CN1944398A - New benzoyl amide compounds and its preparing method and medicine use - Google Patents
New benzoyl amide compounds and its preparing method and medicine use Download PDFInfo
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- CN1944398A CN1944398A CN 200610000813 CN200610000813A CN1944398A CN 1944398 A CN1944398 A CN 1944398A CN 200610000813 CN200610000813 CN 200610000813 CN 200610000813 A CN200610000813 A CN 200610000813A CN 1944398 A CN1944398 A CN 1944398A
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Abstract
The present invention discloses new benzoyl amide compounds in the general expression as shown and their tautomers, antimers, diastereomers and physiologically acceptable salts. The present invention also relates to the use of these compounds in treating tumor, the treating method and medicinal compositions containing these compounds.
Description
Technical field
The present invention relates to new benzamide compound, and their tautomer, enantiomorph, diastereomer and physiologically acceptable salt, the preparation method of these compounds, and the pharmaceutical composition that contains described compound, this compounds with tumour in application.
The research background
Tumour is the common disease that threatens the human life, the overexpression of visible different tyrosine kinase receptors or excessive activation in many tumours, as the overexpression of common EGFR family receptors in the epithelial cell tumour, the overexpression of somatomedin (PDGFR) acceptor that common thrombocyte is originated in the glioma etc.The overexpression excessive activation receptor system of these acceptors or somatomedin, thus activate the downstream signal approach, finally cause transformation, propagation and prevention apoptosis, thus closely related with generation, the development of tumour.
EGF-R ELISA (epidermal growth factor receptor, EGFR) family is the more tyrosine protein kinase of a class research, they can be transferred to the γ phosphate of ATP on the tyrosine residues of functional protein, cause downstream biological respinse cascade, thereby regulation and control are such as various kinds of cell functions such as mitotic division, cell cycle progression and differentiation.Its receptor family is made up of four hypotypes: EGFR/erbB-1, erbB-2/neu/HER-2, erbB-3/HER-3 and erbB-4/HER-4.Their protein structure is similar, comprises the extracellular ligand land, single span film district, intracellular tyrosine kinase activity district, and the carbon teminal subprovince of containing special tyrosine sequence.EGFR family can with multiple part combination.Acceptor generation dimerization behind the binding partner combines with ATP then, and autophosphorylation takes place.Receptor activation downstream signal protein substrate after the phosphorylation sends the mitotic division signal, starts cell division cycle.When the tyrosine protein kinase overexpression, the adjusting and controlling growth of cell is out of control, is in proliferative state all the time, develops into malignant tumour.Clinical proof, EGFR is relevant with the tumour at positions such as human neck, throat, stomach, chest, lung, pancreas, colorectum, ovary and bladder.The EGFR and the part thereof of high expression level are all arranged in the cancer of these types, and processes such as their expression level and tumor cell proliferation, invasion and attack, transfer, apoptosis, vasculogenesis are closely related.Therefore, the EGFR specific inhibitor has important value to oncotherapy.
The EGFR inhibitor mainly comprises two big classes: a class is the macromole inhibitor, by with the competitive bind receptor film of endogenic ligand outskirt, the disabling signal conduction, as monoclonal antibody, bi-specific antibody, single-chain Fv antibody, immunotoxin conjugate etc.The EGFR monoclonal antibody Cetuximab of treatment bladder cancer of for example having gone on the market and mammary cancer (Etessami, A et al.Cetuximab.Drugs Fut 2000,25 (9): 895); Another kind of is micromolecular inhibitor, and by combine intracellular tyrosine kinase activity district with ATP or substrate competition, the catalytic activity of inhibitory enzyme and the autophosphorylation of tyrosine stop the signal transduction in downstream.In recent years, optionally the EGFR micromolecular inhibitor becomes the focus of antitumor drug research gradually, quinazoline compounds and 3-cyano quinoline compound have shown better inhibited activity, wherein the Iressa of AstraZeneca company in 2003 at U.S. listing (Levin, M et al.Iressa.Drugs Fut 2002,27 (4): 339), other has several micromolecular inhibitors to be in that (Erlotinibhydrochloride:WO 03103676 in each phase clinical study; Lapatinib:ZD-6474:WO 03103676; EKB-569:US 6617333).
On the basis of the constitutional features of analyzing existing each type small molecular inhibitor and biological activity mutual relationship, utilization SARS drug design method, orientation of the present invention has designed and synthesized a class and has had the compound of the inhibition EGFR tyrosine kinase activity of novel texture, and has shown inhibition activity to a certain degree.
Summary of the invention
The objective of the invention is to be to provide the new benzamide compound shown in a kind of formula I.
Another object of the present invention is to provide the method for benzamide compound shown in a kind of preparation formula I and analogue thereof.
Another purpose of the present invention is to provide the purposes of the compound shown in the formula I in suppressing EGF-R ELISA (EGFR) signal transduction, and the purposes in the medicine of the treatment disease relevant with EGFR.
In the formula:
X represents O, S, NH
R1 represents hydrogen, C
1-4Low alkyl group, C
3-8Cycloalkyl
N represents the integer of 0-2
R2 represents hydrogen, C
1-4Low alkyl group, C
3-8Cycloalkyl; If n=2, then R2 can be hydrogen, C independently on arbitrary continuous carbon atom
1-4Low alkyl group, C
3-8Cycloalkyl
Ar represents phenyl, naphthyl, furyl, pyrryl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidyl, pyrazinyl, benzofuryl, benzothienyl, indyl, benzimidazolyl-, benzoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, quinazolyl
R3 be illustrated in aromatic ring the neighbour,, contraposition has 0～3 identical or different following group: C
1-4Low alkyl group, C
3-8Cycloalkyl, phenyl, benzyl, hydroxyl, C
1-4Lower alkoxy, C
3-8Cycloalkyloxy, C
1-4Lower alkoxycarbonyl, C
3-8Cycloalkoxycarbonyl, phenoxy group, benzyloxy, C
1-4Low alkyl group acyloxy, C
3-8Cycloalkyl acyloxy, amino, one or two-C
1-4Low-grade alkyl amino, one or two-C
3-8Cycloalkyl amino, phenylamino, benzyl amino, C
1-4Low alkyl group carboxamido, C
3-8Cycloalkyl carboxamido, halogen substituted benzoyl amido, C
1-4Lower acyl, C
3-8Cycloalkyl acyl group, benzoyl, carboxyl, sulfydryl, cyano group, halogen, nitro, C
1-4Rudimentary hydroxyalkyl, (phenyl hydroxyl) methyl ,-C (O)-R4 or-SO
2-R4,
Wherein R4 represents amino, one or two C
1-4Low-grade alkyl amino, one or two-C
3-8Cycloalkyl amino, halogen substituted-phenyl amino, N-pyrrolidyl, N-piperidyl, N-morpholinyl, N-piperazinyl, N-thio-morpholinyl, perhaps, two R3 on the adjacent carbons combine, and form 5-7 unit carbocyclic ring jointly
M represents the integer of 0-3
Y represents hydrogen, hydroxyl, sulfydryl, amino, C
1-4Low alkyl group, C
3-8Cycloalkyl, C
1-4Lower alkoxy, C
3-8Cycloalkyloxy, C
1-4Low alkyl group acyloxy, C
3-8Cycloalkyl acyloxy, C
1-4Lower alkoxycarbonyl, C
3-8Cycloalkoxycarbonyl, one or two-C
1-4Low-grade alkyl amino, one or two-C
3-8Cycloalkyl amino, C
1-4Low alkyl group carboxamido, C
3-8The cycloalkyl carboxamido
A-B-D-can be substituted in 4-position or 5-position, wherein
D represents O, S, NH, NR5, and R5 can be C
1-4Low alkyl group, C
3-8Cycloalkyl
B represents carbonyl (CO-), alkylsulfonyl (SO
2-)
A represents C
1-4Low alkyl group, C
3-8Cycloalkyl,
R6, R7, R8, R9 independently are separately
C
1-4Low alkyl group, C
3-8Cycloalkyl, vinyl (CH
2=CH-), propylene (CH
3-CH=CH-), ethanoyl, carboxyl, C
1-4Lower alkoxycarbonyl, C
3-8Cycloalkoxycarbonyl, carbamyl, one or two C
1-4Low alkyl group carbamyl, one or two-C
3-8The cycloalkyl carbamyl ,-CH
2-R10, wherein R10 represents hydroxyl, amino, C
1-4Lower alkoxy, C
3-8Cycloalkyloxy, one or two-C
1-4Low-grade alkyl amino, one or two-C
3-8Cycloalkyl amino, N-pyrrolidyl, N-piperidyl, N-morpholinyl, N-piperazinyl, N-thio-morpholinyl
Any low-grade alkyl substituent among the R6-R9 on any substituting group is optionally replaced by one or more following groups: single low alkyl group Ammonia, two single low alkyl group Ammonias, N-pyrrolidyl, N-piperidyl, N-morpholinyl, N-piperazinyl, N-thio-morpholinyl
Preferred X is O, S, NH
Preferred R1 is a hydrogen
Preferred n is 0,1
Preferred R2 is hydrogen, C
1-4Low alkyl group, C
3-8Cycloalkyl
Preferred Ar is a phenyl
Preferred R3 be the neighbour that is illustrated in aromatic ring,, contraposition has 0～3 identical or different following group: C
1-4Low alkyl group, C
3-8Cycloalkyl, phenyl, benzyl, hydroxyl, C
1-4Lower alkoxy, C
3-8Cycloalkyloxy, C
1-4Lower alkoxycarbonyl, C
3-8Cycloalkoxycarbonyl, phenoxy group, benzyloxy, C
1-4Low alkyl group acyloxy, C
3-8Cycloalkyl acyloxy, amino, one or two-C
1-4Low-grade alkyl amino, one or two-C
3-8Cycloalkyl amino, phenylamino, benzyl amino, C
1-4Low alkyl group carboxamido, C
3-8Cycloalkyl carboxamido, halogen substituted benzoyl amido, C
1-4Lower acyl, C
3-8Cycloalkyl acyl group, benzoyl, carboxyl, sulfydryl, cyano group, halogen, nitro, C
1-4Rudimentary hydroxyalkyl, (phenyl hydroxyl) methyl ,-C (O)-R4 or-SO
2-R4, wherein R4 represents amino, one or two C
1-4Low-grade alkyl amino, one or two-C
3-8Cycloalkyl amino, halogen substituted-phenyl amino, N-pyrrolidyl, N-piperidyl, N-morpholinyl, N-piperazinyl, N-thio-morpholinyl, perhaps, two R3 on the adjacent carbons combine, and form 5-7 unit carbocyclic ring jointly
Preferred m is 1,2
Preferred Y is hydrogen, hydroxyl, sulfydryl, amino
Preferred D is O, S, NH, NR5, and R5 can be C
1-4Low alkyl group, C
3-8Cycloalkyl
Preferred B be carbonyl (CO-)
Preferred A is
R6, R7, R8, independently be separately
C
1-4Low alkyl group, C
3-8Cycloalkyl, vinyl (CH
2=CH-), propylene (CH
3-CH=CH-), ethanoyl, carboxyl, C
1-4Lower alkoxycarbonyl, C
3-8Cycloalkoxycarbonyl, carbamyl, one or two C
1-4Low alkyl group carbamyl, one or two-C
3-8The cycloalkyl carbamyl ,-CH
2-R10, wherein R10 represents hydroxyl, amino, C
1-4Lower alkoxy, C
3-8Cycloalkyloxy, one or two-C
1-4Low-grade alkyl amino, one or two-C
3-8Any low-grade alkyl substituent among cycloalkyl amino, N-pyrrolidyl, N-piperidyl, N-morpholinyl, N-piperazinyl, the N-thio-morpholinyl R6-R9 on any substituting group is optionally replaced by one or more following groups: single low alkyl group Ammonia, two single low alkyl group Ammonias, N-pyrrolidyl, N-piperidyl, N-morpholinyl, N-piperazinyl, N-thio-morpholinyl
Compound shown in the preferred general formula (I) is also including but not limited to the compound shown in general formula (Ia):
R3 be selected from fluorine, chlorine, bromine, cyclohexyl, (hydroxyl-phenyl) methyl, methoxy, ethoxy, benzene oxygen ,-4-dihydro indenes-5-base, 3-ethoxycarbonyl, N; N-dimethylamino formyl radical, N-ethyl carbamyl, N; N-diethyl amino formyl radical, N, N-di-isopropyl carbamyl, benzoyl, tetramethyleneimine-1-formyl radical, piperidines-1-formyl radical, morpholine-4-formyl radical.
Compound shown in the preferred general formula (Ia) also including but not limited to
Compound shown in the preferred general formula (I) is also including but not limited to the compound shown in general formula (Ib):
R3 be selected from fluorine, chlorine, bromine, cyclohexyl, (hydroxyl-phenyl) methyl, methoxy, ethoxy, benzene oxygen ,-4-dihydro indenes-5-base, 3-ethoxycarbonyl, N; N-dimethylamino formyl radical, N-ethyl carbamyl, N; N-diethyl amino formyl radical, N, N-di-isopropyl carbamyl, benzoyl, tetramethyleneimine-1-formyl radical, piperidines-1-formyl radical, morpholine-4-formyl radical.
Compound shown in the preferred general formula (Ib) also including but not limited to
Compound shown in the preferred general formula (I) is also including but not limited to the compound shown in general formula (Ic):
R2 is selected from H, C
1-4Low alkyl group
R3 be selected from fluorine, chlorine, bromine, cyclohexyl, (hydroxyl-phenyl) methyl, methoxy, ethoxy, benzene oxygen ,-4-dihydro indenes-5-base, 3-ethoxycarbonyl, N; N-dimethylamino formyl radical, N-ethyl carbamyl, N; N-diethyl amino formyl radical, N, N-di-isopropyl carbamyl, benzoyl, tetramethyleneimine-1-formyl radical, piperidines-1-formyl radical, morpholine-4-formyl radical.
Compound shown in the preferred general formula (Ic) also including but not limited to
Compound shown in the preferred general formula (I) is also including but not limited to the compound shown in general formula (Id):
R3 be selected from fluorine, chlorine, bromine, cyclohexyl, (hydroxyl-phenyl) methyl, methoxy, ethoxy, benzene oxygen ,-4-dihydro indenes-5-base, 3-ethoxycarbonyl, N; N-dimethylamino formyl radical, N-ethyl carbamyl, N; N-diethyl amino formyl radical, N, N-di-isopropyl carbamyl, benzoyl, tetramethyleneimine-1-formyl radical, piperidines-1-formyl radical, morpholine-4-formyl radical.
Compound shown in the preferred general formula (Id) also including but not limited to
Compound shown in the preferred general formula (I) is also including but not limited to the compound shown in general formula (Ie):
R3 be selected from fluorine, chlorine, bromine, cyclohexyl, (hydroxyl-phenyl) methyl, methoxy, ethoxy, benzene oxygen ,-4-dihydro indenes-5-base, 3-ethoxycarbonyl, N; N-dimethylamino formyl radical, N-ethyl carbamyl, N; N-diethyl amino formyl radical, N, N-di-isopropyl carbamyl, benzoyl, tetramethyleneimine-1-formyl radical, piperidines-1-formyl radical, morpholine-4-formyl radical.
Compound shown in the preferred general formula (Ie) also including but not limited to
Compound shown in the preferred general formula (I) is also including but not limited to the compound shown in general formula (If):
A=ring third, dimethyl allene, ethyl
R3 be selected from fluorine, chlorine, bromine, cyclohexyl, (hydroxyl-phenyl) methyl, methoxy, ethoxy, benzene oxygen ,-4-dihydro indenes-5-base, 3-ethoxycarbonyl, N; N-dimethylamino formyl radical, N-ethyl carbamyl, N; N-diethyl amino formyl radical, N, N-di-isopropyl carbamyl, benzoyl, tetramethyleneimine-1-formyl radical, piperidines-1-formyl radical, morpholine-4-formyl radical.
Compound shown in the preferred general formula (If) also including but not limited to
Compound shown in the preferred general formula (I) is also including but not limited to the compound shown in general formula (Ig):
R3 be selected from fluorine, chlorine, bromine, cyclohexyl, (hydroxyl-phenyl) methyl, methoxy, ethoxy, benzene oxygen ,-4-dihydro indenes-5-base, 3-ethoxycarbonyl, N; N-dimethylamino formyl radical, N-ethyl carbamyl, N; N-diethyl amino formyl radical, N, N-di-isopropyl carbamyl, benzoyl, tetramethyleneimine-1-formyl radical, piperidines-1-formyl radical, morpholine-4-formyl radical.
Compound shown in the preferred general formula (Ig) also including but not limited to
Compound shown in the preferred general formula (I) is also including but not limited to the compound shown in general formula (Ih):
R3 be selected from fluorine, chlorine, bromine, cyclohexyl, (hydroxyl-phenyl) methyl, methoxy, ethoxy, benzene oxygen ,-4-dihydro indenes-5-base, 3-ethoxycarbonyl, N; N-dimethylamino formyl radical, N-ethyl carbamyl, N; N-diethyl amino formyl radical, N, N-di-isopropyl carbamyl, benzoyl, tetramethyleneimine-1-formyl radical, piperidines-1-formyl radical, morpholine-4-formyl radical.
Compound shown in the preferred general formula (Ih) also including but not limited to
In order to prepare the described compound of I of the present invention, the present invention finishes with following method:
With the intermediate product of formula II compound and formula III compound reaction generation, with the reaction of formula IV compound, reaction generates compound of Formula I; Or formula III compound and the reaction earlier of formula IV compound, generate compound of Formula I with the reaction of formula II compound again.
A-B-Cl
II III IV
E represents-DH, nitro, and the definition of A, B, D, X, Y, R1, R2, R3, Ar, m, n is same as described above in the formula.
Can use the optically pure isomer that racemize does not have fractionation or the starting raw material of use optically active comes preparation I compound in synthetic.
The invention still further relates to a kind of pharmaceutical composition that contains medicine effective dose as described compound of general formula I and pharmaceutically acceptable carrier.
Pharmaceutical research shows, compound of Formula I of the present invention has the EGFR of inhibition tyrosine kinase activity, and for the tumour relevant with the EGFR overexpression, this compounds can be blocked its downstream signal transduction, suppress tumor cell proliferation, thereby reach the purpose of treatment.
In addition, correlative study finds that in the kidney disease of psoriasis, chronic pancreatitis, hyperplasia glomerulonephritis and diabetes-induced, all there is high expression level in EGFR, so the EGFR inhibitor also can be used for the treatment of other relative diseases.
In order to make medicament, compound of Formula I can be pressed currently known methods mixes with known method with suitable pharmacy carrier substance, perfume compound, seasonings and pigment, and be made into the tablet of tablet or dressing, perhaps itself and other additional substances is suspended or be dissolved in water or the oil.
The compounds of this invention can be with oral methods or the medication of parenteral road.Oral medication can be tablet, capsule, Drug coating, and non-have injection and suppository etc. through the intestines drug formulation.These preparations are according to the known method preparation of those skilled in the art.For making tablet, capsule, the used auxiliary material of Drug coating is the auxiliary agent of conventional usefulness, starch for example, gelatin, gum arabic, silica, polyoxyethylene glycol, the used solvent of liquid dosage form for example has water, ethanol, propylene glycol, plant oil such as Semen Maydis oil, peanut oil, olive wet goods.Containing in the preparation of The compounds of this invention also can have other auxiliary agents, tensio-active agent for example, lubricant, disintegrating agent, sanitas, correctives, pigment etc.
At tablet, capsule, Drug coating, the dosage that contains formula I compound of the present invention in injection or the suppository is to calculate with the compound amount that exists in the unit dosage form.The general content of formula I compound of the present invention is 1-50mg in unit dosage form, and preferred unit dosage form contains 2-10mg.
