CN103980209B - A kind of 4-N-replaces-5-chloro-quinazoline compounds and preparation method and application - Google Patents

A kind of 4-N-replaces-5-chloro-quinazoline compounds and preparation method and application Download PDF

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CN103980209B
CN103980209B CN201410214916.7A CN201410214916A CN103980209B CN 103980209 B CN103980209 B CN 103980209B CN 201410214916 A CN201410214916 A CN 201410214916A CN 103980209 B CN103980209 B CN 103980209B
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chloro
quinazoline
bgreatt
gre
compound
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CN103980209A (en
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杨松
向红梅
薛伟
丁永正
张东阳
施利
尹娟
贺鸣
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Guizhou University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/54—1,3-Diazines; Hydrogenated 1,3-diazines
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/60—1,4-Diazines; Hydrogenated 1,4-diazines

Abstract

Compound-4-<i>N</iGreatT. the GreaT.GT-that the invention discloses a kind of anti-plant pathogen effect replaces preparation method and the biological activity of-5-chloro-quinazoline compounds, is compound represented by following general formula (<b>I</bGreatT.Gr eaT.GT) (<b>II</bGreatT.G reaT.GT) and preparation method thereof.Invention describes with 2-amino-6-chloro-benzoic acid, methane amide, phosphorus oxychloride, concentrated hydrochloric acid, <i>N</iGreatT.Gr eaT.GT-Boc piperazine, replacement benzyl chlorine or benzyl bromine as raw material, with sodium hydride, triethylamine, salt of wormwood for catalyzer, replace-5-chloroquinazoline derivative through three steps or five steps synthesis 4-<i>N</iGreatT. GreaT.GT-.The compounds of this invention <b>I 2</b><bGreatT.Gre aT.GT, </b><bGreatT.Gre aT.GTI 4</b><bGreatT.Gre aT.GT, </b><bGreatT.Gre aT.GTI 8</b><bGreatT.Gre aT.GT, </b><bGreatT.Gre aT.GTII 5</b> has good restraining effect to plant epiphyte, and <b>II 1</b><bGreatT.Gre aT.GT, </b><bGreatT.Gre aT.GTII 7</b><bGreatT.Gre aT.GT, </b><bGreatT.Gre aT.GTII 10</b><bGreatT.Gre aT.GT, </b><bGreatT.Gre aT.GTII 11</b><bGreatT.Gre aT.GT, </b><bGreatT.Gre aT.GTII 16</b><bGreatT.Gre aT.GT, </b><bGreatT.Gre aT.GTII 17</b> shows higher bacteriostatic activity to vegetative bacteria.

Description

A kind of 4-N-replaces-5-chloro-quinazoline compounds and preparation method and application
Technical field
The present invention relates to organic synthesis and technical field of pesticide, specifically a kind of 4- n-replace-5-chloro-quinazoline compounds preparation method and application.
Background technology
In recent years in Agrochemicals, enjoy people to pay close attention to because quinazoline (ketone) compounds has broad-spectrum biological activity and changeable structure type, many compounds containing quinoline ring structure show application and development prospect widely.As sterilization, desinsection, antiviral, anti-inflammatory, antitumor, hypertension, tuberculosis, antimalarial etc., part quinazoline compounds is successfully developed as commercial medicine at present, as sterilant fluquinconazole, miticide fenazaquin and cancer therapy drug Iressa etc.For a long time, people have carried out large quantifier elimination to the control of phytopathogen disease, mainly comprise agricultural measures, biological control and chemical control.Agricultural measures comprises strengthens quarantine, the sick straw of strict process and reinforcement rich water quality management etc., and strict quarantine system of carrying out, prevents disease from passing on a skill of craft to others without lesion.Anosis seed field should be set up, with the development of symptom management in epidemic-stricken area.Biological control is breeding resistant variety mainly, has certain region, seed selection of can suiting measures to local conditions.The medicament of control phytobacterial disease comprises heterogeneous ring compound and the antibiotic such as organophosphorus, organonitrogen, phenyl amide and thiazoles, but up to now, market also there is no the generation of the control phytopathogen disease that a kind of chemical pesticide can be fully effective, therefore, synthesize the novel anti-plant pathogen medicament of low toxicity and become the key issue being badly in need of at present solving.
1, there is the quianzolinones of anti-plant pathogen
(Ryu, the C.K. such as Ryu in 2004; Shim, J.Y.; Yi, Y.J.; Chae, M.J.; Han, J.Y.; Jung, O.J.Synthesisandantifungalactivityof5,8quinazolinedionederivativesmodi-fiedatpositions6and7 [J]. archivesofphamacalResearch; 2004, 27,990-996.) and report novel quinazoline quinoline compounds and bacteriostatic activity thereof, result shows: compound is to Candida albicans (C.albicans), Oidium tropicale (C.tropicalis), candida krusei (C.krusei), black-koji mould (A.niger)mIC value be respectively 6.3,3.2,3.2,0.8 μg/mL, be also all better than or with contrast medicament KETOKONAZOL (MIC) value and (be respectively 6.3,6.3,12.5,12.5 μg/mL) suitable.
(Ouyang, the G.P. such as Ouyang in 2006; Zhang, P.Q.; Xu, G.F.; Song, B.A.; Yang, S.; Jin, L.H.; Xue, W.; Hu, D.Y.; Lu, P.; Chen, Z.Synthesisandantifungalbioactivitiesof3-Alkylquinazolin-4-onederivatives [J]. molecules, 2006, 11,383-392.) and synthesize novel quinazoline quinoline compounds.Biological activity test result illustrates that compound is 50 μunder g/mL drug concentration, to gibberella saubinetii (Gibberellazeae), capsicum wither (Fusariumoxysporum), apple decay (valsamali)the inhibiting rate of three kinds of germs is respectively 47.2%, 50.3%, 40.9%, dislikes the inhibiting rate of mould spirit close to contrast medicament.
2008, height is promoted culture etc., and (height was promoted culture, Cai Xuejian, Yan Kai, and Koryo is beautiful, Wang Heying, Chen Zhuo, Song Baoan .4-(3 hthe synthesis of)-quinazolinones Schiff and activity of resisting tobacco mosaic virus [J]. organic chemistry, 2008, 28,1785-1791.) report 4-(3 h)-quinazolinones Schiff compound, adopts growth rate method to carry out bacteriostatic activity test, 50 μunder g/mL drug concentration, such target compound is to gibberella saubinetii, and capsicum withers, and the inhibiting rate of apple decay three kinds of germs is all below 16%.These are external 500 years old μunder g/mL concentration, part of compounds shows higher activity of resisting tobacco mosaic virus.
(Wang, the X. such as Wang Xiang in 2013; Li, P.; Li, Z.L.; Yin, J.; He, M.; Xue, W.; Chen, Z.W.; Song, B.A.SynthesisandBioactivityEvaluationofNovelAryliminesCo ntaininga3-Aminoethyl-2-[(p-trifluoromethoxy) anilino]
-4 (3H)-quina-zolinoneMoiety [J] .JournalofAgriculturalandFoodChemistry, 2013,61,9575-9582.) synthesized series of new quianzolinones, this compounds has good inhibit activities to tobacco bacterial wilt and rice leaf spot bacteria.Be 50 in concentration μduring g/mL, 20.09 are respectively to the inhibiting rate of rice leaf spot bacteria, 20.83,21.33,20.23.
2, there is the quinazoline compounds of anti-plant pathogen
(Coghlan, the J.M. such as Coghlan in 1994; Dreikorn, A.B.; Jourdan, P.G.; Suhr, R.G.QuinolineDerivatives [P]. uS5296484, ( 1994) .) synthesized 4-amido replace novel quinazoline quinoline compounds, 100 μunder g/mL concentration, the inverse amplification factor of these compounds to wheat powdery mildew, rice blast, tomato late blight, downy mildew of garpe, wheat leaf rust reaches 90%-100%, has good fungistatic effect.
(Barry, the A. such as Barry in 1994; Trilobi, D.; Robert, G.Pyridylethoxy-pyridylEthylamino, andPyridylpropyl-DerivativesofQuinolineandQuinazolineasI nsecticidesandFungicides [P]. wO9404527, ( 1994) .) synthesize 4- n,Othe novel quinazoline quinoline amine, the quinazoline ether compound that replace, 100 μunder g/mL concentration, the inverse amplification factor of these compounds to wheat powdery mildew, rice blast, tomato late blight, downy mildew of garpe, wheat leaf rust reaches 90%-100%, has good bacteriostatic activity.
Liu Gang in 2004 etc. (Liu Gang, Song Baoan, Sang Weijun, Yang Song, Jin Linhong, Ding Xiong. nthe synthesis of-replacement aromatic ring-4-amino-quinazoline compound and bioactivity research [J]. organic chemistry, 2004, 23,1296-1300.) be lead compound with PD153035, designed and synthesized one new n-replace aromatic ring-4-amino novel quinazoline quinoline compounds, be 500 at drug concentration μduring g/mL, compound is to Exserohilum turcicum bacteriostatic test, and the proofread inhibit rate of its spore germination can reach 56.07%.
Liu Gang in 2008 etc. (synthesis of Liu Gang, Liu Chunping, Ji Chunnuan, Sun Lin, Wen Quanwu .4-thioether group quinazoline compounds and bacteriostatic activity research [J]. organic chemistry, 2008, 28,525.) and by 4-chloro-quinazoline and sulfhydryl compound Reactive Synthesis 7 novel 4-thioether group quinazoline compounds in acetone/salt of wormwood system, and adopt growth rate method to determine their bacteriostatic activity; Wherein, wherein 4-(allyl sulfenyl) quinazoline 50 μunder g/mL concentration, 69.5%, 71.9% and 70.8%, EC are respectively to the inhibiting rate of fusarium graminearum, capsicum wilt bacterium and Valsa mali 50(in suppression concentration) difference 25.88,17.08 and 28.77 μg/mL.
Ma Yao in 2008 etc. (synthesis of Ma Yao, Liu Fang, Yan Kai, Song Baoan, Yang Song, Hu Deyu, Jin Linhong, Xue Wei .6-bromo-4-sulfenyl quinazoline compounds and bacteriostatic activity research [J]. organic chemistry, 2008, 28,1268-1272.) and synthesize novel quinazoline quinoline thio-ether type compounds, be 50 in concentration μduring g/mL, be 63.8%, 51.9%, 55.1% to fusarium graminearum, capsicum wilt bacterium, Valsa mali inhibiting rate, to dislike mould clever inhibit activities suitable with contrasting medicament.
(Liu, the F. such as Liu Fang in 2011; Huang, Y.J.Antifungalbioactivityof6-bromo-4-Ethoxyethylthioquin azoline [J]. pesticideBiochemistryandPhysiology, 2011, 101,248-255.) and biological activity test has been carried out to quinazoline compounds, test result shows, this compound has good inhibit activities to plant epiphyte, its EC 50at 17.47-70.79 μg/mL.Take fusarium graminearum as experimental subjects, carry out Mechanism Study to one of them target compound, result shows: the reducing sugar of mycelia declines, and chitosan, soluble proteins, pyruvic acid content, chitinase activity also have downtrending.
