CN108084110B - 3-aminobenzo [ d ] isothiazole, derivative and synthetic method thereof - Google Patents

3-aminobenzo [ d ] isothiazole, derivative and synthetic method thereof Download PDF

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CN108084110B
CN108084110B CN201711399099.7A CN201711399099A CN108084110B CN 108084110 B CN108084110 B CN 108084110B CN 201711399099 A CN201711399099 A CN 201711399099A CN 108084110 B CN108084110 B CN 108084110B
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邓国军
谢浩
肖福红
黄华文
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Xiangtan University
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Abstract

The invention mainly relates to 3-aminobenzene [ d ] isothiazole and derivatives thereof and a synthesis method thereof, wherein a catalyst is not needed during synthesis, and a technical scheme for converting a benzamidine compound and elemental sulfur into the 3-aminobenzene [ d ] isothiazole and derivatives thereof only under the action of alkali and in an air atmosphere is adopted; the method solves the problems that the existing synthesis method of the functionalized 3-aminobenzo [ d ] isothiazole compound has complex synthesis steps, needs a multi-step synthesis process to complete, needs a metal catalyst or peroxide, and has low yield or harsh reaction conditions. The method has the characteristics of simple reaction system, mild reaction conditions, less reaction equipment, simple and convenient experimental operation, wide material sources, high yield, easy expansion of users and application, higher product utilization value, expected market commercialization prospect and the like.

Description

3-aminobenzo [ d ] isothiazole, derivative and synthetic method thereof
Technical Field
The invention relates to an organic compound and a synthetic method thereof, in particular to 3-aminobenzo [ d ] isothiazole, a derivative and a synthetic method thereof.
Background
3-aminobenzo [ d ] isothiazole derivatives are unique motifs common in natural products, pharmaceuticals and many other biologically active products. However, very few methods are available for the synthesis of benzisothiazole. 3-aminobenzo [ d ] isothiazolium chloride is used as a raw material, 3-aminobenzo [ d ] isothiazolium compound is used as a main raw material, a series of benzisothiazolone derivatives (methyl thiosalicylate) between SH and NH groups) are synthesized through S-N bonding reaction, and a high-valence iodine reagent PIFA [ (phenyl iodine (III) bis (trifluoroacetate) ] is used as an oxidant. More recently, Yadav and his colleagues developed a process starting from 2-amino-N '-aryl-benzoyl hydrazine using Lawesson's reagent as a sulfur source, which is mainly suitable for the preparation of 3-substituted benzo [ c ] isothiazoles. It would be highly desirable to prepare a variety of substituted 1, 2-benzisothiazole preparations under simple and mild reaction conditions. So far, no report of directly synthesizing 3-aminobenzo [ d ] isothiazole by using elemental sulfur as a raw material exists.
Disclosure of Invention
Accordingly, it is an object of the present invention to provide 3-aminobenzo [ d ] isothiazole and derivatives thereof.
The invention also aims to provide a synthesis method of the 3-aminobenzo [ d ] isothiazole and the derivatives thereof, which has the advantages of simple process and high yield.
Thus, the present invention provides 3-aminobenzo [ d ] isothiazoles and derivatives thereof having the general formula:
Figure BSA0000156127220000011
wherein
R1 is selected from hydrogen, alkyl, halo;
r2 is selected from hydrogen atom, alkyl;
r3 is selected from a hydrogen atom; a substituted or unsubstituted C6-C12 aryl group;
the invention also provides a method for preparing the 3-aminobenzo [ d ] isothiazole and the derivatives thereof, which is obtained by heating and stirring the benzamidine compound and elemental sulfur under the reaction condition of inorganic base and organic solvent.
Preferably, in the process of the invention, the inorganic base is selected from KHCO3、K2CO3、Na2CO3、K3PO4、K2HPO4、KOH、NaOH、Cs2CO3Potassium tert-butoxide, sodium ethoxide and sodium methoxide.
Preferably, in the method of the present invention, the organic solvent is one or more selected from the group consisting of pyridine, acetonitrile, THF, DMAC, DMF, DMSO, 1, 4-dioxane, and toluene.
Preferably, in the method, the molar ratio of the benzamidine compound to the elemental sulfur to the base is 1: 5: 2-3, and the reaction temperature is 110-140 ℃.
Preferably, in the method of the present invention, the benzamidine compound is selected from the group consisting of C7-C19 aromatic amidines having the formula II:
Figure BSA0000156127220000012
wherein
Wherein
R1 is selected from hydrogen, alkyl, halo;
r2 is selected from hydrogen atom, alkyl;
r3 is selected from a hydrogen atom; a substituted or unsubstituted C6-C12 aryl group;
x is selected from fluorine atom, chlorine atom and bromine atom.
