CN102391207B - N-(2-(substituted benzo- thiazole-2- amino formacyl) -phenyl group) - benzamide, as well as preparation method and usages thereof - Google Patents
N-(2-(substituted benzo- thiazole-2- amino formacyl) -phenyl group) - benzamide, as well as preparation method and usages thereof Download PDFInfo
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Abstract
The invention discloses N-(2-(substituted benzo- thiazole -2- amino formacyl) -phenyl group) - benzamide with an effect of plant virus resistance, and a preparation method thereof. The chemical structure is expressed by a general formula (1). The invention introduces a benzothiazole ring benzoyl aminobenzene methanamide compound containing substituted benzoic acid, which adopts raw materials of substituted benzoic acid, substituted anthranllic acid, substituted benzothiazole amine, thionyl chloride and acetic oxide and is synthesized through four steps of chlorination, acidylation, cyclization and ring opening, and the compound has plant virus resisting activity and anticancer activity.
Description
Technical field
The present invention relates to have synthetic and preparation method thereof containing benzothiazole ring o-benzoyl aminobenzoyl aminated compounds of Antiphytoviral effect.
Background technology
O-benzoyl aminobenzoyl aminated compounds is the Ryanicide receptor analogs that a class has good biological activity, and the Ryanicide acceptor of take has been opened up new field as parent carries out the initiative that structural modification is novel pesticide.At present, existing several commercial products occur, the synthetic pesticide Flubendiamide of the Ryanicide receptor structure of two wide spectrums finding as Japanese agricultural chemicals company, Beyer Co., Ltd and E.I.Du Pont Company and chlorantraniliprole etc.O-benzoyl aminobenzoyl aminated compounds has identical action characteristic with Ryanicide alkali, not only insect is had to excellent insecticidal activity, and to mammalian safe.
(Lahm, the G.P. such as Lahm in 2005, Selby, T.P., Freudenberger, J.H., Stevenson, T.M., Myers, B.J., Seburyamo, G., Smith, B.K., Flexner, L., Clark, C.E., Cordova, D.Insecticidal anthranilic diamides:A new class of potent ryanodine receptor activators[J] .Bioorganic & Medicinal Chemistry Letters, 2005, 25 (22), 4898-4906.) with trifluoroacetic ethyl acetoacetate, substituted phenylhydrazines, replace anthranilic acid, 3-(trifluoromethyl)-1H-pyrazoles, 2, 3-dichloropyridine is the O-formammidotiazol-benzamide compounds of the synthetic series of novel of raw material, the release that wherein part of compounds can suppress intracellular Ca2+ has caused Ryanicide acceptor, to lepidoptera pest fall army worm (Spodoptera frugiperda), Heliothis virescens (HeliothisVirescens), small cabbage moth (Plutella xylostella) has good insecticidal activity.
2006, (Masanori, the T. such as Masanori; Hayami, N.; Kazuyuki, S.; Shinsuke, F.; Hideo, K.; Eiji, K.; Tateki, N; Takashi, F.; Toshiaki, S.; Akira, S.Phthalic acid diamide derivatives, agricultural and horticultural insecticides and a method for application of the insecticides[P] .EP 1700844 (A1), 2006.) reported that a class has good insecticidal activity phthalic acid bisamide derivatives, 500 * 10
-6under concentration, majority of compounds has better activity to agricultural and gardening pest insect.
2006, (Jeanguenat, the A. such as Jeanguenat; Osullivan, A.C.Anthranilamide derivatives as insecticides[P] .WO 2006061200,2006[Chem.Abstr.2006,145,62886] .) reported a class ortho position formamido group benzamide compound, in concentration, be 400mg/L, compound to lethality rates such as cigarette aphid, bean aphid, small cabbage moth, cigarette aphid noctuid, prodenia lituras more than 80%.
2006, (Richards, the M.L. such as Richards; Lio, S.C.; Sinha, A.; Banie, H.; Thomas, R.J.; Major, M.; Tanji, M.; Sircar, J.C.Substituted 2-phenyl-benzimidazole derivativesL:novel compounds that suppress key markers of allergy[J] .Tetrahedron,
2007, Lu, (Lu, the D. such as Ding; Vince, R.Discovery of potent HIV-1 protease inhibitors incorporating sultoximine functionality[J] .Bioorganic & Medicinal Chemistry Letters, 2007,17 (20), 5614-5619.) a series of bisamides containing sulfoximide structure have been synthesized in design, and active testing shows that this compounds has good restraining effect to HIV-1 proteolytic enzyme.Active best compound reaches 87% at 10 μ M to the inhibiting rate of HIV-1 proteolytic enzyme, anti-HIV-1 proteolytic enzyme IC
50iC for 2.5nM, anti-HIV-1
50for 408nM.
2007, (Loiseleur, the O. such as Loiseleur; Durieux, P.; Trah, S.; Edmunds, A.; Jeanguenat, A; Stoller, A.; Hughes, D.J.Preparation of pyrazole derivatives as pesticides[P] .WO 2007093402,2007[Chem.Abstr.2007,147,55334] .) reported the bisamide compounds of a class containing pyrazoles, in concentration, be 400 * 10
-6, this compound to the lethality rate of Heliothis virescens (Heliothis virescens), small cabbage moth (Plutella xvlostella), corn root aphid fly (Diabrotica balteata) all more than 80%.
2008, (the Li Bin such as Li Bin, Yang Wen brightness .1-substituted pyridyl-pyrazol acid amide compounds and application [P] .CN 101333213 thereof, 2008[Chem.Abstr.2008,150,168341] .) reported pyrazole amide compounds, in concentration, be 10mg/L, compound to the lethality rate of beet armyworm more than 90%.
2008, (David, the C.A. such as David; Lahm, G.P.; Smith, B.K.; Barry, J.D.; Clagg, D.G.Synthesis of insecticidal fluorinated anthranilic diamides[J] .Bioorganic & Medicinal Chemistry, 2008,16 (6), 3163-3170.) take chlorantraniliprole as guide, the fluorine-containing anthranilic acid Diamines sterilant of a series of high reactivity has been synthesized in design, biological activity test shows: this compounds is higher to the inhibition activity of black peach aphid and cotten aphid, and wherein part of compounds is 100% under 250 * 10-6 concentration.
2008, Scott, (Scott, the D.A. such as D.A.; Aquila, B.M.; Bebernitz, G.A.; Cook, D.J.; Deegan, T.L.; Hattersley, M.M.; Ioannidis, S.; Lyne, P.D.; Omer, C.A.; Ye, M.; Zheng, X.L.Pyridyl and thiazolyl bisamides CSF-1R inhibitors for the treatment of cancer[J] .Bioorganic & Medicinal Chemistry Letters, 200818 (17), 4794-4797.) with gavaculine, substituted benzoic acid, synthesized the bisamide containing heterocycles such as thiazole, pyridines for raw material design, be somebody's turn to do compound acceptor TYR kinases is had to good inhibition activity, structure activity relationship shows that thiazole derivative IC50 is generally better than pyridine compounds and their.
Benzothiazole compound is also found to have good anti-microbial activity, since U.S.'s Beckman company development sixties in 20th century benthiozole (benthiazole) sterilant, the molecular designing of this compounds is the focus of agricultural chemicals initiative with synthetic and bioactivity research.
2002, (El-Gaby, the M.A. such as El-Gaby, Micky, J., Tahol, N.Antimicrobial activity of some novel thiourea, hydrazine, fused pyrimidine and 2-(4-substituted) aniline benzoazole derivatives containing sulfonamide moieties[J] .Journal of Chinese Chemical Society, 2002, 49, 407-414.) with 4-aminobenzene sulfonamide and thio phosgene reaction, synthesized the lsothiocyanates containing benzsulfamide, this lsothiocyanates again with N, in dinethylformamide and triethylamine, reflux a few hours, synthesized the benzo benzo thiazole derivative with fungicidal activity, adopt growth rate method, this compounds is carried out to fungicidal activity test, active testing shows: under the concentration of 1.0mg/ml, this compounds has higher inhibition active to Bacillus proteus, wherein a compound has medium inhibition active to streptococcus aureus (Staphylococcus aureus), penicillin (Penicillium), another compound to the inhibition activity of Bacterium prodigiosum, Sibutramine Hydrochloride mould a little less than.
2006, (the Hou Xuetai such as Hou Taixue, Wang Min, river rears people. the synthetic and bioactivity research [J] of diazosulfide class and benzothiazole compound. and agricultural chemicals, 2006, 45 (12), on the basis that 812-817.)) to have reported at benzothiazole be precursor structure, take gavaculine as raw material, through over-churning, closed loop, a series of benzothiazole compounds have been synthesized in amidation, biological activity test shows: in vitro, part of compounds at 1.0mg/L to the inhibiting rate of gray mold of cucumber (Botrytis cinereapers) in 60% left and right, at middle in vitro, part of compounds does not have restraining effect to gray mold of cucumber under the concentration of 1.0mg/mL, under condition of living body, also higher to the inhibiting rate of gray mold of cucumber.
From background technology, bisamide compounds is good insecticidal activity as chlorantraniliprole has, to mammalian safe, benzothiazole compound has good anti-microbial activity as benzene metsulfovax, rice sheath blight disease is had to excellent preventive effect, but obtain bisamide containing the pyrazol acid amide of benzothiazole, there is no people and synthesized, and obtain containing the pyrazol acid amide of benzothiazole more unmanned research of research that bisamide is used in plant virus.
