Preparation method of 4-benzamide-5-chloro-2-methyl benzene diazonium salt

Abstract

The invention provides a preparation method of 4-benzamide-5-chloro-2-methyl benzene diazonium salt, and belongs to the technical field of diazonium salt dye preparation. According to the method, 2-chloro-5-methyl-1, 4-phenylenediamine is taken as a raw material, and the 2-chloro-5-methyl-1, 4-phenylenediamine is prepared through five continuous reaction steps of protecting group adding reaction, acylation reaction, protecting group removing reaction, diazotization reaction and salt forming reaction. The method has the advantages that the raw materials are easy to obtain, the synthesis method is simple, the conditions are mild and easy to operate, large-scale production can be realized, the total yield of the obtained 4-benzamide-5-chloro-2-methyl benzene diazonium salt is 80% or above, the purity is 98% or above, and the compound is good in stability and can be stored for a long time.

Description

Technical Field

[0001] The invention relates to the technical field of diazonium salt dye preparation, and in particular to a method for preparing 4-benzamide-5-chloro-2-methylbenzene diazonium salt. Background Art

[0002] 4-Benzamide-5-chloro-2-methylbenzenediazonium chloride is a diazo compound, which is often used in the determination of alkaline phosphatase. Because the compound is not stable enough, it is often salified to make 4-benzamide-5-chloro-2-methylbenzenediazonium salt. For example, 4-benzamide-5-chloro-2-methylbenzenediazonium chloride is salified with zinc chloride, i.e. 4-benzamide-5-chloro-2-methylbenzenediazonium hemichloride zinc salt, commonly known as Fast Red Purple LB salt, and its structural formula is as follows:

[0003]

[0004] The shortcomings of the prior art of 4-benzamide-5-chloro-2-methylbenzene diazonium salt are: difficult preparation, low purity, low yield, and less public synthesis routes. Therefore, how to develop a preparation method of 4-benzamide-5-chloro-2-methylbenzene diazonium salt with high reaction efficiency, high purity, high yield, mass production and good stability, so that it is more beneficial to application, is a technical problem that needs to be solved at present. Summary of the invention

[0005] The object of the present invention is to provide a method for preparing 4-benzamide-5-chloro-2-methylbenzene diazonium salt, so as to solve the technical problems that the existing 4-benzamide-5-chloro-2-methylbenzene diazonium salt is difficult to prepare, has low purity, low yield and few public synthetic routes.

[0006] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0007] The present invention provides a method for preparing 4-benzamide-5-chloro-2-methylbenzene diazonium salt, comprising the following steps:

[0008] 1) dissolving 2-chloro-5-methyl-1,4-phenylenediamine in an organic solvent A, adding a protective reagent and reacting to obtain compound 1;

[0009] 2) adding an acylating agent and an acid binding agent to compound 1 to carry out an acylation reaction to obtain compound 2;

[0010] 3) Compound 2 is added to solvent B to carry out a deprotection reaction to obtain compound 3;

[0011] 4) adding compound 3 to an acid aqueous solution for acidification, and then adding nitrite for diazotization reaction to obtain compound 4;

[0012] 5) adding a salt-forming reagent to compound 4 and performing a salt-forming reaction to obtain 4-benzamide-5-chloro-2-methylbenzene diazonium salt;

[0013] The protective reagent comprises one of tosyl chloride, triphenylmethane chloride, benzyl chloroformate, tert-butyl chloroformate, di-tert-butyl dicarbonate and trifluoroacetyl chloride;

[0014] The preparation route of the benzamide-5-chloro-2-methylbenzene diazonium salt is as follows:

[0015]

[0016] Among them, R 1 is toluenesulfonyl, trityl, benzyloxycarbonyl, tert-butyloxycarbonyl or trifluoroacetyl, R 2 It is zinc hemichloride or tetrafluoroborate.

[0017] Furthermore, in the step 1), the organic solvent A comprises one or more of dichloromethane, chloroform, acetone, tetrahydrofuran, isopropyl ether, petroleum ether, n-hexane, acetonitrile, dioxane and N,N-dimethylformamide; the molar ratio of the 2-chloro-5-methyl-1,4-phenylenediamine to the protective reagent is 1:1-2, and the amount ratio of 2-chloro-5-methyl-1,4-phenylenediamine to the organic solvent A is 1g:5-20mL.

[0018] Furthermore, in the step 1), the reaction temperature is 0 to 50° C., and the reaction time is 1 to 48 hours.

[0019] Further, in the step 2), the acylating agent comprises benzoyl chloride, and the acid-binding agent comprises triethylamine or pyridine; the molar ratio of compound 1 to the acylating agent is 1:1.05-1.13, and the molar ratio of the acylating agent to the acid-binding agent is 0.1 mol:10-25 mL;

[0020] The temperature of the acylation reaction is 0 to 40° C., and the time of the acylation reaction is 1 to 24 hours.

[0021] Furthermore, in the step 3), solvent B is a mixed solvent consisting of an organic solvent and an acid, wherein the organic solvent comprises one or more of methanol, ethanol, isopropanol, acetone, dichloromethane, chloroform, tetrahydrofuran, isopropyl ether, petroleum ether, n-hexane, acetonitrile, dioxane and N,N-dimethylformamide, and the acid water comprises one of hydrochloric acid, sulfuric acid, nitric acid, acetic acid or trifluoroacetic acid.

[0022] Furthermore, the dosage ratio of the compound 2 to the organic solvent is 1 g: 4-5 mL, and the dosage ratio of the compound 2 to the acid is 1 g: 0.8-1 mL; the temperature of the deprotection reaction is 0-75° C., and the time of the deprotection reaction is 0.5-12 h.

