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CN103130696B - Anthranilamide compound as well as preparation method and application thereof - Google Patents

Anthranilamide compound as well as preparation method and application thereof Download PDF

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CN103130696B
CN103130696B CN201310092606.8A CN201310092606A CN103130696B CN 103130696 B CN103130696 B CN 103130696B CN 201310092606 A CN201310092606 A CN 201310092606A CN 103130696 B CN103130696 B CN 103130696B
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phenyl
aminobenzamide
dichloromethane
nitrobenzamide
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赵桂森
梁雯
刘建珍
谢红艳
刘洋
张林娜
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Jiangsu Ruibang Agrochemical Co ltd
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Shandong University
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Abstract

The invention relates to an anthranilamide compound shown in a formula I. The invention further provides a preparation method of the compound and an application of a composition containing the compound in preparation of antitumor medicines.

Description

Anthranilamides and preparation method thereof and application
Technical field
The present invention relates to organic compound and synthesize and medical applications field, relate in particular to anthranilamides and preparation method thereof and pharmaceutical applications.
Background technology
The malignant tumour serious threat mankind's healthy and existence.Along with the further investigation of tumor development mechanism, discovery signals path is brought into play outstanding role in formation of cancer and development, specific effect has been reformed traditional cancer treatment method in the molecular targeted therapy of the required path of growth of tumour cell, the serious toxic side effect that makes patient avoid traditional cellulotoxic chemotherapeutics treatment tumour to bring.In recent years, some occur in order to the medicine of many target spots in Inhibitory signal path, and these many target drugs are blocked several signal paths simultaneously, can in kinds of tumors type, play a role.
AAL993 is the potent vascular endothelial growth factor receptor of highly selective (vascular endothelial growth factor receptor, the VEGFRs) inhibitor of being researched and developed by Novartis of Switzerland.Its action target spot comprises VEGFR-1, VEGFR-2, and VEGFR-3 and platelet derived growth factor receptor (platelet-derived growth factor receptor, PDGFR), have higher selectivity, IC to VEGFR-2 and VEGFR-3 50be respectively 23 ± 6nM, 18 ± 1nM.AAL993 has good physico-chemical property, is easy to permeates cell membranes, can suppress the VEGFR-2 autophosphorylation of VEGF induction, and oral administration biaavailability is high.Melanoma in situ animal model experiment shows, AAL993 can angiogenesis inhibiting, the formation moving of carrying down of the growth of tumor in situ and tumor lympha, and Long-term Oral administration, well-tolerated, without obvious toxic-side effects.Therefore, find the new AAL993 analogue containing anthranilamide and possess good application prospect as antitumor drug.
Summary of the invention
For the deficiencies in the prior art, the invention provides a kind of anthranilamides with anti-tumor activity, the present invention also provides the preparation method of this compound and the purposes in pharmacy.
The present invention is achieved by the following technical solutions:
1, anthranilamides
Anthranilamides of the present invention, structure is as shown in logical formula I:
Wherein, R 1for hydrogen, halogen, cyano group, hydroxyl, trifluoromethyl or amino; X is amino, thioureido, sulfoamido or amide group; R 2for phenyl, substituted-phenyl, substituted benzyl, pyridyl, imidazolyl, substituted imidazole base or picolyl.
Preferably, R 1for fluorine, chlorine, bromine, trifluoromethyl or hydroxyl; X is amino, thioureido, sulfoamido or amide group; R 2for phenyl, cyano group trifluoromethyl di-substituted-phenyl, disubstituted benzyl, methylimidazolyl, pyridyl or picolyl.
Further preferred, anthranilamides of the present invention is one of following:
N-(4-fluorophenyl) 2-(3-(4-cyano group-3-(trifluoromethyl) phenyl) thioureido) benzamide (7a),
N-(4-chloro-phenyl-)-2-(3-(4-cyano group-3-trifluoromethyl) thioureido) benzamide (7b),
N-(3-(trifluoromethyl) phenyl)-2-(3-(4-cyano group-3-(trifluoromethyl) phenyl) thioureido) benzamide (7c),
N-(3-bromophenyl)-2-(3-(4-cyano group-3-(trifluoromethyl) phenyl) thioureido) benzamide (7d),
N-(4-fluorophenyl)-2-(1-methyl isophthalic acid H-imidazoles-4-sulfoamido) benzamide (8a),
N-(4-chloro-phenyl-)-2-(1-methyl isophthalic acid H-imidazoles-4-sulfoamido) benzamide (8b),
N-(3-(trifluoromethyl) phenyl)-2-(1-methyl isophthalic acid H-imidazoles-4-sulfoamido) benzamide (8c),
N-(3-bromophenyl)-2-(1-methyl isophthalic acid H-imidazoles-4-sulfoamido) benzamide (8d),
N-(2-((4-chloro-phenyl-) formamyl) phenyl) Isonicotinamide (9a),
N-(2-((3-(trifluoromethyl) phenyl) formamyl) phenyl) Isonicotinamide (9b),
N-(2-((3-bromophenyl) formamyl) phenyl) Isonicotinamide (9c),
N-(2-((4-chloro-phenyl-) formamyl) phenyl) niacinamide (10a),
N-(2-((3-(trifluoromethyl) phenyl) formamyl) phenyl) niacinamide (10b),
N-(2-((3-bromophenyl) formamyl) phenyl) niacinamide (10c),
N-(2-((3-hydroxy phenyl) formamyl) phenyl) niacinamide (10d),
N-(4-chloro-phenyl-)-2-((2-hydroxyl-5-nitrobenzyl) amino) benzamide (11a) or
N-(3-bromophenyl)-2-((2-hydroxyl-5-nitrobenzyl) amino) benzamide (11b).
In bracket after above-mentioned preferred 18 compound titles, be its corresponding code name, for sake of convenience and be concise in expression, the code name in above-mentioned bracket will directly be applied in the following content of this specification sheets.
2, the preparation method of anthranilamides
The preparation method of anthranilamides of the present invention comprises the following steps:
Synthetic route:
Figure GDA0000485782080000021
Reagent and reaction conditions: (i) thionyl chloride, methylene dichloride, 60 DEG C; (ii) substituted aniline, triethylamine, methylene dichloride; (iii) iron, Glacial acetic acid, ethyl acetate, reflux; (iv) thiophosgene; (v) methylene dichloride, room temperature; (vi) 1-methyl isophthalic acid H-imidazoles-4-SULPHURYL CHLORIDE, pyridine, room temperature; (vii) different nicotinoyl chlorine hydrochloride, tetrahydrofuran (THF), room temperature; (viii) nicotinoyl chlorine hydrochloride, tetrahydrofuran (THF), room temperature; (ix) 5-nitrosalicylaldehyde, sodium cyanoborohydride, Glacial acetic acid, methyl alcohol, room temperature.