Summary of the invention
The object of the invention is to design the o-benzoyl aminobenzoyl amino derivative that has synthesized a series of novel structures, this compounds had both had biamide structure, also contain benzothiazole structure, and this series compound has been carried out the novel pesticide initiative of synthetic method and resisting tobacco mosaic virus sick (TMV) and anti-yellowing melon blossom disease viral disease (CMV) and studied as cancer therapy drug.(I) is as follows for its general structure:
R wherein
1for (1) hydrogen; (2) neighbour,, the monosubstituted or polysubstituted halogen atom of contraposition; (3) C1-6 alkyl; (4) C1-6 alkoxyl group;
R
2for (1) halogen atom; (2) C1-6 alkyl; (3) C1-6 alkoxyl group;
R
3for (1) hydrogen; (2) monosubstituted halogen atom; (3) C1-6 alkyl; (4) C1-6 alkoxyl group.
In content of the present invention, C1-6 alkyl can be methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, tert-pentyl, neo-pentyl, n-hexyl, isohexyl, tertiary hexyl, new hexyl; Halogen atom can be fluorine, chlorine, bromine or iodine.
In content of the present invention, the purposes of compound is as plant virus inhibitor, particularly tobacco mosaic virus disease (TMV) and cucumber mosaic virus (CMV) is had to good activity.
In content of the present invention, the purposes of compound is as anti-tumor agent, particularly human breast cancer cell (Bcap-37) is had to good activity.
The preparation method of general formula of the present invention (I) compound be take substituted benzoic acid, to replace anthranilic acid, replace benzothiazole ammonia, thionyl chloride and acetic anhydride be raw material; synthetic through superchlorination, acidylate, cyclisation and open loop four-step reaction, synthetic route is as follows:
The first step: the preparation of substituted benzoyl chloride
Get a certain amount of substituted benzoic acid (band thermometer, drying tube and device for absorbing tail gas) in the there-necked flask of 100ml, then add wherein thionyl chloride, reflux a few hours, react completely, TLC follows the tracks of, and reacts completely, steam excessive thionyl chloride, obtain product;
Second step: the preparation of 2-substituted benzamide yl benzoic acid
Get a certain amount of 2-amino-substituted benzoic acid in the there-necked flask of 250ml, then in reaction flask, add methylene dichloride, then add wherein triethylamine solution, until solution clarification, then, after the acyl chlorides having prepared being diluted with methylene dichloride, dropwise splash in reaction solution stirring at normal temperature, in reaction system, separate out a large amount of solids, TLC follows the tracks of, and reacts completely, and suction filtration obtains solid, washing, methylene dichloride is washed, and then filtrate precipitation is obtained to solid, washing, suction filtration obtains solid, and two parts of solids are merged to obtain to product;
The preparation of the 3rd step: benzoxazinone
Get a certain amount of amido acid in the there-necked flask of 100ml, add wherein appropriate acetic anhydride in there-necked flask, reflux a few hours, standing, the cooling solid of separating out, suction filtration, washing, obtains product;
The 4th step: the preparation of 2-substituted benzene formyl amido N-(benzo [d] thiazole-2 base) substituted benzamide
In the there-necked flask of 100ml, add appropriate replacement benzoxazinone, then add wherein acetonitrile, stir it is dissolved, then in reaction system, add salt of wormwood (oven dry) and benzothiazole ammonia, reflux, TLC follows the tracks of, and reacts completely, and filters, precipitation, DMF and water recrystallization, suction filtration, obtains product;
This step is applicable to all above-mentioned target compound N-(replace benzothiazole-2-formamyl)-phenyl)-substituted benzamide synthetic.
Embodiment
Embodiment mono-, compound N-(2-(6-ethoxyl benzo thiazole-2-formamyl)-phenyl)-2,4 dichloro benzene methane amide (compound number is a) synthetic:
(1) 2,4 dichlorobenzyl chloride is synthetic
Get 2 of 14.32g (0.075mol), 4-dichlorobenzoic acid is (band thermometer, drying tube and device for absorbing tail gas) in the there-necked flask of 100ml, then add wherein 20ml thionyl chloride, reflux 10 hours, TLC follows the tracks of, react completely, steam excessive thionyl chloride, obtain 10.99g liquid;
(2) 2-(2,4 dichloro benzene formamido-) is benzoic synthetic
Get the anthranilic acid of 8.83g (0.064mol) in the there-necked flask of 250ml, then to the methylene dichloride that adds 30ml in reaction flask, then add wherein 3ml triethylamine solution, until solution is brown clarification, then after the acyl chlorides having prepared being used to the methylene dichloride dilution of 30ml, dropwise splash in reaction solution, stirring at normal temperature, after 1h, in reaction system, separate out a large amount of white solids, 10h reacts completely, suction filtration obtains white solid, washing, methylene dichloride is washed, then filtrate precipitation is obtained to solid, washing, suction filtration obtains solid, two parts of solids are merged to obtain to product, dehydrated alcohol recrystallization, obtain micro-yellow crystals, productive rate: 65%, mp:214-216 ℃,
(3) 2-(2,4 dichloro benzene base)-4H-benzo [d] [synthesizing of 1,3] oxazine-4-ketone
Get 4.48g2-(2,4-dichloro-benzoyl amido) phenylformic acid (0.014mol), in the there-necked flask of 50ml, adds the acetic anhydride of 15ml in there-necked flask, reflux 5h wherein, standing, the cooling white solid of separating out, washing, dries, acetone recrystallization, obtain product, productive rate: 78%, mp:197-198 ℃;
(4) N-(2-(6-ethoxyl benzo thiazole-2-formamyl)-phenyl)-2,4 dichloro benzene methane amide is synthetic
To the 2-(2 that adds 0.61g (0.002mol) in the there-necked flask of 100ml, 4-dichlorophenyl)-4H-benzo [d] [1, synthesizing of 3] oxazine-4-ketone, then add wherein the acetonitrile of 30ml, stirring makes its dissolving, then in reaction system, add the salt of wormwood (oven dry) of 0.27g (0.002mol) and 2-amino-6-ethoxyl benzo thiazole of 0.35g (0.002mol), reflux 8h, react completely, filter precipitation, with DMF and water recrystallization or silica gel column chromatography separating purification, obtain yellow solid, 250 ℃ of productive rate: 47%, mp:>.
Synthesizing of embodiment bis-, compound N-(2-(6-methylbenzothiazole-2-formamyl)-phenyl)-2,4 dichloro benzene methane amide (compound number is b)
(1) 2,4 dichlorobenzyl chloride is synthetic
As synthetic in embodiment mono-(1) condition and method;
(2) 2-(2,4 dichloro benzene formamido-) is benzoic synthetic
As synthetic in embodiment mono-(2) condition and method;
(3) 2-(2,4 dichloro benzene base)-4H-benzo [d] [synthesizing of 1,3] oxazine-4-ketone
As synthetic in embodiment mono-(3) condition and method;
(4) N-(2-(6-methylbenzothiazole-2-formamyl)-phenyl)-2,4 dichloro benzene methane amide is synthetic
As synthetic in embodiment mono-(4) condition and method, difference is to add 0.33g2-amino-6-methylbenzothiazole, and reaction times 6h, obtains faint yellow solid, productive rate: 40%, mp:228-229 ℃.
Synthesizing of embodiment tri-, compound N-(2-(6-chloro benzothiazole-2-formamyl)-phenyl)-2,4 dichloro benzene methane amide (compound number is c)
(1) 2,4 dichlorobenzyl chloride is synthetic
As synthetic in embodiment mono-(1) condition and method;
(2) 2-(2,4 dichloro benzene formamido-) is benzoic synthetic
As synthetic in embodiment mono-(2) condition and method;
(3) 2-(2,4 dichloro benzene base)-4H-benzo [d] [synthesizing of 1,3] oxazine-4-ketone
As synthetic in embodiment mono-(3) condition and method;
(4) N-(2-(6-chloro benzothiazole-2-formamyl)-phenyl)-2,4 dichloro benzene methane amide is synthetic
As synthetic in embodiment mono-(4) condition and method, difference is to add 0.37g2-amino-6-chloro benzothiazole, and reaction times 9h, obtains white solid, productive rate: 250 ℃ of 37%, mp:>.
Synthesizing of embodiment tetra-, compound N-(2-(6-methoxybenzothiazole-2-formamyl)-6-aminomethyl phenyl)-2,4 dichloro benzene methane amide (compound number is d)
(1) 2,4 dichlorobenzyl chloride is synthetic
As synthetic in embodiment mono-(1) condition and method;
(2) 2-(2,4 dichloro benzene formamido-)-3-tolyl acid is synthetic
As synthetic in embodiment mono-(2) condition and method, difference is to add 2-amino-3-tolyl acid;
(3) 8-methyl-2-(2,4 dichloro benzene base)-4H-benzo [d] [synthesizing of 1,3] oxazine-4-ketone
As synthetic in embodiment mono-(3) condition and method, difference is to add 2-(2,4 dichloro benzene formamido-)-3-tolyl acid;
(4) N-(2-(6-methoxybenzothiazole-2-formamyl)-6-aminomethyl phenyl)-2,4 dichloro benzene methane amide is synthetic
As synthetic in embodiment mono-(4) condition and method, difference is to add 0.36g2-amino-6-methoxybenzothiazole, and reaction times 5h, obtains faint yellow solid, productive rate: 34%, mp:218-220 ℃.