[0023] Furthermore, in the step 4), the acid aqueous solution is a hydrochloric acid aqueous solution or a sulfuric acid aqueous solution, the volume concentration of the acid aqueous solution is 9-50%, the dosage ratio of compound 3 and the acid aqueous solution is 1g:15-20mL, the molar ratio of nitrite to compound 3 is 1:1-2, and the nitrite comprises sodium nitrite or potassium nitrite.

[0024] Furthermore, in the step 4), the temperature of the diazotization reaction is -15 to 15°C, and the time of the diazotization reaction is 0.5 to 12 hours.

[0025] Furthermore, in step 5), the salt-forming reagent comprises zinc chloride or tetrafluoroboric acid, and the molar ratio of the salt-forming reagent to compound 4 is 1:0.5-2; the temperature of the salt-forming reaction is -10-30°C, and the time of the salt-forming reaction is 0.5-12h.

[0026] Further, the 4-benzamide-5-chloro-2-methylbenzene diazonium salt includes 4-benzamide-5-chloro-2-methylbenzene diazonium zinc hemichloride or 4-benzamide-5-chloro-2-methylbenzene diazonium tetrafluoroborate.

[0027] Beneficial effects of the present invention:

[0028] 1) The present invention provides a method for preparing 4-benzamide-5-chloro-2-methylbenzene diazonium salt, and the synthetic process route has high yield and high purity;

[0029] 2) A method for preparing 4-benzamide-5-chloro-2-methylbenzene diazonium salt of the present invention has readily available raw materials, a simple synthesis method, mild conditions, easy operation, and can be mass-produced;

[0030] 3) A method for preparing 4-benzamide-5-chloro-2-methylbenzene diazonium salt of the present invention, wherein the obtained 4-benzamide-5-chloro-2-methylbenzene diazonium zinc hemichloride salt or 4-benzamide-5-chloro-2-methylbenzene diazonium tetrafluoroborate has good stability and can be stored for a long time. DETAILED DESCRIPTION

[0031] The present invention provides a method for preparing 4-benzamide-5-chloro-2-methylbenzene diazonium salt, comprising the following steps:

[0032] 1) dissolving 2-chloro-5-methyl-1,4-phenylenediamine in an organic solvent A, adding a protective reagent and reacting to obtain compound 1;

[0033] 2) adding an acylating agent and an acid binding agent to compound 1 to carry out an acylation reaction to obtain compound 2;

[0034] 3) Compound 2 is added to solvent B to carry out a deprotection reaction to obtain compound 3;

[0035] 4) adding compound 3 to an acid aqueous solution for acidification, and then adding nitrite for diazotization reaction to obtain compound 4;

[0036] 5) adding a salt-forming reagent to compound 4 and performing a salt-forming reaction to obtain 4-benzamide-5-chloro-2-methylbenzene diazonium salt;

[0037] The protective reagent comprises one of tosyl chloride, triphenylmethane chloride, benzyl chloroformate, tert-butyl chloroformate, di-tert-butyl dicarbonate and trifluoroacetyl chloride;

[0038] The preparation route of the benzamide-5-chloro-2-methylbenzene diazonium salt is as follows:

[0039]

[0040] Among them, R 1 is toluenesulfonyl, trityl, benzyloxycarbonyl, tert-butyloxycarbonyl or trifluoroacetyl, R 2 It is zinc hemichloride or tetrafluoroborate.

[0041] In the present invention, the protecting agent is preferably one or more of toluenesulfonyl chloride, triphenylmethane chloride, benzyl chloroformate, tert-butyl chloroformate and di-tert-butyl dicarbonate.

[0042] In the present invention, in the step 1), the organic solvent A comprises one or more of dichloromethane, chloroform, acetone, tetrahydrofuran, isopropyl ether, petroleum ether, n-hexane, acetonitrile, dioxane and N,N-dimethylformamide, preferably one or more of dichloromethane, chloroform, acetone, tetrahydrofuran, isopropyl ether, petroleum ether and n-hexane, and further preferably one or more of dichloromethane, acetone and isopropyl ether.

[0043] In the present invention, in the step 1), the molar ratio of the 2-chloro-5-methyl-1,4-phenylenediamine to the protective agent is 1:1-2, preferably 1:1.2-1.8, and more preferably 1:1.4-1.6, and the amount ratio of 2-chloro-5-methyl-1,4-phenylenediamine to the organic solvent A is 1g:5-20mL, preferably 1g:8-18mL, and more preferably 1g:10-15mL.

[0044] In the present invention, in the step 1), the reaction temperature is 0 to 50°C, preferably 10 to 40°C, and more preferably 20 to 30°C; the reaction time is 1 to 48h, preferably 5 to 40h, and more preferably 10 to 35h.

[0045] In the present invention, in the step 2), the acylating agent is preferably benzoyl chloride, and the acid binding agent is preferably triethylamine or pyridine; the molar ratio of compound 1 to the acylating agent is 1:1.05-1.13, preferably 1:1.08-1.11, and more preferably 1:1.1; the molar ratio of the acylating agent to the acid binding agent is 0.1 mol:10-25 mL, preferably 0.1 mol:13-23 mL, and more preferably 0.1 mol:15-20 mL.

[0046] In the present invention, in the step 2), the temperature of the acylation reaction is 0 to 40°C, preferably 10 to 30°C, and more preferably 15 to 25°C; the time of the acylation reaction is 1 to 24h, preferably 5 to 20h, and more preferably 10 to 15h.