Concrete steps are as follows:
(i) raw material o-Carboxynitrobenzene is joined in methylene dichloride, under room temperature, fully stir, treat that solid dissolves completely, slowly drip thionyl chloride, drip and finish, be slowly warming up to 60 DEG C, reaction 3-5h, remove solvent and excessive thionyl chloride under reduced pressure and obtain intermediate ortho-nitrophenyl formyl chloride 2, sealed membrane sealing saves backup;
(ii) substituted aniline and triethylamine are dissolved in to methylene dichloride, are placed under condition of ice bath, treat that temperature is down to 0 DEG C, the ortho-nitrophenyl formyl chloride 2 that upper step is made is dissolved in methylene dichloride, is slowly added drop-wise in above-mentioned substituted aniline solution, drips complete room temperature reaction 2h; Question response is complete, filters, and filtrate decompression is steamed and desolventized, and column chromatographic isolation and purification obtains intermediate N substituted-phenyl-2-nitrobenzamide 3, and eluent system is volume ratio sherwood oil: ethyl acetate=8:1;
(iii) the N-substituted-phenyl-2-nitrobenzamide and the reduced iron powder mol ratio 1:10 that upper step are made join in the mixing solutions of Glacial acetic acid and ethyl acetate, reflux 4 hours, be cooled to after completion of the reaction room temperature, filter, filtrate is with saturated NaCl solution washing, anhydrous sodium sulfate drying, filter, remove solvent under reduced pressure, column chromatographic isolation and purification obtains intermediate N substituted-phenyl-2-aminobenzamide 4, and eluent system is volume ratio sherwood oil: ethyl acetate=6:1;
(iv) thiophosgene is added to the water at 21 DEG C and fully stirs and form nonhomogeneous system, the gradation of 4-amino-2-4-trifluoromethylbenzonitrile is added to above-mentioned nonhomogeneous system, continue fully to stir 1h; React complete, by reaction solution dichloromethane extraction, merge organic phase, saturated sodium-chloride washing, anhydrous MgSO 4dry, filter, remove solvent under reduced pressure, column chromatography obtains intermediate lsothiocyanates 6, and eluent system is volume ratio sherwood oil: ethyl acetate=6:1;
(v) N-substituted-phenyl-2-aminobenzamide 4 is dissolved in to methylene dichloride, under condition of ice bath, slowly drip the dichloromethane solution of 3-itrile group-4-trifluoromethyl lsothiocyanates 6, drip and finish, stirring at room temperature 7h, separate out white solid, filter, a small amount of washed with dichloromethane of filter cake, obtains target compound 7;
(vi) N-substituted-phenyl-2-aminobenzamide 4 is dissolved in anhydrous pyridine, add wherein 1-methyl isophthalic acid H-imidazoles-4-SULPHURYL CHLORIDE hydrochloride, under stirring at room temperature, react 15h, add distilled water, room temperature continues to stir 0.5h, and 2M hydrochloric acid adjust pH is to 5-6, with dichloromethane extraction, merge organic phase, saturated NaCl solution washing, anhydrous MgSO 4dry, filter, remove solvent under reduced pressure, column chromatographic isolation and purification obtains target compound 8, and eluent system is volume ratio sherwood oil: ethyl acetate=4:1;
(vii) and (viii) N-substituted-phenyl-2-aminobenzamide 4 is dissolved in anhydrous tetrahydro furan, add wherein triethylamine and different nicotinoyl chlorine hydrochloride or nicotinoyl chlorine hydrochloride, under stirring at room temperature, reaction is spent the night, filter, remove solvent under reduced pressure, the target compound 9 and 10 of column chromatographic isolation and purification;
(ix) N-substituted-phenyl-2-aminobenzamide 4,5-nitrosalicylaldehyde and Glacial acetic acid are added in methyl alcohol, fully stir, under room temperature, react 12h, add in batches sodium cyanoborohydride, room temperature reaction 12-24h; Remove solvent under reduced pressure, methylene dichloride dissolves, saturated sodium bicarbonate washing, and saturated sodium-chloride washing, anhydrous magnesium sulfate drying, column chromatographic isolation and purification obtains target compound 11, and eluent system is volume ratio sherwood oil: ethyl acetate=5:1.
Preferably, above-mentioned steps (ii) in, substituted aniline is 4-fluoroaniline, 4-chloroaniline, 3-5-trifluoromethylaniline, 3-bromaniline, 3-hydroxyanilines.
Preferably, above-mentioned steps (iii) in, N-substituted-phenyl-2-nitrobenzamide is N-(4-fluorophenyl)-2-nitrobenzamide, N-(4-chloro-phenyl-)-2-nitrobenzamide, N-(3-trifluoromethyl)-2-nitrobenzamide, N-(3-bromophenyl)-2-nitrobenzamide, N-(3-hydroxy phenyl)-2-nitrobenzamide.
Preferably, above-mentioned steps is (v) and (vi), N-substituted-phenyl-2-aminobenzamide is N-(4-fluorophenyl)-2-aminobenzamide, N-(4-chloro-phenyl-)-2-aminobenzamide, N-(3-trifluoromethyl)-2-aminobenzamide, N-(3-bromophenyl)-2-aminobenzamide.
Preferably, above-mentioned steps (vii) in, N-substituted-phenyl-2-aminobenzamide is N-(4-chloro-phenyl-)-2-aminobenzamide, N-(3-trifluoromethyl)-2-aminobenzamide, N-(3-bromophenyl)-2-aminobenzamide.
Preferably, above-mentioned steps (viii) in, N-substituted-phenyl-2-aminobenzamide is N-(4-chloro-phenyl-)-2-aminobenzamide, N-(3-trifluoromethyl)-2-aminobenzamide, N-(3-bromophenyl)-2-aminobenzamide, N-(3-hydroxy phenyl)-2-aminobenzamide.
Preferably, above-mentioned steps (ix) in, N-substituted-phenyl-2-aminobenzamide is N-(4-chloro-phenyl-)-2-aminobenzamide, N-(3-bromophenyl)-2-aminobenzamide, N-(3-hydroxy phenyl)-2-aminobenzamide.
3, the application of the anthranilamides of general formula I of the present invention
Anthranilamides of the present invention, especially 7a, 7b, 7c, 7d, 11a, 11b, has growth of tumour cell and suppresses active, can be for the preparation of antitumor drug.