Synthesizing of embodiment five, compound N-(2-(4-methylbenzothiazole-2-formamyl)-phenyl)-3-chlorobenzamide (compound number is e)
(1) 3-chloro-benzoyl chloride is synthetic
As synthetic in embodiment mono-(1) condition and method, difference is to add 3-chloro-benzoic acid;
(2) 2-(3-chloro-benzoyl amino) is benzoic synthetic
As synthetic in embodiment mono-(2) condition and method, difference is to add 3-chloro-benzoyl chloride;
(3) 2-(3-chloro-phenyl-)-4H-benzo [d] [synthesizing of 1,3] oxazine-4-ketone
As synthetic in embodiment mono-(3) condition and method, difference is to add 2-(3-chloro-benzoyl amino) phenylformic acid;
(4) N-(2-(4-methylbenzothiazole-2-formamyl)-phenyl)-3-chlorobenzamide is synthetic
As synthetic in embodiment mono-(4) condition and method, difference is to add 0.33g (0.002ml) 2-amino-4-methylbenzothiazole, and reaction times 10h, obtains white solid, productive rate: 36%, mp:192-194 ℃.
Synthesizing of embodiment six, compound N-(2-(6-methylbenzothiazole-2-formamyl)-4-aminomethyl phenyl)-3-chlorobenzamide (compound number is f)
(1) 3-chloro-benzoyl chloride is synthetic
As synthetic in embodiment five (1) conditions and method;
(2) 2-(3-chloro-benzoyl amino) is benzoic synthetic
As synthetic in embodiment five (2) conditions and method;
(3) 2-(3-chloro-phenyl-)-4H-benzo [d] [synthesizing of 1,3] oxazine-4-ketone
As synthetic in embodiment five (3) conditions and method;
(4) N-(2-(6-methylbenzothiazole-2-formamyl)-4-aminomethyl phenyl)-3-chlorobenzamide is synthetic
As synthetic in embodiment five (4) conditions and method, difference is to add 0.33g2-amino-4-methylbenzothiazole, and reaction times: 6h, obtains pale yellow powder, productive rate: 41%, and fusing point: 236-238 ℃.
Embodiment seven, compound N-(2-(6-ethoxyl benzo thiazole-2-formamyl)-phenyl)-3,4-dimethoxy benzamide (compound number is g) synthetic
Synthesizing of (1) 3,4-dimethoxy-benzoyl chloride
As synthetic in embodiment mono-(1) condition and method, difference is to add 3,4-dimethoxybenzoic acid;
(2) 2-(3,4-dimethoxy benzoylamino) is benzoic synthetic
As synthetic in embodiment mono-(2) condition and method, difference is to add 3,4-dimethoxy-benzoyl chloride;
(3) 2-(3,4-Dimethoxyphenyl)-4H-benzo [d] [synthesizing of 1,3] oxazine-4-ketone
As synthetic in embodiment mono-(3) condition and method, difference is to add 2-(3,4-dimethoxy benzoylamino) phenylformic acid;
(4) N-(2-(6-ethoxyl benzo thiazole-2-formamyl)-phenyl)-3,4-dimethoxy benzamide synthetic
As synthetic in embodiment mono-(4) condition and method, difference is to add 0.39g2-amino-6-ethoxyl benzo thiazole, and reaction times: 7h, obtains faint yellow solid, productive rate: 250 ℃ of 33%, mp:>.
Embodiment eight, compound N-(2-(4-methylbenzothiazole-2-formamyl)-phenyl)-3,4-dimethoxy benzamide (compound number is h) synthetic
Synthesizing of (1) 3,4-dimethoxy-benzoyl chloride
As synthetic in example seven (1) conditions and method;
(2) 2-(3,4-dimethoxy benzamide) is benzoic synthetic
As synthetic in example seven (2) conditions and method;
(3) 2-(3,4-Dimethoxyphenyl)-4H-benzo [d] [synthesizing of 1,3] oxazine-4-ketone
As synthetic in example seven (3) conditions and method;
(4) N-(2-(4-methylbenzothiazole-2-formamyl)-phenyl)-3,4-dimethoxy benzamide synthetic
As synthetic in example seven (4) conditions and method, difference is to add 2-amino-4-methylbenzothiazole of 0.33g (0.002mol), and reaction times 15h, obtains faint yellow solid, productive rate: 250 ℃ of 33%, mp:>.
Synthesizing of embodiment nine, compound N-(2-(6-ethoxyl benzo thiazole-2-formamyl)-phenyl)-2-methoxy benzamide (compound number is i)
(1) 2-methoxy benzoyl chloride is synthetic
As synthetic in example eight (1) conditions and method, difference is to add O-Anisic Acid;
(2) 2-(2-methoxy benzamide) is benzoic synthetic
As synthetic in example eight (2) conditions and method, difference is to add 2-methoxy benzoyl chloride;
(3) 2-(2-p-methoxy-phenyl)-4H-benzo [d] [synthesizing of 1,3] oxazine-4-ketone
As synthetic in example eight (3) conditions and method, difference is to add 2-(2-methoxy benzamide) phenylformic acid;
(4) N-(2-(6-ethoxyl benzo thiazole-2-formamyl)-phenyl)-2-methoxy benzamide is synthetic
As synthetic in example eight (4) conditions and method, difference is to add amino-6 ethoxyl benzo thiazoles of 2-of 0.39g, and reaction times 10h, obtains faint yellow solid, productive rate: 33%, mp:241-242 ℃.
Synthesizing of embodiment ten, compound N-(2-(4-methylbenzothiazole-2-formamyl)-phenyl)-2-methoxy benzamide (compound number is j)
(1) 2-methoxy benzoyl chloride is synthetic
As synthetic in example nine (1) conditions and method;
(2) 2-(2-methoxy benzamide) is benzoic synthetic
As synthetic in example nine (2) conditions and method;
(3) 2-(2-p-methoxy-phenyl)-4H-benzo [d] [synthesizing of 1,3] oxazine-4-ketone
As synthetic in example nine (3) conditions and method;
(4) N-(2-(4-methylbenzothiazole-2-formamyl)-phenyl)-2-methoxy benzamide is synthetic
As synthetic in example nine (4) conditions and method, difference is to add 2-amino-4-methylbenzothiazole of 0.33g, and reaction times 8h, obtains faint yellow solid, productive rate: 250 ℃ of 40.5%, mp:>.
Synthesizing of embodiment 11, compound N-(2-(6-methoxybenzothiazole-2-formamyl)-phenyl)-2-methoxy benzamide (compound number is k)
(1) 2-methyl benzoyl chloride is synthetic
As synthetic in example nine (1) conditions and method;
(2) 2-(2-methoxy benzamide) is benzoic synthetic
As synthetic in example nine (2) conditions and method;
(3) 2-(2-p-methoxy-phenyl)-4H-benzo [d] [synthesizing of 1,3] oxazine-4-ketone
As synthetic in example nine (3) conditions and method;
(4) N-(2-(6-methoxybenzothiazole-2-formamyl)-phenyl)-2-methoxy benzamide is synthetic
As synthetic in example eight (4) conditions and method, difference is to add 2-amino-6-methoxybenzothiazole of 0.36g, reaction times 7.5h, productive rate: 37%, mp:218-219 ℃.
Synthesizing of embodiment 12, compound N-(2-(6-methylbenzothiazole-2-formamyl)-phenyl)-4-fluorobenzamide (compound number is 1)
(1) 4-fluorobenzoyl chloride is synthetic
As synthetic in example one (1) condition and method, difference is to add 4-fluorobenzoic acid;
(2) 2-(4-fluorobenzamide) is benzoic synthetic
As synthetic in example one (2) condition and method, difference is to add 4-fluorobenzoyl chloride;
(3) 2-(4-fluorophenyl)-4H-benzo [d] [synthesizing of 1,3] oxazine-4-ketone
As synthetic in example one (3) condition and method, difference is to add 2-(4-fluorobenzamide) phenylformic acid;
(4) N-(2-(6-methylbenzothiazole-2-formamyl)-phenyl)-4-fluorobenzamide is synthetic
As synthetic in example one (4) condition and method, difference is to add 2-amino-6-methylbenzothiazole of 0.33g, and reaction times 11h, obtains faint yellow solid, productive rate: 250 ℃ of 47%, mp:>.
Synthesizing of embodiment 13, compound N-(2-(6-fluoro benzothiazole-2-formamyl)-phenyl)-4-fluorobenzamide (compound number is m)
(1) 4-fluorobenzoyl chloride is synthetic
As synthetic in example ten two (1) conditions and method;
(2) 2-(4-fluorobenzamide) is benzoic synthetic
As synthetic in example ten two (2) conditions and method;
(3) 2-(4-fluorophenyl)-4H-benzo [d] [synthesizing of 1,3] oxazine-4-ketone
As synthetic in example ten two (3) conditions and method;
(4) N-(2-(6-fluoro benzothiazole-2-formamyl)-phenyl)-4-fluorobenzoyl is synthetic
As synthetic in example ten two (4) conditions and method, difference is to add 2-amino-6-fluoro benzothiazole of 0.34g, and reaction times 15h, obtains white solid, productive rate: 31%, and fusing point: 234-236 ℃.