Embodiment
Below in conjunction with embodiment invention is further described, but these embodiment do not limit the scope of the invention.
The structure of compound is determined by nucleus magnetic resonance (NMR) or mass spectrum (MS) or high resolution mass spectrum (HRMS).NMR displacement (δ) provides with 1,000,000/(ppm) unit.M.p. be that temperature is correction up not with a ℃ fusing point that provides.Column chromatography generally uses 160～200 or 200～300 order silica gel to be carrier.It is to use INOVA-500 that NMR measures, and the mensuration solvent is CDCl
3, DMSO-D
6, in be designated as TMS, chemical shift is to provide as unit with ppm.The mensuration of MS AutoSpec Ultima-TOF mass spectrograph or Q-Trap LC/MS/MSSystem, Turbo ionspray source mass spectrograph.
Abbreviation:
TLC: thin-layer chromatography
DMSO: dimethyl sulfoxide (DMSO)
CDCl
3: deuterochloroform
DMF:N, dinethylformamide
Min: minute
H: hour
Mol: mole
Mmol: mmole
G: gram
Mg: milligram
Embodiment 1:
The preparation of N-(3-chloro-phenyl-)-2-hydroxyl-5-acrylamide yl-benzamide
A) N-(3-chloro-phenyl-)-2-hydroxyl-5-nitrobenzamide
(2.29g, 12.5mmol) (1.595g 12.5mmol) mixes, and toluene is solvent, is heated to backflow, and (1.717g 12.5mmol), behind the backflow 1h, adds less water, continues backflow 1h to add phosphorus trichloride with the 3-chloroaniline with 2-hydroxyl-5-nitrobenzoic acid.Stop heating, with 10% sodium hydrogen carbonate solution, 1 mol hydrochloric acid soln, saturated common salt water washing, anhydrous magnesium sulfate drying spends the night reaction solution respectively.Remove by filter siccative next day, and filtrate is concentrated into dried, and the gained crude product is with the petroleum ether-ethyl acetate recrystallization, this title compound, be yellow needle-like crystal 2.29g, yield 62.7%, m.p.:222.0～223.9 ℃.
1HNMR(CDCl
3，300MHz)δppm：7.136-7.166(d，1H，ArH)，7.235-7.262(d，1H，ArH)，7.344-7.398(t，1H，ArH)，7.458-7.485(d，1H，ArH)，7.785-7.798(t，1H，ArH)，8.335-8.374(dd，1H，ArH)，8.583-8.575(d，1H，ArH)
MS(EI)：292.1(M)，166.1，127.1
B) N-(3-chloro-phenyl-)-2-acryloxy-5-acrylamide yl-benzamide
(0.293g 1mmol) is dissolved in ethanol, and (0.168g, 3mmol), 3 37% concentrated hydrochloric acid solutions are heated to backflow, stop behind the reaction 3h to add iron powder with N-(3-chloro-phenyl-)-2-hydroxyl-5-nitrobenzamide.Cold slightly, to filter, filtrate is concentrated into dried, gets gray solid, with an amount of acetic acid ethyl dissolution, with saturated common salt water washing organic phase, anhydrous sodium sulfate drying.The filtering siccative, filtrate is concentrated into dried, with an amount of tetrahydrofuran (THF) dissolving, adds triethylamine (0.202g, 2mmol), under the stirring at room, splash into acrylate chloride (181mg with catalytic amount 4-Dimethylamino pyridine, 2mmol), the muddy generation arranged promptly, continue to stop behind the reaction 0.5h.Remove by filter insolubles, obtain crude product after filtrate concentrates, with purification by silica gel column chromatography, this title compound, be white solid 0.135g, yield 36.4%, m.p.:155～158 ℃.
1HNMR(CDCl
3，300MHz)δppm：5.804(s，1H，＝CH-)，6.089-6.124(d，1H，＝CH-)，6.308-6.480(m，3H，＝CH-)，6.642-6.699(d，1H，＝CH-)，7.104(s，1H，ArH)，7.130(s，1H，ArH)，7.381(s，1H，ArH)，7.702(s，1H，ArH)，7.870(s，2H，ArH)，8.320(s，1H，ArH)
MS(FAB)：371.1(M)，244.1，190.1，93.1
C) N-(3-chloro-phenyl-)-2-hydroxyl-5-acrylamide yl-benzamide
(0.109g 0.293mmol) is dissolved in 5ml methyl alcohol, adds 2ml sodium hydroxide solution (6.45mg/ml), stirring at room 15min, stopped reaction with N-(3-chloro-phenyl-)-2-acryloxy-5-acrylamide yl-benzamide.Add 5ml water, regulate about pH to 2 with 1 mol hydrochloric acid, promptly the adularescent needle is separated out, and filters the crude product that obtains with the alcohol-water recrystallization, this title compound, be white needle 70mg, yield 75.4%, m.p.:222.5～224.5 ℃.
1HNMR(DMSO，300MHz)δppm：5.707-5.747(dd，1H，＝CH-)，6.202-6.265(dd，1H，＝CH-)，6.362-6.452(dd，1H，＝CH-)，6.960-6.989(d，1H，ArH)，7.153-7.182(d，1H，ArH)，7.352-7.405(t，1H，ArH)，7.571-7.599(d，1H，ArH)，7.709-7.747(dd，1H，ArH)，7.943(s，1H，ArH)，8.073-8.079(d，1H，ArH)，
MS(EI)：316.2(M)，189.1，135.1
Embodiment 2:
The preparation of N-(3-chloro-phenyl-)-2-hydroxyl-4-acrylamide yl-benzamide
A) 2-hydroxyl-4-acrylamide yl benzoic acid
(0.306g 2mmol) is dissolved in the sodium hydroxide solution of 20ml0.5 mol, and (0.537g 6mmol), continues to stir 1h to stir the acrylate chloride of property adding next time with para-aminosalicylic acid.Under the ice bath, regulate about pH to 2, white precipitate occurs with 1 mol hydrochloric acid soln, filter this title compound, be off-white color solid 360mg, yield 86.9%, m.p.:218～221 ℃.
1HNMR(DMSO，300MHz)δppm：5.787-5.828(dd，1H，＝CH-)，6.254-6.318(dd，1H，＝CH-)，6.386-6.476(dd，1H，＝CH-)，7.092-7.127(dd，1H，ArH)，7.435-7.441(d，1H，ArH)，7.714-7.743(d，1H，ArH)
B) N-(3-chloro-phenyl-)-2-hydroxyl-4-acrylamide yl-benzamide
According to embodiment 1a) described method, (0.207g is 1mmol) with 3-chloroaniline (0.127g with 2-hydroxyl-4-acrylamide yl benzoic acid, 1mmol) obtain this title compound for feedstock production, be white-yellowish solid 100mg, yield 31.6%, m.p.:225～230 ℃.
1HNMR(DMSO，300MHz)δppm：5.781-5.821(dd，1H，＝CH-)，6.254-6.317(dd，1H，＝CH-)，6.398-6.487(dd，1H，＝CH-)，7.139-7.187(m，2H，ArH)，7.353-7.407(t，1H，ArH)，7.523(s，1H，ArH)，7.578-7.605(d，1H，ArH)，7.893-7.922(m，2H，ArH)
MS(EI)：316.3(M)，190.2
Embodiment 3:
The preparation of N-(3-bromophenyl)-2-hydroxyl-4-acrylamide yl-benzamide
A) 2-hydroxyl-4-acrylamide yl benzoic acid
According to embodiment 2a) described method, with para-aminosalicylic acid (1.53g, 10mmol) and acrylate chloride (2.715g 30mmol) for feedstock production obtains this title compound, is white solid 1.97g, yield 95%.
B) N-(3-bromophenyl)-2-hydroxyl-4-acrylamide yl-benzamide
According to embodiment 1a) described method, (0.622g is 3mmol) with 3-bromaniline (0.516g with 2-hydroxyl-4-acrylamide yl benzoic acid, 3mmol) obtain this title compound for feedstock production, be white powder 230mg, yield 21.2%, m.p.:231.9～235.0 ℃.
1HNMR(DMSO，300MHz)δppm：5.781-5.821(dd，1H，＝CH-)，6.253-6.316(dd，1H，＝CH-)，6.397-6.486(dd，1H，＝CH-)，7.137-7.172(dd，1H，ArH)，7.305-7.351(m，2H，ArH)，7.522-7.528(d，1H，ArH)，7.628-7.641(d，1H，ArH)，7.890-7.918(d，1H，ArH)8.051(s，1H，ArH)
MS(EI)：362.3(M)，190.2，136.2
Embodiment 4:
The preparation of N-(3-bromophenyl)-2-hydroxyl-5-acrylamide yl-benzamide
A) N-(3-bromophenyl)-2-hydroxyl-5-nitrobenzamide
According to embodiment 1a) described method, with 2-hydroxyl-5-nitrobenzoic acid (0.916g, 5mmol) and the 3-bromaniline (0.860g 5mmol) for feedstock production obtains this title compound, is light brown crystal 1.23g, yield 73%, m.p.:226.0～226.8 ℃.
B) N-(3-bromophenyl)-2-hydroxyl-5-acrylamide yl-benzamide
(0.674g 2mmol) is dissolved in 10% ammonia soln, and under 40 ℃ of stirrings of outer temperature, (2.61g 15mmol), finishes the back and continues to stir 15min the powder that in batches takes a policy with N-(3-bromophenyl)-2-hydroxyl-5-nitrobenzamide.Regulate about pH to 7 with dilute hydrochloric acid solution, precipitation occurs, filter and obtain greyish-green solid 580mg.After the drying,, add triethylamine (0.202g with an amount of tetrahydrofuran (THF) dissolving, 2mmol), catalytic amount 4-Dimethylamino pyridine is under the stirring at room, (0.168g 1.89mmol), reacts 1h to splash into acrylate chloride, filter, filtrate concentrating obtains thick product, obtains this title compound with silica gel column chromatography separating purification, is orange crystal 190mg, yield 26.3%, m.p.:220～226 ℃.
1HNMR(DMSO，300MHz)δppm：5.707-5.748(dd，1H，＝CH-)，6.199-6.263(dd，1H，＝CH-)，6.358-6.447(dd，1H，＝CH-)，6.959-6.989(d，1H，ArH)，7.280-7.348(m，2H，ArH)，7.610-7.645(m，1H，ArH)，7.699-7.737(dd，1H，ArH)，8.060(s，1H，ArH)，8.069(s，1H，ArH)
MS(EI)：362.3(M)，189.2，135.1
Embodiment 5:
The preparation of N-(4-cyclohexyl phenyl)-2-hydroxyl-4-acrylamide yl-benzamide
A) 2-hydroxyl-4-acrylamide yl benzoic acid
According to embodiment 2a) described method, with para-aminosalicylic acid (1.53g, 10mmol) and acrylate chloride (2.715g 30mmol) for feedstock production obtains this title compound, is white solid 1.68g, yield 81%.
B) N-(4-cyclohexyl phenyl)-2-hydroxyl-4-acrylamide yl-benzamide
With 2-hydroxyl-4-acrylamide yl benzoic acid (0.207g, 1mmol) and I-hydroxybenzotriazole (0.162g 1mmol) is dissolved in DMF, ice bath stirs down, and the adding dicyclohexylcarbodiimide (0.248g, 1.2mmol), (0.175g 1mmol), continues reaction 2h to add 4-cyclohexyl phenylamino behind the 1h.The filtering insolubles in the impouring water, with ethyl acetate extraction, obtains crude product after organic phase concentrates, and silica gel column chromatography separating purification obtains this title compound, is white solid 200mg, yield 54.9%, m.p.:235～240 ℃.
1HNMR(DMSO，300MHz)δppm：1.331-1.399(m，6H，-CH
2-×3)，1.756-1.786(m，4H，-CH
2-×2)，2.478-2.513(m，1H，-CH-Ar)，5.775-5.816(dd，1H，＝CH-)，6.248-6.312(dd，1H，＝CH-)，6.391-6.480(dd，1H，＝CH-)，7.131-7.167(dd，1H，ArH)，7.182-7.211(d，2H，ArH)，7.472-7.479(d，1H，ArH)，7.550-7.578(d，2H，ArH)，7.928-7.956(d，1H，ArH)
MS(EI)：364.3(M)，190.1，175.2
Embodiment 6:
The preparation of N-(4-phenoxy phenyl)-2-hydroxyl-4-acrylamide yl-benzamide
A) 2-hydroxyl-4-acrylamide yl benzoic acid
According to embodiment 2a) described method, with para-aminosalicylic acid (1.53g, 10mmol) and acrylate chloride (2.715g 30mmol) for feedstock production obtains this title compound, is white solid 1.97g, yield 95%.
B) N-(4-phenoxy phenyl)-2-hydroxyl-4-acrylamide yl-benzamide
According to embodiment 5b) described method, (0.207g is 1mmol) with 4-benzene oxygen aniline (0.185mg with 2-hydroxyl-4-acrylamide yl benzoic acid, 1mmol) obtain this title compound for feedstock production, be white solid 150mg, yield 40%, m.p.:209～214 ℃.
1HNMR(DMSO，300MHz)δppm：5.784-5.821(dd，1H，＝CH-)，6.254-6.317(dd，1H，＝CH-)，6.394-6.484(dd，1H，＝CH-)，6.975-7.044(m，4H，ArH)，7.113-7.170(t，2H，ArH)，7.351-7.403(t，2H，ArH)，7.489(s，1H，ArH)，7.678-7.708(d，2H，ArH)，7.929-7.958(d，1H，ArH)
MS(EI)：374.2(M)，190.1，185.1
Embodiment 7:
The preparation of N-(3-chloro-4-fluorophenyl)-2-hydroxyl-5-acrylamide yl-benzamide
A) N-(3-chloro-4-fluorophenyl)-2-hydroxyl-5-nitrobenzamide
According to embodiment 1a) described method, (0.183g is 1mmol) with 3-chloro-4-fluoroaniline (0.146g with 2-hydroxyl-5-nitrobenzoic acid, 1mmol) obtain this title compound for feedstock production, be faint yellow needle 210mg, yield 67.6%, m.p.:247.7～250.7 ℃.
1HNMR(DMSO，300MHz)δppm：7.144-7.175(d，1H，ArH)，7.408-7.468(t，1H，ArH)，7.621-7.673(m，1H，ArH)，8.015-8.046(dd，1H，ArH)，8.266-8.305(dd，1H，ArH)，8.676-7.686(d，1H，ArH)
B) N-(3-chloro-4-fluorophenyl)-2-hydroxyl-5-aminobenzamide
(0.2g 0.64mmol) is dissolved in methyl alcohol, and with Raney-Ni catalysis, normal temperature and pressure is used hydrogen reducing 1h down with N-(3-chloro-4-fluorophenyl)-2-hydroxyl-5-nitrobenzamide.Filtering Raney-Ni, filtrate is concentrated into dried, obtains this title compound, is the deep green solid, dry back 100mg, yield 55.7%, m.p.＞280 ℃
MS(EI)：280(M)，135
C) N-(3-chloro-4-fluorophenyl)-2-hydroxyl-5-acrylamide yl-benzamide
(90mg 0.32mmol) is dissolved in tetrahydrofuran (THF), and (32mg, 0.32mmol), under the stirring at room, (30mg 0.32mmol), reacts 0.5h to splash into acrylate chloride to add triethylamine with N-(3-chloro-4-fluorophenyl)-2-hydroxyl-5-aminobenzamide.Filtering precipitation, filtrate obtains crude product after concentrating, and obtains this title compound with silica gel column chromatography separating purification, is white powder crystal 4 0mg, yield 37.2%, m.p.:224～227 ℃.
1HNMR(DMSO，300MHz)δppm：5.079-5.750(dd，1H，＝CH-)，6.198-6.261(dd，1H，＝CH-)，6.354-6.445(dd，1H，＝CH-)，6.957-6.988(d，1H，ArH)，7.382-7.443(t，1H，ArH)，7.605-7.657(m，1H，ArH)，7.684-7.743(m，1H，ArH)，8.032-8.091(m，2H，ArH)
MS(FAB)：335.0(M+1)
Embodiment 8:
The preparation of N-(3, the 4-dichlorophenyl)-2-hydroxyl-5-acrylamide yl-benzamide
A) N-(3, the 4-dichlorophenyl)-2-hydroxyl-5-nitrobenzamide
According to embodiment 1a) described method, (0.366g is 2mmol) with 3 with 2-hydroxyl-5-nitrobenzoic acid, (0.324g 2mmol) for feedstock production obtains this title compound, is faint yellow solid 440mg to the 4-dichlorphenamide bulk powder, yield 67.3%, m.p.:272.5～274.0 ℃.
1HNMR(DMSO，300MHz)δppm：7.129-7.160(d，1H，ArH)，7.612-7.686(m，2H，ArH)，8.101(s，1H，ArH)，8.256-8.297(dd，1H，ArH)，8.644-8.654(d，1H，ArH)
B) N-(3, the 4-dichlorophenyl)-2-hydroxyl-5-acrylamide yl-benzamide
According to embodiment 7b) 7c) described method; with N-(3; the 4-dichlorophenyl)-2-hydroxyl-5-nitrobenzamide (0.4g; 1.22mmol) and acrylate chloride (110mg 1.22mmol) is raw material, by the reduction, acylation reaction; obtain this title compound; be yellow solid 60mg, two-step reaction yield 14%, m.p.:234～239 ℃.
1HNMR(DMSO，300MHz)δppm：5.704-5.744(dd，1H，＝CH-)，6.196-6.261(dd，1H，＝CH-)，6.355-6.443(dd，1H，＝CH-)，6.962-6.989(d，1H，ArH)，7.586-7.735(m，3H，ArH)，8.052-8.059(d，1H，ArH)，8.123(s，1H，ArH)
MS(EI)：350.0(M)，189，135，55
Embodiment 9
The preparation of N-(3, the 4-dichlorophenyl)-2-hydroxyl-5-(N-sec.-propyl) acrylamide yl-benzamide
A) N-(3, the 4-dichlorophenyl)-2-hydroxyl-5-nitrobenzamide
According to embodiment 1a) described method, (0.366g is 2mmol) with 3 with 2-hydroxyl-5-nitrobenzoic acid, (0.324g 2mmol) for feedstock production obtains this title compound, is faint yellow solid 440mg to the 4-dichlorphenamide bulk powder, yield 67.3%, m.p.:272.5～274.0 ℃.
B) N-(3, the 4-dichlorophenyl)-2-hydroxyl-5-(N-sec.-propyl) acrylamide yl-benzamide
According to embodiment 7b) 7c) described method (the reduction solvent adopts acetone); with N-(3; the 4-dichlorophenyl)-2-hydroxyl-5-nitrobenzamide (0.4g; 1.22mmol) and acrylate chloride (110mg 1.22mmol) is raw material, by the reduction, acylation reaction; prepare this title compound; be light yellow crystal 140mg, two-step reaction yield 32.7%, m.p.:218.9～223 ℃.
1HNMR(DMSO，300MHz)δppm：0.998-1.020(d，6H，-CH
3×2)，4.811-4.857(m，1H，-CH-)，5.488-5.529(dd，1H，＝CH-)，5.777-5.867(dd，1H，＝CH-)，6.092-6.157(dd，1H，＝CH-)，7.043-7.081(d，1H，ArH)，7.231-7.268(dd，1H，ArH)，7.602-7.709(m，3H，ArH)，8.084-8.090(d，1H，ArH)
MS(EI)：392(M)，231，189，96
Embodiment 10
The preparation of N-(3, the 5-dichlorophenyl)-2-hydroxyl-5-acrylamide yl-benzamide
A) N-(3, the 5-dichlorophenyl)-2-hydroxyl-5-nitrobenzamide
According to embodiment 1a) described method, (0.366g, 2mmol) with 3, (0.324g 2mmol) for feedstock production obtains this title compound, is light yellow crystal 520mg, yield 79.5%, m.p.:280 ℃ to the 5-dichlorphenamide bulk powder with 2-hydroxyl-5-nitrobenzoic acid.
