Synthesis of homoursodeoxycholic acid and [11,12-3H]homoursodeoxycholic acid

Homoursodeoxycholic acid and [11,12-3H]homoursodeoxycholic acid were synthesized from ursodeoxycholic acid and homocholic acid, respectively. Ursodeoxycholic acid (Ia) was converted to 3 alpha, 7 beta-diformoxy-5 beta-cholan-24-oic acid (Ib) using formic acid. Reaction of the diformoxy derivative (Ib) with thionyl chloride yielded the acid chloride (II) which was treated with diazomethane to produce 3 alpha, 7 beta-diformoxy-25-diazo-25-homo-5 beta-cholan-24-one (III). Homoursodeoxycholic acid (IV) was formed from the diazoketone (III) by means of the Wolff rearrangement of the Arndt-Eistert synthesis. N-Bromosuccinimide oxidation of homocholic acid (V), which was prepared from cholic acid by the same procedure described above, afforded 3 alpha, 12 alpha-dihydroxy-7-oxo-25-homo-5 beta-cholan-25-oic acid (VI). Reduction of the 7-ketohomodeoxycholic acid (VI) with sodium in 1-propanol gave 3 alpha, 7 beta, 12 alpha-trihydroxy-25-homo-5 beta-cholan-25-oic acid (VII). The methyl ester of 7-epihomocholic acid (VII) was partially acetylated to give methyl 3 alpha, 7 beta-diacetoxy-12 alpha-hydroxy-25-homo-5 beta-cholan-25-oate (VIII) using a mixture of acetic anhydride, pyridine and benzene. Dehydration of the diacetoxy derivative (VIII) with phosphorus oxychloride yielded methyl 3 alpha, 7 beta-diacetoxy-25-homo-5 beta-chol-11-en-25-oate (IX). Reduction of the unsaturated ester (IX) with tritium gas in the presence of platinum oxide catalyst followed by alkaline hydrolysis gave [11,12-3H]homoursodeoxycholic acid.