CN107973807A

CN107973807A - A kind of triazol benzothiazole derivant and its preparation method and application

Info

Publication number: CN107973807A
Application number: CN201810054296.3A
Authority: CN
Inventors: 李艾; 李海花
Original assignee: Tangshan University
Current assignee: Tangshan University
Priority date: 2018-01-19
Filing date: 2018-01-19
Publication date: 2018-05-01
Anticipated expiration: 2038-01-19
Also published as: CN111560029A; CN107973807B; CN111560029B

Abstract

The invention discloses a kind of triazol benzothiazole derivant, its chemical general formula is as shown in I, wherein R₁For hydrogen, halogen, alkyl；R₂For hydrogen, halogen.Meanwhile it is using 2 amino-benzothiazole derivatives and aromatic hydrazide kind compound as starting material, 2 aminobenzothiazoles 1, hydrazine hydrate are under hydrochloric acid effect, and back flow reaction obtains compound 2 in ethylene glycol solvent the invention also discloses the method for synthesizing the derivative；The compound 2 further with to chloromethyl benzoic acid chlorides, reaction obtains compound 4 under phosphorus oxychloride effect, fragrant hydrazides and appropriate KOH are dissolved in ethanol, under room temperature and CS₂Reaction obtains compound 6, and the compound 6 reaction under concentrated sulfuric acid effect obtains compound 7, and compound 4 and compound 7 react in acetonitrile solvent under potassium carbonate catalytic action and obtain target product

Description

A kind of triazol benzothiazole derivant and its preparation method and application

Technical field

The present invention relates to antimicrobial DP finish and preparation method thereof, specifically a kind of triazol benzothiazole derivant and Its preparation method and application.

Background technology

People have found that more and more bacteriums generate sternly existing antibacterials on anti-infective clinical treatment at present The drug resistance of weight, or even there is " superbacteria " that has drug resistance to almost all of antibacterials, in order to tackle increasingly Severe bacterial resistance sex chromosome mosaicism, there is an urgent need to develop go out new significantly more efficient antibacterials.

Nitrogen-containing heterocycle compound has extensive bioactivity, all contains this class formation in many medicines structures, containing thiophene two The compound of azoles has the pharmaceutical activity such as excellent desinsection, sterilization；Triazole class compounds have bioactivity it is good, to human body cell Many advantages, such as small toxicity, be widely used as the multi-medicament such as antiviral, antibacterial, anti-infective, and bactericidal mechanism research shows, and three Azole compounds can pass through the iron knot of the enzyme system cytochrome P-450 of ergosterol in azoles theheterocyclic nitrogen atom and pathogen body Close, disturb enzyme activity, 14 α of ergosterol precursor lanosterol-demethylation reaction is blocked, so as to suppress ergosterol Synthesis, trigger the damage of cell membrane unrepairable, suppress growth of pathogenic bacteria or make its dead.

The content of the invention

It is an object of the invention to provide a kind of benzothiazole derivant containing triazol, while provide the conjunction of the analog derivative Into the application of method and the analog derivative in antibiotic preparation is prepared, to provide more use for clinical treatment bacterium infection Medicine selects.

The purpose of the present invention is what is be achieved through the following technical solutions：A kind of triazol benzothiazole derivant, its change General formula is learned as shown in I：

I

Wherein R₁For hydrogen, halogen, alkyl；R₂For hydrogen, halogen；

Preferably, R₁For hydrogen, chlorine, bromine, fluorine, methyl；R₂For hydrogen, chlorine, bromine, fluorine.

Above chemical general formula is such asThe shown triazol benzothiazole derivant containing thiadiazoles shown by experimental verification, It can be applied with good antibacterial activity in antibacterial medicine preparation is prepared；Meanwhile also intermediate can be used as former Material, for synthesizing the compound with antibacterial activity, is then applied in antibacterial medicine preparation is prepared.

