The Upjohn Co.

Verlan H VanRheenen

Joel E Huber

Edward J Hessler

Disclosed is a process for the production of a .DELTA..sup.17(20) -steroid of the formula ##STR1## which comprises starting with a 16-unsaturated corticoid of the formula ##STR2## and contacting the 16-unsaturated corticoid (I) with a methylating agent in the presence of a copper catalyst and a silylating agent.

16.alpha.-methylation process

C.sub.16 -unsaturated corticoids are readily transformed to the corresponding 16.alpha.-methyl-17.alpha.-hydroxy corticoids by use of a .DELTA..sup.17 (.sup.20)-20-silyl ether.

C.sub.16 -unsaturated corticoids are readily transformed to the corresponding 16.alpha.-methyl-17.alpha.-hydroxy corticoids by use of a .DELTA.17(20)-20-silyl ether.

16.alpha.-methyl-17.alpha. 20-epoxysteroid and process

Using cyanohydrin intermediates, 17-keto steroids are transformed to corticoids and 17.alpha.-acyl progesterones.

11.beta.,17.alpha.-Dihydroxy-17.beta.-cyano-androstanes

16.alpha.-methylated.DELTA.17(20)-corticoids

The process of the present invention transforms 16-methylene-17-keto steroids (I) to the corresponding 17.alpha.-ethynyl-17.beta.-hydroxy-16-methylene steroids (II).

Ethynylation of 16-methylene-17-keto steroids

Cyanohydrin process

16-Methylene-17-keto steroids (III) are transformed to the corresponding 16-methylene-17.alpha.-hydroxyprogesterones (VII) which are intermediates useful in the production of betamethasone, diflorasone diacetate and melengesterol acetate.

16-Methylene-17.alpha.-hydroxy-progesterones

A process is disclosed for the production of 17-keto-16-methylene steroids (III) from the corresponding readily available 17-keto steroid (I) via a novel intermediate (II).

Process for preparing 16-methylene steroids

17-Keto steroids (I) in their protected form (IIa or IIb) are reacted with a metalated olefin (VI) to give a 21-aldehyde (IV) which is readily transformed to a 16-unsaturated pregnane (V) which is useful in the production of commercially important substituted corticoids.

Synthesis of 16-unsaturated pregnanes from 17-keto steroids

2-Aryl-C.sub.2 to C.sub.5 -alkanoic acids and esters thereof are prepared by heating a 2-(2-oxo-3-cyclohexenyl)-alkanoic acid or ester derivative in the presence of a sulfonic acid or a phosphonic acid at 75.degree. C. to 130.degree. C. while providing a means for removing water from the reaction mixture. In the process new butenolide derivative intermediates have been discovered. Alternatively, the 2-aryl-C.sub.2 to C.sub.6 -alkanoic acids can be prepared from the butenolides by forming a mixture of the 2-(2-oxo-3-cyclohexenyl)-alkanoic acid with acetic anhydride in the presence of an acid scavenging base, allowing the mixture to stand for a time sufficient to form an acetate intermediate, heating the resulting mixture to about 75.degree. C. to about 130.degree. C. to form the betenolide intermediates. Thereafter these intermediates can be heated with sulfonic or phosphonic acid as above while removing water to form the 2-aryl-C.sub.2 to C.sub.6 -alkanoic acid or adding a carboxylic acyl halide and water to form acetic acid and mineral acid in the mixture, and this resulting mixture can be heated to 75.degree. C. to 130.degree. C. for a time sufficient to form 2-aryl-C.sub.2 to C.sub.6 -alkanoic acid products which have a variety of uses.

Growing community of inventors

Portage, MI, United States of America

Verlan H VanRheenen