[0047] In the present invention, in the step 3), the solvent B is a mixed solvent composed of an organic solvent and an acid, and the organic solvent comprises one or more of methanol, ethanol, isopropanol, acetone, dichloromethane, chloroform, tetrahydrofuran, isopropyl ether, petroleum ether, n-hexane, acetonitrile, dioxane and N,N-dimethylformamide, preferably one or more of methanol, ethanol, isopropanol, acetone, dichloromethane, chloroform, tetrahydrofuran, isopropyl ether and petroleum ether, and further preferably one or more of methanol, ethanol, isopropanol and acetone;

[0048] The acid comprises one of hydrochloric acid, sulfuric acid, nitric acid, acetic acid or trifluoroacetic acid, preferably hydrochloric acid.

[0049] In the present invention, the dosage ratio of the compound 2 to the organic solvent is 1g:4-5mL, preferably 1g:4.5mL; the dosage ratio of the compound 2 to the acid is 1g:0.8-1mL, preferably 1g:0.9mL; the temperature of the deprotection reaction is 0-75°C, preferably 5-70°C, and more preferably 10-60°C; the time of the deprotection reaction is 0.5-12h, preferably 1-10h, and more preferably 4-8h.

[0050] In the present invention, in the step 4), the acid aqueous solution is a hydrochloric acid aqueous solution or a sulfuric acid aqueous solution, preferably a hydrochloric acid aqueous solution; the volume concentration of the acid aqueous solution is 9-50%, preferably 10-45%, and more preferably 20-30%; the dosage ratio of compound 3 and the acid aqueous solution is 1g:15-20mL, preferably 1g:16-19mL, and more preferably 1g:17-18mL; the molar ratio of nitrite to compound 3 is 1:1-2, preferably 1:1.2-1.8, and more preferably 1:1.4-1.6; the nitrite is preferably sodium nitrite or potassium nitrite.

[0051] In the present invention, in step 4), the temperature of the diazotization reaction is -15 to 15°C, preferably -10 to 10°C, more preferably -5 to 5°C, and more preferably 0°C; the time of the diazotization reaction is 0.5 to 12h, preferably 1 to 10h, and more preferably 2 to 8h.

[0052] In the present invention, in the step 5), the salt-forming reagent comprises zinc chloride or tetrafluoroboric acid, and the molar ratio of the salt-forming reagent to compound 4 is 1:0.5-2; when the salt-forming reagent is zinc chloride, the molar ratio of zinc chloride to compound 4 is 1:0.5-0.8, preferably 1:0.6-0.7; when the salt-forming reagent is tetrafluoroboric acid, the molar ratio of tetrafluoroboric acid to compound 4 is 1:1-2, preferably 1:1.2-1.8, and more preferably 1:1.4-1.6.

[0053] In the present invention, in step 5), the temperature of the salt-forming reaction is -10 to 30°C, preferably -5 to 25°C, and more preferably 0 to 20°C; the time of the salt-forming reaction is 0.5 to 12h, preferably 1 to 10h, and more preferably 2 to 8h.

[0054] In the present invention, the 4-benzamide-5-chloro-2-methylbenzene diazonium salt includes 4-benzamide-5-chloro-2-methylbenzene diazonium zinc hemichloride or 4-benzamide-5-chloro-2-methylbenzene diazonium tetrafluoroborate.

[0055] In the present invention, the starting material of the reaction is 2-chloro-5-methyl-1,4-phenylenediamine. The activity of the amino groups at positions 1 and 4 in the compound is not much different. The product is generally a mixture of two isomers, which is difficult to separate and purify, affecting the purity of the final product and further affecting its use effect. Further research has found that the activity of the amino group at position 4 is slightly higher than that of the amino group at position 1. Therefore, it is necessary to first add a protective group to the amino group at position 4, and then perform an acylation reaction, a deprotection reaction, a diazotization reaction, and a salt-forming reaction. The total yield of the obtained 4-benzamide-5-chloro-2-methylbenzene diazonium salt is above 80%, the purity is above 98%, and the compound has good stability and can be stored for a long time.

[0056] The technical solutions provided by the present invention are described in detail below in conjunction with the embodiments, but they should not be construed as limiting the protection scope of the present invention.

[0057] The preparation route of the benzamide-5-chloro-2-methylbenzene diazonium salt is as follows:

[0058]

[0059] Among them, R 1is tosyl (Tos), trityl (Trt), benzyloxycarbonyl (Cbz), tert-butyloxycarbonyl (Boc) or trifluoroacetyl (Tfa), R 2 It is zinc hemichloride or tetrafluoroborate.

[0060] Example 1: Synthesis of 4-benzamide-5-chloro-2-methylbenzenediazonium tetrafluoroborate

[0061] 1) Add 15.7 g of 2-chloro-5-methyl-1,4-phenylenediamine to a reaction bottle, add 230 mL of dichloromethane, control the temperature at 35°C and stir evenly, add 19.1 g of p-toluenesulfonyl chloride, react for 18 hours, and obtain a reaction solution of 4-amino-5-chloro-2-methylbenzamide (Tos) amide (Compound 1);

[0062] 2) Add 14.2 g of benzoyl chloride to the reaction solution of the previous step, control the temperature at 20°C to react for 6 hours, add 15 mL of pyridine, continue to react for 12 hours, filter, and obtain 4-benzamide-5-chloro-2-methylbenzamide (Tos) (Compound 2), weighing 37.8 g, with a yield of 91.2% and a purity of 94.81%;

[0063] 3) Add 37.8 g of the product from the previous step to the reaction flask, add 170 mL of ethanol, stir evenly, heat to 65 ° C, add 35 mL of trifluoroacetic acid, react for 2 hours, filter, and obtain 4-benzamide-5-chloro-2-methylaniline (compound 3), weighing 21.9 g, with a yield of 92.3% and a purity of 96.82%.