The benzamidine compound of formula II is selected from the group consisting of benzamidine, 2-fluorobenzamidine, 2-chlorobenzamidine, 2-bromobenzamidine, 2-fluoro-N-phenylbenzamidine, 2-chloro-N-phenylbenzamidine, 2-bromo-N-phenylbenzamidine, 2-chloro-N- (p-tolyl) benzamidine, 2-chloro-N- (4-ethylphenyl) benzamidine, 2-chloro-N- (4- (tert-butyl) phenyl) benzamidine, 2-chloro-N- (4-methoxyphenyl) benzamidine, 2-chloro-N- (4-ethoxyphenyl) benzamidine, 2-chloro-N- (4-trifluoromethoxyphenyl) benzamidine, 2-chloro-N- (4-fluorophenyl) benzamidine, 2-chloro-N- (4-chlorophenyl) benzamidine, 2-chloro-N- (4-bromophenyl) benzamidine, 2-chloro-N- ([1, 1' -biphenyl ] -4-yl) benzamidine, 2-chloro-N- (naphthalen-2-yl) benzamidine, 2-chloro-N- (m-tolyl) benzamidine, 2-chloro-N- (m-ethylphenyl) benzamidine, 2-chloro-N- (3-chlorophenyl) benzamidine, 2-chloro-N- (o-tolyl) benzamidine, 2-chloro-N- (2, 4-dimethylphenyl) benzamidine, 2-chloro-N- (3, 4-dimethoxyphenyl) benzamidine, 2-chloro-N- (3, 4, 5-trimethoxyphenyl) benzamidine, 2-chloro-4-methyl-N-phenylbenzamidine, 2-chloro-3-methyl-N-phenylbenzamidine, 2-chloro-4-fluoro-N-phenylbenzamidine, 2-chloro-4-chloro-N-phenylbenzamidine, 2-chloro-4-bromo-N-phenylbenzamidine, 2-chloro-5-trifluoromethyl-N-phenylbenzamidine, 2-chloro-4-trifluoromethyl-N-phenylbenzamidine, 2-chloro-N-methyl-N-phenylbenzamidine.
The technical scheme of the invention has the following advantages:
according to the synthesis method of the compound 3-aminobenzo [ d ] isothiazole and the derivative thereof, a catalyst is not needed, and the benzamidine compound and elemental sulfur are converted into the 3-aminobenzo [ d ] isothiazole and the derivative thereof by taking an organic solvent as a solvent under the action of alkali; the method overcomes the difficulties that the existing synthesis method of the 3-aminobenzo [ d ] isothiazole compound has complex synthesis steps, can be completed by adopting a multi-step synthesis process, and also needs a metal catalyst and peroxide with chemical equivalent; it has stable molecular structure, excellent chemical property, molecular blocks and compound segments containing rich contents of biological activity and pharmacological activity; the method also has the characteristics of simple reaction system, mild reaction conditions, less reaction equipment, simple and convenient experimental operation, wide material sources, high yield, easy expansion of users and applications, higher product utilization value, predictable market commercialization prospect and the like.
Drawings
In order to demonstrate the products of the invention, nuclear magnetic hydrogen and nuclear magnetic carbon spectra of some of the examples of the invention.
FIG. 1-1 nuclear magnetic hydrogen spectrum of the product of example 1.
FIGS. 1-2 nuclear magnetic carbon spectrum of the product of example 1.
FIG. 2-1 nuclear magnetic hydrogen spectrum of the product of example 2.
Figure 2-2 nuclear magnetic carbon spectrum of the product of example 2.
FIG. 3-1 nuclear magnetic hydrogen spectrum of the product of example 3.
Figure 3-2 nuclear magnetic carbon spectrum of the product of example 3.
FIG. 4-1 nuclear magnetic hydrogen spectrum of the product of example 4.
Figure 4-2 nuclear magnetic carbon spectrum of the product of example 4.
FIG. 5-1 nuclear magnetic hydrogen spectrum of the product of example 5.
Figure 5-2 nuclear magnetic carbon spectrum of the product of example 5.
FIG. 6-1 nuclear magnetic hydrogen spectrum of the product of example 6.
Figure 6-2 nuclear magnetic carbon spectrum of the product of example 6.
FIG. 7-1 nuclear magnetic hydrogen spectrum of the product of example 7.
Figure 7-2 nuclear magnetic carbon spectrum of the product of example 7.
FIG. 8-1 nuclear magnetic hydrogen spectrum of the product of example 8.
Figure 8-2 nuclear magnetic carbon spectrum of the product of example 8.
FIG. 9-1 nuclear magnetic hydrogen spectrum of the product of example 9.
Figure 9-2 nuclear magnetic carbon spectrum of the product of example 9.
FIG. 10-1 nuclear magnetic hydrogen spectrum of the product of example 10.
FIG. 10-2 nuclear magnetic carbon spectrum of the product of example 10.