Synthesizing of embodiment 14, compound N-(2-(4-methylbenzothiazole-2-formamyl)-phenyl)-4-fluorobenzamide (compound number is n)
(1) 4-fluorobenzoyl chloride is synthetic
As synthetic in example ten two (1) conditions and method;
(2) 2-(4-fluorobenzamide) is benzoic synthetic
As synthetic in example ten two (2) conditions and method;
(3) 2-(4-fluorophenyl)-4H-benzo [d] [synthesizing of 1,3] oxazine-4-ketone
As synthetic in example ten two (3) conditions and method;
(4) N-(2-(4-methylbenzothiazole-2-formamyl)-phenyl)-4-fluorobenzamide is synthetic
As synthetic in example eight (4) conditions and method, difference is to add 2-amino-4-methylbenzothiazole of 0.33g, and reaction times 13h, obtains micro-yellow powder, productive rate: 33%, and fusing point: 205-207 ℃.
Synthesizing of embodiment 15, compound N-(2-(4-methylbenzothiazole-2-formamyl)-4-aminomethyl phenyl)-4-fluorobenzamide (compound number is o)
(1) 4-fluorobenzoyl chloride is synthetic
As synthetic in example one (1) condition and method;
(2) 2-(4-fluorobenzamide)-3-tolyl acid is synthetic
As synthetic in example one (2) condition and method, difference is to add 2-amino-3-tolyl acid;
(3) 8-methyl-2-(4-fluorophenyl)-4H-benzo [d] [synthesizing of 1,3] oxazine-4-ketone
As synthetic in example one (3) condition and method, difference is to add 2-(4-fluorobenzamide)-3-tolyl acid;
(4) N-(2-(4-methylbenzothiazole-2-formamyl)-4-aminomethyl phenyl)-4-fluorobenzamide is synthetic
As synthetic in example one condition and method, difference is to add 2-amino-4-methylbenzothiazole of 0.33g, and reaction times 13h, obtains micro-yellow powder, obtains yellow powder, productive rate: 44%, and fusing point: 210-211 ℃.
Synthesizing of embodiment 16, compound N-(2-(6-chloro benzothiazole-2-formamyl)-phenyl)-2,4 difluorobenzene methane amide (compound number is p)
(1) 2,4 difluorobenzene formyl chloride is synthetic
As synthetic in example one (1) condition and method, difference is to add 2,4 difluorobenzene formic acid;
(2) 2-(2,4-fluorobenzamide) is benzoic synthetic
As synthetic in example one (2) condition and method, difference is to add 2,4 difluorobenzene formyl chloride;
(3) 2-(2,4 difluorobenzene base)-4H-benzo [d] [synthesizing of 1,3] oxazine-4-ketone
As synthetic in example one (3) condition and method, difference is to add 2-(2,4-fluorobenzamide) phenylformic acid;
(4) N-(2-(6-chloro benzothiazole-2-formamyl)-phenyl)-2,4 difluorobenzene methane amide is synthetic
As synthetic in example one (4) condition and method, difference is to add 2-amino-6-chloro benzothiazole of 0.37g, and reaction times 13h, obtains yellow powder, productive rate: 45%, and fusing point: 214-216 ℃.
Synthesizing of embodiment 17, compound N-(2-(6-fluoro benzothiazole-2-formamyl)-phenyl)-2,4 difluorobenzene methane amide (compound number is q)
(1) 2,4 difluorobenzene formyl chloride is synthetic
As synthetic in example ten six (1) conditions and method;
(2) 2-(2,4 difluorobenzene methane amide) is benzoic synthetic
As synthetic in example ten six (2) conditions and method;
(3) 2-(2,4 difluorobenzene base)-4H-benzo [d] [synthesizing of 1,3] oxazine-4-ketone
As synthetic in example ten six (3) conditions and method;
(4) N-(2-(6-fluoro benzothiazole-2-formamyl)-phenyl)-2,4 difluorobenzene methane amide is synthetic
As synthetic in example ten six (4) conditions and method, difference is to add 2-amino-6-fluoro benzothiazole of 0.34g, and reaction times 13h, obtains micro-yellow powder, productive rate: 47%, and fusing point: 124-126 ℃.
Synthesizing of embodiment 18, compound N-(2-(6-chloro benzothiazole-2-formamyl)-phenyl)-2-methyl benzamide (compound number is r)
(1) 2-methyl benzoyl chloride is synthetic
As synthetic in example one (1) condition and method, difference is 2-tolyl acid;
(2) 2-(2-methyl benzamide) is benzoic synthetic
As synthetic in example one (2) condition and method, difference is to add 2-methyl benzoyl chloride;
(3) 2-(2-aminomethyl phenyl)-4H-benzo [d] [synthesizing of 1,3] oxazine-4-ketone
As synthetic in example one (3) condition and method, difference is to add 2-(2-methyl benzamide) phenylformic acid;
(4) N-(2-(6-chloro benzothiazole-2-formamyl)-phenyl)-2-methyl benzamide is synthetic
As synthetic in example one (4) condition and method, difference is to add 2-amino-6-chloro benzothiazole of 0.37g, and reaction times 13h, obtains light yellow crystal, productive rate: 39%, and fusing point: 210-212 ℃.
The N-of partial synthesis (2-(replacing benzo [d] thiazole-2-formamyl)-phenyl)-benzamide derivatives spectral data is as follows:
Compound a: N-(2-(6-oxyethyl group benzo [d] thiazole-2-formamyl)-phenyl)-2,4 dichloro benzene methane amide yellow solid, yield 47%, fusing point: 268-270 ℃;
1h NMR (500MHz, DMSO-d
6) δ: 12.72 (s, 1H, NH), 8.15 (s, 1H, Ph-H), 7.99 (d, J=7.5Hz, 1H, Ph-H), 7.82 (d, J=8.1Hz, 1H, Ph-H), 7.76 (s, 1H, Ph-H), 7.55-7.62 (m, 3H, Ph-H), 7.47 (s, 1H, Ph-H), 7.28 (t, 1H, Ph-H), 6.98 (dd, J=2.3,2.3Hz, 1H, Ph-H), 4.05 (q, J=6.9Hz, 2H, OCH
2), 1.34 (t, J=6.9Hz, 3H, CH
3);
13c NMR (125MHz, DMSO-d
6) δ: 168.4,164.2,155.5,142.8,138.1,135.8,135.6,133.5,132.3,132.1,131.2,130.2,130.1,128.2,125.9,124.5,122.5,120.7,115.3,105.9,64.1,15.2; IR (KBr) v:3419,2978,2868,1674,1587,1496,1448,1429,1313,1217,1109,1066,918,813,758.Anal.calcd for C
23h
17c
l2n
3o
3s:C, 56.80; H, 3.52; N, 8.64; Found C, 56.35; H, 3.36; N, 8.59.
Compound b:N-(2-(6-methyl benzo [d] thiazole-2-formamyl)-phenyl)-2,4 dichloro benzene methane amide faint yellow solid, yield 40%, fusing point 228-229 ℃;
1h NMR (500MHz, DMSO-d
6) δ: 12.87 (s, 1H, NH), 10.98 (s, 1H, NH), (7.95 s, 1H, Ph-H), 7.91 (s, 1H, Ph-H), 7.76 (s, 2H, Ph-H), 7.72 (d, J=8.6Hz, 1H, Ph-H), 7.63 (q, 3H, Ph-H), 7.35 (t, 1H, Ph-H), 7.27 (d, J=8.0Hz, 1H, Ph-H), 2.42 (s, 3H, CH
3);
13c NMR (125MHz, DMSO-d
6) δ: 165.1,156.3,135.2,136.4,132.0,131.9,131.3,129.5,128.6,125.1,115.7,105.0,19.1; IR (KBr) v:3223,3057,2914,1645,1587,1543,1496,1448,1423,1342,1301,1234,1103,1047,918,754.Anal.calcd for C
22h
15cl
2n
3o
2s:C, 57.90; H, 3.31; N, 9.21; Found C, 57.49; H, 3.54; N, 9.05.
Compound c:N-(2-(6-chlorobenzene is [d] thiazole-2-formamyl also)-phenyl)-2,4 dichloro benzene methane amide white solid, yield 37%, fusing point 283-284 ℃;
1hNMR (500MHz, DMSO-d
6) δ: 8.63 (s, 1H, Ph-H), 8.26 (d, J=7.5Hz, 1H, Ph-H), 8.05 (d, J=8.6Hz, 1H, Ph-H), 7.80 (d, J=9.2Hz, 2H, Ph-H), 7.64 (d, J=8.0Hz, 1H, Ph-H), 7.47 (q, 2H, Ph-H), 7.27 (d, J=8.6Hz, 1H, Ph-H), 7.17 (t, 1H, Ph-H);
13cNMR (125MHz, DMSO-d
6) δ: 170.7,167.7,163.8,135.7,135.6,132.5,131.6,131.4,130.9,130.4,128.4,125.4,125.3,123.2,120.8,120.5; IR (KBr) v:3213,3169,3078,3062,1668,1651,1585,1494,1444,1427,1373,1342,1288,1259,1103,1049,912,845,810,682.Anal.calcd for C
21h
12cl
3n
3o
2s:C, 52.90; H, 2.54; N, 8.81; Found C, 52.73; H, 2.44; N, 8.57.