Invention also provides the preparation method of the thiouracil derivative, comprise the following steps：

（a）Using 2- aminobenzothiazoles 1, hydrazine hydrate as raw material, under hydrochloric acid effect, in ethylene glycol solvent, back flow reaction, obtains Midbody compound 2- hydrazinobenzothiazoles 2；The molar ratio of the 2- aminobenzothiazoles and hydrazine hydrate is 1:4；Compound 2 Structural formula is：

2

R in compound 2₁For hydrogen, halogen, methyl；

（b）2- hydrazinobenzothiazoles 2, after reaction, will be anti-with being reacted under phosphorus oxychloride effect chloromethyl benzoic acid chlorides 3 Answering solution to pour into frozen water has solid precipitation, and filtering, intermediate 4, the 2- diazanyls benzo are obtained after drying through pillar layer separation Thiazole 2 is 1 to the molar ratio of chloromethyl benzoic acid chlorides:1.1；The structural formula of compound 4 is：

4

（c）Fragrant hydrazides 5 and appropriate KOH are dissolved in ethanol, CS is added dropwise under room temperature thereto₂Ethanol solution, separate out it is pale yellow Color solid, filtering, is dried to obtain intermediate 6, the fragrant hydrazides 5, KOH, CS₂Molar ratio be 1:1.5:1.5；Compound 6 structural formula is：

6

R in compound 6₂For hydrogen, halogen；

（d）Intermediate 6 is put into the concentrated sulfuric acid, is reacted under the conditions of 0 ~ 5 DEG C, reaction solution is poured into trash ice water after the completion of reaction In, yellow solid is separated out, is put it into after filtering washing in NaOH solution, is filtered out after insoluble impurity with hydrochloric acid tune solution ph For 5 or so, precipitation is produced, is carried out with ethanol being recrystallized to give 2- dimercaptothiodiazoles derivative 7 after filtering.The structure of compound 7 Formula is：

7

（e）By compound 4 and compound 7 in K₂CO₃Reacted under catalysis in acetonitrile and obtain compound I, the compound 4, Compound 7 and K₂CO₃Molar ratio be 1: 1.1: 3 ；The structural formula of compound I is：

I

Wherein R₁For hydrogen, halogen, methyl；R₂For hydrogen, halogen.

The synthesis step of its overall reaction general formula and compound I are as follows：

Step of the present invention（a）R in the 2- amino-benzothiazole derivatives₁For hydrogen, halogen atom, alkyl.

Preferably, step of the present invention（a）R in the 2- amino-benzothiazole derivatives₁For H, 4-Cl, 4-CH₃。

Step of the present invention（c）R in the aryl hydrazide₂For hydrogen, halogen atom.

Preferably, step of the present invention（c）The aryl hydrazide is benzoyl hydrazine, 2- chlorobenzoyls hydrazine, 2,4 dichloro benzene Formylhydrazine.

The compounds of this invention is uniformly mixed with the carrier that pharmacology allows to use, and can be prepared into according to conventional formulation method Various forms of pharmaceutical preparations for antiseptic.

Compound as the present invention synthesizes is active ingredient, can combine system with components such as water, sucrose, Sionit, fructose It is standby into oral liquid；With excipient（Lactose, glucose, sucrose, mannitol sugar）, disintegrant（Starch）, lubricant（It is stearic Acid, talcum powder）, adhesive（Gelatin, polyvinyl alcohol）Preparation piece agent or capsule are combined etc. component.

The compound that the present invention synthesizes can also be with physiological saline, glucose solution or brine and glucose as active ingredient The mixed carrier of composition is prepared into parenteral solution.

The present invention is 10~20 mg/ people/day in the effective dose for being referred to during clinic, daily 2~3 times.Doctor Taking dose can be drafted according to patient individual difference.

The present invention is using aminobenzothiazole and aryl hydrazide compound as starting material, by aminobenzothiazole and hydrazine hydrate Reaction obtains compound 2, further obtains compound 4, aryl with being reacted under phosphorus oxychloride effect chloromethyl benzoic acid chlorides Hydrazide compound 5 in ethanol/KOH media with CS₂Reaction obtains compound 6, compound 4 and compound 6 and is catalyzed in potassium carbonate Reacted under effect in acetonitrile solvent, successfully synthesize target product.The present invention is using active group splicing method, by thiadiazoles Pharmacophore is incorporated among triazol benzothiazole structure, obtains a series of triazols containing thiadiazoles substituted by special groups Thiadiazoles derivative.At the same time in view of all containing the hetero atom such as multiple S, N in thiadiazoles and Triterpenic acid structure, in biology It is expected to produce strong hydrogen bond action when being combined with target point protein in body, compound is played more preferable bioactivity.Result of the test Show that such compound has good antibacterial activity.Triterpenic acid derivative conduct provided by the invention containing thiadiazoles Antiseptic is the report first in industry, and the successful research and development of the bacteriostatic agent active ingredient, greatly expand the selection of antibacterial medicines Scope, new thinking is provided for the research and development of novel antibacterial medicine.

