Preparation of bile acids and intermediates thereof
Synthetic methods for preparing deoxycholic acid and intermediates thereof are provided.
1. A method for preparing deoxycholic acid (DCA) or a pharmaceutically acceptable salt thereof:
said method comprising
(a) reacting 9α-hydroxyandrost-4-en-3,17-dione 1.0 with H 2 under hydrogenation conditions to form compound 1.1
(b) reacting compound 1.1 with acid to form compound 1.2
(c) reacting compound 1.2 with a reducing agent to form compound 1.3 or a mixture of 1.3 and 1.4
(d) reacting compound 1.3 with a two carbon olefination reagent under olefin forming conditions to form compound 1.5
(e) converting compound 1.5 to a compound of formula 1.6 wherein P is a protecting group
(f) reacting the compound of formula 1.6 with an alkylpropiolate of the formula CH≡CC(O)OR or an alkyl acrylate of the formula CH 2 ═CHC(O)OR, wherein R is alkyl, in the presence of a Lewis acid to form a compound of formula 1.7 wherein P is a protecting group, R is an alkyl, and the dashed line is a single or double bond;
(g) reacting the compound of formula 1.7 with H 2 under hydrogenation conditions to form a compound of formula 1.8 wherein P is a protecting group and R is alkyl
(h) reacting the compound of formula 1.8 with an oxidizing agent to form a compound of formula 1.9 wherein P is a protecting group and R is alkyl
(i) reacting the compound of formula 1.9 with H 2 under hydrogenation conditions to form a compound of formula 2.0 wherein P is a protecting group and R is alkyl
(j) reacting the compound of formula 2.0 with a reducing agent to form a compound of formula 2.1 wherein P is a protecting group and R is alkyl
(k) exposing the compound of formula 2.1 to deprotection and hydrolysis conditions to form deoxycholic acid or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 wherein the hydrogenation conditions of part (a) comprise a Pd/C catalyst.
3. The method of claim 1 wherein the acid of part (b) is a mineral acid.
4. The method of claim 3 wherein the mineral acid is H 2 SO 4 .
5. The method of claim 1 wherein the reducing agent of part (c) is LiAl(OtBu) 3 H.
6. The method of claim 1 wherein the two carbon olefination reagent of part (d) is Ph 3 PCH 2 CH 3 + Br − .
7. The method of claim 1 wherein the protecting group P of compound 1.6-2.1 is —C(O)CH 3 .
8. The method of claim 1 wherein the Lewis acid of part (f) is EtAlCl 2 .
9. The method of claim 1 wherein the alkylpropiolate or alkylacrylate is methylpropriolate or methylacrylate.
10. The method of claim 1 wherein the hydrogenation conditions of part (g) comprise a PtO 2 catalyst.
11. The method of claim 1 wherein the oxidizing agent of part (h) is CrO 3 .
12. The method of claim 1 wherein the hydrogenation conditions of part (i) comprises a Pd/C catalyst.
13. The method of claim 1 wherein the reducing agent of part (j) is LiAl(OtBu) 3 H.
14. The method of claim 1 wherein the deprotection and hydrolysis conditions of part (k) when P is —C(O)CH 3 comprise reacting compound 2.1 with an alkali metal hydroxide, alkali earth alkoxide, or a mixture of both.
15. The method of claim 1 wherein the deprotection and hydrolysis conditions of part (k) when P is —C(O)CH 3 comprise reacting compound 2.1 with LiOH.