合成路线1

Reaction of 2,4,6-trifluorobenzonitrile (VI) with ammonia in hot isopropanol gives 2-amino-4,6-difluorobenzonitrile (VII), which is treated with hot aqueous H2SO4 to afford 2-amino-4,6-difluorobenzamide (VIII). Cyclization of benzamide (VIII) with triethyl orthoformate by means of HCl at 140 °C affords 5,7-difluoroquinazolin-4(3H)-one (IX), which is condensed with 4-hydroxytetrahydropyran (X) by means of t-BuOK in refluxing THF to provide the 5-(tetrahydropyran4-yloxy)quinazoline derivative (XI). Condensation of compound (XI) with 1-(2-hydroxyethyl)-4-methylpiperazine (V) by means of t-BuOK in refluxing THF gives the disubstituted quinazolinone (XII), which is inally condensed with 6-chloro-2,3-methylenedioxyaniline (II) by means of POCl3 in refluxing acetonitrile (2). Scheme 2.
Alternatively, difluoroquinazolinone (IX) is treated with POCl3 and DIEA in hot acetonitrile to give 4-chloro-5,7-difluoroquinazoline (XIII), which is condensed with 5-chloro-1,3-benzodioxol-4-amine (II) by means of DIEA in hot acetonitrile to yield the 4-amino-substituted quinazoline (XIV). Reaction of compound (XIV) with 4-hydroxytetrahydropyran (X) by means of t-BuOK in refluxing THF affords the 5-(tetrahydropyranyloxy)quinazoline derivative (XV), which is finally condensed with 1-(2-hydroxyethyl)-4-methylpiperazine (V) by means of KOH in di(2-methoxyethyl)ether at 120 °C (2). Scheme 2.