Methods for preparing 17-alkynyl-7-hydroxy steroids and related compounds
View Patent ↗The invention relates to processes for preparing 17-alkynyl-7-hydroxy-steroids, such as 17-Ethynyl-10R,13S-dimethyl 2,3,4,7,8R,9S, 10,11,12,13,14S,15,16,17-hexadecahydro-1H-cyclopenta[a]phenanthrene-3R, 7R,17S-triol (also referred to as 17α-ethynyl-androst-5-ene-3β,7β,17β-triol), that are essentially free of process impurities having binding activity at nuclear estrogen receptors.
1. A process for preparation of a 17α-alkynyl-androst-5-ene-3β, 7β, 17β-triol essentially free of steroid side-product(s) lacking an oxygen substituent at position 7 comprising the steps of
(a) contacting a suitably protected dehydroepiandrosterone with an oxidizing agent to directly introduce a ═O (ketone) functional group at position 7;
(b) contacting a suitably protected androst-5-en-7,17-dione-3β-ol with a reducing agent to convert the ═O (ketone) functional group at position 7 to hydroxyl predominantly in the β-configuration; and
(c) contacting an optionally suitably protected alkynyl anion with suitably protected androst-5-en-17-one-3β, 7β-diol to introduce an alkynyl substituent at position 17 predominantly in the α-configuration by addition of the alkynyl anion to the ═O (ketone) functional group at position 17
wherein the 17α-alkynyl-androst-5-ene-3β, 7β,17β-triol obtained from step (c) is essentially free of binding activity at nuclear sex steroid receptors or is essentially free of an estrogenic 17α-alkynyl-androst-5-ene-3β, 17β-diol compound without purification to remove steroid side-product(s) lacking an oxygen substituent at position 7.
2. The process of claim 1 wherein the 17α-alkynyl-androst-5-ene-3β,7β,17β-triol is 17α-ethynyl-androst-5-ene-3β, 7β, 17β-triol.
3. The process of claim 1 wherein the suitably protected dehydroepiandrosterone has the structure of
wherein R 1 is —H, C 1-6 alkyl, C 3 - 6 cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl.
4. The process of claim 1 wherein the suitably protected androst-5-en-7,17-dione-3β-ol has the structure of
wherein R 1 is —H, C 1 - 6 alkyl, C 3 - 6 cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl.
5. The process of claim 1 wherein the suitably protected androst-5-en-17-one-3β,7β-diol has the structure of
wherein each R 3 and each R 4 independently are C 1-6 alkyl or aryl.
6. The process of claim 5 wherein the suitably protected alkynyl anion has the structure of M—C≡C—Si(R 5 ) 3 wherein R 5 independently are C 1-6 alkyl or aryl and M is a Group I, Group II or transition metal.
7. The process of claim 6 wherein M is Li, Mg or Zn.
8. The process of any one of claims 3 , 4 5 and 6 wherein R 1 is —CH 3 , R 3 and R 4 is —CH 3 or R 5 is CH 3 .
9. A process for preparation of 17α-ethynyl-androst-5-ene-3β,7β,17β-triol essentially free of 17α-ethynyl-androst-5-ene-3β,17β-diol comprising the steps of
(a) contacting suitably protected androst-5-en-7,17-dione-3β-ol having the structure of
with a reducing agent to convert the ═O (ketone) functional group at position 7 to hydroxyl predominantly in the β-configuration;
(b) converting the ketal functional group at position 17 in the product from step (a) to the ═O (ketone) functional group; and
(c) converting the acetoxy group at position 3 to 3β-hydroxy or
(b′) converting the acetoxy group at position 3 in the product from step (a) to 3β-hydroxy; and
(c′) converting the ketal group at position 17 to the ═O (ketone) functional group; and
(d) converting the hydroxyl groups at positions 3βand 7βin the product from steps (b) and (c) or steps (b′) and (c′) having the structure of
to Me 3 SiO— groups; and
(e) contacting the product from step (d) with lithium trimethylsilyl-acetylide to introduce an ethynyl substituent at position 17 predominately in the α-configuration by addition of the acetylide to the ═O (ketone) functional group at position 17;
(f) contacting the reaction product from step (e) having the structure of
with an aqueous acid to replace —SiMe 3 with —H,
whereby 17α-ethynyl-androst-5-ene-3β,7β,17β-triol is obtained essentially free of 17α-ethynyl-androst-5-ene-3β,17β-diol.
10. The process of claim 1 or 9 comprising the additional step of purifying 17α-alkynyl-androst-5-ene-3β,7β,17β-triol or 17α-ethynyl-androst-5-ene-3β,7β,17β-triol product by recrystallization.
11. The process of claim 10 wherein the 17α-alkynyl-androst-5-ene-3β,7β,17β-triol product is purified by recrystallization from methanol-water.
12. The process of claim 11 wherein the 17α- alkynyl-androst-5-ene-3β,7β,17β-triol is 17α-ethynyl-androst-5-ene-3β,7β,17β-triol.