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

Abstract

The present invention discloses a preparation method and biological activity of a compound-4-<i>N</i>-substituted-5-chloroquinazoline compound with anti-plant pathogen effect, which is obtained by the following general formula (<b>I </b>) Compounds represented by (<b>II</b>) and methods for their preparation. The present invention introduces the use of 2-amino-6-chlorobenzoic acid, formamide, phosphorus oxychloride, concentrated hydrochloric acid, <i>N</i>-Boc piperazine, substituted benzyl chloride or benzyl bromide as raw materials to hydrogenate Using sodium, triethylamine and potassium carbonate as catalysts, 4-<i>N</i>-substituted-5-chloroquinazoline derivatives were synthesized in three or five steps. Compounds of the invention <b>I ₂ </b><b>, </b><b>I ₄ </b><b>, </b><b>I ₈ </b><b>, </b><b>II ₅ </b> has a better inhibitory effect on plant fungi, while <b>II ₁ </b><b>, </b><b>II ₇ </b><b>,</b><b>II ₁₀ </b><b>, </b><b>II ₁₁ </b><b>, </b><b>II ₁₆ </b ><b>, </b><b>II ₁₇ </b> showed high antibacterial activity against plant bacteria.

Description

A kind of 4-N-substituted-5-chloroquinazoline compound and its preparation method and application

technical field

The invention relates to the technical fields of organic synthesis and pesticides, in particular to a preparation method and application of 4- N -substituted-5-chloroquinazoline compounds.

Background technique

In the development of pesticides in recent years, quinazoline (ketone) compounds have attracted much attention because of their broad-spectrum biological activities and variable structure types. Many compounds containing quinoline ring structures have shown wide application and development prospects. Such as bactericidal, insecticidal, antiviral, anti-inflammatory, anti-tumor, anti-hypertensive, anti-tuberculosis, anti-malarial, etc., some quinazoline compounds have been successfully developed into commercialized drugs, such as the fungicide fluoroquinazole, The mite agent fenazaquin and the anticancer drug Iressa, etc. For a long time, people have done a lot of research on the control of plant pathogenic fungus diseases, mainly including agricultural measures, biological control and chemical control. Agricultural measures include strengthening quarantine, strict treatment of diseased rice straw, and strengthening fertilizer and water management. The quarantine system is strictly implemented to prevent diseases from spreading to disease-free areas. In the epidemic area, disease-free farms should be established to control the development of the disease. Biological control is mainly to breed disease-resistant varieties, which have certain regional characteristics and can be selected according to local conditions. Agents for the prevention and treatment of plant bacterial diseases include organic phosphorus, organic nitrogen, heterocyclic compounds such as phenylamides and thiazoles, and antibiotics, but so far, there is no chemical pesticide on the market that can completely and effectively control the occurrence of plant bacterial diseases. Therefore, Therefore, the synthesis of new low-toxic anti-plant pathogenic bacteria agents has become a key problem that needs to be solved urgently.

1. Quinazolinone compounds with resistance to plant pathogens

In 2004, Ryu et al. (Ryu, CK; Shim, JY; Yi, YJ; Chae, MJ; Han, JY; Jung, OJSynthesis and antifungal activity of 5,8 quinazolinedionederivativesmodi- fiedatpositions6and7 [J]. Phenotype compounds and their antibacterial activity, the results show that: the compound is effective against Candida albicans ( C.albicans), Candida tropicalis (C.tropicalis) , Candida krusei (C.krusei) , Aspergillus niger (A.niger) The MIC values were 6.3, 3.2, 3.2, and 0.8 μg/mL, respectively, which were also better than or equivalent to the contrast drug ketoconazole (MIC) values (6.3, 6.3, 12.5, 12.5 μg/mL, respectively).

2006 Ouyang et al. (Ouyang, GP; Zhang, PQ; Xu, GF; Song, BA; Yang, S.; Jin, LH; Xue, W.; Hu, DY; Lu, P.; Chen, Z. Synthesis and antifungal bioactivities of 3- Alkylquinazolin-4-onederivatives[J]. molecules , 2006 ,11,383-392.) synthesized new quinazoline compounds. The results of biological activity tests showed that the compounds had inhibitory rates of 47.2%, 50.3%, and 40.9% to the three pathogens of Gibberellazeae , Fusarium oxysporum, and valsamali at a concentration of 50 μg/mL, respectively. %, close to the inhibition rate of the control drug hymexazol.

In 2008, Gao Xingwen et al. (Xing Xingwen, Cai Xuejian, Yan Kai, Gao Lili, Wang Heying, Chen Zhuo, Song Baoan. Synthesis and anti-tobacco mosaic virus activity of 4-(3 H )-quinazolinone Schiff base[ J].Organic Chemistry , 2008 , 28, 1785-1791.) reported 4-(3 H )-quinazolinone Schiff base compounds, using the growth rate method to test the antibacterial activity, at 50 μ g/mL drug At the lower concentration, the inhibitory rate of this kind of target compound to wheat gibberella, capsicum wilt and apple rot was all below 16%. In addition, at the concentration of 500 μ g/mL, some compounds showed higher activity against tobacco mosaic virus.

In 2013 Wang Xiang et al. (Wang, X.; Li, P.; Li, Z.L.; Yin, J.; He, M.; Xue, W.; Chen, Z.W.; Song, B.A. Synthesis and Bioactivity Evaluation of NovelAryliminesContaininga3-Aminoethyl-2-[( p-trifluoromethoxy)anilino]

-4(3H)-quina-zolinoneMoiety[J].JournalofAgriculturalandFoodChemistry,2013,61,9575-9582.) synthesized a series of novel quinazolinone compounds, which are effective against tobacco bacterial wilt and rice bacterial wilt have good inhibitory activity. When the concentration was 50 μ g/mL, the inhibition rates against Xanthomonas oryzae were 20.09, 20.83, 21.33, and 20.23, respectively.

2. Quinazoline compounds with resistance to plant pathogens

In 1994, Coghlan et al. (Coghlan, JM; Dreikorn, AB; Jourdan, PG; Suhr, RG Quinoline Derivatives [P]. US5296484 , ( 1994 ).) synthesized 4-amino-substituted novel quinazoline compounds, in 100 μ g At /mL concentration, the control rate of these compounds on wheat powdery mildew, rice blast, tomato late blight, grape downy mildew, and wheat leaf rust can reach 90%-100%, and they have good antibacterial effects.

In 1994, Barry et al. (Barry, A.; Trilobi, D.; Robert, G. Pyridylethoxy-pyridylEthylamino, and Pyridylpropyl-Derivatives of Quinoline and Quinazolineas Insecticides and Fungicides [P]. WO9404527 , ( 1994 ).) synthesized 4- N, O -substituted novel quinazolines Amines, quinazoline ether compounds, at a concentration of 100 μ g/mL, the control rate of these compounds to powdery mildew of wheat, rice blast, tomato late blight, grape downy mildew, wheat leaf rust reaches 90%-100%, It has good antibacterial activity.

In 2004 Liu Gang et al. (Liu Gang, Song Baoan, Sang Weijun, Yang Song, Jin Linhong, Ding Xiong. Synthesis and biological activity of N -substituted aromatic ring-4-aminoquinazoline compounds[J] .Organic Chemistry , 2004 , 23,1296-1300.) With PD153035 as the lead compound, a new N -substituted aromatic ring-4-amino novel quinazoline compound was designed and synthesized. When the concentration of the drug was 500 μ g/mL, the compound was The corrected inhibition rate of spore germination can reach 56.07%.

In 2008, Liu Gang et al. (Liu Gang, Liu Chunping, Ji Chunnuan, Sun Lin, Wen Quanwu. Synthesis and antibacterial activity of 4-sulfide quinazoline compounds [J]. Organic Chemistry , 2008 , 28,525.) passed 4-chloroquine Azolines and mercapto compounds reacted in acetone/potassium carbonate system to synthesize 7 novel 4-thioether-based quinazolines, and their antibacterial activity was determined by the growth rate method; wherein, 4-(allyl Sulfuryl)quinazoline inhibited 69.5%, 71.9% and 70.8% of wheat head blight, capsicum wilt and apple rot at a concentration of 50 μ g/mL, and the EC ₅₀ (inhibition medium concentration) was 25.88, respectively. , 17.08 and 28.77 μ g/mL.