2013 Nian Liu army tigers are waited (Liu Junhu, Liu Yong, not smoothgoing army friend, Bao little Ping. containing 1,2, the synthesis of the novel quinazoline quinoline compounds of 4-triazole Schiff's base and anti-microbial activity research [J] thereof. organic chemistry, 2013, 33,370-374.) with 3-methyl-4-amino-1,2,4-triazole-5-thioketones, aromatic aldehyde and 4-chloro-quinazoline for raw material, synthesized novel quinazoline quinoline compounds through Schiff's base and thioetherification reaction.Preliminary biological activity test result shows: 50 μunder g/mL concentration, compound (E)-3-methyl-5-(quinazoline-4-base sulfenyl)- nthe inhibiting rate of-(4-(trifluoromethyl) benzylidene)-4H-1,2,4-triazole-4-amine to capsicum Fusarium oxysporum, apple decay bacterium and potato late blight bacterium is respectively 71%, 72% and 58%.
Zhang Ying in 2013 (design and synthesis of English .5,6, a 7-tri-alkoxy quinazoline derivant and bioactivity research [D]. ph.D. Dissertation, Guizhou University, 2013, 06.) and synthesize a series of 5,6,7-tri-alkoxy quinazoline derivants, 200 μunder the concentration of g/mL, this series compound has good inhibit activities to rice leaf spot bacteria and tobacco Ralstonia solanacearum.
3, there is quinazoline (ketone) compounds of anti-phytoviral activity
Ma Junan (Ma Junan in 2000, Qiu Dewen, Huang Runqiu, Feng Lei, Chai Youxin. replace synthesis and bioactivity research (V)-analogy chrysanthemic acid 4-diformazan (second) aminobenzaldoxime ester anti-phytoviral activity [J] of formoxime carboxylicesters. Pesticide Science journal 2000, 2 (4): 91-93.) etc. synthesized quinazoline oximinoether, three lives cigarette and Shan Xi cigarette adopt different administrated method respectively, and (concentration is 500 to test this compounds μg/mL) to the inhibiting rate of tobacco mosaic virus (TMV) (TMV).Result shows: this compounds processes on plant has anti-TMV activity equally, and has good systemic action (naked infusion method knot), and under direct acting condition, does not still have good anti-TMV activity and the security to crop with virus at medicament.This compounds can suppress TMV systemic symptom when formerly inoculating rear spray medicine process preferably, and is obviously better than contrast medicine diacetyl dioxo Hexahydrotriazine (DADHT) and Standone (DHT) (500 μg/mL).
High (the GaoX.W. that promotes culture in 2007; CaiX.J.; YanK.; SongB.-A.; Gao, L.L.; ChenZ.SynthesisandAntiviralBioactivitiesof2-phenyl-3-(substitutedbenzalamino)-4 (3H)-quinazoli-noneDerivatives [J]. molecules, 2007, 12:2621-2642.) etc. design and synthesis series of new containing 3-virtue methylene amino-4 ( 3H)-quinazolinones new compound, adopts the withered spot method of half leaf to be 500 in the mass concentration of medicament μduring g/mL, carry out live body treatment tobacco mosaic virus (TMV) biological activity determination, measurement result shows that these compounds all have higher therapeutic action to tobacco mosaic virus (TMV) (TMV) live body, medicament Ningnanmycin is suitable with contrasting, the therapeutic activity of one of them target compound is 55.0%, a little more than Ningnanmycin (54.0%).Study this compound effects mechanism, find that the enzyme content of the PAL enzyme of its activity and tobacco plant, POD enzyme, SOD enzyme has dependency within the regular hour, and find that this compound can induce the up-regulated of PR-1a and PR-5 gene, the system infections of TMV virus and remote invasion and attack can be stoped, thus improve the ability of anti-Resistance In Tobacco virus.
Sieve meeting in 2012 (sieve meeting. containing synthesis and the bioactivity research [D] of the 4-substituted quinazoline derivative of pentadienone structure. ph.D. Dissertation, Guizhou University, 2012, 06.) and synthesize a series of 4-substituted quinazoline derivative containing pentadienone structure, adopt the withered spot method of half leaf 500 μresisting tobacco mosaic virus test is carried out under g/mL concentration, test result shows that this series compound has good activity TMV being infected to live body treatment, inhibiting rate is 51.4%-62.7%, and therapeutic activity and control drug Ningnanmycin are quite (inhibiting rate is 55.4%).
Zhang Ying in 2013 (design and synthesis of English .5,6, a 7-tri-alkoxy quinazoline derivant and bioactivity research [D]. ph.D. Dissertation, Guizhou University, 2013, 06.) and synthesize novel 5,6, the 7-tri-alkoxy quinazoline derivatives of a class, adopt the withered spot method of half leaf to carry out to one of them target compound the therapeutic action that TMV infects live body, test result shows, its inhibiting rate is 48.2%.A little less than contrast medicament Ningnanmycin (54.0%).
Summary of the invention
Based on previous work, find that quinazoline (ketone) compounds has good agricultural biological activity, many compounds containing quinoline ring structure show application and development prospect widely, show as and there is good anti-plant pathogen activity, anti-phytoviral activity, part quinazoline compounds is successfully developed as commercial medicine, at present as sterilant fluquinconazole, miticide fenazaquin etc.The object of the invention, with 2-amino-6-chloro-benzoic acid for starting raw material, the nucleophilic substitution reaction through methane amide closed loop, phosphorus oxychloride chloro, amine has synthesized 11 novel 4-substituted amido-5-chloro-quinazoline compounds (I), be raw material further with chloro-product, with nafter-Boc piperazine carries out nucleophilic reaction hydrolysis obtain 4-piperazine-5-chloro-quinazoline, then with replace benzyl chlorine or replaces benzyl bromine reaction obtain novelty 17 4-[4-(substituted benzyl) piperazine]-5-chloro-quinazoline compounds (II).This compounds replaces containing 5-position chlorine and 4-position contains piperazine fragrance cyclic group; And carried out the innovative research of synthetic method and anti-plant pathogen novel pesticide.
A kind of 4-of the present invention n-replacing-5-chloro-quinazoline compounds, this compounds is represented by having structure general formula:
Wherein R 1for hydrogen or methyl, R 2for substituted benzyl, alkyl, replacement aromatic ring, ror s-replace aromatic ring, indication aromatic ring be adjacent, contraposition contains one or more methyl, ethyl, methoxyl group, halogen atom, halogen atom can be fluorine, chlorine, bromine.R 3for benzyl, substituted benzyl, adjacent in its benzyl rings, in contraposition containing one or more methyl, ethyl, methoxyl group, nitro, cyano group, trifluoromethyl, trifluoromethoxy and halogen atom, halogen atom can be fluorine, chlorine.
Described a kind of 4- n-replace-5-chloro-quinazoline compounds, to synthesize and the compound identified is as follows:
Compound i 1 : n-methyl-5-chloro- n-benzyl-4-amido quinazoline
Compound i 2 : 5-is chloro- n-(3-fluorobenzene ethyl)-4-amido quinazoline
Compound i 3 : 5-is chloro- n-(3,4-Dimethoxyphenethyl)-4-amido quinazoline
Compound i 4 : 5-is chloro- n-(2-fluorobenzene ethyl)-4-amido quinazoline
Compound i 5 : ( s)-5-is chloro- n-(1-hexamethylene ethyl)-4-amido quinazoline
Compound i 6 : ( r)-5-is chloro- n-(1-(4-p-methoxy-phenyl) ethyl)-4-amido quinazoline
Compound i 7 : ( r)-5-is chloro- n-(1-(3-p-methoxy-phenyl) ethyl)-4-amido quinazoline
Compound i 8 : ( s)-5-is chloro- n-(1-(4-fluorophenyl) ethyl)-4-amido quinazoline
Compound i 9 : ( s)-5-is chloro- n-(1-(4-bromophenyl) ethyl)-4-amido quinazoline
Compound i 10 : ( s)-5-is chloro- n-(1-(naphthalene-2-base) ethyl)-4-amido quinazoline
Compound i 11 : ( r)-5-is chloro- n-(1-(naphthalene-2-base) ethyl)-4-amido quinazoline
Compound iI 1 : 4-(4-benzyl diethylenediamine-1-base)-5-chloro-quinazoline
Compound iI 2 : the chloro-4-of 5-(4-(2,4-dichloro benzyl) piperazine-1-base)-quinazoline
Compound iI 3 : the chloro-4-of 5-(4-(2-cyanobenzyls) piperazine-1-base) quinazoline
Compound iI 4 : the chloro-4-of 5-(4-(4-nitrobenzyl) piperazine-1-base) quinazoline
Compound iI 5 : the chloro-4-of 5-(4-(2-chlorobenzyl) piperazine-1-base) quinazoline
Compound iI 6 : the chloro-4-of 5-(4-(3-chlorobenzyl) piperazine-1-base) quinazoline
Compound iI 7 : the chloro-4-of 5-(4-(4-luorobenzyl) piperazine-1-base) quinazoline
Compound iI 8 : the chloro-4-of 5-(4-(2-chlorobenzyl) piperazine-1-base) quinazoline
Compound iI 9 : the chloro-4-of 5-(4-(4-trifluoro-methoxybenzyl) piperazine-1-base) quinazoline
Compound iI 10 : the chloro-4-of 5-(4-(4-methoxy-benzyl) piperazine-1-base) quinazoline
Compound iI 11 : the chloro-4-of 5-(4-(4-methyl-benzyl) piperazine-1-base) quinazoline
Compound iI 12 : the chloro-4-of 5-(4-(2-luorobenzyl) piperazine-1-base) quinazoline
Compound iI 13 : the chloro-4-of 5-(4-(3-luorobenzyl) piperazine-1-base) quinazoline
Compound iI 14 : the chloro-4-of 5-(4-(4-trifluoromethyl benzyl) piperazine-1-base) quinazoline
Compound iI 15 : the chloro-4-of 5-(4-(4-methoxy-benzyl) piperazine-1-base) quinazoline
Compound iI 16 : the chloro-4-of 5-(4-(2-methyl-benzyl) piperazine-1-base) quinazoline
Compound iI 17 : the chloro-4-of 5-(4-(3-methyl-benzyl) piperazine-1-base) quinazoline
Each structural formula of compound is as follows:
table 14-substituted amido-5-chloro-quinazoline (I) compounds
I 1 I 7
I 2 I 8
I 3 I 9
I 4 I 10
I 5 I 11
I 6
show 2-in-1 one-tenth part containing 4-[4-(substituted benzyl) piperazine]-5-chloro-quinazoline (II) compounds
II 1 II 10
II 2 II 11
II 3 II 12
II 4 II 13
II 5 II 14
II 6 II 15
II 7 II 16
II 8 II 17
II 9
A kind of 4-of the present invention nthe synthetic method of-replacement-5-chloro-quinazoline compounds, its synthetic route is: general formula ( i) with 2-amino-6-chloro-benzoic acid, methane amide, phosphorus oxychloride, various substituted amido for raw material, with methane amide, phosphorus oxychloride, ethanol for solvent, take triethylamine as catalyzer, through three steps synthesis form:
Wherein R 1for hydrogen or methyl, R 2for benzyl, cyclohexyl, replacement aromatic ring, ror s-replace aromatic ring, indication aromatic ring be adjacent, contraposition contains one or more methyl, methoxyl group, halogen atom, halogen atom can be fluorine, bromine;
General formula ( iI) with 2-amino-6-chloro-benzoic acid, methane amide, phosphorus oxychloride, n-Boc piperazine, hydrochloric acid, various replacement benzyl chlorine or benzyl bromine are raw material, with methane amide, phosphorus oxychloride, ethanol, acetonitrile for solvent, with hydrochloric acid, sodium hydride, triethylamine, salt of wormwood for catalyzer, form through five step synthesis:
Wherein R 3for benzyl, substituted benzyl, R be neighbour in substituted benzyl, in contraposition containing one or more methyl, methoxyl group, nitro, cyano group, trifluoromethyl, trifluoromethoxy and halogen atom, halogen atom can be fluorine, chlorine.