Compared with prior art, excellent results of the present invention is: the present invention has synthesized the different compound that is guide based on AAL993 of structure, innovative point is the different fragrant heterocycle of the part of pyridine ring in AAL993 to substitute, obtain having the brand-new compound of structure of inhibition tumor cell growth, wherein compound 7a, 7c, 7d, 11a, 11b has obvious cell growth inhibiting activity to CCL188 HCT-116, simultaneously, compared with lead compound AAL993, compound 7a, 7b, 7c, 7d, 11a, 11b obviously improves (table 1) to the growth inhibitory activity of MDA-MB-231.Growth of tumour cell is suppressed to active evaluation method and adopt conventional MTT cytotoxicity assay method (mtt assay).
Numbering, structural formula and the active testing result of table 1. compound
Figure GDA0000485782080000041
Figure GDA0000485782080000051
Figure GDA0000485782080000071
Figure GDA0000485782080000081
Activity experiment result shows, anthranilamides of the present invention has obvious cell growth inhibiting activity, compound 7a, 7b, 7c, 7d, 9a, 11a, 11b growth inhibitory activity and the lead compound to HCT116 cell is similar, and compound 7a, 7b, 7c, 7d, 11a, 11b are obviously better than lead compound to the growth inhibitory activity of MDA-MB-231 cell.
Embodiment
Further describe the present invention below in conjunction with embodiment, understand the present invention and advantage and effect in order to more deep, but described embodiment is only for illustrating the present invention instead of restriction the present invention.
Embodiment 1 intermediate 4a-4e's is synthetic
(1) preparation of 2-nitrobenzoyl chloride 2
O-Carboxynitrobenzene (3.76g, 22.5mmol) is added in 35mL methylene dichloride to stirring at room temperature, solid is dissolved completely, add thionyl chloride 5mL, be warming up to 60 DEG C of reaction 4.5h, remove solvent and excessive thionyl chloride under reduced pressure, obtain faint yellow oily matter, sealed membrane sealing saves backup.
(2) preparation of N-substituted-phenyl-2-nitrobenzamide 3
Substituted aniline (22.5mmol), 5.5mL triethylamine are added in 45mL methylene dichloride, and stirring at room temperature mixes.The ortho-nitrophenyl formyl chloride that upper step is made is dissolved in 25mL methylene dichloride, under condition of ice bath, acyl chlorides is slowly added drop-wise in above-mentioned reaction solution, drips and finishes, and stirring at room temperature 2h, removes solvent under reduced pressure after filtration, and column chromatographic isolation and purification, obtains target product.Eluent system is sherwood oil: ethyl acetate (volume ratio)=8:1.
Above-mentioned substituted aniline is 4-fluoroaniline, 4-chloroaniline, 3-5-trifluoromethylaniline, 3-bromaniline, 3-hydroxyanilines.
3a:N-(4-fluorophenyl)-2-nitrobenzamide, white solid, yield 89.7%, mp:167～171 DEG C. 1H?NMR(600MHz,DMSO-d 6)δ10.04(s,1H),8.16(dd,J=8.4,1.2Hz,1H),7.88(td,J=7.8,1.2Hz,1H),7.78(dd,J=7.8,1.2Hz,1H),7.77(td,J=8.4,1.2Hz,1H),7.21,7.68(A′ABB′,JAB=9.0Hz,4H)。MS(calcd/found)[M+H] +:261.06/261.2。
3b:N-(4-chloro-phenyl-)-2-nitrobenzamide, white solid, yield 73.9%, mp:185～187 DEG C. 1H?NMR(600MHz,DMSO-d 6)δ10.81(s,1H),8.17(dd,J=8.1,1.2Hz,1H),7.88(td,J=8.1,1.2Hz,1H),7.79(dd,J=8.1,1.2Hz,1H),7.77(td,J=8.1,1.2Hz,1H),7.69(dd,J=8.7,2.4Hz,2H),7.44(dd,J=8.7,2.4Hz,2H)。MS(calcd/found)[M+H] +:277.03/277.3。
3c:N-(3-(trifluoromethyl) phenyl)-2-nitrobenzamide, white solid, yield 75.9%, mp:135～137 DEG C. 1HNMR(600MHz,DMSO-d 6)δ11.02(s,1H),8.19(dd,J=8.4Hz,1.2Hz,1H),8.16(s,1H),7.91(td,J=7.8Hz,1.2Hz,1H),7.85(d,J=8.4Hz,1H),7.82(dd,J=7.8Hz,1.2Hz,1H),7.79(td,J=8.4Hz,1.2Hz,1H),7.62(dd,J=8.4Hz,7.5Hz,1H),7.50(d,J=7.5Hz,1H)。MS(calcd/found)[M+H] +:311.06/311.3.
3d:N-(3-bromophenyl)-2-nitrobenzamide, white solid, yield 89.5%, mp:168～170 DEG C. 1H?NMR(600MHz,DMSO-d 6)δ10.85(s,1H),8.17(d,J=7.8Hz,1H),8.01(s,1H),7.89(dd,J=7.8Hz,6.9Hz,1H),7.80(d,J=7.8Hz,1H),7.78(dd,J=7.8Hz,6.9Hz,1H),7.57(d,J=8.4Hz,1H),7.32-7.34(m,2H)。MS(calcd/found)[M+H] +:320.98/321.2。
3e:N-(3-hydroxy phenyl)-2-nitrobenzamide, white solid, yield 32.9%, mp:177～180 DEG C. 1H?NMR(600MHz,DMSO-d 6)δ10.53(s,1H),9.49(br?s,1H),8.14(d,J=7.80Hz,1H),7.86(t,J=7.20Hz,1H),7.73-7.76(m,2H),7.26(s,1H),7.26(d,J=1.8Hz,1H),7.12(dd,J=8.40Hz,7.8Hz,1H),7.02(d,J=7.80Hz,1H),6.52(dd,J=7.80Hz,1.80Hz,1H)。MS(calcd/found)[M+H] +:259.23/259.1。
(3) preparation of N-substituted-phenyl-2-aminobenzamide 4
By N-substituted-phenyl-2-this methane amide of nitro (15mmol), reduced iron powder (10eqv.) joins in reaction flask, and adds successively Glacial acetic acid 30mL, ethyl acetate 80mL, heating reflux reaction 4h.React complete, be cooled to room temperature, filter, filtrate is washed with saturated nacl aqueous solution (35mL × 3), and anhydrous sodium sulfate drying filters, and removes solvent under reduced pressure, and column chromatographic isolation and purification obtains target compound.Eluent system is sherwood oil: ethyl acetate (volume ratio)=6:1.
