4-(biphenyl-4-formamide)-5-chloro-2-methyl benzene diazonium salt as well as preparation method and application thereof

Abstract

The invention relates to the technical field of compound preparation, in particular to 4-(biphenyl-4-formamide)-5-chloro-2-methyl benzene diazonium salt and a preparation method of the 4-(biphenyl-4-formamide)-5-chloro-2-methyl benzene diazonium salt. The 4-(biphenyl-4-formamide)-5-chlorine-2-methyl benzene diazonium salt is 4-(biphenyl-4-formamide)-5-chlorine-2-methyl benzene diazonium zinc chloride salt or 4-(biphenyl-4-formamide)-5-chlorine-2-methyl benzene diazonium tetrafluoroborate, and the 4-(biphenyl-4-formamide)-5-chlorine-2-methyl benzene diazonium tetrafluoroborate is 4-(biphenyl-4-formamide)-5-chlorine-2-methyl benzene diazonium zinc chloride salt or 4-(biphenyl-4-formamide)-5-chlorine-2-methyl benzene diazonium tetrafluoroborate. The invention solves the defects of the existing fast red violet LB salt, provides a novel fast red violet LB salt analogue and provides a preparation method, the total yield of the synthesis process is high and reaches 80% or above, the purity is high and reaches 98% or above, 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, and the method is suitable for industrial production. The obtained 4-(biphenyl-4-formamide)-5-chloro-2-methyl benzene diazonium salt zinc hemicelluloride or 4-(biphenyl-4-formamide)-5-chloro-2-methyl benzene diazonium salt tetrafluoroborate has the advantages of favorable compound fat solubility and favorable preparation stability, and is beneficial to the application in dry chemical detection reagents.

Description

Technical Field

[0001] The invention relates to the technical field of compound preparation, and in particular to a 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzene diazonium salt and a preparation method and application thereof. Background Art

[0002] Fast Red Violet LB salt, chemically named 4-benzamide-5-chloro-2-methylbenzenediazonium hemichloride zinc salt, is a diazo dye, commonly used for the determination of alkaline phosphatase, and its structural formula is as follows:

[0003]

[0004] The disadvantages of the prior art of Fast Red Violet LB Salt are that the compound is difficult to prepare, has a low yield, low purity, poor fat solubility, and is not stable enough in dry chemical preparations.

[0005] Therefore, in order to address the problems of difficulty in preparation, low yield, low purity, low fat solubility and insufficient stability in dry chemical preparations of the above-mentioned compounds, a new Fast Red Purple LB salt analogue with high reaction efficiency, high yield, high purity, mass production, better fat solubility, easy use, higher preparation stability and its preparation method and application can be designed. Summary of the invention

[0006] In order to overcome the problems of difficult preparation, low yield, low purity, low fat solubility and insufficient stability in dry chemical preparations.

[0007] The technical scheme of the present invention is: a 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzene diazonium salt, wherein the 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzene diazonium salt is 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzene diazonium zinc hemichloride or 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzene diazonium tetrafluoroborate, and its structural formula is as follows:

[0008]

[0009] The preparation method of 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzene diazonium salt comprises the 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzene diazonium salt as described above, and the steps are: using 2-chloro-5-methyl-1,4-phenylenediamine as a raw material, and undergoing a protecting group reaction, an acylation reaction, a deprotecting group reaction, a diazotization reaction, and a salt-forming reaction to obtain the obtained product. The reaction technical route is as follows:

[0010]

[0011] In the formula, R1 is benzyloxycarbonyl (Cbz), trityl (Trt), p-toluenesulfonyl (Tos), tert-butyloxycarbonyl (Boc) or trifluoroacetyl (Tfa); R2 is hemichlorozinc salt or tetrafluoroborate.

[0012] The present invention discloses a 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzene diazonium salt, which comprises the following steps:

[0013] (1) dissolving 2-chloro-5-methyl-1,4-phenylenediamine in solvent A, adding an amino protecting agent, and reacting under controlled temperature to obtain compound 1;

[0014] (2) adding an acylating agent to the reaction system of compound 1 and an acid binding agent, and reacting at a controlled temperature to obtain compound 2;

[0015] (3) adding compound 2 to solvent B and reacting under controlled temperature to obtain compound 3;

[0016] (4) adding compound 3 to an acid aqueous solution for acidification, adding nitrite, and reacting under controlled temperature to obtain compound 4;

[0017] (5) Add a salt-forming reagent to the reaction solution of compound 4 and react under controlled temperature to obtain compound 5 (4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzene diazonium salt).