[0064] 4) Add 21.9 g of the product from the previous step to the reaction flask, add 500 mL of sulfuric acid aqueous solution (sulfuric acid / water volume ratio is 1:3) and stir evenly, cool to 0°C, add 8.9 g of sodium nitrite, control the temperature at 0°C and react for 1 hour to obtain a reaction solution of 4-benzamide-5-chloro-2-methylbenzenediazonium chloride (Compound 4);

[0065] 5) Add 13.0 mL of tetrafluoroboric acid to the reaction solution in the previous step, control the temperature at 5° C. to react for 1 hour, filter, and dry to obtain 4-benzamide-5-chloro-2-methylbenzenediazonium tetrafluoroborate, weighing 28.9 g, with a total yield of 80.4% and a purity of 98.94%.

[0066] 4-Benzamide-5-chloro-2-methylbenzenediazonium tetrafluoroborate, its structural formula is as follows:

[0067]

[0068] Example 2: Synthesis of 4-benzamide-5-chloro-2-methylbenzenediazonium hemichloride zinc salt

[0069] 1) Add 15.7 g of 2-chloro-5-methyl-1,4-phenylenediamine to a reaction bottle, add 160 mL of chloroform, stir evenly, add 21.2 g of p-toluenesulfonyl chloride, control the temperature at 25° C. and react for 24 hours to obtain a reaction solution of 4-amino-5-chloro-2-methylbenzamide (Tos) amide (Compound 1);

[0070] 2) Add 14.5 g of benzoyl chloride to the reaction solution of the previous step, control the temperature at 25° C. to react for 6 hours, add 23 mL of triethylamine, continue to react for 8 hours, filter, and obtain 4-benzamide-5-chloro-2-methylbenzamide (Tos) (Compound 2), weighing 38.4 g, with a yield of 92.6% and a purity of 95.66%;

[0071] 3) Add 38.4 g of the product from the previous step to the reaction flask, add 150 mL of acetonitrile solvent, stir evenly, heat to 55 ° C, add 30 mL of concentrated hydrochloric acid, react for 5 hours, filter, and obtain 4-benzamide-5-chloro-2-methylaniline (compound 3), weighing 22.6 g, with a yield of 93.5% and a purity of 97.45%.

[0072] 4) Add 22.6 g of the product from the previous step to the reaction flask, add 400 mL of aqueous hydrochloric acid solution (concentrated hydrochloric acid / water volume ratio is 1:6), stir evenly, cool to -5°C, add 8.5 g of sodium nitrite, and react at 5°C for 1 hour to obtain a reaction solution of 4-benzamide-5-chloro-2-methylbenzenediazonium chloride (Compound 4);

[0073] 5) Add 5.8 g of zinc chloride to the reaction solution in the previous step, control the temperature at 0° C. to react for 2 hours, filter, and dry to obtain 4-benzamide-5-chloro-2-methylbenzenediazonium hemichloride zinc salt, weighing 30.4 g, with a total yield of 80.9% and a purity of 98.31%.

[0074] Example 3: Synthesis of 4-benzamide-5-chloro-2-methylbenzenediazonium tetrafluoroborate

[0075] 1) Add 15.7 g of 2-chloro-5-methyl-1,4-phenylenediamine and 230 mL of dioxane to a reaction bottle, control the temperature at 35°C and stir evenly, add 27.9 g of triphenylmethane, and react for 18 hours to obtain a reaction solution of 4-amino-5-chloro-2-methylbenzamide (Trt) amide (Compound 1);

[0076] 2) Add 15.5 g of benzoyl chloride to the reaction solution of the previous step, control the temperature at 20° C. to react for 6 hours, add 15 mL of pyridine, continue to react for 12 hours, filter, and obtain 4-benzamide-5-chloro-2-methylbenzamide (Trt) (Compound 2), weighing 46.1 g, with a yield of 91.6% and a purity of 94.81%;

[0077] 3) Add 46.1 g of the product from the previous step to the reaction flask, add 170 mL of ethanol, stir evenly, heat to 60 ° C, add 45 mL of trifluoroacetic acid, react for 3 hours, filter, and obtain 4-benzamide-5-chloro-2-methylaniline (compound 3), weighing 22.1 g, with a yield of 92.7% and a purity of 96.82%.

[0078] 4) Add 22.1 g of the product from the previous step to the reaction flask, add 500 mL of sulfuric acid aqueous solution (volume ratio of sulfuric acid to water is 1:3.5), stir evenly, cool to 0°C, add 9.2 g of sodium nitrite, control the temperature at 0°C and react for 1 hour to obtain a reaction solution of 4-benzamide-5-chloro-2-methylbenzenediazonium chloride (Compound 4);

[0079] 5) Add 14.5 mL of tetrafluoroboric acid to the reaction solution in the previous step, control the temperature at 5° C. to react for 1 hour, filter, and dry to obtain 4-benzamide-5-chloro-2-methylbenzenediazonium tetrafluoroborate, weighing 29.2 g, with a total yield of 81.1% and a purity of 98.94%.

