Bisulfite → Eprosartan

Beteiligte Stoffe

Reaktionsschritte

Alternately, 4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid or the bisulfite addition compound of 4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid and (2-thienylmethyl)propanedioic acid, mono-ethyl ester are reacted to give (E)-α-[[2-butyl-1-[(4carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene]-2-thiophene propanoic acid by heating the two substrates in toluene at reflux under reduced pressure and in the presence of piperidine as catalyst followed by hydrolysis of the intermediate ester ethyl (ethyl (E)-α-[[2-butyl-1-[(4-carboxyphenyl)methyl]-1H-imidazol-5-yl]methylene]-2-thiophenepropanoate). In this preparation, 4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid or the bisulfite addition compound of 4-[(2-n-butyl-5-formyl-1H-imidazol-1-yl)methyl]benzoic acid, (2-thienylmethyl)propanedioic acid, mono-ethyl ester, and toluene are charged to a glass lined steel vessel and are initially heated to 55-60° C. to afford a homogenous solution. The catalyst (66 mol % piperidine) is added and the reaction is heated to reflux (70-75° C.) under reduced pressure. Reflux conditions are maintained for 20-35 hours and additional (2-thienylmethyl)-propanedioic acid, mono-ethyl ester is added. Once the reaction is complete, water and aqueous sodium hydroxide are added to the vessel and the reaction mixture heated at reflux under atmospheric conditions for 1-3 hours. The reaction is deemed complete when the level of ethyl (E)-α-[[2-butyl-1-[(4-carboxyphenyl)-methyl]-1H-imidazol-5-yl]methylene]-2-thiophene propanoate is less than 2.0%. The reaction is cooled to 45-50° C. and the aqueous and organic phases separated. The toluene phase is discarded. Ethanol is added to the aqueous phase and the solution is acidified with aqueous hydrochloric acid until a pH of 5.0 to 5.4 is achieved, maintaining the temperature at 50-55° C. The product slurry is cooled and allowed to stir at 10-15° C. for 2 hours. The product is isolated by centrifugation, washed and stored. Thereafter, pharmaceutically acceptable salts may be prepared as described above.

Herkunft & Nachweise