合成路线1

By condensation of anthranilic acid (o-aminobenzoic acid) (I) with 3,4-dimethoxycinnamoyl chloride (II) by means of pyridine in refluxing chloroform.

合成路线2

By condensation of 2,4-dichlorobenzoic acid (I) with anthranilic acid (II) by means of K2CO3, powdered Cu and a small amount of I2 in refluxing isoamyl alcohol.

合成路线3

Nitroacetaldehyde oxime (I) is formed from nitromethane in the presence of NaOH and is converted in acidic media with 2-aminobenzoic acid (II) to 2-(2-nitroethylideneamino)benzoic acid (III). Cyclization of (III) in acetic anhydride by means of potassium acetate yields 4-hydroxy-3-nitroquinoline (IV), which is converted to 4-chloro-3-nitroquinoline (V) in boiling POCl3. Reaction of (V) with morpholinecarboximidamide (VIII) (formed from morpholine (VI) and S-methylisothiourea hemisulfate (VII) in ethanol) affords troquidazole.

合成路线4

6) Synthesis of the quinoline (XXI): Anthranilic acid (LI) is tolylated with tosyl chloride and treated with PCl5 in 1,2-dichloroethane to give the corresponding acyl chloride (LII), which is submitted to a Friedel Crafts condensation with fluorobenzene (LIII)/AlCl3 yielding 2-amino-4'-fluorobenzophenone (LIV). The cyclization of (LIV) with ethyl 2-(cyclopropylcarbonyl)acetate (LV) [obtained by condensation of cyclopropyl methyl ketone (LVI) and diethyl carbonate (LVII) with H2SO4] by means of p-toluenesulfonic acid yields 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-carboxylic acid ethyl ester (LVIII), which is submitted to a decarboxylative iodination with I2 and acetyl peroxide to afford 2-cyclopropyl-4-(4-fluorophenyl)-3-iodoquinoline (XXI). 7) Synthesis of the quinoline (XXXVII): The reduction of the quinolinecarboxylate (LVIII) with LiAlH4 in THF gives the corresponding methanol derivative (LIX), which is then treated with diphenyl disulfide (LX) and tri-butylphosphine in pyridine to afford 2-cyclopropyl-4-(4-fluorophenyl)-3-(phenylsulfanylmethyl)quinoline (XXXVII).

合成路线5

The protection of aniline (I) with di-tert-butyl dicarbonate in THF gives the carbamate (II), which is treated with BuLi and 14C labeled CO2 in THF yielding 2-(tert-butoxycarbonylamino)benzoic acid (III). The deprotection of (III) with TFA in dichloromethane affords labeled 2-aminobenzoic acid (IV), which is diazotized with NaNO2 /HCl and treated with Na2S, S and NaOH to give the disulfide (V). The reaction of (V) with refluxing SOCl2 yields the acid dichloride (VI), which is condensed with L-isoleucine tert-butyl ester (VII), by means of N-methylmorpholine (NMM) in dichloromethane to afford the final intermediate (VIII). Finally, this compound is deprotected with TFA in dichloromethane to give the labeled target compound.

合成路线6

The protection of aniline (I) with di-tert-butyl dicarbonate in THF gives the carbamate (II), which is treated with BuLi and 14C labeled CO2 in THF yielding 2-(tert-butoxycarbonylamino)benzoic acid (III). The deprotection of (III) with TFA in dichloromethane affords labeled 2-aminobenzoic acid (IV), which is diazotized with NaNO2 /HCl and treated with Na2S, S and NaOH to give the disulfide (V). The reaction of (V) with refluxing SOCl2 yields the acid dichloride (VI), which is condensed with L-isoleucine tert-butyl ester (VII), by means of N-methylmorpholine (NMM) in dichloromethane to afford the intermediate (VIII). The deprotectionof (VIII) with TFA in dichloromethane to give the labeled dimeric isoleucine derivative (IX), which is finally cyclized to the target benazoisothiazolone by oxidative cyclization with Br2 in dichloromethane.

合成路线7

The title urea derivative was obtained by condensation of 3-(trifluoromethyl)phenyl isocyanate (I) with anthranilic acid (II).

合成路线8

Anthranitic acid (I) is reacted with cyclohexanone (II) to give 5-hydroxy-1,2,3,4-tetrahydroacridine (III). The hydroxy compound (III) is then reacted with phosphorous oxychloride to give 5-chloro-1,2,3,4-tetrahydroacridine (IV). Aminolysis of (IV) with n-butylamine affords centbucridine.

合成路线9

The intermediate 6-methyldiphenylamine-2,2'-dicarboxylic acid (V) has been synthesized in two similar ways. 1. By Jourdan-Ullman copper-catalyzed condensation of 6-methylbenzoic acid (I) with 2-aminobenzoic acid (II); and 2. By the same type of condensation, but using 2-amino-3-methylbenzoic acid (III) and 2-chlorobenzoic acid (IV). The cyclization of the intermediate dicarboxylic acid (V) under acidic conditions gives 5-methyl-9-oxo-9,10-dihydroacridine-4-carboxylic acid (VI), which is treated with hot SOCl2 and DMF to yield 9-choloro-5-methylacridine-4-carbonyl chloride (VII). The reaction of (VII) with N,N-dimethylethylenediamine (VIII) in dichloromethane affords the corresponding amide (IX), which is finally treated first with phenol at 100 C and then with a stream of dry ammonia at 110-20 C to obtain the target 9-aminoacridine derivative.

合成路线10

The title compound can be synthesized by two routes. Condensation of anthranilic acid (I) with acid chloride (II) provides benzooxazinone (III). Refluxing of (III) with amine (IV) in the presence of p-toluenesulfonic acid yields a mixture of the target quinazolinone and the uncyclized diamide (V), which can be cyclized to the title compound by heating in H2SO4/HOAc.

合成路线11

Condensation of anthranilic acid (I) with 4-chloro-3-nitrobenzenesulfonyl chloride (II) in the presence of Na2CO3 affords sulfonamide (III). Electrophilic chlorination of (III) employing sulfuryl chloride in hot AcOH leads to (IV). After activation of acid (IV) as the corresponding acid chloride (V), coupling with 4-chloroaniline (VI) furnishes the target anthranilamide.

合成路线12

Sulfonylation of anthranilic acid (I) with p-toluenesulfonyl chloride under Schotten-Baumann conditions furnishes N-tosyl anthranilic acid (II). After conversion of acid (II) to the corresponding acid chloride (III), Friedel-Crafts condensation with benzene in the presence of AlCl3 leads to the benzophenone (IV). The N-tosyl group of (IV) is then removed upon heating with concentrated sulfuric acid to provide 2-aminobenzophenone (V). Acylation of amine (V) with 4-(aminosulfonyl)benzoyl chloride (VI) yields amide (VII). This is finally cyclized to the target indole compound under McMurry conditions employing an in situ generated low valent titanium reagent.

合成路线13