Syntheses estrogen receptor modulator

In conclusion, we have developed an efficient asymmetric synthesis of the selective estrogen receptor modulator 1. This process was scaled up in the pilot plant for the early steps in the synthetic route and in kilo laboratory scale for the later steps and finally 4 kg of the final product was made. The key process development and project support milestones are summarized below ... 

Pigeon P, Top S, Vessieres A, Huche M, Hillard EA, Salomon E, Jaouen G (2005) Selective estrogen receptor modulators in the ruthenocene series. Synthesis and biological behavior. J Med Chem 48 2814-2821... 

Top S, Kaloun EB, Vessieres A, Lai os I, Leclercq G, Jaouen G (2002) The first titanocenyl dichloride moiety vectorised by a selective estrogen receptor modulator (SERM). Synthesis and preliminary biochemical behavior. J Organomet Chem 643-644 350-356... 

Renaud J, Bischoff SF, Buhl T, Floersheim P, Fournier B, Geiser M, Halleux C, Kallen J, Keller H, Ramage P. Selective estrogen receptor modulators with conformationally restricted side chains Synthesis and structure-activity relationship of ERalpha-selective tetrahydroisoquinoline ligands. J Med Chem 2005 48 364-79. 

I The clinical uses of anastrozole (decreases estrogen synthesis), danazol (decreases ovarian steroid j synthesis), domiphene (decreases feedback inhibition), and the selective estrogen-receptor modulators j tamoxifen and raloxifene are considered. 

A Bischler-Mohlau indole synthesis was also pivotal in constructing the indole ring of bazedoxifene acetate (Viviant), Wyeth s novel and highly selective indole estrogen. It is a selective estrogen receptor modulator (SERM) for the treatment of and prevention of osteoporosis. It was found... 

Meegan, M. J., Hughes, R. B., Lloyd, D. G., Williams, D. C., Zisterer, D. M. (2001). Flexible estrogen receptor modulators, design, synthesis, and antagonistic effects in human MCF-7 breast cancer cells. J. Med. Chem., 44,1072-1084. 

U.A. Kshirsagar, R. Parnes, H. Goldshtein, R. Oftr, R. Zarivach, D. Pappo, Aerobic iron-based cross-dehydrogenative coupling enables efficient diversity-oriented synthesis of coumestrol-based selective estrogen receptor modulators, Chem. Eur. J. 19 (2013) 13575-13583. 

A convergent synthesis of SERM 2, a selective estrogen receptor modulator is described. This approach incorporates the acylation of 6-methoxy-2-tetralone with [4-[2-(l-piperidinyl)ethoxy]benzoyl]chloride as a key step. In streamlining the process, 6-methoxy-2-tetralone was prepared in situ from 4-methoxyphenyl acetic acid. 

In summary, a highly convergent, practical and efficient synthesis of the selective estrogen receptor modulator SERM 2 is now available that is suitable for pilot plant preparation. Key to the success of the process is the generation of 6-methoxy-2-tetralone. The developed laboratory synthesis is a seven step process with an overall yield of >27%. 

This coupling reaction of alkenylgermanes can be applied to the synthesis of estrogen receptor modulator tamoxifen (112), which is used in the clinical treatment of estrogen-dependent breast cancer (Fig. 40). The benzoyl triethylgermane (108) is olefinated with ynolate to give the aUcenylgermane 109, which is coupled... 

Synthesis of an Estrogen Receptor Modulator The selective estrogen receptor modulator 14... 

Song ZJ, King AO, Waters MS, Lang F, Zewge D, Bio M, Leazer Jr.JL, Javadi G, Kassim A, Tschaen DM, Reamer RA, Rosner T, Chilenski JR, Mathre DJ, Volante RP, liflyer R. An efficient asymmetric synthesis of an estrogen receptor modulator by sulfoxide-directed borane reduction. Proc. Natl. Acad. Sci. USA 2004 101 5776-5781. 

The dihydrobenzoxathiin 408, a potent selective estrogen receptor alpha modulator, is metabolized to the bridged dibenzo[, 4]thiopyran derivative 409. It seems logical to assume that 409 is formed by initial cleavage of the O-C bond followed by an intramolecular acylation to generate the thiopyran ring. A 19-step total synthesis from resorcinol confirmed the structure of 409 (Equation 115) <20050L411>. 

Coronary heart disease and atherosclerosis are major contributors to morbidity and mortality in the United States and other developed countries. Epidemiological studies suggest that decreased mortality from coronary heart disease is associated with moderate consumption of alcohol, and especially of red wine [7], Numerous studies indicate that resveratrol inhibits platelet aggregation [8-10, 12, 16, 54, 55], alters eicosanoid synthesis [15, 55], modulates lipoprotein mechanisms [14, 56-58], inhibits vascular smooth muscle cell proliferation [59], and acts as an estrogen receptor agonist [60]. On the other hand, at least one earlier study indicated that it promoted atherosclerotic development, rather than protected against it, by a mechanism that appeared to be independent of observed... 

Huffman MA, Rosen JD, Farr RN, Lynch JE. Synthesis of a selective estrogen receptor (3-modulator via asymmetric phase-transfer catalysis. Tetrahedron 2007 63(21) 4459-4463. 

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