[0080] Example 4: Synthesis of 4-benzamide-5-chloro-2-methylbenzenediazonium hemichloride zinc salt

[0081] 1) Add 15.7 g of 2-chloro-5-methyl-1,4-phenylenediamine and 160 mL of acetone to a reaction bottle, stir evenly, add 32.0 g of triphenylmethane, and react at 25° C. for 24 hours to obtain a reaction solution of 4-amino-5-chloro-2-methylbenzamide (Trt) amide (compound 1);

[0082] 2) Add 15.7 g of benzoyl chloride to the reaction solution of the previous step, control the temperature at 35° C. to react for 2 hours, add 22 mL of triethylamine, continue to react for 6 hours, filter, and obtain 4-benzamide-5-chloro-2-methylbenzamide (Trt) (Compound 2), weighing 46.9 g, with a yield of 93.3% and a purity of 97.61%;

[0083] 3) Add 46.9 g of the product from the previous step to the reaction flask, add 150 mL of methanol solvent, stir evenly, heat to 50 ° C, add 40 mL of concentrated hydrochloric acid, react for 5 hours, filter, and obtain 4-benzamide-5-chloro-2-methylaniline (compound 3), weighing 22.5 g, with a yield of 92.6% and a purity of 97.14%.

[0084] 4) Add 22.5 g of the product from the previous step to the reaction flask, add 400 mL of aqueous hydrochloric acid solution (concentrated hydrochloric acid / water volume ratio is 1:4.5), stir evenly, cool to -5 ° C, add 9.0 g of sodium nitrite, and react at 5 ° C for 1 hour to obtain a reaction solution of 4-benzamide-5-chloro-2-methylbenzenediazonium chloride (Compound 4);

[0085] 5) Add 6.8 g of zinc chloride to the reaction solution in the previous step, control the temperature at 5° C. to react for 3 hours, filter, and dry to obtain 4-benzamide-5-chloro-2-methylbenzenediazonium hemichloride zinc salt, weighing 30.6 g, with a total yield of 81.3% and a purity of 98.72%.

[0086] Example 5: Synthesis of 4-benzamide-5-chloro-2-methylbenzenediazonium tetrafluoroborate

[0087] 1) Add 15.7 g of 2-chloro-5-methyl-1,4-phenylenediamine and 230 mL of tetrahydrofuran to a reaction bottle, control the temperature at 35°C and stir evenly, add 17.1 g of benzyl chloroformate, and react for 18 hours to obtain a reaction solution of 4-amino-5-chloro-2-methylbenzamide (Cbz) amide (Compound 1);

[0088] 2) Add 20.3 g of benzoyl chloride to the reaction solution of the previous step, control the temperature at 20° C. to react for 6 hours, add 17 mL of pyridine, continue to react for 12 hours, filter, and obtain 4-benzamide-5-chloro-2-methylbenzamide (Cbz) (Compound 2), weighing 36.4 g, with a yield of 92.3% and a purity of 94.36%;

[0089] 3) Add 36.4 g of the product from the previous step to the reaction flask, add 170 mL of ethanol, stir evenly, heat to 60 ° C, add 30 mL of trifluoroacetic acid, react for 3 hours, filter, and obtain 4-benzamide-5-chloro-2-methylaniline (compound 3), weighing 22.3 g, with a yield of 92.6% and a purity of 96.14%.

[0090] 4) Add 22.3 g of the product from the previous step to the reaction bottle, add 500 mL of sulfuric acid aqueous solution (sulfuric acid / water volume ratio is 1:5) and stir evenly, cool to 0°C, add 9.3 g of sodium nitrite, control the temperature at 0°C and react for 1 hour to obtain a reaction solution of 4-benzamide-5-chloro-2-methylbenzenediazonium chloride (Compound 4);

[0091] 5) Add 12.7 mL of tetrafluoroboric acid to the reaction solution in the previous step, control the temperature at 5° C. to react for 1 hour, filter, and dry to obtain 4-benzamide-5-chloro-2-methylbenzenediazonium tetrafluoroborate, weighing 29.3 g, with a total yield of 81.5% and a purity of 98.54%.

[0092] Example 6: Synthesis of 4-benzamide-5-chloro-2-methylbenzenediazonium zinc hemichloride

[0093] 1) Add 15.7 g of 2-chloro-5-methyl-1,4-phenylenediamine and 160 mL of isopropyl ether to a reaction bottle, stir evenly, add 19.5 g of benzyl chloroformate, and react at 25° C. for 24 hours to obtain a reaction solution of 4-amino-5-chloro-2-methylbenzamide (Cbz) amide (Compound 1);

[0094] 2) Add 18.6 g of benzoyl chloride to the reaction solution of the previous step, control the temperature at 25° C. to react for 6 hours, add 20 mL of triethylamine, continue to react for 8 hours, filter, and obtain 4-benzamide-5-chloro-2-methylbenzamide (Cbz) (Compound 2), weighing 36.2 g, with a yield of 91.7% and a purity of 94.87%;

[0095] 3) Add 36.2 g of the product from the previous step to the reaction flask, add 150 mL of acetone solvent, stir evenly, heat to 50 ° C, add 35 mL of concentrated hydrochloric acid, react for 5 hours, filter, and obtain 4-benzamide-5-chloro-2-methylaniline (compound 3), weighing 22.7 g, with a yield of 94.8% and a purity of 97.34%.

[0096] 4) Add 22.7 g of the product from the previous step to the reaction flask, add 400 mL of aqueous hydrochloric acid solution (concentrated hydrochloric acid / water volume ratio is 1:6), stir evenly, cool to -5°C, add 9.5 g of sodium nitrite, and react at 5°C for 1 hour to obtain a reaction solution of 4-benzamide-5-chloro-2-methylbenzenediazonium chloride (Compound 4);

[0097] 5) Add 7.3 g of zinc chloride to the reaction solution in the previous step, control the temperature at 0° C. to react for 0.5 hour, filter, and dry to obtain 4-benzamide-5-chloro-2-methylbenzenediazonium hemichloride zinc salt, weighing 30.7 g, with a total yield of 81.7% and a purity of 98.15%.

