Preparation and uses of obeticholic acid
The present invention relates to obeticholic acid: or a pharmaceutically acceptable salt, solvate or amino acid conjugate thereof. Obeticholic acid is useful for the treatment or prevention of a FXR mediated disease or condition, cardiovascular disease or cholestatic liver disease, and for reducing HDL cholesterol, for lowering triglycerides in a mammal, or for inhibition of fibrosis. The present invention also relates to processes for the synthesis of obeticholic acid.
1. A process of preparing non-crystalline obeticholic acid comprising less than 1% of chenodeoxycholic acid comprising the step of
converting crystalline obeticholic acid to non-crystalline obeticholic acid, wherein the crystalline obeticholic acid is prepared by a process comprising,
reacting E- or E/Z-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid with Pd/C and hydrogen gas to form 3α-hydroxy-6α-ethyl-7-keto-5β-cholan-24-oic acid,
reacting 3α-hydroxy-6α-ethyl-7-keto-5β-cholan-24-oic acid with NaBH 4 to form crude obeticholic acid, and
at least one step of crystallizing crude obeticholic acid using at least one organic solvent,
wherein converting crystalline obeticholic acid to non-crystalline obeticholic acid comprises the step of dissolving crystalline obeticholic acid in aqueous NaOH solution and adding HCl.
2. The process of claim 1 , further comprising the step of
reacting E- or E/Z-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid methyl ester with NaOH to form E- or E/Z-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid.
3. The process of claim 2 , further comprising the step of
reacting 3α,7-ditrimethylsilyloxy-5β-chol-6-en-24-oic acid methyl ester with CH 3 CHO to form E- or E/Z-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid methyl ester.
4. The process of claim 3 , further comprising the step of:
reacting 3α-hydroxy-7-keto-5β-cholan-24-oic acid methyl ester with Li[N(CH(CH 3 ) 2 ) 2 ] and Si(CH 3 ) 3 Cl to form 3α,7-ditrimethylsilyloxy-5β-chol-6-en-24-oic acid methyl ester.
5. The process of claim 4 , further comprising the step of:
reacting 3α-hydroxy-7-keto-5β-cholan-24-oic acid with CH 3 OH and H 2 SO 4 to form 3α-hydroxy-7-keto-5β-cholan-24-oic acid methyl ester.
6. The process of claim 5 , wherein reacting 3α-hydroxy-6α-ethyl-7-keto-5β-cholan-24-oic acid with NaBH 4 to form crude obeticholic acid is carried out at a temperature at about 85° C. to about 110° C. in a basic aqueous solution.
7. The process of claim 5 , wherein reacting E- or E/Z-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid with Pd/C and hydrogen gas to form 3α-hydroxy-6α-ethyl-7-keto-5β-cholan-24-oic acid is carried out at a temperature at about 90° C. to about 110° C.
8. The process of claim 5 , wherein reacting E- or E/Z-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid methyl ester with NaOH to form E- or E/Z-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid is carried out at a temperature at about 20° C. to about 60° C.
9. The process of claim 5 , wherein reacting 3α,7-ditrimethylsilyloxy-5β-chol-6-en-24-oic acid methyl ester with CH 3 CHO to form E- or E/Z-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid methyl ester is carried out in a polar aprotic solvent at a temperature at about −50° C. to about −70° C. in the presence of BF 3 .
10. The process of claim 5 , wherein reacting 3α-hydroxy-7-keto-5β-cholan-24-oic acid methyl ester with Li[N(CH(CH 3 ) 2 ) 2 ] and Si(CH 3 ) 3 Cl to form 3α,7-ditrimethylsilyloxy-5β-chol-6-en-24-oic acid methyl ester is carried out in a polar aprotic solvent at a temperature at about −10° C. to about −30° C.
11. The process of claim 5 , wherein reacting 3α-hydroxy-7-keto-5β-cholan-24-oic acid with CH 3 OH and H 2 SO 4 to form 3α-hydroxy-7-keto-5β-cholan-24-oic acid methyl ester is heated for about 3 hours and the pH of the reaction mixture is adjusted with an aqueous basic solution.
12. A process of claim 1 , wherein preparing crystalline obeticholic acid comprises at least one step of crystallizing crude obeticholic acid using at least one organic solvent selected from the group consisting of acetonitrile, heptane, nitromethane, and n-butyl acetate.
13. The process of claim 12 , wherein the at least one organic solvent is n-butyl acetate.
14. The process of claim 12 , wherein the crystalline obeticholic acid is characterized by a differential scanning calorimetry thermogram having an endothermic peak at 98±2° C.
15. A process of preparing non-crystalline obeticholic acid, comprising the steps of
reacting 3α-hydroxy-7-keto-5β-cholan-24-oic acid with CH 3 OH and H 2 SO 4 to form 3α-hydroxy-7-keto-5β-cholan-24-oic acid methyl ester in which the reaction is heated for about 3 hours and the pH of the reaction mixture is adjusted with an aqueous basic solution;
reacting 3α-hydroxy-7-keto-5β-cholan-24-oic acid methyl ester with Li[N(CH(CH 3 ) 2 ) 2 ] and Si(CH 3 ) 3 Cl to form 3α,7-ditrimethylsilyloxy-5β-chol-6-en-24-oic acid methyl ester in which the carried out in a polar aprotic solvent at a temperature at about −10° C. to about −30° C.;
reacting 3α,7-ditrimethylsilyloxy-5β-chol-6-en-24-oic acid methyl ester with CH 3 CHO to form E- or E/Z-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid methyl ester is which the carried out in a polar aprotic solvent at a temperature at about −50° C. to about −70° C. in the presence of BF 3 ;
reacting E- or E/Z-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid methyl ester with NaOH to form E- or E/Z-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid in which the reaction is carried out at a temperature at about 20° C. to about 60° C.;
reacting E- or E/Z-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid with Pd/C and hydrogen gas to form 3α-hydroxy-6α-ethyl-7-keto-5β-cholan-24-oic acid is which the reaction is carried out at a temperature at about 90° C. to about 110° C.;
reacting 3α-hydroxy-6α-ethyl-7-keto-5β-cholan-24-oic acid with NaBH 4 to form crude obeticholic acid is carried out at a temperature at about 85° C. to about 110° C. in a basic aqueous solution; and
converting crystalline obeticholic acid to non-crystalline obeticholic acid by dissolving crystalline obeticholic acid in aqueous NaOH solution and adding HCl, wherein the crystalline obeticholic acid is prepared by a process comprising at least one step of crystallizing crude obeticholic acid using at least one organic solvent.