The preparation method of Triterpenic acid derivative provided by the invention containing thiadiazoles is easy to operate, operation easily, It is easy to large-scale production, the compound I of preparation passes through verification experimental verification, it, can be in antibacterial medicines with stronger bacteriostatic activity Extensive use in preparation.

Embodiment

Example below is used to the present invention be further described, but the invention is not limited in any way.

Embodiment 1

（1）3 mL85% hydrazine hydrates are added in 100 mL flasks（40 mmol）, then dripped while stirring under the conditions of ice-water bath Add 2 mL concentrated hydrochloric acids（20 mmol）.2- amino-benzothiazole derivatives are added after being added dropwise（10 mmol）With 15 mL second two Alcohol, when back flow reaction 10 is small, after reaction, cooling, separates out solid, filters, and washing, compound 2 is obtained with ethyl alcohol recrystallization （White crystal）.Its chemical reaction process is：

Wherein R₁For hydrogen, halogen, alkyl, preferably one kind in hydrogen, chlorine, bromine, fluorine, methyl；

（2）Take 100 mL to dry flask, add compound 2（2 mmol）, to chloromethyl benzoic acid chlorides 3（2.1 mmol）And trichlorine Oxygen phosphorus（11 mL）, when heating reflux reaction 8 is small under stirring, after reaction, cooling, then reaction solution is poured into frozen water, separate out Solid, filtering, is dried to obtain midbody compound 4；Its chemical reaction process is：

（3）10 mmol compounds, 5,15 mmol KOH and 30 mL ethanol are added in 100 mL flasks, are stirred well to clear Clearly, 15 mmol CS are slowly added dropwise at room temperature₂With the mixed solution of 10 mL ethanol, be added dropwise after the reaction was continued 2 it is small when, There are a large amount of yellow solids, filter, be dried to obtain midbody compound 6；Its chemical reaction process is：

Wherein R₂For hydrogen, halogen, preferably one kind in hydrogen, chlorine, bromine, fluorine；

（4）The 20 mL concentrated sulfuric acids are added in 100 mL flasks, by step under the conditions of maintaining the temperature at 0 ~ 5 DEG C（3）Gained compound 6 It is added portionwise, insulation reaction is after reaction poured into reaction solution in frozen water to homogeneous, has a large amount of yellow solids to separate out, and filters, Washing, obtained solid are dissolved in 5%NaOH solution, filter out insoluble matter, are 5 ~ 6 by filtrate tune pH, filtering, ethyl alcohol recrystallization obtains To midbody compound 7；Its chemical reaction process is：

（5）100 dry mL flasks are taken, add 0.5 mmol compounds 4 and 0.5 mmol compounds 7 and 1.5 mmol K₂CO₃, 25 mL acetonitriles are added, electromagnetic agitation, back flow reaction, TLC monitoring reactions, after reaction, rotate solvent afforded crude material, It is washed with water, filters, dry, column chromatography purifying（Ethyl acetate）, obtain target product；Its chemical reaction process is：

When the raw material is 2- aminobenzothiazoles, i.e. R₁For H, the aryl hydrazide is benzoyl hydrazine, i.e. R₂For H when, according to Method made above obtains final product compound Ia, is named as：3- (4- (((5- phenyl-1,3,4-thiadiazoles-2- bases) sulfenyl) Methyl) phenyl) benzo [4,5] thiazole [2,3-c] [1,2,4] triazole；Compound Ia structures are as follows：