In 2008, Ma Yao et al. (Ma Yao, Liu Fang, Yan Kai, Song Baoan, Yang Song, Hu Deyu, Jin Linhong, Xue Wei. Synthesis and antibacterial activity of 6-bromo-4-hydrocarbylthioquinazoline compounds[ J].Organic Chemistry , 2008 ,28,1268-1272.) Synthesized a new type of quinazoline sulfide compound, when the concentration was 50 μ g/mL, it inhibited wheat scab, capsicum wilt and apple rot The rates were 63.8%, 51.9%, and 55.1%, which were comparable to the inhibitory activity of the control drug hymexazol.

In 2011, Liu Fang et al. (Liu, F.; Huang, YJ Antifungal bioactivity of 6-bromo-4-Ethoxyethylthioquinazoline [J]. Pesticide Biochemistry and Physiology, 2011 , 101, 248-255.) tested the biological activity of quinazoline compounds, and the test results showed that the The compound has good inhibitory activity against plant fungi, and its EC ₅₀ is in the range of 17.47-70.79 μ g/mL. Taking Fusarium rubella as the experimental object, the mechanism of one of the target compounds was studied, and the results showed that the reducing sugar in mycelia decreased, and the content of chitosan, soluble protein, pyruvate, and chitinase activity also decreased.

In 2013, Liu Junhu et al. (Liu Junhu, Liu Yong, Jian Junyou, Bao Xiaoping. Synthesis and antibacterial activity of new quinazoline compounds containing 1,2,4-triazole Schiff base[J].Organic Chemistry , 2013 ,33,370-374.) Using 3-methyl-4-amino-1,2,4-triazole-5-thione, aromatic aldehyde and 4-chloroquinazoline as raw materials, through Schiff base and thioetherification The reaction synthesized novel quinazoline compounds. Preliminary biological activity test results show: at 50 μ g/mL concentration, compound (E)-3-methyl-5-(quinazolin-4 - ylthio)-N-(4-(trifluoromethyl )benzylidene)-4H-1,2,4-triazol-4-amine had an inhibitory rate of 71%, 72% and 58% against Fusarium wilt of capsicum, fungus apple rot and Phytophthora infestans, respectively.

In 2013, Zhang Ying (Zhang Ying. Design, synthesis and biological activity research of 5,6,7-trialkoxyquinazoline derivatives [D]. Doctoral dissertation , Guizhou University, 2013 , 06.) synthesized a series of 5,6,7-trialkoxyquinazoline derivatives, at a concentration of 200 μ g/mL, this series of compounds have good inhibitory activity against Xanthomonas oryzae and Ralstonia solanacearum.

3. Quinazoline (ketone) compounds with anti-plant virus activity

In 2000 Ma Junan (Ma Junan, Qiu Dewen, Huang Runqiu, Feng Lei, Chai Youxin. Synthesis and biological activity of substituted formaldehyde oxime carboxylates (V)-pyrethroid 4-dimethyl (b) aminobenzaldehyde oxime ester against plant Viral activity[J]. Acta Pesticide Science, 2000 , 2(4):91-93.) and others synthesized quinazoline oxime ether compounds, and used different drug methods on Sansheng Tobacco and Shanxi Tobacco to test the Inhibition rate of tobacco mosaic virus (TMV) by similar compounds (concentration is 500 μ g/mL). The results show that this kind of compound also has anti-TMV activity when treated on plants, and has better systemic effect (bare root soaking method), and still has better anti-TMV activity under the condition that the drug does not directly interact with the virus. TMV activity and safety to crops. This type of compound can better inhibit the symptoms of TMV system when spraying after inoculation, and it is obviously better than the control drugs diacetyldioxohexahydrotriazine (DADHT) and dihydrotestosterone (DHT) (500 μ g /mL).

2007 Gao X.W.; CaiX.J.; YanK.; SongB.-A.; Gao, LL; ChenZ. Synthesis and Antiviral Bioactivities of 2-phenyl-3-(substituted benzalamino)-4(3H)-quinazoli-noneDerivatives[J ]. Molecules , 2007 ,12:2621-2642.) etc. designed and synthesized a series of new compounds containing 3-aryl imethyleneamino-4( 3H )-quinazolinones, and used half leaf dead spot method When the mass concentration was 500 μ g/mL, the bioactivity assay for the treatment of tobacco mosaic virus in vivo was carried out, and the measurement results showed that these compounds had a higher therapeutic effect on the living body of tobacco mosaic virus (TMV). The therapeutic activity of one of the target compounds was 55.0%, which was slightly higher than that of Ningnanmycin (54.0%). Studying the mechanism of action of the compound, it was found that its activity was correlated with the enzyme content of PAL enzyme, POD enzyme, and SOD enzyme in tobacco plants within a certain period of time, and it was found that the compound could induce the upregulation of PR-1a and PR-5 gene expression , can prevent the systemic infection and long-distance invasion of TMV virus, thereby improving the ability of anti-tobacco anti-virus.

In 2012, Luo Hui (Luo Hui. Synthesis and biological activity research of 4-substituted quinazoline derivatives containing pentadienone structure [D]. Doctoral dissertation , Guizhou University, 2012 , 06.) synthesized a series of The 4-substituted quinazoline derivatives of the pentadienone structure were tested against tobacco mosaic virus at a concentration of 500 μg /mL by the semi-leaf scorching method. The test results showed that this series of compounds had a good effect on TMV infection. In vivo therapeutic activity, the inhibition rate was 51.4%-62.7%, and the therapeutic activity was comparable to that of the control drug Ningnanmycin (inhibition rate was 55.4%).

In 2013, Zhang Ying (Zhang Ying. Design, synthesis and biological activity research of 5,6,7-trialkoxyquinazoline derivatives [D]. Doctoral dissertation , Guizhou University, 2013 , 06.) synthesized a class of The novel 5,6,7-trialkoxyquinazoline derivatives used half-leaf scab method to treat one of the target compounds in TMV-infected living organisms. The test results showed that the inhibition rate was 48.2%. Slightly lower than the control drug Ningnanmycin (54.0%).

Contents of the invention

On the basis of previous work, it has been found that quinazoline (ketone) compounds have good agricultural biological activity, and many compounds containing quinoline ring structures have shown wide application and development prospects, showing good resistance to plant pathogens Activity, anti-plant virus activity, some quinazoline compounds have been successfully developed into commercialized drugs, such as the fungicide fluquinazole and the acaricide fenazaquin. Object of the present invention, with 2-amino-6-chlorobenzoic acid as starting raw material, synthesized 11 novel 4-substituted amino- 5-Chloroquinazoline compound (I) , further use the chlorinated product as raw material, carry out nucleophilic reaction with N -Boc piperazine and hydrolyze to obtain 4-piperazine-5-chloroquinazoline, then combine with substituted benzyl chloride or substituted benzyl The bromine reaction yielded 17 novel 4-[4-(substituted benzyl)piperazine]-5-chloroquinazoline compounds (II) . This type of compound contains 5-position chlorine substitution and 4-position contains piperazine aromatic ring group; and the synthesis method and the research on the creation of new pesticides against plant pathogens have been carried out.

A kind of 4- N -substituted-5-chloroquinazoline compound of the present invention, this class compound is represented by following structural general formula:

Wherein R ₁ is hydrogen or methyl, R ₂ is substituted benzyl, alkyl, substituted aromatic ring, R or S -substituted aromatic ring, and the referred aromatic ring contains one or more methyl groups in the ortho, meta or para positions , ethyl, methoxy, halogen atom, the halogen atom can be fluorine, chlorine, bromine. _R3 is benzyl, substituted benzyl, and its benzyl ring contains one or more methyl, ethyl, methoxy, nitro, cyano, trifluoromethyl, trifluoro Methoxy group and halogen atom, the halogen atom may be fluorine or chlorine.

