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Details for Patent: 8,362,285

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Details for Patent: 8,362,285

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:Jan 20, 2011
Application Number:13/010,727
Claims:1. A method for preparing deoxycholic acid or a salt thereof which method comprises: a) hydrogenation of a compound of formula 129: ##STR00029## with hydrogen so as to provide compound of formula 130: ##STR00030## where P is a hydroxyl protecting group and R is C.sub.1-C.sub.6 alkyl; b) contacting compound 130 with lithium aluminum tri-t-butoxy hydride to provide compound 131: ##STR00031## and c) deprotection and hydrolysis of compound 131 to provide for deoxycholic acid or a salt thereof.

2. The method of claim 1, wherein P is acetyl and R is methyl.

3. A method for preparing deoxycholic acid or a salt thereof which method comprises: a) hydrogenation of a compound of formula 129a: ##STR00032## wherein Ac is acetyl, with hydrogen in the presence of 10% palladium on carbon and ethyl acetate to provide compound of formula 130a: ##STR00033## b) contacting compound 130a with lithium aluminum tri-t-butoxy hydride in the presence of tetrahydrofuran to provide compound 131a: ##STR00034## and c) deacetylation and hydrolysis of compound 131a in the presence of sodium hydroxide and a mixture of tetrahydrofuran and methanol to provide for deoxycholic acid or a salt thereof.

4. The method of claim 3 which further comprises crystallization of deoxycholic acid or a salt thereof as produced in part c).

5. A method for preparing a compound of formula 1.1: ##STR00035## comprising hydrogenation of a compound of formula 1.0: ##STR00036## with H.sub.2 in the presence of a Pd/C catalyst and DMF.

6. The method of claim 5, wherein the Pd/C catalyst is 10% Pd/C.

7. The method of claim 6, wherein the compound of formula 1.1 is more than 99% pure.

8. A method for preparing deoxycholic acid (DCA) or a pharmaceutically acceptable salt thereof: ##STR00037## said method comprising (a) hydrogenation of 9.alpha.-hydroxyandrost-4-en-3,17-dione 1.0 with H.sub.2 in the presence of 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 LiA1(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 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) hydrogenation of the compound of formula 1.7 with H.sub.2 to form a compound of formula 1.8 ##STR00044## (h) oxidation of the compound of formula 1.8 to form a compound of formula 1.9 ##STR00045## (i) hydrogenation of the compound of formula 1.9 with H.sub.2 in the presence of 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## and (k) deacetylation and hydrolysis of the compound of formula 2.1 to form deoxycholic acid or a pharmaceutically acceptable salt thereof.

9. The method of claim 8 which further comprises crystallization of deoxycholic acid or a salt thereof as produced in part (k).

10. The method of claim 8, wherein the Pd/C catalyst in step (a) is 10% Pd/C.

11. The method of claim 8, wherein the hydrogenation is carried out in DMF.
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