FIG. 11 is a reaction scheme of the present invention.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the accompanying drawings, and it should be understood that the described embodiments are some, but not all embodiments of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
In addition, the technical features involved in the different embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
Combining the synthetic route of the compound of the invention and the synthetic principle of the 3-aminobenzo [ d ] isothiazole and the derivative thereof, the method comprises the technical scheme that under the action of alkali, pyridine, acetonitrile, THF, DMAC, DMF, DMSO, 1, 4-dioxane, toluene and other organic solvents are used as solvents to convert the benzamidine compound and elemental sulfur into the 3-aminobenzo [ d ] isothiazole and the derivative thereof without using a catalyst for the first time; the method overcomes the difficulties that the existing synthesis method of the 3-aminobenzo [ d ] isothiazole compound has complex synthesis steps, can be completed by adopting a multi-step synthesis process, and also needs a metal catalyst and peroxide with chemical equivalent; it has stable molecular structure, excellent chemical property, molecular blocks and compound segments containing rich contents of biological activity and pharmacological activity; the method also has the characteristics of simple reaction system, mild reaction conditions, less reaction equipment, simple and convenient experimental operation, wide material sources, high yield, easy expansion of users and applications, higher product utilization value, predictable market commercialization prospect and the like.
3-aminobenzo [ d ] isothiazoles and derivatives thereof having the general formula I:
Figure BSA0000156127220000031
wherein
R1 is selected from hydrogen, alkyl, halo;
r2 is selected from hydrogen atom, alkyl;
r3 is selected from a hydrogen atom; a substituted or unsubstituted C6-C12 aryl group;
in order to realize the method for synthesizing the 3-aminobenzo [ d ] isothiazole and the derivative thereof, under the action of alkali, a benzamidine compound, elemental sulfur and an organic solvent are mixed for reaction and purification to obtain a product.
In order to improve the comprehensive performance of the invention and realize the optimization of structure and effect, the invention has the further measures that:
said base is selected from KHCO3、K2CO3、Na2CO3、K3PO4、K2HPO4、KOH、NaOH、Cs2CO3One or more of potassium tert-butoxide, sodium ethoxide and sodium methoxide; the organic agent is pyridine, acetonitrile, THF, DMAC, DMF, DMSO, 1, 4-dioxane and toluene, the molar ratio of the benzamidine compound to the elemental sulfur to the alkali is 1: 5: 2, and the reaction temperature is 135 ℃.
The benzamidine compound is selected from C7-C19 aromatic amidines, and the general formula is as follows:
Figure BSA0000156127220000032
wherein
R1 is selected from hydrogen, alkyl, halo;
r2 is selected from hydrogen atom, alkyl;
r3 is selected from a hydrogen atom; a substituted or unsubstituted C6-C12 aryl group;
x is selected from fluorine atom, chlorine atom and bromine atom.
The benzamidine compound of the formula II is preferably selected from the group consisting of benzamidine, 2-fluorobenzamidine, 2-chlorobenzamidine, 2-bromobenzamidine, 2-fluoro-N-phenylbenzamidine, 2-chloro-N-phenylbenzamidine, 2-bromo-N-phenylbenzamidine, 2-chloro-N- (p-tolyl) benzamidine, 2-chloro-N- (4-ethylphenyl) benzamidine, 2-chloro-N- (4- (tert-butyl) phenyl) benzamidine, 2-chloro-N- (4-methoxyphenyl) benzamidine, 2-chloro-N- (4-ethoxyphenyl) benzamidine, 2-chloro-N- (4-trifluoromethoxyphenyl) benzamidine, 2-chloro-N- (4-fluorophenyl) benzamidine, 2-chloro-N- (4-chlorophenyl) benzamidine, 2-chloro-N- (4-bromophenyl) benzamidine, 2-chloro-N- ([1, 1' -biphenyl ] -4-yl) benzamidine, 2-chloro-N- (naphthalen-2-yl) benzamidine, 2-chloro-N- (m-tolyl) benzamidine, 2-chloro-N- (m-ethylphenyl) benzamidine, 2-chloro-N- (3-chlorophenyl) benzamidine, 2-chloro-N- (o-tolyl) benzamidine, 2-chloro-N- (2, 4-dimethylphenyl) benzamidine, 2-chloro-N- (3, 4-dimethoxyphenyl) benzamidine, 2-chloro-N- (3, 4, 5-trimethoxyphenyl) benzamidine, 2-chloro-4-methyl-N-phenylbenzamidine, 2-chloro-3-methyl-N-phenylbenzamidine, 2-chloro-4-fluoro-N-phenylbenzamidine, 2-chloro-4-chloro-N-phenylbenzamidine, 2-chloro-4-bromo-N-phenylbenzamidine, 2-chloro-5-trifluoromethyl-N-phenylbenzamidine, 2-chloro-4-trifluoromethyl-N-phenylbenzamidine, 2-chloro-N-methyl-N-phenylbenzamidine.