Described a kind of 4- N -substituted-5-chloroquinazoline compounds, synthesized and identified compounds are as follows:

Compound I ₁ : N -methyl-5-chloro- N -benzyl-4-aminoquinazoline

Compound I ₂ : 5-Chloro- N- (3-fluorophenethyl)-4-aminoquinazoline

Compound I ₃ : 5-chloro- N- (3,4-dimethoxyphenethyl)-4-aminoquinazoline

Compound I ₄ : 5-Chloro- N- (2-fluorophenethyl)-4-aminoquinazoline

Compound I ₅ : ( S )-5-chloro- N- (1-cyclohexylethyl)-4-aminoquinazoline

Compound I ₆ : ( R )-5-chloro- N- (1-(4-methoxyphenyl)ethyl)-4-aminoquinazoline

Compound I ₇ : ( R )-5-chloro- N- (1-(3-methoxyphenyl)ethyl)-4-aminoquinazoline

Compound I ₈ : ( S )-5-chloro- N- (1-(4-fluorophenyl)ethyl)-4-aminoquinazoline

Compound I ₉ : ( S )-5-chloro- N- (1-(4-bromophenyl)ethyl)-4-aminoquinazoline

Compound I ₁₀ : ( S )-5-chloro- N- (1-(naphthalene-2-yl)ethyl)-4-aminoquinazoline

Compound I ₁₁ : ( R )-5-chloro- N- (1-(naphthalen-2-yl)ethyl)-4-aminoquinazoline

Compound II ₁ : 4-(4-benzylpiperazin-1-yl)-5-chloroquinazoline

Compound II ₂ : 5-chloro-4-(4-(2,4-dichlorobenzyl)piperazin-1-yl)-quinazoline

Compound II ₃ : 5-chloro-4-(4-(2-cyanobenzyl)piperazin-1-yl)quinazoline

Compound II ₄ : 5-chloro-4-(4-(4-nitrobenzyl)piperazin-1-yl)quinazoline

Compound II ₅ : 5-chloro-4-(4-(2-chlorobenzyl)piperazin-1-yl)quinazoline

Compound II ₆ : 5-chloro-4-(4-(3-chlorobenzyl)piperazin-1-yl)quinazoline

Compound II ₇ : 5-chloro-4-(4-(4-fluorobenzyl)piperazin-1-yl)quinazoline

Compound II ₈ : 5-chloro-4-(4-(2-chlorobenzyl) piperazin-1-yl) quinazoline

Compound II ₉ : 5-chloro-4-(4-(4-trifluoromethoxybenzyl)piperazin-1-yl)quinazoline

Compound II ₁₀ : 5-chloro-4-(4-(4-methoxybenzyl)piperazin-1-yl)quinazoline

Compound II ₁₁ : 5-chloro-4-(4-(4-methylbenzyl)piperazin-1-yl)quinazoline

Compound II ₁₂ : 5-chloro-4-(4-(2-fluorobenzyl)piperazin-1-yl)quinazoline

Compound II ₁₃ : 5-chloro-4-(4-(3-fluorobenzyl)piperazin-1-yl)quinazoline

Compound II ₁₄ : 5-chloro-4-(4-(4-trifluoromethylbenzyl)piperazin-1-yl)quinazoline

Compound II ₁₅ : 5-chloro-4-(4-(4-methoxybenzyl)piperazin-1-yl)quinazoline

Compound II ₁₆ : 5-chloro-4-(4-(2-methylbenzyl)piperazin-1-yl)quinazoline

Compound II ₁₇ : 5-chloro-4-(4-(3-methylbenzyl)piperazin-1-yl)quinazoline

The structural formula of each compound is as follows:

Table 14-substituted amino-5-chloroquinazoline (I) compounds

I ₁ I ₇ I ₂ I ₈ I ₃ i ₉ I ₄ I ₁₀ I ₅ I ₁₁ I ₆

The synthetic part of table 2 contains 4-[4-(substituted benzyl) piperazine]-5-chloroquinazoline (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 synthetic method of 4- N -substituted-5-chloroquinazoline compound of the present invention, its synthetic route is: general formula ( I ) with 2-amino-6-chlorobenzoic acid, formamide, trichloro Oxyphosphorus and various substituted amino groups are used as raw materials, formamide, phosphorus oxychloride, and ethanol are used as solvents, triethylamine is used as a catalyst, and it is synthesized in three steps:

Wherein R ₁ is hydrogen or methyl, R ₂ is benzyl, cyclohexyl, substituted aromatic ring, R or S -substituted aromatic ring, and the referred aromatic ring contains one or more methyl groups on the ortho, meta, para positions, Methoxy, halogen atom, halogen atom can be fluorine, bromine;

The general formula ( II ) uses 2-amino-6-chlorobenzoic acid, formamide, phosphorus oxychloride, N -Boc piperazine, hydrochloric acid, various substituted benzyl chloride or benzyl bromide as raw materials, and formamide, oxytrichloride Phosphorus, ethanol, and acetonitrile are used as solvents, hydrochloric acid, sodium hydride, triethylamine, and potassium carbonate are used as catalysts, and it is synthesized in five steps:

Wherein _R3 is benzyl, substituted benzyl, and R is that the ortho, meta, and para positions in substituted benzyl contain one or more methyl, methoxyl, nitro, cyano, trifluoromethyl, trifluoro Methoxy group and halogen atom, the halogen atom may be fluorine or chlorine.

The preparation method of a kind of 4- N -substituted-5-chloroquinazoline compound of the present invention, synthetic steps and processing condition are:

The synthetic method of general formula ( I ):

The first step: the preparation of 5-chloroquinazolin-4 (3H) -one

Mix a small amount of 2-amino-6-chlorobenzoic acid and formamide and heat to reflux. Follow the reaction process by TLC. After the raw material point disappears, stop stirring, add an appropriate amount of water, stir until a large amount of solids are precipitated, then stir and cool to room temperature, pump Filter and recrystallize to obtain a light brown powder, wherein the molar ratio of 2-amino-6-chlorobenzoic acid to formamide is 1:3.5-4.5, the reaction temperature is 120-150°C, the reaction time is 5-7h, and the amount of water added is 0.86g2 - Add 20-24mL of water to amino-6-chlorobenzoic acid, add in two times;

The second step: the preparation of 4,5-dichloroquinazoline

A small amount of 5-chloroquinazolin-4( 3H )-one, an appropriate amount of phosphorus oxychloride and triethylamine were mixed and heated to reflux, followed by TLC until the raw material point disappeared, the reaction was stopped, and excess trichloride was distilled off under reduced pressure. Oxyphosphorus, cooling, adding an appropriate amount of dichloromethane to dissolve the reaction product under ice bath conditions, then slowly pouring into an appropriate amount of glacial hydrochloric acid, washing the reaction bottle with an appropriate amount of glacial hydrochloric acid, combining the two parts of the solution, shaking and layering, The organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was stirred with anhydrous potassium carbonate until the pH value was neutral, filtered, concentrated under reduced pressure, and column chromatography gave a white needle-like solid, in which 5-chloroquinazoline-4 ( 3H )-ketone, phosphorus oxychloride and triethylamine mol ratio is 1:12:5.5-1:14:6.5, reaction time 7-9h, 5-chloroquinazolin-4 ( 3H )-ketone and dichloromethane The molar ratio is 1:26.5-1:27.5, for every 1.00g of 5-chloroquinazolin-4( 3H )-one, add 32-34mL of 1mol/L glacial hydrochloric acid, and add in two times;

The third step: the preparation of 4-substituted amino-5-chloroquinazoline ( I ) compounds

Mix a small amount of 4,5-dichloroquinazoline, amine and ethanol, then add a small amount of triethylamine dropwise, react under reflux conditions, TLC traces to the point where there is no raw material, stop the reaction, separate by column chromatography, and obtain a milky white oil or solid, wherein the molar ratio of 4,5-dichloroquinazoline, amine and ethanol is 1:1.45:1.15-1:1.55:1.25, every 0.5mmol4,5-dichloroquinazoline is dripped with triethylamine 3~6 drop, the reaction time is 2.5-5h.

The synthetic method of general formula ( II ):

The first step: the preparation of 5-chloroquinazolin-4 (3H) -one

Mix a small amount of 2-amino-6-chlorobenzoic acid and formamide and heat to reflux. Follow the reaction process by TLC. After the raw material point disappears, stop stirring, add an appropriate amount of water, stir until a large amount of solids are precipitated, then stir and cool to room temperature, pump Filter and recrystallize to obtain a light brown powder, wherein the molar ratio of 2-amino-6-chlorobenzoic acid to formamide is 1:3.5-4.5, the reaction temperature is 120-150°C, the reaction time is 5-7h, and the amount of water added is 0.86g2 - Add 20-24mL of water to amino-6-chlorobenzoic acid, add in two times;

The second step: the preparation of 4,5-dichloroquinazoline

A small amount of 5-chloroquinazolin-4( 3H )-one, an appropriate amount of phosphorus oxychloride and triethylamine were mixed and heated to reflux, TLC followed the reaction until the raw material point disappeared, the reaction was stopped, and excess trichloride was distilled off under reduced pressure. Oxyphosphorus, cooling, adding an appropriate amount of dichloromethane to dissolve the reaction product in an ice bath, then slowly pouring into an appropriate amount of glacial hydrochloric acid, washing the reaction bottle with an appropriate amount of glacial hydrochloric acid, combining the two parts of the solution, shaking and stratifying, The organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was stirred with anhydrous potassium carbonate until the pH value was neutral, filtered, concentrated under reduced pressure, and column chromatography gave a white needle-like solid, in which 5-chloroquinazoline-4 ( 3H )-ketone, phosphorus oxychloride and triethylamine mol ratio is 1:12:5.5-1:14:6.5, reaction time 7-9h, 5-chloroquinazolin-4 ( 3H )-ketone and dichloromethane The molar ratio is 1:26.5-1:27.5, for every 1.00g of 5-chloroquinazolin-4( 3H )-one, add 32-34mL of 1mol/L glacial hydrochloric acid, and add in two times;