[0018] In step (1) of the present invention, the amino protecting agent is one of benzyl chloroformate (Cbz-Cl), triphenylmethane chloride (Trt-Cl), p-toluenesulfonyl chloride (Tos-Cl), tert-butyl chloroformate (Boc-Cl), di-tert-butyl dicarbonate (Boc anhydride), and trifluoroacetyl chloride (Tfa-Cl); the feed ratio of 2-chloro-5-methyl-1,4-phenylenediamine to the amino protecting agent is 1 mol: (1.0-2.0) mol; the solvent A is one of dichloromethane, chloroform, acetone, tetrahydrofuran, petroleum ether, isopropyl ether, n-hexane, acetonitrile, dioxane, triethylamine or N,N-dimethylformamide; the ratio of the raw material to the amino protecting agent is 1 g: 5 ml-20 ml; the temperature control temperature is 0-60° C.; and the reaction time is 1-48 hours.

[0019] In step (2) of the present invention, the acylating agent is biphenyl-4-carbonyl chloride; the feeding ratio of compound 1 to the acylating agent is 1 mol: (1.05-1.13) mol; the acid binding agent is triethylamine or pyridine; the amount of the acyl chloride reagent and the amount of the acid binding agent are 1 mol: (1.0-3.0) mol; the temperature control temperature is 0-50° C.; and the reaction time is 1-48 h.

[0020] In step (3) of the present invention, solvent B is a mixed solvent consisting of an organic solvent and an acid aqueous solution, the organic solvent is one of methanol, ethanol, isopropanol, acetone, dichloromethane, chloroform, tetrahydrofuran, petroleum ether, isopropyl ether, n-hexane, acetonitrile, dioxane or N,N-dimethylformamide, and the acid aqueous solution is one of hydrochloric acid, sulfuric acid aqueous solution, nitric acid aqueous solution, acetic acid aqueous solution or trifluoroacetic acid aqueous solution;

[0021] The ratio of compound 2 to organic solvent is 1 g: 4-5 mL; the ratio of compound 2 to acid aqueous solution is 1 g: 0.8-1 mL; the temperature control temperature is 0-80° C.; and the reaction time is 0.5-24 hours.

[0022] In step (4) of the present invention, the acid aqueous solution is a hydrochloric acid aqueous solution or a sulfuric acid aqueous solution; the ratio of acid to water in the acid aqueous solution is 1 mL: 1-10 mL; the ratio of compound 3 to the acid aqueous solution is 1 g: 15-20 mL; the nitrite is sodium nitrite or potassium nitrite; the molar ratio of nitrite to compound 3 is 1: 1.0-2.0; the temperature is controlled at -10°C to 20°C; and the reaction time is 0.5 to 12 hours.

[0023] In step (5) of the present invention, the salt-forming reagent is zinc chloride or tetrafluoroboric acid, the molar ratio of zinc chloride to compound 4 is 1:0.5 to 0.8 times, and the molar ratio of tetrafluoroboric acid to compound 4 is 1:1.0 to 2.0; the temperature is controlled at 0°C to 30°C; and the reaction time is 0.5 to 12 hours;

[0024] When the salt-forming reagent is zinc chloride, 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium zinc chloride hemichloride is obtained; when the salt-forming reagent is tetrafluoroboric acid, 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium tetrafluoroborate is obtained.

[0025] The invention discloses an application of 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium salt in dry chemical detection reagents, in particular in the detection of alkaline phosphatase or tartrate-resistant acid phosphatase.

[0026] The beneficial effects of the present invention are as follows: the shortcomings of the existing fast red violet LB salt are solved, a new fast red violet LB salt analogue with good fat solubility and good preparation stability is provided, and a preparation method is provided. The preparation method has a high total yield of more than 80%, a high purity of more than 98%, easy-to-obtain raw materials, a simple synthesis method, mild conditions, easy operation, and can be mass-produced. DETAILED DESCRIPTION

[0027] The technical scheme of the present invention is: a 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzene diazonium salt, wherein the 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzene diazonium salt is 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzene diazonium zinc hemichloride or 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzene diazonium tetrafluoroborate, and its structural formula is as follows:

[0028]

[0029] The preparation method of 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzene diazonium salt comprises the 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzene diazonium salt as described above, and the steps are: using 2-chloro-5-methyl-1,4-phenylenediamine as a raw material, and undergoing a protecting group reaction, an acylation reaction, a deprotecting group reaction, a diazotization reaction, and a salt-forming reaction to obtain the obtained product. The reaction technical route is as follows:

[0030]

[0031] In the formula, R1 is benzyloxycarbonyl (Cbz), trityl (Trt), p-toluenesulfonyl (Tos), tert-butyloxycarbonyl (Boc) or trifluoroacetyl (Tfa); R2 is hemichlorozinc salt or tetrafluoroborate.

[0032] As a preference, the steps are as follows:

[0033] (1) dissolving 2-chloro-5-methyl-1,4-phenylenediamine in solvent A, adding an amino protecting agent, and reacting under controlled temperature to obtain compound 1;

[0034] (2) adding an acylating agent to the reaction system of compound 1 and an acid binding agent, and reacting under temperature control to obtain compound 2;

[0035] (3) adding compound 2 to solvent B and reacting under controlled temperature to obtain compound 3;

[0036] (4) adding compound 3 to an acid aqueous solution for acidification, adding nitrite, and reacting under controlled temperature to obtain compound 4;

[0037] (5) Add a salt-forming reagent to the reaction solution of compound 4 and react under controlled temperature to obtain compound 5 (4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzene diazonium salt).

