Condensation of cyano ester (I) with formamidine in the presence of NaOEt afforded the pyrimidinone derivative (II). Acetal hydrolysis of (II) with concomitant intramolecular cyclization under acidic conditions produced the pyrrolopyrimidinone (III), which was further chlorinated to (IV) in refluxing POCl3. Displacement of the 4-chloro of (IV) with 3-chloro-4-fluoroaniline (V) in the presence of silver triflate in hot DMF afforded the anilino pyrrolopyrimidine (VI). Oxidation of (VI) using pyridinium bromide perbromide furnished the alpha,alpha-dibromo lactam (VII). Reductive debromination of (VII) by means of zinc dust in AcOH gave intermediate (VIII).
Vilsmeier-Haack formylation of ethyl 4-methylpyrrole-2-carboxylate (IX) using POCl3 in DMF furnished the pyrrole aldehyde (X). Subsequent basic hydrolysis of the ethyl ester group of (X) gave 5-formyl-4-methylpyrrole-2-carboxylic acid (XI), which was further coupled to cis-2,6-dimethylpiperazine (XII) producing amide (XIII). The title compound was finally prepared by aldol condensation between the pyrrole aldehyde (XIII) and lactam (VIII) in the presence of piperidine.
Condensation of 2-cyano-4,4-diethoxybutyric acid ethyl ester (I) with formamidine hydrochloride (II) in the presence of NaOEt provides the pyrimidine derivative (III). Subsequent hydrolysis of the diethyl acetal of (III) under acidic conditions leads to the pyrrolopyrimidinone (IV). This is converted to the 4-chloro derivative (V) upon treatment with POCl3. Then, oxidation of (V) by means of pyridinium bromide perbromide furnishes the dibromo pyrrolopyridinone (VI), which is further debrominated to (VII) employing zinc dust in AcOH
Vilsmeier formylation of ethyl 4-methylpyrrole-2-carboxylate (VIII) affords aldehyde (IX). The ethyl ester group of (IX) is subsequently hydrolyzed under alkaline conditions to provide acid (X). Coupling of (X) with 4-(2-aminoethyl)morpholine (XI) gives amide (XII). Then, condensation between aldehyde (XII) and lactam (VII) in the presence of piperidine leads to adduct (XIII). The 4-chloro group of (XIII) is finally displaced with 3-chloro-4-fluoroaniline (XIV) in hot NMP to provide the title compound