large scale syntheses of (Z)-(1-bromobut-1-ene-1,2diyl)dibenzene are described. The first is a three-step synthetic sequence from trimethyl(phenylethynyl)silane in 63% overall yield. The key transformations involved the stereospecific carbometalation reaction of trimethyl(phenylethynyl)silane followed by a bromination. Subsequent Miyaura-Suzuki coupling with phenylboronic acid and transformation of the vinyltrimethylsilane to a vinyl bromide afforded the target. In an improved synthesis, a stereoselective nickel acetylacetonate catalyzed PhZnEt addition to but-1-ynylbenzene, generated an organozincate intermediate, which was brominated in 58-62% overall yield. A key feature of this work was the production of highly regiopure olefin. The optimization effort that resulted in the utilization of substoichiometric amounts of Ph2Zn and the safety precautions taken to facilitate process scale-up are discussed.
Introduction Breast cancer is the most common malignancy in women and it is estimated that nearly one in nine women will develop the disease within their lifetimes.1 The current therapy for these patients include selective estrogen receptor modulators (SERMs)2 with tamoxifen being the most widely prescribed medication for estrogen receptor (ER)-positive breast cancer.3 Tamoxifen is a partial estrogen agonist/antagonist SERM to which nearly 50% of hormone-induced breast cancer patients respond, but most patients eventually relapse with tamoxifen* To whom correspondence should be addressed. Telephone (732) 227-7964. E-mail:
[email protected]. † Current address: Department of Chemical Development, Boehringer Ingelheim Pharmaceutical, Inc., 900 Ridgebury Road, Ridgefield, CT 06877. ‡ Current address: DuPont Crop Protection, Stine-Haskell 1090 Elkton Rd., Newark, DE 19711. § Current address: Department of Medicinal Chemistry, Respiratory and Inflammation Centre of Excellence for Drug Discovery, GlaxoSmithKline Parmaceuticals, 709 Swedeland Road, King Of Prussia, PA 19406.
(1) (a) DeGregorio, M. W.; Weibe, V. J. Tamoxifen and Breast cancer; Yale University Press: New Haven, CT, 1994. (b) Cancer Facts and Figures; American Cancer Society: New York, 1997. (2) (a) For recent reviews on SERMs: Jordan, V. C. J. Med. Chem. 2003, 46, 883–908. (b) Jordan, V. C. J. Med. Chem. 2003, 46, 1081–1111. (c) Meegan, M. J.; Lioyd, D. G. Curr. Med. Chem. 2003, 10, 181– 210. (d) Bryant, H. U. Endocrine and Metabolism Disorders 2002, 3, 231–241. (3) (a) Lerner, H. J.; Band, P. R.; Israel, L.; Leund, B. S. Cancer Treat. Rep. 1976, 60, 1431–1435. (b) Lerner, L. J.; Jordan, V. C. Cancer Res. 1990, 50, 4177–4189. (c) Howell, A.; Dodwell, D. J.; Anderson, H.; Redford, J. Ann. Oncol. 1992, 3, 611–617. 10.1021/op100112r 2010 American Chemical Society Published on Web 09/02/2010
resistant tumors.4 Moreover, due to the estrogen agonistic activity of tamoxifen, postmenopausal patients undergoing longterm treatment with tamoxifen are prone to increased incidence of endometrial hyperplasia cancer.5 There is, therefore, a substantial unmet medical need for the development of a pharmaceutical agent that inhibits estrogen induced metastatic breast cancer without stimulating uterine endometrial tissue growth. (Z)-3-(4-((Z)-1,2-Diphenylbut-1-enyl)phenyl)acrylic acid (1), is a SERM that was originally discovered by Glaxo-Wellcome6 and was later shown to be effective against estrogen induced cancers in animal studies. It was also shown to have a low potential to induce endometrial cancer growth. Further work demonstrated that 1 has attractive estrogen agonist and antagonist properties desirable for the treatment of breast cancer patients that have failed tamoxifen treatment.7 Moreover, the low toxicity and the potent activity makes 1 a promising drug for the treatment of other hormone induced diseases. As part of the development of a scalable synthesis of 1,8,9 a key issue was the control of isomeric impurities. The specification for the (E)-isomer 2, a known estrogen agonist in rats,10 was set at