Above-mentioned N-substituted-phenyl-2-nitrobenzamide is N-(4-fluorophenyl)-2-nitrobenzamide, N-(4-chloro-phenyl-)-2-nitrobenzamide, N-(3-trifluoromethyl)-2-nitrobenzamide, N-(3-bromophenyl)-2-nitrobenzamide, N-(3-hydroxy phenyl)-2-nitrobenzamide.
4a:N-(4-fluorophenyl)-2-aminobenzamide, white solid, yield 87.8%, mp:130～132 DEG C. 1H?NMR(600MHz,DMSO-d 6)δ10.04(s,1H),7.72(AA′of?A′ABB′,2H),7.61(dd,J=7.8Hz,1.2Hz,1H),7.15-7.21(m,3H),6.75(dd,J=7.8Hz,1.2Hz,1H),6.59(td,J=7.8Hz,1.2Hz,1H),6.32(s,2H)。MS(calcd/found)[M+H] +:231.09/231.3。
4b:N-(4-chloro-phenyl-)-2-aminobenzamide, white solid, yield 83.7%, mp:148～150 DEG C. 1H?NMR(600MHz,DMSO-d 6)δ10.11(s,1H),7.75(dd,J=7.8Hz,1.5Hz,2H),7.61(dd,J=8.1Hz,1.2Hz,1H),7.38(dd,J=7.8Hz,1.5Hz,2H),7.21(td,J=8.1Hz,1.2Hz,1H),6.75(dd,J=8.1Hz,0.6Hz,1H),6.59(td,J=8.1Hz,0.6Hz,1H),6.33(s,2H)。MS(calcd/found)[M+H] +:247.06/247.3。
4c:N-(3-(trifluoromethyl) phenyl)-2-aminobenzamide, white solid, yield 85.5%, mp:136～138 DEG C. 1H?NMR(600MHz,DMSO-d 6)δ10.28(s,1H),8.21(s,1H),7.97(d,J=7.8Hz,1H),7.65(dd,J=8.1Hz,1.5Hz,1H),7.57(t,J=7.8Hz,1H),7.42(d,J=7.8Hz,1H),7.22(td,J=8.1Hz,1.5Hz,1H),6.77(dd,J=8.1Hz,0.6Hz,1H),6.60(td,J=8.1Hz,0.6Hz,1H),6.38(s,2H)。MS(calcd/found)[M+H] +:281.08/281.3。
4d:N-(3-bromophenyl)-2-aminobenzamide, white solid, yield 79.4%, mp:137～141 DEG C. 1H?NMR(600MHz,DMSO-d 6)δ10.12(s,1H),8.06(t,J=1.8Hz,1H),7.68(dt,J=7.8Hz,1.8Hz,1H),7.61(dd,J=8.4Hz,1.2Hz,1H),7.30(t,J=7.8Hz,1H),7.26(dt,J=7.8Hz,1.8Hz,1H),7.21(td,J=8.4Hz,1.2Hz,1H),6.76(dd,J=8.4Hz,1.2Hz,1H),6.59(td,J=8.4Hz,1.2Hz,1H),6.35(s,2H)。MS(calcd/found)[M+H] +:291.01/291.2。
4e:N-(3-hydroxy phenyl)-2-aminobenzamide, light brown solid, yield 63.1%, mp:128～131 DEG C. 1H?NMR(600MHz,DMSO-d 6)δ9.86(s,1H),9.35(s,1H),7.58(dd,J=7.8Hz,1.5Hz,1H),7.28(d,J=2.4Hz,1H),7.19(td,J=7.8Hz,1.5Hz,1H),7.08-7.09(m,2H),6.74(dd,J=7.8Hz,1.2Hz,1H),6.58(td,J=7.8Hz,1.2Hz,1H),6.47(dt,J=6.6Hz,2.4Hz,1H),6.27(s,2H)。MS(calcd/found)[M+H] +:229.09/229.2。
Embodiment 2 target compound 7a-7d's is synthetic
(1) intermediate 3-trifluoromethyl-4-itrile group thiocarbanil 6 is synthetic
Thiophosgene (1mL, 13mmol) is added in 22mL water and fully stirs and form nonhomogeneous system at 21 DEG C, gradation in 4-amino-2-4-trifluoromethylbenzonitrile (2.23g, 12mmol) is in 15min is added to above-mentioned nonhomogeneous system, continue fully to stir 1h.React complete, by reaction solution dichloromethane extraction, merge organic phase, saturated sodium-chloride washing, anhydrous MgSO 4dry, filter, remove solvent under reduced pressure, column chromatography obtains intermediate 3-trifluoromethyl-4-itrile group thiocarbanil.Eluent system is sherwood oil: ethyl acetate (volume ratio)=6:1.
3-trifluoromethyl-4-itrile group thiocarbanil, off-white color solid, yield 78%.Mp:38～40℃。 1H?NMR(600MHz,DMSO-d 6)δ7.94(dd,J=8.4Hz,1.8Hz,1H),8.11(d,J=1.8Hz,1H),8.25(d,J=8.4Hz,1H)。
(2) N-substituted-phenyl-2-(3-(4-itrile group-3 trifluoromethyl) thioureido) benzamide 7 synthetic
By N-substituted-phenyl-2-amino-benzamide (4,1mmol) be dissolved in 15mL methylene dichloride, under condition of ice bath, the dichloromethane solution that slowly drips 3-trifluoromethyl-4-itrile group thiocarbanil (1mmol), drips and finishes, stirring at room temperature 7h, separate out white solid, filter, filter cake washed with dichloromethane, obtains white solid.
Above-mentioned N-substituted-phenyl-2-aminobenzamide is N-(4-fluorophenyl)-2-aminobenzamide, N-(4-chloro-phenyl-)-2-aminobenzamide, N-(3-trifluoromethyl)-2-aminobenzamide, N-(3-bromophenyl)-2-aminobenzamide.
