Method of synthesizing alkylated bile acid derivatives
A novel, improved method of synthesizing alkylated bile acid derivatives is provided. Such derivatives include, but are not limited to the active, potent, and selective FXR receptor agonist such as 6-ECDCA and other CA, DCA and CDCA derivatives. The first step of the synthesis selectively oxidates CDCA, CD, or DCA related starting material. An efficient combined deprotonation, trapping, ethylation, deprotection and reduction system is used to produce the desired alkylated bile acid derivatives. This practical synthesis offers a simple and economical pathway suitable for a large-scale manufacturing of alkylated bile acid derivatives including, but not limited to, 6-ECDCA.
1. A method for producing 6α-ethylchenodeoxycholic acid (6-ECDCA) from chenodeoxycholic acid (CDCA) comprising the following steps:
(i) oxidizing CDCA with pyridinium chlorochromate (PCC) to produce 5β-cholanicacid-3α-ol-7-one
(ii) contacting a solution of 5β-cholanicacid-3α-ol-7-one with (a) 3,4-dihydro-2H-pyran and (b) p-toluenesulfonic acid to result 3α-tetrahydropyranyloxy-7-keto-5β-cholan-24-oic acid;
(iii) contacting a solution of 3α-tetrahydropyranyloxy-7-keto-5β-cholan-24-oic acid with ethyl iodine to produce 3α-tetrahydropyranyloxy-6α-ethyl-7-keto-5β-cholan-24-oic acid;
(iv) contacting 3α-tetrahydropyranyloxy-6α-ethyl-7-keto-5β-cholan-24-oic acid with pyridinium p-toluenesulfonate (PPTS) to result 3α-hydroxy-6α-ethyl-7-keto-5β-cholan-24-oic acid; and
(v) reducing 3α-hydroxy-6α-ethyl-7-keto-5β-cholan-24-oic acid with NaBH 4 to produce 6-ECDCA
2. The method of claim 1 , wherein the method is used for large scale production.
3. The method of claim 1 , wherein the method yields at least 20% 6-ECDCA.
4. The method of claim 1 , wherein the method yields at least 50% 6-ECDCA.