[0038] Preferably, the amino protecting agent in step (1) is one of benzyl chloroformate (Cbz-Cl), triphenylmethane chloride (Trt-Cl), p-toluenesulfonyl chloride (Tos-Cl), tert-butyl chloroformate (Boc-Cl), di-tert-butyl dicarbonate (Boc anhydride), and trifluoroacetyl chloride (Tfa-Cl); the feed ratio of 2-chloro-5-methyl-1,4-phenylenediamine to the amino protecting agent is 1 mol: (1.0-2.0) mol; solvent A is one of dichloromethane, chloroform, acetone, tetrahydrofuran, petroleum ether, isopropyl ether, n-hexane, acetonitrile, dioxane, triethylamine or N,N-dimethylformamide; the ratio of raw material to amino protecting agent is 1 g: 5 ml-20 ml; the temperature control temperature is 0-60° C.; and the reaction time is 1-48 hours.

[0039] Preferably, the acylating agent in step (2) is biphenyl-4-carbonyl chloride; the feed ratio of compound 1 to the acylating agent is 1 mol:(1.05-1.13) mol; the acid binding agent is triethylamine or pyridine; the amount of the acyl chloride reagent and the amount of the acid binding agent are 1 mol:(1.0-3.0) mol; the temperature control temperature is 0-50° C.; and the reaction time is 1-48 h.

[0040] Preferably, the solvent B in step (3) is a mixed solvent consisting of an organic solvent and an acid aqueous solution, the organic solvent is one of methanol, ethanol, isopropanol, acetone, dichloromethane, chloroform, tetrahydrofuran, petroleum ether, isopropyl ether, n-hexane, acetonitrile, dioxane or N,N-dimethylformamide, and the acid aqueous solution is one of hydrochloric acid, sulfuric acid aqueous solution, nitric acid aqueous solution, acetic acid aqueous solution or trifluoroacetic acid aqueous solution;

[0041] Preferably, in step (3), the ratio of compound 2 to organic solvent is 1 g: 4-5 mL; the ratio of compound 2 to acid aqueous solution is 1 g: 0.8-1 mL; the temperature control temperature is 0-80° C.; and the reaction time is 0.5-24 hours.

[0042] Preferably, the acid aqueous solution in step (4) is a hydrochloric acid aqueous solution or a sulfuric acid aqueous solution; the ratio of acid to water in the acid aqueous solution is 1 mL: 1-10 mL; the ratio of compound 3 to the acid aqueous solution is 1 g: 15-20 mL; the nitrite is sodium nitrite or potassium nitrite; the molar ratio of nitrite to compound 3 is 1: 1.0-2.0; the temperature is controlled at -10°C to 20°C; and the reaction time is 0.5 to 12 hours.

[0043] Preferably, the salt-forming reagent in step (5) is zinc chloride or tetrafluoroboric acid, the molar ratio of zinc chloride to compound 4 is 1:0.5 to 0.8 times, and the molar ratio of tetrafluoroboric acid to compound 4 is 1:1.0 to 2.0; the temperature is controlled at 0°C to 30°C; the reaction time is 0.5 to 12 hours;

[0044] When the salt-forming reagent is zinc chloride, 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium zinc chloride hemichloride is obtained; when the salt-forming reagent is tetrafluoroboric acid, 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium tetrafluoroborate is obtained.

[0045] The invention discloses an application of 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium salt in detecting alkaline phosphatase or tartrate-resistant acid phosphatase, especially in dry chemical detection.

[0046] The invention has the beneficial effects of solving the shortcomings of the existing fast red violet LB salt, providing a new fast red violet LB salt analogue, and providing a preparation method. The preparation method has a high total yield of more than 80%, a high purity of more than 98%, easy raw materials, a simple synthesis method, mild conditions, easy operation, and large-scale production. The obtained 4-(biphenyl-4-formamide)-5-chloro-2-methylbenzene diazonium salt zinc hemichloride or 4-(biphenyl-4-formamide)-5-chloro-2-methylbenzene diazonium salt tetrafluoroborate has good fat solubility and good preparation stability, and is beneficial to the application in dry chemical detection reagents.

[0047] 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.

