Preparation method of carboxamide triazole intermediate

Abstract

The invention discloses a preparation method of a carboxamide triazole intermediate, which comprises the following steps: reacting (4-bromo-3, 5-dichlorophenyl) oxy) (tert-butyl) dimethylsilane with p-chlorobenzoyl chloride under the catalysis of a metal organic magnesium lithium complex, and removing a hydroxyl protecting group to obtain the carboxamide triazole intermediate. The activity of the metal organic magnesium lithium complex is far lower than that of the butyl lithium, the safety is higher, the whole reaction does not need to be carried out at an ultralow temperature, and the activity of the metal organic magnesium lithium complex is lower, so that small impurities generated by coupling are much less than those generated by using the butyl lithium; and when hydrochloric acid is used for deprotection, the purity of the product in the reaction liquid is increased by nearly 10%, the purification difficulty is greatly reduced, and the product yield is increased. The (4-bromo-3, 5-dichlorophenyl) oxy) (tert-butyl) dimethylsilane can also be obtained through self-preparation, the whole process route is simple, the reaction raw materials are easy to obtain, the synthesis cost is low, the reaction conditions are mild, and the safety is high.

Description

Technical Field

[0001] The invention relates to the technical field of biomedicine, and in particular to a method for preparing a carboxyamine triazole intermediate. Background Art

[0002] The applicant's previously authorized invention patent CN20211028077 discloses a method for preparing 3,5-dichlorobenzyl alcohol and carboxyamine triazole intermediates. The synthesis route is as follows, wherein the core carboxyamine triazole intermediate (4-chlorophenyl)-[2,6-dichloro-4-(hydroxymethyl)phenyl]-methanone is prepared from 3,5-dichlorobenzyl alcohol by tert-butyldimethylchlorosilane; wherein the hydroxyl group of 3,5-dichlorobenzyl alcohol is protected by tert-butyldimethylchlorosilane, and then hydrogen is extracted by butyl lithium and coupled with p-chlorobenzoyl chloride, and then deprotected by concentrated hydrochloric acid to obtain the product.

[0003]

[0004] The above reaction has the following problems. First, butyl lithium reagent is needed for hydrogen extraction. Since butyl lithium reagent is very active, many impurities will be generated during the reaction. In addition, butyl lithium reagent itself has a short shelf life and cannot be exposed to air and water. It must be kept at low or even ultra-low temperature during use. Once a leak occurs, the sparks generated greatly increase the risk of explosion in the production workshop. Therefore, the production environment requirements are very high during industrial production. Second, the reaction needs to be hydrogenated with butyl lithium at about -80°C, and then coupled with p-chlorobenzoyl chloride. The ultra-low temperature reaction process has high requirements for industrial reaction equipment; a large amount of liquid nitrogen is needed during the cooling process, and liquid nitrogen leakage has a suffocating production risk; therefore, the production personnel's operating skills are also required to be high, and the cooling process takes a long time. The equipment cost and time cost of the entire reaction are high, and the safety risk is also high. Summary of the invention

[0005] The present invention aims to overcome at least one defect of the above-mentioned prior art and provide a method for preparing a carboxyamine triazole intermediate to achieve the purpose of mild reaction conditions and high safety.

[0006] Specifically, the present invention protects a method for preparing a carboxyamine triazole intermediate, the preparation method comprising: reacting (4-bromo-3,5-dichlorophenyl)oxy)(tert-butyl)dimethylsilane with p-chlorobenzoyl chloride under the catalysis of a metal organic magnesium lithium complex, and then removing the hydroxy protecting group to obtain a carboxyamine triazole intermediate; the structure of the carboxyamine triazole intermediate is shown below:

[0007]

[0008] Preferably, the molar ratio of (4-bromo-3,5-dichlorophenyl)oxy)(tert-butyl)dimethylsilane to p-chlorobenzoyl chloride is 1:1.4-1.6.

[0009] Preferably, the molar ratio of the (4-bromo-3,5-dichlorophenyl)oxy)(tert-butyl)dimethylsilane to the metal organic magnesium lithium complex is 1:1.0-1.2.

[0010] Preferably, the reaction temperature is ≤20°C.

[0011] Preferably, the solvent of the reaction is one or more of tetrahydrofuran, methyltetrahydrofuran, isopropyl ether, dioxane and the like. More preferably, the solvent of the reaction is one or more of tetrahydrofuran and methyltetrahydrofuran.

[0012] Preferably, the metal organic magnesium lithium complex is one or more of propylmagnesium chloride lithium chloride, sec-butylmagnesium chloride lithium chloride, and isopropylmagnesium chloride lithium chloride.