[0098] Example 7: Synthesis of 4-benzamide-5-chloro-2-methylbenzenediazonium tetrafluoroborate

[0099] 1) Add 15.7 g of 2-chloro-5-methyl-1,4-phenylenediamine and 230 mL of dioxane to a reaction bottle, control the temperature at 35°C and stir evenly, add 13.5 g of trifluoroacetyl chloride, and react for 18 hours to obtain a reaction solution of 4-amino-5-chloro-2-methylbenzamide (Tfa) amide (Compound 1);

[0100] 2) Add 20.5 g of benzoyl chloride to the reaction solution of the previous step, control the temperature at 20° C. to react for 6 hours, add 17 mL of pyridine, continue to react for 12 hours, filter, and obtain 4-benzamide-5-chloro-2-methylbenz(Tfa)amide (Compound 2), weighing 32.7 g, with a yield of 91.7% and a purity of 94.93%;

[0101] 3) Add 32.7 g of the product from the previous step to the reaction bottle, add 170 mL of ethanol, stir evenly, heat to 60 ° C, add 45 mL of trifluoroacetic acid, react for 3 hours, filter, and obtain 4-benzamide-5-chloro-2-methylaniline (compound 3), weighing 22.2 g, with a yield of 92.8% and a purity of 96.59%.

[0102] 4) Add 22.2 g of the product from the previous step to the reaction flask, add 500 mL of sulfuric acid aqueous solution (sulfuric acid / water volume ratio is 1:4) and stir evenly, cool to 0°C, add 8.6 g of sodium nitrite, control the temperature at 0°C and react for 1 hour to obtain a reaction solution of 4-benzamide-5-chloro-2-methylbenzenediazonium chloride (Compound 4);

[0103] 5) Add 12.9 mL of tetrafluoroboric acid to the reaction solution in the previous step, control the temperature at 5° C. to react for 1 hour, filter, and dry to obtain 4-benzamide-5-chloro-2-methylbenzenediazonium tetrafluoroborate, weighing 29.7 g, with a total yield of 82.6% and a purity of 98.73%.

[0104] Example 8: Synthesis of 4-benzamide-5-chloro-2-methylbenzenediazonium hemichloride zinc salt

[0105] 1) Add 15.7 g of 2-chloro-5-methyl-1,4-phenylenediamine to a reaction bottle, add 160 mL of n-hexane, stir evenly, add 15.3 g of trifluoroacetyl chloride, control the temperature at 25° C. and react for 24 hours to obtain a reaction solution of 4-amino-5-chloro-2-methylbenzamide (Tfa) amide (Compound 1);

[0106] 2) Add 22.0 g of benzoyl chloride to the reaction solution of the previous step, control the temperature at 25° C. to react for 6 hours, add 17 mL of triethylamine, continue to react for 8 hours, filter, and obtain 4-benzamide-5-chloro-2-methylbenzamide (Tfa) (Compound 2), weighing 32.4 g, with a yield of 90.9% and a purity of 95.66%;

[0107] 3) Add 32.4 g of the product from the previous step to the reaction flask, add 150 mL of acetonitrile solvent, stir evenly, heat to 50 ° C, add 40 mL of concentrated hydrochloric acid, react for 5 hours, filter, and obtain 4-benzamide-5-chloro-2-methylaniline (compound 3), weighing 22.2 g, with a yield of 93.6% and a purity of 97.39%.

[0108] 4) Add 22.2 g of the product from the previous step to the reaction flask, add 400 mL of aqueous hydrochloric acid solution (concentrated hydrochloric acid / water volume ratio is 1:5), stir evenly, cool to -5°C, add 8.9 g of sodium nitrite, and react at 5°C for 1 hour to obtain a reaction solution of 4-benzamide-5-chloro-2-methylbenzenediazonium chloride (Compound 4);

[0109] 5) Add 6.5 g of zinc chloride to the reaction solution in the previous step, control the temperature at 0° C. to react for 0.5 hour, filter, and dry to obtain 4-benzamide-5-chloro-2-methylbenzenediazonium hemichloride zinc salt, weighing 30.6 g, with a total yield of 81.3% and a purity of 98.56%.

[0110] Example 9: Synthesis of 4-benzamide-5-chloro-2-methylbenzenediazonium tetrafluoroborate

[0111] 1) Add 15.7 g of 2-chloro-5-methyl-1,4-phenylenediamine and 230 mL of dioxane to a reaction bottle, control the temperature at 35°C and stir evenly, add 30 mL of tert-butyl chloroformate, and react for 18 hours to obtain a reaction solution of 4-amino-5-chloro-2-methylbenzamide (Boc) amide (Compound 1);

[0112] 2) Add 15.5 g of benzoyl chloride to the reaction solution of the previous step, control the temperature at 20°C to react for 6 hours, add 16 mL of pyridine, continue to react for 12 hours, filter, and obtain 4-benzamide-5-chloro-2-methylbenzamide (Boc) (Compound 2), weighing 32.9 g, with a yield of 91.2% and a purity of 94.81%;

[0113] 3) Add 32.9 g of the product from the previous step to the reaction flask, add 170 mL of ethanol, stir evenly, heat to 60 ° C, add 35 mL of trifluoroacetic acid, react for 3 hours, filter, and obtain 4-benzamide-5-chloro-2-methylaniline (compound 3), weighing 22.2 g, with a yield of 93.5% and a purity of 96.82%.