A kind of 4-of the present invention nthe preparation method of-replacement-5-chloro-quinazoline compounds, synthesis step and processing condition are:
General formula ( i) synthetic method:
The first step: 5-chloro-quinazoline-4 (3H)the preparation of-one
A small amount of 2-amino-6-chloro-benzoic acid and methane amide are mixed and heated to backflow, and TLC follows the tracks of reaction process, after raw material point disappears, stop stirring, add suitable quantity of water, when being stirred to a large amount of solid of precipitation, stir again and be cooled to room temperature, suction filtration, obtains light tan powder after recrystallization, and wherein 2-amino-6-chloro-benzoic acid and methane amide mol ratio are 1:3.5-4.5, temperature of reaction 120-150 DEG C, reaction times 5-7h, the every 0.86g2-amino of amount of water-6-chloro-benzoic acid adds water 20-24mL, adds at twice;
Second step: the preparation of 4,5-dichloroquinazoline
By a small amount of 5-chloro-quinazoline-4 ( 3H)-one, appropriate phosphorus oxychloride and triethylamine are mixed and heated to backflow, TLC follows the tracks of reaction to raw material point and disappears, stopped reaction, underpressure distillation removes unnecessary phosphorus oxychloride, cooling, appropriate methylene dichloride solubilizing reaction product is added under condition of ice bath, then in the cryosel acid that slowly impouring is appropriate, use appropriate cryosel acid elution reaction flask again, merge two portions solution, vibration layering, organic over anhydrous dried over sodium sulfate, filter, it is neutral that filtrate Anhydrous potassium carbonate is stirred to pH value, filter, concentrating under reduced pressure, column chromatography obtains white needles, wherein 5-chloro-quinazoline-4 ( 3H)-one, phosphorus oxychloride and triethylamine mol ratio be 1:12:5.5-1:14:6.5, reaction times 7-9h, 5-chloro-quinazoline-4 ( 3H) mol ratio of-one and methylene dichloride is 1:26.5-1:27.5, the 5-chloro-quinazoline of every 1.00g-4 ( 3H)-one add 1mol/L cryosel acid 32-34mL, add at twice,
3rd step: 4-substituted amido-5-chloro-quinazoline ( i) preparation of compounds
A small amount of 4,5-dichloroquinazolines, amine and ethanol are mixed, then drips a small amount of triethylamine, under reflux conditions react, TLC tracks to without raw material point, stopped reaction, and column chromatography is separated, obtain class oyster white oily or solid, wherein the mol ratio of 4,5-dichloroquinazolines, amine and ethanol is 1:1.45:1.15-1:1.55:1.25, every 0.5mmol4,5-dichloroquinazoline drips triethylamine 3 ~ 6, reaction times 2.5-5h.
General formula ( iI) synthetic method:
The first step: 5-chloro-quinazoline-4 (3H)the preparation of-one
A small amount of 2-amino-6-chloro-benzoic acid and methane amide are mixed and heated to backflow, and TLC follows the tracks of reaction process, after raw material point disappears, stop stirring, add suitable quantity of water, when being stirred to a large amount of solid of precipitation, stir again and be cooled to room temperature, suction filtration, obtains light tan powder after recrystallization, and wherein 2-amino-6-chloro-benzoic acid and methane amide mol ratio are 1:3.5-4.5, temperature of reaction 120-150 DEG C, reaction times 5-7h, the every 0.86g2-amino of amount of water-6-chloro-benzoic acid adds water 20-24mL, adds at twice;
Second step: the preparation of 4,5-dichloroquinazoline
By a small amount of 5-chloro-quinazoline-4 ( 3H)-one, appropriate phosphorus oxychloride and triethylamine are mixed and heated to backflow, TLC follows the tracks of reaction to raw material point and disappears, stopped reaction, underpressure distillation removes unnecessary phosphorus oxychloride, cooling, appropriate methylene dichloride solubilizing reaction product is added under condition of ice bath, then in the cryosel acid that slowly impouring is appropriate, use appropriate cryosel acid elution reaction flask again, merge two portions solution, vibration layering, organic over anhydrous dried over sodium sulfate, filter, it is neutral that filtrate Anhydrous potassium carbonate is stirred to pH value, filter, concentrating under reduced pressure, column chromatography obtains white needles, wherein 5-chloro-quinazoline-4 ( 3H)-one, phosphorus oxychloride and triethylamine mol ratio be 1:12:5.5-1:14:6.5, reaction times 7-9h, 5-chloro-quinazoline-4 ( 3H) mol ratio of-one and methylene dichloride is 1:26.5-1:27.5, the 5-chloro-quinazoline of every 1.00g-4 ( 3H)-one add 1mol/L cryosel acid 32-34mL, add at twice,
3rd step: 4-( n-Boc piperazine) synthesis of-5-chloro-quinazoline
By 4,5-dichloroquinazoline, n-Bocpiperazine, DMF and sodium hydride mix, and stir under normal temperature, and TLC follows the tracks of reaction extremely without raw material point, stopped reaction, saturated ammonium chloride solution washs, dichloromethane extraction, precipitation, column chromatography separating-purifying, obtains oily matter, wherein 4,5-dichloroquinazolines, n-Bocthe mol ratio of piperazine, DMF and sodium hydride is 1:1.15:3.5:1.4-1:1.25:4.5:1.6, reaction times 7-10h;
4th step: 4-piperazine-5-chloro-quinazoline (intermediate 1) synthesis
By 4-( n-Boc piperazine)-5-chloro-quinazoline and hydrochloric acid normal temperature mix and blend, after stirring for some time, TLC tracks to without raw material point, and stopped reaction, uses anhydrous K 2cO 3adjust pH to be neutral or weakly alkaline, dichloromethane extraction precipitation, column chromatography purification obtains oily matter, and wherein the massfraction of hydrochloric acid is 15-20%, and every 0.45g4-(N-Boc piperazine)-5-chloro-quinazoline adds 15-20% hydrochloric acid 7-9mL, reaction times 5-7h;
5th step: target compound iIsynthesis
By intermediate 1, replace benzyl chlorine (replacing benzyl bromine), ethanol and triethylamine mixing, react under reflux, TLC tracks to without raw material point, stopped reaction, and column chromatography and thin layer chromatography separating-purifying, obtain class yellow oil or solid, wherein intermediate 1, to replace benzyl chlorine (replacing benzyl bromine), ethanol and triethylamine mol ratio be 1:1.15:11:1.4-1:1.25:13:1.6, the reaction times is 3-6h.
A kind of 4-of the present invention n-replace the application of-5-chloro-quinazoline compounds, be the medicine for the preparation of plant epiphyte resisting or anti-vegetative bacteria and medicament.
A kind of 4-of the present invention nthe application of-replacement-5-chloro-quinazoline compounds is the medicine for the preparation of anti-fusarium graminearum, capsicum wilt bacterium, Valsa mali, rice leaf spot bacteria, tobacco ralstonia solanacearum and medicament.
A kind of 4-of the present invention nthe application of-replacement-5-chloro-quinazoline compounds, is i 2 , i 4 , i 5 , i 8 preparation anti-fusarium graminearum, capsicum wilt bacterium, Valsa mali and iI 1 , iI 7 , iI 10 , iI 11 preparing rice leaf spot bacteria, the medicine of tobacco ralstonia solanacearum and medicament.
Embodiment
Example one, 5-are chloro- n-(3-fluorobenzene ethyl)-4-amido quinazoline (being numbered of compound i 2 ) synthesis
(1) synthesis of 5-chloro-quinazoline-4 (3H)-one
To in the there-necked flask of 25mL, drop into 2-amino-6-chloro-benzoic acid 0.86g (0.005mol), add 3mL (0.020mol) methane amide, be mixed and heated to backflow (140 DEG C) reaction 6h, add 10mL water afterwards, when to be stirred to temperature be 60 DEG C, then add suitable quantity of water, be cooled to room temperature, suction filtration, obtain light tan powder 0.61g, yield 67.8%, m.p.212 ~ 214 DEG C (literature value 210 DEG C);
The synthesis of (2) 4,5-dichloroquinazolines
To in the there-necked flask of 50mL, drop into 5-chloro-quinazoline-4 (3H)-one 1.00g (5.42mmol), add 13.0mLPOCl 3with 6mL triethylamine, be mixed and heated to backflow 8h, underpressure distillation removes unnecessary POCl 3, cooling, adds 30mLCH under condition of ice bath 2cl 2solubilizing reaction product, then CH 2cl 2in the cryosel acid of solution slowly impouring 33mL1mol/L, then use the cryosel acid elution reaction flask of 33mL1mol/L, merge two portions solution, vibration layering, organic over anhydrous dried over sodium sulfate, filters, filtrate anhydrous K 2cO 3be stirred to pH value for neutral, filter, concentrating under reduced pressure, column chromatography obtains product 0.71g, yield 65.8%, m.p.135 ~ 138 DEG C (literature value 131.5 ~ 133 DEG C);
(3) 5-is chloro- nthe synthesis of-(3-fluorobenzene ethyl)-4-amido quinazoline
In 25mL there-necked flask, add (0.5mmol) 4,5-dichloroquinazoline, 0.75mmol trifluoro-benzene ethamine, 6mL ethanol and 3 ~ 4 triethylamines, react 4h under reflux, TLC tracks to without raw material point, stopped reaction, column chromatography is separated, and obtains Off-white solid, productive rate 86.2%;
5-is chloro-for example two n(compound number is-(3,4-Dimethoxyphenethyl)-4-amido quinazoline i 3 ) synthesis
(1) synthesis of 5-chloro-quinazoline-4 (3H)-one
As embodiment one (1) synthesis step and processing condition, difference is that 2-amino-6-chloro-benzoic acid and methane amide mol ratio are 1:3.5, temperature of reaction 120 DEG C, and the reaction times is 5h, the every 0.86g2-amino of amount of water-6-chloro-benzoic acid adds water 20mL, adds at twice;
The synthesis of (2) 4,5-dichloroquinazolines
As embodiment one (2) synthesis step and processing condition, difference be 5-chloro-quinazoline-4 ( 3H)-one, phosphorus oxychloride and triethylamine mol ratio be 1:12:5.5, reaction times 9h, 5-chloro-quinazoline-4 ( 3H) mol ratio of-one and methylene dichloride is 1:26.5, the 5-chloro-quinazoline of every 1.00g-4 ( 3H)-one add 1mol/L cryosel acid 32mL, add at twice;
(3) 5-is chloro- nthe synthesis of-(3,4-Dimethoxyphenethyl)-4-amido quinazoline
As example one (3) condition and method synthesis, difference is 4,5-dichloroquinazoline, 3, the mol ratio of 4-dimethoxy-phenylethylamine and ethanol is 1:1.45:1.15, and every 0.5mmol4,5-dichloroquinazoline drips triethylamine 4, reaction times 5h, obtains Off-white solid, productive rate 79.5%;
5-is chloro-for example three n-(2-fluorobenzene ethyl) (compound number is-4-amido quinazoline i 4 ) synthesis
(1) synthesis of 5-chloro-quinazoline-4 (3H)-one
As embodiment one (1) synthesis step and processing condition, difference is that 2-amino-6-chloro-benzoic acid and methane amide mol ratio are 1:4.5, temperature of reaction 150 DEG C, and the reaction times is 7h, the every 0.86g2-amino of amount of water-6-chloro-benzoic acid adds water 24mL, adds at twice;
The synthesis of (2) 4,5-dichloroquinazolines
As embodiment one (2) synthesis step and processing condition, difference be 5-chloro-quinazoline-4 ( 3H)-one, phosphorus oxychloride and triethylamine mol ratio be 1:14:6.5, reaction times 7h, 5-chloro-quinazoline-4 ( 3H) mol ratio of-one and methylene dichloride is 1:27.5, the 5-chloro-quinazoline of every 1.00g-4 ( 3H)-one add 1mol/L cryosel acid 34mL, add at twice;
(3) 5-is chloro- nthe synthesis of-(2-fluorobenzene ethyl)-4-amido quinazoline
As example one (3) synthesis step and processing condition, difference is that the mol ratio of 4,5-dichloroquinazoline, 2-fluorophenethylamine and ethanol is 1:1.55:1.25, every 0.5mmol4,5-dichloroquinazoline drips triethylamine 6, reaction times 4h, obtain yellow solid, productive rate 66.3%.
