METHOD FOR PREPARING SUBSTITUTED 3,7-DIHYDROXY STEROIDS
The invention relates to a 17α-alkynyl-androst-5-ene-3β,7β,17β-triol compound essentially free of steroid side-product lacking an oxygen substituent at position 7 and processes for preparing the same.
1 . A 17α-alkynyl-androst-5-ene-3β,7β,17β-triol compound essentially free of steroid side-product lacking an oxygen substituent at position 7, made by a process comprising the steps of,
(a) contacting a compound having the structure
with a reducing agent to convert the ═O functional group at position 7 to hydroxy predominantly in the β-configuration, wherein R 1 is —H, C 1-6 alkyl, C 3-6 cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl and R 2 is —H, C 1-6 alkyl or aryl;
(b) converting the ═NOR 2 group at position 17 in the reaction product from step (a) to a ═O group to obtain a 7β-hydroxy-17-one compound;
(c) converting the —OC(O)R 1 group at position 3 of the 7β-hydroxy-17-one compound to a 3β-hydroxy derivative of the 7β-hydroxy-17-one;
(d) converting the hydroxy groups at positions 3 and 7 in the 3β-hydroxy derivative of the 7β-hydroxy-17-one compound from step (c) to (R 3 ) 3 SiO— groups, wherein each R 3 independently is C 1-6 alkyl or aryl; and
(e) contacting the reaction product of step (d) with an compound having 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, wherein 17α-alkynyl-androst-5-ene-3β,7β,17β-triol essentially free of 17α-alkynyl-androst-5-ene-3β,17β-diol is obtained.
2 . The compound of claim 1 , wherein R 1 is C 1-6 alkyl or phenyl.
3 . The compound of claim 2 , wherein R 1 is —CH 3 .
4 . The compound of claim 2 , wherein R 1 and R 2 are —CH 3 .
5 . The compound of claim 1 , wherein M is Li, Mg or Zn.
6 . The compound of claim 1 , wherein R 5 is —CH 3 .
7 . The compound of claim 1 , wherein M is Li and R 5 is —CH 3 .
8 . The compound of claim 1 , comprising the additional step of purifying the 7α-alkynyl-androst-5-ene-3β, 7β, 17β-triol compound of step (f) by recrystalization.
9 . The compound of claim 8 , wherein R 1 is —CH 3 .
10 . The compound of claim 8 , wherein R 1 and R 2 are —CH 3 .
11 . The compound of claim 8 , wherein M is Li, Mg or Zn.
12 . The compound of claim 8 , wherein R 5 is —CH 3 .
13 . The compound of claim 8 , wherein M is Li and R 5 is —CH 3 .
14 . The compound of claim 8 , wherein the 17α-alkynyl-androst-5-ene-3β,7β,17β-triol compound of step (f) is purified by recrystallization from methanol-water.
15 . The compound of claim 14 , wherein R 1 is —CH 3 .
16 . The compound of claim 14 , wherein M is Li, Mg or Zn.
17 . The compound of claim 14 , wherein R 5 is —CH 3 .
18 . The compound of claim 1 , wherein the 17α-alkynyl-androst-5-ene-3β,7β,17β-triol compound is 17α-ethynyl-androst-5-ene-3β,7β,17β-triol.
19 . The compound of claim 8 wherein the 17α-alkynyl-androst-5-ene-3β,7β,17β-triol compound is 17α-ethynyl-androst-5-ene-3β,7β,17β-triol.
20 . The compound of claim 14 , wherein the 17α-alkynyl-androst-5-ene-3β,7β,17β-triol compound is 17α-ethynyl-androst-5-ene-3β,7β,17β-triol.