The Upjohn Co.

Bridge Organics Co.

Verlan H Van Rheenen

Edward J Hessler

James B Heather

Joseph M Timko

Kenneth P Shephard

Dae Y Cha

A novel process for making estra-4,9(10)-diene-3,17-dione steroids from readily available 19-nor-androst-4-ene-3-one steroids by a straightforward three-step process. Products of this process are important intermediates in the preparation of biologically active substances.

Process for making estra-4,9(10)-diene steroids

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

Cyanohydrin process

The process of the present invention uses an amine to prepare monolithium acetylide which is sufficiently stable at up to 0.degree. and yet is sufficiently reactive to react with 16-substituted-17-keto steroids producing the useful 17.alpha.-ethynyl-17.beta.-hydroxy-16-substituted steroids.

Process to prepare stabilized monolithium acetylide

The present invention relates to processes for the conversion of a 3-protected steroidal 17-ketone to a 17-spiro-.gamma.-lactone having the appropriate 17-stereochemistry for spironolactone. Novel intermediates (II, II', II', II'', II.sup.a, II.sup.b, II.sup.c, II.sup.d, II.sub.x, II'.sub.x and II'.sub.x) are also disclosed.

Spironalactone process

.DELTA..sup.4 -3-keto, .DELTA..sup.1,4 -3-keto and 3.beta.-hydroxy 17-keto steroids (I) are transformed into the corresponding 16-.beta.-methyl-17-keto steroids (IV) by first activating the C-16 position, then methylating. By protecting the C-3 position of the .DELTA..sup.4 -3-keto and 3.beta.-hydroxy steroids the yields are greatly increased.

16.beta.-Methyl steroid process

17.alpha.-Hydroxy-6,16-dimethylenepregn-4-ene-3,20-dione simultaneously isomerized and acylated to 17.alpha.-hydroxy-6-methyl-16-methylenepregna-4,6-diene-3,20-dione 17-acetate.

Isomerization-acylation process

The process of the invention permits acylation of hindered steroidal tertiary alcohols without the undesirable side reactions which accompany previously known acylation reactions.

Phosphate catalyzed acylation of steroidal tertiary alcohols

A process for preparing optically active 2(S) or 2(R) tricyclic lactone glycols of the formula ##STR1## wherein W is 1-pentyl, 1-pent-cis-2-enyl, or 1-pent-2-ynyl. This process is useful for preparing stereospecifically prostaglandins having pharmacological utility.

Process for preparing a 2(R) or 2(S) tricyclic lactone glycol

This invention discloses a general process for the production of corticoids from androstenes. This invention provides an economically viable alternative synthesis of 17.alpha.-hydroxyprogesterones and the corticoids.

Process for the preparation of 17.alpha.-hydroxyprogesterones and

Process for preparing lactones of the formula ##SPC1## Wherein G is R.sub.9, 1-hydroxyhexyl, or 1-hydroxy-cis-3-hexenyl, wherein R.sub.9 is hydrogen, alkyl of one to 12 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with one, 2, or 3 alkyl of one to 4 carbon atoms, inclusive; wherein M is hydrogen or a blocking group; wherein R.sub.1 is hydrogen, alkyl of one to 12 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with one, 2, or 3 chloro or alkyl of one to 4 carbon atoms, inclusive, or ethyl substituted in the .beta.-position with 3 chloro, 2 or 3 bromo, or 1, 2, or 3 iodo; and wherein .about. indicates attachment in alpha or beta configuration. The lactones are useful intermediates in preparing prostaglandins having pharmacological utility.

Lactone intermediates

Tricyclic lactone glycol sulfonates of the formula ##SPC1## Or ##SPC2## Wherein R.sub.3 is alkyl of one to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with one or 2 halo or alkyl of one to 4 carbon atoms, inclusive; Wherein R.sub.4 is alkyl of one to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, or phenyl substituted with one or 2 halo or alkyl of one to 4 carbon atoms, inclusive; and Wherein W is 1-pentyl, 1-pent-cis-2-enyl, or 1-pent-2-ynyl. These compounds are useful in preparing stereo-specifically prostaglandins having pharmacological utility.

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Portage, MI, United States of America

Verlan H Van Rheenen