CN107556266B - 2-mercapto-4-substituted-6-fluorobenzothiazole and preparation method and application thereof - Google Patents
2-mercapto-4-substituted-6-fluorobenzothiazole and preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the field of chemical bactericides, and particularly relates to a preparation method and application of 2-mercapto-4-substituted-6-fluorobenzothiazole and 2-mercapto derivatives. The synthesis of the target compound 2-mercapto-4-substituted-6-fluorobenzothiazole is realized by taking 4-fluoro-2-substituted aniline as a raw material and sulfur and alkyl xanthate under the condition of a solvent through an acid-alkali two-stage method, and a target molecule is purified and then reacts with a derivatization reagent to form a 2-mercapto derivative. The route has the characteristics of safety, easy operation, simple post-treatment, high yield and low cost. The 2-mercapto-4-substituted-6-fluorobenzothiazole and the 2-mercapto derivative have the inhibiting effect on staphylococcus aureus, escherichia coli and salmonella as broad-spectrum bactericides.
Description
Technical Field
The invention belongs to the field of chemical bactericides, and particularly relates to a preparation method and application of 2-mercapto-4-substituted-6-fluorobenzothiazole and 2-mercapto derivatives.
Background
Plant diseases cause great losses to agriculture, whereby crops all over the world are reduced in yield by about 500Mt per year on average, and the use of fungicides is an economically efficient method for controlling plant diseases.
2-Mercaptobenzothiazole (MBT) can be used as sulfenamide and thiazole vulcanization accelerators and industrial water treatment, can be used as corrosion inhibitors of copper and copper alloy materials and can be used for measuring silver, cadmium, iridium, lead and platinum in the field of analytical chemistry, and has the functions of resisting cancer, resisting bacteria and the like in medicine, so the economic value of the MBT is valued by various countries.
2-mercaptobenzothiazole is synthesized by 3 methods, namely an o-nitrochlorobenzene method, an aniline method and a nitrobenzene and aniline mixing method, in most industries. Wherein the o-nitrochlorobenzene method has high raw material price and complex production process; the mixed method of nitrobenzene and aniline has the problems of difficult control of reaction and high requirement on the material of a reactor; the aniline method has limitations of a high-temperature and high-pressure reaction apparatus.
Fluorine is the element with the largest electronegativity in nature, and the aromatic fluoride has the characteristics of excellent chemical stability, surface activity, temperature resistance and the like. The pesticide using heterocyclic compounds as raw materials has strong performance, and the introduction of fluorine can further improve the performance of the pesticide.
The molecules of the 2-mercapto-4-substituted-6-fluorobenzothiazole and the 2-mercapto derivative are not reported, and the invention provides a synthetic method of the specific structure.
Disclosure of Invention
In order to overcome the defects and shortcomings in the prior art, the invention mainly aims to provide 2-mercapto-4-substituted-6-fluorobenzothiazole and a 2-mercapto derivative.
The invention also aims to provide a preparation method of the 2-mercapto-4-substituted-6-fluorobenzothiazole and the 2-mercapto derivative. The method has the characteristics of safety, easy operation, simple post-treatment, high yield and low cost.
The invention also aims to provide the application of the 2-mercapto-4-substituted-6-fluorobenzothiazole and the 2-mercapto derivative.
The purpose of the invention is realized by the following technical scheme:
a2-mercapto-4-substituted-6-fluorobenzothiazole has a structural general formula shown in formula (1):
wherein R is hydroxyl, acetamido, methoxyl, benzyloxy, C1-C4 alkyl, halogen, nitryl, carboxyl or ester group.
The preparation method of the 2-mercapto-4-substituted-6-fluorobenzothiazole comprises the following steps:
dissolving an initial raw material 2-substituted-4-fluoroaniline by using a solvent under the atmosphere of inert gas (nitrogen or argon), then adding sulfur, alkyl xanthate and an organic acid catalyst, reacting for 2-4 hours at 60-120 ℃, cooling to 0-room temperature, adding alkali to adjust the pH value to be neutral, heating to 120-240 ℃ for reacting for 2-4 hours, cooling to room temperature, adding water for washing, drying an organic solvent layer after layering, and concentrating under reduced pressure to obtain a crude product of the 2-mercapto-4-substituted-6-fluorobenzothiazole. The room temperature range of the invention is 15-35 ℃.