The third step: the synthesis of 4-( N -Boc piperazine)-5-chloroquinazoline

Mix 4,5-dichloroquinazoline, N-Boc piperazine, N,N-dimethylformamide and sodium hydride, stir at room temperature, TLC traces the reaction to the point where there is no raw material, stop the reaction, and saturated ammonium chloride solution Washing, dichloromethane extraction, desolvation, separation and purification by column chromatography, to obtain an oil, in which 4,5-dichloroquinazoline, N-Boc piperazine, N,N-dimethylformamide and sodium hydride The molar ratio is 1:1.15:3.5:1.4-1:1.25:4.5:1.6, and the reaction time is 7-10h;

The fourth step: the synthesis of 4-piperazine-5-chloroquinazoline (intermediate 1 )

Mix and stir 4-( N -Boc-piperazine)-5-chloroquinazoline and hydrochloric acid at room temperature. After stirring for a period of time, TLC traces to the point of no raw material, stop the reaction, and adjust the pH to neutral or weak with anhydrous K ₂ CO ₃ Alkalinity, dichloromethane extraction and desolvation, column chromatography purification to obtain oily matter, wherein the mass fraction of hydrochloric acid is 15-20%, every 0.45g4-(N-Boc piperazine)-5-chloroquinazoline is added with 15- 20% hydrochloric acid 7-9mL, reaction time 5-7h;

The fifth step: the synthesis of target compound II

Mix intermediate 1 , substituted benzyl chloride (substituted benzyl bromide), ethanol and triethylamine, react under reflux, TLC traces to no raw material point, stop the reaction, separate and purify by column chromatography and thin layer chromatography to obtain Yellowish oil or solid, wherein the molar ratio of intermediate 1 , substituted benzyl chloride (substituted benzyl bromide), ethanol and triethylamine is 1:1.15:11:1.4-1:1.25:13:1.6, and the reaction time is 3- 6h.

The application of a 4- N -substituted-5-chloroquinazoline compound described in the present invention is to prepare anti-plant fungus or anti-plant anti-bacteria drugs and medicaments.

The application of a 4- N -substituted-5-chloroquinazoline compound described in the present invention is used to prepare anti-wheat scab, capsicum wilt, apple rot, rice bacterial blight, tobacco solanacearum Medicines and potions for germs.

The application of a 4- N -substituted-5-chloroquinazoline compound of the present invention is that I ₂ , I ₄ , I ₅ , and I ₈ are used in the preparation of resistance to wheat scab, capsicum wilt, and apple rot. and II ₁ , II ₇ , II ₁₀ , and II ₁₁ are used in the preparation of medicines and medicaments for rice bacterial blight and tobacco bacterial wilt.

detailed description

Example 1. Synthesis of 5-chloro- N- (3-fluorophenethyl)-4-aminoquinazoline (the compound number is I ₂ )

(1) Synthesis of 5-chloroquinazolin-4(3H)-one

Put 0.86g (0.005mol) of 2-amino-6-chlorobenzoic acid into a 25mL three-necked flask, add 3mL (0.020mol) of formamide, mix and heat to reflux (140°C) for 6 hours, then add 10mL of water, and stir When the temperature is 60°C, add an appropriate amount of water, cool to room temperature, and filter with suction to obtain 0.61 g of light brown powder, with a yield of 67.8%, m.p.212~214°C (literature value 210°C);

(2) Synthesis of 4,5-dichloroquinazoline

Into a 50mL three-necked flask, put 1.00g (5.42mmol) of 5-chloroquinazolin-4(3H)-one, add 13.0mLPOCl ₃ and 6mL triethylamine, mix and heat to reflux for 8h, and distill off excess POCl under reduced pressure _3. Cool, add 30mL CH ₂ Cl ₂ to dissolve the reaction product under ice bath conditions, then slowly pour the CH ₂ Cl ₂ solution into 33mL 1mol/L glacial hydrochloric acid, wash the reaction flask with 33mL 1mol/L glacial hydrochloric acid, and combine The two parts of the solution _were shaken and separated, the organic layer was dried with anhydrous sodium _sulfate , filtered, and the filtrate was stirred with anhydrous K2CO3 until the pH value was neutral, filtered, concentrated under reduced pressure, and column chromatography gave 0.71 g of the product. Rate 65.8%, mp135~138℃ (literature value 131.5~133℃);

(3) Synthesis of 5-chloro- N- (3-fluorophenethyl)-4-aminoquinazoline

In a 25mL three-neck flask, add (0.5mmol) 4,5-dichloroquinazoline, 0.75mmol trifluorophenethylamine, 6mL ethanol and 3~4 drops of triethylamine, react under reflux for 4h, TLC traces to no raw materials Point, stop reaction, separate by column chromatography, obtain milky white solid, productive rate 86.2%;

Example 2 Synthesis of 5-chloro- N- (3,4-dimethoxyphenethyl)-4-aminoquinazoline (compound number is I ₃ )

(1) Synthesis of 5-chloroquinazolin-4(3H)-one

As in Example 1 (1) synthesis steps and process conditions, the difference is that the molar ratio of 2-amino-6-chlorobenzoic acid to formamide is 1:3.5, the reaction temperature is 120°C, the reaction time is 5h, and the amount of water added per 0.86g2- Add 20mL of water to amino-6-chlorobenzoic acid, add in two times;

(2) Synthesis of 4,5-dichloroquinazoline

As in Example one (2) synthesis steps and process conditions, the difference is that the mol ratio of 5-chloroquinazolin-4( 3H )-one, phosphorus oxychloride and triethylamine is 1:12:5.5, and the reaction time is 9h, 5 The molar ratio of -chloroquinazolin-4( 3H )-one to dichloromethane is 1:26.5, add 1mol/L glacial hydrochloric acid 32mL for every 1.00g of 5-chloroquinazolin-4( 3H )-one, divide into two times join in;

(3) Synthesis of 5-chloro- N- (3,4-dimethoxyphenethyl)-4-aminoquinazoline

Synthesize as example one (3) conditions and methods, the difference is that the molar ratio of 4,5-dichloroquinazoline, 3,4-dimethoxyphenethylamine and ethanol is 1:1.45:1.15, every 0.5mmol4,5 -dichloroquinazoline was added dropwise with 4 drops of triethylamine, and the reaction time was 5h to obtain a milky white solid with a yield of 79.5%;

Example 3 Synthesis of 5-chloro- N- (2-fluorophenethyl)-4-aminoquinazoline (compound number is I ₄ )

(1) Synthesis of 5-chloroquinazolin-4(3H)-one

As in Example 1 (1) synthesis steps and process conditions, the difference is that the molar ratio of 2-amino-6-chlorobenzoic acid to formamide is 1:4.5, the reaction temperature is 150°C, the reaction time is 7h, and the amount of water added per 0.86g2- Add 24mL of water to amino-6-chlorobenzoic acid, add in two times;

(2) Synthesis of 4,5-dichloroquinazoline

As in Example 1 (2) synthesis steps and process conditions, the difference is that the mol ratio of 5-chloroquinazolin-4( 3H )-one, phosphorus oxychloride and triethylamine is 1:14:6.5, and the reaction time is 7h, 5 The molar ratio of -chloroquinazolin-4( 3H )-one to dichloromethane is 1:27.5, every 1.00g of 5-chloroquinazolin-4( 3H )-one adds 34mL of 1mol/L glacial hydrochloric acid, divides twice join in;

(3) Synthesis of 5-chloro- N- (2-fluorophenethyl)-4-aminoquinazoline

As example one (3) synthesis steps and processing conditions, the 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 6 drops of triethylamine were added dropwise to morphine, and the reaction time was 4 hours to obtain a yellow solid with a yield of 66.3%.

Synthesis of Example 4 (S)-5-chloro- N- (1-cyclohexylethyl)-4-aminoquinazoline (compound number is I ₅ )

(1) Synthesis of 5-chloroquinazolin-4 (3H)-one: as in Example 1 (1) Synthetic steps and process conditions

(2) Synthesis of 4,5-dichloroquinazoline: as in Example 1 (2) synthetic steps and process conditions

(3) Synthesis of (S)-5-chloro- N- (1-cyclohexylethyl)-4-aminoquinazoline: as in example one (3) synthesis steps and process conditions, the difference is to add 0.75mmol ( R)-1-cyclohexylethylamine to obtain a white solid with a yield of 82.8%.

