Process and intermediates for the synthesis of Vitamin D.sub.3 metabolites and chenodeoxycholic acid
AssigneeHoffmann-La Roche Inc.
InventorsAndrew D. Batcho, Milan R. Uskokovic, Peter M. Wovkulich
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Abstract
The present disclosure is directed to a process for the synthesis of chenodeoxychloic acid, 25-hydroxycholesterol and 1.alpha.,25-dihydroxycholesterol from 17-keto steroids. A cholic acid side chain is stereospecifically introduced by reaction of the appropriate 17-keto steroid with ethyltriphenylphosphonium halides to produce the 17-ethylidene derivative which is allowed to react with acrylic acid esters or propiolic acid esters followed by hydrogenation.
Claims43
A process for the synthesis of chenodeoxycholic acid as characterized by the formula ##STR35## which process comprises the steps of (a) reacting a compound of the formula ##STR36## with an ethyltriphenylphosphonium halide in the presence of strong base to yield a compound of the formula ##STR37## (b) reacting the reaction product of step (a) with an acylating agent in the presence of weak base at temperatures ranging from 0.degree. to 150.degree. C. so as to yield compounds of the formula ##STR38## wherein R.sup.1 and R.sup.2 are acyloxy;
- (c) reacting the reaction product of step (b) with an acrylic acid ester in the presence of Lewis acid catalysts selected from the group consisting of lower alkyl aluminum dihalides and aluminum trihalides in weak base in an inert solvent at temperatures ranging from -20.degree. to 45.degree. C. so as to yield a compound of the formula ##STR39## wherein R.sup.1 and R.sup.2 are acyloxy;
- and R.sup.3 is lower alkyl;
- (d) reacting the reaction product of step (c) with hydrogen in the presence of a conventional hydrogenation catalyst thereby reducing the .DELTA..sup.16 double bond so as to yield a compound of the formula ##STR40## wherein R.sup.1 and R.sup.2 are acyloxy;
- and R.sup.3 is lower alkyl;
- (e) reacting the reaction product of step (d) with aqueous base at temperatures ranging from room temperature to reflux temperature so as to yield chenodeoxycholic acid as characterized by the formula ##STR41##
A process for the synthesis of compounds of the formula ##STR42## wherein R.sup.1' is hydrogen or hydroxy;
- and R.sup.3 is lower alkyl, which comprises the steps of
- (a) reacting a compound of the formula ##STR43## wherein R.sup.1' is hydrogen or hydroxy, with an ethyltriphenylphosphonium halide in the presence of strong base to yield a compound of the formula ##STR44## wherein R.sup.1' is hydrogen or hydroxy;
- (b) reacting the reaction product of step (a) with acrylic acid esters in an inert solvent at temperatures ranging from -20.degree. to 45.degree. C. in the presence of Lewis acids selected from the group consisting of lower alkyl aluminum dihalides and aluminum trihalides in weak base to yield compounds of the formula ##STR45## wherein R.sup.1' is hydrogen or hydroxy;
- and R.sup.3 is lower alkyl, or, alternatively;
- (c) reacting the reaction product of step (a) with propiolic acid esters in an inert solvent at temperatures ranging from -20.degree. to 45.degree. C. in the presence of Lewis acids selected from the group consisting of lower alkyl aluminum dihalides and aluminum trihalides in weak base to yield compounds of the formula ##STR46## wherein R.sup.1' is hydrogen or hydroxy;
- (d) reacting the reaction product of step (a) or (b) with hydrogen in an inert solvent in the presence of a hydrogenation catalyst at temperatures ranging from 0.degree. to 48.degree. C. to yield compounds of the formula ##STR47## wherein R.sup.1' is hydrogen or hydroxy;
- and R.sup.3 is lower alkyl.
A process for the synthesis of compounds of the formula ##STR48## wherein R.sup.1" is hydrogen, hydroxy or acyloxy;
- and R.sup.2" is hydroxy or acyloxy,
- which comprises the steps of
- (a) reacting a compound of the formula ##STR49## wherein R.sup.1 is hydrogen, hydroxy or acyloxy;
- and R.sup.2 is hydroxy or acyloxy,
- with acrylic acid esters in an inert solvent at temperatures ranging from -20.degree. to 45.degree. C. in the presence of Lewis acids selected from the group consisting of lower alkyl aluminum dihalides and aluminum trihalides in weak base to yield compounds of the formula ##STR50## wherein R.sup.1" is hydrogen, hydroxy or acyloxy;
- R.sup.2" is hydroxy or acyloxy;
- and R.sup.3 is lower alkyl;
- or, alternatively;
- (b) reacting the reaction product of step (a) with propiolic acid esters in an inert solvent at temperatures ranging from -20.degree. to 45.degree. C. in the presence of Lewis acids selected from the group consisting of lower alkyl aluminum dihalides and aluminum trihalides in weak base to yield compounds of the formula ##STR51## wherein R.sup.1" is hydrogen, hydroxy or acyloxy;
- R.sup.2" is hydroxy or acyloxy;
- and R.sup.3 is lower alkyl;
- (c) reacting the reaction product from step (a) or (b) with hydrogen in an inert solvent in the presence of a hydrogenation catalyst at temperatures ranging from 0.degree. to 40.degree. C. to yield compounds of the formula ##STR52## wherein R.sup.1" is hydrogen, hydroxy or acyloxy;
- R.sup.2" is hydroxy or acyloxy;
- and R.sup.3 is lower alkyl.
Compounds of the formula ##STR53## wherein R.sup.1' is hydrogen or hydroxy;
- and R.sup.3 is lower alkyl.
Compounds of the formula ##STR54## wherein R.sup.1' is hydrogen or hydroxy;
- and R.sup.3 is lower alkyl.
Compounds of the formula ##STR55## wherein R.sup.1" is hydrogen, hydroxy or acyloxy;
- R.sup.2" is hydroxy or acyloxy;
- and R.sup.3 is lower alkyl.
Compounds of the formula ##STR56## wherein R.sup.1" is hydrogen, hydroxy or acyloxy;
- R.sup.2" is hydroxy or acyloxy;
- and R.sup.3 is lower alkyl.
(Z)-3.alpha.,5.beta.,7.alpha.-pregn-17(20)-ene-3,7-diol as characterized by the formula ##STR57##
(Z)-3.alpha.,5.beta.,7.alpha.-pregn-17(20)-ene-3,7-diol diacetate as characterized by the formula ##STR58## wherein R.sup.1 and R.sup.2 are acyloxy.
3.alpha.,5.beta.,7.alpha.-3,7-diacetyloxychol-16-en-24-oic acid methyl ester as characterized by the formula ##STR59## wherein R.sup.1 and R.sup.2 are acyloxy.
Dependencies are inferred from the claim text.