Preferably, the structural formula of the 2-substituted-4-fluoroaniline is shown as the formula (2):
wherein R is hydroxyl, acetamido, methoxyl, benzyloxy, C1-C4 alkyl, halogen, nitryl, carboxyl or ester group.
Preferably, the molar ratio of the 2-substituted-4-fluoroaniline, the sulfur, the alkyl xanthate, the organic acid catalyst and the base is 1 (1.05-2): (1.05-2):(1.05-2):(1.05-2).
Preferably, the alkyl xanthate is at least one of potassium methyl xanthate, sodium methyl xanthate, potassium ethyl xanthate and sodium ethyl xanthate.
Preferably, the solvent is at least one of o-xylene, m-xylene, p-xylene, diphenyl ether, diphenyl methyl ether, cyclohexanone, 1, 2-dichloroethane, tetrachloroethane, chloroisooctane, N-methylpyrrolidone, dimethylformamide, dimethylacetamide and dimethylsulfoxide.
Preferably, the organic acid catalyst is at least one of formic acid, acetic acid, propionic acid, butyric acid, caprylic acid, adipic acid, oxalic acid, malonic acid, succinic acid, benzoic acid, o-chlorobenzoic acid, m-chlorobenzoic acid, p-chlorobenzoic acid, o-nitrobenzoic acid, m-nitrobenzoic acid, p-nitrobenzoic acid, o-cyanobenzoic acid, m-cyanobenzoic acid, p-cyanobenzoic acid, phthalic acid, isophthalic acid, terephthalic acid, benzenesulfonic acid, o-chlorobenzenesulfonic acid, m-chlorobenzenesulfonic acid, p-chlorobenzenesulfonic acid, o-methylbenzenesulfonic acid, m-methylbenzenesulfonic acid, p-methylbenzenesulfonic acid, o-nitrobenzenesulfonic acid, m-nitrobenzenesulfonic acid, and p-nitrobenzenesulfonic acid.
Preferably, the base is at least one of lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, triethylamine, pyridine, 4-dimethylaminopyridine, 1, 4-diazabicyclo [ 2.2.2 ] octane and 2-methyl-1, 4-diazabicyclo [ 2.2.2 ] octane.
Preferably, the drying and concentration under reduced pressure are performed by separating the organic solvent layer with a separatory funnel, drying with anhydrous sodium sulfate or magnesium sulfate, separating the drying agent by suction filtration, and finally concentrating under reduced pressure.
Preferably, the 2-mercapto-4-substituted-6-fluorobenzothiazole crude product is purified by column chromatography or crystallization to obtain a 2-mercapto-4-substituted-6-fluorobenzothiazole pure product.
The reaction formula for preparing the 2-mercapto-4-substituted-6-fluorobenzothiazole is shown as the formula (3):
a2-mercapto derivative has a general structural formula shown in formula (4):
wherein R is hydroxyl, acetamido, methoxyl, benzyloxy, C1-C4 alkyl, halogen, nitryl, carboxyl or ester group; r' is methyl, butyl, 4-bromobutyl, benzyl, methyl acetate, propyl acetate, tert-butyl acetate, allyl, or propargyl.
The preparation method of the 2-mercapto derivative comprises the following steps:
dissolving a compound 2-mercapto-4-substituted-6-fluorobenzothiazole shown in the formula (1) in a solvent under the atmosphere of inert gas, adding a derivatization reagent and alkali, reacting at 0-80 ℃ for 2-4 hours, cooling to 0-room temperature, adding acid to adjust the pH value to be neutral, adding water to wash, layering, drying an organic solvent layer, and concentrating under reduced pressure to obtain a crude product of the 2-mercapto derivative.
Preferably, the molar ratio of the 2-mercapto-4-substituted-6-fluorobenzothiazole, the derivatization reagent, the acid and the base is 1 (1.05-1.5) to (1.05-1.5).
Preferably, the derivatization reagent is at least one of methyl iodide, butyl bromide, 1, 4-dibromobutane, benzyl chloride, benzyl bromide, methyl chloroacetate, methyl bromoacetate, ethyl chloroacetate, ethyl bromoacetate, tert-butyl chloroacetate, tert-butyl bromoacetate, 3-chloropropene, 3-bromopropylene, 3-chloropropyne and 3-bromopropyne.