[0048] Example 1: Synthesis of 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium hemichloride zinc salt

[0049] (1) Add 15.66 g of 2-chloro-5-methyl-1,4-phenylenediamine and 240 mL of dioxane to a reaction bottle, stir evenly, add 24.8 g of benzyl chloroformate, and react at 40° C. for 24 hours to obtain a 4-amino-5-chloro-2-methylbenzamide reaction solution;

[0050] (2) Add 23.8 g of biphenyl-4-carbonyl chloride to the reaction solution of the previous step, control the temperature at 30° C. to react for 4 hours, add 8 mL of pyridine, continue to control the temperature at 30° C. to react for 16 hours, filter, collect the filter cake, and dry to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzamide (Cbz), weighing 43.5 g, with a yield of 92.3% and a purity of 94.8%;

[0051] (3) Add 43.5 g of the product of the previous step to the reaction flask, add 170 mL of dichloromethane, stir evenly, add 40 mL of trifluoroacetic acid, control the temperature at 35° C. to react for 4 hours, filter, collect the filter cake, and dry to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylaniline, weighing 29.1 g, with a yield of 93.5% and a purity of 95.9%;

[0052] (4) Add 29.1 g of the product from the previous step to the reaction bottle, add 600 mL of hydrochloric acid aqueous solution (concentrated hydrochloric acid / water volume ratio is 1:4), stir evenly, cool to -5°C, add 7 g of sodium nitrite, control the temperature at -5°C and react for 1 hour to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium chloride reaction solution;

[0053] (5) Add 5.5 g of zinc chloride to the reaction solution in the previous step, control the temperature to 0° C. and react for 1 hour, filter, collect, and dry to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium hemichloride zinc salt, weighing 34.8 g, with a total yield of 83.5% and a purity of 98.2%.

[0054] Example 2: Synthesis of 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium tetrafluoroborate

[0055] (1) Add 15.66 g of 2-chloro-5-methyl-1,4-phenylenediamine, 160 mL of isopropyl ether, and 28 mL of benzyl chloroformate to a reaction bottle, and stir and react at 50° C. for 20 hours to obtain a 4-amino-5-chloro-2-methylbenzamide reaction solution;

[0056] (2) Add 24.5 g of biphenyl-4-carbonyl chloride to the reaction solution of the previous step, control the temperature at 40° C. to react for 2 hours, add 28 mL of triethylamine solvent, continue to control the temperature at 40° C. to react for 6 hours, filter, collect, and dry to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzamide (Cbz), weighing 43.0 g, with a yield of 91.2% and a purity of 96.4%;

[0057] (3) Add 43.0 g of the product of the previous step to the reaction bottle, add 200 mL of dichloromethane, add 55 mL of concentrated hydrochloric acid, control the temperature to 45° C. for 5 hours, filter, collect, and dry to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzene heavy amine, weighing 29.0 g, with a yield of 94.2% and a purity of 96.8%.

[0058] (4) Add 29.0 g of the product of the previous step to the reaction bottle, add 520 mL of sulfuric acid aqueous solution (concentrated sulfuric acid / water is 1:3), cool to -10°C, add 8.3 g of sodium nitrite, control the temperature at -10°C and react for 2 hours to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium chloride reaction solution;

[0059] (5) Add 8.8 mL of tetrafluoroboric acid solvent to the reaction solution in the previous step, control the temperature at 10° C. to react for 2 hours, filter, collect, and dry to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium tetrafluoroborate, weighing 36.0 g, with a total yield of 82.6% and a purity of 98.81%.

[0060] Example 3: Synthesis of 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium hemichloride zinc salt

[0061] 1) Add 15.7 g of 2-chloro-5-methyl-1,4-phenylenediamine to a reaction bottle, add 300 mL of acetone, stir evenly, add 28.2 g of triphenylmethane, control the temperature at 40°C and react for 24 hours to obtain a 4-amino-5-chloro-2-methylbenzamide (Trt) reaction solution;

[0062] (2) Add 25.3 g of biphenyl-4-carbonyl chloride to the reaction solution of the previous step, control the temperature at 30° C. to react for 4 hours, add 8 mL of pyridine, continue to control the temperature at 30° C. to react for 16 hours, filter, collect the filter cake, and dry to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzamide (Trt), weighing 53.1 g, with a yield of 91.7% and a purity of 95.2%;

[0063] (3) Add 53.1 g of the product of the previous step to the reaction bottle, add 200 mL of chloroform, stir evenly, add 45 mL of trifluoroacetic acid, control the temperature to 45° C. and react for 4 hours, filter, collect the filter cake, and dry to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylaniline, weighing 29.1 g, with a yield of 94.1% and a purity of 94.21%.

[0064] (4) Add 29.1 g of the product from the previous step to the reaction bottle, add 580 mL of a hydrochloric acid aqueous solution (the volume ratio of concentrated hydrochloric acid to water is 1:4), stir evenly, cool to -5°C, add 6.8 g of sodium nitrite, control the temperature at -2°C and react for 1 hour to obtain a 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium chloride reaction solution;

[0065] (5) Add 5.9 g of zinc chloride to the reaction solution of the previous step, control the temperature at 2° C. to react for 1 hour, filter, collect, and dry to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium hemichloride zinc salt, weighing 34.3 g, with a total yield of 82.2% and a purity of 98.76%.