The 3-aminobenzo [ d ] isothiazole and the derivative thereof formed by the formula II are synthesized into the general formula of the reaction system of the invention, and the general formula is shown as follows:
Figure BSA0000156127220000041
the method comprises the following steps:
(1) adding alkali, a benzamidine compound, elemental sulfur and an organic solvent into a reaction vessel;
(2) fully mixing the reactants, and heating;
(3) purifying after the reaction to obtain a product;
wherein the organic solvent is a polar organic solvent, such as: pyridine, acetonitrile, THF, DMAC, DMF, DMSO, 1, 4-dioxane and toluene;
DMSO and toluene are preferably selected, and the volume ratio is 1: 2;
in order to achieve better synthesis effect, the molar ratio of the benzamidine compound, the elemental sulfur and the alkali is preferably 1: 3-5: 2-3, and the optimal scheme is preferably 1: 5: 2;
the base used is KHCO3、K2CO3、Na2CO3、K3PO4、K2HPO4、KOH、NaOH、Cs2CO3One or more of potassium tert-butoxide, sodium ethoxide and sodium methoxide;
particularly preferably K3PO4；
The reaction temperature T is 110-140 ℃;
preferably 135 deg.c.
3-aminobenzo [ d ] isothiazole and derivatives thereof can be obtained from the process of the synthetic reaction system of the compound, and the compound can convert benzamidine compounds and elemental sulfur into 3-aminobenzo [ d ] isothiazole for the first time under the condition of not using a catalyst and only needing alkali.
As an important molecular block, the compound of the formula I has a stable molecular structure and excellent chemical properties, has certain physiological activity, can further synthesize a plurality of compound fragments containing a 3-aminobenzo [ d ] isothiazole structure by converting functional groups, and has strong physiological activity and pharmacological activity;
in a word, the compound has the advantages that the reaction raw materials are cheap and easy to obtain, and pretreatment is not needed; the reaction does not need to use a catalyst and peroxide; only alkali is used as an accelerant, the reaction is directly synthesized in one pot, and the like; the method solves the problems of high cost and the like caused by the conventional multi-step synthesis method; the reaction condition is mild, and the temperature required by the reaction is greatly lower than the reaction temperature of the previous multi-step synthesis; a series of synthesized 3-aminobenzo [ d ] isothiazole compounds have quite high potential application value.
Examples 1 to 29
Examples 1-29 were all synthesized using the following procedure:
(1) adding alkali, a benzamidine compound, elemental sulfur and an organic solvent into a reaction vessel;
(2) fully mixing the reactants, and heating;
(3) purifying after the reaction to obtain a product;
the benzamidine compounds and the reaction conditions are shown in the table.
Table: reactants, reaction conditions and yields of examples 1-29
Figure BSA0000156127220000042
Figure BSA0000156127220000051
Figure BSA0000156127220000061
It should be noted that the reaction time is not only 36h, but can be very long, here the 36h standard is set only for comparison of the yield.
The nuclear magnetic and mass spectral data of the products of some of the examples are:
the nuclear magnetic and mass spectral data of the product of example 1 are as follows:
1H NMR(400MHz，DMSO-d6，ppm)δ9.60(s，1H)，8.49(d，J＝8.1Hz，1H)，8.06(d，J＝8.1Hz，1H)，7.96(d，J＝7.7Hz，2H)，7.60(t，J＝7.5Hz，1H)，7.51(t，J＝7.5Hz，1H)，7.34(t，J＝8.0Hz，2H)，6.97(t，J＝7.3Hz，1H)；13C NMR(100MHz，DMSO-d6，ppm)δ155.3，149.9，141.3，128.8，128.5，127.5，124.5，122.8，121.4，120.6，117.9；HRMS calcd.for：C13H11N2S[M+H]+227.0638，found 227.0636.
the nuclear magnetic and mass spectral data of the product of example 2 are as follows:
1H NMR(400MHz，CDCl3，ppm)δ7.83(d，J＝8.1Hz，1H)，7.77(d，J＝8.1Hz，1H)，7.61(d，J＝8.3Hz，2H)，7.52(t，J＝7.3Hz，1H)，7.40(t，J＝7.5Hz，1H)，7.17(d，J＝8.2Hz，2H)，6.98(s，1H)，2.33(s，3H)；13C NMR(100MHz，CDCl3，ppm)δ154.7，151.0，137.7，131.9，129.6，128.1，127.0，124.1，120.8，120.4，118.5，20.8；HRMS calcd.for：C14H13N2S[M+H]+241.0794，found 241.0790.
the nuclear magnetic and mass spectral data of the product of example 3 are as follows:
1H NMR(400MHz，CDCl3，ppm)δ7.84(d，J＝8.1Hz，1H)，7.77(d，J＝8.7Hz，1H)，7.64(d，J＝8.5Hz，2H)，7.52(t，J＝7.6Hz，1H)，7.41(t，J＝7.6Hz，1H)，7.20(d，J＝8.2Hz，2H)，6.98(s，1H)，2.64(q，J＝7.6Hz，2H)，1.24(t，J＝7.6Hz，3H)；13C NMR(100MHz，CDCl3，ppm)δ154.6，151.0，138.4，137.8，128.4，128.1，127.0，124.1，120.8，120.4，118.5，28.2，15.7；HRMS calcd.for：C15H15N2S[M+H]+255.0951，found 255.0949.