Example 5 Synthesis of (S)-5-chloro- N- (1-(4-fluorophenyl)ethyl)-4-aminoquinazoline (compound number is class I ₈ )

(1) Synthesis of 5-chloroquinazolin-4 (3H)-one: as in Example 1 (1) Synthetic steps and process conditions

(2) Synthesis of 4,5-dichloroquinazoline: as in Example 1 (2) synthetic steps and process conditions

(3) Synthesis of (S)-5-chloro- N- (1-(4-fluorophenyl) ethyl)-4-aminoquinazoline: as example one (3) synthetic steps and process conditions, difference After adding 0.75 mmol of 4-fluorophenethylamine, a yellow solid was obtained with a yield of 72.8%.

The spectral data of the synthetic 4- N -substituted-5-chloroquinazoline compound is as follows:

N -methyl-5-chloro- N -benzyl-4-aminoquinazoline (I ₁ )

Ayellowsolid, yield81.0%, mp61~64℃; ¹ HNMR (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(dd,1H,H-6ofquinazoline, J =7.4Hz),7.59(t,1H,H-7ofquinazoline, J =7.5Hz),7.77(dd,1H,H-8ofquinazoline, J =7.0 Hz), 8.59(s,1H,H-2ofquinazoline). ¹³ CNMR(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-chloro- N- (3-fluorophenethyl)-4-aminoquinazoline (I ₂ )

Amilkysolid,yield86.2%,mp67~71℃; ¹ HNMR(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). ¹³ CNMR (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-Chloro- N- (3,4-dimethoxyphenethyl)-4-aminoquinazoline (I ₃ )

Amilkysolid, yield79.5%, mp78~80℃; ¹ HNMR (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(dd,1H,H-6ofquinazoline, J =6.3Hz),7.46(t,1H,H-7ofquinazoline, J =8.0Hz),7.66(dd,1H, H-8ofquinazoline, J =7.5Hz),7.66(q,1H,NH, J =7.5Hz),8.56(s,1H,H-2ofquinazoline). ¹³ CNMR(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-chloro- N- (2-fluorophenethyl)-4-aminoquinazoline (I ₄ )

Ayellowsolid,yield66.3%,mp80~83℃; ¹ HNMR(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). ¹³ CNMR(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-chloro- N- (1-cyclohexylethyl)-4-aminoquinazoline (I ₅ )

Amilkysolid,yield82.8%,mp58~59℃; ¹ HNMR(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 =6.3 Hz), 8.50 (s, 1H, H-2ofquinazoline). ¹³ CNMR (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-chloro- N- (1-(4-methoxyphenyl)ethyl)-4-aminoquinazoline (I ₆ )

Ayellowsolid, yield76.5%, mp98~104℃; ¹ HNMR(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(dd,1H,H-7ofquinazoline, J =6.9Hz),7.60~7.65(m,2H,H-6,8ofquinazoline),8.37(s,1H,H-2ofquinazoline). ¹³ CNMR (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-chloro- N- (1-(3-methoxyphenyl)ethyl)-4-aminoquinazoline (I ₇ )

Awhitesolid, yield72.4%, mp49~51℃; ¹ HNMR(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). ¹³ CNMR(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-chloro- N- (1-(4-fluorophenyl)ethyl)-4-aminoquinazoline (I ₈ )

Ayellowsolid,yield72.8%,mp57~59℃; ¹ HNMR(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). ¹³ CNMR(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-chloro- N- (1-(4-bromophenyl)ethyl)-4-aminoquinazoline (I ₉ )

Ayellowsolid, yield72.8%, mp79~84℃; ¹ HNMR(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). ¹³ CNMR(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-chloro- N- (1-(naphthalene-2-yl)ethyl)-4-aminoquinazoline (I ₁₀ )

Awhitesolid, yield79.8%, mp100~103℃; ¹ HNMR(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). ¹³ CNMR(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-chloro- N- (1-(naphthalene-2-yl)ethyl)-4-aminoquinazoline (I ₁₁ )

Awhitesolid, yield81.4%, mp109~110℃; ¹ HNMR(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(dd,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). ¹³ CNMR(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.

The general formula ( II ) of the present invention uses 2-amino-6-chlorobenzoic acid, formamide, phosphorus oxychloride, N -Boc piperazine, hydrochloric acid, various substituted benzyl chlorides or benzyl bromides as raw materials, and formsamide, tris Phosphorus oxychloride, ethanol, and acetonitrile are used as solvents, and hydrochloric acid, sodium hydride, triethylamine, and potassium carbonate are used as catalysts. It is synthesized in five steps. The synthetic route is as follows:

Wherein _R3 is benzyl, substituted benzyl, and R is that the ortho, meta, and para positions in substituted benzyl contain one or more methyl, methoxyl, nitro, cyano, trifluoromethyl, trifluoro Methoxy group and halogen atom, the halogen atom may be fluorine or chlorine.

Synthetic steps and process conditions:

The first step: the preparation of 5-chloroquinazolin-4 (3H) -one

Mix a small amount of 2-amino-6-chlorobenzoic acid and formamide and heat to reflux. Follow the reaction process by TLC. After the raw material point disappears, stop stirring, add an appropriate amount of water, stir until a large amount of solids are precipitated, then stir and cool to room temperature, pump Filter and recrystallize to obtain a light brown powder, wherein the molar ratio of 2-amino-6-chlorobenzoic acid to formamide is 1:3.5-4.5, the reaction temperature is 120-150°C, the reaction time is 5-7h, and the amount of water added is 0.86g2 - Add 20-24mL of water to amino-6-chlorobenzoic acid, add in two times;

The second step: the preparation of 4,5-dichloroquinazoline

A small amount of 5-chloroquinazolin-4( 3H )-one, an appropriate amount of phosphorus oxychloride and triethylamine were mixed and heated to reflux, followed by TLC until the raw material point disappeared, the reaction was stopped, and excess trichloride was distilled off under reduced pressure. Oxyphosphorus, cooling, adding an appropriate amount of dichloromethane to dissolve the reaction product under ice bath conditions, then slowly pouring into an appropriate amount of glacial hydrochloric acid, washing the reaction bottle with an appropriate amount of glacial hydrochloric acid, combining the two parts of the solution, shaking and layering, The organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was stirred with anhydrous potassium carbonate until the pH value was neutral, filtered, concentrated under reduced pressure, and column chromatography gave a white needle-like solid, in which 5-chloroquinazoline-4 ( 3H )-ketone, phosphorus oxychloride and triethylamine mol ratio is 1:12:5.5-1:14:6.5, reaction time 7-9h, 5-chloroquinazolin-4 ( 3H )-ketone and dichloromethane The molar ratio is 1:26.5-1:27.5, for every 1.00g of 5-chloroquinazolin-4( 3H )-one, add 32-34mL of 1mol/L glacial hydrochloric acid, and add in two times;

The third step: the synthesis of 4-( N -Boc piperazine)-5-chloroquinazoline

Mix 4,5-dichloroquinazoline, N-Boc piperazine, N,N-dimethylformamide and sodium hydride, stir at room temperature, TLC traces the reaction to the point where there is no raw material, stop the reaction, and saturated ammonium chloride solution Washing, dichloromethane extraction, desolvation, separation and purification by column chromatography, to obtain an oil, in which 4,5-dichloroquinazoline, N-Boc piperazine, N,N-dimethylformamide and sodium hydride The molar ratio is 1:1.15:3.5:1.4-1:1.25:4.5:1.6, and the reaction time is 7-10h;

The fourth step: the synthesis of 4-piperazine-5-chloroquinazoline (intermediate 1 )

Mix and stir 4-( N -Boc-piperazine)-5-chloroquinazoline and hydrochloric acid at room temperature. After stirring for a period of time, TLC traces to the point of no raw material, stop the reaction, and adjust the pH to neutral or weak with anhydrous K ₂ CO ₃ Alkalinity, dichloromethane extraction and desolvation, column chromatography purification to obtain oily matter, wherein the mass fraction of hydrochloric acid is 15-20%, every 0.45g4-(N-Boc piperazine)-5-chloroquinazoline is added with 15- 20% hydrochloric acid 7-9mL, reaction time 5-7h;

The fifth step: the synthesis of target compound II

Mix intermediate 1 , substituted benzyl chloride (substituted benzyl bromide), ethanol and triethylamine, react under reflux, TLC traces to no raw material point, stop the reaction, separate and purify by column chromatography and thin layer chromatography to obtain Yellowish oil or solid, wherein the molar ratio of intermediate 1 , substituted benzyl chloride (substituted benzyl bromide), ethanol and triethylamine is 1:1.15:11:1.4-1:1.25:13:1.6, and the reaction time is 3- 6h.