Preferably, the solvent is at least one of diethyl ether, tetrahydrofuran, 1, 4-dioxane, toluene, dichloromethane, 1, 2-dichloroethane, acetonitrile, acetone, 2-butanone and cyclohexanone.
Preferably, the alkali is at least one of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, pyridine and 4-dimethylamino pyridine.
Preferably, the acid is at least one of hydrochloric acid, phosphoric acid, sodium bisulfate, potassium bisulfate, sodium dihydrogen phosphate, potassium dihydrogen phosphate, ammonium chloride and ammonium bisulfate.
Preferably, the drying and concentration under reduced pressure are performed by separating the organic solvent layer with a separatory funnel, drying with anhydrous sodium sulfate or magnesium sulfate, separating the drying agent by suction filtration, and finally concentrating under reduced pressure.
Preferably, the crude 2-mercapto derivative is purified by column chromatography or crystallization to obtain a pure 2-mercapto derivative.
The reaction formula for preparing the 2-mercapto derivative is shown as the formula (5):
the 2-mercapto-4-substituted-6-fluorobenzothiazole and the 2-mercapto derivative provided by the invention have an inhibiting effect on staphylococcus aureus, escherichia coli and salmonella, and can be used as broad-spectrum bactericides applied to the field of agriculture or medicines.
Compared with the prior art, the invention has the following advantages and beneficial effects:
the synthesis of the target compound 2-mercapto-4-substituted-6-fluorobenzothiazole is realized by taking 4-fluoro-2-substituted aniline as a raw material and sulfur and alkyl xanthate under the condition of a solvent through an acid-alkali two-stage method, and a target molecule is purified and then reacts with a derivatization reagent to form a 2-mercapto derivative. The route has the characteristics of safety, easy operation, simple post-treatment, high yield and low cost.
Detailed Description
The present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited thereto. The reagents used in the examples are commercially available without specific reference.
Example 1: preparation of 6-fluoro-4-methoxybenzothiazole-2-thiol
In a 250 ml dry three-neck round-bottom flask with a reflux condenser tube at normal temperature, 14.11 g (0.10 mol) of 2-methoxy-4-fluoroaniline and 200 ml of o-xylene are added and stirred for dissolution under the protection of nitrogen; then 4.81 g of sulfur (0.15 mol), 24.05 g (0.15 mol) of potassium ethyl xanthate and 1.58 g (0.01 mol) of benzenesulfonic acid are added, and the temperature is raised to 100 ℃ for reaction for 4 hours; cooling to normal temperature, adding 4-dimethylaminopyridine to adjust the pH value to be neutral under high-speed stirring, heating to 140 ℃ for reaction for 2 hours, cooling to normal temperature, adding water for washing, separating an organic solvent layer by a separating funnel, adding anhydrous magnesium sulfate for drying, performing suction filtration and separation of a drying agent, performing reduced pressure evaporation to remove o-xylene to obtain a crude product of 6-fluoro-4-substituted-benzothiazole-2-thiol, performing column chromatography separation (300-mesh 400-mesh silica gel powder) on the crude product by using petroleum ether and ethyl acetate as an eluent to obtain light yellow powder of 6-fluoro-4-methoxybenzothiazole-2-thiol with the purity of more than 99 percent of 17.57g, wherein the separation yield is 81.6 percent and the melting point is 192-mesh 194 ℃. Nuclear magnetic resonance data:1H NMR(DMSO-D6，TMS)δ(ppm)：4.12(3H)，7.37(m，1H，J＝8.2Hz)， 7.81(m，1H，J＝8.4Hz)，13.66(brs，1H)。
example 2: preparation of 6-fluoro-4-cyanobenzothiazole-2-thiol