After testing, compoundA 3- (4- (((5- phenyl -1,3,4- thiadiazoles -2- bases) sulfenyl) methyl) phenyl) benzo [4, 5] thiazole [2,3-c] [1,2,4] triazole：Light yellow solid, 211.5 ~ 212.8 DEG C of yield 58.3 %, m.p.;¹H NMR (DMSO-d ₆, 600 MHz) δ: 8.45 (d, J=7.8 Hz, 2H, ArH), 8.06 (d, J= 8.4 Hz, 2H, ArH), 7.98 (d, J=7.2 Hz, 1H, ArH), 7.90 (d, J=4.2 Hz, 1H, ArH), 7.58 (m, 2H, ArH), 7.49 (m,2H, ArH), 7.42 (m, 1H, ArH), 7.33 (d, J=7.2 Hz, 2H, ArH), 4.42 (s, 2H, CH₂);¹³C NMR (DMSO-d ₆, 150 MHz) δ: 38.6, 121.3, 121.6, 121.8, 124.5, 125.3, 124.6, 125.3, 125.8, 125.9, 128.3, 129.5, 130.9, 133.3, 132.9, 137.3, 137.2, 150.4, 164.2, 174.2; MS (ESI) m/z: 456.1 ([M-H]⁺).

Embodiment 2

When the raw material is 2- aminobenzothiazoles, i.e. R₁For H, the aryl hydrazide is 2- chlorobenzoyl hydrazines, i.e. R₂For 2- chlorine When, final product compound Ib is obtained according to the preparation method of embodiment 1, is named as：3- (4- (((5- (2- chlorphenyls) -1,3,4- Thiadiazoles -2- bases) sulfenyl) methyl) phenyl) benzo [4,5] thiazole [2,3-c] [1,2,4] triazole；Compound Ib structures are as follows：

After testing, compoundb:Light yellow solid, 214.2 ~ 216.3 DEG C of yield 55.2 %, m.p.;¹H NMR (DMSO-d ₆, 600 MHz) δ: 8.48 (d, J=7.8 Hz, 2H, ArH), 8.07 (d, J= 8.4 Hz, 2H, ArH), 7.94 (d, J=7.2 Hz, 1H, ArH), 7.56 (m, 2H, ArH), 7.52 (m,2H, ArH), 7.44 (m, 1H, ArH), 7.36 (d, J=7.2 Hz, 2H, ArH), 4.40 (s, 2H, CH₂);¹³C NMR (DMSO-d ₆, 150 MHz) δ: 38.3, 121.6, 121.7, 123.5, 124.3, 124.8, 125.9, 128.3, 128.6, 128.9, 129.5, 130.9, 133.3, 132.9, 137.3, 137.8, 150.4, 161.2, 164.2, 174.2; MS (ESI) m/z: 491.1 ([M-H]⁺).

Embodiment 3

When the raw material is 2- aminobenzothiazoles, i.e. R₁For H, the aryl hydrazide is 2,4- dichloro-benzoyl hydrazines, i.e. R₂For During 2,4- dichloro, final product compound Ic is obtained according to the preparation method of embodiment 1, is named as：3- (4- (((5- (2,4- dichloros Phenyl) -1,3,4- thiadiazoles -2- bases) sulfenyl) methyl) phenyl) benzo [4,5] thiazole [2,3-c] [1,2,4] triazole；Compound Ic structures are as follows：

After testing, compoundc：Light yellow solid, 225.0 ~ 227.3 DEG C of yield 53.4 %, m.p.;¹H NMR (DMSO-d ₆, 600 MHz) δ: 8.50 (d, J = 7.2 Hz, 2H, ArH), 8.01 (d, J = 7.8 Hz, 2H, ArH), 7.95 (d, J = 7.2 Hz, 1H, ArH), 7.58(m, 1H, ArH), 7.50 (m,2H, ArH), 7.45 (m, 1H, ArH), 7.41 (d, J = 7.2 Hz, 2H, ArH), 4.43 (s, 2H, CH₂);¹³C NMR (DMSO-d ₆, 150 MHz) δ: 38.1, 120.7, 121.3, 122.5, 124.7, 125.5, 125.9, 128.1, 128.6, 129.2, 129.5, 131.9, 133.3, 137.2, 137.9, 150.2, 162.2, 163.2, 172.2; MS (ESI) m/z: 525.4 ([M-H]⁺).

