合成路线1

Elinogrel potassium is prepared as follows. Condensation of methyl 2-amino-4,5-difluorobenzoate (I) with 4-nitrophenyl chloroformate (II) in refluxing CH2Cl2 gives the 4-nitrophenyl carbamate (III), which is condensed with 4-(Boc-amino)aniline (IV) in the presence of Et3N in THF at 60-70 °C to yield the diaryl urea (V), which, without isolation, is cyclized to the quinazoline-2,4-dione (VI) upon treatment with methanolic NaOMe or DBU. Alternatively, diaryl urea (V) is prepared by treatment of anthranilate (I) with COCl2 in toluene to yield isocyanate (VII) and/or carbamoyl chloride (VIII), which are then condensed with 4-(Boc-amino)aniline (IV) in the presence of Et3N in DMF . Deprotection of the amino group in compound (VI) by removal of the Boc group by means of HCl in dioxane provides 3-(4-aminophenyl)-6,7-difluoroquinazoline-2,4(1H,3H)-dione hydrochloride (IX), which undergoes selective fluoride displacement with methylamine (X) in DMSO at 110 °C to provide 3-(4-aminophenyl)-6-fluoro-7-(methylamino)quinazoline-2,4(1H,3H)-dione (XI). Subsequent carbamoylation of the primary amino group of quinazoline (XI) with ethyl N-(5-chlorothien-2-ylsulfonyl)carbamate (XII) in refluxing DMSO or acetonitrile yields elinogrel (XIII) , which is finally converted to its potassium salt by treatment with KOH in acetonitrile/H2O at 45-55 °C .