Methods for stereoselective reduction
The invention is directed to a method to reduce a C—C double bond of an enone of a steroidal compound to produce a mixture of β ketone product and α ketone product, comprising treating a solution or suspension of the steroidal compound in a solvent with hydrogen gas in the presence of a catalyst and a substituted pyridine.
1. A method of making a mixture of a compound having formula V and a compound having formula VI:
the method comprising treating a compound having formula VII:
in a solvent with hydrogen gas in the presence of a palladium on carbon catalyst and a substituted pyridine, wherein the ratio of the β ketone product V to the α ketone product VI is at least 3:1.
2. The method of claim 1 , wherein the ratio of the compound of formula V to compound of formula VI is at least 10:1, or the ratio of the compound of formula V to compound of formula VI is at least 20:1, or the ratio of the compound of formula V to compound of formula VI is at least 30:1, or the ratio of the compound of formula V to compound of formula VI is at least 40:1.
3. The method of claim 1 , wherein the substituted pyridine is a 3-substituted pyridine.
4. The method of claim 3 , wherein the 3-substituted pyridine is 3-picoline.
5. The method of claim 1 , wherein the substituted pyridine is a 4-substituted pyridine.
6. The method of claim 5 , wherein the 4-substituted pyridine is selected from 4-picoline and 4-methoxypyridine.
7. The method of claim 1 , wherein the solvent comprises the substituted pyridine.
8. The method of claim 7 , wherein the solvent comprises 3-picoline.
9. The method of claim 1 , further comprising adding an aqueous solution of citric acid and isolating the salt of compounds V and VI.
10. The method of claim 9 further comprising making a compound of formula XV:
the method further comprising the steps of:
(a) treating a compound of formula IX:
wherein X − is citrate, CBzCl to produce a compound of formula XI:
wherein PG is CBz;
(b) treating the compound of formula XI with a K-Selectride to produce an alcohol of formula XII:
(c) converting the alcohol of formula XII to an amine of formula XIII:
(d) treating the amine of formula XIII with mewl chloride to produce a sulfonamide of formula XIV:
and
(e) deprotecting the sulfonamide of formula XIV to produce the compound of formula XV.
11. The method of claim 10 , wherein step (c) comprises:
(1) converting the alcohol to a mesylate leaving group to produce a compound of formula XVI:
wherein LG is mesylate;
(2) treating the compound of formula XVI with sodium azide to produce a compound of formula XVII:
and
(3) treating the compound of formula XVII with triphenylphosphine to form the amine of formula XIII.
12. The method of claim 10 , wherein the sulfonamide of formula XIV is deprotected by treatment with hydrogen gas in the presence of a catalyst to form the compound of formula XV.
13. The method of claim 10 , wherein the compound of formula XV has the following absolute stereochemistry:
14. The method of claim 10 , further comprising the step of treating the compound of formula XV with HCl to produce a compound of formula XIX:
wherein X − is chloride.
15. A mixture comprising a compound of formula V, or a pharmaceutically acceptable salt thereof:
and a compound of formula 2c, or a pharmaceutically acceptable salt thereof:
16. The mixture of claim 15 , wherein the compound of formula 2c is present in less than 1%.