Embodiment 6, the synthesis of compound 4-(4-benzylpiperazin-1-yl)quinazoline (compound number is II ₁ )

(1) Synthesis of 5-chloroquinazolin-4(3H)-one

Put 0.86g (0.005mol) of 2-amino-6-chlorobenzoic acid into a 25mL three-necked flask, add 3mL (0.020mol) of formamide, mix and heat to 140°C, react for 6h, stop the reaction, add 10mL of water, and stir When the temperature is 60°C, add an appropriate amount of water, cool to room temperature, and filter with suction to obtain 0.61 g of light brown powder, with a yield of 67.8%, m.p.212~214°C (literature value 210°C);

(2) Synthesis of 4,5-dichloroquinazoline

Into a 50mL three-necked flask, put 1.00g (5.42mmol) of 5-chloroquinazolin-4(3H)-one, add 13.0mLPOCl ₃ and 6mL triethylamine, mix and heat to reflux for 8h, and distill off excess POCl under reduced pressure _3. Cool, add 30mL CH ₂ Cl ₂ to dissolve the reaction product under ice bath conditions, then slowly pour the CH ₂ Cl ₂ solution into 33mL 1mol/L glacial hydrochloric acid, wash the reaction flask with 33mL 1mol/L glacial hydrochloric acid, and combine The two parts of the solution _were shaken and separated, the organic layer was dried with anhydrous sodium _sulfate , filtered, and the filtrate was stirred with anhydrous K2CO3 until the pH value was neutral, filtered, concentrated under reduced pressure, and column chromatography gave 0.71 g of the product. Rate 65.8%, mp135~138℃ (literature value 131.5~133℃);

(3) Synthesis of 4-( N -Boc piperazine)-5-chloroquinazoline

In a 25mL three-necked flask, mix (1.5mmol) 4,5-dichloroquinazoline and (1.8mmol) N-Boc piperazine, 6mL anhydrous N,N-dimethylformamide, and 2.25mmol sodium hydride at room temperature Stir for 8 hours, stop the reaction, wash with saturated ammonium chloride solution, extract with dichloromethane, remove the solvent, and separate and purify by column chromatography to obtain 0.45 g of oil, with a yield of 86.0%;

(4) Synthesis of 4-piperazine-5-chloroquinazoline (intermediate 1 )

In a 25mL three-necked flask, mix 0.45g of 4-(N-Boc-piperazine)-5-chloroquinazoline and 8mL of 18% hydrochloric acid at room temperature and stir. After 6 hours, TLC traces to a point where there is no raw material, stop the reaction, and use anhydrous K ₂ CO ₃ Adjust the pH to be neutral or slightly alkaline, extract and desolventize with dichloromethane, and purify by column chromatography to obtain 0.20 g of oil, with a yield of 70.0%;

(5) Synthesis of 4-(4-benzylpiperazin-1-yl)quinazoline

In a 25mL three-necked flask, add (0.5mmol) intermediate 1 , (0.60mmol) benzyl chloride, 6mL ethanol and 100 μL (0.75mmol) triethylamine, and react under reflux for 4h. TLC traces to the point where there is no raw material, and stops the reaction. Separation and purification by column chromatography and thin layer chromatography gave a yellow solid with a yield of 78.7%.

Example seven, the synthesis of compound 5-chloro-4-(4-(4-chlorobenzyl)piperazin-1-yl)quinazoline (compound number is II ₅ )

(1) Preparation of 5-chloroquinazolin-4 (3H) -one

As in Example 6 (1) synthesis steps and process conditions, the difference is that the molar ratio of 2-amino-6-chlorobenzoic acid to formamide is 1:3.5, the reaction temperature is 120°C, the reaction time is 7h, and the amount of water added per 0.86g2- Add 20mL of water to amino-6-chlorobenzoic acid, add in two times;

(2) Synthesis of 4,5-dichloroquinazoline

As in Example six (2) synthesis steps and process conditions, the difference is that the mol ratio of 5-chloroquinazolin-4( 3H )-one, phosphorus oxychloride and triethylamine is 1:12:5.5, and the reaction time is 9h, 5 The molar ratio of -chloroquinazolin-4( 3H )-one to dichloromethane is 1:26.5, add 1mol/L glacial hydrochloric acid 32mL for every 1.00g of 5-chloroquinazolin-4( 3H )-one, divide into two times join in;

(3) Synthesis of 4-(N-Boc piperazine)-5-chloroquinazoline

As in Example six (3) synthesis steps and process conditions, the difference is that the mol ratio of 4,5-dichloroquinazoline, N-Boc piperazine, N,N-dimethylformamide and sodium hydride is 1:1.15: 3.5:1.4, reaction time 10h;

(4) Synthesis of 4-piperazine-5-chloroquinazoline (intermediate 1 )

Such as embodiment six (4) synthesis steps and process conditions, its difference is that the massfraction of hydrochloric acid is 15%, every 0.45g4-(N-Boc piperazine)-5-chloroquinazoline adds 15% hydrochloric acid 9mL, reaction time 7h ;

(5) Synthesis of 5-chloro-4-(4-(4-chlorobenzyl)piperazin-1-yl)quinazoline

As in Example six (4) synthesis steps and process conditions, the difference is that the mol ratio of intermediate 1 , p-chlorobenzyl chloride, ethanol and triethylamine is 1:1.15:11:1.4, and the reaction time is 3h to obtain a yellow oil, Yield 75.0%.

Example 8. Synthesis of compound 5-chloro-4-(4-(4-fluorobenzyl)piperazin-1-yl)quinazoline (compound number II ₇ )

(1) Preparation of 5-chloroquinazolin-4 (3H) -one

As in Example 6 (1) synthesis steps and process conditions, the difference is that the molar ratio of 2-amino-6-chlorobenzoic acid to formamide is 1:4.5, the reaction temperature is 150°C, the reaction time is 5h, and the amount of water added per 0.86g2- Add 24mL of water to amino-6-chlorobenzoic acid, add in two times;

(2) Synthesis of 4,5-dichloroquinazoline

As in Example six (2) synthesis steps and process conditions, the difference is that the mol ratio of 5-chloroquinazolin-4( 3H )-one, phosphorus oxychloride and triethylamine is 1:14:6.5, and the reaction time is 7h, 5 The molar ratio of -chloroquinazolin-4( 3H )-one to dichloromethane is 1:27.5, every 1.00g of 5-chloroquinazolin-4( 3H )-one adds 34mL of 1mol/L glacial hydrochloric acid, divides twice join in;

(3) Synthesis of 4-(N-Boc piperazine)-5-chloroquinazoline

As in Example six (3) synthesis steps and process conditions, the difference is that the mol ratio of 4,5-dichloroquinazoline, N-Boc piperazine, N,N-dimethylformamide and sodium hydride is 1:1.25: 4.5:1.6, reaction time 7h;

(4) Synthesis of 4-piperazine-5-chloroquinazoline (intermediate 1 )

Such as embodiment six (4) synthesis steps and process conditions, its difference is that the massfraction of hydrochloric acid is 20%, every 0.45g4-(N-Boc piperazine)-5-chloroquinazoline adds 20% hydrochloric acid 7mL, reaction time 5h ;

(5) Synthesis of 5-chloro-4-(4-(4-fluorobenzyl)piperazin-1-yl)quinazoline

As in Example six (4) synthesis steps and process conditions, the difference is that the mol ratio of intermediate 1 , p-fluorobenzyl chloride, ethanol and triethylamine is 1:1.25:13:1.6, and the reaction time is 6h to obtain a yellow solid, producing The rate is 78.7%.

Example 9, the synthesis of compound 5-chloro-4-(4-(4-methoxybenzyl)piperazin-1-yl)quinazoline (compound number is II ₁₀ )

(1) Preparation of 5-chloroquinazolin-4 (3H) -ketone: as in Example six (1) synthesis steps and process conditions

(2) Synthesis of 4,5-dichloroquinazoline: as in Example six (2) synthetic steps and process conditions

(3) Synthesis of 4-(N-Boc piperazine)-5-chloroquinazoline: such as embodiment six (3) synthetic steps and process conditions

(4) Synthesis of 4-piperazine-5-chloroquinazoline (intermediate 1 ): such as embodiment six (4) synthetic steps and process conditions

(5) Synthesis of 5-chloro-4-(4-(4-methoxybenzyl)piperazin-1-yl)quinazoline: as in Example six (4) synthesis steps and process conditions, the difference is the addition of (0.60mmol) p-methoxybenzyl chloride to obtain a yellow oil with a yield of 81.3%.

