Process for preparing high puritiy allopregnanolone and intermediates thereof
The invention relates to an efficient and industrially applicable process for the preparation and purification of allopregnanolone and intermediates thereof without the assistance of column chromatography.
1. A chromatography-free process for preparing allopregnanolone which comprises:
reacting isoallopregnanolone with a strong carboxylic acid having a pKa≤3 under suitable Mitsunobu conditions, thereby obtaining a 3-carboxylic ester of allopregnanolone;
precipitating the 3-carboxylic ester of allopregnanolone in a solvent system comprising water and an organic solvent;
purifying the precipitate of the 3-carboxylic ester of allopregnanolone by recrystallizing in a non-polar solvent; and
subjecting the purified 3-carboxylic ester of allopregnanolone to hydrolysis, thereby obtaining allopregnanolone.
2. The process according to claim 1 , wherein the hydrolysis occurs under (i) neutral conditions, (ii) mild basic conditions by treatment with a base whose conjugate acid has a pKa≤11, or (iii) energetic basic conditions by treatment with a base whose conjugate acid has a pKa≥12.
3. The process according to claim 1 , wherein the strong carboxylic acid is selected from the group consisting of mono-, di-, and trifluoroacetic acid, mono-, di-, and trichloroacetic acid, cyanoacetic acid, and ortho-nitrobenzoic- and dinitrobenzoic acid.
4. The process according to claim 1 , wherein the 3-carboxylic ester of allopregnanolone is precipitated in a solvent system comprising water and a water-soluble organic solvent.
5. The process according to claim 1 , wherein the 3-carboxylic ester of allopregnanolone is precipitated in a solvent system comprising water and a water-soluble organic solvent selected from 1,4-dioxane, acetone, acetonitrile, DMF, methanol, ethanol, isopropanol, and mixtures thereof,
and/or
the precipitate of the 3-carboxylic ester of allopregnanolone is recrystallized in a non-polar solvent selected from group consisting of hexane, cyclohexane, heptane, toluene, iPr 2 O, MeOtBu, and mixtures thereof.
6. The process according to claim 2 , wherein the 3-carboxylic ester of allopregnanolone is subjected to hydrolysis under neutral conditions with an alcohol without adding any acid or base.
7. The process according to claim 2 , wherein the 3-carboxylic ester of allopregnanolone is subjected to hydrolysis with a base whose conjugate acid has a pKa≤11.
8. The process according to claim 7 , wherein the base whose conjugate acid has a pKa≤11 is an alkali or alkaline earth carbonate or bicarbonate.
9. The process according to claim 2 , wherein the 3-carboxylic ester of allopregnanolone is subjected to hydrolysis with a base whose conjugate acid has a pKa≥12 for a time and at a temperature suitable to keep the level of 3α-hydroxy-5α,17α-pregnan-20-one in an amount of 0.5% or less.
10. The process according to claim 9 , wherein the base whose conjugate acid has a pKa≥12 is an alkali or alkaline earth C 1-6 alkoxide or hydroxide.
11. The process according to claim 9 , wherein the hydrolysis is carried out for not more than about 2 h and/or at a temperature of about 15-40° C.
12. The process according to claim 1 , wherein following precipitation and recrystallization, the allopregnanolone has a total content of 5α-pregn-2-en-20-one and 3α-hydroxy-5α,17α-pregnan-20-one of about 0.15% or below.
13. The process according to claim 2 , wherein the hydrolysis under energetic basic conditions is carried out for not more than about 2 h and/or at a temperature of about 15-40° C.
14. The process according to claim 1 , wherein the suitable Mitsunobu conditions comprise use of at least one phosphine, at least one azodicarboxylate, and optionally a tertiary amine additive, wherein the at least one phosphine is selected from the group consisting of triphenyl phosphine, dicyclohexylphenylphosphine, diethylphenylphosphine, tributylphosphine, diphenyl-2-pyridylphosphine, 4-(dimethylamino) phenyldiphenylphosphine, isopropyldiphenylphosphine, tri-tert-butylphosphine, tri-n-octylphosphine, tricyclohexylphosphine, polystyryldiphenylphosphine, and a mixture thereof, and wherein the at least one azodicarboxylate is selected from the group consisting of diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), di-t-butyl azodicarboxylate, 1,1′-(azocarbonyl) dipiperidine, dibenzyl azodicarboxylate, and a mixture thereof.
15. The process according to claim 1 , wherein the purified 3-carboxylic ester of allopregnanolone contains an amount of 5α-pregn-2-en-20-one of about 0.5% or less.
16. The process according to claim 5 , wherein the ratio of water to water-soluble organic solvent is about 0.2:1 to 1:0.2.