1HNMR(DMSO，300MHz)δppm：7.145-7.176(d，1H，ArH)，7.364-7.376(t，1H，ArH)，7.823-7.828(d，2H，ArH)，8.265-8.304(dd，1H，ArH)，8.626-8.635(d，1H，ArH)
B) N-(3, the 5-dichlorophenyl)-2-hydroxyl-5-acrylamide yl-benzamide
According to embodiment 7b) 7c) described method; with N-(3; 5 dichlorophenyls)-2-hydroxyl-5-nitrobenzamide (0.5g; 1.38mmol) and acrylate chloride (125mg 1.38mmol) is raw material, by the reduction, acylation reaction; prepare this title compound; be faint yellow solid 200mg, two-step reaction yield 41.3%, m.p.:260.0～264.5 ℃.
1HNMR(DMSO，300MHz)δppm：5.710-5.749(dd，1H，＝CH-)，6.197-6.261(dd，1H，＝CH-)，6.352-6.442(dd，1H，＝CH-)，6.966-6.995(d，1H，ArH)，7.327(s，1H，ArH)，7.697-7.732(dd，1H，ArH)，7.832-7.838(d，2H，ArH)，8.031-8.037(d，1H，ArH)
MS(EI)：350.0(M)，189，135
Embodiment 11:
The preparation of N-(4-cyclohexyl phenyl)-2-hydroxyl-5-acrylamide yl-benzamide
A) N-(4-cyclohexyl phenyl)-2-hydroxyl-5-nitrobenzamide
According to embodiment 1a) described method, with 2-hydroxyl-5-nitrobenzoic acid (0.366g, 2mmol) and 4-cyclohexyl aniline (0.350g 2mmol) for feedstock production obtains this title compound, is white solid 420mg, yield 61.8%, m.p.:203～206 ℃.
1HNMR(DMSO，300MHz)δppm：1.335-1.403(m，6H，-CH
2-×3)，1.669-1.787(m，4H，-CH
2-×2)，2.489(m，1H，-CH-Ar)，7.138-7.168(d，1H，ArH)，7.205-7.232(d，2H，ArH)，7.583-7.613(d，2H，ArH)，8.261-8.301(dd，1H，ArH)，8.774-8.784(d，1H，ArH)
B) N-(4-cyclohexyl phenyl)-2-hydroxyl-5-acrylamide yl-benzamide
According to embodiment 7b) 7c) described method; with N-(4-cyclohexyl phenyl)-2-hydroxyl-5-nitrobenzamide (400mg; 1.18mmol) and acrylate chloride (107mg; 1.18mmol) be raw material; by reduction, acylation reaction, prepare this title compound, be incarnadine solid 280mg; two-step reaction yield 65%, m.p.:229～232 ℃.
1HNMR(DMSO，300MHz)δppm：1.330-1.401(m，6H，-CH
2-×3)，1.668-1.786(m，4H，-CH
2-×2)，2.491(m，1H，-CH-Ar)，5.709-5.750(dd，1H，＝CH-)，6.198-6.262(dd，1H，＝CH-)，6.360-6.448(dd，1H，＝CH-)，6.944-6.974(d，1H，ArH)，7.183-7.210(d，2H，ArH)，7.568-7.598(d，2H，ArH)，7.689-7.727(d，1H，ArH)，8.091-8.101(d，1H，ArH)
MS(EI)：364(M)，175
Embodiment 12:
The preparation of N-(4-phenoxy phenyl)-2-hydroxyl-5-acrylamide yl-benzamide
A) N-(4-phenoxy phenyl)-2-hydroxyl-5-nitrobenzamide
According to embodiment 1a) described method, (0.366g is 2mmol) with 4-benzene oxygen aniline (0.370g with 2-hydroxyl-5-nitrobenzoic acid, 2mmol) obtain this title compound for feedstock production, be light yellow crystal 500mg, yield 71.4%, m.p.:194.5～196.5 ℃.
1HNMR(DMSO，300MHz)δppm：6.982-7.063(d×2，4H，ArH)，7.094-7.171(m，2H，ArH)，7.354-7.408(t，2H，ArH)，7.708-7.738(d，2H，ArH)，8.264-8.305(dd，1H，ArH)，8.764-8.774(d，1H，ArH)
B) N-(4-phenoxy phenyl)-2-hydroxyl-5-acrylamide yl-benzamide
According to embodiment 7b) 7c) described method; N-(4-phenoxy phenyl)-2-hydroxyl-5-nitrobenzamide (500mg; 1.43mmol) and acrylate chloride (130mg; 1.43mmol) be raw material; by reduction, acylation reaction, prepare this title compound, be pale solid 330mg; two-step reaction yield 61.7%, m.p.:226～231 ℃.
1HNMR(DMSO，300MHz)δppm：5.710-5.750(dd，1H，＝CH-)，6.200-6.263(dd，1H，＝CH-)，6.359-6.449(dd，1H，＝CH-)，6.951-6.998(d×2，3H，ArH)，7.019-7.048(d，2H，ArH)，7.084-7.132(t，1H，ArH)，7.348-7.401(t，2H，ArH)，7.686-7.731(dd+d，3H，ArH)，8.092-8.101(d，1H，ArH)
MS(EI)：374(M)，185，108
Embodiment 13:
The preparation of N-(dihydro indenes-5-yl)-2-hydroxyl-5-acrylamide yl-benzamide
A) N-(dihydro indenes-5-yl)-2-hydroxyl-5-nitrobenzamide
According to embodiment 1a) described method, (0.366g is 2mmol) with the amino dihydro indenes of 5-(0.266g with 2-hydroxyl-5-nitrobenzoic acid, 2mmol) obtain this title compound for feedstock production, be yellow crystals 400mg, yield 67%, m.p.:224.4～226.0 ℃.
1HNMR(DMSO，300MHz)δppm：1.966-2.065(m，2H，-CH
2-×2)，2.081-2.884(m，4H，-CH
2-Ar×2)，7.125-7.169(dd，1H，ArH)，7.194-7.221(d，1H，ArH)，7.395-7.421(d，1H，ArH)，7.604(s，1H，ArH)，8.262-8.301(dd，1H，ArH)，8.785-8.794(d，1H，ArH)
B) N-(dihydro indenes-5-yl)-2-hydroxyl-5-acrylamide yl-benzamide
According to embodiment 7b) 7c) described method; N-(dihydro indenes-5-yl)-2-hydroxyl-5-nitrobenzamide (400mg; 1.34mmol) and acrylate chloride (121mg; 1.34mmol) be raw material; by reduction, acylation reaction, prepare this title compound, be brick-red solid 200mg; two-step reaction yield 46.3%, m.p.:220～225 ℃.
1HNMR(DMSO，300MHz)δppm：1.973-2.060(m，2H，-CH
2-)，2.793-2.877(m，4H，-CH
2Ar×2)，5.707-5.748(dd，1H，＝CH-)，6.191-6.261(dd，1H，＝CH-)，6.358-6.449(dd，1H，＝CH-)，6.942-6.972(d，1H，ArH)，7.171-7.198(d，1H，ArH)，7.370-7.397(d，1H，ArH)，7.593(s，1H，ArH)，7.694-7.721(d，1H，ArH)，8.092-8.099(d，1H，ArH)
MS(EI)：322(M)，133
Embodiment 14:
N-[4-(hydroxyl-phenyl) aminomethyl phenyl]-preparation of 2-hydroxyl-5-acrylamide yl-benzamide
A) N-(4-benzoyl phenyl)-2-hydroxyl-5-nitrobenzamide
According to embodiment 1a) described method, (0.366g is 2mmol) with 4-benzanilide (0.394g with 2-hydroxyl-5-nitrobenzoic acid, 2mmol) obtain this title compound for feedstock production, be light yellow crystal 300mg, yield 41.4%, m.p.:204.0～208.5 ℃.
1HNMR(DMSO，300MHz)δppm：7.153-7.191(dd，1H，ArH)，7.540-7.589(t，2H，ArH)，7.648-7.672(d，1H，ArH)，7.697-7.741(t，2H，ArH)，7.783-7.812(d，2H，ArH)，7.902-7.932(d，2H，ArH)，8.272-8.311(dd，1H，ArH)，8.678-8.687(d，1H，ArH)
B) N-[4-(hydroxyl-phenyl) aminomethyl phenyl]-preparation of 2-hydroxyl-5-acrylamide yl-benzamide
According to embodiment 7b) 7c) described method; N-(4-benzoyl phenyl)-2-hydroxyl-5-nitrobenzamide (250mg; 0.67mmol) and acrylate chloride (60mg; 0.67mmol) be raw material; by reduction, acylation reaction, prepare this title compound, be gray solid 140mg; two-step reaction yield 52.5%, m.p.:197～200 ℃.
1HNMR(DMSO，300MHz)δppm：5.662(s，1H，HO-CH-)，5.704-5.743(dd，1H，＝CH-)，6.193-6.256(dd，1H，＝CH-)，6.351-6.441(dd，1H，＝CH-)，6.937-6.966(d，1H，ArH)，7.186-7.210(m，1H，ArH)，7.263-7.371(m，6H，ArH)，7.594-7.622(d，2H，ArH)，7.683-7.720(dd，1H，ArH)，8.078-8.086(d，1H，ArH)
MS(ESI)：389.5(M+1)，371.5
Embodiment 15:
The preparation of N-(2, the 5-dichlorophenyl)-2-hydroxyl-5-acrylamide yl-benzamide
A) N-(2, the 5-dichlorophenyl)-2-hydroxyl-5-nitrobenzamide
According to embodiment 1a) described method, (0.366g, 2mmol) and 2, (0.324g 2mmol) for feedstock production obtains this title compound, is yellow solid 300mg to the 5-dichlorphenamide bulk powder, yield 45.9%, m.p.:255～257 ℃ with 2-hydroxyl-5-nitrobenzoic acid.
1HNMR(DMSO，300MHz)δppm：7.165-7.195(d，1H，ArH)，7.232-7.269(dd，1H，ArH)，7.569-7.600(d，1H，ArH)，8.271-8.312(dd，1H，ArH)，8.528-8.534(d，1H，ArH)，8.791-8.801(d，1H，ArH)
B) N-(2, the 5-dichlorophenyl)-2-hydroxyl-5-acrylamide yl-benzamide
According to embodiment 7b) 7c) described method; with N-(2; 5 dichlorophenyls)-2-hydroxyl-5-nitrobenzamide (0.3g; 0.92mmol) and acrylate chloride (83mg 0.92mmol) is raw material, by the reduction, acylation reaction; prepare this title compound; be near-white solid 80mg, two-step reaction yield 24.8%, m.p.:199～202 ℃.
1HNMR(DMSO，300MHz)δppm：5.710-5.745(d，1H，＝CH-)，6.206-6.261(d，1H，＝CH-)，6.358-6.449(dd，1H，＝CH-)，6.953-6.982(d，1H，ArH)，7.088-7.135(t，1H，ArH)，7.331-7.381(t，1H，ArH)，7.683-7.733(m，2H，ArH)，8.099(s，1H，ArH)
MS(EI)：350.0(M)，189，135，93
Embodiment 16:
N-[3-(N, N-diethyl amino formyl radical) phenyl]-preparation of 2-hydroxyl-5-acrylamide yl-benzamide
A) N, N-diethyl-3-nitrobenzamide
(1.671g is a raw material 10mmol) to M-NITROBENZOIC ACID, is solvent with the thionyl chloride, and backflow 2h steams and removes unnecessary thionyl chloride, with an amount of tetrahydrofuran (THF) dissolving; With diethylamine (0.731g, 10mmol) and triethylamine (1.01g 10mmol) mixes, and is solvent with the tetrahydrofuran (THF), under the stirring at room, splashes into the tetrahydrofuran solution of acyl chlorides, and reaction 1h stops.The filtering insolubles, filtrate is concentrated into dried, and the gained solid is used saturated sodium bicarbonate solution, 1 mol hydrochloric acid soln, saturated common salt water washing respectively, anhydrous magnesium sulfate drying with acetic acid ethyl dissolution.Behind the filtering siccative, after filtrate concentrates crude product, the petroleum ether-ethyl acetate recrystallization obtains this title compound, is light yellow crystal 1.7g, yield 76.5%, m.p.:64.0～65.7 ℃.
B) N, N-diethyl-3-aminobenzamide
With N, (1.6g 7.2mmol) is dissolved in the methyl alcohol N-diethyl-3-nitrobenzamide, Raney-Ni catalysis, under the normal temperature and pressure with hydrogen reducing 2h, filtration catalizer, reaction solution is concentrated into dried, obtains this title compound, be orange crystal 1.25g, yield 90%, m.p.:64.0～65.7 ℃.
C) N-[3-(N, N-diethyl amino formyl radical) phenyl]-2-hydroxyl-5-nitrobenzamide
According to embodiment 1a) described method, with 2-hydroxyl-5-nitrobenzoic acid (0.366g, 2mmol) and N, (0.384g 2mmol) for feedstock production obtains this title compound, is light yellow crystal 250mg to N-diethyl-3-aminobenzamide, yield 35%, m.p.:169～172 ℃.
1HNMR(DMSO，300MHz)δppm：1.103-1.130(d，6H，CH
3-×2)，3.370(s，4H，-NCH
2-×2)，7.092-7.118(d，1H，ArH)，7.150-7.180(d，1H，ArH)，7.406-7.458(s，1H，ArH)，7.701-7.730(d，1H，ArH)，7.770(s，1H，ArH)，8.266-8.305(dd，1H，ArH)，8.718-8.728(d，1H，ArH)
D) N-[3-(N, N-diethyl amino formyl radical) phenyl]-2-hydroxyl-5-acrylamide yl-benzamide
According to embodiment 7b) 7c) described method; with N-[3-(N; N-diethyl amino formyl radical) phenyl]-2-hydroxyl-5-nitrobenzamide (250mg; 0.7mmol) and acrylate chloride (63mg 0.7mmol) is raw material, by the reduction, acylation reaction; prepare this title compound; be white solid 70mg, two-step reaction yield 26.2%, m.p.:170.5～172.0 ℃.
1HNMR(DMSO，300MHz)δppm：1.133(s，6H，-CH
3×2)，3.403-3.471(m，4H，-NCH
2-×2)，5.707-5.748(dd，1H，＝CH-)，6.196-6.261(dd，1H，＝CH-)，6.355-6.443(dd，1H，＝CH-)，6.955-6.982(d，1H，ArH)，7.053-7.080(d，1H，ArH)，7.381-7.434(t，1H，ArH)，7.661-7.688(d，1H，ArH)，7.725(d，1H，ArH)，7.782(s，1H，ArH)，8.075-8.086(d，1H，ArH)
MS(EI)：381(M)，308，193，135，120
Embodiment 17:
The preparation of N-(3-hydroxy phenyl)-2-hydroxyl-5-acrylamide yl-benzamide
A) N-(3-acetoxyl group phenyl)-2-hydroxyl-5-nitrobenzamide
According to embodiment 1a) described method, (0.549g is 3mmol) with 3-acetoxyl group aniline (0.454g with 2-hydroxyl-5-nitrobenzoic acid, 3mmol) obtain this title compound for feedstock production, be white-yellowish solid 240mg, yield 25.3%, m.p.:205～208 ℃.
1HNMR(DMSO，300MHz)δppm：2.276(s，3H，CH
3-)，6.892-6.925(dd，1H，ArH)，7.137-7.168(d，1H，ArH)，7.373-7.426(t，1H，ArH)，7.505-7..533(d，1H，ArH)，7.622-7.634(t，1H，ArH)，8.258-8.299(dd，1H，ArH)，8.693-8.702(d，1H，ArH)
B) N-(3-hydroxy phenyl)-2-hydroxyl-5-acrylamide yl-benzamide
According to embodiment 7b) 7c) described method; with N-(3-acetoxyl group phenyl)-2-hydroxyl-5-nitrobenzamide (240mg; 0.76mmol) and acrylate chloride (69mg; 0.76mmol) be raw material; by reduction, acylation reaction; the product that obtains is directly with 1 mol sodium hydroxide solution room temperature hydrolysis; regulate about pH to 2 with 1 mol hydrochloric acid soln again; ethyl acetate extraction, drying, concentrate after; gained crude product recrystallization obtains this title compound, is yellow solid 90mg; three-step reaction total recovery 39.7%, m.p.:231～235 ℃.
1HNMR(DMSO，300MHz)δppm：5.707-5.744(dd，1H，＝CH-)，6.196-6.261(dd，1H，＝CH-)，6.355-6.446(dd，1H，＝CH-)，6.493-6.520(dd，1H，ArH)，6.942-6.969(d，1H，ArH)，7.006-7.036(d，1H，ArH)，7.094-7.148(t，1H，ArH)，7.286(s，1H，ArH)，7.698-7.728(d，1H，ArH)，8..069-8.079(d，1H，ArH)
MS(EI)：298(M)，190，135，109
Embodiment 18:
The preparation of N-(3-phenelyl)-2-hydroxyl-5-acrylamide yl-benzamide
A) N-(3-phenelyl)-2-hydroxyl-5-nitrobenzamide
According to embodiment 1a) described method, (0.366g is 2mmol) with 3-phenetidine (0.274g with 2-hydroxyl-5-nitrobenzoic acid, 2mmol) obtain this title compound for feedstock production, be brick-red solid 300mg, yield 49.6%, m.p.:222～224 ℃.
1HNMR(DMSO，300MHz)δppm：1.303-1.350(t，3H，CH
3-)，3.981-4.049(q，2H，-CH
2-)，6.690-6.731(m，1H，ArH)，7.142-7.172(d，1H，ArH)，7.240(s，1H，ArH)，7.260(s，1H，ArH)，7.385(s，1H，ArH)，8.259-8.299(dd，1H，ArH)，8.731-8.741(d，1H，ArH)
B) N-(3-phenelyl)-2-hydroxyl-5-acrylamide yl-benzamide
According to embodiment 7b) 7c) described method; with N-(3-phenelyl)-2-hydroxyl-5-nitrobenzamide (300mg; 0.99mmol) and acrylate chloride (90mg; 0.99mmol) be raw material; by reduction, acylation reaction, prepare this title compound, be yellow-white crystal 130mg; two-step reaction yield 40.3%, m.p.:184～186 ℃.
1HNMR(DMSO，300MHz)δppm：1.303-1.350(t，3H，CH
3-)，3.978-4.045(q，2H，-CH
2-)，5.708-5.745(dd，1H，＝CH-)，6.198-6.262(dd，1H，＝CH-)，6.359-6.451(dd，1H，＝CH-)，6.663-6.687(d，1H，ArH)，6.946-6.977(d，1H，ArH)，7.189-7.267(m，2H，ArH)，7.392(s，1H，ArH)，7.705-7.732(dd，1H，ArH)，8.083-8.090(d，1H，ArH)
MS(EI)：326(M)，190，137，109
Embodiment 19:
The preparation of N-(3-carbethoxy phenyl)-2-hydroxyl-5-acrylamide yl-benzamide
A) N-(3-carbethoxy phenyl)-2-hydroxyl-5-nitrobenzamide
According to embodiment 1a) described method, (0.366g is 2mmol) with 3-subcutin (0.330g with 2-hydroxyl-5-nitrobenzoic acid, 2mmol) obtain this title compound for feedstock production, be faint yellow solid 480mg, yield 72.7%, m.p.:203～208 ℃.
