17alpha, 21-dihydroxypregnene esters as antiandrogenic agents
The present application provides 17 and/or 21 esters of 17α,21-Dihydroxypregna-4,9(11)-diene-3,20-dione and 17α,21-dihydroxypregna-4-ene-3,20-dione having remarkable antiandrogenic activity, methods of using these compounds, and processes for their preparation.
1. A method of preparing a compound according to formula II:
wherein R 2 is a C 3 -C 18 acyl group, the method comprising:
selectively esterifying a compound of Formula III
to give a compound of Formula IV
wherein R 1 is an alcohol protecting group capable of being removed with a palladium catalyst;
esterifying the compound of Formula IV to give a compound of Formula V
and;
selectively deprotecting the compound of Formula V to give the compound of Formula II.
2. The method of claim 1 , where R 2 is —C(O)CH 2 CH 3 .
3. The method of claim 1 , wherein R 1 is allyloxycarbonyl or benzyloxycarbonyl.
4. The method of claim 1 , wherein selectively esterifying a compound of Formula III to give a compound of Formula IV comprises reacting the compound of Formula III with allyloxycarbonyl chloride, benzyloxycarbonyl chloride, or tert-butylcarbonyl chloride.
5. The method of claim 4 , wherein the reacting takes place in a solvent at from −5° C. to 40° C.
6. The method of claim 5 , wherein the solvent is dimethylformamide or isobutene.
7. The method of claim 1 , wherein esterifying the compound of Formula IV to give a compound of Formula V comprises reacting the compound of Formula IV with a carboxylic acid anhydride in the presence of a catalyst.
8. The method of claim 7 , wherein the catalyst is 4-dimethylaminopyridine.
9. The method of claim 1 , wherein esterifying the compound of Formula IV to give a compound of Formula V comprises reacting the compound of Formula IV with a carboxylic acid in the presence of a carbodiimide.
10. The method of claim 9 , wherein the carbodiimide is dicyclohexylcarbodiimide.
11. The method of claim 1 , wherein esterifying the compound of Formula IV to give a compound of Formula V comprises reacting the compound of Formula IV with an active ester.
12. The method of claim 11 , wherein the active ester is a trifluoroethyl active ester, an N-acylphthalimide active ester, or an N-acylbenzotriazole active ester.
13. The method of claim 1 , wherein selectively deprotecting the compound of Formula V comprises reacting the compound of Formula V with a palladium catalyst.
14. The method of claim 13 , wherein the palladium catalyst is tetrakis(triphenylphosphine) palladium.
15. The method of claim 13 , reacting the compound of Formula V with a palladium catalyst takes place in dichloromethane or tetrahydrofuran.