Compound d:N-(2-(6-methoxyl group benzo [d] thiazole-2-formamyl)-6-aminomethyl phenyl)-2,4 dichloro benzene methane amide
Faint yellow solid, yield 34%, fusing point 218-220 ℃;
1hNMR (500MHz, DMSO-d
6) 12.65 (s, 1H, NH), 10.22 (s, 1H, NH), 7.72 (s, 1H, Ph-H), 7.67 (d, J=8.0Hz, 1H, Ph-H), 7.59 (s, 3H, Ph-H), 7.52 (dd, J=6.9,7.5Hz, 2H, Ph-H), 7.36 (q, 2H, Ph-H), 7.04 (d, J=8.6Hz, 1H, Ph-H), 3.82 (s, 3H, OCH
3), 2.36 (s, 3H, OCH
3);
13cNMR (125MHz, DMSO-d
6) δ: 167.0,164.8,156.9,156.7,143.3,136.2,136.1,135.3,133.8,133.6,132.5,131.6,130.6,129.7,127.9,127.0,121.7,115.4,105.2,56.2,18.5; IR (KBr) v:3443,3419,2991,1666,1647,1602,1541,1533,1469,1296,1261,1244,1220,1147,1101,1058,1028,958,827,738,648.Anal.calcd for C
23h
17cl
2n
3o
3s:C, 56.80; H, 3.52; N, 8.64; Found C, 56.48; H, 3.68; N, 8.31.
Verbindung: N-(2-(4-methyl benzo [d] thiazole-2-formamyl)-phenyl)-3-chlorobenzamide
White solid, yield 36%, fusing point: 192-194 ℃;
1h NMR (500MHz, DMSO-d
6) δ: 12.90 (s, 1H, NH), 10.96 (s, 1H, NH), 8.19-8.15 (m, 1H, Ph-H), 7.99-7.92 (m, 2H, Ph-H), 7.87 (d, J=5.7Hz, 1H, Ph-H), 7.80 (d, J=7.5Hz, 1H, Ph-H), 7.77-7.75 (m, 1H, Ph-H), 7.69-7.62 (m, 2H, Ph-H), 7.33 (t, 1H, Ph-H), 7.26 (d, J=6.9Hz, 1H, Ph-H), 7.22 (d, J=7.5Hz, 1H, Ph-H), 2.73 (s, 3H, CH
3);
13c NMR (125MHz, DMSO-d
6) δ: 164.3,162.8,159.2,155.7,146.5,137.5,132.9,131.6,129.5,128.7,127.9,127.7,127.6,126.9,40.0,36.3,31.3,18.6; IR (KBr) v:3072,2920,2850,1759,1647,1600,1525,1473,1319,1246,1220,1057,1036,1004,923,798,767,688.Anal.calcd for C
22h
16clN
3o
2s:C, 62.63; H, 3.82; N, 9.96; Found C, 62.74; H, 3.91; N, 9.49.
Compound f:N-(2-(6-methyl benzo [d] thiazole-2-formamyl)-4-aminomethyl phenyl)-3-chlorobenzamide
Pale yellow powder, yield 41%, fusing point: 236-238 ℃;
1h NMR (500MHz, DMSO-d
6) δ: 12.88 (s, 1H, NH), 11.42 (s, 1H, NH), 8.06 (s, 1H, Ph-H), 8.00 (s, 2H, Ph-H), 7.87 (d, J=6.9Hz, 1H, Ph-H), 7.85 (s, 1H, Ph-H), 7.68 (d, J=6.9Hz, 1H, Ph-H), 7.59 (t, 1H, Ph-H), 7.61 (t, 1H, Ph-H), 7.43 (d, J=8.6Hz, 1H, Ph-H), 7.25 (d, J=8.0Hz, 1H, Ph-H), 2.42 (s, 3H, CH
3), 2.38 (s, 3H, CH
3);
13cNMR (125MHz, DMSO-d
6) δ: 164.0,137.3,134.0,133.7,133.4,132.2,131.2,130.6,127.9,127.8,126.6,124.7,121.9,119.7,21.5,20.9; IR (KBr) v:3334,3145,2916,1647,1606,1550,1518,1456,1313,1290,1267,1199,952,898,858,810,771,740,700; Anal.calcd for C
23h
18clN
3o
2s:C, 63.37; H, 4.16; N, 9.64; Found C, 63.01; H, 3.75; N, 9.66.
Compound g:N-(2-(6-oxyethyl group benzo [d] thiazole-2-formamyl)-phenyl)-3,4-dimethoxy benzamide
Faint yellow solid, yield 33%, fusing point: 273-274 ℃;
1h NMR (500MHz, DMSO-d
6) δ: 12.81 (s, 1H, NH), 11.23 (s, 1H, NH), 8.41 (s, 1H, Ph-H), 8.12 (s, 1H, Ph-H), 7.61-7.50 (m, 5H, Ph-H), 7.10 (t, 3H, Ph-H), 4.05 (s, 2H, OCH
2), 3.82 (s, 6H, OCH
3), 1.33 (s, 3H, CH
3).
13c NMR (125MHz, DMSO-d
6) δ: 164.9,156.1,149.1,133.5,127.2,123.7,122.3,121.0,116.0,111.8,111.0,106.0,64.2,56.3,56.1,15.2; IR (KBr) v:3153,3126,2972,2929,1660,1647,1600,1392,1346,1217,1176,1138,945,908,864,752; Anal.calcd for C
25h
23n
3o
5s:C, 62.88; H, 4.85; N, 8.80; Found C, 62.67; H, 5.02; N, 8.60.
Compound h:N-(2-(4-methyl benzo [d] thiazole-2-formamyl)-phenyl)-3,4-dimethoxy benzamide
Faint yellow solid, yield is 33%, 300 ℃ of fusing point >.
1H?NMR(500MHz，DMSO-d
6)δ：12.97(s，1H，NH)，11.25(s，1H，NH)，8.20(s，1H，Ph-H)，7.81(m，4H，Ph-H)，7.25(m，5H，Ph-H)，3.82(s，6H，OCH
3)，2.47(s，3H，CH
3).
13C?NMR(125MHz，DMSO-d
6)δ：164.9，152.4，149.1，133.5，130.2，127.2，123.6，122.5，121.0，119.6，111.8，111.0，56.2，56.0，18.6；IR(KBr)v：3286，3259，3134，2987，2931，1662，1643，1604，1446，1328，1219，1128，1024，945，912，854，823，767，750；Anal.calcd?for?C
24H
21N
3O
4S：C，64.41；H，4.73；N，9.39；Found?C，64.85；H，4.71；N，9.12.
Compound i:N-(2-(6-oxyethyl group benzo [d] thiazole-2-formamyl)-phenyl)-2-methoxy benzamide
Faint yellow solid, yield 33%, fusing point: 241-242 ℃;
1h NMR (500MHz, DMSO-d
6) δ: 12.91 (s, 1H, NH), 11.76 (s, 1H, NH), 8.60 (d, J=8.6Hz, 1H, Ph-H), 8.01 (s, 2H, Ph-H), 7.56 (t, 4H, Ph-H), (7.23 d, J=7.5Hz, 4H, Ph-H), 4.10-3.31 (m, 5H, OCH
3+ OCH
2), 1.34 (t, 3H, J=6.9Hz, CH
3);
13c NMR (125MHz, DMSO-d
6) δ: 163.7,157.8,156.1,139.0,134.3,133.3,132.1,130.0,123.6,122.5,121.8,121.4,116.1,112.8,112.7,105.8,64.1,56.6,15.2; IR (KBr) v:3020,2976,2926,2879,1658,1639,1597,1550,1510,1458,1440,1269,1215,1022,948,918,869,799,750; Anal.calcd for C
24h
21n
3o
4s:C 64.41, and H 4.73, and N 9.39; Found C, 64.45, H 5.03, and N 8.94
Compound j:N-(2-(4-methyl benzo [d] thiazole-2-formamyl)-phenyl)-2-methoxy benzamide
Faint yellow solid, yield 40.5%, 300 ℃ of fusing point >;
1h NMR (500MHz, DMSO-d
6) δ: 13.08 (s, 1H, NH), 11.70 (s, 1H, NH), 8.58 (d, 1H, J=7.5Hz, Ph-H), 8.01 (s, 2H, Ph-H), 7.56 (d, J=17.8Hz, 2H, Ph-H), 7.23 (m, 5H, Ph-H), 4.12 (s, 3H, OCH
3), 2.52 (s, 3H, CH
3);
13c NMR (125MHz, DMSO-d
6) δ: 167.8,163.7,157.8,148.1,134.3,133.4,132.1,130.2,127.3,124.3,123.6,122.6,121.8,121.4,119.7,112.8,56.6,18.6; IR (KBr) v:3251,3172,2943,2918,1670,1645,1598,1583,1446,1406,1296,1267,1242,1228,1159,1072,1016,918,891,856,744; Anal.calcd for C
23h
19n
3o
3s:C, 66.17; H, 4.59; N, 10.07; Found C, 66.22; H, 4.92; N, 10.21.