1HNMR(DMSO，300MHz)δppm：1.303-1.349(t，3H，CH
3-)，4.294-4.365(q，2H，-CH
2-)，7.148-7.179(d，1H，ArH)，7.504-7.557(t，1H，ArH)，7.240-7.750(d，1H，ArH)，7.956-7.986(d，1H，ArH)，8.272-8.311(dd，1H，ArH)，8.373(s，1H，ArH)，8.739-8.748(d，1H，ArH)
B) N-(3-carbethoxy phenyl)-2-hydroxyl-5-acrylamide yl-benzamide
According to embodiment 7b) 7c) described method; with N-(3-carbethoxy phenyl)-2-hydroxyl-5-nitrobenzamide (480mg; 1.45mmol) and acrylate chloride (131mg; 1.45mmol) be raw material; by reduction, acylation reaction, prepare this title compound, be white solid 200mg; two-step reaction yield 39%, m.p.:250～257 ℃.
1HNMR(DMSO，300MHz)δppm：1.303-1.350(t，3H，CH
3-)，4.291-4.362(q，2H，-CH
2-)，5.712-5.752(dd，1H，＝CH-)，6.204-6.268(dd，1H，＝CH-)，6.366-6.454(dd，1H，＝CH-)，6.960-6.990(d，1H，ArH)，7.479-7.533(t，1H，ArH)，7.692-7.719(d，2H，ArH)，7.925-7.952(d，1H，ArH)，8.101-8.110(d，1H，ArH)，8.377(s，1H，ArH)
MS(EI)：354(M)，189，165，135
Embodiment 20:
The preparation of 2-hydroxyl-5-acrylamido benzanilide
A) 2-hydroxyl-5-nitrobenzanilide
According to embodiment 1a) described method, with 2-hydroxyl-5-nitrobenzoic acid (0.916g, 5mmol) and aniline (0.466g 5mmol) for feedstock production obtains this title compound, is faint yellow solid 900mg, yield 69.7%, m.p.:225～227 ℃.
B) 2-hydroxyl-5-acrylamido benzanilide
According to embodiment 7b) 7c) described method; with 2-hydroxyl-5-nitrobenzanilide (900mg; 3.48mmol) and acrylate chloride (315mg; 3.48mmol) be raw material; by reduction, acylation reaction, prepare this title compound, be nearly red solid 560mg; two-step reaction yield 56.9%, m.p.:223.5～228.5 ℃.
1HNMR(DMSO，300MHz)δppm：5.708-5.748(dd，1H，＝CH-)，6.200-6.244(dd，1H，＝CH-)，6.363-6.452(dd，1H，＝CH-)，6.950-6.979(d，1H，ArH)，7.089-7.136(t，1H，ArH)，7.332-7.383(t，2H，ArH)，7.683-7.742(m，3H，ArH)，8.100-8.109(d，1H，ArH)
MS(EI)：282.4(M)，189.3，135.2
Embodiment 21:
The preparation of N-phenmethyl-2-hydroxyl-5-acrylamide yl-benzamide
A) N-phenmethyl-2-hydroxyl-5-nitrobenzamide
According to embodiment 1a) described method, with 2-hydroxyl-5-nitrobenzoic acid (0.916g, 5mmol) and benzylamine (0.589g 5.5mmol) for feedstock production obtains this title compound, is light yellow crystal 800mg, yield 58.7%, m.p.:148～150 ℃.
B) N-phenmethyl-2-hydroxyl-5-acrylamide yl-benzamide
According to embodiment 7b) 7c) described method; with N-phenmethyl-2-hydroxyl-5-nitrobenzamide (800mg; 2.94mmol) and acrylate chloride (266mg; 2.94mmol) be raw material; by reduction, acylation reaction, prepare this title compound, be near-white solid 550mg; two-step reaction yield 63.2%, m.p.:170～173 ℃.
1HNMR(DMSO，300MHz)δppm：4.489-4.509(d，2H，-CH
2-)，5.698-5.739(dd，1H，＝CH-)，6.188-6.251(dd，1H，＝CH-)，6.351-6.441(dd，1H，＝CH-)，6.879-6.908(d，1H，ArH)，7.226-7.334(m，5H，ArH)，7.571-7.610(dd，1H，ArH)，8.096-8.104(d，1H，ArH)
MS(EI)：296.3(M)，189.1，135.1，91.1
Embodiment 22:
The preparation of D-(+)-N-(1-phenylethyl)-2-hydroxyl-5-acrylamide yl-benzamide
A) D-(+)-N-(1-phenylethyl)-2-hydroxyl-5-nitrobenzamide
According to embodiment 1a) described method, with 2-hydroxyl-5-nitrobenzoic acid (0.916g, 5mmol) and D-(+)-benzylamine (0.727g, 6mmol) obtain this title compound for feedstock production, be faint yellow solid 610mg, yield 42.3%, m.p.:178～181 ℃.
B) D-(+)-N-(1-phenylethyl)-2-hydroxyl-5-acrylamide yl-benzamide
According to embodiment 7b) 7c) described method; with D-(+)-N-(1-phenylethyl)-2-hydroxyl-5-nitrobenzamide (610mg; 2.12mmol) and acrylate chloride (192mg; 2.12mmol) be raw material; by reduction, acylation reaction, prepare this title compound, be near-white solid 220mg; two-step reaction yield 33.3%, m.p.:135～138 ℃.
1HNMR(DMSO，300MHz)δppm：1.474-1.498(d，3H，CH
3-)，5.148-5.196(m，1H，-CH-)，5.700-5.740(dd，1H，＝CH-)，6.192-6.257(dd，1H，＝CH-)，6.356-6.446(dd，1H，＝CH-)，6.862-6.893(d，1H，ArH)，7.211-7.258(t，1H，ArH)，7.306-7.402(m，4H，ArH)，7.615-7.653(dd，1H，ArH)，8.051-8.059(d，1H，ArH)
MS(EI)：310.2(M)，206.1，189.1，105.1
Embodiment 23:
The preparation of L-(-)-N-(1-phenylethyl)-2-hydroxyl-5-acrylamide yl-benzamide
A) L-(-)-N-(1-phenylethyl)-2-hydroxyl-5-nitrobenzamide
According to embodiment 1a) described method, with 2-hydroxyl-5-nitrobenzoic acid (0.916g, 5mmol) and L-(-)-benzylamine (0.727g, 6mmol) obtain this title compound for feedstock production, be faint yellow solid 520mg, yield 36.1%, m.p.:166～171 ℃.
B) L-(-)-N-(1-phenylethyl)-2-hydroxyl-5-acrylamide yl-benzamide
According to embodiment 7b) 7c) described method; with L-(-)-N-(1-phenylethyl)-2-hydroxyl-5-nitrobenzamide (520mg; 1.8mmol) and acrylate chloride (163mg; 1.8mmol) be raw material; by reduction, acylation reaction, prepare this title compound, be yellowish pink solid 280mg; two-step reaction yield 49.7%, m.p.:138.3～140.0 ℃.
1HNMR(DMSO，300MHz)δppm：1.471-1.494(d，3H，CH
3-)，5.121-5.217(m，1H，-CH-)，5.704-5.744(dd，1H，＝CH-)，6.193-6.257(dd，1H，＝CH-)，6.355-6.445(dd，1H，＝CH-)，6.864-6.893(d，1H，ArH)，7.211-7.258(t，1H，ArH)，7.307-7.402(m，4H，ArH)，7.617-7.655(dd，1H，ArH)，8.051-8.059(d，1H，ArH)
MS(EI)：310.2(M)，206.1，189.1，105.1
Embodiment 24:
The preparation of N-(4-phenoxy phenyl)-3-acrylamide yl-benzamide
A) N-(4-phenoxy phenyl)-3-nitrobenzamide
(401mg, 2.4mmol) reflux 2h in thionyl chloride steam and remove excessive solvent, add the tetrahydrofuran (THF) dissolving with M-NITROBENZOIC ACID; Will be to benzene oxygen aniline (0.37g, 2mmol) and triethylamine (0.202g, 2mmol) mix, an amount of tetrahydrofuran (THF) dissolves, and splashes into the tetrahydrofuran (THF) liquid of acyl chlorides under the stirring at room, reaction 2h, filter, filtrate concentrates, and the gained solid is with acetic acid ethyl dissolution, respectively with saturated sodium bicarbonate solution, 1 mol hydrochloric acid soln, saturated common salt water washing, anhydrous magnesium sulfate drying.Filtering siccative, filtrate are concentrated into dried crude product, and the petroleum ether-ethyl acetate recrystallization obtains this title compound, is light brown crystal 5 90mg, yield 88%, m.p.:140～143 ℃.
B) N-(4-phenoxy phenyl)-3-acrylamide yl-benzamide
According to embodiment 7b) 7c) described method; with N-(4-phenoxy phenyl)-3-nitrobenzamide (500mg; 1.5mmol) and acrylate chloride (136mg; 1.5mmol) be raw material; by reduction, acylation reaction, prepare this title compound, be white solid 230mg; two-step reaction yield 42.8%, m.p.:195.5～198.5 ℃.
1HNMR(DMSO，300MHz)δppm：5.766-5.805(dd，1H，＝CH-)，6.252-6.309(dd，1H，＝CH-)，6.408-6.498(dd，1H，＝CH-)，6.967-6.995(d，2H，ArH)，7.018-7.047(d，2H，ArH)，7.080-7.128(t，1H，ArH)，7.347-7.399(t，2H，ArH)，7.453-7.505(t，1H，ArH)，7.633-7.659(d，1H，ArH)，7.763-7.793(d，2H，ArH)，7.908-7.935(d，1H，ArH)，8.151(s，1H，ArH)
MS(EI)：358.4(M)，174.1
Embodiment 25:
The preparation of N-(3-chloro-4-fluorophenyl)-3-acrylamide yl-benzamide
A) N-(3-chloro-4-fluorophenyl)-3-nitrobenzamide
According to embodiment 24a) described method, with M-NITROBENZOIC ACID (401mg, 2.4mmol)) and 3-chloro-4-fluoroaniline (0.765g, 2.4mmol) obtain this title compound for feedstock production, be faint yellow needle 510mg, yield 86.5%, m.p.:172.5～175.5 ℃.
B) N-(3-chloro-4-fluorophenyl)-3-acrylamide yl-benzamide
According to embodiment 7b) 7c) described method; with N-(3-chloro-4-fluorophenyl)-3-nitrobenzamide (295mg; 1mmol) and acrylate chloride (90mg; 1mmol) be raw material; by reduction, acylation reaction, prepare this title compound, be white powder 190mg; two-step reaction yield 60%, m.p.:191～194 ℃.
1HNMR(DMSO，300MHz)δppm：5.766-5.805(dd，1H，＝CH-)，6.251-6.308(dd，1H，＝CH-)，6.405-6.494(dd，1H，＝CH-)，7.387-7.447(t，1H，ArH)，7.464-7.515(t，1H，ArH)，7.623-7.648(d，1H，ArH)，7.681-7.734(m，1H，ArH)，7.903-7.930(d，1H，ArH)，8.049-8.078(dd，1H，ArH)，8.164(s，1H，ArH)
MS(EI)：318.2(M)，174.1
Embodiment 26:
N-[3-(N, N-diethyl amino formyl radical) phenyl]-preparation of 3-acrylamide yl-benzamide
A) N, N-diethyl-3-nitrobenzamide
According to embodiment 16a) described method, with M-NITROBENZOIC ACID (1.671g, 10mmol) and diethylamine (0.731g, 10mmol) for feedstock production obtains this title compound, light yellow crystal 1.7g, yield 76.5%.
B) N, N-diethyl-3-aminobenzamide
According to embodiment 16b) described method, with N, N-diethyl-3-nitrobenzamide (1.6g, 7.2mmol) for feedstock production obtains this title compound, orange crystal 1.25g, yield 90%.
C) N-[3-(N, N-diethyl amino formyl radical) phenyl]-the 3-nitrobenzamide
According to embodiment 24a) described method, with M-NITROBENZOIC ACID (197mg, 1.2mmol) and N, (0.192g 1mmol) for feedstock production obtains this title compound, is yellowish pink crystal 3 20mg to N-diethyl-3-aminobenzamide, yield 93.7%, m.p.:127.5～130.5 ℃.
D) N-[3-(N, N-diethyl amino formyl radical) phenyl]-3-acrylamide yl-benzamide
According to embodiment 7b) 7c) described method; with N-[3-(N; N-diethyl amino formyl radical) phenyl]-3-nitrobenzamide (320mg; 0.94mmol) and acrylate chloride (85mg 0.94mmol) is raw material, by the reduction, acylation reaction; prepare this title compound; be white solid 150mg, two-step reaction yield 43.8%, m.p.:87～92 ℃.
1HNMR(DMSO，300MHz)δppm：1.102-1.178(s，6H，CH
3-×2)，3.209-3.406(m，4H，-CH
2-×2)，5.764-5.803(dd，1H，＝CH-)，6.258-6.320(dd，1H，＝CH-)，6.414-6.503(dd，1H，＝CH-)，7.043-7.067(d，1H，ArH)，7.376-7.429(t，1H，ArH)，7.458-7.511(t，1H，ArH)，7.648-7.674(d，1H，ArH)，7.789-7.819(d，2H，ArH)，7.916-7.941(d，1H，ArH)，8.177(s，1H，ArH)
MS(EI)：360.5(M)，292.9，174.0
Embodiment 27:
The preparation of N-(4-phenoxy phenyl)-2-methoxyl group-5-acrylamide yl-benzamide
A) 2-methoxyl group-5-nitrobenzoic acid
With 2-hydroxyl-5-nitrobenzoic acid (3.66g 20mmol) is dissolved in 50ml acetone, add 4 times of amounts salt of wormwood, methyl-sulfates (10.09g, 80mmol), stirring at room 2 days.Add less water reflux 1h, add 2 mol sodium hydroxide solution 25ml again, backflow 6h, reaction finishes.The acetone in the reaction solution is removed in decompression, in the residual reaction liquid impouring 250ml water, regulates about pH to 2 with concentrated hydrochloric acid under the ice bath, the adularescent insolubles is separated out, and leaves standstill, filters, drying, obtains this title compound, be white powder 3.79g, yield 95.9%, m.p.:154.8～160.3 ℃.
B) N-(4-phenoxy phenyl)-2-methoxyl group-5-nitrobenzamide
According to embodiment 24a) described method, (217mg is 1.1mmol) with to benzene oxygen aniline (0.185g with 2-methoxyl group-5-nitrobenzoic acid, 1mmol) obtain this title compound for feedstock production, be yellow needle 290mg, yield 86.7%, m.p.:140.5～132.0 ℃.
C) N-(4-phenoxy phenyl)-2-methoxyl group-5-acrylamide yl-benzamide
According to embodiment 7b) 7c) described method; with N-(4-phenoxy phenyl)-2-methoxyl group-5-nitrobenzamide (290mg; 0.88mmol) and acrylate chloride (80mg; 0.88mmol) be raw material; by reduction, acylation reaction, prepare this title compound, be white needle 190mg; two-step reaction yield 61.5%, m.p.:168.8～170.5 ℃.
1HNMR(DMSO，300MHz)δppm：3.877(s，3H，CH
3-)，5.720-5.761(dd，1H，＝CH-)，6.207-6.271(dd，1H，＝CH-)，6.357-6.447(dd，1H，＝CH-)，6.957-6.984(d，2H，ArH)，6.999-7.050(d，2H，ArH)，7.072-7.122(t，1H，ArH)，7.145-7.175(d，1H，ArH)，7.339-7.392(t，2H，ArH)，7.731-7.760(d，2H，ArH)，7.830-7.868(dd，1H，ArH)，7.903-7.910(d，1H，ArH)
MS(EI)：388.2(M)，204.1
Embodiment 28:
The preparation of N-(3-chloro-4-fluorophenyl)-2-methoxyl group-5-acrylamide yl-benzamide
A) 2-methoxyl group-5-nitrobenzoic acid
According to embodiment 27a) described method, with 2-hydroxyl-5-nitrobenzoic acid (3.66g, 20mmol) for feedstock production obtains this title compound, white powder 3.79g, yield 95.9%.
B) N-(3-chloro-4-fluorophenyl)-2-methoxyl group-5-nitrobenzamide
According to embodiment 24a) described method, (434mg is 2.2mmol) with 3-chloro-4-fluoroaniline (291mg with 2-methoxyl group-5-nitrobenzoic acid, 2mmol) obtain this title compound for feedstock production, be pale solid 500mg, yield 77%, m.p.:203.3～205.0 ℃.
C) N-(3-chloro-4-fluorophenyl)-2-methoxyl group-5-acrylamide yl-benzamide
According to embodiment 7b) 7c) described method; with N-(3-chloro-4-fluorophenyl)-2-methoxyl group-5-nitrobenzamide (324mg; 1mmol) and acrylate chloride (90mg; 1mmol) be raw material; by reduction, acylation reaction, prepare this title compound, be yellowish pink crystal 160mg; two-step reaction yield 45.9%, m.p.:170.0～172.5 ℃.
1HNMR(DMSO，300MHz)δppm：3.867(s，3H，CH
3-)，5.719-5.759(dd，1H，＝CH-)，6.203-6.267(dd，1H，＝CH-)，6.352-6.441(dd，1H，＝CH-)，7.149-7.180(d，1H，ArH)，7.372-7.433(t，1H，ArH)，7.634-7.687(m，1H，ArH)，7.824-7.862(dd，1H，ArH)，7.899-7.906(d，1H，ArH)，8.029-8.060(dd，1H，ArH)
MS(EI)：348.2(M)，204.2
Embodiment 29:
N-[3-(N, N-diethyl amino formyl radical) phenyl]-preparation of 2-methoxyl group-5-acrylamide yl-benzamide
A) N, N-diethyl-3-nitrobenzamide
According to embodiment 16a) described method, with M-NITROBENZOIC ACID (1.671g, 10mmol) and diethylamine (0.731g, 10mmol) for feedstock production obtains this title compound, light yellow crystal 1.7g, yield 76.5%.
B) N, N-diethyl-3-aminobenzamide
According to embodiment 16b) described method, with N, N-diethyl-3-nitrobenzamide (1.6g, 7.2mmol) for feedstock production obtains this title compound, orange crystal 1.25g, yield 90%.
C) 2-methoxyl group-5-nitrobenzoic acid
According to embodiment 27a) described method, with 2-hydroxyl-5-nitrobenzoic acid (3.66g, 20mmol) for feedstock production obtains this title compound, white powder 3.79g, yield 95.9%.
D) N-[3-(N, N-diethyl amino formyl radical) phenyl]-2-methoxyl group-5-nitrobenzamide
According to embodiment 24a) described method, with 2-methoxyl group-5-nitrobenzoic acid (217mg, 1.1mmol) and N, (192mg 1mmol) for feedstock production obtains this title compound, is faint yellow solid 360mg to N-diethyl-3-aminobenzamide, yield 97%, m.p.:155.5～157.5 ℃.
E) N-[3-(N, N-diethyl amino formyl radical) phenyl]-2-methoxyl group-5-acrylamide yl-benzamide
According to embodiment 7b) 7c) described method; with N-[3-(N; N-diethyl amino formyl radical) phenyl]-2-methoxyl group-5-nitrobenzamide (360mg; 0.97mmol) and acrylate chloride (88mg 0.97mmol) is raw material, by the reduction, acylation reaction; prepare this title compound; be yellowish pink needle 180mg, two-step reaction yield 47%, m.p.:139.1～141.0 ℃.
