Process for preparing high puritiy allopregnanolone and intermediates thereof

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.