Compound k:N-(2-(6-methoxyl group benzo [d] thiazole-2-formamyl)-phenyl)-2-methoxy benzamide
Faint yellow solid, yield is 37%, fusing point 218-219 ℃;
1h NMR (500MHz, DMSO-d
6) δ: 12.91 (s, 1H, NH), 11.74 (s, 1H, NH), 8.60 (d, J=8.1Hz, 1H, Ph-H), 8.01 (s, 2H, Ph-H), 7.59 (t, J=17.7Hz, 2H, Ph-H), 7.23 (m, 4H, Ph-H), 4.12 (s, 3H, OCH
3), 3.31 (s, 3H, OCH
3);
13c NMR (125MHz, DMSO-d
6) δ: 163.7,157.8,156.9,139.0,134.3,133.3,132.2,130.1,123.6,122.5,122.1,115.8,112.8,105.2,56.6,56.2; IR (KBr) v:3250,3099,2935,2833,1734,1654,1639,1550,1315,1296,1219,1126,1076,1022,948,920,837,808,752,684; Anal.calcd for C
23h
19n
3o
4s:C, 63.73; H, 4.42; N, 9.69; Found C, 63.56; H, 4.53; N, 9.38.
Compound l:N-(2-(6-methyl benzo [d] thiazole-2-formamyl)-phenyl)-4-fluorobenzamide
Faint yellow solid, yield 47%, fusing point: 266-268 ℃;
1hNMR (500MHz, DMSO-d
6) δ: 8.87 (d, J=8.1Hz, 1H, Ph-H), 8.80 (q, 2H, Ph-H), 8.28 (dd, J=1.8,1.8Hz, 1H, Ph-H), 7.61 (d, J=8.0Hz, 1H, Ph-H), 7.56 (s, 1H, Ph-H), 7.46-7.41 (m, 3H, Ph-H), 7.15 (t, 2H, Ph-H), 2.40 (s, 3H, CH
3);
13cNMR (125MHz, DMSO-d
6) δ: 170.0,167.4,165.8,163.9,163.7,149.0,140.9,133.7,131.9,131.7,131.6,131.1,131.0,130.4,126.4,125.7,122.5,121.2,119.5,116.0,115.9,21.6; IR (KBr) v:3115,3070,3051,2918,1666,1602,1585,1506,1454,1382,1319,1298,1242,1134,1111,925,885,844,812,756; Anal.calcd for C
22h
16fN
3o
2s:C, 65.17; H, 3.98; N, 10.36; Found C, 64.73; H, 3.67; N, 10.38.
Compound m:N-(2-(6-fluorobenzene is [d] thiazole-2-formamyl also)-phenyl)-4-fluorobenzamide
White powder, yield 31%, fusing point 234-236 ℃;
1hNMR (500MHz, DMSO-d
6) δ: 13.00 (s, 1H, NH), 11.83 (s, 1H, NH), 8.50 (d, J=8.6Hz, 1H, Ph-H), 8.04-7.63 (m, 6H, Ph-H), 7.43-7.32 (m, 3H, Ph-H), 7.14 (t, 1H, Ph-H);
13cNMR (125MHz, DMSO-d
6) δ: 167.8,164.5,163.9,163.8,162.8,160.1,158.2,133.2,130.7,130.6,129.9,129.8,124.0,121.6,116.3,116.2,116.1,116.0,114.9,114.7,114.6; IR (KBr) v:3442,3419,3300,3230,3177,1647,1600,1558,1505,1437,1342,1286,1253,1234,1195,1163,852,758,692; Anal.calcd for C
21h
13fN
3o
2s:C, 61.61; H, 3.20; N, 10.26; Found C, 61.99; H, 3.09; N, 10.14.
Compound n:N-(2-(4-methyl benzo [d] thiazole-2-formamyl)-phenyl)-4-fluorobenzamide
Micro-yellow powder, yield 33%, fusing point: 205-207 ℃;
1hNMR (500MHz, DMSO-d
6) δ: 12.98 (s, 1H, NH), 11.83 (s, 1H, NH), 8.48 (d, J=8.0Hz, 1H, Ph-H), 8.05 (s, 1H, Ph-H), 7.80 (s, 1H, Ph-H), 7.70-7.62 (m, 2H, Ph-H), 7.34-7.12 (m, 6H, Ph-H), 2.60 (s, 3H, CH
3);
13cNMR (125MHz, DMSO-d
6) δ: 167.8,165.8,164.5,164.0,163.8,162.8,133.2,130.7,130.6,129.9,129.8,124.0,116.3,116.2,116.1,18.6; IR (KBr) v:3479,3471,3462,1651,1604,1585,1531,1506,1449,1427,1327,1290,1265,1230,1161,920,846,744; Anal.calcd for C
22h
16fN
3o
2s:C, 65.17; H, 3.98; N, 10.36; Found C, 64.96; H, 4.16; N, 10.21.
Compound o:N-(2-(4-methyl benzo [d] thiazole-2-formamyl)-4-aminomethyl phenyl)-4-fluorobenzamide
Yellow powder, yield 44%, fusing point: 210-211 ℃;
1h NMR (500MHz, DMSO-d
6) δ: 12.88 (s, 1H, NH), 11.02 (s, 1H, NH), 8.01 (s, 3H, Ph-H), 7.80 (s, 2H, Ph-H), 7.45 (s, 1H, Ph-H), 7.41 (s, 2H, Ph-H), 7.28 (s, 1H, Ph-H), 7.22 (s, 1H, Ph-H), 2.61 (s, 3H, CH
3), 2.38 (s, 3H, CH
3);
13c NMR (125MHz, DMSO-d
6) δ: 168.0,165.7,164.3,163.8,158.0,148.1,133.8,131.6,130.5,130.4,124.2,123.2,116.3,116.2,60.3,20.8,18.5; IR (KBr) v:3296,3109,2916,1680,1653,1602,1589,1521,1506,1473,1404,1317,1282,1259,1232,1201,1159,1074,948,875,842,746; Anal.calcd for C
22h
18fN
3o
2s:C, 65.86; H, 4.33; N, 10.02; Found C, 65.78; H, 4.27; N, 10.16.
Compound p:N-(2-(6-chlorobenzene is [d] thiazole-2-formamyl also)-phenyl)-2,4 difluorobenzene methane amide
Yellow powder, yield 45%, fusing point: 214-216 ℃;
1hNMR (500MHz, DMSO-d
6) δ: 13.10 (s, 1H, NH), 11.11 (s, 1H, NH), 8.18 (s, 3H, Ph-H), 7.78 (d, J=8.0Hz, 1H, Ph-H), 7.67 (t, 1H, Ph-H), 7.49 (t, 3H, Ph-H), 7.36 (t, 1H, Ph-H), 7.33 (t, 1H, Ph-H);
13cNMR (125MHz, DMSO-d
6) δ: 165.5,162.8,161.6,161.4,137.9,133.4,133.2,133.1,130.0,128.3,126.9,124.7,123.8,123.1,122.0,120.3,120.2,112.9,112.7,105.7,105.5,105.2; IR (KBr) v:3454,3442,3331,1685,1651,1597,1556,1442,1315,1265,1139,1101,966,918,856,808,759; Anal.calcd for C
21h
12clF
2n
3o
2s:C, 56.83; H, 2.73; N, 9.47; Found C, 56.37; H, 3.25; N, 9.90.
Compound q:N-(2-(6-fluorobenzene is [d] thiazole-2-formamyl also)-phenyl)-2,4 difluorobenzene methane amide
Micro-yellow powder, yield 47%, fusing point: 124-126 ℃;
1hNMR (500MHz, DMSO-d
6) δ: 13.05 (s, 1H, NH), 11.15 (s, 1H, NH), 8.21 (s, 1H, Ph-H), 7.96 (q, 2H, Ph-H), 7.80-7.64 (m, 3H, Ph-H), 7.51 (t, 1H, Ph-H), 7.35-7.24 (m, 3H, Ph-H);
13cNMR (125MHz, DMSO-d
6) δ: 161.6,161.5,160.2,159.6,158.3,133.3,133.2,133.1,130.1,124.6,123.7,115.0,114.8,113.0,112.8,105.7,105.5; IR (KBr) v:3442,3419,3336,1680,1614,1587,1556,1525,1463,14421288,1253,1197,1072,972,850,827,806; Anal.calcd for C
21h
12f
3n
5o
2s:C, 59.01; H, 2.83; N, 9.83; Found C, 58.67; H, 3.21; N, 9.44.
Compound r:N-(2-(6-chlorobenzene is [d] thiazole-2-formamyl also)-phenyl)-2-methyl benzamide
Light yellow crystal, yield 39%, fusing point 210-212 ℃;
1h NMR (500MHz, DMSO-d
6) δ: 12.95 (s, 1H, NH), 11.51 (s, 1H, NH), 8.06 (s, 2H, Ph-H), 7.95 (d, J=6.9Hz, 1H, Ph-H), 7.71-7.57 (m, 3H, Ph-H), 7.43-7.27 (m, 5H, Ph-H), 2.43 (s, 3H, CH
3);
13cNMR (125MHz, DMSO-d
6) δ: 168.0,136.7,136.5,132.6,131.4,130.6,130.0,127.9,126.7,125.4,121.8,20.1; IR (KBr) v:3251,3207,3061,2958,1651,1587,1523,1446,1367,1273,1103,921,852,812,748,686; Anal.calcd for C
22h
16clN
3o
2s:C, 62.63; H, 3.82; N, 9.96; Found C, 62.41; H, 4.13; N, 9.56.
