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

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 Ph 2 Zn and the safety precautions taken to facilitate process scale-up are discussed.

Advances in Carbolithiation

“…Following this strategy, a concise and highly stereoselective synthesis of tetrasubstituted alkenes was reported, with particular application to the synthesis of the leading therapeutic agent for the treatment of estrogen-dependent breast cancer [55], (Z)-tamoxifen (Scheme 11.23) [56].…”

Diversification of pharmaceutical manufacturing processes: Taking the plunge into the non-PGM catalyst pool

“…In 2010, scientists at BMS developed a process taking advantage of the catalyst Ni(acac)2 to produce multikilogram quantities of alkenyl bromide 6 (Scheme 1), 56 a key intermediate for the synthesis of alkene derivative 7 that has attractive properties as estrogen agonist/antagonist which are desirable for the treatment of breast cancer. With a relatively high loading of the inexpensive Ni(acac)2 (25 mol%), carbometallation of but-1-ynylbenzene 5 with diphenylzinc/diethylzinc can proceed under moderate temperature, followed by bromination with N,N'-dibromo-5,5-dimethylhydantoin under well-defined conditions, yielding 6 in 65% isolated yield with high stereoselectivity (Scheme 1).…”

Recent advances in transition-metal-catalyzed intermolecular carbomagnesiation and carbozincation

“…Not only diphenylzinc reagent but also dimethyl- and diethylzinc reagents were employed. Chemists at the Bristol-Myers Squibb company developed a scalable synthesis of ( Z )-1-bromo-2-ethylstilbene ( 4b ), a key intermediate of a selective estrogen-receptor modulator, using the modified Knochel’s carbozincation method (Scheme 28) [101]. It is noteworthy that the modified nickel-catalyzed reaction could be performed at 20 °C to afford 57 kg of the corresponding phenylated product (58% yield) from 44 kg of 1-phenyl-1-butyne.…”