Method for preparing substituted 3,7-dihydroxy steroids
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 method to make 17α-ethynyl-androst-5-ene-3β,7β,17β-triol essentially free of steroid side-product lacking an oxygen substituent at position 7 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 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 compound;
(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-ethynyl-androst-5-ene-3β,7β,17β-triol essentially free of 17α-alkynyl-androst-5-ene-3β,17β-diol is obtained.
2. The method of claim 1 wherein R 1 is C 1-6 alkyl or phenyl.
3. The method of claim 2 wherein R 1 is —CH 3 .
4. The method of claim 2 wherein R 1 and R 2 are —CH 3 .
5. The method of claim 1 wherein M is Li, Mg or Zn.
6. The method of claim 1 wherein R 5 is —CH 3 .
7. The method of claim 1 wherein M is Li and R 5 is —CH 3 .
8. The method of claim 1 wherein comprising the additional step of purifying the 17α-ethynyl-androst-5-ene-3β,7β,17β-trial of step (e) by recrystallization.
9. The method of claim 8 wherein R 1 is —CH 3 .
10. The method of claim 8 wherein R 1 and R 2 are —CH 3 .
11. The method of claim 8 wherein M is Li, Mg or Zn.
12. The method of claim 8 wherein R 5 is —CH 3 .
13. The method of claim 8 wherein M is Li and R 5 is —CH 3 .
14. The method of claim 8 wherein the 17α-ethynyl-androst-5-ene-3β,7β,17β-triol of step (e) is purified by recrystallization from methanol-water.
15. The method of claim 14 wherein R 1 is —CH 3 .
16. The method of claim 14 wherein M is Li, Mg or Zn.
17. The method of claim 14 wherein R 5 is —CH 3 .