Compound s:N-(2-(benzo [d] thiazole-2-formamyl)-6-aminomethyl phenyl)-2-methyl benzamide
White roll body, yield 31%, fusing point: 214-216 ℃;
1h NMR (500MHz, DMSO-d
6) δ: 12.74 (s, 1H, NH), 9.96 (s, 1H, NH), 8.01 (d, J=8.0Hz, 1H, Ph-H), 7.77 (d, j=8.0Hz, 1H, Ph-H), 7.50 (m, 3H, Ph-H), 7.45 (t, 1H, Ph-H), 730 (q, 3H, Ph-H), 7.28-7.23 (m, 2H, Ph-H), 2.37 (s, 3H, CH3), 2.34 (s, 3H, CH
3);
13cNMR (125MHz, DMSO-d
6) δ: 168.5,167.4,159.0,149.2,137.3,136.2,136.1,134.6,133.6,132.5,132.1,130.9,130.0,127.8,127.0,126.7,126.0,124.0,122.2,121.0,19.8,18.6; IR (KBr) v:3273,3178,3064,1662,1597,1541,1300,1099,1012,960,867,744; Anal.calcd forC
23h
19n
3o
2s:C, 68.81; H, 4.77; N, 10.47; Found C, 68.46; H, 4.67; N, 10.13.
Compound t:N-(2-(benzo [d] thiazole-2-formamyl)-4-aminomethyl phenyl)-2-methyl benzamide
Yellow solid, yield 37%, fusing point: 180-181 ℃;
1h NMR (500MHz, DMSO-d
6) δ: 12.76 (s, 1H, NH), 10.70 (s, 1H, NH), 7.98 (d, J=8.0Hz, 1H, Ph-H), 7.78 (s, 1H, Ph-H), 7.74 (d, J=8.1Hz, 1H, Ph-H), 7.58 (d, J=7.5Hz, 1H, Ph-H), 7.47-7.43 (m, 2H, Ph-H), 7.40 (t, 1H, Ph-H), 7.32 (q, 3H, Ph-H), 2.40 (s, 3H, CH
3), 2.38 (s, 3H, CH
3);
13cNMR (125MHz, DMSO-d
6) δ: 167.9,137.0,136.4,133.7,133.4,131.4,130.5,130.3,127.7,126.8,126.3,124.2,122.4,20.9,20.0; IR (KBr) v:3252,3238,3057,2920,1683,1653,1591,1525,1440,1317,1271,1226,1195,950,829,752,719; Anal.calcd for C
23h
19n
3o
2s:C, 68.81; H, 4.77; N, 10.47; Found C, 68.73; H, 4.54; N, 10.35..
Compound u:N-(2-(4-methyl benzo [d] thiazole-2-formamyl)-phenyl)-4-chlorobenzamide
Clear crystal, yield 45%, 300 ℃ of fusing point >;
1h NMR (500MHz, DMSO-d
6) δ: 8.85 (d, J=8.0Hz, 1H, Ph-H), 8.74 (d, J=8.6Hz, 2H, Ph-H), 8.26 (dd, J=1.7,1.8Hz, 1H, Ph-H), 7.68 (d, J=5.0Hz, 2H, Ph-H), 7.56 (t, 2H, Ph-H), 7.42 (t, 1H, Ph-H), 7.14-7.11 (m, 2H, Ph-H), 3.81 (s, 3H, OCH
3);
13c NMR (125MHz, DMSO-d
6) δ: 170.0,163.7,140.7,137.0,134.2,131.2,131.0,126.5,125.6,121.2,119.7,119.4,21.6; IR (KBr) v:3163,3120,3101,1653,1591,1552,1506,1491,1456,1381,1334,1249,1113,918,815,756; Anal.calcd for C
22h
16clN
3o
2s:C, 62.63; H, 3.82; N, 9.96; Found C, 62.76; H, 3.72; N, 9.70.
Compound v:N-(2-(6-methyl benzo [d] thiazole-2-formamyl)-phenyl)-4-chlorobenzamide clear crystal, yield 34%, 300 ℃ of fusing point >;
1h NMR (500MHz, DMSO-d
6) δ: 8.85 (d, J=8.0Hz, 1H, Ph-H), 8.64 (d, J=8.6Hz, 2H, Ph-H), 8.27 (dd, J=1.7,1.2Hz, 1H, Ph-H), 7.68 (d, J=8.6Hz, 2H, Ph-H), 7.56 (d, J=7.5Hz, 1H, Ph-H), 7.42 (t, 1H, Ph-H), 7.13 (q, 2H, Ph-H), 6.99 (t, 1H, Ph-H), 2.70 (s, 3H, CH
3);
13c NMR (125MHz, DMSO-d
6) δ: 172.1,163.2,140.2,136.8,134.0,131.2,131.6,126.9,125.6,121.9,119.1,118.7,21.1; IR (KBr) v:3051,3032,1666,1585,1508,1467,1444,1381,1319,1255,1113,1009,921,839,756; Anal.calcd for C
22h
16clN
3o
2s:C, 62.63; H, 3.82; N, 9.96; Found C, 62.63; H, 3.82; N, 9.96.
Compound w:N-(2-(6-fluorobenzene is [d] thiazole-2-formamyl also)-phenyl)-4-chlorobenzamide
Clear crystal, yield 34%, 300 ℃ of fusing point >;
1h NMR (500MHz, DMSO-d
6) δ: 13.06 (s, 1H, NH), 8.10-7.96 (m, 4H, Ph-H), 7.77 (s, 1H, Ph-H), 7.64 (d, J=8.0Hz, 4H, Ph-H), 7.34-7.30 (m, 2H, Ph-H);
13c NMR (125MHz, DMSO-d
6) δ: 164.6,160.2,158.3,137.3,133.8,133.1,130.1,129.8,129.3,124.6,114.9,114.7,108.9,108.6; IR (KBr) v:3523,3448,3419,3169,3149,3115,3064,1654,1593,1552,1506,1489,1437,1348,1253,1196,752; Anal.calcd for C
21h
13clFN
3o
2s:C, 59.23; H, 3.08; N, 9.87; Found C, 59.50; H, 3.01; N, 9.67.
Compound x:N-(2-(6-methyl benzo [d] thiazole-2-formamyl)-4-aminomethyl phenyl)-4-chlorobenzamide
Faint yellow solid, yield 38%, fusing point: 237-238 ℃;
1h NMR (500MHz, DMSO-d
6) δ: 12.77 (s, 1H, NH), 11.19 (s, 1H, NH), 8.07 (s, 1H, Ph-H), 7.95 (d, J=7.5Hz, 2H, Ph-H), 7.87 (s, 1H, Ph-H), 7.77 (s, 1H, Ph-H), 7.64 (d, J=8.1Hz, 3H, Ph-H), 7.45 (d, J=8.0Hz, 1H, Ph-H), 7.27 (d, J=8.1Hz, 1H, Ph-H), 2.42 (s, 3H, CH
3), 2.37 (s, 3H, CH
3);
13cNMR (125MHz, DMSO-d
6) δ: 174.7,166.4,31.4,24.8; IR (KBr) v:3155,3076,2920,1653,1595,1504,1454,1419,1338,1193,1116,1093,1010,939,896,844,806,742; Anal.calcd for C
23h
18clN
3o
2s:C, 63.37; H, 4.16; N, 9.64; Found C, 63.32; H, 3.92; N, 9.55.
Compound y:N-(2-(benzo [d] thiazole-2-formamyl)-4-aminomethyl phenyl)-4-chlorobenzamide
Yellow powder, yield 42%, fusing point: 242-244 ℃;
1h NMR (500MHz, DMSO-d
6) δ: 12.91 (s, 1H, NH), 11.25 (s, 1H, NH), 8.08 (s, 1H, Ph-H), 7.98 (d, J=6.0Hz, 2H, Ph-H), 7.88 (s, 1H, Ph-H), 7.74 (s, 1H, Ph-H), 7.64 (d, J=8.6Hz, 2H, Ph-H), 7.45 (d, J=9.7Hz, 3H, Ph-H), 7.32 (d, J=6.9Hz, 1H, Ph-H), 2.38 (s, 3H, CH
3);
13c NMR (125MHz, DMSO-d
6) δ: 164.4,133.7,130.6,129.7,129.3,126.8,124.2,122.4,20.9; IR (KBr) v:3066,2920,1654,1595,1570,1539,1506,1496,1462,1450,1400,1338,1309,1284,1249,1220,1197,825,742,677; Anal.calcd for C
22h
16clN
3o
2s:C, 62.63; H, 3.82; N, 9.96; Found C, 62.46; H, 3.79; N, 10.08.