the nuclear magnetic and mass spectral data of the product of example 4 are as follows:
1H NMR(400MHz，CDCl3，ppm)δ7.84(d，J＝8.1Hz，1H)，7.78(d，J＝8.1Hz，1H)，7.65(d，J＝8.4Hz，2H)，7.52(t，J＝7.6Hz，1H)，7.43-7.35(m，3H)，6.98(s，1H)，1.33(s，9H)；13C NMR(100MHz，CDCl3，ppm)δ154.6，151.0，145.3，137.6，128.1，127.0，125.9，124.1，120.8，120.4，118.1，34.2，31.4；HRMS calcd.for：C17H19N2S[M+H]+283.1264，found 283.1264.
the nuclear magnetic and mass spectral data of the product of example 5 are as follows:
1H NMR(400MHz，CDCl3，ppm)δ7.80(d，J＝8.1Hz，1H)，7.73(d，J＝8.1Hz，1H)，7.64-7.57(m，2H)，7.49(t，J＝7.3Hz，1H)，7.36(t，J＝7.5Hz，1H)，6.96-6.84(m，3H)，3.78(s，3H)；13C NMR(100MHz，CDCl3，ppm)δ155.3，155.1，151.0，133.6，128.0，126.9，124.0，120.8，120.4，120.3，114.3，55.5；HRMS calcd.for：C14H13N2OS[M+H]+257.0743，found 257.0743.
the nuclear magnetic and mass spectral data of the product of example 6 are as follows:
1H NMR(400MHz，CDCl3，ppm)δ7.80(d，J＝8.1Hz，1H)，7.72(d，J＝8.1Hz，1H)，7.64-7.55(m，2H)，7.49(t，J＝7.5Hz，1H)，7.35(t，J＝7.5Hz，1H)，6.98-6.83(m，3H)，4.00(q，J＝7.0Hz，2H)，1.39(t，J＝7.0Hz，3H)；13C NMR(100MHz，CDCl3，ppm)δ155.1，154.6，151.0，133.5，128.0，126.9，124.0，120.9，120.4，120.3，115.0，63.7，14.8；HRMS calcd.for：C15H15N2OS[M+H]+271.0900，found 271.0894.
the nuclear magnetic and mass spectral data of the product of example 7 are as follows:
1H NMR(400MHz，CDCl3，ppm)δ7.84(d，J＝8.1Hz，1H)，7.82-7.72(m，3H)，7.53(t，J＝7.6Hz，1H)，7.41(t，J＝7.5Hz，1H)，7.19(d，J＝8.8Hz，2H)，7.07(s，1H)；13C NMR(100MHz，CDCl3，ppm)δ154.0，151.0，143.7(q，J＝1.7，1.7Hz)，139.0，128.3，126.9，124.3，121.9，120.6，120.6(q，J＝254.7Hz)，120.5，118.9；HRMS calcd.for：C14H10F3N2OS[M+H]+311.0461，found 311.0458.
the nuclear magnetic and mass spectral data of the product of example 8 are as follows:
1H NMR(400MHz，CDCl3，ppm)δ7.85(d，J＝8.1Hz，1H)，7.77(d，J＝8.1Hz，1H)，7.73-7.66(m，2H)，7.56-7.52(m，1H)，7.44-7.40(m，1H)，7.10-7.03(m，2H)，6.98(s，1H)；13C NMR(100MHz，CDCl3，ppm)δ158.3(d，J＝239.6Hz)，154.5，151.1，136.3(d，J＝2.5Hz)，128.3，126.8，124.3，120.7，120.5，119.9(d，J＝7.7Hz)，115.7(d，J＝22.3Hz)；HRMS calcd.for：C13H10FN2S[M+H]+245.0543，found 245.0543.
the nuclear magnetic and mass spectral data of the product of example 9 are as follows:
1H NMR(400MHz，CDCl3，ppm)δ7.86(d，J＝8.1Hz，1H)，7.78(d，J＝8.1Hz，1H)，7.71(d，J＝8.8Hz，2H)，7.55(t，J＝7.6Hz，1H)，7.43(t，J＝7.5Hz，1H)，7.31(d，J＝8.7Hz，2H)，7.07(s，1H)；13C NMR(100MHz，CDCl3，ppm)δ154.0，151.0，138.8，129.0，128.3，126.9，126.9，124.3，120.7，120.5，119.2；HRMS calcd.for：C13H10ClN2S[M+H]+261.0248，found 261.0244.
the nuclear magnetic and mass spectral data of the product of example 10 are as follows:
1H NMR(400MHz，CDCl3，ppm)δ7.85(d，J＝8.1Hz，1H)，7.77(d，J＝8.0Hz，1H)，7.66(d，J＝7.8Hz，2H)，7.54(t，J＝7.5Hz，1H)，7.48-7.38(m，3H)，7.01(s，1H)；13C NMR(100MHz，CDCl3，ppm)δ153.9，151.0，139.3，131.9，128.3，126.9，124.3，120.6，120.5，119.5，114.3；HRMS calcd.for：C13H10BrN2S[M+H]+304.9743，found304.9746.