Example four (S)-5-is chloro- n-(1-hexamethylene ethyl) (compound number is-4-amido quinazoline i 5 ) synthesis
(1) synthesis of 5-chloro-quinazoline-4 (3H)-one: as embodiment one (1) synthesis step and processing condition
The synthesis of (2) 4,5-dichloroquinazolines: as embodiment one (2) synthesis step and processing condition
(3) (S)-5-is chloro- nthe synthesis of-(1-hexamethylene ethyl)-4-amido quinazoline: as example one (3) synthesis step and processing condition, difference is to add 0.75mmol (R)-1-cyclohexylethylamine, obtains white solid, productive rate 82.8%.
Example five (S)-5-is chloro- n-(1-(4-fluorophenyl) ethyl) (compound number is class to-4-amido quinazoline i 8 ) synthesis
(1) synthesis of 5-chloro-quinazoline-4 (3H)-one: as embodiment one (1) synthesis step and processing condition
The synthesis of (2) 4,5-dichloroquinazolines: as embodiment one (2) synthesis step and processing condition
(3) (S)-5-is chloro- nthe synthesis of-(1-(4-fluorophenyl) ethyl)-4-amido quinazoline: as example one (3) synthesis step and processing condition, difference is to add 0.75mmol4-fluorophenethylamine, obtains yellow solid, productive rate 72.8%.
The 4-of synthesis nthe spectral data of-replacement-5-chloro-quinazoline compounds is as follows:
n-methyl-5-chloro- n-benzyl-4-amido quinazoline (I 1 )
Ayellowsolid,yield81.0%,m.p.61~64℃; 1HNMR(500MHz,CDCl 3):δ3.02(s,3H,CH 3-N),4.88(s,2H,CH 2-N),7.22(d,2H,Ar-H-2,6, J=6.9Hz),7.27(d,1H,Ar-H-4, J=5.2Hz),7.31(t,2H,Ar-H-3,5, J=8.6Hz),7.45(d-d,1H,H-6ofquinazoline, J=7.4Hz),7.59(t,1H,H-7ofquinazoline, J=7.5Hz),7.77(d-d,1H,H-8ofquinazoline, J=7.0Hz),8.59(s,1H,H-2ofquinazoline). 13CNMR(125MHz,CDCl 3):δ40.3,56.8,113.9,126.5,127.5,127.6,128.3(2C),128.7(2C),130.2,132.0,136.8,152.9,154.2,163.4.MS(ESI):m/z(M+H) +284.3.
5-is chloro- n-(3-fluorobenzene ethyl)-4-amido quinazoline (I 2 )
Amilkysolid,yield86.2%,m.p.67~71℃; 1HNMR(500MHz,CDCl 3):δ3.03(t,2H,NH-CH 2-CH 2, J=6.9Hz),3.92(q,2H,NH-CH 2-CH 2, J=6.9Hz),6.95(t,1H,Ph-H-2, J=6.3Hz),7.00(d,1H,Ph-H-4, J=7.5Hz),7.06(d,1H,Ph-H-6, J=7.5Hz),7.27~7.31(m,1H,Ph-H-5),7.36(d,1H,H-6ofquinazoline, J=7.5Hz),7.53(t,1H,H-7ofquinazoline, J=8.0Hz),7.71(d,1H,H-8ofquinazoline, J=8.6Hz),7.71(t,1H,NH, J=8.6Hz),8.59(s,1H,H-2ofquinazoline). 13CNMR(125MHz,CDCl 3):δ34.7,42.9,113.2,113.7,115.8,124.6,128.2,128.5,130.3,131.9,141.5,152.3,155.5,159.0,162.1,164.1.m/z(M+H) +302.2.
5-is chloro- n-(3,4-Dimethoxyphenethyl)-4-amido quinazoline (I 3 )
Amilkysolid,yield79.5%,m.p.78~80℃; 1HNMR(500MHz,CDCl 3):δ2.96(t,2H,NH-CH 2-CH 2, J=6.9Hz),3.87(q,2H,NH-CH 2-CH 2, J=5.2Hz),3.85(s,6H,Ph-OCH 3-3,4),6.80(d,2H,Ph-H-5,6, J=13.8Hz),6.81(s,1H,Ph-H-2),7.29(d-d,1H,H-6ofquinazoline, J=6.3Hz),7.46(t,1H,H-7ofquinazoline, J=8.0Hz),7.66(d-d,1H,H-8ofquinazoline, J=7.5Hz),7.66(q,1H,NH, J=7.5Hz),8.56(s,1H,H-2ofquinazoline). 13CNMR(125MHz,CDCl 3):δ34.4,43.2,55.8,55.9,111.4,111.9,113.0,120.9,127.9,128.4,131.3,131.8,147.8,149.1,152.0,155.3(2C),158.9.m/z(M+H) +344.3.
5-is chloro- n-(2-fluorobenzene ethyl)-4-amido quinazoline (I 4 )
Ayellowsolid,yield66.3%,m.p.80~83℃; 1HNMR(500MHz,CDCl 3):δ3.10(t,2H,NH-CH 2-CH 2, J=6.3Hz),3.93(q,2H,NH-CH 2-CH 2, J=7.5Hz),7.04~7.11(m,2H,Ph-H-2,4),7.27(d,1H,Ph-H-6, J=7.5Hz),7.27~7.31(m,1H,Ph-H-5),7.37(d,1H,H-6ofquinazoline, J=8.1Hz),7.54(t,1H,H-7ofquinazoline, J=8.0Hz),7.71(d,1H,H-8ofquinazoline, J=6.9Hz),7.72(t,1H,NH, J=6.9Hz),8.59(s,1H,H-2ofquinazoline). 13CNMR(125MHz,CDCl 3):δ28.4,42.0,113.2,115.6,124.3,125.8,128.1,128.5,128.6,131.3,131.89,152.3,155.5,159.1,160.5,162.4.m/z(M+H) +302.2.
( s)-5-is chloro- n-(1-hexamethylene ethyl)-4-amido quinazoline (I 5 )
Amilkysolid,yield82.8%,m.p.58~59℃; 1HNMR(500MHz,CDCl 3):δ0.98~1.21(m,8H,cyclohexylH-2,3,4,5,6andCH 3-CH-NH),1.59~1.83(m,6H,cyclohexylH-1,2,3,4,5,6),4.37(q,1H,CH 3-CH-NH, J=6.9Hz),7.55(t,1H,H-7ofquinazoline, J=5.9Hz),7.65(d,1H,H-6ofquinazoline, J=8.1Hz),7.70(d,1H,H-8ofquinazoline, J=6.3Hz),7.70(t,1H,NH, J=6.3Hz),8.50(s,1H,H-2ofquinazoline). 13CNMR(125MHz,CDCl 3):δ17.2,26.2,26.3,26.3,29.1,29.3,42.4,51.4,112.7,128.2,128.3,128.4,132.8,152.5,155.5,158.3.m/z(M+H) +290.3.
( r)-5-is chloro- n-(1-(4-p-methoxy-phenyl) ethyl)-4-amido quinazoline (I 6 )
Ayellowsolid,yield76.5%,m.p.98~104℃; 1HNMR(500MHz,CDCl 3):δ1.61(d,3H,CH-CH3, J=6.8Hz),3.29(s,3H,Ar-OCH 3),5.46(q,1H,CH-CH 3, J=6.9Hz),6.89(d,2H,Ar-H-3,5, J=6.9Hz),7.35(d,2H,Ar-H-2,6, J=8.6Hz),7.51(d-d,1H,H-7ofquinazoline, J=6.9Hz),7.60~7.65(m,2H,H-6,8ofquinazoline),8.37(s,1H,H-2ofquinazoline). 13CNMR(125MHz,CDCl 3):δ21.1,50.8,54.4,112.6,113.8(2C),126.5,127.1(2C),128.5,128.6,132.5,135.2,151.2,154.8,158.0,159.1.m/z(M+H) +314.3.
( r)-5-is chloro- n-(1-(3-p-methoxy-phenyl) ethyl)-4-amido quinazoline (I 7 )
Awhitesolid,yield72.4%,m.p.49~51℃; 1HNMR(500MHz,CDCl 3):δ1.66(d,3H,CH-CH 3, J=6.9Hz),3.81(s,3H,Ar-OCH 3),5.55(q,1H,CH-CH 3, J=6.9Hz),6.82(d,1H,Ar-H-4, J=8.1Hz),7.02(t,2H,Ar-H-2,6, J=7.4Hz),7.27~7.31(m,1H,Ar-H-5),7.42(d,1H,H-6ofquinazoline, J=7.5Hz),7.55(t,1H,H-7ofquinazoline, J=7.8Hz),7.72(d,1H,H-8ofquinazoline, J=8.6Hz),8.07(s,1H,NH),8.54(s,1H,H-2ofquinazoline). 13CNMR(125MHz,CDCl 3):δ22.6,51.0,55.3,112.4(2C),113.2,118.5,128.2,128.3,128.5,129.9,131.9,145.2,152.4,155.5,158.1,159.9.m/z(M+H) +314.3.
( s)-5-is chloro- n-(1-(4-fluorophenyl) ethyl)-4-amido quinazoline (I 8 )
Ayellowsolid,yield72.8%,m.p.57~59℃; 1HNMR(500MHz,CDCl 3):δ1.66(d,3H,CH-CH3, J=9.8Hz),5.55(q,1H,CH-CH 3, J=8.6Hz),7.05(d,2H,Ar-H-3,5 J=9.2Hz),7.41~7.45(m,3H,Ar-H-2,6andH-6ofquinazoline),7.56(t,1H,H-7ofquinazoline, J=9.7Hz),7.72(d,1H,H-8ofquinazoline, J=9.2Hz),8.03(s,1H,NH),8.53(s,1H,H-2ofquinazoline). 13CNMR(125MHz,CDCl 3):δ22.6,50.0,113.08,115.5,115,7127.8,127.9,128.2,128.3,128.5,132.0,139.2,152.4,155.5,158.1,162.8.m/z(M+H) +302.2.
( s)-5-is chloro- n-(1-(4-bromophenyl) ethyl)-4-amido quinazoline (I 9 )
Ayellowsolid,yield72.8%,m.p.79~84℃; 1HNMR(500MHz,CDCl 3):δ1.64(d,3H,CH-CH3, J=6.9Hz),5.51(q,1H,CH-CH 3, J=8.6Hz),7.31(d,2H,Ar-H-2,6 J=8.6Hz),7.43(d,1H,H-6ofquinazoline J=7.4Hz),7.47(d,2H,Ar-H-3,5 J=8.6Hz),7.72(t,1H,H-7ofquinazoline, J=8.1Hz),7.72(d,1H,H-8ofquinazoline, J=8.6Hz),8.03(d,1H,NH J=6.3Hz),8.52(s,1H,H-2ofquinazoline). 13CNMR(125MHz,CDCl 3):δ22.6,50.5,113.1,121.1,128.0(2C),128.2,128.4128.4,131.9(2C),132.0,142.6,152.4,155.4,158.1.m/z(M+H) +364.1.
