Morpholine → Thieno[3,4-C]pyridine

The thieno[3,4-c]pyridine compounds of formula I are prepared as follows: 3-Acetylthiopene 18 is reacted with sulfur in morpholine at reflux temperatures, and the resultant product is hydrolyzed in aqueous sodium hydroxide to give acid 19 (R12 =H) as a solid. Esterification in an alcoholic solvent, such as methanol or ethanol, using sulfuric acid catalysis yields the ester 19 (R11 =CH3 or C2H5). Ester 19 is acetylated with acetyl chloride using a metal halide catalyst, such as tin tetrachloride, to give 20. Reaction of 20 with concentrated ammonium hydroxide produces a mixture of amide 21 and thienopyridinol 22. Ring closure of 21 is effected by dissolution in trifluoroacetic acid to give 22; alternatively, the mixture of 21 and 22 obtained from the ammonolysis could be converted to 22 directly by the action of trifluoroacetic acid. Compound 23, wherein R2, R3 and R4 are as previously described, can be prepared as previously described in Schemes 1 and 2.