The reaction of 5-carboxy-2-acetylthiophene (I) first with SOCl2 in refluxing toluene, and then with aqueous ammonia gives 5-carbamoyl-2-acetylthiophene (II), which is brominated with Br2 in hot acetic acid yielding 5-carbamoyl-2-bromoacetylthiophene (III). The cyclization of (III) with ammonium dithiocarbamate (A) in refluxing methanol-DMF affords 2-mercapto-4-(5'-carbamoyl-2'-thienyl)thiazole (IV), which is finally condensed with 1-chloro-3-tert-butylaminoisopropanol (V) by means of NaOH in water methanol.
Ursodeoxycholic acid (I) was activated as the mixed anhydride (II) with ethyl chloroformate and triethylamine, and subsequently coupled with the triethylamine salt of taurine (III) to produce the title conjugated bile acid. Optionally, the mixed anhydride (II) was previously converted to the active phenol ester (V) by treatment with p-hydroxypropiophenone (IV), and subsequently condensed with taurine (III). Alternatively, ursodeoxycholic acid (I) was directly coupled to taurine (III) employing as the coupling reagents 2-isobutyl-N-isobutyloxycarbonyl-1,2-dihydroquinoline (IIDQ), diethylphosphorocyanidate (DEPC), or 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) under microwave irradiation.