( s)-5-is chloro- n-(1-(naphthalene-2-base) ethyl)-4-amido quinazoline (I 10 )
Awhitesolid,yield79.8%,m.p.100~103℃; 1HNMR(500MHz,CDCl 3):δ1.75(d,3H,CH-CH3, J=6.9Hz),5.70~5.76(m,1H,NH-CH-CH 3),7.42(d,1H,Ar-H-2 J=7.5Hz),7.45~7.49(m,2H,Ar-H-5,6),7.53~7.56(m,2H,Ar-H-8andH-7ofquinazoline),7.72(d,1H,H-6ofquinazoline, J=8.6Hz),7.82~7.87(m,4H,Ar-H-3,4,7andH-8ofquinazoline),8.17(d,1H,NH J=6.3Hz),8.54(s,1H,H-2ofquinazoline). 13CNMR(125MHz,CDCl 3):δ22.5,51.2,113.1,124.7,124.8,126.0,126.4,127.8,128.0,128.2,128.3,128.6,128.7,131.9,132.9,133.5,140.8,152.4,155.6,158.2.m/z(M+H) +334.3.
( r)-5-is chloro- n-(1-(naphthalene-2-base) ethyl)-4-amido quinazoline (I 11 )
Awhitesolid,yield81.4%,m.p.109~110℃; 1HNMR(500MHz,CDCl 3):δ1.75(d,3H,CH-CH3, J=6.9Hz),5.70~5.76(m,1H,NH-CH-CH 3),7.41(d,1H,Ar-H-2 J=6.9Hz),7.43~7.48(m,2H,Ar-H-5,6),7.52~7.56(m,2H,Ar-H-8andH-7ofquinazoline),7.72(d-d,1H,H-6ofquinazoline, J=7.5Hz),7.81~7.87(m,4H,Ar-H-3,4,7andH-8ofquinazoline),8.17(d,1H,NH J=6.3Hz),8.54(s,1H,H-2ofquinazoline). 13CNMR(125MHz,CDCl 3):δ22.5,51.2,113.2,124.7,124.7,126.0,126.4,127.8,128.0,128.2,128.3,128.6,128.8,131.9,132.9,133.5,140.8,152.4,155.6,158.2.m/z(M+H) +334.3.
General formula of the present invention ( iI) with 2-amino-6-chloro-benzoic acid, methane amide, phosphorus oxychloride, n-Boc piperazine, hydrochloric acid, various replacement benzyl chlorine or benzyl bromine are raw material, and with methane amide, phosphorus oxychloride, ethanol, acetonitrile for solvent, with hydrochloric acid, sodium hydride, triethylamine, salt of wormwood for catalyzer, form through five step synthesis, its synthetic route is:
Wherein R 3for benzyl, substituted benzyl, R be neighbour in substituted benzyl, in contraposition containing one or more methyl, methoxyl group, nitro, cyano group, trifluoromethyl, trifluoromethoxy and halogen atom, halogen atom can be fluorine, chlorine.
Synthesis step and processing condition:
The first step: 5-chloro-quinazoline-4 (3H)the preparation of-one
A small amount of 2-amino-6-chloro-benzoic acid and methane amide are mixed and heated to backflow, and TLC follows the tracks of reaction process, after raw material point disappears, stop stirring, add suitable quantity of water, when being stirred to a large amount of solid of precipitation, stir again and be cooled to room temperature, suction filtration, obtains light tan powder after recrystallization, and wherein 2-amino-6-chloro-benzoic acid and methane amide mol ratio are 1:3.5-4.5, temperature of reaction 120-150 DEG C, reaction times 5-7h, the every 0.86g2-amino of amount of water-6-chloro-benzoic acid adds water 20-24mL, adds at twice;
Second step: the preparation of 4,5-dichloroquinazoline
By a small amount of 5-chloro-quinazoline-4 ( 3H)-one, appropriate phosphorus oxychloride and triethylamine are mixed and heated to backflow, TLC follows the tracks of reaction to raw material point and disappears, stopped reaction, underpressure distillation removes unnecessary phosphorus oxychloride, cooling, appropriate methylene dichloride solubilizing reaction product is added under condition of ice bath, then in the cryosel acid that slowly impouring is appropriate, use appropriate cryosel acid elution reaction flask again, merge two portions solution, vibration layering, organic over anhydrous dried over sodium sulfate, filter, it is neutral that filtrate Anhydrous potassium carbonate is stirred to pH value, filter, concentrating under reduced pressure, column chromatography obtains white needles, wherein 5-chloro-quinazoline-4 ( 3H)-one, phosphorus oxychloride and triethylamine mol ratio be 1:12:5.5-1:14:6.5, reaction times 7-9h, 5-chloro-quinazoline-4 ( 3H) mol ratio of-one and methylene dichloride is 1:26.5-1:27.5, the 5-chloro-quinazoline of every 1.00g-4 ( 3H)-one add 1mol/L cryosel acid 32-34mL, add at twice,
3rd step: 4-( n-Boc piperazine) synthesis of-5-chloro-quinazoline
By 4,5-dichloroquinazoline, n-Bocpiperazine, DMF and sodium hydride mix, and stir under normal temperature, and TLC follows the tracks of reaction extremely without raw material point, stopped reaction, saturated ammonium chloride solution washs, dichloromethane extraction, precipitation, column chromatography separating-purifying, obtains oily matter, wherein 4,5-dichloroquinazolines, n-Bocthe mol ratio of piperazine, DMF and sodium hydride is 1:1.15:3.5:1.4-1:1.25:4.5:1.6, reaction times 7-10h;
4th step: 4-piperazine-5-chloro-quinazoline (intermediate 1) synthesis
By 4-( n-Boc piperazine)-5-chloro-quinazoline and hydrochloric acid normal temperature mix and blend, after stirring for some time, TLC tracks to without raw material point, and stopped reaction, uses anhydrous K 2cO 3adjust pH to be neutral or weakly alkaline, dichloromethane extraction precipitation, column chromatography purification obtains oily matter, and wherein the massfraction of hydrochloric acid is 15-20%, and every 0.45g4-(N-Boc piperazine)-5-chloro-quinazoline adds 15-20% hydrochloric acid 7-9mL, reaction times 5-7h;
5th step: target compound iIsynthesis
By intermediate 1, replace benzyl chlorine (replacing benzyl bromine), ethanol and triethylamine mixing, react under reflux, TLC tracks to without raw material point, stopped reaction, and column chromatography and thin layer chromatography separating-purifying, obtain class yellow oil or solid, wherein intermediate 1, to replace benzyl chlorine (replacing benzyl bromine), ethanol and triethylamine mol ratio be 1:1.15:11:1.4-1:1.25:13:1.6, the reaction times is 3-6h.
Embodiment six, (compound number is quinazoline compound 4-(4-benzyl diethylenediamine-1-base) iI 1 ) synthesis
(1) synthesis of 5-chloro-quinazoline-4 (3H)-one
To in the there-necked flask of 25mL, drop into 2-amino-6-chloro-benzoic acid 0.86g (0.005mol), add 3mL (0.020mol) methane amide, be mixed and heated to 140 DEG C, reaction 6h, adds 10mL water after stopped reaction, when to be stirred to temperature be 60 DEG C, add suitable quantity of water again, be cooled to room temperature, suction filtration, obtain light tan powder 0.61g, yield 67.8%, m.p.212 ~ 214 DEG C (literature value 210 DEG C);
The synthesis of (2) 4,5-dichloroquinazolines
To in the there-necked flask of 50mL, drop into 5-chloro-quinazoline-4 (3H)-one 1.00g (5.42mmol), add 13.0mLPOCl 3with 6mL triethylamine, be mixed and heated to backflow 8h, underpressure distillation removes unnecessary POCl 3, cooling, adds 30mLCH under condition of ice bath 2cl 2solubilizing reaction product, then CH 2cl 2in the cryosel acid of solution slowly impouring 33mL1mol/L, then use the cryosel acid elution reaction flask of 33mL1mol/L, merge two portions solution, vibration layering, organic over anhydrous dried over sodium sulfate, filters, filtrate anhydrous K 2cO 3be stirred to pH value for neutral, filter, concentrating under reduced pressure, column chromatography obtains product 0.71g, yield 65.8%, m.p.135 ~ 138 DEG C (literature value 131.5 ~ 133 DEG C);
(3) 4-( n-Boc piperazine) synthesis of-5-chloro-quinazoline
In 25mL there-necked flask, by (1.5mmol) 4,5-dichloroquinazoline and (1.8mmol) N-Boc piperazine and anhydrous DMF of 6mL, the mixing of 2.25mmol sodium hydride, stirring at normal temperature 8h, stopped reaction, saturated ammonium chloride solution washs, dichloromethane extraction, precipitation, column chromatography separating-purifying, obtains oily matter 0.45g, productive rate 86.0%;
(4) 4-piperazine-5-chloro-quinazoline (intermediate 1) synthesis
In 25mL there-necked flask, by 0.45g4-(N-Boc piperazine)-5-chloro-quinazoline and 8mL18% hydrochloric acid normal temperature mix and blend, after 6h, TLC tracks to without raw material point, and stopped reaction, uses anhydrous K 2cO 3adjust pH to be neutral or weakly alkaline, dichloromethane extraction precipitation, column chromatography purification obtains oily matter 0.20g, productive rate 70.0%;
(5) synthesis of 4-(4-benzyl diethylenediamine-1-base) quinazoline
In 25mL there-necked flask, add (0.5mmol) intermediate 1, (0.60mmol) benzyl chlorine, 6mL ethanol and 100 μ L (0.75mmol) triethylamines, react 4h under reflux, TLC tracks to without raw material point, stopped reaction, column chromatography method and thin layer chromatography separating-purifying, obtain yellow solid, productive rate 78.7%.
Example seven, (compound number is quinazoline the chloro-4-of compound 5-(4-(4-chlorobenzyl) piperazine-1-base) iI 5 ) synthesis
(1) 5-chloro-quinazoline-4 (3H)the preparation of-one
As embodiment six (1) synthesis step and processing condition, difference is that 2-amino-6-chloro-benzoic acid and methane amide mol ratio are 1:3.5, temperature of reaction 120 DEG C, and the reaction times is 7h, the every 0.86g2-amino of amount of water-6-chloro-benzoic acid adds water 20mL, adds at twice;
The synthesis of (2) 4,5-dichloroquinazolines
As embodiment six (2) synthesis step and processing condition, difference be 5-chloro-quinazoline-4 ( 3H)-one, phosphorus oxychloride and triethylamine mol ratio be 1:12:5.5, reaction times 9h, 5-chloro-quinazoline-4 ( 3H) mol ratio of-one and methylene dichloride is 1:26.5, the 5-chloro-quinazoline of every 1.00g-4 ( 3H)-one add 1mol/L cryosel acid 32mL, add at twice;
(3) synthesis of 4-(N-Boc piperazine)-5-chloro-quinazoline
As embodiment six (3) synthesis step and processing condition, difference be 4,5-dichloroquinazoline, n-Bocthe mol ratio of piperazine, DMF and sodium hydride is 1:1.15:3.5:1.4, reaction times 10h;
(4) 4-piperazine-5-chloro-quinazoline (intermediate 1) synthesis
As embodiment six (4) synthesis step and processing condition, its difference is that the massfraction of hydrochloric acid is 15%, and every 0.45g4-(N-Boc piperazine)-5-chloro-quinazoline adds 15% hydrochloric acid 9mL, reaction times 7h;
(5) synthesis of the chloro-4-of 5-(4-(4-chlorobenzyl) piperazine-1-base) quinazoline
As embodiment six (4) synthesis step and processing condition, difference is intermediate 1, be 1:1.15:11:1.4 to benzyl chloride chlorine, ethanol and triethylamine mol ratio, the reaction times is 3h, obtains yellow oil, productive rate 75.0%.