1HNMR(DMSO，300MHz)δppm：1.103(s，6H，CH
3-×2)，3.187-3.408(m，4H，-CH
2-×2)，3.871(s，3H，CH
3O-)，5.719-5.757(d，1H，＝CH-)，6.211-6.262(d，1H，＝CH-)，6.353-6.443(dd，1H，＝CH-)，7.028-7.054(d，1H，ArH)，7.147-7.177(d，1H，ArH)，7.359-7.412(t，1H，ArH)，7.705-7.733(d，1H，ArH)，7.787(s，1H，ArH)，7.828-7.864(dd，1H，ArH)，7.894(s，1H，ArH)
MS(EI)：395.0(M)，203.9
Embodiment 30:
N-[3-(N, N-di-isopropyl carbamyl) phenyl]-preparation of 2-hydroxyl-5-acrylamide yl-benzamide
A) N, N-di-isopropyl-3-nitrobenzamide
According to embodiment 16a) described method, with M-NITROBENZOIC ACID (1.671g, 10mmol) and Diisopropylamine (1.01g 10mmol) for feedstock production obtains this title compound, is the brilliant 1.65g of no color lump, yield 66%, m.p.:74.0～75.5 ℃.
B) N, N-di-isopropyl-3-aminobenzamide
According to embodiment 16b) described method, with N, N-di-isopropyl-3-nitrobenzamide (1.65g, 6.6mmol) for feedstock production obtains this title compound, yellowish pink crystal 1.36g, yield 92.8%, m.p.:172.5～175.5 ℃.
C) 2-methoxyl group-5-nitrobenzoic acid
According to embodiment 27a) described method, with 2-hydroxyl-5-nitrobenzoic acid (3.66g, 20mmol) for feedstock production obtains this title compound, white powder 3.79g, yield 95.9%.
D) N-[3-(N, N-di-isopropyl carbamyl) phenyl]-2-methoxyl group-5-nitrobenzamide
According to embodiment 24a) described method, with 2-methoxyl group-5-nitrobenzoic acid (591mg, 3mmol) and N, (660mg 3mmol) for feedstock production obtains this title compound, is white crystal 1.04g to N-di-isopropyl-3-aminobenzamide, yield 86.8%, m.p.:204～206 ℃.
1HNMR(DMSO，300MHz)δppm：1.142-1.374(d，12H，CH
3-×4)，3.657(m，2H，-CH-×2)，4.006(s，3H，CH
3O-)，6.999-7.025(d，1H，ArH)，7.367-7.418(m，2H，ArH)，7.670-7.698(d，2H，ArH)，8.373-8.408(d，2H，ArH)
E) N-[3-(N, N-di-isopropyl carbamyl) phenyl]-2-hydroxyl-5-nitrobenzamide
With N-[3-(N, N-di-isopropyl carbamyl) phenyl]-(399mg 1mmol) is dissolved in the 10ml methylene dichloride 2-methoxyl group-5-nitrobenzamide, under the ice bath, splashes into 5ml 1 mol boron trichloride-dichloromethane solution, reaction 1h.In the impouring water, dichloromethane extraction, organic phase is with anhydrous sodium sulfate drying.The filtering siccative concentrates the crude product obtain with the petroleum ether-ethyl acetate recrystallization, obtains this title compound, is white solid 360mg, yield 93.5%, m.p.:236～242 ℃.
F) N-[3-(N, N-di-isopropyl carbamyl) phenyl]-2-hydroxyl-5-acrylamide yl-benzamide
According to embodiment 7b) 7c) described method; with N-[3-(N; N-di-isopropyl carbamyl) phenyl]-2-hydroxyl-5-nitrobenzamide (360mg; 0.935mmol) and acrylate chloride (85mg 0.935mmol) is raw material, by the reduction, acylation reaction; prepare this title compound; be faint yellow solid 210mg, two-step reaction yield 54.8%, m.p.:141.0～144.4 ℃.
1HNMR(DMSO，300MHz)δppm：1.054-1.369(d，12H，CH
3-×4)，3.664(m，2H，-CH-×2)，5.706-5.746(dd，1H，＝CH-)，6.198-6.260(dd，1H，＝CH-)，6.359-6.448(dd，1H，＝CH-)，6.952-6.981(d，1H，ArH)，6.994-7.019(d，1H，ArH)，7.365-7.418(t，1H，ArH)，7.639-7.667(d，1H，ArH)，7.691-7.720(m，2H，ArH)，8.089-8.097(d，1H，ArH)
MS(FAB)：410.3(M+1)，409.3(M)，309.2
Embodiment 31:
N-[3-(N, N-diformazan carbamyl) phenyl]-preparation of 2-hydroxyl-5-acrylamide yl-benzamide
A) N, N-dimethyl-3-nitrobenzamide
According to embodiment 16a) described method, with M-NITROBENZOIC ACID (1.671g, 10mmol) and dimethylamine solution (33%) (1.37g 10mmol) for feedstock production obtains this title compound, is colourless prism 1.4g, yield 72%, m.p.:79～80 ℃.
B) N, N-dimethyl-3-aminobenzamide
According to embodiment 16b) described method, with N, N-dimethyl-3-nitrobenzamide (1.4g, 7.2mmol) for feedstock production obtains this title compound, yellowish pink crystal 930mg, yield 79%, m.p.:79～81 ℃.
C) 2-methoxyl group-5-nitrobenzoic acid
According to embodiment 27a) described method, with 2-hydroxyl-5-nitrobenzoic acid (3.66g, 20mmol) for feedstock production obtains this title compound, white powder 3.79g, yield 95.9%.
D) N-[3-(N, N-diformazan carbamyl) phenyl]-2-methoxyl group-5-nitrobenzamide
According to embodiment 24a) described method, with 2-methoxyl group-5-nitrobenzoic acid (591mg, 3mmol) and N, (493mg 3mmol) for feedstock production obtains this title compound, is white solid 0.7g to N-dimethyl-3-aminobenzamide, yield 68%, m.p.:166.0～168.5 ℃.
1HNMR(DMSO，300MHz)δppm：2.920(s，3H，CH
3-)，2.978(s，3H，CH
3-)，4.006(s，3H，CH
3O-)，7.112-7.138(d，1H，ArH)，7.387-7.434(m，2H，ArH)，7.712-7.738(d，1H，ArH)，7.787(s，1H，ArH)，8.373-8.382(d，1H，ArH)，8.400-8.408(d，1H，ArH)
E) N-[3-(N, N-diformazan carbamyl) phenyl]-2-hydroxyl-5-nitrobenzamide
According to embodiment 30e) described method, with N-[3-(N, N-diformazan carbamyl) phenyl]-2-methoxyl group-5-nitrobenzamide (343mg; 1mmol) obtain this title compound for feedstock production; be white solid 240mg, yield 73%, m.p.:215.0～217.5 ℃.
F) N-[3-(N, N-diformazan carbamyl) phenyl]-2-hydroxyl-5-acrylamide yl-benzamide
According to embodiment 7b) 7c) described method; with N-[3-(N; N-diformazan carbamyl) phenyl]-2-hydroxyl-5-nitrobenzamide (240mg; 0.73mmol) and acrylate chloride (85mg 0.73mmol) is raw material, by the reduction, acylation reaction; prepare this title compound; be white crystal 100mg, two-step reaction yield 38.8%, m.p.:192.0～193.5 ℃.
1HNMR(DMSO，300MHz)δppm：2.924(s，3H，CH
3-)，2.980(s，3H，CH
3-)，5.706-5.746(d，1H，＝CH-)，6.205-6.260(d，1H，＝CH-)，6.359-6.448(dd，1H，＝CH-)，6.953-6.983(d，1H，ArH)，7.109-7.134(d，1H，ArH)，7.383-7.434(t，1H，ArH)，7.698-7.725(d，2H，ArH)，7.793(s，1H，ArH)，8.086-8.093(d，1H，ArH)
MS(FAB)：354.2(M+1)，309.2
Embodiment 32:
N-[3-(tetramethyleneimine-1-formyl radical) phenyl]-preparation of 2-hydroxyl-5-acrylamide yl-benzamide
A) (3-nitrophenyl)-pyrrolidyl-1-ketone
According to embodiment 16a) described method, with M-NITROBENZOIC ACID (1.671g, 10mmol) and tetramethyleneimine (0.71g 10mmol) for feedstock production obtains this title compound, is yellow crystals 1.68g, yield 76.4%, m.p.:55～58 ℃.
B) (3-aminophenyl)-pyrrolidyl-1-ketone
According to embodiment 16b) described method, (1.68g 7.64mmol) for feedstock production obtains this title compound, is dope 780mg, yield 53.7% with (3-nitrophenyl)-pyrrolidyl-1-ketone.
C) 2-methoxyl group-5-nitrobenzoic acid
According to embodiment 27a) described method, with 2-hydroxyl-5-nitrobenzoic acid (3.66g, 20mmol) for feedstock production obtains this title compound, white powder 3.79g, yield 95.9%.
D) N-[3-(tetramethyleneimine-1-formyl radical) phenyl]-2-methoxyl group-5-nitrobenzamide
According to embodiment 24a) described method, with 2-methoxyl group-5-nitrobenzoic acid (789mg, 4mmol) with (3-aminophenyl)-pyrrolidyl-1-ketone (780mg, 4.1mmol) obtain this title compound for feedstock production, be white solid 1.4g, yield 94.7%, m.p.:163.4～165.6 ℃.
1HNMR(DMSO，300MHz)δppm：1.792-1.891(m，4H，-CH
2-×2)，3.365-3.405(t，2H，-CH
2-)，3.438-3.482(t，2H，-CH
2-)，4.009(s，3H，CH
3O-)，7.232-7.258(d，1H，ArH)，7.386-7.434(m，2H，ArH)，7.726-7.752(d，1H，ArH)，7.902(s，1H，ArH)，8.374-8.410(d，2H，ArH)
E) N-[3-(tetramethyleneimine-1-formyl radical) phenyl]-2-hydroxyl-5-nitrobenzamide
According to embodiment 30e) described method; with N-[3-(tetramethyleneimine-1-formyl radical) phenyl]-(369mg 1mmol) for feedstock production obtains this title compound, gets near-white solid 310mg to 2-methoxyl group-5-nitrobenzamide; yield 87.3%, m.p.:167.3～170.0 ℃.
F) N-[3-(tetramethyleneimine-1-formyl radical) phenyl]-2-hydroxyl 5-acrylamide yl-benzamide
According to embodiment 7b) 7c) described method; with N-[3-(tetramethyleneimine-1-formyl radical) phenyl]-2-hydroxyl-5-nitrobenzamide (310mg; 0.87mmol) and acrylate chloride (79mg; 0.87mmol) be raw material; by reduction, acylation reaction, prepare this title compound, be white powder 120mg; two-step reaction yield 36.3%, m.p.:203～206 ℃.
1HNMR(DMSO，300MHz)δppm：1.791-1.890(m，4H，-CH
2-×2)，3.372-3.412(t，2H，-CH
2-)，3.441-3.483(t，2H，-CH
2-)，5.709-5.746(d，1H，＝CH-)，6.205-6.258(d，1H，＝CH-)，6.361-6.450(dd，1H，＝CH-)，6.955-6.984(d，1H，ArH)，7.226-7.252(d，1H，ArH)，7.383-7.434(t，1H，ArH)，7.703-7.731(d，2H，ArH)，7.910(s，1H，ArH)，8.093(s，1H，ArH)
MS(FAB)：380.2(M+1)，309.2，191.2
Embodiment 33:
N-[3-(piperidines-1-formyl radical) phenyl]-preparation of 2-hydroxyl-5-acrylamide yl-benzamide
A) (3-nitrophenyl)-piperidyl-1-ketone
According to embodiment 16a) described method, with M-NITROBENZOIC ACID (1.671g, 10mmol) and piperidines (0..851g 10mmol) for feedstock production obtains this title compound, is light yellow crystal 1.68g, yield 94%, m.p.:73.0～76.5 ℃.
B) (3-aminophenyl)-piperidyl-1-ketone
According to embodiment 16b) described method, (2.23g 9.4mmol) for feedstock production obtains this title compound, is light yellow crystal 1.76g, yield 90.5%, m.p.:117.3～119.0 ℃ with (3-nitrophenyl)-piperidyl-1-ketone.
C) 2-methoxyl group-5-nitrobenzoic acid
According to embodiment 27a) described method, with 2-hydroxyl-5-nitrobenzoic acid (3.66g, 20mmol) for feedstock production obtains this title compound, white powder 3.79g, yield 95.9%.
D) N-[3-(piperidines-1-formyl radical) phenyl]-2-methoxyl group-5-nitrobenzamide
According to embodiment 24a) described method, with 2-methoxyl group-5-nitrobenzoic acid (493mg, 2.5mmol) and (3-aminophenyl)-piperidyl-1-ketone (511mg, 2.5mmol) obtain this title compound for feedstock production, be white powder 0.77g, yield 80.3%, m.p.:156.0～157.5 ℃.
1HNMR(DMSO，300MHz)δppm：1.497-1.619(s×2，6H，-CH
2-×3)，3.317(s，2H，-CH
2-)，3.567(s，2H，-CH
2-)，4.006(s，3H，CH
3O-)，7.078-7.103(d，1H，ArH)，7.383-7.434(m，2H，ArH)，7.707-7.734(d，1H，ArH)，7.777(s，1H，ArH)，8.382-8.408(d，2H，ArH)
E) N-[3-(piperidines-1-formyl radical) phenyl]-2-hydroxyl-5-nitrobenzamide
According to embodiment 30e) described method; with N-[3-(piperidines-1-formyl radical) phenyl]-(383mg 1mmol) for feedstock production obtains this title compound, gets near-white solid 360mg to 2-methoxyl group-5-nitrobenzamide; yield 97%, m.p.:215～220 ℃.
F) N-[3-(piperidines-1-formyl radical) phenyl]-2-hydroxyl-5-acrylamide yl-benzamide
According to embodiment 7b) 7c) described method; with N-[3-(piperidines-1-formyl radical) phenyl]-2-hydroxyl-5-nitrobenzamide (360mg; 0.97mmol) and acrylate chloride (88mg; 0.97mmol) be raw material; by reduction, acylation reaction, prepare this title compound, be white powder 140mg; two-step reaction yield 36.5%, m.p.:186.3～189.0 ℃.
1HNMR(DMSO，300MHz)δppm：1.506-1.606(s×2，6H，-CH
2-×3)，3.319(s，2H，-CH
2-)，3.573(s，2H，-CH
2-)，5.706-5.746(dd，1H，＝CH-)，6.205-6.255(dd，1H，＝CH-)，6.359-6.448(dd，1H，＝CH-)，6.953-6.983(d，1H，ArH)，7.076-7.102(d，1H，ArH)，7.383-7.436(t，1H，ArH)，7.681-7.734(m，2H，ArH)，7.791(s，1H，ArH)，8.086-8.093(d，1H，ArH)
MS(FAB)：394.2(M+1)，393.2(M)，309.2，205.2
Embodiment 34:
N-[3-(morpholine-4-formyl radical) phenyl]-preparation of 2-hydroxyl-5-acrylamide yl-benzamide
A) (3-nitrophenyl)-morpholinyl-4-ketone
According to embodiment 16a) described method, with M-NITROBENZOIC ACID (1.671g, 10mmol) and morpholine (0..870g 10mmol) for feedstock production obtains this title compound, is light yellow crystal 1.96g, yield 83.1%, m.p.:81.0～83.6 ℃.
B) (3-aminophenyl)-morpholinyl-4-ketone
According to embodiment 16b) described method, (1.96g 8.3mmol) for feedstock production obtains this title compound, is dope 850mg, yield 49.7% with (3-nitrophenyl)-morpholinyl-4-ketone.
C) 2-methoxyl group-5-nitrobenzoic acid
According to embodiment 27a) described method, with 2-hydroxyl-5-nitrobenzoic acid (3.66g, 20mmol) for feedstock production obtains this title compound, white powder 3.79g, yield 95.9%.
D) N-[3-(morpholine-4-formyl radical) phenyl]-2-methoxyl group-5-nitrobenzamide
According to embodiment 24a) described method, with 2-methoxyl group-5-nitrobenzoic acid (1.183g, 6mmol) with (3-aminophenyl)-morpholinyl-4-ketone (1.238g, 6mmol) obtain this title compound for feedstock production, be white solid 2.05g, yield 88.6%, m.p.:200.0～202.5 ℃.
1HNMR(DMSO，300MHz)δppm：3.581-3.599(s，8H，-CH
2-×4)，4.006(s，3H，CH
3O-)，7.127-7.153(d，1H，ArH)，7.387-7.451(m，2H，ArH)，7.733-7.760(d，1H，ArH)，7.806(s，1H，ArH)，8.384-8.406(d，2H，ArH)
E) N-[3-(morpholine-4-formyl radical) phenyl]-2-hydroxyl-5-nitrobenzamide
According to embodiment 30e) described method; with N-[3-(morpholine-4-formyl radical) phenyl]-(385g 1mmol) for feedstock production obtains this title compound, gets near-white solid 360mg to 2-methoxyl group-5-nitrobenzamide; yield 97.3%, m.p.:176～182 ℃.
F) N-[3-(morpholine-4-formyl radical) phenyl]-2-hydroxyl-5-acrylamide yl-benzamide
According to embodiment 7b) 7c) described method; with N-[3-(morpholine-4-formyl radical) phenyl]-2-hydroxyl-5-nitrobenzamide (360mg; 0.97mmol) and acrylate chloride (88mg; 0.97mmol) be raw material; by reduction, acylation reaction, prepare this title compound, be white powder 150mg; two-step reaction yield 39.1%, m.p.:194～197 ℃.
1HNMR(DMSO，300MHz)δppm：3.600(s，8H，-CH
2-×4)，5.708-5.746(dd，1H，＝CH-)，6.205-6.262(dd，1H，＝CH-)，6.359-6.448(dd，1H，＝CH-)，6.955-6.984(d，1H，ArH)，7.123-7.149(d，1H，ArH)，7.400-7.453(t，1H，ArH)，7.698-7.738(m，2H，ArH)，7.811(s，1H，ArH)，8.087-8.095(d，1H，ArH)
MS(FAB)：396.2(M+1)，309.2，190.2
Embodiment 35:
N-[3-(N-ethyl carbamyl) phenyl]-preparation of 2-hydroxyl-5-acrylamide yl-benzamide
A) N-ethyl-3-nitrobenzamide
According to embodiment 16a) described method, with M-NITROBENZOIC ACID (1.671g, 10mmol) and ethylamine solution (65%) (0.692g, 10mmol) obtain this title compound for feedstock production, be white crystal 1.7g, yield 87.6%, m.p.:113.6～116.0 ℃.
B) N-ethyl-3-aminobenzamide
According to embodiment 16b) described method, (1.7g 8.76mmol) for feedstock production obtains this title compound, is dope 920mg, yield 64% with N-ethyl-3-nitrobenzamide.
C) 2-methoxyl group-5-nitrobenzoic acid
According to embodiment 27a) described method, with 2-hydroxyl-5-nitrobenzoic acid (3.66g, 20mmol) for feedstock production obtains this title compound, white powder 3.79g, yield 95.9%.
D) N-[3-(N-ethyl carbamyl) phenyl]-2-methoxyl group-5-nitrobenzamide
According to embodiment 24a) described method, (1.183g is 6mmol) with N-ethyl-3-aminobenzamide (920g with 2-methoxyl group-5-nitrobenzoic acid, 5.6mmol) obtain this title compound for feedstock production, be white solid 1.7g, yield 88.4%, m.p.:181.0～184.5 ℃.
1HNMR(DMSO，300MHz)δppm：1.091-1.140(t，3H，CH
3-)，3.233-3.299(q，2H，-CH
2-)，3.963-4.014(s，3H，CH
3O-)，7.389-7.453(m，2H，ArH)，7.542-7.570(d，1H，ArH)，7.841-7.866(d，1H，ArH)，8.375-8.408(m，2H，ArH)，8.446-8.483(t，1H，ArH)
E) N-[3-(N-ethyl carbamyl) phenyl]-2-hydroxyl-5-nitrobenzamide
According to embodiment 30e) described method; with N-[3-(N-ethyl carbamyl) phenyl]-(343g 1mmol) for feedstock production obtains this title compound, gets pale solid 290mg to 2-methoxyl group-5-nitrobenzamide; yield 88%, m.p.:204.5～210.0 ℃.