[0066] Example 4: Synthesis of 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium tetrafluoroborate

[0067] (1) Add 15.7 g of 2-chloro-5-methyl-1,4-phenylenediamine, 160 mL of chloroform, and 30.5 g of triphenylmethane to a reaction flask, and stir to react at 50° C. for 20 hours to obtain a 4-amino-5-chloro-2-methylbenzamide (Trt) amide reaction solution;

[0068] (2) Add 25.5 g of biphenyl-4-carbonyl chloride to the reaction solution of the previous step, control the temperature at 40° C. to react for 2 hours, add 20 mL of triethylamine solvent, continue to control the temperature at 40° C. to react for 3 hours, filter, collect, and dry to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzamide (Trt), weighing 53.4 g, with a yield of 92.2% and a purity of 95.33%;

[0069] (3) Add 53.4 g of the product of the previous step to the reaction bottle, add 200 mL of methanol, add 40 mL of concentrated hydrochloric acid, control the temperature to 57° C. for 3 hours, filter, collect, and dry to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzene heavy amine, weighing 29.4 g, with a yield of 94.8% and a purity of 96.81%.

[0070] (4) Add 29.4 g of the product from the previous step to the reaction bottle, add 520 mL of a hydrochloric acid aqueous solution (concentrated hydrochloric acid / water is 1:3), cool to -5°C, add 8.6 g of sodium nitrite, control the temperature at 0°C and react for 2 hours to obtain a 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium chloride reaction solution;

[0071] (5) Add 11.8 mL of tetrafluoroboric acid solvent to the reaction solution in the previous step, control the temperature at 5° C. to react for 1 hour, filter, collect, and dry to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium tetrafluoroborate, weighing 36.4 g, with a total yield of 83.5% and a purity of 98.81%.

[0072] Example 5: Synthesis of 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium hemichloride zinc salt

[0073] (1) Add 15.66 g of 2-chloro-5-methyl-1,4-phenylenediamine to a reaction bottle, add 240 mL of dichloromethane, stir evenly, add 24.8 g of p-toluenesulfonyl chloride, control the temperature at 40° C. to react for 24 hours, and obtain a 4-amino-5-chloro-2-methylbenzamide reaction solution;

[0074] (2) Add 23.8 g of biphenyl-4-carbonyl chloride to the reaction solution of the previous step, control the temperature at 30° C. to react for 4 hours, add 8 mL of pyridine, continue to control the temperature at 30° C. to react for 16 hours, filter, collect the filter cake, and dry to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzamide (Tos), weighing 44.5 g, with a yield of 90.7% and a purity of 94.8%;

[0075] (3) Add 44.5 g of the product of the previous step to the reaction flask, add 170 mL of dichloromethane, stir evenly, add 50 mL of concentrated hydrochloric acid, control the temperature to 45° C. and react for 4 hours, filter, collect the filter cake, and dry to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylaniline, weighing 28.5 g, with a yield of 93.5% and a purity of 95.9%.

[0076] (4) Add 28.5 g of the product of the previous step to the reaction bottle, add 600 mL of hydrochloric acid aqueous solution (concentrated hydrochloric acid / water volume ratio is 1:4), stir evenly, cool to -5°C, add 7 g of sodium nitrite, control the temperature at -5°C and react for 1 hour to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium chloride reaction solution;

[0077] (5) Add 6.8 g of zinc chloride to the reaction solution in the previous step, control the temperature to 0° C. and react for 1 hour, filter, collect, and dry to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium hemichloride zinc salt, weighing 33.8 g, with a total yield of 81.0% and a purity of 98.2%.

[0078] Example 6: Synthesis of 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium tetrafluoroborate

[0079] (1) Add 15.66 g of 2-chloro-5-methyl-1,4-phenylenediamine, 160 mL of n-hexane, and 28 mL of p-toluenesulfonyl chloride to a reaction flask, and stir at 50° C. for 20 hours to obtain a 4-amino-5-chloro-2-methylbenzamide reaction solution;

[0080] (2) Add 24.5 g of biphenyl-4-carbonyl chloride to the reaction solution of the previous step, control the temperature at 40° C. to react for 2 hours, add 28 mL of triethylamine solvent, continue to control the temperature at 40° C. to react for 6 hours, filter, collect, and dry to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzamide (Tos), weighing 44.8 g, with a yield of 91.2% and a purity of 96.4%;

[0081] (3) Add 44.8 g of the product of the previous step, 200 mL of dichloromethane, and 55 mL of trifluoroacetic acid to the reaction flask, control the temperature at 45° C. to react for 5 hours, filter, collect, and dry to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzene heavy amine, weighing 28.7 g, with a yield of 93.5% and a purity of 96.8%.

[0082] (4) Add 28.7 g of the product from the previous step to the reaction bottle, add 520 mL of sulfuric acid aqueous solution (concentrated sulfuric acid / water is 1:3), cool to -10°C, add 8.3 g of sodium nitrite, control the temperature at -10°C and react for 2 hours to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium chloride reaction solution;

[0083] (5) Add 8.5 mL of tetrafluoroboric acid solvent to the reaction solution in the previous step, control the temperature at 10° C. to react for 2 hours, filter, collect, and dry to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium tetrafluoroborate, weighing 35.2 g, with a total yield of 80.8% and a purity of 98.81%.