Example eight, (compound number is quinazoline the chloro-4-of compound 5-(4-(4-luorobenzyl) piperazine-1-base) iI 7 ) synthesis
(1) 5-chloro-quinazoline-4 (3H)the preparation of-one
As embodiment six (1) synthesis step and processing condition, difference is that 2-amino-6-chloro-benzoic acid and methane amide mol ratio are 1:4.5, temperature of reaction 150 DEG C, and the reaction times is 5h, the every 0.86g2-amino of amount of water-6-chloro-benzoic acid adds water 24mL, adds at twice;
The synthesis of (2) 4,5-dichloroquinazolines
As embodiment six (2) synthesis step and processing condition, difference be 5-chloro-quinazoline-4 ( 3H)-one, phosphorus oxychloride and triethylamine mol ratio be 1:14:6.5, reaction times 7h, 5-chloro-quinazoline-4 ( 3H) mol ratio of-one and methylene dichloride is 1:27.5, the 5-chloro-quinazoline of every 1.00g-4 ( 3H)-one add 1mol/L cryosel acid 34mL, add at twice;
(3) synthesis of 4-(N-Boc piperazine)-5-chloro-quinazoline
As embodiment six (3) synthesis step and processing condition, difference be 4,5-dichloroquinazoline, n-Bocthe mol ratio of piperazine, DMF and sodium hydride is 1:1.25:4.5:1.6, reaction times 7h;
(4) 4-piperazine-5-chloro-quinazoline (intermediate 1) synthesis
As embodiment six (4) synthesis step and processing condition, its difference is that the massfraction of hydrochloric acid is 20%, and every 0.45g4-(N-Boc piperazine)-5-chloro-quinazoline adds 20% hydrochloric acid 7mL, reaction times 5h;
(5) synthesis of the chloro-4-of 5-(4-(4-luorobenzyl) piperazine-1-base) quinazoline
As embodiment six (4) synthesis step and processing condition, difference is intermediate 1, be 1:1.25:13:1.6 to fluorine benzyl chlorine, ethanol and triethylamine mol ratio, the reaction times is 6h, obtains yellow solid, productive rate 78.7%.
Example nine, (compound number is quinazoline the chloro-4-of compound 5-(4-(4-methoxy-benzyl) piperazine-1-base) iI 10 ) synthesis
(1) 5-chloro-quinazoline-4 (3H)the preparation of-one: as embodiment six (1) synthesis step and processing condition
The synthesis of (2) 4,5-dichloroquinazolines: as embodiment six (2) synthesis step and processing condition
(3) synthesis of 4-(N-Boc piperazine)-5-chloro-quinazoline: as embodiment six (3) synthesis step and processing condition
(4) 4-piperazine-5-chloro-quinazoline (intermediate 1) synthesis: as embodiment six (4) synthesis step and processing condition
(5) synthesis of the chloro-4-of 5-(4-(4-methoxy-benzyl) piperazine-1-base) quinazoline: as embodiment six (4) synthesis step and processing condition, difference is to add (0.60mmol) p-methoxybenzyl chloride, obtain yellow oil, productive rate 81.3%.
Example ten, the chloro-4-of compound 5-(4-(4-methyl-benzyl) piperazine-1-base) quinazoline
(compound number is iI 11 ) synthesis
(1) 5-chloro-quinazoline-4 (3H)the preparation of-one: as embodiment six (1) synthesis step and processing condition
The synthesis of (2) 4,5-dichloroquinazolines: as embodiment six (2) synthesis step and processing condition
(3) synthesis of 4-(N-Boc piperazine)-5-chloro-quinazoline: as embodiment six (3) synthesis step and processing condition
(4) 4-piperazine-5-chloro-quinazoline (intermediate 1) synthesis: as embodiment six (4) synthesis step and processing condition
(5) synthesis of the chloro-4-of 5-(4-(4-methyl-benzyl) piperazine-1-base) quinazoline: as embodiment six (4) synthesis step and processing condition, difference is to add (0.60mmol) to methyl benzyl chlorine, obtain yellow solid, productive rate 79.4%.
Example 11, the chloro-4-of compound 5-(4-(2-methyl-benzyl) piperazine-1-base) quinazoline
(compound number is iI 16 ) synthesis
(1) 5-chloro-quinazoline-4 (3H)the preparation of-one: as embodiment six (1) synthesis step and processing condition
The synthesis of (2) 4,5-dichloroquinazolines: as embodiment six (2) synthesis step and processing condition
(3) synthesis of 4-(N-Boc piperazine)-5-chloro-quinazoline: as embodiment six (3) synthesis step and processing condition
(4) 4-piperazine-5-chloro-quinazoline (intermediate 1) synthesis: as embodiment six (4) synthesis step and processing condition
(5) synthesis of the chloro-4-of 5-(4-(2-methyl-benzyl) piperazine-1-base) quinazoline: as embodiment six (4) synthesis step and processing condition, difference is to add (0.60mmol) adjacent methyl benzyl chlorine, obtain yellow oil, productive rate 61.9%.
Example 12, the chloro-4-of compound 5-(4-(3-methyl-benzyl) piperazine-1-base) quinazoline
(compound number is iI 17 ) synthesis
(1) 5-chloro-quinazoline-4 (3H)the preparation of-one: as embodiment six (1) synthesis step and processing condition
The synthesis of (2) 4,5-dichloroquinazolines: as embodiment six (2) synthesis step and processing condition
(3) synthesis of 4-(N-Boc piperazine)-5-chloro-quinazoline: as embodiment six (3) synthesis step and processing condition
(4) 4-piperazine-5-chloro-quinazoline (intermediate 1) synthesis: as embodiment six (4) synthesis step and processing condition
(5) synthesis of the chloro-4-of 5-(4-(3-methyl-benzyl) piperazine-1-base) quinazoline: as embodiment six (4) synthesis step and processing condition, difference is to add (0.60mmol) adjacent methyl benzyl chlorine, obtain yellow oil, productive rate 60.4%.
Synthesis 4-[4-(substituted benzyl) piperazine]-5-chloro-quinazoline ( iI) spectral data of compounds is as follows:
the chloro-4-of 5-(4-benzyl diethylenediamine-1-base) quinazoline (II 1 )
Ayellowsolid,yield78.7%,m.p.87~90℃; 1HNMR(500MHz,CDCl 3):δ2.58(t,4H,H-3,5ofpiperazine),3.60(t,4H,H-2,6ofpiperazine),3.54(s,2H,CH 2-Ar),7.26~7.33(m,5H,H-2,3,4,5,6ofAr-H),7.43(d,1H,H-6ofquinazoline, J=7.5Hz),7.57(t,1H,H-7ofquinazoline, J=8.1Hz),7.75(d,1H,H-8ofquinazoline J=8.8Hz),8.59(s,1H,H-2ofquinazoline). 13CNMR(125MHz,CDCl 3):δ50.4(2C),52.92(2C),63.1,114.1,126.9,127.3,127.8,128.4(2C),129.3(2C),129.9,131.9,137.9,153.0,154.2,162.6.m/z(M+H) +339.3.
the chloro-4-of 5-(4-(2,4-dichloro benzyl) piperazine-1-base) quinazoline (II 2 )
Ayellowsolid,yield67.8%,m.p.163~166℃; 1HNMR(500MHz,CDCl 3):δ2.64(t,4H,H-3,5ofpiperazine),3.69(t,4H,H-2,6ofpiperazine),3.61(s,2H,CH 2-Ar),7.23(d-d,1H,H-6ofAr-H),7.38(d,1H,H-5ofAr-H, J=1.8Hz),7.43~7.46(m,2H,H-3ofAr-HandH-6ofquinazoline),7.59(t,1H,H-7ofquinazoline, J=7.5Hz),7.76(d,1H,H-8ofquinazoline J=8.6Hz),8.60(s,1H,H-2ofquinazoline). 13CNMR(125MHz,CDCl 3):δ50.4(2C),52.8(2C),58.7,114.0,127.0,127.1,127.9,129.4,129.9,131.6,132.0,133.2,134.3,135.0,153.0,154.2,162.7.m/z(M+H) +407.2.
the chloro-4-of 5-(4-(2-cyanobenzyls) piperazine-1-base) quinazoline (II 3 )
Ayellowsolid,yield77.9%,m.p.130~136℃; 1HNMR(500MHz,CDCl 3):δ2.65(t,4H,H-3,5ofpiperazine),3.70(t,4H,H-2,6ofpiperazine),3.74(s,2H,CH 2-Ar),7.38(m,1H,H-4ofAr-H),7.45(d,1H,H-6ofAr-H, J=7.5Hz),7.56~7.60(m,3H,H-3,5ofAr-HandH-7ofquinazoline),7.67(d,1H,H-6ofquinazoline, J=8.0Hz),7.76(d,1H,H-8ofquinazoline J=8.0Hz),8.59(s,1H,H-2ofquinazoline). 13CNMR(125MHz,CDCl 3):δ50.3(2C),52.7(2C),60.5,113.2,114.1,117.8,126.9,127.9,127.9,129.9,130.1,132.0,132.7,133.2,142.1,152.9,154.1,162.6.m/z(M+H) +364.3.
the chloro-4-of 5-(4-(4-nitrobenzyl) piperazine-1-base) quinazoline (II 4 )
Ayellowsolid,yield78.7%,m.p.152~154℃; 1HNMR(500MHz,CDCl 3):δ2.60(t,4H,H-3,5ofpiperazine),3.71(t,4H,H-2,6ofpiperazine),3.64(s,2H,CH 2-Ar),7.46(d,1H,H-6ofquinazoline, J=8.2Hz),7.54(d,2H,H-2,6ofAr-H, J=6.9Hz),7.59(t,1H,H-7ofquinazoline, J=7.5Hz),7.77(d,1H,H-8ofquinazoline J=8.6Hz),8.20(d,2H,H-3,5ofAr-H, J=6.3Hz),8.60(s,1H,H-2ofquinazoline). 13CNMR(125MHz,CDCl 3):δ50.3(2C),52.9(2C),62.1,114.2,123.7(2C),127.0,128.0,129.6(2C),129.8,132.1,145.9,147.3,152.9,154.1,162.7.m/z(M+H) +384.3.
the chloro-4-of 5-(4-(4-chlorobenzyl) piperazine-1-base) quinazoline (II 5 )
Ayellowoilmatter,yield75.0%; 1HNMR(500MHz,CDCl 3):δ2.56(t,4H,H-3,5ofpiperazine),3.67(t,4H,H-2,6ofpiperazine),3.50(s,2H,CH 2-Ar),7.27~7.33(m,4H,H-2,3,5,6ofAr-H),7.44(d,1H,H-6ofquinazoline, J=7.4Hz),7.58(t,1H,H-7ofquinazoline, J=7.4Hz),7.75(d,1H,H-8ofquinazoline J=8.6Hz),8.59(s,1H,H-2ofquinazoline). 13CNMR(125MHz,CDCl 3):δ50.4(2C),52.8(2C),62.3,114.2,126.9,127.9,128.6(2C),129.9,130.5(2C),132.0,133.0,136.5,153.0,154.2,163.0.m/z(M+H) +373.3.