7a:N-(4-fluorophenyl)-2-(3-(4-itrile group-3-trifluoromethyl) thioureido) benzamide, white solid, yield 78.98%, mp:188～191 DEG C. 1H?NMR(600MHz,DMSO-d 6)δ10.94(s,1H),10.51(s,1H),10.50(s,1H),8.38(d,J=1.8Hz,1H),8.06(d,J=8.7Hz,1H),8.04(dd,J=8.7Hz,1.8Hz,1H),7.79(d,J=8.1Hz,1H),7.71(dd,J=7.2Hz,1.2Hz,1H),7.56(td,J=8.1Hz,1.2Hz,1H),7.37(dd,J=8.1Hz,7.2Hz,1H),7.17,7.70(AA′BB′,J AB=J A′B′=9.0Hz,4H)。HRMS(ESI)m/z?calcd?for?C 22H 15F 4N 4OS[M+H] +:459.0897found459.0899。
7b:N-(4-chloro-phenyl-)-2-(3-(4-itrile group-3-trifluoromethyl) thioureido) benzamide, white solid, yield 76.32%, mp:182～185 DEG C. 1H?NMR(600MHz,DMSO-d 6)δ10.91(s,1H),10.57(s,1H),10.46(s,1H),8.37(d,J=1.8Hz,1H),8.05(d,J=8.4Hz,1H),8.03(dd,J=8.4Hz,1.8Hz,1H),7.69-7.75(m,4H),7.56(dd,J=8.4Hz,7.5Hz,1H),7.39(d,J=8.4Hz,2H),7.37(t,J=7.5Hz,1H).HRMS(ESI)m/z?calcd?for?C 22H 15F 3ClN 4OS[M+H] +:475.0602,found475.0602。
7c:N-(3-trifluoromethyl)-2-(3-(4-itrile group-3-trifluoromethyl) thioureido) benzamide, white solid, yield 80.14%, mp:178～180 DEG C. 1H?NMR(600MHz,DMSO-d 6)δ10.89(s,1H),10.75(s,1H),10.47(s,1H),8.36(d,J=1.5Hz,1H),8.17(s,1H),8.03(d,J=8.4Hz,1H),8.01(dd,J=8.4Hz,1.5Hz,1H),7.88(d,J=7.8Hz,1H),7.74(d,J=7.8Hz,1H),7.73(d,J=7.2Hz,1H),7.58(dd,J=7.8Hz,7.2Hz,1H),7.57(t,J=7.8Hz,1H),7.44(d,J=7.2Hz,1H),7.39(dd,J=7.8Hz,7.2Hz,1H)。HRMS(ESI)m/z?calcd?for?C 23H 15F 6N 4OS[M+H] +:509.0865,found509.0869。
7d:N-(3-bromophenyl)-2-(3-(4-itrile group-3-trifluoromethyl) thioureido) benzamide, white solid, yield 81.90%, mp:191～193 DEG C. 1H?NMR(600MHz,DMSO-d 6)δ10.91(s,1H),10.57(s,1H),10.46(s,1H),8.37(s,1H),8.05(d,J=8.1Hz,1H),8.03(d,J=8.1Hz,1H),7.74(d,J=7.8Hz,1H),7.69-7.21(m,3H),7.55(dd,J=8.4Hz,7.8Hz,1H),7.35-7.39(m,3H)。HRMS(ESI)m/z?calcd?for?C 22H 15F 3BrN 4OS[M+H] +:519.0097,found519.0099。
Embodiment 3N-substituted-phenyl-2-(1-methyl isophthalic acid H-imidazoles-4-sulfoamido) benzamide 8 synthetic
By N-substituted-phenyl-2-aminobenzamide (4,1mmol) be dissolved in anhydrous pyridine, add wherein the hydrochloride (1mmol) of 1-methyl isophthalic acid H-imidazoles-4-SULPHURYL CHLORIDE, stirring at room temperature reaction 15h, add 5ml distilled water, with methylene dichloride (10mL × 4) extraction, merge organic phase, saturated sodium-chloride washing, anhydrous magnesium sulfate drying, filter, steaming desolventizes, column chromatographic isolation and purification.Eluent system is sherwood oil: ethyl acetate=4:1.
Above-mentioned N-substituted-phenyl-2-aminobenzamide is N-(4-fluorophenyl)-2-aminobenzamide, N-(4-chloro-phenyl-)-2-aminobenzamide, N-(3-trifluoromethyl)-2-aminobenzamide, N-(3-bromophenyl)-2-aminobenzamide.
8a:N-(4-fluorophenyl)-2-(1-methyl isophthalic acid H-imidazoles-4-sulfoamido) benzamide, white solid, yield 71.3%, mp:171～173 DEG C. 1H?NMR(600MHz,DMSO-d 6)δ10.67(s,1H),10.50(s,1H),7.90(d,J=1.2Hz,1H),7.80(d,J=6.6Hz,1H),7.70-7.73(m,3H),7.59(d,J=8.1Hz,1H),7.50(dd,J=8.1Hz,6.6Hz,1H),7.18-7.24(m,3H),3.62(s,3H)。HRMS(ESI)m/z?calcd?for?C 17H 16FN 4O 3S[M+H] +:375.0922,found375.0925。
8b:N-(4-chloro-phenyl-)-2-(1-methyl isophthalic acid H-imidazoles-4-sulfoamido) benzamide, white solid, yield 74.2%, mp:178～180 DEG C. 1H?NMR(600MHz,DMSO-d 6)δ10.58(s,1H),10.57(s,1H),7.90(s,1H),7.80(d,J=7.8Hz,1H),7.75(d,J=8.7Hz,2H),7.70(s,1H),7.59(d,J=8.4Hz,1H),7.50(dd,J=8.4Hz,7.2Hz,1H),7.45(d,J=8.7Hz,2H),7.21(dd,J=7.8Hz,7.2Hz,1H),3.62(s,3H)。HRMS(ESI)m/zcalcd?for?C 17H 16ClN 4O 3S[M+H] +:391.0626.found375.0621。
8c:N-(3-trifluoromethyl)-2-(1-methyl isophthalic acid H-imidazoles-4-sulfoamido) benzamide, white solid, yield 82.1%, mp:168～170 DEG C. 1H?NMR(600MHz,DMSO-d 6)δ10.74(s,1H),10.52(s,1H),8.18(s,1H),7.97(d,J=7.8Hz,1H),7.90(s,1H),7.81(d,J=6.9Hz,1H),7.70(s,1H),7.63(dd,J=8.4Hz,7.8Hz,1H),7.59(d,J=7.8Hz,1H),7.50-7.53(m,2H),7.22(dd,J=7.8Hz,6.9Hz,1H),3.62(s,3H).HRMS(ESI)m/z?calcd?for?C 18H 16F 3N 4O 3S[M+H] +:425.0890,found425.0893。
8d:N-(3-bromophenyl)-2-(1-methyl isophthalic acid H-imidazoles-4-sulfoamido) benzamide, white solid, yield 79.37%, mp:157～160 DEG C. 1H?NMR(600MHz,DMSO-d 6)δ10.58(s,1H),10.51(s,1H),8.03(s,1H),7.90(s,1H),7.79(dd,J=7.5Hz,6.6Hz,1H),7.75(d,J=8.7Hz,1H),7.70(s,1H),7.58(d,J=8.1Hz,1H),7.50(dd,J=8.1Hz,7.8Hz,1H),7.45(d,J=7.5Hz,1H),7.35(d,J=6.6Hz,1H),7.21(dd,J=8.7Hz,7.8Hz,1H),3.62(s,3H)。HRMS(ESI)m/z?calcd?for?C 17H 16BrN 4O 3S[M+H] +:435.0121,found435.0124。
Embodiment 4N-(2-((4-substituted-phenyl) carbamyl) phenyl) Isonicotinamide 9 synthetic
By N-substituted-phenyl-2-aminobenzamide (4,1mmol) be dissolved in methylene dichloride, add wherein 1mL triethylamine, under condition of ice bath, drip the dichloromethane solution of different nicotinoyl chlorine (1mmol) to above-mentioned reaction solution, stirring at room temperature reaction 2h, add saturated sodium bicarbonate solution extremely without bubble formation, divide and get organic phase, methylene dichloride for water (10mL × 4) extraction, merges organic phase, saturated sodium-chloride washing, anhydrous magnesium sulfate drying, filter, steaming desolventizes, and column chromatographic isolation and purification obtains target compound 9.Eluent system is sherwood oil: ethyl acetate=4:1.