[0084] Example 7: Synthesis of 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium hemichloride zinc salt

[0085] (1) Add 15.66 g of 2-chloro-5-methyl-1,4-phenylenediamine to a reaction bottle, add 240 mL of acetonitrile, stir evenly, add 24.8 g of trifluoroacetyl chloride, control the temperature at 40° C. to react for 24 hours, and obtain a 4-amino-5-chloro-2-methylbenzamide (Tfa) reaction solution;

[0086] (2) Add 23.8 g of biphenyl-4-carbonyl chloride to the reaction solution of the previous step, control the temperature at 30° C. to react for 4 hours, add 8 mL of pyridine, continue to control the temperature at 30° C. to react for 16 hours, filter, collect the filter cake, and dry to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzamide (Tfa), weighing 39.3 g, with a yield of 90.7% and a purity of 94.8%;

[0087] (3) Add 39.3 g of the product of the previous step to the reaction bottle, add 170 mL of dichloromethane, stir evenly, add 40 mL of trifluoroacetic acid, control the temperature at 45° C. to react for 4 hours, filter, collect the filter cake, and dry to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylaniline, weighing 28.4 g, with a yield of 92.8% and a purity of 95.9%.

[0088] (4) Add 28.4 g of the product from the previous step to the reaction bottle, add 600 mL of hydrochloric acid aqueous solution (concentrated hydrochloric acid / water volume ratio is 1:4), stir evenly, cool to -5°C, add 7 g of sodium nitrite, control the temperature at -5°C and react for 1 hour to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium chloride reaction solution;

[0089] (5) Add 7.2 g of zinc chloride to the reaction solution of the previous step, control the temperature to 0° C. and react for 1 hour, filter, collect, and dry to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium hemichloride zinc salt, weighing 33.6 g, with a total yield of 80.5% and a purity of 98.2%.

[0090] Example 8: Synthesis of 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium tetrafluoroborate

[0091] (1) Add 15.66 g of 2-chloro-5-methyl-1,4-phenylenediamine, 160 mL of tetrahydrofuran, and 28 mL of trifluoroacetyl chloride to a reaction bottle, and stir and react at 50° C. for 20 hours to obtain a 4-amino-5-chloro-2-methylbenzamide (Tfa) amide reaction solution;

[0092] (2) Add 24.5 g of biphenyl-4-carbonyl chloride to the reaction solution of the previous step, control the temperature at 40° C. to react for 2 hours, add 28 mL of triethylamine solvent, continue to control the temperature at 40° C. to react for 6 hours, filter, collect, and dry to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzamide (Tfa), weighing 40.3 g, with a yield of 93.1% and a purity of 96.4%;

[0093] (3) Add 40.3 g of the product of the previous step to the reaction bottle, add 200 mL of dichloromethane, add 40 mL of concentrated hydrochloric acid, control the temperature to 45° C. for 5 hours, filter, collect, and dry to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzene heavy amine, weighing 29.2 g, with a yield of 93.0% and a purity of 96.8%.

[0094] (4) Add 29.2 g of the product of the previous step to the reaction bottle, add 520 mL of sulfuric acid aqueous solution (concentrated sulfuric acid / water is 1:3), cool to -10°C, add 8.3 g of sodium nitrite, control the temperature at -10°C and react for 2 hours to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium chloride reaction solution;

[0095] (5) Add 8.9 mL of tetrafluoroboric acid solvent to the reaction solution in the previous step, control the temperature at 10° C. to react for 2 hours, filter, collect, and dry to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium tetrafluoroborate, weighing 35.4 g, with a total yield of 81.3% and a purity of 98.81%.

[0096] Example 9: Synthesis of 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium hemichloride zinc salt

[0097] (1) Add 15.7 g of 2-chloro-5-methyl-1,4-phenylenediamine and 240 mL of triethylamine to a reaction bottle, stir evenly, add 24.8 g of di-tert-butyl dicarbonate, and react at 40° C. for 24 hours to obtain a 4-amino-5-chloro-2-methylbenzamide (Boc) amide reaction solution;

[0098] (2) Add 23.8 g of biphenyl-4-carbonyl chloride to the reaction solution of the previous step, control the temperature at 30° C. to react for 4 hours, add 8 mL of pyridine, continue to control the temperature at 30° C. to react for 16 hours, filter, collect the filter cake, and dry to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzamide (Boc), weighing 40.5 g, with a yield of 92.7% and a purity of 94.81%;

[0099] (3) Add 40.5 g of the product of the previous step to the reaction flask, add 170 mL of dichloromethane, stir evenly, add 45 mL of trifluoroacetic acid, control the temperature to 45 ° C. and react for 4 hours, filter, collect the filter cake, and dry to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylaniline, weighing 29.2 g, with a yield of 93.5% and a purity of 95.93%.