Brought back at 250 ml under normal temperatureIn a dry three-neck round-bottom flask with a flow condenser, 13.6 g (0.10 mol) of 2-cyano-4-fluoroaniline and 200 ml of diphenyl ether are added under the protection of argon and stirred for dissolution; then, 6.41 g of sulfur (0.20 mol), 34.5 g (0.20 mol) of sodium butyl xanthate and 31.34 g (0.20 mol) of o-chlorobenzoic acid are added in sequence, and the temperature is raised to 140 ℃ for reaction for 3 hours; cooling to normal temperature, adding lithium hydroxide to adjust the pH value to be neutral under high-speed stirring, heating to 230 ℃ for reaction for 2 hours, cooling to normal temperature, adding water for washing, separating an organic solvent layer by a separating funnel, adding anhydrous sodium sulfate for drying, carrying out suction filtration and separation of a drying agent, carrying out reduced pressure evaporation to remove diphenyl ether to obtain a crude product of 6-fluoro-4-cyano-benzothiazole-2-thiol, carrying out column chromatography separation (300-mesh 400-mesh silica gel powder) on the crude product by using petroleum ether and ethyl acetate as an eluent by gradient elution to obtain a light yellow powder of 6-fluoro-4-cyano-benzothiazole-2-thiol with the purity of more than 99%, wherein the separation yield is 93.1%, and the melting point is 251-mesh 253 ℃. 600MHz NMR data:1H NMR(DMSO-D6，TMS)δ(ppm)：7.51 (m，1H，J＝8.4Hz)，8.08(m，1H，J＝8.5Hz)，13.85(brs，1H)。
example 3: preparation of 6-fluoro-4-methoxybenzothiazole-2-dimethylsulfide derivative
Under the condition of normal temperature, 21.53 g (0.10 mol) of 6-fluoro-4-methoxybenzothiazole-2-thiol and 200 ml of tetrahydrofuran are added into a 250 ml of dry three-neck round-bottom flask with a reflux condenser pipe under the protection of nitrogen for dissolution; then 21.29 g (0.15 mol) of methyl iodide and 15.90 g (0.15 mol) of sodium carbonate are added to react for 2 hours at the temperature of 60 ℃, the temperature is reduced to room temperature, ammonium chloride is added to adjust the pH value to be neutral, water is added to wash the mixture, an organic solvent layer is separated by a separating funnel, anhydrous magnesium sulfate is added to dry the mixture, a drying agent is separated by suction filtration and reduced pressure evaporation to remove tetrahydrofuran to obtain a crude product of 6-fluoro-4-methoxy-benzothiazole-2-methyl sulfide, the crude product is eluted by petroleum ether and ethyl acetate in a gradient manner, column chromatography separation (300-mesh 400-mesh silica gel powder) is carried out to obtain 18.37 g of light yellow solid 6-fluoro-4-methoxy benzothiazole-2-methyl sulfide with the purity of more than 99 percent, and the yield is 80.13 percent. The melting point is 75-77 ℃. Nuclear magnetic resonance data:1H NMR(DMSO-D6，TMS)δ(ppm)：2.57(s，3H)，4.15(3H)， 7.32(m，1H，J＝7.9Hz)，7.75(m，1H，J＝8.1Hz)。
example 4: preparation of 6-fluoro-4-cyanobenzothiazole-2-propene thioether derivative
Under the condition of normal temperature, 21.02 g (0.10 mol) of 6-fluoro-4-cyanobenzothiazole-2-thiol and 200 ml of cyclohexanone are added into a 250 ml of dry three-mouth round-bottom flask with a reflux condenser pipe under the protection of nitrogen for dissolution; then adding 13.31 g (0.11 mol) of 3-bromopropylene and 13.43 g (0.11 mol) of 4-dimethylaminopyridine, reacting for 2 hours at 100 ℃, cooling to room temperature, adding sodium dihydrogen phosphate to adjust the pH value to be neutral, adding water for washing, separating an organic solvent layer by a separating funnel, adding anhydrous magnesium sulfate for drying, performing suction filtration and separation of a drying agent, performing reduced pressure evaporation to remove tetrahydrofuran to obtain a crude product of 6-fluoro-4-methoxy-benzothiazole-2-propene thioether, performing column chromatography separation (300-400-mesh silica gel powder by using petroleum ether and ethyl acetate as an eluent and adopting gradient elution to obtain a light yellow solid 6-fluoro-4-cyanobenzothiazole-2-propene thioether with the purity of more than 99 percent 23.24 g, the yield of 92.86 percent and the melting point of 107-109 ℃. 600MHz NMR data:1H NMR(DMSO-D6，TMS)δ(ppm)： 3.75(m，2H)，5.25(m，1H)，5.43(m，1H)，7.65(m，1H，8.7Hz)，8.41 (m，1H，8.9Hz)。