[0114] 4) Add 22.2 g of the product from the previous step to the reaction flask, add 500 mL of sulfuric acid aqueous solution (sulfuric acid / water volume ratio is 1:4) and stir evenly, cool to 0°C, add 8.2 g of sodium nitrite, control the temperature at 0°C and react for 1 hour to obtain a reaction solution of 4-benzamide-5-chloro-2-methylbenzenediazonium chloride (Compound 4);

[0115] 5) Add 14.5 mL of tetrafluoroboric acid to the reaction solution in the previous step, control the temperature at 5° C. to react for 1 hour, filter, and dry to obtain 4-benzamide-5-chloro-2-methylbenzenediazonium tetrafluoroborate, weighing 29.3 g, with a total yield of 81.4% and a purity of 98.94%.

[0116] Example 10: Synthesis of 4-benzamide-5-chloro-2-methylbenzenediazonium hemichloride zinc salt

[0117] 1) Add 15.7 g of 2-chloro-5-methyl-1,4-phenylenediamine and 160 mL of N,N-dimethylformamide to a reaction bottle, stir evenly, add 23 g of di-tert-butyl dicarbonate, and react at 25° C. for 24 hours to obtain a reaction solution of 4-amino-5-chloro-2-methylbenzamide (Boc) amide (Compound 1);

[0118] 2) Add 16.5 g of benzoyl chloride to the reaction solution of the previous step, control the temperature at 25° C. to react for 6 hours, add 15 mL of triethylamine, continue to react for 8 hours, filter, and obtain 4-benzamide-5-chloro-2-methylbenzamide (Boc) (Compound 2), weighing 33.1 g, with a yield of 91.7% and a purity of 97.61%;

[0119] 3) Add 33.1 g of the product from the previous step to the reaction flask, add 150 mL of acetone solvent, stir evenly, heat to 35 ° C, add 30 mL of concentrated hydrochloric acid, react for 5 hours, filter, and obtain 4-benzamide-5-chloro-2-methylaniline (compound 3), weighing 22.6 g, with a yield of 94.6% and a purity of 97.14%.

[0120] 4) Add 22.6 g of the product from the previous step to the reaction flask, add 400 mL of aqueous hydrochloric acid solution (concentrated hydrochloric acid / water volume ratio is 1:5), stir evenly, cool to -5°C, add 8.4 g of sodium nitrite, and react at 5°C for 1 hour to obtain a reaction solution of 4-benzamide-5-chloro-2-methylbenzenediazonium chloride (Compound 3);

[0121] 5) Add 7.2 g of zinc chloride to the reaction solution in the previous step, control the temperature at 0° C. to react for 0.5 hour, filter, and dry to obtain 4-benzamide-5-chloro-2-methylbenzenediazonium hemichloride zinc salt, weighing 30.4 g, with a total yield of 80.7% and a purity of 98.72%.

[0122] Example 11: Comparison of water solubility and stability of 4-benzamide-5-chloro-2-methylbenzene diazonium salt and 4-benzamide-5-chloro-2-methylbenzene diazonium chloride.

[0123] 1) Comparison of water solubility: The water solubility of three compound samples, 4-benzamide-5-chloro-2-methylbenzene diazonium tetrafluoroborate prepared in Example 1, 4-benzamide-5-chloro-2-methylbenzene zinc diazonium hemichloride prepared in Example 2, and 4-benzamide-5-chloro-2-methylbenzene diazonium chloride, was compared at room temperature. The experimental results are shown in Table 1:

[0124] Table 1 Comparison of water solubility

[0125]

[0126]

[0127] As can be seen from Table 1, 4-benzamide-5-chloro-2-methylbenzenediazonium tetrafluoroborate is more soluble in water than 4-benzamide-5-chloro-2-methylbenzenediazonium zinc hemichloride salt, and both are less soluble in water than 4-benzamide-5-chloro-2-methylbenzenediazonium chloride.

[0128] 2) Stability comparison: The three compound samples of 4-benzamide-5-chloro-2-methylbenzene diazonium tetrafluoroborate prepared in Example 1, 4-benzamide-5-chloro-2-methylbenzene zinc diazonium hemichloride prepared in Example 2, and 4-benzamide-5-chloro-2-methylbenzene diazonium chloride were subjected to long-term room temperature stability test under sealed conditions at room temperature to detect compound changes. The experimental results are shown in Table 2:

[0129] Table 2 Stability comparison

[0130] Compound Name stability 4-Benzamide-5-chloro-2-methylbenzenediazonium chloride After 15 days, the purity dropped to <95%; 4-Benzamide-5-chloro-2-methylbenzene zinc diazonium hemichloride After 280 days, the purity dropped to <96%; 4-Benzamide-5-chloro-2-methylbenzenediazotetrafluoroborate After 360 days, the purity dropped to <97%;

[0131] As can be seen from Table 2, 4-benzamide-5-chloro-2-methylbenzene zinc diazonium semichloride and 4-benzamide-5-chloro-2-methylbenzene diazonium tetrafluoroborate have better stability than 4-benzamide-5-chloro-2-methylbenzene diazonium chloride, among which 4-benzamide-5-chloro-2-methylbenzene diazonium tetrafluoroborate has better stability than 4-benzamide-5-chloro-2-methylbenzene diazonium semichloride.

