Imidazole → (E)-ethyl 2-acetamido-3-(dimethylamino)but-2-enoate

Participants

Reaction Conditions

Reaction Steps

Another approach toward imidazole intermediate is described in Reaction Scheme 3. The original reaction sequence was published by F. Hoffmann-La Roche A G [F. Hoffmann-La Roche A G, WO 2005/003117, 2005]. N-acetylglycine (14) and phosphorous oxychloride are mixed and dimethylacetamide is added thereto dropwise slowly at low temperature (exothermic). The reaction mixture is then stirred and warmed at 45° C. In this way, (E)-4-(1-(dimethylamino)ethylidene)-2-methyloxazol-5(4H)-one (15) is generated in 50% yield. The oxazolone (15) is cleaved with in situ generated ethoxide to produce (E)-ethyl 2-acetamido-3-(dimethylamino)but-2-enoate (16). Next, an amine (17) is subjected to a reaction with the compound (16) in acetic acid at rt overnight to give a Michael adduct (18). The crude intermediate (18) is then refluxed together with fine powdered ammonium sulfate in hexamethyldisilazane at 145° C. to provide the corresponding imidazole ester (19) in 55˜73% yield for the three steps from the oxazolone (15). The imidazole ester (19) is hydrolyzed with sodium hydroxide to produce the corresponding sodium carboxylate (20) uneventfully.

Provenance & Evidence