Embodiment 4

When the raw material is 2- amino -4- methylbenzothiazoles, i.e. R₁For 4- methyl, the aryl hydrazide is benzoyl hydrazine, i.e., R₂For H when, obtain final product compound Id according to the preparation method of embodiment 1, be named as：5- methyl -3- (4- (((5- (2,4- Dichlorophenyl) -1,3,4- thiadiazoles -2- bases) sulfenyl) methyl) phenyl) benzo [4,5] thiazole [2,3-c] [1,2,4] triazole；Change Compound Id structures are as follows：

After testing, compoundd：Light yellow solid, 211.0 ~ 213.3 DEG C of yield 59.1 %, m.p.;¹H NMR (DMSO-d ₆, 600 MHz) δ: 8.43 (d, J = 7.8 Hz, 2H, ArH), 7.98 (d, J = 7.2 Hz, 2H, ArH), 7.83 (d, J = 7.2 Hz, 1H, ArH), 7.53(m, 2H, ArH), 7.44 (m,1H, ArH), 7.45 (m, 2H, ArH), 7.35 (d, J = 7.2 Hz, 1H, ArH), 7.29 (d, J = 7.8 Hz, 2H, ArH), 4.45 (s, 2H, CH₂), 1.93 (s, 2H, CH₃);¹³C NMR (DMSO-d ₆, 150 MHz) δ: 15.9, 38.4, 121.7, 123.5, 124.9, 125.6, 126.9, 128.1, 129.3, 129.8, 131.7, 134.5, 136.2, 138.9, 151.2, 162.3, 165.2, 171.2; MS (ESI) m/z: 470.6 ([M-H]⁺).

Embodiment 5

When the raw material is 2- amino -4- methylbenzothiazoles, i.e. R₁For 4- methyl, the aryl hydrazide is 2- chlorobenzoyls Hydrazine, i.e. R₂For 2- chlorine when, obtain final product compound Ie according to the preparation method of embodiment 1, be named as：3-(4-(((5-(2- Chlorphenyl) -1,3,4- thiadiazoles -2- bases) sulfenyl) methyl) phenyl) -5- methyl benzo [4,5] thiazole [2,3-c] [1,2,4] three Azoles；Compound Ie structures are as follows：

After testing, compounde：Light yellow solid, 215.5 ~ 218.3 DEG C of yield 50.5 %, m.p.;¹H NMR (DMSO-d ₆, 600 MHz) δ: 8.50 (d, J = 7.8 Hz, 2H, ArH), 7.88 (d, J = 7.2 Hz, 1H, ArH), 7.73 (d, J = 7.2 Hz, 1H, ArH), 7.56(m, 1H, ArH), 7.44 (m,1H, ArH), 7.42 (m, 2H, ArH), 7.35 (m, 2H, ArH), 7.27 (d, J = 7.8 Hz, 1H, ArH), 4.46 (s, 2H, CH₂), 1.92 (s, 2H, CH₃);¹³C NMR (DMSO-d ₆, 150 MHz) δ: 15.7, 38.3, 120.5, 122.3, 124.2, 125.5, 126.5, 128.5, 129.3, 129.9, 131.3, 133.5, 135.2, 138.4, 150.2, 161.3, 165.5, 170.2; MS (ESI) m/z:505.1 ([M-H]⁺).

Embodiment 6

When the raw material is 2- amino -4- methylbenzothiazoles, i.e. R₁For 4- methyl, the aryl hydrazide is 2,4- dichloro-benzenes first Hydrazides, i.e. R₂For 2,4- dichloros when, obtain final product compound If according to the preparation method of embodiment 1, be named as：3-(4- (((5- (2,4 dichloro benzene base) -1,3,4- thiadiazoles -2- bases) sulfenyl) methyl) phenyl) -5- methyl benzo [4,5] thiazole [2, 3-c] [1,2,4] triazole；Compound If structures are as follows：

After testing, compoundf：Light yellow solid, 220.5 ~ 224.3 DEG C of yield 45.5 %, m.p.;¹H NMR (DMSO-d ₆, 600 MHz) δ: 8.48 (d, J = 7.8 Hz, 2H, ArH), 7.92 (d, J = 7.2 Hz, 1H, ArH), 7.73 (d, J = 7.2 Hz, 1H, ArH), 7.56(m, 1H, ArH), 7.44 (m,1H, ArH), 7.42 (m, 2H, ArH), 7.35 (m, 2H, ArH), 4.46 (s, 2H, CH₂), 1.92 (s, 2H, CH₃);¹³C NMR (DMSO-d ₆, 150 MHz) δ: 15.7, 38.3, 120.5, 122.3, 124.2, 125.5, 126.5, 128.5, 129.3, 129.9, 131.3, 133.5, 135.2, 138.4, 150.2, 161.3, 165.5, 170.2; MS (ESI) m/z:539.4 ([M-H]⁺).