F) N-[3-(N-ethyl carbamyl) phenyl]-2-hydroxyl-5-acrylamide yl-benzamide
According to embodiment 7b) 7c) described method; with N-[3-(N-ethyl carbamyl) phenyl]-2-hydroxyl-5-nitrobenzamide (290mg; 0.88mmol) and acrylate chloride (80mg; 0.88mmol) be raw material; by reduction, acylation reaction, prepare this title compound, be white powder 130mg; two-step reaction yield 41.8%, m.p.:244～248 ℃.
1HNMR(DMSO，300MHz)δppm：1.094-1.142(t，3H，CH
3-)，3.233-3.299(q，2H，-CH
2-)，5.709-5.748(d，1H，＝CH-)，6.209-6.260(d，1H，＝CH-)，6.364-6.454(dd，1H，＝CH-)，6.961-6.990(d，1H，ArH)，7.403-7.456(t，1H，ArH)，7.548-7.573(d，1H，ArH)，7.709-7.740(dd，1H，ArH)，7.852-7.877(d，1H，ArH)，8.095-8.133(d，1H，ArH)，8.457-8.473(t，1H，ArH)
MS(FAB)：354.2(M+1)，353.2(M)，309.2
Embodiment 36:
N-[4-(N, N-diethyl amino formyl radical) phenyl]-preparation of 2-hydroxyl-5-acrylamide yl-benzamide
A) N, N-diethyl-4-nitrobenzamide
According to embodiment 16a) described method, with p-nitrobenzoic acid (1.671g, 10mmol) and diethylamine (0.731g 10mmol) for feedstock production obtains this title compound, is light yellow crystal 1.86g, yield 83.8%, m.p.:62.5～64.0 ℃.
B) N, N-diethyl-4-aminobenzamide
According to embodiment 16b) described method, with N, N-diethyl-4-nitrobenzamide (1.86g, 8.4mmol) for feedstock production obtains this title compound, white crystal 1.15g, yield 71.4%, m.p.:106.5～108.7 ℃.
C) N-[4-(N, N-diethyl amino formyl radical) phenyl]-2-hydroxyl-5-nitrobenzamide
According to embodiment 1a) described method, with 2-hydroxyl-5-nitrobenzoic acid (0.366g, 2mmol) and N, (0.384g 2mmol) for feedstock production obtains this title compound, is white powder 370mg to N-diethyl-4-aminobenzamide, yield 51.8%, m.p.:230～236 ℃.
D) N-[4-(N, N-diethyl amino formyl radical) phenyl]-2-hydroxyl-5-acrylamide yl-benzamide
According to embodiment 7b) 7c) described method; with N-[4-(N; N-diethyl amino formyl radical) phenyl]-2-hydroxyl-5-nitrobenzamide (357mg; 1mmol) and acrylate chloride (90mg 1mmol) is raw material, by the reduction, acylation reaction; prepare this title compound; be faint yellow solid 170mg, two-step reaction yield 43.1%, m.p.:188.8～190.8 ℃.
1HNMR(DMSO，300MHz)δppm：1.095(s，6H，-CH
3×2)，3.296(s，4H，-NCH
2-×2)，5.706-5.746(dd，1H，＝CH-)，6.199-6.263(dd，1H，＝CH-)，6.359-6.449(dd，1H，＝CH-)，6.957-6.987(d，1H，ArH)，7.332-7.360(d，2H，ArH)，7.713-7.722(d，1H，ArH)，7.743-7.771(d，2H，ArH)，8.083-8.091(d，1H，ArH)
MS(EI)：381.0(M)，308.9，120.0
Embodiment 37:
N-[3-(hydroxyl-phenyl) aminomethyl phenyl]-preparation of 2-hydroxyl-5-acrylamide yl-benzamide
A) N-(3-benzoyl phenyl)-2-hydroxyl-5-nitrobenzamide
According to embodiment 1a) described method, (0.366g is 2mmol) with 3-benzanilide (0.394g with 2-hydroxyl-5-nitrobenzoic acid, 2mmol) obtain this title compound for feedstock production, be light yellow crystal 250mg, yield 34.5%, m.p.:179～185 ℃.
B) N-[3-(hydroxyl-phenyl) aminomethyl phenyl]-2-hydroxyl-5-acrylamide yl-benzamide
According to embodiment 7b) 7c) described method; N-(3-benzoyl phenyl)-2-hydroxyl-5-nitrobenzamide (250mg; 0.67mmol) and acrylate chloride (60mg; 0.67mmol) be raw material; by reduction, acylation reaction, prepare this title compound, be white solid 50mg; two-step reaction yield 18.7%, m.p.:195.9～198.0 ℃.
1HNMR(DMSO，300MHz)δppm：5.677(s，1H，HO-CH-)，5.704-5.745(dd，1H，＝CH-)，6.197-6.260(dd，1H，＝CH-)，6.358-6.448(dd，1H，＝CH-)，6.933-6.963(d，1H，ArH)，7.098-7.124(d，1H，ArH)，7.170-7.321(m，4H，ArH)，7.364-7.389(d，2H，ArH)，7.568-7.593(d，1H，ArH)，7.690-7.720(m，2H，ArH)，8.094-8.102(d，1H，ArH)
MS(EI)：388.2(M)，370.1，199.1
Embodiment 38:
The preparation of N-(3-phenoxy phenyl)-2-hydroxyl-5-acrylamide yl-benzamide
A) N-(3-phenoxy phenyl)-2-hydroxyl-5-nitrobenzamide
According to embodiment 1a) described method, (0.366g is 2mmol) with 3-benzene oxygen aniline (0.370g with 2-hydroxyl-5-nitrobenzoic acid, 2mmol) obtain this title compound for feedstock production, be yellow solid 550mg, yield 78.4%, m.p.:151.9～156.0 ℃.
B) N-(3-phenoxy phenyl)-2-hydroxyl-5-acrylamide yl-benzamide
According to embodiment 7b) 7c) described method; N-(3-phenoxy phenyl)-2-hydroxyl-5-nitrobenzamide (550mg; 1.57mmol) and acrylate chloride (142mg; 1.57mmol) be raw material; by reduction, acylation reaction, prepare this title compound, be incarnadine solid 300mg; two-step reaction yield 51%, m.p.:189.3～192.6 ℃.
1HNMR(DMSO，300MHz)δppm：5.699-5.740(dd，1H，＝CH-)，6.189-6.254(dd，1H，＝CH-)，6.347-6.438(dd，1H，＝CH-)，6.734-6.766(dd，1H，ArH)，6.930-6.960(d，1H，ArH)，7.032-7.059(dd，1H，ArH)，7.127-7.176(t，1H，ArH)，7.321-7.431(m，5H，ArH)，7.501-7.508(t，1H，ArH)，7.683-7.721(dd，1H，ArH)，8.044-8.052(d，1H，ArH)
MS(EI)：374.0(M)，185.0
Embodiment 39:
The preparation of N-(4-phenoxy phenyl)-2-hydroxyl-5-propionamido benzamide
A) N-(4-phenoxy phenyl)-2-hydroxyl-5-nitrobenzamide
According to embodiment 1a) described method, (0.916g is 5mmol) with 4-benzene oxygen aniline (0.370g with 2-hydroxyl-5-nitrobenzoic acid, 2mmol) obtain this title compound for feedstock production, be light yellow crystal 1.15g, yield 65.6%, m.p.:194.5～196.5 ℃.
B) N-(4-phenoxy phenyl)-2-hydroxyl-5-propionamido benzamide
According to embodiment 7b) 7c) described method; N-(4-phenoxy phenyl)-2-hydroxyl-5-nitrobenzamide (350mg; 1mmol) and propionyl chloride (92mg; 1mmol) be raw material; by reduction, acylation reaction, prepare this title compound, be brick-red solid 210mg; two-step reaction yield 55.8%, m.p.:225～230 ℃.
1HNMR(DMSO，300MHz)δppm：1.043-1.094(t，3H，CH
3-)，2.241-2.316(q，2H，-CH
2-)，6.906-6.935(d，1H，ArH)，6.972-7.045(d×2，4H，ArH)，7.081-7.131(t，1H，ArH)，7.347-7.398(t，2H，ArH)，7.594-7.630(dd，1H，ArH)，7.694-7.725(d，2H，ArH)，8.018-8.025(d，1H，ArH)
MS(EI)：376.5(M)，185.3
Embodiment 40:
The preparation of N-(4-phenoxy phenyl)-2-hydroxyl-5-(3, the 3-dimethyl) acrylamide yl-benzamide
A) N-(4-phenoxy phenyl)-2-hydroxyl-5-nitrobenzamide
According to embodiment 1a) described method, (0.916g is 5mmol) with 4-benzene oxygen aniline (0.370g with 2-hydroxyl-5-nitrobenzoic acid, 2mmol) obtain this title compound for feedstock production, be light yellow crystal 1.15g, yield 65.6%, m.p.:194.5～196.5 ℃.
B) N-(4-phenoxy phenyl)-2-hydroxyl-5-(3, the 3-dimethyl) acrylamide yl-benzamide
According to embodiment 7b) 7c) described method; N-(4-phenoxy phenyl)-2-hydroxyl-5-nitrobenzamide (350mg; 1mmol) with 3; (119mg 1mmol) is raw material to the 3-dimethyl acryloyl chloride, by reduction, acylation reaction; prepare this title compound; be faint yellow solid 190mg, two-step reaction yield 47.3%, m.p.:189.1～191.9 ℃.
1HNMR(DMSO，300MHz)δppm：1.842(s，3H，CH
3-)，2.141(s，3H，CH
3-)，5.827(s，1H，＝CH-)，6.906-6.935(d，1H，ArH)，6.972-6.999(d，2H，ArH)，7.017-7.047(d，2H，ArH)，7.081-7.131(t，1H，ArH)，7.347-7.400(t，2H，ArH)，7.612-7.648(dd，1H，ArH)，7.698-7.727(d，2H，ArH)，8.071-8.080(d，1H，ArH)
MS(EI)：402.4(M)，185.2
Embodiment 41
N-(4-phenoxy phenyl)-2-hydroxyl-5-encircles the preparation of the third formamido group benzamide
A) N-(4-phenoxy phenyl)-2-hydroxyl-5-nitrobenzamide
According to embodiment 1a) described method, (0.916g is 5mmol) with 4-benzene oxygen aniline (0.370g with 2-hydroxyl-5-nitrobenzoic acid, 2mmol) obtain this title compound for feedstock production, be light yellow crystal 1.15g, yield 65.6%, m.p.:194.5～196.5 ℃.
B) N-(4-phenoxy phenyl)-2-hydroxyl-5-encircles the third formamido group benzamide
According to embodiment 7b) 7c) described method; N-(4-phenoxy phenyl)-2-hydroxyl-5-nitrobenzamide (350mg; 1mmol) with the ring third formyl chloride (105mg; 1mmol) be raw material; by reduction, acylation reaction, prepare this title compound, be yellowish pink solid 120mg; two-step reaction yield 31%, m.p.:249.6～256.0 ℃.
1HNMR(DMSO，300MHz)δppm：0.749-0.774(m，4H，-CH
2-×2)，1.709-1.747(q，1H，-CH-)，6.906-6.935(d，1H，ArH)，6.972-6.997(d，2H，ArH)，7.016-7.045(d，2H，ArH)，7.081-7.131(t，1H，ArH)，7.347-7.400(t，2H，ArH)，7.590-7.628(dd，1H，ArH)，7.694-7.723(d，2H，ArH)，8.020-8.029(d，1H，ArH)
MS(EI)：388.4(M)，185.2
Embodiment 42:
The preparation of N-(3-chloro-4-fluorophenyl)-2-hydroxyl-5-propionamido benzamide
A) N-(3-chloro-4-fluorophenyl)-2-hydroxyl-5-nitrobenzamide
According to embodiment 1a) described method, (0.916g is 5mmol) with 3-chloro-4-fluoroaniline (0.728g with 2-hydroxyl-5-nitrobenzoic acid, 5mmol) obtain this title compound for feedstock production, be faint yellow needle 1.1g, yield 70.8%, m.p.:247.2～250.7 ℃.
B) N-(3-chloro-4-fluorophenyl)-2-hydroxyl-5-propionamido benzamide
According to embodiment 7b) 7c) described method; with N-(3-chloro-4-fluorophenyl)-2-hydroxyl-5-nitrobenzamide (0.311g; 1mmol) and propionyl chloride (93mg; 1mmol) be raw material; by reduction, acylation reaction, prepare this title compound, be near-white solid 100mg; two-step reaction yield 30%, m.p.:217.2～220.0 ℃.
1HNMR(DMSO，300MHz)δppm：1.045-1.094(t，3H，CH
3-)，2.239-2.316(q，2H，-CH
2-)，，6.915-6.946(d，1H，ArH)，7.380-7.440(t，1H，ArH)，7.603-7.654(m，2H，ArH)，7.985-7.992(d，1H，ArH)，8.027-8.058(d，1H，ArH)
MS(EI)：336.2(M)，191.1，135.0
Embodiment 43:
The preparation of N-(3-chloro-4-fluorophenyl)-2-hydroxyl-5-(3, the 3-dimethyl) acrylamide yl-benzamide
A) N-(3-chloro-4-fluorophenyl)-2-hydroxyl-5-nitrobenzamide
According to embodiment 1a) described method, (0.916g is 5mmol) with 3-chloro-4-fluoroaniline (0.728g with 2-hydroxyl-5-nitrobenzoic acid, 5mmol) obtain this title compound for feedstock production, be faint yellow needle 1.1g, yield 70.8%, m.p.:247.2～250.7 ℃.
B) N-(3-chloro-4-fluorophenyl)-2-hydroxyl-5-(3, the 3-dimethyl) acrylamide yl-benzamide
According to embodiment 7b) 7c) described method; with N-(3-chloro-4-fluorophenyl)-2-hydroxyl-5-nitrobenzamide (0.311g; 1mmol) with 3; (119mg 1mmol) is raw material to the 3-dimethyl acryloyl chloride, by reduction, acylation reaction; prepare this title compound; be near-white solid 100mg, two-step reaction yield 27.5%, m.p.:186.5～190.0 ℃.
1HNMR(DMSO，300MHz)δppm：1.844(s，3H，CH
3-)，2.137(s，3H，CH
3-)，5.825(s，1H，＝CH-)，6.915-6.944(d，1H，ArH)，7.380-7.440(t，1H，ArH)，7.610-7.648(dd，2H，ArH)，8.031-8.060(m，2H，ArH)
MS(EI)：362.3(M)，280.2，135.0
Embodiment 44:
N-(3-chloro-4-fluorophenyl)-2-hydroxyl-5-encircles the preparation of the third formamido group benzamide
A) N-(3-chloro-4-fluorophenyl)-2-hydroxyl-5-nitrobenzamide
According to embodiment 1a) described method, (0.916g is 5mmol) with 3-chloro-4-fluoroaniline (0.728g with 2-hydroxyl-5-nitrobenzoic acid, 5mmol) obtain this title compound for feedstock production, be faint yellow needle 1.1g, yield 70.8%, m.p.:247.2～250.7 ℃.
B) N-(3-chloro-4-fluorophenyl)-2-hydroxyl-5-encircles the third formamido group benzamide
According to embodiment 7b) 7c) described method; with N-(3-chloro-4-fluorophenyl)-2-hydroxyl-5-nitrobenzamide (0.311g; 1mmol) with the ring third formyl chloride (105mg; 1mmol) be raw material; by reduction, acylation reaction, prepare this title compound, be near-white solid 100mg; two-step reaction yield 28.7%, m.p.:248～253 ℃.
1HNMR(DMSO，300MHz)δppm：0.749-0.774(m，4H，-CH
2-×2)，1.707-1.746(q，1H，-CH-)，6.913-6.942(d，1H，ArH)，7.378-7.438(t，1H，ArH)，7.599-7.652(m，2H，ArH)，7.987-7.994(d，1H，ArH)，8.023-8.055(dd，1H，ArH)
MS(EI)：348.1(M)，203.0，135.1
Embodiment 45:
N-[3-(N, N-diethyl amino formyl radical) phenyl]-preparation of 2-hydroxyl-5-propionamido benzamide
A) N, N-diethyl-3-nitrobenzamide
According to embodiment 16a) described method, with M-NITROBENZOIC ACID (1.671g, 10mmol) and diethylamine (0.731g, 10mmol) for feedstock production obtains this title compound, light yellow crystal 1.7g, yield 76.5%.
B) N, N-diethyl-3-aminobenzamide
According to embodiment 16b) described method, with N, N-diethyl-3-nitrobenzamide (1.6g, 7.2mmol) for feedstock production obtains this title compound, orange crystal 1.25g, yield 90%.
C) N-[3-(N, N-diethyl amino formyl radical) phenyl]-2-hydroxyl-5-nitrobenzamide
According to embodiment 1a) described method, (1.1g, 6mmol) and N, (1.15g 6mmol) for feedstock production obtains this title compound, is light yellow crystal 570mg, yield 26.6% to N-diethyl-3-aminobenzamide with 2-hydroxyl-5-nitrobenzoic acid.
D) N-[3-(N, N-diethyl amino formyl radical) phenyl]-2-hydroxyl-5-propionamido benzamide
According to embodiment 7b) 7c) described method; with N-[3-(N; N-diethyl amino formyl radical) phenyl]-2-hydroxyl-5-nitrobenzamide (190mg; 0.53mmol) and propionyl chloride (50mg 0.53mmol) is raw material, by the reduction, acylation reaction; prepare this title compound; be white solid 100mg, two-step reaction yield 49%, m.p.:178.8～181.0 ℃.
1HNMR(DMSO，300MHz)δppm：1.045-1.094(m，9H，CH
3-×3)，2.239-2.316(q，2H，-C(O)CH
2-×2)，3.207-3.412(t，4H，-NCH
2-×2)，6.913-6.942(d，1H，ArH)，7.052-7.078(d，1H，ArH)，7.378-7.429(t，1H，ArH)，7.597-7.636(dd，1H，ArH)，7.658-7.683(d，1H，ArH)，7.780(s，1H，ArH)，8.003-8.012(d，1H，ArH)
MS(FAB)：384.3(M+1)，383.3(M)，311.2，193.2
Embodiment 46:
N-[3-(N, N-diethyl amino formyl radical) phenyl]-preparation of 2-hydroxyl-5-(3, the 3-dimethyl) acrylamide yl-benzamide
A) N, N-diethyl-3-nitrobenzamide
According to embodiment 16a) described method, with M-NITROBENZOIC ACID (1.671g, 10mmol) and diethylamine (0.731g, 10mmol) for feedstock production obtains this title compound, light yellow crystal 1.7g, yield 76.5%.
B) N, N-diethyl-3-aminobenzamide
According to embodiment 16b) described method, with N, N-diethyl-3-nitrobenzamide (1.6g, 7.2mmol) for feedstock production obtains this title compound, orange crystal 1.25g, yield 90%.
C) N-[3-(N, N-diethyl amino formyl radical) phenyl]-2-hydroxyl-5-nitrobenzamide
According to embodiment 1a) described method, (1.1g, 6mmol) and N, (1.15g 6mmol) for feedstock production obtains this title compound, is light yellow crystal 570mg, yield 26.6% to N-diethyl-3-aminobenzamide with 2-hydroxyl-5-nitrobenzoic acid.
D) N-[3-(N, N-diethyl amino formyl radical) phenyl]-2-hydroxyl-5-(3, the 3-dimethyl) acrylamide yl-benzamide
According to embodiment 7b) 7c) described method; with N-[3-(N; N-diethyl amino formyl radical) phenyl]-2-hydroxyl-5-nitrobenzamide (190mg, 0.53mmol) with 3,3-dimethyl acryloyl chloride (60mg; 0.53mmol) be raw material; by reduction, acylation reaction, prepare this title compound, be near-white solid 50mg; two-step reaction yield 25%, m.p.:102.0～108.2 ℃.