[0100] (4) Add 29.2 g of the product of the previous step to the reaction bottle, add 600 mL of hydrochloric acid aqueous solution (concentrated hydrochloric acid / water volume ratio is 1:4), stir evenly, cool to -5°C, add 7.1 g of sodium nitrite, control the temperature at -5°C and react for 1 hour to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium chloride reaction solution;

[0101] (5) Add 5.3 g of zinc chloride to the reaction solution of the previous step, control the temperature at 0° C. to react for 1 hour, filter, collect, and dry to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium hemichloride zinc salt, weighing 34.8 g, with a total yield of 83.5% and a purity of 98.20%.

[0102] Example 10: Synthesis of 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium tetrafluoroborate

[0103] (1) Add 15.7 g of 2-chloro-5-methyl-1,4-phenylenediamine, 160 mL of N,N-dimethylformamide, and 28 mL of tert-butyl chloroformate to a reaction bottle, and stir and react at 50° C. for 10 hours to obtain a 4-amino-5-chloro-2-methylbenzamide (Boc) amide reaction solution;

[0104] (2) Add 24.5 g of biphenyl-4-carbonyl chloride to the reaction solution of the previous step, control the temperature at 40° C. to react for 2 hours, add 18 mL of triethylamine solvent, continue to control the temperature at 40° C. to react for 6 hours, filter, collect, and dry to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzamide (Boc), weighing 40.3 g, with a yield of 92.2% and a purity of 96.45%;

[0105] (3) Add 40.3 g of the product of the previous step to the reaction bottle, add 200 mL of dichloromethane, add 45 mL of concentrated hydrochloric acid, control the temperature to 45° C. for 5 hours, filter, collect, and dry to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzene heavy amine, weighing 29.3 g, with a yield of 94.2% and a purity of 96.80%.

[0106] (4) Add 29.3 g of the product from the previous step to the reaction bottle, add 520 mL of sulfuric acid aqueous solution (concentrated sulfuric acid / water is 1:3), cool to -10°C, add 8.3 g of sodium nitrite, control the temperature at -10°C and react for 2 hours to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium chloride reaction solution;

[0107] (5) Add 8.3 mL of tetrafluoroboric acid solvent to the reaction solution of the product in the previous step, control the temperature at 10° C. to react for 2 hours, filter, collect, and dry to obtain 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium tetrafluoroborate, weighing 36.0 g, with a total yield of 82.6% and a purity of 98.81%.

[0108] Example 11: Comparison of lipid solubility and water solubility of compounds

[0109] At room temperature, three compound samples, 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium hemichloride zinc salt prepared in Example 1, 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium tetrafluoroborate prepared in Example 2, and 4-benzamide-5-chloro-2-methylbenzenediazonium salt, were added to 0.1 L of ethyl acetate or 0.1 L of water respectively until completely dissolved and measured. The experimental results are as follows:

[0110]

[0111] As can be seen from the above table, 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium hemichloride zinc salt and 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium tetrafluoroborate are slightly more water-soluble than 4-benzamide-5-chloro-2-methylbenzenediazonium hemichloride zinc salt, but have better fat solubility.

[0112] Example 12: Comparison of Stability of Compound Formulations

[0113] At room temperature, protected from light, weigh 0.1 g of 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium hemichloride zinc salt prepared in Example 1, 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium tetrafluoroborate prepared in Example 2, and 4-benzamide-5-chloro-2-methylbenzenediazonium hemichloride zinc salt, respectively, and dissolve them in 0.1 L of ethyl acetate and 0.1 L of water, and observe the changes in the solution. The experimental results are as follows:

[0114]

[0115] As can be seen from the above table, 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium hemichloride zinc salt and 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium tetrafluoroborate have better preparation stability than 4-benzamide-5-chloro-2-methylbenzenediazonium hemichloride zinc salt, among which 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium hemichloride zinc salt has better preparation stability than 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium tetrafluoroborate.

[0116] The embodiments of the present invention are described in detail above, but the present invention is not limited to the above embodiments, and various changes can be made within the knowledge scope of those skilled in the art without departing from the spirit of the present invention.

Claims

1. A 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzene diazonium salt, characterized in that: The 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzene diazonium salt is 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzene diazonium zinc hemichloride or 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzene diazonium tetrafluoroborate, and its structural formula is as follows:

2. A method for preparing 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzene diazonium salt, characterized in that The method comprises the 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzene diazonium salt according to claim 1, wherein the method comprises the following steps: using 2-chloro-5-methyl-1,4-phenylenediamine as a raw material, and subjecting the raw material to a protection reaction, an acylation reaction, a deprotection reaction, a diazotization reaction, and a salt-forming reaction, wherein the reaction technical route is as follows: In the formula, R1 is benzyloxycarbonyl (Cbz), trityl (Trt), p-toluenesulfonyl (Tos), tert-butyloxycarbonyl (Boc) or trifluoroacetyl (Tfa); R2 is hemichlorozinc salt or tetrafluoroborate.