Above-mentioned N-substituted-phenyl-2-aminobenzamide is N-(4-chloro-phenyl-)-2-aminobenzamide, N-(3-trifluoromethyl)-2-aminobenzamide, N-(3-bromophenyl)-2-aminobenzamide.
9a:N-(2-((4-chloro-phenyl-) carbamyl) phenyl) Isonicotinamide, white solid, yield 65.3%, Mp:231-233 DEG C. 1H?NMR(600MHz,DMSO-d 6)δ11.56(s,1H),10.65(s,1H),8.81(dd,J=4.8Hz,1.8Hz,2H),8.29(dd,J=7.8Hz,1.2Hz,1H),7.90(dd,J=7.8Hz,1.8Hz,1H),7.80(dd,J=4.8Hz,1.8Hz,2H),7.75(d,J=9.0Hz,2H),7.64(td,J=7.8Hz,1.8Hz,1H),7.42(d,J=9.0Hz,2H),7.35(td,J=7.8Hz,1.2Hz,1H)。HRMS(ESI)m/z?calcd?for?C 19H 15Cl?N 3O 2[M+H] +:352.0847found352.0850。
9b:N-(2-((3-trifluoromethyl) carbamyl) phenyl) Isonicotinamide, white solid, yield 53.5%, Mp:229-231 DEG C. 1H?NMR(600MHz,DMSO-d 6)δ11.38(s,1H),10.78(s,1H),8.80(dd,J=6.0Hz,1.2Hz,2H),8.20(d,J=7.8Hz,1H),8.11(s,1H),8.00(d,J=8.4Hz,1H),7.89(d,J=7.8Hz,1H),7.80(dd,J=6.0Hz,1.2Hz,2H),7.65(t,J=7.8Hz,1H),7.60(dd,J=8.4Hz,7.8Hz,1H),7.47(d,J=7.8Hz,1H),7.37(t,J=7.8Hz,1H)。HRMS(ESI)m/z?calcd?for?C 20H 15F 3N 3O 2[M+H] +:386.1111found386.1113。
9c:N-(2-((3-bromophenyl) carbamyl) phenyl) Isonicotinamide, white solid, yield 51.7%, Mp:231-233 DEG C. 1H?NMR(600MHz,DMSO-d 6)δ11.43(s,1H),10.65(s,1H),8.82(d,J=6.0Hz,2H),8.23(d,J=7.8Hz,1H),8.00(s,1H),7.87(d,J=7.8Hz,1H),7.80(d,J=6.0Hz,2H),7.69(d,J=7.2Hz,1H),7.64(t,J=7.8Hz,1H),7.36(t,J=7.8Hz,1H),7.30-7.33(m,2H)。HRMS(ESI)m/z?calcd?forC 19H 15BrN 3O 2[M+H] +:396.0342found396.0346。
Embodiment 5N-(2-((4-substituted-phenyl) carbamyl) phenyl) niacinamide 10 synthetic
By N-substituted-phenyl-2-aminobenzamide (4,1mmol) be dissolved in methylene dichloride, add wherein 1mL triethylamine, under condition of ice bath, drip the dichloromethane solution of nicotinoyl chlorine (1mmol) to above-mentioned reaction solution, stirring at room temperature reaction 2h, add saturated sodium bicarbonate solution extremely without bubble formation, divide and get organic phase, methylene dichloride for water (10mL × 4) extraction, merges organic phase, saturated sodium-chloride washing, anhydrous magnesium sulfate drying, filter, steaming desolventizes, and column chromatographic isolation and purification obtains target compound 10.Eluent system is sherwood oil: ethyl acetate=4:1.
Above-mentioned N-substituted-phenyl-2-aminobenzamide is N-(4-chloro-phenyl-)-2-aminobenzamide, N-(3-trifluoromethyl)-2-aminobenzamide, N-(3-bromophenyl)-2-aminobenzamide.
