METHODS FOR ONAPRISTONE SYNTHESIS DEHYDRATION AND DEPROTECTION
Methods and systems for making onapristone (ONA) using acidic hydrolysis and dehydration with sulfuric acid in an alcoholic solution are provided.
1 . A method of making onapristone comprising:
reacting the compound of Formula I:
with sulfuric acid in a solvent to deprotect and dehydrate the compound of Formula I;
maintaining the reaction temperature below about 60° C.;
neutralizing the reaction with an inorganic base to form a solution; and
extracting the compound of Formula II
from the solution.
2 . The method of claim 1 , wherein the sulfuric acid is diluted up to 80% with water.
3 . The method of claim 2 , wherein the sulfuric acid is diluted from 30 to 60% with water.
4 . The method of claim 3 , wherein the sulfuric acid is diluted with 50% water.
5 . The method of claim 1 , wherein the solvent is selected from the group consisting of methanol, ethanol, acetone, n-propanol and isopropanol.
6 . The method of claim 5 , wherein the solvent is methanol.
7 . The method of claim 1 , wherein the temperature is maintained between about −50 to about 60° C.
8 . The method of claim 7 , wherein the temperature is maintained between about −10 and 30° C.
9 . The method of claim 8 , wherein the temperature is maintained from about 0 to about 15° C.
10 . The method of claim 1 , wherein the inorganic base is selected from the group consisting of sodium hydrogen carbonate, sodium phosphate or ammonia.
11 . The method of claim 10 , wherein the inorganic base is ammonia with a concentration between about 5 and 30%.
12 . The method of claim 11 , wherein the inorganic base is 30% ammonia.
13 . The method of claim 1 , wherein the reaction with the inorganic base is performed at a temperature from about 0 to about 30° C.
14 . The method of claim 13 , wherein the reaction with the inorganic base is performed at a temperature from about 0 to about 15° C.
15 . The method of claim 1 , wherein extraction of the compound of Formula II is performed with ethyl acetate.
16 . The method of claim 1 , wherein extraction of the compound of Formula II is performed by crystallization.
17 . The method of claim 1 , further comprising concentrating the solution.
18 . The method of claim 17 , wherein the solution is concentrated by vacuum distillation.