It is known that the physiological actions of vitamin D, namely the maintenance of calcium and phosphate homeostasis and the proper mineralization of bone, is dependent on the in vivo metabolism of the vitamin to hydroxlyated derivatives. Particularly important are 1-hydroxylated vitamin D metabolites, and one of these, 1.alpha.,25-dihydroxyvitamin D.sub.3, is indeed generally regarded as the physiologically active hormonal form of vitamin D.sub.3. This compound and certain of its 1-hydroxylated structural analogues, e.g. 1.alpha.-hydroxyvitamin D.sub.3, 1.alpha.-hydroxyvitamin D.sub.2 and 1.alpha.,25-dihydroxyvitamin D.sub.2, and related compounds are therefore of great interest as therapeutic agents, being useful for the treatment and prophylaxis of various human and animal diseases related to calcium imbalance. As a result, there has been much effort directed towards the synthesis of such 1-hydroxyvitamin D compounds, and a variety of useful procedures are documented in the patent and other literature.
Of relevance to the present application is the synthetic method described by Paaren et al. in J. Org. Chem. 45, 3253 (1980) and DeLuca et al. in U.S. Pat. Nos. 4,195,027 and 4,260,549 which disclosures relate to the preparation of 1.alpha.-hydroxyvitamin D derivatives from vitamin D compounds by hydroxylation at carbon 1. Briefly, this method involves the tosylation of a vitamin D compound at the C-3-hydroxy group, followed by tosyl displacement with formation of a 3,5-cyclovitamin D derivative, and subsequent oxidation of that intermediate to a 1.alpha.-hydroxy-3,5-cyclovitamin D which is then converted to the C-1-acyloxy derivative and subsequently solvolyzed under acid catalysis to obtain a mixture of the 5,6-cis- and 5,6-trans-1.alpha.-hydroxyvitamin D 1-O-acylates. Alternatively, the free 1.alpha.-hydroxy-3,5-cyclovitamin D intermediate can be directly solvolyzed in an acid medium (e.g. a low-molecular-weight organic acid, such as formic or acetic acid) to obtain a mixture of the 5,6-cis- and 5,6-trans-1.alpha.-hydroxy-vitamin D 3-O-acylates, where the acyl group originates, in this case, from the said medium used.
It will be noted, that the methods taught by the prior art produce the 1- or 3-O-acyl derivatives of the 1.alpha.-hydroxyvitamin D compounds, and since the free (unprotected) 1.alpha.-hydroxyvitamins are generally the desired products, these acyl groups must be removed by a subsequent hydrolysis or reduction step.
USPTO Backgrounds
USPTO Backgrounds