Example ten, compound 5-chloro-4-(4-(4-methylbenzyl)piperazin-1-yl)quinazoline

(compound number is II ₁₁ ) synthesis

(1) Preparation of 5-chloroquinazolin-4 (3H) -ketone: as in Example six (1) synthesis steps and process conditions

(2) Synthesis of 4,5-dichloroquinazoline: as in Example six (2) synthetic steps and process conditions

(3) Synthesis of 4-(N-Boc piperazine)-5-chloroquinazoline: such as embodiment six (3) synthetic steps and process conditions

(4) Synthesis of 4-piperazine-5-chloroquinazoline (intermediate 1 ): such as embodiment six (4) synthetic steps and process conditions

(5) Synthesis of 5-chloro-4-(4-(4-methylbenzyl) piperazin-1-yl) quinazoline: as in Example six (4) synthetic steps and process conditions, the difference is the addition of ( 0.60mmol) p-methylbenzyl chloride to obtain a yellow solid with a yield of 79.4%.

Example eleven, compound 5-chloro-4-(4-(2-methylbenzyl)piperazin-1-yl)quinazoline

(compound number is II ₁₆ ) synthetic

(1) Preparation of 5-chloroquinazolin-4 (3H) -ketone: as in Example six (1) synthesis steps and process conditions

(2) Synthesis of 4,5-dichloroquinazoline: as in Example six (2) synthetic steps and process conditions

(3) Synthesis of 4-(N-Boc piperazine)-5-chloroquinazoline: such as embodiment six (3) synthetic steps and process conditions

(4) Synthesis of 4-piperazine-5-chloroquinazoline (intermediate 1 ): such as embodiment six (4) synthetic steps and process conditions

(5) Synthesis of 5-chloro-4-(4-(2-methylbenzyl) piperazin-1-yl) quinazoline: as in Example six (4) synthetic steps and process conditions, the difference is to add ( 0.60mmol) o-methylbenzyl chloride to obtain a yellow oil with a yield of 61.9%.

Example twelve, compound 5-chloro-4-(4-(3-methylbenzyl)piperazin-1-yl)quinazoline

(compound number is II ₁₇ ) synthetic

(1) Preparation of 5-chloroquinazolin-4 (3H) -ketone: as in Example six (1) synthesis steps and process conditions

(2) Synthesis of 4,5-dichloroquinazoline: as in Example six (2) synthetic steps and process conditions

(3) Synthesis of 4-(N-Boc piperazine)-5-chloroquinazoline: such as embodiment six (3) synthetic steps and process conditions

(4) Synthesis of 4-piperazine-5-chloroquinazoline (intermediate 1 ): such as embodiment six (4) synthetic steps and process conditions

(5) Synthesis of 5-chloro-4-(4-(3-methylbenzyl) piperazin-1-yl) quinazoline: as in Example six (4) synthetic steps and process conditions, the difference is to add ( 0.60mmol) o-methylbenzyl chloride to obtain a yellow oil with a yield of 60.4%.

The spectral data of synthetic 4-[4-(substituted benzyl)piperazine]-5-chloroquinazoline ( II ) compounds are as follows:

5-chloro-4-(4-benzylpiperazin-1-yl)quinazoline (II ₁ )

Ayellowsolid,yield78.7%,mp87~90℃; ¹ HNMR(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). ¹³ CNMR(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.

5-Chloro-4-(4-(2,4-dichlorobenzyl)piperazin-1-yl)quinazoline (II ₂ )

Ayellowsolid,yield67.8%,mp163~166℃; ¹ HNMR(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(dd,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) ^.13 CNMR (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.

5-Chloro-4-(4-(2-cyanobenzyl)piperazin-1-yl)quinazoline (II ₃ )

Ayellowsolid,yield77.9%,mp130~136℃; ¹ HNMR(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). ¹³ CNMR (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.

5-chloro-4-(4-(4-nitrobenzyl)piperazin-1-yl)quinazoline (II ₄ )

Ayellowsolid,yield78.7%,mp152~154℃; ¹ HNMR(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). ¹³ CNMR(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.

5-Chloro-4-(4-(4-chlorobenzyl)piperazin-1-yl)quinazoline (II ₅ )

Ayellowoilmatter,yield75.0%; ¹ HNMR(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). ¹³ CNMR(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.

5-chloro-4-(4-(3-chlorobenzyl)piperazin-1-yl)quinazoline (II ₆ )

Ayellowoilmatter,yield73.6%; ¹ HNMR(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). ¹³ CNMR(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.

5-chloro-4-(4-(4-fluorobenzyl)piperazin-1-yl)quinazoline (II ₇ )

Ayellowsolid,yield78.7%,mp73~75℃; ¹ HNMR(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). ¹³ CNMR(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.

5-chloro-4-(4-(2-chlorobenzyl)piperazin-1-yl)quinazoline (II ₈ )

Ayellowoilmatter,yield74.6%; ¹ HNMR(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). ¹³ CNMR(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.

5-Chloro-4-(4-(4-trifluoromethoxybenzyl)piperazin-1-yl)quinazoline (II ₉ )

Ayellowsolid,yield51.7%,mp89~91℃; ¹ HNMR(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(dd,1H,H-6ofquinazoline, J =7.5Hz),7.59(t,1H,H-7ofquinazoline, J =7.4Hz),7.76(dd,1H,H-8ofquinazoline J =8.6Hz),8.59( s,1H,H-2ofquinazoline). ¹³ CNMR(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.

5-chloro-4-(4-(4-methoxybenzyl)piperazin-1-yl)quinazoline (II ₁₀ )

Ayellowoilmatter,yield81.3%; ¹ HNMR(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). ¹³ CNMR(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.

5-chloro-4-(4-(4-methylbenzyl)piperazin-1-yl)quinazoline (II ₁₁ )

Ayellowsolid, yield79.4%, mp89~91℃; ¹ HNMR (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). ¹³ CNMR(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.

5-chloro-4-(4-(2-fluorobenzyl)piperazin-1-yl)quinazoline (II ₁₂ )

Amilkysolid,yield68.5%,mp86~89℃; ¹ HNMR(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). ¹³ CNMR(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.

5-chloro-4-(4-(3-fluorobenzyl)piperazin-1-yl)quinazoline (II ₁₃ )

Ayellowoilmatter,yield64.8%; ¹ HNMR(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). ¹³ CNMR(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.

5-Chloro-4-(4-(4-trifluoromethylbenzyl)piperazin-1-yl)quinazoline (II ₁₄ )

Ayellowsolid,yield71.2%,mp112~115℃; ¹ HNMR(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). ¹³ CNMR(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.

5-Chloro-4-(4-(3-methoxybenzyl)piperazin-1-yl)quinazoline (II ₁₅ )

Ayellowsolid,yield71.9%m,mp88~91℃; ¹ HNMR(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). ¹³ CNMR(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.

5-chloro-4-(4-(2-methylbenzyl)piperazin-1-yl)quinazoline (II ₁₆ )

Ayellowoilmatter,yield61.9%; ¹ HNMR(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). ¹³ CNMR(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.

5-chloro-4-(4-(3-methylbenzyl)piperazin-1-yl)quinazoline (II ₁₇ )

Ayellowoilmatter,yield60.4%; ¹ HNMR(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). ¹³ CNMR(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 is to the bacteriostasis activity test method of three kinds of plant plant fungi

The in vitro growth rate method was used to test the inhibitory activity of the compounds against plant pathogenic fungi. The test objects were Gibberellazeae , Fusarium oxysporum and Cytosporamandshurica . Potato Grape Agar (PDA) medium is mainly used, and 90 mL of the medium is respectively taken and packed in 200 mL Erlenmeyer flasks for sterilization. The preparation of drug-containing medium was carried out under sterile conditions, and the concentration of each drug was set at 50 μg /mL. Weigh each drug into a 10mL volumetric flask, add 0.1% sterilized water to prepare a certain concentration of drug, add it to 90mL PDA medium (40~50°C), shake well, and pour it into a 9cm diameter flask In the sterilized petri dish, three repetitions were set, and an equal amount of solvent was added as a blank control. During primary screening, wheat scab, pepper fusarium wilt, and apple rot are used as screening objects, and the normal growth colony is punched with a puncher (inner diameter 4mm) to make some fungus cakes for later use. Connect to the center of the plate, connect a bacterium cake to each plate, and place it in a constant temperature incubator with saturated humidity at 27°C for cultivation. When the control is overgrown, measure the diameter of the colony. Each colony is measured twice by the cross method, and the average number represents the colony size. The calculation formula of the bacteriostatic rate is as follows:

I(%)=(C-T)/(C-0.4)×100

Where I is the inhibition rate, C is the diameter of the blank control (cm), and T is the diameter of the treatment (cm).

