合成路线1

The condensation of 2,5-difluoronitrobenzene (I) with ethyl 2-amino-5-methylthiophene-3-carboxylate (II) by means of triethylamine in hot DMSO or 2-methoxyethanol giving ethyl 2-(4-fluoro-2-nitroanilino)-5-methylthiophene-3-carboxylate (III), which is reduced with H2 over Pd/C in ethanol to ethyl 2-(4-fluoro-2-aminoanilino)-5-methylthiophene-3-carboxylate (IV). The cyclization of (IV) by means of NaH in DMSO affords 9,10-dihydro-7-fluoro-2-methyl-4H-thieno[2,3b][1,5]benzodiazepin-2-one (V), which is finally condensed with N-methylpiperazine by means of TiCl4 in anisole at 120 C.

合成路线2

The title compound has been obtained by two related ways: Condensation of glycine ethyl ester (II) with 2,4-difluoronirobenzene (I) provided the N-arylglycine (III), which was further reduced to the phenylenediamine derivative (IV) by catalytic hydrogenation. Acylation of diamine (IV) with ethyl chloroglyoxylate, followed by ring closure in refluxing ethanol, yielded the quinoxalinedione (V). Subsequent electrophyllic nitration of (V) furnished the 6-nitroquinoxaline (VI). The fluoride group of (III) was then displaced with imidazole (VII) in hot DMF yielding the imidazolyl quinoxaline (VIII). Finally, basic hydrolysis of the ethyl ester function of (VIII) gave the target carboxylic acid.

合成路线3

The intermediate arylpiperazine (VI) was prepared as follows: Reaction of 2,4-difluoronitrobenzene (I) with trifluoroethanol (II) in the presence of potassium tert-butoxide yielded the trifluoroethyl ether (III). After catalytic hydrogenation of the nitro group of (III), the resultant aniline (IV) was cyclized with bis(2-chloroethyl) amine hydrochloride (V) in a refluxing mixture of o-dichlorobenzene and n-hexanol to afford the target piperazine (VI).

合成路线4

Treatment of 2,4-difluoronitrobenzene (I) with isopropylamine in the presence of K2CO3 in THF afforded 2-isopropylamino-4-fluoronitrobenzene (II). Subsequent condensation of (II) with 2,3-difluorophenylacetonitrile (III) by means of potassium tert-butoxide, followed by oxidative treatment of the intermediate nitrile (IV) with H2O2 generated benzophenone (V). The nitro group of (V) was then reduced by hydrogenation over Raney Nickel yielding diamine (VI), which was cyclized to benzimidazole (VII) upon treatment with cyanogen bromide. Addition of the lithium anion of N-methyl-N-(trimethylsilyl)acetamide to (VII) gave beta-hydroxyamide (VIII). Finally, acid promoted dehydration of (VIII) furnished the corresponding alpha,beta-unsaturated amide.

合成路线5

Treatment of 2,4-difluoronitrobenzene (I) with isopropylamine in the presence of K2CO3 in THF afforded 2-isopropylamino-4-fluoronitrobenzene (II). Subsequent condensation of (II) with 2,3-difluorophenylacetonitrile (III) by means of potassium tert-butoxide, followed by oxidative treatment of the intermediate nitrile (IV) with H2O2 generated benzophenone (V). The nitro group of (V) was then reduced by hydrogenation over Raney Nickel yielding diamine (VI), which was cyclized to benzimidazole (VII) upon treatment with cyanogen bromide. Addition of the lithium anion of bis(trimethylsilyl)acetamide to (VII) gave beta-hydroxyamide (VIII). Finally, acid promoted dehydration of (VIII) furnished the corresponding alpha,beta-unsaturated amide, which was isoalted as the hydrochloride salt.

合成路线6

Treatment of 2,4-difluoronitrobenzene (I) with cyclopentylamine (II) in the presence of K2CO3 in THF afforded 2-cyclopentylamino-4-fluoronitrobenzene (III). Subsequent condensation of (III) with 2-fluorophenylacetonitrile (IV) by means of potassium tert-butoxide, followed by oxidative treatment of the intermediate nitrile (V) with H2O2 generated benzophenone (VI). The nitro group of (VI) was then reduced by hydrogenation over Raney Nickel yielding diamine (VII), which was cyclized to benzimidazole (VIII) upon treatment with cyanogen bromide. Addition of the lithium anion of N-methyl-N-(trimethylsilyl)acetamide to (VIII) gave beta-hydroxyamide (IX). Finally, acid promoted dehydration of (IX) furnished the corresponding alpha,beta-unsaturated amide, whic was isolated as the hydrochloride salt.

合成路线7

The condensation of 2,4-difluoronitrobenzene (I) with 2(S)-aminobutyric acid (II) by means of triethylamine in refluxing acetone gives 2(S)-(5-fluoro-2-nitrophenylamino)butyric acid (III), which is reductocyclized with H2 over Raney-Ni in methanol/acetic acid, yielding 3(S)-ethyl-6-fluoro-1,2,3,4-tetrahydroquinoxalin-2-one (IV). Finally, this compound is treated with isopropyl chloroformate (V) and 4-methylpyridine in dichloromethane.

合成路线8

The condensation of ethyl 2-aminobenzo[b]thiophene-3-carboxylate (I) with 2,4-difluoronitrobenzene (II) afforded the diaryl amine (III). The nitro group of (III) was then reduced to amine (IV) by catalytic hydrogenation over Pd/C. Then, cyclization of amino ester (IV) with N-methylpiperazine (V) using TiCl4 in hot anisole produced the target benzothienobenzodiazepine, which was finally isolated as the corresponding maleate salt.

合成路线9

In a related procedure, the condensation of 2-aminobenzo[b]thiophene-3-carbonitrile (VI) with 2,4-difluoronitrobenzene (II) produced the diaryl amine (VII). Reduction of the nitro group of (VII) using sodium hydrosulfite yielded diamine (VIII). Subsequent cyclization of amino nitrile (VIII) upon acidic treatment gave rise to the tetracyclic system (IX). This was then treated with refluxing N-methylpiperazine (V) to provide the title compound.

合成路线10

合成路线11

Reaction of 2,4-difluoronitrobenzene (I) with liquid ammonia gives 5-fluoro-2-nitroaniline (IIa) , which by subsequent displacement of the remaining fluoride group with N-methylpiperazine (III) in the presence of Et3N in NMP at 100 °C provides the piperazinyl aniline (IV) . Alternatively, nitroaniline (IV) can be prepared by condensation of 5-chloro-2-nitroaniline (IIb) with N-methylpiperazine (III) in hot EtOH , ethylene glycol or aqueous NaCl, optionally in the presence of NaOH . Catalytic hydrogenation of nitroaniline (IV) over Pd/C in EtOH at 40-45 °C yields the phenyldiamine (V) , wh ich by condensa t ion with ethyl 3-ethoxy-3-iminopropionate hydrochloride (VI) at reflux produces benzimidazole (VII) . Cyclocondensation of ethyl ester (VII) with 2-amino-6-fluorobenzonitrile (VIII) by means of LiHMDS , KHMDS or t-BuOK in THF or toluene furnishes dovitinib (IX ) , which is finally treated with racemic lactic acid in EtOH/H2O .