Preparation of bile acids and intermediates thereof
Synthetic methods for preparing deoxycholic acid and intermediates thereof are provided.
1. A compound selected from the group consisting of
9α-hydroxy-5β-androstan-3,17-dione (1.1);
5β-androst-9(11)-en-3,17-dione (1.2);
(Z)-3α-hydroxy-5β-pregna-9(11),17(20)-diene (1.5);
(Z)-3α-acetoxy-5β-pregna-9(11),17(20)-diene (1.6);
(E)-methyl 3α-acetoxy-5β-chol-9(11), 16, 22-trien-24-oate (1.7a); and
methyl 3α-acetoxy-5β-chol-9(11), 16-dien-24-oate (1.7b).
2. The compound of claim 1 , which is 9α-hydroxy-5β-androstan-3,17-dione (1.1).
3. The compound of claim 1 , which is 5β-androst-9(11)-en-3,17-dione (1.2).
4. The compound of claim 1 , which is (Z)-3α-hydroxy-5β-pregna-9(11),17(20)-diene (1.5).
5. The compound of claim 1 , which is (Z)-3α-acetoxy-5β-pregna-9(11),17(20)-diene (1.6).
6. The compound of claim 1 , which is (E)-methyl 3α-acetoxy-5β-chol-9(11), 16,22-trien-24-oate (1.7a).
7. The compound of claim 1 , which is methyl 3α-acetoxy-5β-chol-9(11), 16-dien-24-oate (1.7b).
8. A method of preparing a compound of formula 1.9:
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 the compound of formula 1.9 wherein P is a protecting group and R is alkyl.
9. 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 comprising a Pd/C catalyst to form compound 1.1
(b) reacting compound 1.1 with H 2 SO 4 to form compound 1.2
(c) reacting compound 1.2 with LiAl(OtBu) 3 H to form compound 1.3 or a mixture of 1.3 and 1.4
(d) reacting compound 1.3 with Ph 3 PCH 2 CH 3 + Br under olefin forming conditions to form compound 1.5
(e) converting compound 1.5 to a compound of formula 1.6
(f) reacting the compound of formula 1.6 with methylpropiolate of the formula CH≡CC(O)OCH 3 or methyl acrylate of the formula CH 2 ═CHC(O)OCH 3 , in the presence of EtAlCl 2 to form a compound of formula 1.7 wherein, and the dashed line is a single or double bond;
(g) reacting the compound of formula 1.7 with H 2 under hydrogenation conditions comprising a PtO 2 catalyst to form a compound of formula 1.8
(h) reacting the compound of formula 1.8 with CrO 3 to form a compound of formula 1.9
(i) reacting the compound of formula 1.9 with H 2 under hydrogenation conditions comprising a Pd/C catalyst to form a compound of formula 2.0
(j) reacting the compound of formula 2.0 with LiAl(OtBu) 3 H to form a compound of formula 2.1
(k) exposing the compound of formula 2.1 to deprotection and hydrolysis conditions comprising LiOH to form deoxycholic acid or a pharmaceutically acceptable salt thereof.