[0132] It can be seen from the above embodiments that the present invention provides a method for preparing 4-benzamide-5-chloro-2-methylbenzene diazonium salt. The present invention provides a method for preparing 4-benzamide-5-chloro-2-methylbenzene diazonium salt, the synthesis process route has high yield and high purity; the method has easy-to-obtain raw materials, a simple synthesis method, mild conditions, easy operation, and can be mass-produced, and the obtained 4-benzamide-5-chloro-2-methylbenzene diazonium zinc hemichloride or 4-benzamide-5-chloro-2-methylbenzene diazonium tetrafluoroborate has good stability and can be stored for a long time.

[0133] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing 4-benzamide-5-chloro-2-methylbenzene diazonium salt, characterized in that: The following steps are involved: 1) dissolving 2-chloro-5-methyl-1,4-phenylenediamine in an organic solvent A, adding a protective reagent and reacting to obtain compound 1; 2) adding an acylating agent and an acid binding agent to compound 1 to carry out an acylation reaction to obtain compound 2; 3) Compound 2 is added to solvent B to carry out a deprotection reaction to obtain compound 3; 4) adding compound 3 to an acid aqueous solution for acidification, and then adding nitrite for diazotization reaction to obtain compound 4; 5) adding a salt-forming reagent to compound 4 and performing a salt-forming reaction to obtain 4-benzamide-5-chloro-2-methylbenzene diazonium salt; The protective reagent comprises one of tosyl chloride, triphenylmethane chloride, benzyl chloroformate, tert-butyl chloroformate, di-tert-butyl dicarbonate and trifluoroacetyl chloride; The preparation route of the benzamide-5-chloro-2-methylbenzene diazonium salt is as follows: Wherein, R1 is toluenesulfonyl, trityl, benzyloxycarbonyl, tert-butyloxycarbonyl or trifluoroacetyl, and R2 is zinc hemichloride or tetrafluoroborate.

2. The preparation method of 4-benzamide-5-chloro-2-methylbenzene diazonium salt according to claim 1, characterized in that, In the step 1), the organic solvent A comprises one or more of dichloromethane, chloroform, acetone, tetrahydrofuran, isopropyl ether, petroleum ether, n-hexane, acetonitrile, dioxane and N,N-dimethylformamide; the molar ratio of the 2-chloro-5-methyl-1,4-phenylenediamine to the protective reagent is 1:1-2, and the amount ratio of 2-chloro-5-methyl-1,4-phenylenediamine to the organic solvent A is 1g:5-20mL.

3. The preparation method of 4-benzamide-5-chloro-2-methylbenzene diazonium salt according to claim 1 or 2, characterized in that, In the step 1), the reaction temperature is 0 to 50° C. and the reaction time is 1 to 48 hours.

4. The preparation method of 4-benzamide-5-chloro-2-methylbenzene diazonium salt according to claim 1, characterized in that, In the step 2), the acylating agent comprises benzoyl chloride, and the acid-binding agent comprises triethylamine or pyridine; the molar ratio of compound 1 to the acylating agent is 1:1.05-1.13, and the molar ratio of the acylating agent to the acid-binding agent is 0.1 mol:10-25 mL; The temperature of the acylation reaction is 0 to 40° C., and the time of the acylation reaction is 1 to 24 hours.

5. The preparation method of 4-benzamide-5-chloro-2-methylbenzene diazonium salt according to claim 1, 2 or 4, characterized in that, In the step 3), solvent B is a mixed solvent consisting of an organic solvent and an acid, wherein the organic solvent comprises one or more of methanol, ethanol, isopropanol, acetone, dichloromethane, chloroform, tetrahydrofuran, isopropyl ether, petroleum ether, n-hexane, acetonitrile, dioxane and N,N-dimethylformamide, and the acid comprises one of hydrochloric acid, sulfuric acid, nitric acid, acetic acid or trifluoroacetic acid.

6. The method for preparing 4-benzamide-5-chloro-2-methylbenzene diazonium salt according to claim 5, wherein: The dosage ratio of the compound 2 to the organic solvent is 1 g: 4-5 mL, and the dosage ratio of the compound 2 to the acid is 1 g: 0.8-1 mL; the temperature of the deprotection reaction is 0-75° C., and the time of the deprotection reaction is 0.5-12 h.

7. The preparation method of 4-benzamide-5-chloro-2-methylbenzene diazonium salt according to claim 1 or 6, characterized in that, In the step 4), the acid aqueous solution is a hydrochloric acid aqueous solution or a sulfuric acid aqueous solution, the volume concentration of the acid aqueous solution is 9-50%, the dosage ratio of compound 3 to the acid aqueous solution is 1g:15-20mL, the molar ratio of nitrite to compound 3 is 1:1-2, and the nitrite comprises sodium nitrite or potassium nitrite.

8. The method for preparing 4-benzamide-5-chloro-2-methylbenzene diazonium salt according to claim 7, wherein: In the step 4), the temperature of the diazotization reaction is -15 to 15°C, and the time of the diazotization reaction is 0.5 to 12 hours.

9. The preparation method of 4-benzamide-5-chloro-2-methylbenzene diazonium salt according to claim 1, 2 or 8, characterized in that, In the step 5), the salt-forming reagent comprises zinc chloride or tetrafluoroboric acid, and the molar ratio of the salt-forming reagent to compound 4 is 1:0.5-2; the temperature of the salt-forming reaction is -10-30°C, and the time of the salt-forming reaction is 0.5-12h.

10. The method for preparing 4-benzamide-5-chloro-2-methylbenzene diazonium salt according to claim 9, characterized in that: The 4-benzamide-5-chloro-2-methylbenzene diazonium salt includes 4-benzamide-5-chloro-2-methylbenzene diazonium zinc hemichloride or 4-benzamide-5-chloro-2-methylbenzene diazonium tetrafluoroborate.

Images