合成路线1

Bromination of 3-chloro-4-methylaniline (I) in HOAc-Et2O afforded a mixture of the desired 2-bromo-5-chloro-4-methylaniline (II) and the dibromo derivative (III), which were separated by column chromatography. In an alternative procedure, aniline (I) was converted to the acetanilide (IV), which was then brominated to give (V). Subsequent acid hydrolysis of amide (V) provided the bromo aniline (II). Treatment of (II) with CuCN in hot NMP furnished nitrile (VI). This was hydrolyzed to the corresponding carboxylic acid (VII) using potassium hydroperoxide generated in situ. Cyclization of (VII) with chloroacetonitrile in the presence of NaOMe generated the quinazolinone system (VIII). The acetate ester (IX) was then obtained by displacement of the chloride group of (VIII) with cesium acetate in hot DMF. Further N-alkylation of quinazoline (IX) using methyl iodide and NaH produced (X). The bromomethyl derivative (XI) was prepared by benzylic bromination of (X) with N-bromosuccinimide in the presence of benzoyl peroxide. Condensation of bromide (XI) with tert-butyl 4-(N-propargylamino)benzoate (XII) yielded adduct (XIII). The acetate ester of (XIII) was then hydrolyzed with NaOH to give the hydroxymethyl quinazoline (XIV), which was subsequently converted to the mesylate (XV) upon treatment with methanesulfonic anhydride and Et3N.