10a:N-(2-((4-chloro-phenyl-) carbamyl) phenyl) niacinamide, white solid, yield 55.4%, Mp:207-210 DEG C. 1H?NMR(600MHz,DMSO-d 6)δ11.47(s,1H),10.63(s,1H),9.07(d,J=1.5Hz,1H),8.78(dd,J=5.1Hz,1.5Hz,1H),8.27(d,J=8.4Hz,1H),8.24(dt,J=7.8Hz,1.5Hz,1H),7.88(d,J=7.8Hz,1H),7.76(d,J=8.4Hz,2H),7.63(dd,J=8.4Hz,7.2Hz,1H),7.60(dd,J=7.8Hz,5.1Hz,1H),7.42(d,J=8.4Hz,2H),7.34(dd,J=7.8Hz,7.2Hz,1H)。HRMS(ESI)m/z?calcd?for?C 19H 15ClN 3O 2[M+H] +:352.0847found352.0849。
10b:N-(2-((4-trifluoromethyl) carbamyl) phenyl) niacinamide, white solid, yield 63.9%, Mp:218-220 DEG C. 1H?NMR(600MHz,DMSO-d 6)δ11.30(s,1H),10.78(s,1H),9.08(d,J=1.8Hz,1H),8.77(dd,J=5.4Hz,1.8Hz,1H),8.24(dt,J=8.4Hz,1.8Hz,1H),8.19(d,J=8.4Hz,1H),8.14(s,1H),8.00(d,J=8.4Hz,1H),7.88(d,J=7.8Hz,1H),7.58-7.65(m,3H),7.47(d,J=7.8Hz,1H),7.36(dd,J=7.8Hz,7.2Hz,1H)。HRMS(ESI)m/z?calcd?for?C 20H 15F 3N 3O 2[M+H] +:386.1111found386.1115。
10c:N-(2-((3-bromophenyl) carbamyl) phenyl) niacinamide, white solid, yield 51.3%, Mp:199-201 DEG C. 1H?NMR(600MHz,DMSO-d 6)δ11.53(s,1H),10.64(s,1H),9.08(d,J=1.8Hz,1H),8.78(dd,J=4.8Hz,1.8Hz,1H),8.25(dt,J=7.8Hz,1.8Hz,1H),8.21(d,J=8.1Hz,1H),8.02(s,1H),7.86(d,J=8.1Hz,1H),7.69(dd,J=7.2Hz,1.8Hz,1H),7.64(td,J=8.1Hz,1.8Hz,1H),7.60(dd,J=7.8Hz,4.8Hz,1H),7.30-7.36(m,3H)。HRMS(ESI)m/z?calcd?for?C 19H 15BrN 3O 2[M+H] +:396.0342found396.0348。
10d:N-(2-((3-hydroxy phenyl) carbamyl) phenyl) niacinamide, white solid, yield 52.2%, Mp:207-210 DEG C. 1H?NMR(600MHz,DMSO-d 6)δ11.61(s,1H),10.41(s,1H),9.45(s,1H),9.08(d,J=1.8Hz,1H),8.79(dd,J=4.8Hz,1.8Hz,1H),8.33(d,J=7.8Hz,1H),8.25(dt,J=7.8Hz,1.8Hz,1H),7.88(d,J=7.8Hz,1H),7.60-7.64(m,2H),7.30-7.34(m,2H),7.09-7.14(m,2H),6.53(dt,J=7.2Hz,1.8Hz,1H)。HRMS(ESI)m/z?calcd?for?C 19H 16N 3O 3[M+H] +:334.1186found334.1189。
Embodiment 6N-substituted-phenyl-2-(2-hydroxyl-5-nitrobenzyl amido) benzamide 11 synthetic
Be dissolved in 10mL methyl alcohol by N-substituted-phenyl-2-aminobenzamide (4,0.75mmol) with AcOH(2.9mmol), add 2-hydroxyl-5 nitrobenzaldehydes (1mmol), stirring at room temperature reaction 8h.Sodium cyanoborohydride (1mmol) is dissolved in to 10mL methyl alcohol, is slowly added drop-wise to above-mentioned reaction solution, drip and finish, room temperature reaction 24 hours.Remove solvent under reduced pressure, residue dissolves with 15mL methylene dichloride, and with saturated sodium bicarbonate (10mL × 2) washing, saturated sodium-chloride (10mL × 2) washing, anhydrous sodium sulfate drying, filters, and steaming desolventizes, the target compound 11 of column chromatographic isolation and purification.
Above-mentioned N-substituted-phenyl-2-aminobenzamide is N-(4-chloro-phenyl-)-2-aminobenzamide, N-(3-bromophenyl)-2-aminobenzamide.
11a:N-chloro-phenyl--2-(2-hydroxyl-5-nitrobenzyl amido) benzamide, yellow solid, productive rate 52.7%, Mp:168-169 DEG C. 1H?NMR(600MHz,DMSO-d 6)δ11.41(s,1H),10.28(s,1H),8.08(d,J=3.0Hz,1H),8.04(dd,J=9.0Hz,3.0Hz,1H),7.86(br?t,d=5.4Hz,1H),7.76(d,J=8.7Hz,2H),7.68(d,J=7.8Hz,1H),7.40(d,J=8.7Hz,2H),7.29(dd,J=8.7Hz,7.2Hz,1H),7.01(d,J=8.7Hz,1H),6.63-6.67(m,2H),4.40(d,J=5.4Hz,2H)。HRMS(ESI)m/z?calcd?for?C 20H 17ClN 3O 4[M+H] +:398.0902found398.0904。
11b:N-bromophenyl-2-(2-hydroxyl-5-nitrobenzyl amido) benzamide, yellow solid, productive rate 55.6%, Mp:146-149 DEG C. 1h NMR (600MHz, DMSO-d 6) δ 11.41 (s, 1H), 10.30 (s, 1H), 8.10 (s, 1H), 8.08 (d, J=2.4Hz, 1H), 8.05 (dd, J=8.7Hz, 2.4Hz, 1H), 7.87 (br t, J=6.0Hz, 1H), 7.69 (d, J=7.8Hz, 1H), 7.68 (d, J=8.4Hz, 1H), 7.27-7.33 (m, 3H), 7.01 (d, J=8.4Hz, 1H), 6.66 (dd, J=7.8Hz, 7.2Hz, 1H), 6.63 (d, J=8.7Hz, H), 4.41 (d, J=6.0Hz, 2H).HRMS(ESI)m/z?calcd?for?C 20H 17BrN 3O 4[M+H] +:442.0397found442.0399。

Claims (7)

1.邻氨基苯甲酰胺类化合物，结构如通式I所示，1. anthranilamide compound, the structure is as shown in general formula I,
Figure FDA0000485782070000011
Figure FDA0000485782070000011
 其中，R1为氟、氯、溴或三氟甲基。Wherein, R 1 is fluorine, chlorine, bromine or trifluoromethyl. 2.权利要求1所述的化合物的制备方法如下：2. The preparation method of the compound described in claim 1 is as follows: 合成路线：synthetic route: 试剂与反应条件：(i)二氯亚砜，二氯甲烷，60℃；(ii)取代苯胺，三乙胺，二氯甲烷；(iii)铁，冰醋酸，乙酸乙酯，加热回流；(iv)硫光气；(v)二氯甲烷，室温；Reagents and reaction conditions: (i) thionyl chloride, dichloromethane, 60°C; (ii) substituted aniline, triethylamine, dichloromethane; (iii) iron, glacial acetic acid, ethyl acetate, heated to reflux; ( iv) Thiophosgene; (v) Dichloromethane, room temperature; R1如权利要求1所述；R 1 as described in claim 1; 具体步骤如下：Specific steps are as follows: （i）将原料邻硝基苯甲酸加入到二氯甲烷中，室温下充分搅拌，待固体完全溶解，缓慢滴加二氯亚砜，滴毕，缓慢升温至60℃，反应3-5h，减压蒸除溶剂和过量的二氯亚砜得中间体邻硝基苯甲酰氯2，封口膜封口保存备用；(i) Add the raw material o-nitrobenzoic acid into dichloromethane, stir well at room