the nuclear magnetic and mass spectral data of the product of example 11 are as follows:
1H NMR(400MHz，DMSO-d6，ppm)δ9.75(s，1H)，8.53(d，J＝8.1Hz，1H)，8.08(d，J＝8.8Hz，3H)，7.70-7.67(m，4H)，7.63(t，J＝7.5Hz，1H)，7.54(t，J＝7.5Hz，1H)，7.45(t，J＝7.6Hz，2H)，7.32(t，J＝7.3Hz，1H)；13C NMR(100MHz，DMSO-d6，ppm)δ155.29，149.99，140.9，140.1，133.0，129.0，128.6，127.6，127.0，126.8，126.2，124.5，122.8，120.7，118.2；HRMS calcd.for：C19H15N2S[M+H]+303.0951，found 303.0946.
the nuclear magnetic and mass spectral data of the product of example 12 are as follows:
1H NMR(400MHz，CDCl3，ppm)δ8.53(d，J＝1.7Hz，1H)，7.89-7.77(m，5H)，7.61-7.53(m，2H)，7.45(q，J＝7.0Hz，2H)，7.38-7.34(m，1H)，7.22(s，1H)；13C NMR(100MHz，CDCl3，ppm)δ154.3，151.0，137.7，134.4，129.7，128.8，128.2，127.5，127.4，127.2，126.4，124.3，124.1，120.7，120.5，119.3，113.4；HRMS calcd.for：C17H13N2S[M+H]+277.0794，found 277.0790.
the nuclear magnetic and mass spectral data of the product of example 13 are as follows:
1H NMR(400MHz，CDCl3，ppm)δ7.84(d，J＝8.0Hz，1H)，7.77(d，J＝8.0Hz，1H)，7.57-7.50(m，3H)，7.40(t，J＝7.4Hz，1H)，7.24(t，J＝7.7Hz，1H)，6.99(s，1H)，6.86(d，J＝7.3Hz，1H)，2.37(s，3H)；13C NMR(100MHz，CDCl3，ppm)δ154.4，151.0，140.2，139.0，128.9，128.1，127.1，124.1，123.2，120.7，120.4，118.7，115.2，21.6；HRMS calcd.for：C14H13N2S[M+H]+241.0794，found 241.0790.
the nuclear magnetic and mass spectral data of the product of example 14 are as follows:
1H NMR(400MHz，CDCl3，ppm)δ7.84(d，J＝8.1Hz，1H)，7.78(d，J＝8.1Hz，1H)，7.61-7.49(m，3H)，7.41(t，J＝7.6Hz，1H)，7.28(t，J＝7.8Hz，1H)，7.01(s，1H)，6.90(d，J＝7.6，1H)，2.68(q，J＝7.6Hz，2H)，1.27(t，J＝7.6Hz，3H)；13C NMR(100MHz，CDCl3，ppm)δ154.4，151.0，145.4，140.2，129.0，128.1，127.1，124.1，121.9，120.7，120.4，117.6，115.5，29.0，15.5；HRMS calcd.for：C15H15N2S[M+H]+255.0951，found 255.0949.
the nuclear magnetic and mass spectral data of the product of example 15 are as follows:
1H NMR(400MHz，CDCl3，ppm)δ7.93(t，J＝2.0Hz，1H)，7.86(d，J＝8.1Hz，1H)，7.78(d，J＝8.1Hz，1H)，7.55(t，J＝7.6Hz，2H)，7.44(t，J＝7.4Hz，1H)，7.27(tJ＝6.5Hz，1H)，7.09(s，1H)，7.01(d，J＝7.9，1H)；13C NMR(100MHz，CDCl3，ppm)δ153.7，151.0，141.4，134.8，130.1，128.3，126.9，124.4，122.2，120.6，120.5，117.8，115.9；HRMS calcd.for：C13H10ClN2S[M+H]+261.0248，found 261.0244.
the nuclear magnetic and mass spectral data of the product of example 16 are as follows:
1H NMR(400MHz，CDCl3，ppm)δ8.22(d，J＝8.0Hz，1H)，7.84(d，J＝8.1Hz，1H)，7.73(d，J＝8.1Hz，1H)，7.54-7.50(m，1H)，7.40(t，J＝7.3Hz，1H)，7.28-7.21(m，2H)，7.01(t，J＝7.1Hz，1H)，6.82(s，1H)，2.38(s，3H)；13C NMR(100MHz，CDCl3，ppm)δ154.9，151.3，138.5，130.5，128.1，127.2，127.0，126.5，124.2，122.9，120.9，120.5，119.7，17.7；HRMS calcd.for：C14H13N2S[M+H]+241.0794，found 241.0795.
the nuclear magnetic and mass spectral data of the product of example 17 are as follows:
1H NMR(400MHz，CDCl3，ppm)δ7.95(d，J＝8.6Hz，1H)，7.83(d，J＝8.1Hz，1H)，7.72(d，J＝8.1Hz，1H)，7.56-7.49(m，1H)，7.43-7.36(m，1H)，7.07-7.05(m，2H)，6.75(s，1H)，2.3(s，3H)，2.3(s，3H)；13C NMR(100MHz，CDCl3，ppm)δ155.5，151.3，135.8，133.0，131.3，128.1，127.7，127.5，127.0，124.1，121.0，120.8，120.5，20.8，17.7；HRMS calcd.for：C15H15N2S[M+H]+255.0951，found 255.0948.