bactericidal performance detection analysis
Tests prove that the prepared 6-fluoro-4-methoxybenzothiazole-2-thiol, 6-fluoro-4-cyanobenzothiazole-2-thiopropene derivative and 6-fluoro-4-methoxybenzothiazole-2-thiomethyl derivative have an inhibiting effect on staphylococcus aureus, escherichia coli and salmonella. The experimental data for 6-fluoro-4-methoxybenzothiazole-2-thiol are given as examples:
the synthetic 6-fluoro-4-methoxybenzothiazole-2-thiol is used for carrying out in-vitro antibacterial activity comparison tests by using animal-derived gram-positive bacteria (Staphylococcus aureus), gram-negative bacteria (Escherichia coli and Salmonella) as antibacterial test objects and vancomycin, cefoxitin, ciprofloxacin and tetracycline as reference substances by adopting a two-fold agar dilution method. The test result shows that: the 6-fluoro-4-methoxybenzothiazole-2-thiol has a certain inhibiting effect on Staphylococcus aureus (Staphylococcus aureus), has a remarkable inhibiting effect on Escherichia coli (Escherichia coli) and Salmonella (Salmonella), and specific bioactivity test result data are shown in table 1.
TABLE 16 biological Activity test results for fluoro-4-methoxybenzothiazole-2-thiol
Note: the parent nucleus, without antibacterial activity, is 2-mercaptobenzothiazole and the composition is 6-fluoro-4-methoxybenzothiazole-2-thiol prepared in example 1.
As can be seen from the data in Table 1, the parent nucleus compound 2-mercaptobenzothiazole has no antibacterial activity against Staphylococcus aureus, Escherichia coli, Salmonella.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (5)
1. A2-mercapto-4-substituted-6-fluorobenzothiazole is characterized in that the structural general formula is shown as formula (1):
wherein R is methoxyl.
2. The process for preparing 2-mercapto-4-substituted-6-fluorobenzothiazole according to claim 1, comprising the steps of:
dissolving an initial raw material 2-substituted-4-fluoroaniline by using a solvent under the atmosphere of inert gas, then adding sulfur, alkyl xanthate and an organic acid catalyst, reacting for 2-4 hours at 60-120 ℃, cooling to 0-room temperature, adding alkali to adjust the pH value to be neutral, heating to 120-phase and 240 ℃ for reacting for 2-4 hours, cooling to the room temperature, adding water for washing, layering, drying an organic solvent layer, and concentrating under reduced pressure to obtain a crude product of the 2-mercapto-4-substituted-6-fluorobenzothiazole.
3. The method for preparing 2-mercapto-4-substituted-6-fluorobenzothiazole according to claim 2, wherein the structural formula of the 2-substituted-4-fluoroaniline is represented by formula (2):
wherein R is methoxy;
the alkyl xanthate is at least one of potassium methyl xanthate, sodium methyl xanthate, potassium ethyl xanthate and sodium ethyl xanthate;
the molar ratio of the 2-substituted-4-fluoroaniline, the sulfur, the alkyl xanthate, the organic acid catalyst and the alkali is 1 (1.05-2): (1.05-2):(1.05-2):(1.05-2).
4. The method for preparing 2-mercapto-4-substituted-6-fluorobenzothiazole according to claim 2, wherein the solvent is at least one of o-xylene, m-xylene, p-xylene, diphenyl ether, and diphenyl methyl ether;
the organic acid catalyst is at least one of benzoic acid, o-chlorobenzoic acid, m-chlorobenzoic acid, p-chlorobenzoic acid, benzenesulfonic acid, o-chlorobenzenesulfonic acid, m-chlorobenzenesulfonic acid and p-chlorobenzenesulfonic acid;
the alkali is 4-dimethylamino pyridine.
5. Use of the 2-mercapto-4-substituted-6-fluorobenzothiazole compound as claimed in claim 1 for the preparation of broad spectrum antibacterial agents including staphylococcus aureus, escherichia coli and salmonella.
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