Embodiment 7

When the raw material is 2- amino -4- chloro benzothiazoles, i.e. R₁For 4- chlorine, the aryl hydrazide is benzoyl hydrazine, i.e. R₂For During hydrogen, final product compound Ig is obtained according to the preparation method of embodiment 1, is named as：3- (4- (((5- phenyl -1,3,4- thiophenes two Azoles -2- bases) sulfenyl) methyl) phenyl) -5- chlorobenzenes simultaneously [4,5] thiazole [2,3-c] [1,2,4] triazole；Compound Ig per structure is as follows：

After testing, compoundg：Light yellow solid, 210.5 ~ 213.1 DEG C of yield 55.1 %, m.p.;¹H NMR (DMSO-d ₆, 600 MHz) δ: 8.44 (d, J = 7.2 Hz, 2H, ArH), 8.01 (d, J = 7.8 Hz, 2H, ArH), 7.85 (d, J = 7.2 Hz, 1H, ArH), 7.55(m, 1H, ArH), 7.51 (m,2H, ArH), 7.46 (m, 1H, ArH), 7.41 (m, 1H, ArH), 7.26 (d, J = 7.2 Hz, 2H, ArH), 4.43 (s, 2H, CH₂);¹³C NMR (DMSO-d ₆, 150 MHz) δ: 38.5, 120.6, 121.6, 123.2, 125.6, 126.3, 127.5, 129.1, 129.8, 131.4, 133.4, 135.4, 137.4, 151.2, 160.3, 163.5, 170.5; MS (ESI) m/z: 491.1 ([M-H]⁺).

Embodiment 8

When the raw material is 2- amino -4- chloro benzothiazoles, i.e. R₁For 4- chlorine, the aryl hydrazide is 2- chlorobenzoyl hydrazines, i.e., R₂For 2- chlorine when, obtain final product compound Ih according to the preparation method of embodiment 1, be named as：3- (4- (((5- (2- chlorine) benzene Base -1,3,4- thiadiazoles -2- bases) sulfenyl) methyl) phenyl) -5- chlorobenzenes simultaneously [4,5] thiazole [2,3-c] [1,2,4] triazole；Chemical combination Thing Ih structures are as follows：

After testing, compoundh：Light yellow solid, 217.5 ~ 219.1 DEG C of yield 50.1 %, m.p.;¹H NMR (DMSO-d ₆, 600 MHz) δ: 8.50 (d, J = 7.8 Hz, 2H, ArH), 7.87 (d, J = 7.8 Hz, 1H, ArH), 7.75 (d, J = 8.4 Hz, 1H, ArH), 7.58(d, J = 7.8 Hz, 2H, ArH), 7.53 (d, J = 7.2 Hz, 1H, ArH), 7.45 (m, 1H, ArH), 7.38 (m, 1H, ArH), 7.33 (m, 1H, ArH), 7.27 (d, J = 7.8 Hz, 1H, ArH), 4.45 (s, 2H, CH₂);¹³C NMR (DMSO-d ₆, 150 MHz) δ: 38.6, 121.1, 122.4, 123.3, 125.3, 126.7, 127.4, 129.4, 129.9, 130.4, 133.5, 136.4, 137.5, 151.5, 160.1, 163.2, 170.3; MS (ESI) m/z: 525.3 ([M-H]⁺).

Embodiment 9

When the raw material is 2- amino -4- chloro benzothiazoles, i.e. R₁For 4- chlorine, the aryl hydrazide is 2,4- dichloro-benzoyls Hydrazine, i.e. R₂For 2- chlorine when, obtain final product compound Ii according to the preparation method of embodiment 1, be named as：3-(4-(((5-(2, 4-3 dichloros) phenyl -1,3,4- thiadiazoles -2- bases) sulfenyl) methyl) phenyl) and -5- chlorobenzenes simultaneously [4,5] thiazole [2,3-c] [1,2, 4] triazole；Compound Ii structures are as follows：