the nuclear magnetic and mass spectral data of the product of example 18 are as follows:
1H NMR(400MHz，CDCl3，ppm)δ7.84(d，J＝8.1Hz，1H)，7.78(d，J＝8.1Hz，1H)，7.55-7.50(m，2H)，7.43-7.37(m，1H)，7.15(dd，J＝8.6，2.3Hz，1H)，7.00(s，1H)，6.87(d，J＝8.6Hz，1H)，3.92(s，3H)，3.88(s，3H)；13C NMR(100MHz，CDCl3，ppm)δ155.0，150.9，149.2，144.6，134.1，128.1，126.9，124.1，120.9，120.3，111.8，110.5，103.9，56.2，55.8；HRMS calcd.for：C15H15N2O2S[M+H]+287.0849，found 287.0848.
the nuclear magnetic and mass spectral data of the product of example 19 are as follows:
1H NMR(400MHz，CDCl3，ppm)δ7.83(dd，J＝10.5，8.2Hz，2H)，7.53(t，J＝7.4Hz，1H)，7.40（t，J＝7.7Hz，1H)，7.08(s，3H)，3.88(s，6H)，3.83(s，3H)；13C NMR(100MHz，CDCl3，ppm)δ154.5，153.5，150.9，136.6，133.2，128.2，127.0，124.2，120.8，120.4，96.1，61.0，56.1；HRMS calcd.for：C16H17N2O3S[M+H]+317.0955，found 317.0954.
the nuclear magnetic and mass spectral data of the product of example 20 are as follows:
1H NMR(400MHz，CDCl3，ppm)δ7.76-7.68(m，2H)，7.63-7.54(m，2H)，7.34(t，J＝7.9Hz，2H)，7.18(d，J＝8.2Hz，1H)，7.02(t，J＝7.4Hz，1H)，6.96(s，1H)，2.47(s，3H)；13C NMR(100MHz，CDCl3，ppm)δ154.2，151.4，140.3，138.7，129.1，126.0，125.2，122.1，120.3，120.1，117.9，21.6；HRMS calcd.for：C14H13N2S[M+H]+241.0794，found 241.0794.
the nuclear magnetic and mass spectral data of the product of example 21 are as follows:
1H NMR(400MHz，CDCl3，ppm)δ7.77-7.72(m，2H)，7.61(d，J＝7.9Hz，1H)，7.38-7.28(m，4H)，7.04(t，J＝7.4Hz，1H)，7.00(s，1H)，2.53(s，3H)；13C NMR(100MHz，CDCl3，ppm)δ155.0，151.4，140.3，130.7，129.1，128.2，126.9，125.0，122.2，118.2，118.0，19.9；HRMS calcd.for：C14H13N2S[M+H]+241.0794，found 241.0790.
the nuclear magnetic and mass spectral data of the product of example 22 are as follows:
1H NMR(400MHz，CDCl3，ppm)δ7.75-7.68(m，3H)，7.49(dd，J＝8.2，2.0Hz，1H)，7.36(t，J＝7.9Hz，2H)，7.14(td，J＝8.6，2.1Hz，1H)，7.05(t，J＝7.4Hz，1H)，6.96(s，1H)；13C NMR(100MHz，CDCl3，ppm)δ162.8(d，J＝249.7Hz)，153.8，152.8(d，J＝10.2Hz)，140.0，129.1，123.8，122.5，122.2(d，J＝10.2Hz)，118.2，113.5(d，J＝25.4Hz)，106.4(d，J＝25.2Hz)；HRMS calcd.for：C13H10FN2S[M+H]+245.0543，found 245.0549.
the nuclear magnetic and mass spectral data of the product of example 23 are as follows:
1H NMR(400MHz，CDCl3，ppm)δ7.82(d，J＝1.6Hz，1H)，7.72-7.67(m，3H)，7.39-7.34(m，3H)，7.08-7.04(m，1H)，7.00(s，1H)；13C NMR(100MHz，CDCl3，ppm)δ153.9，152.4，140.0，135.1，129.2，125.6，125.1，122.6，121.6，120.0，118.1；HRMS calcd.for：C13H10ClN2S[M+H]+261.0248，found 261.0245.
the nuclear magnetic and mass spectral data of the product of example 24 are as follows:
1H NMR(400MHz，CDCl3，ppm)δ7.96(d，J＝1.4Hz，1H)，7.69(dd，J＝8.6，0.9Hz，2H)，7.59(d，J＝8.6Hz，1H)，7.48(dd，J＝8.6，1.6Hz，1H)，7.38-7.33(m，2H)，7.05(t，J＝7.4Hz，1H)，6.97(s，1H)；13C NMR(100MHz，CDCl3，ppm)δ154.0，152.7，139.9，129.1，127.6，125.9，123.3，123.0，122.5，121.7，118.1；HRMS calcd.for：C13H10BrN2S[M+H]+304.9743，found 304.9741.