3. The method for preparing 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzene diazonium salt according to claim 2, characterized in that: The steps are as follows: (1) dissolving 2-chloro-5-methyl-1,4-phenylenediamine in solvent A, adding an amino protecting agent, and reacting under controlled temperature to obtain compound 1; (2) adding an acylating agent to the reaction system of compound 1 and an acid binding agent, and reacting under temperature control to obtain compound 2; (3) adding compound 2 to solvent B and reacting under controlled temperature to obtain compound 3; (4) adding compound 3 to an acid aqueous solution for acidification, adding nitrite, and reacting under controlled temperature to obtain compound 4; (5) Add a salt-forming reagent to the reaction solution of compound 4 and react under controlled temperature to obtain compound 5 (4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzene diazonium salt).

4. The method for preparing 4-(biphenyl-4-formamide)-5-chloro-2-methylbenzene diazonium salt according to claim 3, characterized in that: The amino protecting agent in step (1) is one of benzyl chloroformate (Cbz-Cl), triphenylmethane chloride (Trt-Cl), p-toluenesulfonyl chloride (Tos-Cl), tert-butyl chloroformate (Boc-Cl), di-tert-butyl dicarbonate (Boc anhydride), and trifluoroacetyl chloride (Tfa-Cl); the feed ratio of 2-chloro-5-methyl-1,4-phenylenediamine and the amino protecting agent is 1 mol: (1.0-2.0) mol; the solvent A is one of dichloromethane, chloroform, acetone, tetrahydrofuran, petroleum ether, isopropyl ether, n-hexane, acetonitrile, dioxane, triethylamine or N,N-dimethylformamide; the ratio of the raw material to the amino protecting agent is 1 g: 5 ml-20 ml; the temperature control temperature is 0-60° C.; and the reaction time is 1-48 hours.

5. The method for preparing 4-(biphenyl-4-formamide)-5-chloro-2-methylbenzene diazonium salt according to claim 3, characterized in that: The acylating agent in step (2) is biphenyl-4-carbonyl chloride; the feed ratio of compound 1 to the acylating agent is 1 mol: (1.05-1.13) mol; the acid binding agent is triethylamine or pyridine; the amount of the acyl chloride reagent and the amount of the acid binding agent are 1 mol: (1.0-3.0) mol; the temperature control temperature is 0-50° C.; and the reaction time is 1-48 h.

6. The method for preparing 4-(biphenyl-4-formamide)-5-chloro-2-methylbenzene diazonium salt according to claim 3, characterized in that: The solvent B in step (3) is a mixed solvent consisting of an organic solvent and an acid aqueous solution, the organic solvent is one of methanol, ethanol, isopropanol, acetone, dichloromethane, chloroform, tetrahydrofuran, petroleum ether, isopropyl ether, n-hexane, acetonitrile, dioxane or N,N-dimethylformamide, and the acid aqueous solution is one of hydrochloric acid, sulfuric acid aqueous solution, nitric acid aqueous solution, acetic acid aqueous solution or trifluoroacetic acid aqueous solution; The ratio of compound 2 to organic solvent is 1 g: 4-5 mL; the ratio of compound 2 to acid aqueous solution is 1 g: 0.8-1 mL; the temperature control temperature is 0-80° C.; and the reaction time is 0.5-24 hours.

7. The method for preparing 4-(biphenyl-4-formamide)-5-chloro-2-methylbenzene diazonium salt according to claim 3, characterized in that: The acid aqueous solution in step (4) is a hydrochloric acid aqueous solution or a sulfuric acid aqueous solution; the ratio of acid to water in the acid aqueous solution is 1 mL: 1-10 mL; the ratio of compound 3 to the acid aqueous solution is 1 g: 15-20 mL; the nitrite is sodium nitrite or potassium nitrite; the molar ratio of nitrite to compound 3 is 1: 1.0-2.0; the temperature is controlled at -10°C to 20°C; and the reaction time is 0.5 to 12 hours.

8. The method for preparing 4-(biphenyl-4-formamide)-5-chloro-2-methylbenzene diazonium salt according to claim 3, characterized in that: The salt-forming reagent in step (5) is zinc chloride or tetrafluoroboric acid, the molar ratio of zinc chloride to compound 4 is 1:0.5-0.8 times, and the molar ratio of tetrafluoroboric acid to compound 4 is 1:1.0-2.0; the temperature is controlled at 0°C-30°C; the reaction time is 0.5-12 hours; When the salt-forming reagent is zinc chloride, 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium zinc chloride hemichloride is obtained; when the salt-forming reagent is tetrafluoroboric acid, 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium tetrafluoroborate is obtained.

9. Use of 4-(biphenyl-4-carboxamide)-5-chloro-2-methylbenzenediazonium salt in dry chemical detection reagents, especially in detecting alkaline phosphatase or tartrate-resistant acid phosphatase.

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