After testing, compoundi：Light yellow solid, 225.5 ~ 228.1 DEG C of yield 46.1 %, m.p.;¹H NMR (DMSO-d ₆, 600 MHz) δ: 8.51 (d, J = 8.4 Hz, 2H, ArH), 7.91 (d, J = 7.8 Hz, 1H, ArH), 7.77 (s, 1H, ArH), 7.68(d, J = 7.8 Hz, 1H, ArH), 7.58 (d, J = 7.2 Hz, 1H, ArH), 7.48 (m, 1H, ArH), 7.42 (d, J = 7.8 Hz, 1H, ArH), 7.28 (d, J = 7.8 Hz, 2H, ArH), 4.46 (s, 2H, CH₂);¹³C NMR (DMSO-d ₆, 150 MHz) δ: 38.4, 121.4, 122.6, 123.4, 125.1, 125.7, 126.1, 128.4, 129.3, 130.3, 133.1, 136.1, 137.7, 151.1, 160.2, 161.2, 170.1; MS (ESI) m/z: 559.9 ([M-H]⁺).

Derivative bacteriostatic activity detection prepared by 10 present invention of embodiment

Experimental method：

（1）For trying pathogenic bacteria：1 plant of Gram-negative bacteria：Escherichia coli；3 plants of gram-positive bacterias：Staphylococcus aureus, sand Men Shi bacillus and bacillus subtilis.

（2）The preparation of sample and culture medium：The preparation of test sample（50 μg/mL）：0.1 mg medicines are taken, add 300 μ L DMSO dissolve, and then add 1.7 mL distilled water, shake up.

NA culture mediums：1 g of peptone, 3 g of beef extract, agar 20 g, NaCl 5 g, 1000 mL of distilled water；

NB culture mediums：Agar is removed in the liquid form of NA culture mediums, i.e. NA culture mediums；

PDA culture medium：200 g of potato decortication, is placed in 900 mL water and boils 20-30 min, four layers of filter-cloth filtering.Add in filtrate Enter glucose 10-20 g, 20 g of agar, stirring fusing, constant volume to 1000 mL, it is 6.7 to adjust pH, is dispensed, sterilizing.

（3）Bacterium bacteriostasis rate measures（The method of plate culture count）

1. the preparation of Drug plates：The accurate compound for weighing embodiment 1-9 preparations, using etc. quality Norfloxacin to contrast, After being dissolved with a small amount of DMSO, add in different culture mediums after being mixed to the final concentration of 25 μ g/mL of medicine and be down flat plate, after solidification It is spare；

2. the preparation of pathogen bacteria suspension：In superclean bench, one, pathogen inclined-plane is taken, add 10 mL sterile waters, with going out Bacterium bamboo stick gently scrapes the lawn of media surface, breaks up, and vortex oscillator shaken well, is made bacteria suspension.

3. the gradient dilution of pathogen bacteria suspension：1 mL of bacteria suspension is taken to be added in 9 mL sterile waters, concussion is uniformly made 10^-1Dilution.1 mL 10 is drawn again^-1Dilution is added in 9 mL sterile waters, and concussion is uniformly made 10^-2Dilution；With this Analogize, prepare graded series bacteria suspension.

4. bacterium colony counts：It is each to draw 10^-6Or 10^-770 μ L of gradient bacteria suspension, are added separately to Drug plates and not dosing NA culture medium flat plates (control) on, it is uniform to scrape coating with sterilizing triangle, carries out mark, is placed in 37 DEG C of constant incubators and cultivates 24 h；After 24 h, bacterium colony counting is carried out.Every group of setting parallel test three times, as a result takes the average value tested three times.

Bacteriostasis rate=（Control group clump count-Drug plates clump count）/ control group clump count * 100%

The bacteriostasis rate of each compound under 1. 25 μ g/mL concentration of table

By table 1 as it can be seen that the compounds of this invention is to for trying bacterium（Escherichia coli, salmonella, S. aureus L-forms, bacillus subtilis）Tool There is stronger inhibitory activity, some compounds are suitable with the activity of positive control Norfloxacin.Especially compoundR in structure₁ For 2- chlorine and R₂For there is higher inhibitory activity, such as compound to bacterium during 2,4- dichlorosf、The antibacterial activity of i is obvious It is higher thana、D, shows the introducing of chlorine atom, is conducive to improve the antibacterial activity of such triazol benzothiazole derivant, the above The analysis of structure-activity relationship, design, synthesis for the antiseptic of follow-up high activity have great importance.