the chloro-4-of 5-(4-(3-chlorobenzyl) piperazine-1-base) quinazoline (II 6 )
Ayellowoilmatter,yield73.6%; 1HNMR(500MHz,CDCl 3):δ2.57(t,4H,H-3,5ofpiperazine),3.69(t,4H,H-2,6ofpiperazine),3.51(s,2H,CH 2-Ar),7.21~7.25(m,3H,H-4,5,6ofAr-H),7.36(s,1H,H-2ofAr-H),7.44(d,1H,H-6ofquinazoline, J=8.0Hz),7.58(t,1H,H-7ofquinazoline, J=8.6Hz),7.76(d,1H,H-8ofquinazoline J=8.1Hz),8.59(s,1H,H-2ofquinazoline). 13CNMR(125MHz,CDCl 3):δ50.4(2C),52.9(2C),62.4,113.8,126.9,127.2,127.5,127.9,129.1,129.7,129.9,132.0,134.3,140.1,153.0,154.1,162.6.m/z(M+H) +373.3.
the chloro-4-of 5-(4-(4-luorobenzyl) piperazine-1-base) quinazoline (II 7 )
Ayellowsolid,yield78.7%,m.p.73~75℃; 1HNMR(500MHz,CDCl 3):δ2.65(t,4H,H-3,5ofpiperazine),3.76(t,4H,H-2,6ofpiperazine),3.60(s,2H,CH 2-Ar),7.03(t,2H,H-3,5ofAr-H, J=8.6Hz),7.36(t,1H,H-2ofAr-H, J=6.3Hz),7.46(d,1H,H-6ofquinazoline, J=7.5Hz),7.60(t,1H,H-7ofquinazoline, J=7.5Hz),7.77(d,1H,H-8ofquinazoline J=8.6Hz),8.59(s,1H,H-2ofquinazoline). 13CNMR(125MHz,CDCl 3):δ49.9(2C),52.5(2C),61.9,114.0,115.3,115.5,126.9,128.1(2C),129.8,131.0,131.1,132.2,152.8,153.9,161.3,162.5.m/z(M+H) +357.3.
the chloro-4-of 5-(4-(2-chlorobenzyl) piperazine-1-base) quinazoline (II 8 )
Ayellowoilmatter,yield74.6%; 1HNMR(500MHz,CDCl 3):δ2.66(t,4H,H-3,5ofpiperazine),3.70(t,4H,H-2,6ofpiperazine),3.53(s,2H,CH 2-Ar),7.19~7.25(m,2H,H-4,6ofAr-H),7.36(d,1H,H-5ofAr-H, J=7.4Hz),7.44(d,1H,H-3ofAr-H, J=7.5Hz),7.48(d,1H,H-6ofquinazoline, J=8.0Hz),7.58(t,1H,H-7ofquinazoline, J=8.6Hz),7.76(d,1H,H-8ofquinazoline J=8.6Hz),8.59(s,1H,H-2ofquinazoline). 13CNMR(125MHz,CDCl 3):δ50.4(2C),52.9(2C),59.3114.1,126.7,126.9,127.9,128.4,129.6,129.9,130.8,132.00,134.5,135.6,153.0,154.3,162.6.m/z(M+H) +373.3.
the chloro-4-of 5-(4-(4-trifluoro-methoxybenzyl) piperazine-1-base) quinazoline (II 9 )
Ayellowsolid,yield51.7%,m.p.89~91℃; 1HNMR(500MHz,CDCl 3):δ2.58(t,4H,H-3,5ofpiperazine),3.68(t,4H,H-2,6ofpiperazine),3.66(s,2H,CH 2-Ar),7.17(d,2H,H-3,5ofAr-H, J=8.0Hz),7.36(d,2H,H-2,6ofAr-H, J=8.6Hz),7.44(d-d,1H,H-6ofquinazoline, J=7.5Hz),7.59(t,1H,H-7ofquinazoline, J=7.4Hz),7.76(d-d,1H,H-8ofquinazoline J=8.6Hz),8.59(s,1H,H-2ofquinazoline). 13CNMR(125MHz,CDCl 3):δ50.5(2C),52.9(2C),62.2,114.2,120.9(2C),127.0,127.9,129.9,130.4(2C),132.0,136.8,148.5,152.1,153.0,154.2,162.7.m/z(M+H) +423.2.
the chloro-4-of 5-(4-(4-methoxy-benzyl) piperazine-1-base) quinazoline (II 10 )
Ayellowoilmatter,yield81.3%; 1HNMR(500MHz,CDCl 3):δ2.34(s,3H,OCH 3-Ar),2.57(t,4H,H-3,5ofpiperazine),3.67(t,4H,H-2,6ofpiperazine),3.50(s,2H,CH 2-Ar),7.13(d,2H,H-3,5ofAr-H, J=7.4Hz),7.21(d,2H,H-2,6ofAr-H, J=5.8Hz),7.43(d,1H,H-6ofquinazoline, J=6.3Hz),7.58(t,1H,H-7ofquinazoline, J=5.2Hz),7.74(d,1H,H-8ofquinazoline J=8.6Hz),8.57(s,1H,H-2ofquinazoline). 13CNMR(125MHz,CDCl 3):δ50.4(2C),52.9(2C),53.5,62.81,114.1,126.9,127.8,129.1(2C),129.3(2C),129.9,131.9,134.7,136.9,153.0,154.2,162.6.m/z(M+H) +369.3.
the chloro-4-of 5-(4-(4-methyl-benzyl) piperazine-1-base) quinazoline (II 11 )
Ayellowsolid,yield79.4%,m.p.89~91℃; 1HNMR(500MHz,CDCl 3):δ2.34(s,3H,CH 3-Ar),2.57(t,4H,H-3,5ofpiperazine),3.69(t,4H,H-2,6ofpiperazine),3.50(s,2H,CH 2-Ar),7.13(d,2H,H-3,5ofAr-H, J=8.0Hz),7.21(d,2H,H-2,6ofAr-H, J=8.0Hz),7.43(d,1H,H-6ofquinazoline, J=7.6Hz),7.57(t,1H,H-7ofquinazoline, J=8.1Hz),7.75(d,1H,H-8ofquinazoline J=7.5Hz),8.58(s,1H,H-2ofquinazoline). 13CNMR(125MHz,CDCl 3):δ21.1,50.3(2C),52.8(2C),62.7,114.0,126.8,127.7,129.0(2C),129.1(2C),129.8,131.9,134.6,136.9,152.9,154.1,162.5.m/z(M+H) +353.3.
the chloro-4-of 5-(4-(2-luorobenzyl) piperazine-1-base) quinazoline (II 12 )
Amilkysolid,yield68.5%,m.p.86~89℃; 1HNMR(500MHz,CDCl 3):δ2.62(t,4H,H-3,5ofpiperazine),3.68(t,4H,H-2,6ofpiperazine),3.62(s,2H,CH 2-Ar),7.03(t,1H,H-3ofAr-H, J=9.2Hz),7.12(t,1H,H-5ofAr-H, J=7.4Hz),7.25(t,1H,H-2ofAr-H, J=7.5Hz),7.38(t,1H,H-6ofAr-H, J=7.5Hz),7.43(d,1H,H-6ofquinazoline, J=7.4Hz),7.57(t,1H,H-7ofquinazoline, J=8.6Hz),7.74(d,1H,H-8ofquinazoline J=8.5Hz),8.58(s,1H,H-2ofquinazoline). 13CNMR(125MHz,CDCl 3):δ50.3(2C),52.7(2C),55.3,115.3,115.5,124.0,126.9,127.8,129.0,129.1,129.9,131.6,131.9,153.0,154.2,160.6,162.6.m/z(M+H) +357.3.
the chloro-4-of 5-(4-(3-luorobenzyl) piperazine-1-base) quinazoline (II 13 )
Ayellowoilmatter,yield64.8%; 1HNMR(500MHz,CDCl 3):δ2.58(t,4H,H-3,5ofpiperazine),3.69(t,4H,H-2,6ofpiperazine),3.53(s,2H,CH 2-Ar),6.95(t,1H,H-2ofAr-H, J=8.0Hz),7.09(d,2H,H-4,6ofAr-H, J=6.9Hz),7.28(t,1H,H-5ofAr-H, J=7.5Hz),7.44(d,1H,H-6ofquinazoline, J=6.9Hz),7.59(t,1H,H-7ofquinazoline, J=7.5Hz),7.76(d,1H,H-8ofquinazoline J=8.6Hz),8.58(s,1H,H-2ofquinazoline). 13CNMR(125MHz,CDCl 3):δ50.4(2C),52.8(2C),62.4,114.1,114.3,115.9,124.6,126.9,127.9,129.8,129.9,132.0,140.6,153.0,154.2,162.6,164.1.m/z(M+H) +357.3.
the chloro-4-of 5-(4-(4-trifluoromethyl benzyl) piperazine-1-base) quinazoline (II 14 )
Ayellowsolid,yield71.2%,m.p.112~115℃; 1HNMR(500MHz,CDCl 3):δ2.59(t,4H,H-3,5ofpiperazine),3.69(t,4H,H-2,6ofpiperazine),3.59(s,2H,CH 2-Ar),7.44~7.48(m,3H,H-2,6ofAr-HandH-6ofquinazoline),7.58~7.60(m,3H,H-3,5ofAr-HandH-7ofquinazoline),7.77(d,1H,H-8ofquinazoline J=8.6Hz),8.60(s,1H,H-2ofquinazoline). 13CNMR(125MHz,CDCl 3):δ50.4(2C),52.9(2C),62.5,114.3,123.2,125.4(2C),127.0,127.9,129.3(2C),129.9,132.0(2C),142.2,153.0,154.2,162.7.m/z(M+H) +407.2.
the chloro-4-of 5-(4-(3-methoxy-benzyl) piperazine-1-base) quinazoline (II 15 )
Ayellowsolid,yield71.9%m,m.p.88~91℃; 1HNMR(500MHz,CDCl 3):δ3.81(s,3H,OCH 3-Ar ),2.58(t,4H,H-3,5ofpiperazine),3.69(t,4H,H-2,6ofpiperazine),3.52(s,2H,CH 2-Ar),6.81(d,1H,H-6ofAr-H, J=8.1Hz),6.92(t,2H,H-2,4ofAr-H, J=6.9Hz),7.24(t,1H,H-5ofAr-H, J=8.0Hz),7.43(d,1H,H-6ofquinazoline, J=7.5Hz),7.58(t,1H,H-7ofquinazoline, J=7.5Hz),7.75(d,1H,H-8ofquinazoline J=8.1Hz),8.59(s,1H,H-2ofquinazoline). 13CNMR(125MHz,CDCl 3):δ50.4(2C),52.9(2C),55.3,62.9,112.7,114.1,114.6,121.5,126.9,127.8,129.4,129.9,131.9,139.6,153.0,154.3,159.8,162.6.m/z(M+H) +369.3.
the chloro-4-of 5-(4-(2-methyl-benzyl) piperazine-1-base) quinazoline (II 16 )
Ayellowoilmatter,yield61.9%; 1HNMR(500MHz,CDCl 3):δ2.38(s,3H,CH 3-Ar),2.57(t,4H,H-3,5ofpiperazine),3.67(t,4H,H-2,6ofpiperazine),3.52(s,2H,CH 2-Ar),7.15(m,3H,H-3,4,5ofAr-H,),7.25(d,1H,H-6ofAr-H, J=6.3Hz),7.43(d,1H,H-6ofquinazoline, J=7.5Hz),7.57(t,1H,H-7ofquinazoline, J=7.5Hz),7.75(d,1H,H-8ofquinazoline J=8.0Hz),8.59(s,1H,H-2ofquinazoline). 13CNMR(125MHz,CDCl 3):δ19.3,50.5(2C),52.9(2C),60.9,114.1,125.6,126.9,127.3,127.8,129.9,130.0,130.4,131.9,136.0,137.7,153.0,154.2,162.6.m/z(M+H) +353.3.
the chloro-4-of 5-(4-(3-methyl-benzyl) piperazine-1-base) quinazoline (II 17 )
Ayellowoilmatter,yield60.4%; 1HNMR(500MHz,CDCl 3):δ2.34(s,3H,OCH 3-Ar),2.56(t,4H,H-3,5ofpiperazine),3.68(t,4H,H-2,6ofpiperazine),3.48(s,2H,CH 2-Ar),7.06(d,1H,H-2ofAr-H, J=7.5Hz),7.12(t,2H,H-4,6ofAr-H, J=9.7Hz),7.20(t,1H,H-5ofAr-H, J=7.5Hz),7.41(d,1H,H-6ofquinazoline, J=7.5Hz),7.55(t,1H,H-7ofquinazoline, J=8.0Hz),7.74(d,1H,H-8ofquinazoline J=8.6Hz),8.58(s,1H,H-2ofquinazoline). 13CNMR(125MHz,CDCl 3):δ21.5,50.4(2C),52.9(2C),63.1,114.1,114.1,126.3,126.9,127.8,128.1,129.9,130.0,131.9,137.7,138.0,153.0,154.2,162.6.m/z(M+H) +353.3.
