合成路线1

Monodemethylation of 6,7-dimethoxyquinazolin-4(3H)-one (I) in refluxing methanesulfonic acid in the presence of L-methionine provides 6-hydroxy-7-methoxyquinazolin-4(3H)-one (II), which is acetylated with acetic anhydride and pyridine at 100 C to give the acetate (III). Treatment of compound (III) with refluxing SOCl2 and a catalytic amount of DMF yields chloride (IV), which by condensation with 3-chloro-4-fluoroaniline (V) in boiling isopropanol affords the anilinoquinazoline (VI). Hydrolysis of the acetate group of (VI) by treatment with NH4OH in refluxing MeOH gives the 6-hydroxyquinazoline derivative (VII), which finally is alkylated with 3-(4-morpholinyl)-propyl chloride (VIII) or 3-(4-morpholinyl)propyl bromide (IX).

合成路线2

The alkylation of 4-hydroxy-3-methoxybenzoic acid methyl ester (I) with 3-(4-morpholinyl)propyl chloride (II) and tetrabutylammonium chloride in refluxing butanone gives 3-methoxy-4-[3-(4-morpholinyl)propoxy]benzoic acid methyl ester (III), which is nitrated with HNO3 in hot acetic acid to yield 5-methoxy-4-[3-(4-morpholinyl)propoxy]-2-nitrobenzoic acid methyl ester (IV). The reduction of (III) with H2 over Pd/C in methanol/ethyl acetate to afford the corresponding 2-amino ester (V), which is condensed with dimethylformamide dimethylacetal (VI) by heating at 100 C to provide the 2-(dimethylaminomethyleneamino) derivative (VII). The cyclization of (VII) with acetonitrile (VIII) by means of BuLi and CO2 in THF gives 6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-oxo-1,4-dihydroquinoline-3-carbonitrile (IX), which is treated with refluxing SOCl2 to yield the 4-chloroquinoline derivative (X). Finally, this compound is condensed with 2-bromo-5-methoxyaniline by means of pyridine hydrochloride in 2-ethoxyethanol or NaH in THF (or DMF).

合成路线3

合成路线4

合成路线5

合成路线6

Reaction of 2-nitrovanillin (III) with NH4OH and I2 in H2O/THF yields nitrile (XVIII), which is then condensed with 4-(3-chloropropyl)morpholine hydrochloride (XII) —prepared by alkylation of morpholine (XIX) with 1-bromo-3-chloropropane (XX) in toluene at 84 °C— by means of Cs2CO3 in DMF at 75 °C to give the morpholinopropyl ether (XXI). Reduction of the nitro group in compound (XXI) with Fe and AcOH affords amine (XXII), which by cyclization with ethylenediamine (VII) and sulfur at 100 °C produces the imidazoline derivative (XXIII). Finally, aminoimidazoline (XXIII) is then subjected to ring closure with cyanogen bromide (IX) in the presence of Et3N in CH2Cl2 .