1HNMR(DMSO，300MHz)δppm：1.100(s，6H，CH
3×2)，1.844(s，3H，CH
3-C＝C-)，2.139(s，3H，CH
3-C＝C-)，3.211-3.414(m，4H，-NCH
2-×2)，5.827(s，1H，＝CH-)，6.913-6.942(d，1H，ArH)，7.052-7.078(d，1H，ArH)，7.380-7.431(t，1H，ArH)，7.623-7.683(t，2H，ArH)，7.768(s，1H，ArH)，8.062(s，1H，ArH)
MS(FAB)：410.3(M+1)，409.3(M)，328.3，193.2
Embodiment 47:
N-[3-(N, N-diethyl amino formyl radical) phenyl]-2-hydroxyl-5-encircles the preparation of the third formamido group benzamide
A) N, N-diethyl-3-nitrobenzamide
According to embodiment 16a) described method, with M-NITROBENZOIC ACID (1.671g, 10mmol) and diethylamine (0.731g, 10mmol) for feedstock production obtains this title compound, light yellow crystal 1.7g, yield 76.5%.
B) N, N-diethyl-3-aminobenzamide
According to embodiment 16b) described method, with N, N-diethyl-3-nitrobenzamide (1.6g, 7.2mmol) for feedstock production obtains this title compound, orange crystal 1.25g, yield 90%.
C) N-[3-(N, N-diethyl amino formyl radical) phenyl]-2-hydroxyl-5-nitrobenzamide
According to embodiment 1a) described method, (1.1g, 6mmol) and N, (1.15g 6mmol) for feedstock production obtains this title compound, is light yellow crystal 570mg, yield 26.6% to N-diethyl-3-aminobenzamide with 2-hydroxyl-5-nitrobenzoic acid.
D) N-[3-(N, N-diethyl amino formyl radical) phenyl]-2-hydroxyl-5-encircles the third formamido group benzamide
According to embodiment 7b) 7c) described method; with N-[3-(N; N-diethyl amino formyl radical) phenyl]-2-hydroxyl-5-nitrobenzamide (190mg; 0.53mmol) and (56mg 0.53mmol) is raw material, by reduction, acylation reaction to encircle third formyl chloride; prepare this title compound; be faint yellow solid 110mg, two-step reaction yield 53.9%, m.p.:154.7～158.0 ℃.
1HNMR(DMSO，300MHz)δppm：0.739-0.774(t，4H，-CH
2-×2)，1.100(s，6H，CH
3-×2)，1.707-1.753(m，1H，-CH-)，3.209-3.417(m，4H，-NCH
2-×2)，6.913-6.942(d，1H，ArH)，7.052-7.078(d，1H，ArH)，7.378-7.431(t，1H，ArH)，7.595-7.634(dd，1H，ArH)，7.659-7.685(d，1H，ArH)7.782(s，1H，ArH)，8.011-8.018(d，1H，ArH)
MS(FAB)：396.3(M+1)，395.3(M)，323.2，193.2
Embodiment 48:
The preparation of 2-amino-4-acrylamido-N-(3-chloro-phenyl-)-benzamide hydrochloride salt
A. 2-methyl-5-acetylaminohydroxyphenylarsonic acid oil of mirbane
With 4-methyl-3-nitro-aniline (15.214g, 100mmol), triethylamine (10.119g, 100mmol) and the DMAP of catalytic amount drop among the 150mlTHF.Dripping acetyl chloride (7.85g, 100mmol).Continue to stir 4h.The TLC monitoring reaction is finished.THF is removed in decompression, adds water, with ethyl acetate extraction, and successively with 10% sodium hydroxide solution, 1N hydrochloric acid soln and saturated common salt water washing, anhydrous sodium sulfate drying.Filter, remove the back gained solid that desolvates and get solid 14.410g with the water recrystallization, productive rate 74.2%.m.p.：140.5-142.0℃。
B. 2-nitro-4-acetylaminohydroxyphenylarsonic acid phenylformic acid
With 2-methyl-5-acetylaminohydroxyphenylarsonic acid oil of mirbane (1.941g, 10mmol) and sal epsom (2.407g 20mmol) drops in the 300ml water, drips potassium permanganate (9.482g, 60mmol) aqueous solution.Backflow 2h.The TLC monitoring reaction is finished.Cooling transfers to pH=2～4 with concentrated hydrochloric acid, adds excessive sodium bisulfite to remove unreacted oxidant.Cooling.Filter solid 1.1g.Filtrate is with ethyl acetate extraction, saturated common salt water washing, anhydrous sodium sulfate drying.Except that getting second crowd of solid 0.300g after desolvating.Obtain solid 1.4g altogether, productive rate 62.5%.m.p.：202-205℃。
C. 2-nitro-4-acetylaminohydroxyphenylarsonic acid N-(3-chloro-phenyl-)-benzamide
With 2-nitro-4-acetylaminohydroxyphenylarsonic acid phenylformic acid (1.121g, 5mmol), oxalyl chloride (1.263g, 10mmol) and the DMF of catalytic amount drop among the 30mlTHF.Stirring at room 6h.THF and excessive oxalul chloride are removed in decompression, get 2-nitro-4-acetylaminohydroxyphenylarsonic acid Benzoyl chloride, and it is standby to be dissolved in 20mlTHF.
With m-chloro aniline (0.702g, 5.5mmol), triethylamine (0.557g, 5.5mmol) and the DMAP of catalytic amount drop into 20mlTHF.Drip the THF solution of 2-nitro-4-acetylaminohydroxyphenylarsonic acid Benzoyl chloride.Continue to stir 6h.The TLC monitoring reaction is finished.Filter, filtrate uses column chromatography.Products therefrom gets crystal 0.667g, productive rate 40% with ethyl acetate-sherwood oil recrystallization.m.p.：193-195.5℃。
1H-NMR(DMSO，300MHz)δppm：10.761(s，1H，Ar-CONH-Ar)，10.577(s，1H，Me-CONH-Ar)，8.439-8.432(d，1H，J＝2.1Hz，ArH)，7.906-7.870(dd，1H，J＝2.1Hz，J＝8.7Hz，ArH)，7.840(s，1H，ArH)，7.730-7.703(d，1H，J＝8.1Hz，ArH)，7.519-7.491(d，1H，J＝8.4Hz，ArH)，7.403-7.349(t，1H，J＝2.7Hz，J＝8.1Hz，ArH)，7.187-7.157(d，1H，J＝9.0Hz，ArH)，2.110(s，3H，-COCH
3)。MS(EI)：335.3(M
++2)，333.3(M
+)，207.2(100)，165.2。
D. 2-nitro-4-amino-N-(3-chloro-phenyl-)-benzamide
(0.501g 1.5mmol) drops in the 20ml ethanol with 2-nitro-4-acetylaminohydroxyphenylarsonic acid N-(3-chloro-phenyl-)-benzamide.Add 5mol/L sodium hydroxide solution (5ml).Backflow 1h.The TLC monitoring reaction is finished.Ethanol is removed in decompression.Pour frozen water into, filter.With re-crystallizing in ethyl acetate, get yellow crystals 0.366g, productive rate 83.6%.m.p.：204.8-206.8℃。
1H-NMR(DMSO，300MHz)δppm：10.528(s，1H，Ar-CONH-Ar)，7.828(s，1H，ArH)，7.524-7.497(d，1H，J＝8.1Hz，ArH)，7.442-7.413(d，1H，J＝8.7Hz，ArH)，7.369-7.315(t，1H，J＝8.1Hz，J＝8.1Hz，ArH)，7.143-7.111(dd，1H，J＝1.8Hz，J＝8.1Hz，ArH)，7.089-7.083(d，1H，J＝2.1Hz，ArH)，6.850-6.814(dd，1H，J＝2.4Hz，J＝8.4Hz，ArH)，6.216(s，NH
2)。
E. 2-nitro-4-acrylamido-N-(3-chloro-phenyl-)-benzamide
With 2-nitro-4-amino-N-(3-chloro-phenyl-)-benzamide (0.350g, 1.2mmol) and pyridine (0.095g 1.2mmol) drops among the 20mlTHF.The ice bath cooling drips acrylate chloride (0.217g, THF solution 2.4mmol) down.Continue to stir 2h.The TLC monitoring reaction is finished.THF is removed in decompression.Add water, with ethyl acetate extraction, successively with 1N hydrochloric acid, water, saturated sodium bicarbonate solution and saturated common salt water washing, anhydrous sodium sulfate drying.Filter, except that after desolvating, column chromatography for separation gets solid 0.219g, productive rate 52.8%.m.p.：172.0-174.0℃。
1H-NMR(DMSO，300MHz)δppm：10.800(s，1H，Ar-CONH-Ar)，10.791(s，1H，Vinyl-CONH-Ar)，8.532-8.528(d，1H，J＝1.2Hz，ArH)，8.007-7.980(d，1H，J＝8.1Hz，ArH)，7.850(s，1H，ArH)，7.773-7.745(d，1H，J＝8.4Hz，ArH)，7.524-7.497(d，1H，J＝8.1Hz，ArH)，7.409-7.354(t，1H，J＝8.4Hz，J＝8.1Hz，ArH)，7.193-7.167(d，1H，J＝7.8Hz，ArH)，6.487-6.399(dd，1H，J＝9.3Hz，J＝17.1Hz)，6.372-6.308(dd，1H，J＝16.8Hz，J＝2.7Hz)，5.892-5.854(dd，1H，J＝2.1Hz，J＝9.3Hz)。MS(FAB)：348.0(M
++3)，346.0(M
++1)，219.0，185.1，154.0，137.0，93.0(100)。
F. 2-amino-4-acrylamido-N-(3-chloro-phenyl-)-benzamide hydrochloride salt
With 2-nitro-4-acrylamido-N-(3-chloro-phenyl-)-benzamide (0.345g, 1mmol), 2ml hydrochloric acid drops in the 8ml methyl alcohol.Add two hydrated stannous chlorides (2.256g, 10mmol).Backflow 1h.The TLC monitoring reaction is finished.Methyl alcohol is removed in decompression.Transfer to pH=13 with 10% sodium hydroxide solution, use extracted with diethyl ether, saturated common salt water washing, anhydrous sodium sulfate drying.Filter.Remove ether, add the saturated ethanolic soln of 5ml hydrogenchloride, stirring at room is separated out solid.Filter, get white solid 0.1g, productive rate 28.4%.m.p.：194-198℃。
1H-NMR(DMSO，300MHz)δppm：10.308(s，1H，Ar-CONH-Ar)，10.158(s，1H，Vinyl-CONH-Ar)，7.906(s，1H，ArH)，7.696-7.667(d，1H，J＝8.7Hz，ArH)，7.643-7.616(d，1H，J＝8.1Hz，ArH)，7.389(s，1H，ArH)，7.374-7.319(t，1H，J＝8.1Hz，J＝8.4Hz，ArH)，7.133-7.107(d，1H，J＝7.8Hz，ArH)，7.027-6.999(d，1H，J＝8.4Hz，ArH)，6.516-6.427(dd，1H，J＝9.9Hz，J＝17.1Hz)，6.293-6.6.236(dd，1H，J＝17.1Hz，J＝1.2Hz)，5.792-5.753(dd，1H，J＝1.2Hz，J＝10.5Hz)。
MS(ESI)：318.2(M
++3)，316.2(M
++1)，189.2(100)，135.9。
Embodiment 49:
The preparation of 2-amino-4-acrylamido-N-(3-bromophenyl)-benzamide hydrochloride salt
A. 2-nitro-4-acetylaminohydroxyphenylarsonic acid N-(3-bromophenyl)-benzamide
According to the described method of embodiment 50c, and the usefulness m-bromoaniline (0.946,5.5mmol) make this title compound, get solid 0.978g, productive rate 51.7%.m.p.：188.7-190.7℃。
1H-NMR(DMSO，300MHz)δppm：10.763(s，1H，Ar-CONH-Ar)，10.598(s，1H，Me-CONH-Ar)，8.440-8.434(d，1H，J＝1.8Hz，ArH)，7.982(s，1H，ArH)，7.899-7.865(dd，1H，ArH)，7.729-7.702(d，1H，J＝8.1Hz，ArH)，7.560-7.531(t，1H，ArH)，7.320-7.302(d，2H，ArH)，2.109(s，3H，-COCH
3)。MS(EI)：379.3(M
++2)，377.3(M
+)，207.2(100)，165.2。
B. 2-nitro-4-acrylamido-N-(3-bromophenyl)-benzamide
According to embodiment 50d and the described method of 50e, nitro-(0.567g 1.5mmol) makes this title compound to 4-acetylaminohydroxyphenylarsonic acid N-(3-bromophenyl)-benzamide, and column chromatography for separation gets solid 0.132g, overall yield 23% with 2-.m.p.：173.6-175.5℃。
1H-NMR(DMSO，300MHz)δppm：10.775(s，2H，Ar-CONH-Ar，Vinyl-CONH-Ar)，8.530-8.526(d，1H，J＝1.2Hz，ArH)，7.992-7.983(d，2H，ArH)，7.771-7.744(d，1H，J＝8.4Hz，ArH)，7.555-7.542(d，1H，ArH)，7.325-7.308(m，2H，ArH)，6.489-6.401(dd，1H，J＝9.3Hz，J＝17.1Hz)，6.373-6.311(dd，1H，J＝16.8Hz，J＝2.4Hz)，5.892-5.854(dd，1H，J＝2.1Hz，J＝9.3Hz)。MS(EI)：391.3(M
++2)，389.3(M
+)，219.2(100)，165.2。
C. 2-amino-4-acrylamido-N-(3-bromophenyl)-benzamide hydrochloride salt
According to the described method of embodiment 50f, (0.390g 1mmol) makes this title compound, gets solid 60mg, productive rate 15.0% with 2-nitro-4-acrylamido-N-(3-bromophenyl)-benzamide.m.p.：201-203℃。
1H-NMR(DMSO，300MHz)δppm：10.134(s，1H，Ar-CONH-Ar)，9.997(s，1H，Vinyl-CONH-Ar)，8.033(s，1H，ArH)，7.674-7.610(t，2H，ArH)，7.306-7.253(m，3H，ArH)，6.875(s，1H，ArH)，6.492-6.403(dd，1H，J＝9.9Hz，J＝16.8Hz)，6.284-6.229(d，1H，J＝16.8Hz)，5.781-5.742(d，1H，J＝11.7Hz)。
MS(ESI)：362.3(M
++3)，360.3(M
++1，100)，279.3，189.3。
Embodiment 50:
The preparation of 2-amino-4-acrylamido-N-(3-p-methoxy-phenyl)-benzamide hydrochloride salt
A. 2-nitro-4-acetylaminohydroxyphenylarsonic acid N-(3-p-methoxy-phenyl)-benzamide
According to the described method of embodiment 50c, and the usefulness m-anisidine (0.677,5.5mmol) make this title compound, get solid 1.032g, productive rate 57.0%.m.p.：173.3-175.3℃。
1H-NMR(DMSO，300MHz)δppm：10.561(s，1H，Ar-CONH-Ar)，10.551(s，1H，Me-CONH-Ar)，8.422-8.417(d，1H，J＝1.5Hz，ArH)，7.894-7.859(dd，1H，J＝2.1Hz，J＝8.4Hz，ArH)，7.711-7.681(d，1H，J＝9.0Hz，ArH)，7.334-7.321(t，1H，ArH)，7.272-7.177(m，2H，ArH)，6.706-6.668(m，1H，ArH)，3.732(s，3H，-OCH
3)，2.111(s，3H，-COCH
3)。
MS(EI)：329.2(M
+)，207.1(100)，165.1。
B. 2-nitro-4-acrylamido-N-(3-p-methoxy-phenyl)-benzamide
According to embodiment 50d and the described method of 50e, nitro-(0.494g 1.5mmol) makes this title compound to 4-acetylaminohydroxyphenylarsonic acid N-(3-p-methoxy-phenyl)-benzamide, and column chromatography for separation gets solid 0.230g, overall yield 45% with 2-.m.p.：142.0-144.0℃。
1H-NMR(DMSO，300MHz)δppm：10.774(s，1H，Ar-CONH-Ar)，10.587(s，1H，Vinyl-CONH-Ar)，8.516-8.509(d，1H，J＝2.1Hz，ArH)，7.994-7.959(dd，1H，J＝2.1Hz，J＝8.1Hz，ArH)，7.748-7.720(d，1H，J＝8.4Hz，ArH)，7.333(s，1H，ArH)，7.276-7.248(d，1H，J＝8.4Hz，ArH)，7.224-7.181(t，1H，J＝7.8Hz，J＝5.1Hz，ArH)，7.193-7.167(d，1H，J＝2.1Hz，J＝8.4Hz，ArH)，6.488-6.400(dd，1H，J＝9.3Hz，J＝17.1Hz)，6.372-6.308(dd，1H，J＝16.8Hz，J＝2.4Hz)，5.890-5.850(dd，1H，J＝2.4Hz，J＝9.6Hz)，3.734(s，3H，-OCH
3)。MS(EI)：341.3(M
+)，219.1(100)，165.1。
C. 2-amino-4-acrylamido-N-(3-p-methoxy-phenyl)-benzamide hydrochloride salt
According to the described method of embodiment 50f, (0.202g 0.5mmol) makes this title compound, gets solid 50mg, productive rate 24.5% with 2-nitro-4-acrylamido-N-(3-p-methoxy-phenyl)-benzamide.m.p.：157-164℃。
1H-NMR(DMSO，300MHz)δppm：10.227(s，1H，Ar-CONH-Ar)，9.968(s，1H，Vinyl-CONH-Ar)，7.687-7.658(d，1H，J＝8.7Hz，ArH)，7.391(s，2H，ArH)，7.314-7.286(d，1H，J＝8.4Hz，ArH)，7.241-7.186(t，1H，J＝8.4Hz，J＝8.1Hz，ArH)，7.028(s，1H，ArH)，6.662-6.637(d，1H，J＝7.5Hz，ArH)，6.514-6.425(dd，1H，J＝9.9Hz，J＝16.5Hz)，6.295-6.233(dd，1H，J＝1.8Hz，J＝16.8Hz)，5.790-5.750(dd，1H，J＝9.9Hz，J＝1.8Hz)，3.734(s，3H，-OCH
3)。
MS(ESI)：312.3(M
++1，100)，189.2。
Embodiment 51:
The preparation of 2-amino-4-acrylamido-N-(3-chloro-4-fluoro-phenyl)-benzamide hydrochloride salt
A. 2-nitro-4-acetylaminohydroxyphenylarsonic acid N-(3-chloro-4-fluoro-phenyl)-benzamide
According to the described method of embodiment 50c, and usefulness 3-chloro-4-fluoro-aniline (0.801,5.5mmol) make this title compound, get solid 0.835g, productive rate 43.1%.m.p.：201.5-203.0℃。
1H-NMR(DMSO，300MHz)δppm：10.796(s，1H，Ar-CONH-Ar)，10.583(s，1H，Me-CONH-Ar)，8.441-8.434(d，1H，J＝2.1Hz，ArH)，7.969-7.938(dd，1H，J＝2.7Hz，J＝6.6Hz，ArH)，7.911-7.878(dd，1H，J＝1.8Hz，J＝8.1Hz，ArH)，7.736-7.709(d，1H，J＝8.1Hz，ArH)，7.560-7.510(m，1H，ArH)，7.446-7.385(t，1H，ArH)，2.112(s，3H，-COCH
3)。MS(EI)：353.2(M
++2)，351.2(M
+)，207.1(100)，165.1。
B. 2-nitro-4-acrylamido-N-(3-chloro-4-fluoro-phenyl)-benzamide
According to embodiment 50d and the described method of 50e, nitro-(3-chloro-4-fluoro-phenyl)-(0.528g 1.5mmol) makes this title compound to benzamide to 4-acetylaminohydroxyphenylarsonic acid N-, and column chromatography for separation gets solid 0.218g, overall yield 40% with 2-.m.p.：196.5-199.0℃。
1H-NMR(DMSO，300MHz)δppm：10.815(s，1H，Ar-CONH-Ar)，10.780(s，1H，Vinyl-CONH-Ar)，8.528-8.522(d，1H，J＝1.8Hz，ArH)，8.012-7.941(m，2H，ArH)，7.773-7.744(d，1H，J＝8.7Hz，ArH)，7.565-7.513(m，1H，ArH)，7.450-7.390(t，1H，J＝9.0Hz，J＝12.0Hz，ArH)，6.487-6.400(dd，1H，J＝9.6Hz，J＝16.5Hz，ArH)，6.373-6.309(dd，1H，J＝17.1Hz，J＝2.4Hz)，5.890-5.852(dd，1H，J＝2.1Hz，J＝9.3Hz)。MS(EI)：365.2(M
++2)，363.2(M
+)，219.1(100)，165.1。
C. 2-amino-4-acrylamido-N-(3-chloro-4-fluoro-phenyl)-benzamide hydrochloride salt
