Synthesis of alfaxalone

Claims

1. A method for obtaining a compound of formula (1a), alfaxalone, including: a) treating a mixture of a 3α-hydroxy compound of formula (1a) and a 3β-hydroxy compound of formula (1b) an acylating agent in the presence of a catalyst in at least one aprotic solvent to obtain a mixture of acetylated 3α-compound of formula (2a) and 3β-compound of formula (2b) where R 1 is a substituted or unsubstituted alkyl, wherein said alkyl may contain at least one or more substituents selected from hydroxy, chloro and oxo; b) separating the compounds of formula (2a) and formula (2b) to obtain essentially their individual stereoisomers; c) hydrolyzing the acetylated compound of formula (2a) under basic conditions in one or more solvents to obtain the compound of formula (1a) as essentially a single stereoisomer containing a mixture of 17α- and 17β-epimers, and optionally d) enrichment of the epimer mixture with epimers, comprising epimerizing the 17α-epimer in an aqueous alkaline solution containing 1 to 2 molar equivalents of sodium hydroxide or potassium hydroxide in methanol and water or ethanol and water, and then recrystallizing the resulting product from a mixture of acetone and hexane, methanol and water, or ethanol and water to obtain >95% of the 17β-epimer.

2. The method of claim 1, wherein the acetylation in step (a) is carried out using an acetylating agent selected from the group consisting of acetic anhydride, acetyl chloride, propionic anhydride and propionyl chloride; wherein the aprotic solvent used in step (a) is selected from the group consisting of tetrahydrofuran, pyridine, ether, dimethylformamide, dioxane, triethylamine or mixtures thereof; wherein the catalyst is selected from the group consisting of 4-dimethylaminopyridine, 1-hydroxy-7-azabenzotriazole and 1-hydroxy-7-azabenzotriazole.

3. The method according to claim 2, wherein the acetylating agent is acetic anhydride or acetyl chloride, and the aprotic solvent is a mixture of tetrahydrofuran and pyridine.

4. The method of claim 3, wherein the acetylating agent is acetic anhydride, and the ratio of tetrahydrofuran to pyridine is approximately 4:

1.

5. The method of claim 4, wherein the catalyst is 4-dimethylaminopyridine.

6. The method of claim 1, step (b), wherein the compound of formula (2a) is separated from the compound of formula (2b) by dissolving said compounds in ethyl acetate or acetone, followed by recrystallizing the compounds from a mixture of a solvent and an antisolvent, wherein the solvent is acetone and the antisolvent is hexane, in a ratio of about 1:2 to 1:10, respectively, and then filtering the solvent / antisolvent mixture to obtain the compound of formula (2a).

7. The method according to claim 1, wherein the hydrolysis in step (c) is carried out by using an alkali salt selected from the group consisting of potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate and calcium carbonate, wherein the solvent is selected from acetone, methanol or ethanol.

8. The method according to claim 7, wherein the alkali salt is sodium hydroxide, wherein the molar equivalent of sodium hydroxide is at least 1 to 2 moles relative to the amount of the compound of formula (1a).

9. The method according to claim 1, characterized in that the proposed method further comprises step (d), wherein the enrichment of epimers to the 17β-epimer is carried out by epimerization of the 17α-epimer in a sodium hydroxide solution with a concentration of 1 or 2 molar equivalents in methanol and water, wherein the 17β-product is recrystallized from a mixture of acetone and hexane, methanol and water, or ethanol and water.

10. The method of claim 9, wherein the mixture of acetone and hexane is used in a ratio of about 1:4 or about 2:5; the mixture of methanol and water or ethanol and water are each used in a ratio of about 1:1 to 1:2, respectively.

11. The method according to claim 10, wherein the 17β-product is recrystallized from a mixture of methanol and water or ethanol and water, wherein the ratio of the components in each mixture is from about 1:1 to 1:2, respectively, and preferably 1:1.

5.

12. A method for obtaining a compound of formula (1a), alfaxalone, including: a) treating a mixture of a 3α-hydroxy compound of formula (1a) and a 3β-hydroxy compound of formula (1b) acetic anhydride in a solvent mixture of tetrahydrofuran and pyridine in the presence of a catalyst consisting of 4-dimethylaminopyridine; at a temperature of about 15 to 30°C for about 5 to 40 hours; to obtain a mixture of 3-acetoxyalfaxalone compounds of formula (2a') and formula (2b') b) separating the compounds of formula (2a') and formula (2b') to obtain substantially individual stereoisomers by fractional crystallization in a mixture of acetone and hexane in a ratio of from about 1:2 to about 1:10; c) hydrolyzing the compound of formula (2a') under basic conditions using an aqueous solution of 1 molar equivalent of sodium hydroxide relative to the amount of compound of formula (2a') in methanol and water or ethanol and water to obtain the compound of formula (1a) as essentially a single stereoisomer containing a mixture of 17α- and 17β-epimers; and optionally d) enriching the epimers in an aqueous solution containing 1 or 2 molar equivalents of sodium hydroxide in methanol and water or ethanol and water, and recrystallizing the resulting product from a mixture of acetone and hexane, methanol and water, or ethanol and water to obtain >95% of the 17β-epimer.

13. The method of claim 12, further comprising step (d), wherein the sodium hydroxide in step (d) is used in an amount of about 1 molar equivalent, wherein the 17β-product is recrystallized from a mixture of acetone and hexane in a ratio of about 1:4 or 2:

5.

14. The method of claim 13, wherein in step (d) sodium hydroxide is used in an amount of 2 molar equivalents, wherein the resulting product is recrystallized from a mixture of methanol and water or ethanol and water; wherein the ratio of the components in each mixture is from about 1:1 to 1:2, and preferably about 1:1.

5.

15. A method for obtaining a compound of formula (1a), alfaxalone, including: a) treating a mixture of a 3α-hydroxy compound of formula (1a) and a 3β-hydroxy compound of formula (1b) acetic anhydride in a solvent mixture of tetrahydrofuran and pyridine in a ratio of about 1:4, in the presence of a catalyst consisting of 4-dimethylaminopyridine; at a temperature of about 15 to 30°C for about 5 to 40 hours; to obtain a mixture of 3-acetoxyalfaxalone compounds of formula (2a') and formula (2b') b) separating the compounds of formula (2a') and formula (2b') to obtain substantially individual stereoisomers by fractional crystallization in a mixture of acetone and hexane in a ratio of from about 1:2 to about 1:10; c) hydrolysis of the compound of formula (2a') under alkaline conditions using an aqueous solution of sodium hydroxide in an amount of 2 molar equivalents relative to the compound of formula (2a') in methanol and water to obtain the compound of formula (1a) as essentially a single stereoisomer containing a mixture of 17α- and 17β-epimers; and d) enriching the epimers of the epimers by recrystallizing the 17β-product in a mixture of methanol and water or ethanol and water, wherein the ratio of the components in each mixture is from about 1:1 to 1:2, respectively, and preferably 1:1.5.