Embodiment 13, compound are to the bacteriostatic activity testing method of three kind of plant plant epiphytes
Adopt isolated growth rate method test compounds to the inhibit activities of plant pathogenic fungi, subjects be fusarium graminearum ( gibberellazeae), capsicum wilt bacterium ( fusariumoxysporum), Valsa mali ( cytosporamandshurica).Main employing potato grape nutrient agar (PDA) substratum, measuring 90mL substratum respectively, to be divided in sterilizing in 200mL triangular flask for subsequent use.The preparation of pastille substratum is all aseptically carried out, and often kind of drug concentration is set to 50 μg/mL.Take various medicament respectively in 10mL volumetric flask, the aqua sterilisa added containing 0.1% is mixed with certain density medicament, add in 90mLPDA substratum (40 ~ 50 DEG C), fully shake up, be poured in the culture dish after the sterilizing of diameter 9cm, if three times are repeated, to add the solvent of equivalent for blank.During primary dcreening operation, with fusarium graminearum, capsicum wilt bacterium, Valsa mali for screening object, with punch tool (internal diameter 4mm), some bacterium cakes are made in normal for growth bacterium colony punching for subsequent use, with inoculating needle bacterium cake moved and receive dull and stereotyped central authorities, every ware connects a bacterium cake, be placed in 27 DEG C of saturated humidity constant incubators to cultivate, when contrast is covered with, measure colony diameter.Each bacterium colony measures 2 times by right-angled intersection method, represents bacterium colony size with its mean number, and the calculation formula of bacteriostasis rate is as follows:
I(%)=(C-T)/(C-0.4)×100
Wherein I is inhibiting rate, and C is blank diameter (cm), T is process diameter (cm).
Same method be also applicable to compound to capsicum wilt bacterium ( fusariumoxysporum), Valsa mali ( cytosporamandshurica) inhibit activities test.
Embodiment 14, compound are to the bacteriostatic activity testing method of two kind of plant bacteriums
Adopt nephelometry test compounds to the inhibit activities of planting disease bacterium, subjects be (tobacco ralstonia solanacearum ( ralstoniasolanacearum) and rice leaf spot bacteria ( xanthomonasOryzae)).
(1) testing method of tobacco bacterial wilt: the concentration of tested compound is respectively 100 and 200 μg/mL, DMSO dissolve in the medium as blank, and Thiodiazole-copper compares medicament, carries out streak culture by former for tobacco bacterial wilt bacterium on NA solid medium, is placed in 30 DEG C of constant incubators and cultivates, until grow single bacterium colony.Choosing central authorities' pink, the more single bacterium colony of white edge with connecing collarium, being put in NB liquid nutrient medium, 30 DEG C, shaking culture is for subsequent use to logarithmic phase in 180rpm constant-temperature table.It is 100,200 that medicament (compound and contrast medicament) is configured to concentration μthe toxic NB liquid nutrient medium 5mL of g/mL joins in test tube, adds 40 μl contains in the NB liquid nutrient medium of the former bacterium of tobacco bacterial wilt, at 30 DEG C, shaking culture 48h in 180rpm constant-temperature table, the bacterium liquid of each concentration is measured OD on spectrophotometer 595value, and the toxic aseptic NB liquid nutrient medium OD measuring corresponding concentration in addition 595value.
Correction OD value=containing bacterium culture medium OD value-aseptic culture medium OD value
Inhibiting rate %=[(the rear control medium bacterium liquid OD value of correction-correct toxic substratum OD value)/correct rear control medium bacterium liquid OD value] × 100
(2) testing method of bacterial blight of rice: the concentration of tested compound is respectively 100 and 200 μg/mL, DMSO dissolve in the medium as blank, and bismerthiazol compares medicament, carries out streak culture by former for bacterial blight of rice bacterium on M210 solid medium, is placed in 30 DEG C of constant incubators and cultivates, until grow single bacterium colony.Choosing the yellow single bacterium colony of central authorities with connecing collarium, being put in M210 liquid nutrient medium, 30 DEG C, shaking culture is for subsequent use to logarithmic phase in 180rpm constant-temperature table.It is 100,200 that medicament (compound and contrast medicament) is configured to concentration μthe toxic M210 liquid nutrient medium 5mL of g/mL joins in test tube, adds 40 μl contains in the M210 liquid nutrient medium of the former bacterium of bacterial blight of rice, at 30 DEG C, shaking culture 36h in 180rpm constant-temperature table, the bacterium liquid of each concentration is measured OD on spectrophotometer 595value, and the toxic aseptic M210 liquid nutrient medium OD measuring corresponding concentration in addition 595value.
Correction OD value=containing bacterium culture medium OD value-aseptic culture medium OD value
Inhibiting rate %=[(the rear control medium bacterium liquid OD value of correction-correct toxic substratum OD value)/correct rear control medium bacterium liquid OD value] × 100
EC 50(medianeffectiveconcentration) be evaluate phytopathogen to the important indicator of compound responsive, when being also to target compound study on mechanism simultaneously, the important parameter that compound concentration is arranged.In concentration gradient experiment, adopt doubling dilution setting concentration, finally by the relative inhibition probability value of medicament to phytopathogen, drug concentration is converted into logarithmic value, obtains virulence curve, calculate EC by the regression analysis of SPSS software 50.
From table 3, table 4can find out, be 50 in concentration μcompound during g/mL i 2 , i 4 , i 5 , i 8 have certain inhibit activities to fusarium graminearum, capsicum wilt bacterium, Valsa mali, inhibiting rate all more than 50%, especially i 2 be 73.2% to the inhibiting rate of fusarium graminearum, i 5 be 75.1% to the inhibiting rate of capsicum wilt bacterium.Compound iI 5 also have certain inhibit activities to capsicum wilt bacterium, inhibiting rate is 56.2%.
Note: it is negative value that "-" representative detects its inhibiting rate, "/" representative detects.
From table 5find out i 2 , i 4 , i 8 better to the inhibit activities of rice leaf spot bacteria, 100 μunder g/mL concentration, (bismerthiazol is 100 more than 63.0% for preventive effect μduring g/mL concentration, preventive effect is 30.9%); And i 2 certain inhibit activities is had, 200 to tobacco ralstonia solanacearum μunder g/mL concentration, preventive effect is that 68.9%(thiophene bacterium ketone is 200 μduring g/mL concentration, preventive effect is 100%).From table 6can find out, first, iI 1 , iI 7 , iI 10 , iI 11 better to the inhibit activities of rice leaf spot bacteria, 100 μunder g/mL concentration, (bismerthiazol is 100 more than 90.0% for preventive effect μduring g/mL concentration, preventive effect is 30.9%).Secondly iI 16 , iI 17 have certain inhibit activities to rice leaf spot bacteria, inhibiting rate is respectively 64.0%, and 71.4%.
table 7 part 4-[4-(substituted benzyl) piperazine]-5-chloro-quinazoline (II) is to the medium effective concentration of rice leaf spot bacteria
Compound EC 50( μG/mL) value
II 1 51.7±2.7
II 7 39.8±3.2
II 10 42.4±5.7
II 11 29.3±3.0
II 17 43.0±5.1
From table 7can find out, test 5 target compounds iIto the half-inhibition concentration of rice leaf spot bacteria, result shows, compound iI 1 , iI 7 , iI 10 , iI 11 , iI 17 to the EC of rice leaf spot bacteria 50value is respectively 51.7 ± 2.7 μg/mL, 39.8 ± 3.2 μg/mL, 42.4 ± 5.7 μg/mL, 29.3 ± 3.0 μg/mL, 43.0 ± 5.1 μg/mL.Compound iI 1 , iI 7 , iI 10 , iI 11 , iI 17 eC 50be worth far above contrast medicament bismerthiazol (EC 50value is 217.3 ± 3.6 μg/mL), these five target compounds all have further researching value, especially target compound iI 11 .
The embodiment of the present invention is aided with explanation technical scheme of the present invention, but the content of embodiment is not limited thereto.
Effect of the present invention is that synthetic route is simple, productive rate is high, obtains low toxicity, novel, efficient anti-plant pathogen medicine and medicament.

Claims (3)

1. a 4- n-replacing-5-chloro-quinazoline compounds, particular compound is as follows:
Compound i 2 :
5-is chloro- n-(3-fluorobenzene ethyl)-4-amido quinazoline
Compound i 4 :
5-is chloro- n-(2-fluorobenzene ethyl)-4-amido quinazoline
Compound i 5 :
( s)-5-is chloro- n-(1-hexamethylene ethyl)-4-amido quinazoline
Compound i 8 :
( s)-5-is chloro- n-(1-(4-fluorophenyl) ethyl)-4-amido quinazoline
Compound iI 1 :
4-(4-benzyl diethylenediamine-1-base)-5-chloro-quinazoline
Compound iI 7 :
The chloro-4-of 5-(4-(4-luorobenzyl) piperazine-1-base) quinazoline
Compound iI 10 :
The chloro-4-of 5-(4-(4-methoxy-benzyl) piperazine-1-base) quinazoline
Compound iI 11 :
The chloro-4-of 5-(4-(4-methyl-benzyl) piperazine-1-base) quinazoline
Compound iI 17 :
The chloro-4-of 5-(4-(3-methyl-benzyl) piperazine-1-base) quinazoline
Each structural formula of compound is as follows:
I 2 I 8 I 4 I 5
II 1 II 10 II 7 II 11 II 17
。
2. a kind of 4-according to claim 1 nthe application of-replacement-5-chloro-quinazoline compounds, is characterized in that the medicine for the preparation of anti-fusarium graminearum, capsicum wilt bacterium, Valsa mali, rice leaf spot bacteria, tobacco ralstonia solanacearum and medicament.
3. a kind of 4-according to claim 2 nthe application of-replacement-5-chloro-quinazoline compounds, is characterized in that i 2 , i 4 , i 5 preparation anti-fusarium graminearum, capsicum wilt bacterium, Valsa mali and iI 1 , iI 7 , iI 10 , iI 11 preparing rice leaf spot bacteria, the medicine of tobacco ralstonia solanacearum and medicament.
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