According to the described method of embodiment 50f, (0.182g 0.5mmol) makes this title compound, gets solid 30mg, productive rate 16.2% with 2-nitro-4-acetylaminohydroxyphenylarsonic acid N-(3-chloro-4-fluoro-phenyl)-benzamide.m.p.：207.2-213.8℃。
1H-NMR(DMSO，300MHz)δppm：10.228(s，1H，Ar-CONH-Ar)，10.118(s，1H，Vinyl-CONH-Ar)，8.022-7.991(dd，1H，J＝2.4Hz，J＝6.9Hz，ArH)，7.667-7.614(m，2H，ArH)，7.412-7.352(t，1H，J＝9.3Hz，J＝8.7Hz，ArH)，7.327-7.321(d，1H，J＝1.8Hz，ArH)，6.957-6.933(dd，1H，J＝1.5Hz，J＝7.2Hz，ArH)，6.505-6.416(dd，1H，J＝9.9Hz，J＝17.1Hz)，6.289-6.227(dd，1H，J＝1.8Hz，J＝17.1Hz)，5.786-5.746(dd，1H，J＝9.9Hz，J＝2.1Hz)。
MS(ESI)：336.4(M
++2)，334.4(M
+，100)。
Embodiment 52:
The preparation of 2-amino-4-acrylamido-N-(4-benzoyl-phenyl)-benzamide hydrochloride salt
A. 2-nitro-4-acetylaminohydroxyphenylarsonic acid N-(4-benzoyl-phenyl)-benzamide
According to the described method of embodiment 50c, and usefulness 4-benzoyl-aniline (1.085,5.5mmol) make this title compound, get solid 1.200g, productive rate 54.1%.m.p.：249.0-251.0℃。
1H-NMR(DMSO，300MHz)δppm：10.963(s，1H，Ar-CONH-Ar)，10.592(s，1H，Me-CONH-Ar)，8.466-8.459(d，1H，J＝2.1Hz，ArH)，7.923-7.889(dd，1H，J＝2.1Hz，J＝8.1Hz，ArH)，7.850-7.713(m，7H，ArH)，7.666-7.642(d，1H，J＝7.2Hz，ArH)，7.581-7.532(t，2H，ArH)，2.119(s，3H，-COCH
3).MS(EI)：403.3(M
+)，207.1(100)，165.1。
B. 2-nitro-4-acrylamido-N-(4-benzoyl-phenyl)-benzamide
According to embodiment 50d and the described method of 50e, nitro-(0.605g 1.5mmol) makes this title compound to 4-acetylaminohydroxyphenylarsonic acid N-(4-benzoyl-phenyl)-benzamide, and column chromatography for separation gets solid 0.243g, overall yield 39% with 2-.m.p.：218-220℃。
1H-NMR(DMSO，300MHz)δppm：11.007(s，1H，Ar-CONH-Ar)，10.812(s，1H，Vinyl-CONH-Ar)，8.560-8.554(d，1H，J＝1.8Hz，ArH)，8.024-7.990(dd，1H，J＝1.8，J＝8.7Hz，ArH)，7.914-7.645(m，8H，ArH)，7.585-7.534(t，2H，ArH)，6.495-6.407(dd，1H，J＝16.8Hz，J＝9.6Hz)，6.380-6.316(dd，1H，J＝2.1Hz，J＝17.1Hz)，5.900-5.861(dd，1H，J＝2.1Hz，J＝9.6Hz)。MS(EI)：415.2(M
+)，219.1(100)，165.1。
C. 2-amino-4-acrylamido-N-(4-benzoyl-phenyl)-benzamide hydrochloride salt
According to the described method of embodiment 50f, (0.208g 0.5mmol) makes this title compound, gets solid 30mg, productive rate 14.2% with 2-nitro-4-acetylaminohydroxyphenylarsonic acid N-(4-benzoyl-phenyl)-benzamide.m.p.：194-200℃。
1H-NMR(DMSO，300MHz)δppm：10.240(s，1H，Ar-CONH-Ar)，10.173(s，1H，Vinyl-CONH-Ar)，7.921-7.892(d，2H，J＝8.7Hz，ArH)，7.764-7.636(m，6H，ArH)，7.581-7.531(t，2H，J＝8.4Hz，ArH)，7.288(t，1H，ArH)，6.902-6.873(d，1H，J＝8.7Hz，ArH)，6.502-6.410(dd，1H，J＝10.5Hz，J＝17.1Hz)，6.291-6.229(dd，1H，J＝1.8Hz，J＝17.1Hz)，5.786-5.746(dd，1H，J＝10.2Hz，J＝1.8Hz)。
MS(ESI)：386.4(M
++1)，189.2(100)。
Embodiment 53:
The preparation of 2-amino-4-acrylamido-N-benzyl-benzamide hydrochloride salt
A. 2-nitro-4-acetylaminohydroxyphenylarsonic acid N-benzyl-benzamide
According to the described method of embodiment 50c, and the usefulness benzylamine (0.589,5.5mmol) make this title compound, get solid 0.700g, productive rate 40.6%.m.p.：226.8-229℃。
1H-NMR(DMSO，300MHz)δppm：10.511(s，1H，Me-CONH-Ar)，9.136-9.096(t，1H，J＝6.0Hz，ArCONHCH
2Ar)，8.315-8.308(d，1H，J＝2.1Hz，ArH)，7.816-7.780(dd，1H，J＝2.1Hz，J＝8.7Hz，ArH)，7.608-7.580(d，1H，ArH)，7.347-7.234(m，5H，ArH)，4.433-4.414(d，2H，J＝6.0，-CH
2-Ar)，2.090(s，3H，-COCH
3)。MS(FAB)：314.1(M
++1，100)。
B. 2-nitro-4-acrylamido-N-benzyl-benzamide
According to embodiment 50d and the described method of 50e, nitro-(0.470g 1.5mmol) makes this title compound to 4-acetylaminohydroxyphenylarsonic acid N-benzyl-benzamide, and column chromatography for separation gets solid 0.171g, overall yield 35% with 2-.m.p.：193-195℃。
1H-NMR(DMSO，300MHz)δppm：10.714(s，1H，Vinyl-CONH-Ar)，9.164-9.124(t，1H，J＝6.0Hz，Ar-CONH-CH
2Ar)，8.406-8.400(d，1H，J＝1.8Hz，ArH)，7.917-7.882(dd，1H，J＝2.1Hz，J＝8.4Hz，ArH)，7.643-7.615(d，1H，J＝8.4Hz，ArH)，7.351-7.240(m，5H，ArH)，6.470-6.382(dd，1H，J＝16.8Hz，J＝9.6Hz)，6.353-6.289(dd，1H，J＝2.4Hz，J＝16.8Hz)，5.872-5.833(dd，1H，J＝2.1Hz，J＝9.6Hz)，4.441-4.422(d，2H，J＝6.0，ArCONH-CH
2-Ar)。MS(FAB)：326.1(M
++1，100)。
C. 2-amino-4-acrylamido-N-benzyl-benzamide hydrochloride salt
According to the described method of embodiment 50f, (0.163g 0.5mmol) makes this title compound, gets solid 30mg, productive rate 20.2% with 2-nitro-4-acetylaminohydroxyphenylarsonic acid N-benzyl-benzamide.m.p.：132.0-134.0℃。
1H-NMR(DMSO，300MHz)δppm：10.175(s，1H，Vinyl-CONH-Ar)，8.690-8.652(t，1H，J＝5.7Hz，Ar-CONH-CH
2Ar)，7.540-7.511(d，1H，J＝8.7Hz，ArH)，7.337-7.214(m，5H，ArH)，7.140-7.135(d，1H，J＝1.5Hz，ArH)，6.769-6.735(dd，1H，J＝2.1Hz，J＝8.1Hz，ArH)，6.470-6.380(dd，1H，J＝16.8Hz，J＝9.9Hz)，6.263-6.200(dd，1H，J＝2.1Hz，J＝16.8Hz)，5.760-5.719(dd，1H，J＝2.1Hz，J＝10.2Hz)，4.404-4.386(d，2H，J＝5.4，ArCONH-CH
2-Ar)。
MS(FAB)：296.1(M
++1)，185.1，189.0，93.0(100)。
Evaluated biological activity
A) screening method:
Enzyme-linked immunosorbent assay (ELISA) working sample is to the influence of Tyrosylprotein kinase protein-active
B) principle:
(poly-Glu, Tyr) the bag quilt adds reactions such as EGFR protein kinase, sample, ATP one hour in enzyme plate, filters washing with polypeptide reaction substrate PGT.Add mouse anti-phosphotyrosine monoclonal antibody, it is combined with substrate after the phosphorylation, filter, wash.Add the sheep anti-mouse igg of HRP (horseradish peroxidase) mark, it is combined with mouse anti-phosphotyrosine monoclonal antibody residual and on the target, filter, washing.With OPD (O-Phenylene Diamine) is developer, detects the substrate phosphorylation degree.Establish no sample control group simultaneously, thereby obtain the influence of sample enzymic activity.
C) experimental observation index:
The OD490nm value is observed in colorimetric reaction.
D) judge of experimental result and explanation:
To the proteic relative inhibition of Tyrosylprotein kinase, calculation formula is as follows at different concns for the mensuration medicine:
Inhibiting rate=(control group OD value-experimental group OD value)/control group OD value * 100%
More than each concentration of experiment repeats 2 times, and the mean value of obtaining 2 relative inhibiting rates suppresses the final index of ability as this concentration.
E) tyrosine kinase activity suppresses the body outer screening test result:
Screening method: enzyme-linked immunosorbent assay (ELISA)
Receptor kinase: EGFR (Sigma);
Action time: 1h
Inhibiting rate % to tyrosine kinase activity
| 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 PD0153035 | 17.4 63.9 44.0 14.6 11.9 26.4 29.7 0.0 0.0 82.2 56.3 81.1 61.1 6.3 42.6 74.3 16.2 87.8 79.0 72.8 23.9 30.0 86.7 83.3 48.5 32.7 26.9 0.0 29.4 18.1 46.6 32.9 24.0 50.6 52.4 | - 54.4 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - | - 40.4 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 69.6 | - 14.1 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 36.5 | Positive control |
Annotate: "-" expression undetermined activity
PD0153035 is the EGFR Tyrosylprotein kinase micromolecular inhibitor in the I phase clinical study.
Claims (16)
1. suc as formula the compound of I
In the formula:
X represents O, S, NH
R1 represents hydrogen, C
1-4Low alkyl group, C
3-8Cycloalkyl
N represents the integer of 0-2
R2 represents hydrogen, C
1-4Low alkyl group, C
3-8Cycloalkyl; If n=2, then R2 can be hydrogen, C independently on arbitrary continuous carbon atom
1-4Low alkyl group, C
3-8Cycloalkyl
Ar represents phenyl, naphthyl, furyl, pyrryl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidyl, pyrazinyl, benzofuryl, benzothienyl, indyl, benzimidazolyl-, benzoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, quinazolyl
R3 be illustrated in aromatic ring the neighbour,, contraposition has 0～3 identical or different following group: C
1-4Low alkyl group, C
3-8Cycloalkyl, phenyl, benzyl, hydroxyl, C
1-4Lower alkoxy, C
3-8Cycloalkyloxy, C
1-4Lower alkoxycarbonyl, C
3-8Cycloalkoxycarbonyl, phenoxy group, benzyloxy, C
1-4Low alkyl group acyloxy, C
3-8Cycloalkyl acyloxy, amino, one or two-C
1-4Low-grade alkyl amino, one or two-C
3-8Cycloalkyl amino, phenylamino, benzyl amino, C
1-4Low alkyl group carboxamido, C
3-8Cycloalkyl carboxamido, halogen substituted benzoyl amido, C
1-4Lower acyl, C
3-8Cycloalkyl acyl group, benzoyl, carboxyl, sulfydryl, cyano group, halogen, nitro, C
1-4Rudimentary hydroxyalkyl, (phenyl hydroxyl) methyl ,-C (O)-R4 or-SO
2-R4,
Wherein R4 represents amino, one or two C
1-4Low-grade alkyl amino, one or two-C
3-8Cycloalkyl amino, halogen substituted-phenyl amino, N-pyrrolidyl, N-piperidyl, N-morpholinyl, N-piperazinyl, N-thio-morpholinyl, perhaps, two R3 on the adjacent carbons combine, and form 5-7 unit carbocyclic ring jointly
M represents the integer of 0-3
Y represents hydrogen, hydroxyl, sulfydryl, amino, C
1-4Low alkyl group, C
3-8Cycloalkyl, C
1-4Lower alkoxy, C
3-8Cycloalkyloxy, C
1-4Low alkyl group acyloxy, C
3-8Cycloalkyl acyloxy, C
1-4Lower alkoxycarbonyl, C
3-8Cycloalkoxycarbonyl, one or two-C
1-4Low-grade alkyl amino, one or two-C
3-8Cycloalkyl amino, C
1-4Low alkyl group carboxamido, C
3-8The cycloalkyl carboxamido
A-B-D-can be substituted in 4-position or 5-position, wherein
D represents O, S, NH, NR5, and R5 can be C
1-4Low alkyl group, C
3-8Cycloalkyl
B represents carbonyl (CO-), alkylsulfonyl (SO
2-)
A represents C
1-4Low alkyl group, C
3-8Cycloalkyl,
R6, R7, R8, R9 independently are separately
C
1-4Low alkyl group, C
3-8Cycloalkyl, vinyl (CH
2=CH-), propylene (CH
3-CH=CH-), ethanoyl, carboxyl, C
1-4Lower alkoxycarbonyl, C
3-8Cycloalkoxycarbonyl, carbamyl, one or two C
1-4Low alkyl group carbamyl, one or two-C
3-8The cycloalkyl carbamyl ,-CH
2-R10, wherein R10 represents hydroxyl, amino, C
1-4Lower alkoxy, C
3-8Cycloalkyloxy, one or two-C
1-4Low-grade alkyl amino, one or two-C
3-8Cycloalkyl amino, N-pyrrolidyl, N-piperidyl, N-morpholinyl, N-piperazinyl, N-thio-morpholinyl
Any low-grade alkyl substituent among the R6-R9 on any substituting group is optionally replaced by one or more following groups: single low alkyl group Ammonia, two single low alkyl group Ammonias, N-pyrrolidyl, N-piperidyl, N-morpholinyl, N-piperazinyl, N-thio-morpholinyl.
2. the described compound of claim 1, wherein X is O, S, NH.
3. the described compound of claim 1, wherein R1 is a hydrogen.
4. the described compound of claim 1, wherein n is 0,1.
5. the described compound of claim 1, wherein R2 is hydrogen, C
1-4Low alkyl group, C
3-8Cycloalkyl.
6. the described compound of claim 1, wherein Ar is a phenyl.
7. the described compound of claim 1, wherein R3 be the neighbour that is illustrated in aromatic ring,, contraposition has 0～3 identical or different following group: C
1-4Low alkyl group, C
3-8Cycloalkyl, phenyl, benzyl, hydroxyl, C
1-4Lower alkoxy, C
3-8Cycloalkyloxy, C
1-4Lower alkoxycarbonyl, C
3-8Cycloalkoxycarbonyl, phenoxy group, benzyloxy, C
1-4Low alkyl group acyloxy, C
3-8Cycloalkyl acyloxy, amino, one or two-C
1-4Low-grade alkyl amino, one or two-C
3-8Cycloalkyl amino, phenylamino, benzyl amino, C
1-4Low alkyl group carboxamido, C
3-8Cycloalkyl carboxamido, halogen substituted benzoyl amido, C
1-4Lower acyl, C
3-8Cycloalkyl acyl group, benzoyl, carboxyl, sulfydryl, cyano group, halogen, nitro, C
1-4Rudimentary hydroxyalkyl, (phenyl hydroxyl) methyl ,-C (O)-R4 or-SO
2-R4, wherein R4 represents amino, one or two C
1-4Low-grade alkyl amino, one or two-C
3-8Cycloalkyl amino, halogen substituted-phenyl amino, N-pyrrolidyl, N-piperidyl, N-morpholinyl, N-piperazinyl, N-thio-morpholinyl, perhaps, two R3 on the adjacent carbons combine, and form 5-7 unit carbocyclic ring jointly.
8. the described compound of claim 1, wherein m is 1,2.
9. the described compound of claim 1, wherein Y is hydrogen, hydroxyl, sulfydryl, amino.
10. the described compound of claim 1, wherein D is O, S, NH, NR5, R5 can be C
1-4Low alkyl group, C
3-8Cycloalkyl.
11. the described compound of claim 1, wherein B be carbonyl (CO-).
12. the described compound of claim 1, wherein A is
R6, R7, R8, independent separately be C
1-4Low alkyl group, C
3-8Cycloalkyl, vinyl (CH
2=CH-), propylene (CH
3-CH=CH-), ethanoyl, carboxyl, C
1-4Lower alkoxycarbonyl, C
3-8Cycloalkoxycarbonyl, carbamyl, one or two C
1-4Low alkyl group carbamyl, one or two-C
3-8The cycloalkyl carbamyl ,-CH
2-R10, wherein R10 represents hydroxyl, amino, C
1-4Lower alkoxy, C
3-8Cycloalkyloxy, one or two-C
1-4Low-grade alkyl amino, one or two-C
3-8Any low-grade alkyl substituent among cycloalkyl amino, N-pyrrolidyl, N-piperidyl, N-morpholinyl, N-piperazinyl, the N-thio-morpholinyl R6-R9 on any substituting group is optionally replaced by one or more following groups: single low alkyl group Ammonia, two single low alkyl group Ammonias, N-pyrrolidyl, N-piperidyl, N-morpholinyl, N-piperazinyl, N-thio-morpholinyl
13. the method for the compound of preparation claim 1-12 is characterized in that,
With the intermediate product of formula II compound and formula III compound reaction generation, with the reaction of formula IV compound, reaction generates compound of Formula I;
Or formula III compound and the reaction earlier of formula IV compound, generate compound of Formula I with the reaction of formula II compound again.
A-B-Cl
II III IV
E represents-DH, nitro, and the definition of A, B, D, X, Y, R1, R2, R3, Ar, m, n is identical with claim 1-12 in the formula.
14. a pharmaceutical composition is characterized in that, contains described arbitrary compound of claim 1-12 and pharmaceutical carrier.
15. as the application in the medicine of the described compound treatment of claim 1-12 EGF-R ELISA relative disease.
16. application as the described compound treatment of claim 1-12 cancer drug.
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