the nuclear magnetic and mass spectral data of the product of example 25 are as follows:
1H NMR(400MHz，CDCl3，ppm)δ7.94(d，J＝1.3Hz，1H)，7.72(d，J＝8.5Hz，3H)，7.62(dd，J＝8.6，1.7Hz，1H)，7.42-7.34(m，2H)，7.08(t，J＝7.4Hz，1H)，6.97(s，1H)；13C NMR(100MHz，CDCl3，ppm)δ153.4，149.9，139.9，131.3，129.2，128.7，123.7，122.6，121.7，118.2，118.0；HRMS calcd.for：C13H10BrN2S[M+H]+304.9743，found 304.9747.
the nuclear magnetic and mass spectral data of the product of example 26 are as follows:
1H NMR(400MHz，CDCl3，ppm)δ8.05(s，1H)，7.94(d，J＝8.5Hz，1H)，7.74(dd，J＝8.6，1.0Hz，3H)，7.42-7.34(m，2H)，7.13-7.01(m，2H)；13C NMR(100MHz，CDCl3，ppm)δ154.5，154.3，139.8，129.2，126.9(q，J＝32.7Hz)，126.8，124.5(q，J＝2.8Hz)，124.1(q，J＝270.6Hz)，122.8，121.1，118.4，118.3；HRMS calcd.for：C14H10F3N2S[M+H]+295.0512，found 295.0515.
the nuclear magnetic and mass spectral data of the product of example 27 are as follows:
1H NMR(400MHz，CDCl3，ppm)δ8.13(s，1H)，7.88(d，J＝8.4Hz，1H)，7.73(d，J＝8.4Hz，2H)，7.63(d，J＝8.4Hz，1H)，7.38(t，J＝7.6Hz，2H)，7.09-7.05(m，2H)；13C NMR(100MHz，CDCl3，ppm)δ154.1，151.2，139.8，130.3(q，J＝32.5Hz)，129.2，128.9，123.9(q，J＝271.3Hz)，122.8，121.6，121.0(q，J＝3.2Hz)，118.2，117.9(q，J＝4.3Hz)；HRMS calcd.for：C14H10F3N2S[M+H]+295.0512，found 295.0515.
the nuclear magnetic and mass spectral data of the product of example 28 are as follows:
1H NMR(400MHz，CDCl3，ppm)δ7.81(d，J＝8.2Hz，1H)，7.71(d，J＝8.1Hz，1H)，7.53-7.48(m，1H)，7.38(t，J＝7.5Hz，1H)，4.69(s，2H)；13C NMR(100MHz，CDCl3，ppm)δ158.6，151.9，128.0，126.3，124.0，121.6，120.4；HRMS calcd.for：C7H7N2S[M+H]+151.0325，found 151.0321.
the nuclear magnetic and mass spectral data of the product of example 29 are as follows:
1H NMR(400MHz，CDCl3，ppm)δ7.76(d，J＝8.2Hz，1H)，7.38-7.31(m，3H)，7.22-7.14(m，3H)，7.04-7.00(m，1H)，6.91-6.88(m，1H)，3.60(s，3H)；13C NMR(100MHz，CDCl3，ppm)δ160.7，152.7，147.9，129.4，127.7，127.2，125.2，125.0，124.6，123.5，120.1，42.3；HRMS calcd.for：C14H13N2S[M+H]+241.0794，found 241.0788.
it should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. And are neither required nor exhaustive of all embodiments. And obvious variations or modifications therefrom are within the scope of the invention.

Claims (3)

1. A method for synthesizing 3-aminobenzo [ d ] isothiazole and derivatives thereof is characterized in that the benzamidine compound and elemental sulfur are heated and stirred under the reaction condition of alkali and organic solvent to obtain the compound;
the structural general formula of the benzamidine compound is shown as formula II:
Figure FSB0000192679330000011
wherein
R1 is selected from hydrogen, alkyl, halo;
r2 is selected from hydrogen atom, alkyl;
r3 is selected from a hydrogen atom; a substituted or unsubstituted C6-C12 aryl group;
x is selected from fluorine atom, chlorine atom and bromine atom;
3-aminobenzo [ d ] isothiazoles and derivatives thereof having the general formula I:
Figure FSB0000192679330000012
said base is selected from KHCO3、K2CO3、Na2CO3、K3PO4、K2HPO4、KOH、NaOH、Cs2CO3Potassium tert-butoxide, sodium ethoxide and sodium methoxide.
2. The method according to claim 1, wherein the organic solvent is selected from one or more of pyridine, acetonitrile, THF, DMAC, DMF, DMSO, 1, 4-dioxane, toluene.
3. The method of claim 1 or 2, wherein the molar ratio of the benzamidine compound to the elemental sulfur to the base is 1: 3 to 5: 2 to 3, and the reaction temperature is 110 ℃ to 140 ℃.
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