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

4,5-Dimethoxy-2-nitrobenzoic acid (I) was treated with thionyl chloride to form acid chloride (II), followed by reaction with ammonia to yield 4,5-dimethoxy-2-nitrobenzamide (III). This was reduced with sodium borohydride in the presence of copper sulfate to give aminobenzamide (IV), which was refluxed with formic acid to afford 6,7-dimethoxyquinazoline-4(3H)-one (V). Subsequent treatment of (V) with phosphoryl chloride gave the chloroquinazoline (VI). The title compound was then prepared by condensation of (VI) with 2-bromo-4-aminophenol (VII) in refluxing ethanol.

合成路线3

4,5-Dimethoxy-2-nitrobenzoic acid (I) was treated with thionyl chloride to form acid chloride (II), followed by reaction with ammonia to yield 4,5-dimethoxy-2-nitrobenzamide (III). This was reduced with sodium borohydride in the presence of copper sulfate to give aminobenzamide (IV), which was refluxed with formic acid to afford 6,7-dimethoxyquinazoline-4(3H)-one (V). Subsequent treatment of (V) with phosphoryl chloride gave the chloroquinazoline (VI). The title compound was then prepared by condensation of (VI) with 4-aminophenol (VII) in refluxing ethanol.

合成路线4

6,7-Dimethoxy-4-quinazolone (II) was prepared by condensation of methyl 4,5-dimethoxyanthranilate (I) with formamide at 160 C. Chlorination of (II) by means of phosphorus oxychloride provided the 4-chloro quinazoline (III). Substitution of the 4-chloro group of (III) by the sodium salt of 4-amino-3-chlorophenol (IV) gave rise to the quinazolinyl ether (V). Finally, condensation of amine (V) with triphosgene, followed by addition of n-propylamine furnished the title urea derivative.

合成路线5

合成路线6

Chlorination of 4,5-dimethoxy-2-nitrobenzoic acid (X) with SOCl2, followed by reaction with aqueous ammonia yields the nitrobenzamide (XI), which is reduced to the corresponding aminobenzamide (XII) by means of NaBH4 in the presence of catalytic amounts of CuSO4. Anthranilamide (XII) is then cyclized to quinazolinone (XIII) by refluxing in formic acid . Alternatively, cyclization of 4,5-dimethoxyanthranilic acid (XIV), either by heating with formamide at 190 °C or with formamidine hydrochloride at 210 °C , gives rise to quinazolinone (XIII) . Subsequent chlorination of compound (XIII) to the corresponding 4-chloroquinazoline (XV) is accomplished by treatment with either POCl3 , SOCl2 or (COCl)2 in the presence of catalytic amounts of DMF. Chloroquinazoline (XV) is then condensed with 3-bromoaniline (VIII) in refluxing EtOH or i-PrOH to produce anilinoquinazoline (XVI) , which is finally demethylated by either treatment with BBr3 in THF or by heating with pyridinium chloride at 205 °C .