Embodiment 11

Compound prepared by Example 9I7 mg, 55 mg of lactose, 25 mg of dehydrated potato powder, 3 mg of polyvinyl alcohol, stearic acid 2 mg of magnesium, is prepared into oral tablet.

Similarly, with embodiment 1-9, any one compound prepared is uniformly mixed with the carrier that pharmacology allows to use, according to Conventional formulation method can be prepared into the various forms of pharmaceutical preparations for antiseptic.

The embodiment that the present invention enumerates is intended to illustrate preparation method and such change of the benzothiazole derivant containing triazol For compound to the inhibitory activity of bacterium, embodiment is not singly to illustrate the synthetic method and antibacterial of the specific compound described in itself Activity, while the type and quantity of explanation feed change are may also be used for, its homologue and analog are synthesized, without to the present invention Scope form any restrictions.

Claims

1. a kind of triazol benzothiazole derivant, it is characterised in that the chemical general formula of the derivative is as shown in I：

I

Wherein R₁For hydrogen, halogen, alkyl；R₂For hydrogen, halogen.

2. triazol benzothiazole derivant according to claim 1, it is characterised in that the R₁For hydrogen, chlorine, bromine, fluorine, Methyl；R₂For hydrogen, chlorine, bromine, fluorine.

3. a kind of preparation method of triazol benzothiazole derivant, it is characterised in that comprise the following steps：

（a）Using 2- aminobenzothiazoles 1, hydrazine hydrate as raw material, under hydrochloric acid effect, in ethylene glycol solvent, back flow reaction, obtains Midbody compound 2- hydrazinobenzothiazoles 2；The molar ratio of the 2- aminobenzothiazoles and hydrazine hydrate is 1:4；

（b）2- hydrazinobenzothiazoles derivative 2 in phosphorus oxychloride with reacting chloromethyl benzoic acid chlorides, after reaction, will Reaction solution, which is poured into frozen water, solid precipitation, and filtering, intermediate 4, the 2- diazanyls benzene are obtained after drying through pillar layer separation And thiazole 2 is 1 to the molar ratio of chloromethyl benzoic acid chlorides:1.1；

（c）Fragrant hydrazides 5 and appropriate KOH are dissolved in ethanol, CS is added dropwise under room temperature thereto₂Ethanol solution, separate out it is light yellow Solid, filtering, is dried to obtain intermediate 6, the fragrant hydrazides 5, KOH, CS₂Molar ratio be 1:1.5:1.5；

（d）Intermediate 6 is put into the concentrated sulfuric acid, is reacted under the conditions of 0 ~ 5 DEG C, reaction solution is poured into trash ice water after the completion of reaction In, yellow solid is separated out, is put it into after filtering washing in NaOH solution, is filtered out after insoluble impurity with hydrochloric acid tune solution ph For 5, precipitation is produced, is carried out with ethanol being recrystallized to give 2- dimercaptothiodiazoles derivative 7 after filtering；

（e）By compound 4 and compound 7 in K₂CO₃Reaction obtains compound I in acetonitrile under catalysis, the compound 4 with The molar ratio of compound 7 is 1:1.1.

4. the preparation method of triazol benzothiazole derivant according to claim 3, it is characterised in that step（a）Institute The aminobenzothiazole stated is 2- aminobenzothiazoles, halo 2- aminobenzothiazoles, alkyl substitute 2- aminobenzothiazoles.

5. the preparation method of triazol benzothiazole derivant according to claim 3, it is characterised in that step（a）Institute The aminobenzothiazole stated is 2- aminobenzothiazoles, 2- amino -4- chloro benzothiazoles, 2- amino -4- methylbenzothiazoles, is changed R in compound I₁For hydrogen, 4- chlorine, 4- methyl.

6. the preparation method of triazol benzothiazole derivant according to claim 3, it is characterised in that step（c）Institute The fragrant hydrazides stated is benzoyl hydrazine, 2- chlorobenzoyls hydrazine, 2,4- dichloro-benzoyl hydrazines, R in compound I₂For hydrogen, 2- chlorine, 2,4- Dichloro.

7. application of the triazol benzothiazole derivant in antibacterial medicine preparation is prepared described in claim 1.