The Preparation of (1α,3β)-3-Hydroxycholestane-4,6-diene- 1,25-diol Diacetate from a 5,7-Diene Precursor:  A New Method for the Synthesis of Heteroannular Dienes

Abstract

Starting from the 7alpha-bromide 5a, a regioselective synthesis of (1alpha,3beta)-3-hydroxycholestane-4,6-diene-1,25-diol diacetate (2) is described. The preparative removal of contaminating 5,7-diene 9 was accomplished by the formation of the corresponding Diels-Alder adduct 11. Acetylation of the diacetate 2 followed by acid-catalyzed elimination and rearrangement yielded styrene 13.

Selective Crystallization of an Allylic 7α-Bromide: A Facile Synthesis of (1α,3β)-3-Hydroxycholeste-5,7-diene-1,25-diol Diacetate

“…Within the Process Research and Development department at Bristol-Meyers Squibb, Kiau and others have recently reported on the experimental development of an efficient crystallization procedure which utilized crystallization-induced dynamic resolution to isolate a chiral α-bromo carboxylic acid, and in this work as well, tetrabutylammonium bromide was the soluble halide source . We have shown that the use of tetrabutylammonium iodide is an effective way to alter the ratios of halides . The requirement for this soluble halide source is that it can alter the ratio of halides, and removal of the 7α-bromide 6a by crystallization will perturb the equilibrium.…”

“…For the Roche patented process in which the three hydroxy groups were protected as acetates, the yield of the crude bromide from the triacetate is quantitative, and the overall yield from the crude bromide to the 5,7-diene triacetate is 64% . In addition to the dehydrobromination step, this process includes an acid-catalyzed elimination to convert the 4,6-diene triacetate to less polar products. , Because of this transformation, a chromatographic purification of the 5,7-diene triacetate is possible . For comparative purposes, the TBDMS process yields a 5,7-diene precursor 6a at essentially the same yield without a chromatographic separation.…”

“…During the course of chemical development studies for the synthesis of (1α,3β)-3-hydroxycholeste-5,7-diene-1,25-diol diacetate ( 1 ), a process was required in which there was control over the formation of the undesired 4,6-diene impurity and in which only the diacetate ( 1 ) would be formed (Scheme ). In the original work by Uskokovíc, these requirements were met by an acid-catalyzed conversion of the 4,6-diene triacetate to less polar molecules, which could be readily removed by chromatography, and by a selective saponification of the 5,7-diene triacetate.…”

Steroids: partial synthesis in medicinal chemistry

“…The preparation of 1a,25-diacetoxy-3b-hydroxycholesta-4,6-diene 42 from a 5,7-diene has been reported. 110 Efficient methods for the separation of lanosterol and dihydrolanosterol from commercial mixtures and for the preparation of epimerically pure derivatives have been described. 119 The side chain lactam 44 has been reported 120 to be a vitamin D antagonist.…”

The Boulton–Katritzky rearrangement of isocarboxazid

“…The melding of a mechanistic knowledge of impurity pathways coupled with solid process development has led to a generalized approach for statistical process control and control of impurity formation [2]. The necessity to characterize impurities and to synthesize quantities for analytical method development has afforded new synthetic methodology [3]. When an understanding of reactivity is required to elucidate potential degradation pathways in the drug product, experimental and computational methods have proven to be useful to accomplish this goal [4].…”