temperature, wait until the solid is completely dissolved, slowly add thionyl chloride dropwise, after the drop is completed, slowly raise the temperature to 60°C, react for 3-5h, reduce Pressure steaming to remove solvent and excess thionyl chloride to obtain intermediate o-nitrobenzoyl chloride 2, sealed with a parafilm and preserved for later use; （ii）将取代苯胺和三乙胺溶于二氯甲烷，置于冰浴条件下，待温度降至0℃，将上步制得的邻硝基苯甲酰氯2溶于二氯甲烷，缓慢滴加到上述取代苯胺溶液中，滴毕室温反应2h；待反应完毕，过滤，将滤液减压蒸除溶剂，柱层析分离纯化得中间体N-取代苯基-2-硝基苯甲酰胺，洗脱体系为体积比石油醚：乙酸乙酯=8:1；(ii) Dissolve the substituted aniline and triethylamine in dichloromethane, place in an ice bath, and when the temperature drops to 0°C, dissolve the o-nitrobenzoyl chloride 2 prepared in the previous step in dichloromethane, slowly Add dropwise to the above-mentioned substituted aniline solution, and react at room temperature for 2 hours after dropping; after the reaction is completed, filter, evaporate the filtrate to remove the solvent under reduced pressure, separate and purify by column chromatography to obtain the intermediate N-substituted phenyl-2-nitrobenzamide , the elution system is a volume ratio of petroleum ether: ethyl acetate = 8:1; （iii）将上步制得的N-取代苯基-2-硝基苯甲酰胺和还原铁粉摩尔比1:10加入到冰醋酸和乙酸乙酯的混合溶液中，加热回流4小时，反应完毕后冷却至室温，过滤，滤液用饱和NaCl溶液洗涤，无水硫酸钠干燥，过滤，减压蒸除溶剂，柱层析分离纯化得中间体N-取代苯基-2-氨基苯甲酰胺4，洗脱体系为体积比石油醚：乙酸乙酯=6:1；(iii) Add the N-substituted phenyl-2-nitrobenzamide prepared in the previous step and the reduced iron powder in a molar ratio of 1:10 to the mixed solution of glacial acetic acid and ethyl acetate, heat and reflux for 4 hours, and react After completion, cool to room temperature, filter, wash the filtrate with saturated NaCl solution, dry over anhydrous sodium sulfate, filter, evaporate the solvent under reduced pressure, separate and purify by column chromatography to obtain the intermediate N-substituted phenyl-2-aminobenzamide 4 , the elution system is a volume ratio of petroleum ether: ethyl acetate = 6:1; （iv）将硫光气加入水中21℃下充分搅拌形成非均相体系，将4-氨基-2-三氟甲基苯腈分次加入上述非均相体系，继续充分搅拌1h；反应完毕，将反应液用二氯甲烷萃取，合并有机相，饱和氯化钠洗涤，无水MgSO4干燥，过滤，减压蒸除溶剂，柱层析得中间体异硫氰酸酯6，洗脱体系为体积比石油醚：乙酸乙酯=6:1；(iv) Add thiophosgene to water and stir fully at 21°C to form a heterogeneous system, add 4-amino-2-trifluoromethylbenzonitrile to the above heterogeneous system in portions, and continue stirring for 1 hour; the reaction is complete, The reaction solution was extracted with dichloromethane, the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous MgSO4 , filtered, the solvent was evaporated under reduced pressure, and the intermediate isothiocyanate 6 was obtained by column chromatography. The elution system was Volume ratio of petroleum ether: ethyl acetate = 6:1; （v）将N-取代苯基-2-氨基苯甲酰胺4溶于二氯甲烷，在冰浴条件下缓慢滴加3-腈基-4-三氟甲基苯基异硫氰酸酯6的二氯甲烷溶液，滴毕，室温搅拌7h，析出白色固体，过滤，滤饼用少量二氯甲烷洗涤，得目标化合物。(v) N-substituted phenyl-2-aminobenzamide 4 was dissolved in dichloromethane, and 3-cyano-4-trifluoromethylphenylisothiocyanate 6 was slowly added dropwise under ice bath conditions dichloromethane solution, dropwise, stirred at room temperature for 7h, a white solid precipitated, filtered, and the filter cake was washed with a small amount of dichloromethane to obtain the target compound. 3.权利要求2所述的化合物的制备方法，其特征在于，步骤（ii）中取代苯胺为4-氟苯胺，4-氯苯胺，3-三氟甲基苯胺，3-溴苯胺。3. The preparation method of the compound according to claim 2, wherein the substituted aniline in step (ii) is 4-fluoroaniline, 4-chloroaniline, 3-trifluoromethylaniline, 3-bromoaniline. 4.权利要求2所述的化合物的制备方法，其特征在于，步骤（iii）中，N-取代苯基-2-硝基苯甲酰胺为N-（4-氟苯基）-2-硝基苯甲酰胺，N-（4-氯苯基）-2-硝基苯甲酰胺，N-（3-三氟甲基苯基）-2-硝基苯甲酰胺，N-（3-溴苯基）-2-硝基苯甲酰胺。4. The preparation method of the compound described in claim 2, characterized in that, in step (iii), N-substituted phenyl-2-nitrobenzamide is N-(4-fluorophenyl)-2-nitrobenzamide phenylbenzamide, N-(4-chlorophenyl)-2-nitrobenzamide, N-(3-trifluoromethylphenyl)-2-nitrobenzamide, N-(3-bromo phenyl)-2-nitrobenzamide. 5.权利要求2所述的化合物的制备方法，其特征在于，步骤（v）中，N-取代苯基-2-氨基苯甲酰胺为N-（4-氟苯基）-2-氨基苯甲酰胺，N-（4-氯苯基）-2-氨基苯甲酰胺，N-（3-三氟甲基苯基）-2-氨基苯甲酰胺，N-（3-溴苯基）-2-氨基苯甲酰胺。5. The preparation method of the compound described in claim 2, characterized in that, in step (v), N-substituted phenyl-2-aminobenzamide is N-(4-fluorophenyl)-2-aminobenzene Formamide, N-(4-chlorophenyl)-2-aminobenzamide, N-(3-trifluoromethylphenyl)-2-aminobenzamide, N-(3-bromophenyl)- 2-aminobenzamide. 6.一种抗肿瘤药物组合物，包含权利要求1所述化合物或其药学上可接受的盐以及一种或多种药学上可接受载体或赋形剂。6. An antitumor pharmaceutical composition, comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients. 7.权利要求1所述化合物在制备抗肿瘤的药物中的应用。7. The use of the compound of claim 1 in the preparation of antitumor medicaments.
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