合成路线1

4,5-Dimethoxy-2-nitrobenzoic acid (I) was converted to the corresponding acid chloride (II) upon treatment with SOCl2, and this was further coupled to aniline (III), producing amide (IV). Catalytic hydrogenation of the nitro group of (IV) afforded amine (V). Acid chloride (VII) --obtained by chlorination of 3-quinolinecarboxylic acid (VI) with SOCl2-- was then condensed with amine (V) to furnish the title diamide.

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

Treatment of 4,5-dimethoxy-2-nitro benzoic acid (I) with H2SO4 in EtOH allows formation of the corresponding ethyl ester (II), the nitro group of which is then reduced by hydrogenation over Pd/C in EtOH to provide substituted aniline (III). Finally, the desired product is obtained by condensation of (III) with acid chloride (IV) in CH2Cl2 by means of Et3N (acid chloride (IV) can be obtained by treatment of the corresponding benzoic acid (V) with SOCl2 in refluxing chloroform).

合成路线5

Chlorination of 2-nitro-4,5-dimethoxybenzoic acid (I) by using oxalyl chloride and DMF provides acid chloride (II), which is subsequently coupled to hydroxyproline methyl ester (III) to yield amide (IV). Catalytic hydrogenation of the nitro group of (IV), followed by intramolecular cyclization leads to the tricyclic lactam (V). In order to protect the lactam NH of (V), the hydroxyl group is first converted into the silyl ether (VI), which is further treated with trimethylsilylethoxymethyl chloride and NaH to give the SEM-lactam (VII). Selective O desilylation of (VII) is accomplished by means of tetrabutylammonium fluoride, providing alcohol (VIII). Oxidation of (VIII) under Swern reaction conditions gives rise to ketone (IX).

合成路线6

合成路线7

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 .