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Generated: September 26, 2017

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Title:Preparation of bile acids and intermediates thereof
Abstract: Synthetic methods for preparing deoxycholic acid and intermediates thereof are provided.
Inventor(s): Prasad; Achampeta Rathan (Hyderabad, IN), Swaringen, Jr.; Roy A. (Durham, NC), Reid; John Gregory (Niskayuma, NY), Moriarty; Robert M. (Michiana Shores, IN), Sahoo; Akhila Kumar (Bhubaneswar, IN)
Assignee: Kythera Biopharmaceuticals, Inc. (Calabasas, CA)
Filing Date:Nov 06, 2009
Application Number:12/613,969
Claims:1. A compound selected from the group consisting of 9.alpha.-hydroxy-5.beta.-androstan-3,17-dione (1.1); 5.beta.-androst-9(11)-en-3,17-dione (1.2); (Z)-3.alpha.-hydroxy-5.beta.-pregna-9(11),17(20)-diene (1.5); (Z)-3.alpha.-acetoxy-5.beta.-pregna-9(11),17(20)-diene (1.6); (E)-methyl 3.alpha.-acetoxy-5.beta.-chol-9(11), 16, 22-trien-24-oate (1.7a); and methyl 3.alpha.-acetoxy-5.beta.-chol-9(11), 16-dien-24-oate (1.7b).

2. The compound of claim 1, which is 9.alpha.-hydroxy-5.beta.-androstan-3,17-dione (1.1).

3. The compound of claim 1, which is 5.beta.-androst-9(11)-en-3,17-dione (1.2).

4. The compound of claim 1, which is (Z)-3.alpha.-hydroxy-5.beta.-pregna-9(11),17(20)-diene (1.5).

5. The compound of claim 1, which is (Z)-3.alpha.-acetoxy-5.beta.-pregna-9(11),17(20)-diene (1.6).

6. The compound of claim 1, which is (E)-methyl 3.alpha.-acetoxy-5.beta.-chol-9(11), 16,22-trien-24-oate (1.7a).

7. The compound of claim 1, which is methyl 3.alpha.-acetoxy-5.beta.-chol-9(11), 16-dien-24-oate (1.7b).

8. A method of preparing a compound of formula 1.9: ##STR00029## said method comprising: (a) reacting 9.alpha.-hydroxyandrost-4-en-3,17-dione 1.0 with H.sub.2 under hydrogenation conditions to form compound 1.1 ##STR00030## (b) reacting compound 1.1 with acid to form compound 1.2 ##STR00031## (c) reacting compound 1.2 with a reducing agent to form compound 1.3 or a mixture of 1.3 and 1.4 ##STR00032## (d) reacting compound 1.3 with a two carbon olefination reagent under olefin forming conditions to form compound 1.5 ##STR00033## (e) converting compound 1.5 to a compound of formula 1.6 wherein P is a protecting group ##STR00034## (f) reacting the compound of formula 1.6 with an alkylpropiolate of the formula CH.ident.CC(O)OR or an alkyl acrylate of the formula CH.sub.2.dbd.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; ##STR00035## (g) reacting the compound of formula 1.7 with H.sub.2 under hydrogenation conditions to form a compound of formula 1.8 wherein P is a protecting group and R is alkyl ##STR00036## (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: ##STR00037## said method comprising (a) reacting 9.alpha.-hydroxyandrost-4-en-3,17-dione 1.0 with H.sub.2 under hydrogenation conditions comprising a Pd/C catalyst to form compound 1.1 ##STR00038## (b) reacting compound 1.1 with H.sub.2SO.sub.4 to form compound 1.2 ##STR00039## (c) reacting compound 1.2 with LiAl(OtBu).sub.3H to form compound 1.3 or a mixture of 1.3 and 1.4 ##STR00040## (d) reacting compound 1.3 with Ph.sub.3PCH.sub.2CH.sub.3.sup.+Br under olefin forming conditions to form compound 1.5 ##STR00041## (e) converting compound 1.5 to a compound of formula 1.6 ##STR00042## (f) reacting the compound of formula 1.6 with methylpropiolate of the formula CH.ident.CC(O)OCH.sub.3 or methyl acrylate of the formula CH.sub.2.dbd.CHC(O)OCH.sub.3, in the presence of EtAlCl.sub.2 to form a compound of formula 1.7 wherein, and the dashed line is a single or double bond; ##STR00043## (g) reacting the compound of formula 1.7 with H.sub.2 under hydrogenation conditions comprising a PtO.sub.2 catalyst to form a compound of formula 1.8 ##STR00044## (h) reacting the compound of formula 1.8 with CrO.sub.3 to form a compound of formula 1.9 ##STR00045## (i) reacting the compound of formula 1.9 with H.sub.2 under hydrogenation conditions comprising a Pd/C catalyst to form a compound of formula 2.0 ##STR00046## (j) reacting the compound of formula 2.0 with LiAl(OtBu).sub.3H to form a compound of formula 2.1 ##STR00047## (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.
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