合成路线1

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2

3(S)-(Allyloxycarbonylamino)-1-chloro-5-phenyl-2-pentanone (VI) is linked to a carbazate resin (VII) to yield the resin-supported compound (VIII) suitable for solid-phase synthesis. The condensation of (VIII) with 3-phenylpropylmercaptan (IX) by means of DIEA in DMF affords the adduct (X), which is deprotected at the allyloxycarbonylamino group by means of Pd(PPh3)4 to provide the amino resin (XI). The condensation of (XI) with the previously described intermediate (V) by means of PyBOP, HOAt and DIEA in DMF gives dipeptide resin (XII). Finally, the cleavage of the target compound from the resin (XII) is performed by means of TFA in trifluoroethanol/water.

合成路线3