Embodiment 15, the compound inhibition activity test test method sick to cucumber mosaic virus (CMV)
(1) test method
With the consistent Chenopodium amaranticolor of growing way (Chenopodium amaranticolor), be withered spot host, with writing brush by the artificial frictional inoculation of virus on the of the right age blade sprinkled with silicon carbide, with clear water, leaf cleaning is clean after 0.5h, illumination cultivation 1.5h.Accurately take appropriate test compound in weighing bottle, add solvent DMF 30 μ L that it is fully dissolved, if insoluble, add to 50 μ L, with the redistilled water containing 1%Tween20, be made into the compound solution of 500mg/L.Separately get 125 μ L2% Ningnanmycin aquas, add solvent DMF 30 μ L, containing the redistilled water 5mL of 1%Tween20, be made into the Ningnanmycin solution of 500mg/L.Spread respectively 500mg/L test compound and Ningnanmycin at Zuo Banye, right half leaf be take solvent as contrast.Every chemicals treatment 3 strains, 6 leaves of every strain.In illumination box, moisturizing is cultivated subsequently, controls 28 ± 1 ℃ of temperature, and illumination 10000Lux observes and record the number that produces withered spot after 6～7d.Withered spot inhibiting rate calculation formula:
X％＝(CK-T)/CK×100％
X: relative inhibition (%), CK: control group (right half leaf) withered spot number (individual)
T: compound treatment group (Zuo Banye) withered spot number (individual)
(2) test-results
Adopt aforesaid method, when drug concentration is 500 μ g/mL, part of compounds having been carried out to cucumber mosaic virus (CMV) live body therapeutic activity measures, the results are shown in Table 1. after tested, compound i, j, k, s, u are that the live body treatment inhibiting rate that 500 μ g/mL infect CMV is respectively 44.4,52.3,45.1,47.3,45.6% in concentration, show certain anti-phytoviral activity.
Table 1 bisamide is active to the inhibition of CMV
Embodiment 16, the compound inhibition activity test test method sick to tobacco mosaic virus (TMV) (TMV)
Select the Nicotiana glutinosa that growing way is consistent, with phosphoric acid buffer, TMV crude extract is diluted to suitable concentration, with the artificial frictional inoculation of writing brush on the of the right age blade sprinkled with silicon carbide (full leaf virus inoculation, every blade is manually smeared virus once gently, the left and right half leaf dynamics of smearing is accomplished evenly as far as possible), after inoculation, with clear water, rinse.After blade is dry (being generally 2h), at Zuo Banye, spread compound solution, the solvent that right half leaf spreads matched doses compares.In illumination box, moisturizing is cultivated subsequently, controls 23 ± 1 ℃ of temperature, and illumination 10000Lux observes and record the number that produces withered spot after 3～4d.Every chemicals treatment is established 3 strains, 3～4 leaves of every strain.Every medicament carries out 3 repetitions as stated above.
On half leaf of blank, present obvious withered spot, after test 3-4d, just can investigate, record respectively the withered spot number of left and right half leaf of every leaf, be calculated as follows out the inhibiting rate of test compound to plant virus, be i.e. relative effect.
Expression mode: Y=(C-A)/C * 100
Wherein: Y is the inhibiting rate of compound to plant virus,
C is control group (right half leaf) withered spot number, unit: individual
A is compound treatment group (Zuo Banye) withered spot number, unit: individual
Wherein control group (right half leaf) withered spot number and compound treatment group (Zuo Banye) withered spot number can be joined mean number or each the withered spot sum of organizing repetition repeating by each group.Each process be with oneself second half in contrast, then the processing that one group of commodity Ningnanmycin is set is as a comparison.
Test the live body therapeutic activity of target compound to tobacco mosaic virus (TMV), the results are shown in Table 2.Result shows that compound d, l, n, u, w show higher resisting tobacco mosaic virus inhibition activity under 500 μ g/mL concentration, and inhibiting rate is respectively 44.3,47.7,45.7,44.3,49.0%.
Table 2 part bisamide is to the inhibition of TMV (500 μ g/mL)
Embodiment 17, compound suppress activity test method to the in-vitro multiplication to two kinds of cancer cells
By sterilizing intermediate water edge sealing for the uplink and downlink of 96 orifice plates, every hole 200 μ L.The cell in vegetative period of taking the logarithm, after conventional digestion, is resuspended in the RPMI 1640 or DMDM substratum containing 10%FBS, with 2 * 10
4the final concentration of individual/mL is inoculated in 96 well culture plates, every hole 100 μ L, and the rightmost side one is classified blank group as, adds acellular serum RPMI 1640 substratum that have.Be placed in 37 ℃, 5%CO
2saturated humidity incubator in cultivate 24h and make cell attachment.Sop up substratum, add the blood serum medium that has containing different pharmaceutical concentration, every hole 200 μ L, notice that in substratum, DMSO final concentration can not surpass 0.1%, and the every hole of blank group adds 200 μ L perfect mediums.Process respectively the requirement of experiment time, remove supernatant, add the MTT of 100 μ L/well concentration 0.5mg/mL.Cultivate 10% the SDS that adds again 100 μ Lwell after 4h.At 37 ℃, 10h makes crystallisate fully dissolve rear taking-up, and 5min is swung in microseism, places 30min under room temperature, at A
595under wavelength, survey OD value, and calculate cytoactive, inhibiting rate and P value.
Take drug level or treatment time as transverse axis, and OD value or inhibiting rate are the longitudinal axis, curve plotting.Every concentration of specimens repeats six holes, and each is tested in triplicate, averages as net result.
Experimental result is carried out variance analysis with SPSS software, is significant difference during p < 0.05, is that difference is extremely remarkable during p < 0.01.The inhibiting rate calculation formula of cell proliferation is as follows:
Table 3 bisamide is to the inhibiting rate to PC3 and BGC-823 tumour cell
As can be seen from Table 3, when concentration is 10 μ M, compound h, m, n, x, y are respectively 74.2,73.2,76.2,70.8,76.3% to the inhibiting rate of prostate cancer cell, the inhibiting rate of breast cancer cell is respectively to 77.8,68.1,62.2,62.0,72.8%, and above-claimed cpd has good restraining effect to prostate cancer cell and breast cancer cell.
The embodiment of the present invention is aided with explanation technical scheme of the present invention, but the content of embodiment is not limited to this.
Claims (2)
1.N-(2-(the replacing benzothiazole-2-formamyl)-phenyl) application of-benzamide derivatives in preparing Antiphytoviral medicine, its compound structure general formula is as follows:
R wherein
1for (1) hydrogen; (2) neighbour,, the monosubstituted or polysubstituted halogen atom of contraposition; (3) C1-6 alkyl; (4) C1-6 alkoxyl group;
R
2for (1) hydrogen; (2) monosubstituted halogen atom; (3) C1-6 alkyl; (4) C1-6 alkoxyl group;
R
3for (1) hydrogen; (2) monosubstituted halogen atom; (3) C1-6 alkyl; (4) C1-6 alkoxyl group.
2. according to claim 1 containing N-(2-(replace benzothiazole-2-formamyl)-phenyl) preparation method of-benzamide derivatives; the preparation method who it is characterized in that general formula (I) compound be take substituted benzoic acid, to replace anthranilic acid, replace benzothiazole ammonia, thionyl chloride and acetic anhydride be raw material; through superchlorination, acidylate, cyclisation and open loop four-step reaction; synthetic containing benzothiazole ring o-benzoyl aminobenzoyl aminated compounds, its synthetic route is:
R wherein
1for (1) hydrogen; (2) neighbour,, the monosubstituted or polysubstituted halogen atom of contraposition; (3) C1-6 alkyl; (4) C1-6 alkoxyl group;
R
2for (1) hydrogen; (2) monosubstituted halogen atom; (3) C1-6 alkyl; (4) C1-6 alkoxyl group;
R
3for (1) hydrogen; (2) monosubstituted halogen atom; (3) C1-6 alkyl; (4) C1-6 alkoxyl group.
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| WO2006137376A1 (en) * | 2005-06-21 | 2006-12-28 | Mitsui Chemicals, Inc. | Amide derivative and pesticide containing such compound |
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| WO2010010435A2 (en) * | 2008-07-22 | 2010-01-28 | Glenmark Pharmaceutical S.A. | Fused oxazole and thiazole derivatives as trpms modulators |
| CN101701018A (en) * | 2009-11-05 | 2010-05-05 | 东南大学 | 2-(4-aminoquinazoline) benzo [d] thiazole derivative and application thereof |
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2011
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN86102102A (en) * | 1985-03-30 | 1987-01-07 | 日本特殊农药制造株式会社 | Preparation technology of new benzamides and uses thereof |
| CN1738808A (en) * | 2003-01-07 | 2006-02-22 | 弗·哈夫曼-拉罗切有限公司 | Cyclization process for substituted benzothiazole derivatives |
| US20050130974A1 (en) * | 2003-10-17 | 2005-06-16 | Rigel Pharmaceuticals, Inc. | Benzothiazole compositions and their use as ubiquitin ligase inhibitors |
| CN1950369A (en) * | 2004-04-01 | 2007-04-18 | 艾文蒂斯药品公司 | Novel benzothiazoles and the use thereof as medicaments |
| WO2006137376A1 (en) * | 2005-06-21 | 2006-12-28 | Mitsui Chemicals, Inc. | Amide derivative and pesticide containing such compound |
| WO2010010435A2 (en) * | 2008-07-22 | 2010-01-28 | Glenmark Pharmaceutical S.A. | Fused oxazole and thiazole derivatives as trpms modulators |
| CN101701018A (en) * | 2009-11-05 | 2010-05-05 | 东南大学 | 2-(4-aminoquinazoline) benzo [d] thiazole derivative and application thereof |
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