Synthesis of 19-nor vitamin D compounds
AssigneeWisconsin Alumni Research Foundation
InventorsHector F. DeLuca, Heinrich K. Schnoes, Kato L. Perlman, Rolf E. Swenson
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Abstract
A convergent synthesis of 19-nor-vitamin D compounds, specifically 19-nor-1.alpha.,25-dihydroxyvitamin D.sub.3, is disclosed. The synthesis can also readily be utilized for preparing other 1.alpha.-hydroxylated 19-nor-vitamin D compounds. The key step in the synthesis is a suitable application of Lythgoe's procedure i.e. a Horner-Wittig reaction of the lithium anion of a phosphine oxide with a Windaus Grundmann ketone to give, after any necessary deprotection, the desired 19-nor-vitamin D compound.
Claims5
A method of making 19-nor-vitamin D compounds which comprises the steps of converting an ester having the structure
- where X.sup.1 and X.sup.2 are each a hydroxy-protecting group and where X.sup.3 is hydrogen or hydroxy, to a ketone of the structure ##STR9## where X.sup.1, X.sup.2 and X.sup.3 are as defined above, by ester reduction and diol cleavage, condensing said ketone in the presence of a base to obtain an ester having the structure ##STR10## where X.sup.1, X.sup.2 and X.sup.3 are as defined above, with the proviso that when X.sup.3 in the above ketone is a hydroxy function, that hydroxy function be first protected with a hydroxy-protecting group prior to the base-promoted condensation reaction, reducing said ester to obtain the corresponding alcohol having the structure ##STR11## where X.sup.1 and X.sup.2 are as defined above, with the proviso that if X.sup.3 in the above ester is a hydroxy function or a protec removed by reaction with a hydrogen radical source and a radical initiator prior to the above reduction reaction, converting said alcohol to a derivative having the structure ##STR12## where Y.sup.1 is halogen or an O-sulfonyl group, and where X.sup.1 and X.sup.2, which may be the same or different, are hydroxy-protecting groups,
- converting said derivative to the phosphine oxide ##STR13## where X.sup.1 and X.sup.2 are as defined above by treatment of said derivative with a metal diphenylphosphide and subsequent peroxide oxidation;
- reacting the phosphine oxide with a ketone of the structure ##STR14## where R is any desired side chain to produce a 19-nor-vitamin D compound of the structure ##STR15## wherein X.sup.1 X.sup.2 and R as defined above, and subsequently removing the hydroxy-protecting groups.
Dependencies are inferred from the claim text.