合成路线1

By condensation of 1-ethyl 6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (I) with 2-methylpiperazine (II) in refluxing pyridine.

合成路线2

The reaction of 1-bromo-2,4,5-trifluoro-3-methoxybenzene (I) with CuCN and N-methyl-2-pyrrolidone at 150 C gives 2,4,5-trifluoro-3-methoxybenzonitrile (II), which by treatment with concentrated H2SO4 yields the benzamide (III). The hydrolysis of (III) with H2SO4 - water at 110 C affords 2,4,5-trifluoro-2-methoxybenzoic acid (IV), which by reaction with SOCl2 is converted into the acyl chloride (V). The condensation of (V) with diethyl malonate by means of magnesium ethoxide in toluene affords diethyl 2-(2,4,5-trifluoro-3-methoxybenzoyl)malonate (VI), which by treatment with p-toluenesulfonic acid in refluxing water gives ethyl 2-(2,4,5-trifluoro-3-methoxybenzoyl)acetate (VII). The condensation of (VII) with triethyl orthoformate in refluxing acetic anhydride yields 3-ethoxy-2-(2,4,5-trifluoro-3-methoxybenzoyl)acrylic acid ethyl ester (VIII), which is treated with cyclopropylamine (IX) to afford the corresponding cyclopropylamino derivative (X). The cyclization of (X) by means of NaF in refluxing DMF gives 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (XI), which is hydrolyzed with H2SO4 in acetic acid to yield the corresponding free acid (XII). Finally, this compound is condensed with 2-methylpiperazine (XIII) in hot DMSO.

合成路线3

The methylation of 1-bromo-2,4,5-trifluoro-3-(trimethylsilyl)benzene (I) with methyl trifluoromethylsulfonate (II) by means of diisopropylamine and butyllithium in THF gives 2-bromo-3,5,6-trifluoro-4-(trimethylsilyl)toluene (III), which is carbonated with butyllithium and CO2 in ether to yield 2,4,5-trifluoro-6-methyl-3-(trimethylsilyl)benzoic acid (IV). Elimination of the silyl group with CsF in acetonitrile affords the corresponding benzoic acid (V). The condensation of (V) with malonic acid monoethyl ester (VI) by means of oxalyl chloride and butyllithium in THF affords 3-(3,4,6-trifluoro-2-methylphenyl)-2-oxopropionic acid ethyl ester (VII), which by condensation with triethyl orthoformate in refluxing acetic anhydride is converted into the ethoxymethylene derivative (VIII). The cyclization of (VIII) with cyclopropylamine (IX) by means of sodium hydride in THF gives 1-cyclopropyl-6,7-difluoro-5-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid ethyl ester (X), which is hydrolyzed with refluxing 6N HCl to yield the corresponding free acid (XI) (1). Finally, this compound is condensed with 2-methylpiperazine (XII) by means of triethylamine in refluxing acetonitrile.

合成路线4

5) Compound (XVIII): The esterification of 7-bromo-1-cyclopropyl-6-fluoro-5-methyl-4-oxo-1,4-dihydroquinoline-3-ca rboxylic acid (XII) with SOCl2/methanol gives the corresponding methyl ester (XIII), which is brominated with N-bromosuccinimide (NBS) and benzoyl peroxide (BPO) in refluxing CCl4 yielding the corresponding bromomethyl derivative (XIV). The reaction of (XIV) with sodium acetate in hot DMF affords the expected acetoxymethyl derivative (XV), which is saponified with K2CO3 in methanol/water to give 1-cyclopropyl-6-fluoro-5-(hydroxymethyl)-4-oxo-1,4-dihydroquinoline-3-c arboxylic acid (XVI). Finally, this compound is condensed with 2-methylpiperazine (XVII) by heating at 110 C. 6) Compound (XX): The condensation of the hydroxymethylquinolone (XVI) with the benzylamine (VI) as before gives 6-fluoro-5-(hydroxymethyl)-4-(4-methoxybenzylamino)-4-oxo-1,4-dihydroqu inoline-3-carboxylic acid (XIX), which is then debenzylated with trifluoroacetic acid an H2SO4 as before.

合成路线5