Methods for the preparation of obeticholic acid and derivatives thereof
The present application relates to a safe method of preparing a bile acid derivative or a pharmaceutical acceptable salt, solvate, or amino acid conjugate thereof, on a large scale from 7-keto lithocholic acid (KLCA), comprising reacting Compound 2 with paraldehyde to form Compound 3 at a temperature between 10° C. and 30° C.:
1. A method of preparing obeticholic acid (OCA)
or a pharmaceutically acceptable salt, solvate, or amino acid conjugate thereof, comprising:
a) reacting Compound 2 with paraldehyde to form Compound 3:
wherein the reaction is conducted at a temperature between 10° C. and 30° C.,
b) reacting Compound 3 with a base to form Compound 4:
c) hydrogenating Compound 4 to form Compound 5:
and
d) reducing the keto group at the C-7 position of Compound 5 to form OCA:
2. A method of claim 1 , wherein reacting Compound 2 with paraldehyde to form Compound 3 is conducted in the presence of a triflimide catalyst:
3. The method of claim 2 , wherein the triflimide catalyst is selected from (Tf) 2 NH, (Tf) 2 N—(C 1 -C 3 alkyl), and (Tf) 2 N-tri-C 1 -C 3 alkylsilyl.
4. The method of claim 3 , wherein the triflimide catalyst is (Tf) 2 N-trimethylsilyl.
5. The method of claim 1 , wherein the reaction of Compound 2 with paraldehyde to form Compound 3 is conducted in neat paraldehyde:
6. The method of claim 1 , wherein the molar ratio of paraldehyde to Compound 2 is between 3:1 and 6:1.
7. The method of claim 2 , wherein the reaction is conducted for 10 min to 4 hr.
8. The method of claim 1 , wherein Compound 3 is reacted with a base selected from metal hydroxide, C 1 -C 6 alkoxide, and metal hydride to form Compound 4:
9. The method of claim 8 , wherein the metal hydroxide is sodium hydroxide or potassium hydroxide.
10. The method of claim 9 , wherein the metal hydroxide is potassium hydroxide.
11. The method of claim 8 , wherein the reaction is conducted in a solvent selected from methanol, ethanol, propanol, isopropanol, water, and a mixture thereof.
12. The method of claim 11 , wherein the solvent is a mixture of ethanol and water, at an ethanol/water ratio of between 1:3 to 3:1 (vol/vol).
13. The method of claim 1 , wherein hydrogenating Compound 4 to form Compound 5 is conducted in the presence of a palladium catalyst:
14. The method of claim 1 , wherein reducing the keto group at the C-position of Compound 5 is conducted with sodium borohydride or sodium triacetoxyborohydride to form OCA:
15. The method of claim 1 , further comprising reacting Compound 1 with an alkyl silyl halide to form Compound 2:
16. The method of claim 15 , further comprising esterifying 7-keto lithocholic acid (KLCA) to form Compound 1:
17. The method of claim 12 , wherein the solvent is a mixture of ethanol and water, at an ethanol/water ratio of between 1:2 to 2:1 (vol/vol).
18. The method of claim 17 , wherein the solvent is a mixture of ethanol and water, at an ethanol/water ratio of between 1:1.5 to 1.5:1 (vol/vol).
19. The method of claim 18 , wherein the solvent is a mixture of ethanol and water, at an ethanol/water ratio of between 1:1.2 to 1.2:1 (vol/vol).
20. The method of claim 19 , wherein the solvent is a mixture of ethanol and water, at an ethanol/water ratio of between 1:1 to 1:1 (vol/vol).