The same method is also applicable to the test of the inhibitory activity of the compound on Fusarium oxysporum and Cytosporamandshurica .

Embodiment 14, compound is to the bacteriostatic activity test method of two kinds of plant bacteria

The inhibitory activity of the compounds on plant disease bacteria was tested by turbidity method, and the test objects were ( Ralstonia solanacearum and Xanthomonas Oryzae ).

(1) Test method for tobacco bacterial wilt: the concentrations of the tested compounds were 100 and 200 μ g/mL, DMSO was dissolved in the culture medium as a blank control, and thiabactin was used as a control agent. Streak culture was carried out on the solid medium, and cultured in a constant temperature incubator at 30°C until a single colony grew. Use the inoculation loop to select a single colony with pink in the center and more white edges, put it in NB liquid medium, and shake it in a constant temperature shaker at 30°C and 180rpm until the logarithmic growth phase is ready for use. Medicament (compound and control agent) is configured to the concentration and is 100, 200 μ g/mL the poisonous NB liquid culture medium 5mL joins in the test tube, adds in 40 μ L and contains the NB liquid culture medium of R. solanacearum, at 30 ℃, 180rpm constant temperature shaker for 48h, the bacterial liquid of each concentration was measured on the spectrophotometer OD ₅₉₅ value, and the OD ₅₉₅ value of the corresponding concentration of toxic sterile NB liquid medium was also measured.

Corrected OD value = OD value of bacteria-containing medium - OD value of sterile medium

Inhibition rate% = [(OD value of the control medium after correction - OD value of the corrected toxic medium) / OD value of the control medium after correction] × 100

(2) Test method for rice bacterial blight: the concentrations of the tested compounds were 100 and 200 μ g/mL respectively, DMSO was dissolved in the culture medium as a blank control, and Yebuzol was used as a control agent, and the rice bacterial blight pathogen Streak culture was carried out on M210 solid medium, and placed in a constant temperature incubator at 30°C for culture until a single colony grew. Use the inoculation loop to select the central yellow single colony, put it into M210 liquid medium, shake it in a constant temperature shaker at 30°C and 180rpm until the logarithmic growth phase is ready for use. The medicament (compound and control agent) is configured to the concentration of 100, 200 μ g/mL poisonous M210 liquid medium 5mL is added in the test tube, add 40 μ L in the M210 liquid medium containing the rice bacterial blight pathogen, in Shake culture in a constant temperature shaker at 30°C and 180rpm for 36 hours, measure the OD ₅₉₅ value of each concentration of bacterial liquid on a spectrophotometer, and additionally measure the OD ₅₉₅ value of the corresponding concentration of toxic sterile M210 liquid medium.

Corrected OD value = OD value of bacteria-containing medium - OD value of sterile medium

Inhibition rate% = [(OD value of the control medium after correction - OD value of the corrected toxic medium) / OD value of the control medium after correction] × 100

EC ₅₀ (median effective concentration) is an important indicator for evaluating the sensitivity of plant pathogens to compounds, and it is also an important parameter for setting the concentration of compounds when studying the mechanism of action of target compounds. In the concentration gradient experiment, the concentration was set by the double dilution method. Finally, the probability value of the relative inhibition rate of the agent against plant pathogenic bacteria and the concentration of the agent were converted into logarithmic values. The toxicity curve was obtained through regression analysis with SPSS software, and the EC ₅₀ was calculated.

It can be seen from Table 3 and Table 4 that when the concentration is 50 μ g/mL, compounds I ₂ , I ₄ , I ₅ , and I ₈ have certain inhibitory activities against wheat scab, capsicum wilt and apple rot , the inhibition rate was above 50%, especially the inhibition rate of I ₂ to Fusarium wilt of wheat was 73.2%, and the inhibition rate of I ₅ to Fusarium wilt of pepper was 75.1%. Compound II ₅ also had certain inhibitory activity against Fusarium wilt of pepper, and the inhibition rate was 56.2%.

Note: "-" means that the inhibition rate of detection is negative, and "/" means no detection.

It can be seen from Table 5 that I ₂ , I ₄ , and I ₈ have better inhibitory activity on rice bacterial blight, and at a concentration of 100 μ g/mL, the control effect is above 63.0% (Ectilazole at 100 μ g/mL concentration, the control effect was 30.9%); while I2 had a certain inhibitory activity on R. solanacearum, and at a concentration of ₂₀₀ μg/mL, the control effect was 68.9% (when thioprofen was at a concentration of 200 μg /mL, The control effect is 100%). It can be seen from Table 6 that, firstly, II ₁ , II ₇ , II ₁₀ , and II ₁₁ have better inhibitory activity against rice bacterial blight, and at a concentration of 100 μ g/mL, the control effect is above 90.0% (leaf blight When azole was at a concentration of 100 μg /mL, the control effect was 30.9%). Secondly, II ₁₆ and II ₁₇ had certain inhibitory activity against Xanthomonas oryzae, and the inhibition rates were 64.0% and 71.4%, respectively.

Table 7 part 4-[4-(substituted benzyl) piperazine]-5-chloroquinazoline (II) to the half maximal effective concentration of rice bacterial blight

compound _EC50 ( μ g/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

As can be seen from Table 7 , the half-inhibitory concentrations of five target compounds II against Xanthomonas oryzae were tested, and the results showed that compounds II ₁ , II ₇ , II ₁₀ , II ₁₁ , and II ₁₇ were effective against Xanthomonas oryzae The _EC50 values were 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, respectively. The EC ₅₀ values of compounds II ₁ , II ₇ , II ₁₀ , II ₁₁ , and II ₁₇ are much higher than those of the control drug, iebutazole (EC ₅₀ value is 217.3±3.6 μg/mL), and these five target compounds are worthy of further study value, especially target compound II ₁₁ .

The embodiment of the present invention is supplemented to illustrate the technical solution of the present invention, but the content of the embodiment is not limited thereto.

The effect of the invention is that the synthesis route is simple, the yield is high, and low-toxicity, novel and high-efficiency anti-plant pathogen drugs and medicaments are obtained.

Claims (3)

1. A 4- N -substituted-5-chloroquinazoline compound, the specific compound is as follows: Compound I ₂ : 5-Chloro- N- (3-fluorophenethyl)-4-aminoquinazoline Compound I ₄ : 5-Chloro- N- (2-fluorophenethyl)-4-aminoquinazoline Compound I ₅ : ( S )-5-Chloro- N- (1-cyclohexylethyl)-4-aminoquinazoline _Compound I8 : ( S )-5-Chloro- N- (1-(4-fluorophenyl)ethyl)-4-aminoquinazoline Compound II ₁ : 4-(4-Benzylpiperazin-1-yl)-5-chloroquinazoline Compound II ₇ : 5-Chloro-4-(4-(4-fluorobenzyl)piperazin-1-yl)quinazoline Compound II ₁₀ : 5-Chloro-4-(4-(4-methoxybenzyl)piperazin-1-yl)quinazoline Compound II ₁₁ : 5-Chloro-4-(4-(4-methylbenzyl)piperazin-1-yl)quinazoline Compound II ₁₇ : 5-Chloro-4-(4-(3-methylbenzyl)piperazin-1-yl)quinazoline The structural formula of each compound is as follows: I ₂ I ₈ I ₄ I ₅ II ₁ II ₁₀ II ₇ II ₁₁ II ₁₇ . 2. the application of a kind of 4- N -substituted-5-chloroquinazoline compounds according to claim 1 is characterized in that it is used to prepare anti-wheat scab, capsicum wilt, apple rot fungus, rice white leaf Drugs and agents for R. solanacearum and R. solanacearum. 3. the application of a kind of 4- N -substituted-5-chloroquinazoline compounds according to claim 2 is characterized in that I ₂ , I ₄ , I ₅ are used in the preparation of resistance to wheat scab, capsicum wilt, Apple rot fungus and II ₁ , II ₇ , II ₁₀ , II ₁₁ are used in the preparation of medicines and medicaments for rice bacterial blight and tobacco bacterial wilt.