[0013] Furthermore, the method for removing the hydroxyl protecting group of the present invention is: removing the tert-butyldimethylsilyl group under acidic conditions at room temperature to obtain a carboxyamine triazole intermediate.

[0014] Preferably, the acidic condition is adjusted by adding a protonic acid.

[0015] Furthermore, the preparation method of the present invention also includes a method for synthesizing (4-bromo-3,5-dichlorophenyl)oxy)(tert-butyl)dimethylsilane, wherein the (4-bromo-3,5-dichlorophenyl)oxy)(tert-butyl)dimethylsilane is prepared by reacting 4-bromo-3,5-dichlorobenzyl alcohol with TBDMSCl.

[0016] Preferably, the 4-bromo-3,5-dichlorobenzyl alcohol reacts with TBDMSCl under alkaline conditions, and the alkaline conditions are adding an organic base to the reaction solution.

[0017] Preferably, the organic base is imidazole and / or triethylamine.

[0018] Preferably, the molar ratio of the 4-bromo-3,5-dichlorobenzyl alcohol to TBDMSCl is 1:1.3-1.8; the molar ratio of the TBDMSCl to the organic base is 1:1.0-1.2.

[0019] Furthermore, the preparation method of the present invention also includes a method for synthesizing 4-bromo-3,5-dichlorobenzyl alcohol; the 4-bromo-3,5-dichlorobenzyl alcohol is prepared by a reduction reaction of ethyl 4-bromo-3,5-dichlorobenzoate; or by a bromine substitution reaction of 4-amino-3,5-dichlorobenzyl alcohol with nitrite, hydrobromic acid and a copper-containing catalyst.

[0020] Furthermore, the 4-bromo-3,5-dichlorobenzoic acid ethyl ester is prepared by a bromine substitution reaction of 4-amino-3,5-dichlorobenzoic acid ethyl ester with nitrite, hydrobromic acid and a copper-containing catalyst.

[0021] Furthermore, the method for the bromine substitution reaction is to drip hydrobromic acid into an aqueous solution of nitrite under low temperature with stirring; then add a solvent and a copper-containing catalyst to the reaction solution, stir sufficiently, add 4-amino-3,5-dichlorobenzyl alcohol or 4-amino-3,5-dichlorobenzoic acid ethyl ester, and heat the reaction to obtain the product.

[0022] Preferably, the nitrite is one or more of sodium nitrite and potassium nitrite; the solvent is one or more of acetonitrile, dioxane or dimethyl sulfoxide; and the copper-containing catalyst is one of copper bromide, copper oxide and copper hydroxide.

[0023] Preferably, the low temperature is no higher than 10°C; and the temperature of the heating reaction is 50-80°C.

[0024] Preferably, the molar ratio of the 4-amino-3,5-dichlorobenzyl alcohol or 4-amino-3,5-dichlorobenzoic acid ethyl ester to the nitrite is 1:2-2.5; the mass volume ratio of nitrite to water in the aqueous solution of nitrite is 1g:2-5ml; the molar ratio of the 4-amino-3,5-dichlorobenzyl alcohol or 4-amino-3,5-dichlorobenzoic acid ethyl ester to hydrobromic acid is 1:2.0-2.5; the molar ratio of the 4-amino-3,5-dichlorobenzyl alcohol or 4-amino-3,5-dichlorobenzoic acid ethyl ester to the copper-containing catalyst is 1:0.2-1.0; the mass volume ratio of the 4-amino-3,5-dichlorobenzyl alcohol or 4-amino-3,5-dichlorobenzoic acid ethyl ester to the solvent is 1g:5-15ml.

[0025] More preferably, the molar ratio of the 4-amino-3,5-dichlorobenzyl alcohol or 4-amino-3,5-dichlorobenzoic acid ethyl ester to the nitrite is 1:2.2; the mass volume ratio of nitrite to water in the aqueous solution of nitrite is 1g:3-4ml; the molar ratio of the 4-amino-3,5-dichlorobenzyl alcohol or 4-amino-3,5-dichlorobenzoic acid ethyl ester to the copper-containing catalyst is 1:0.5; the mass volume ratio of the 4-amino-3,5-dichlorobenzyl alcohol or 4-amino-3,5-dichlorobenzoic acid ethyl ester to the solvent is 1g:10ml.

[0026] Furthermore, the bromine substitution reaction also includes the step of adding alcohol while adding nitrite, and the alcohol is C4-C7 alcohol.

[0027] Preferably, the C4-C7 alcohol is one of tert-butyl alcohol, n-butyl alcohol and tert-amyl alcohol. The molar ratio of the 4-amino-3,5-dichlorobenzyl alcohol or ethyl 4-amino-3,5-dichlorobenzoate to the C4-C7 alcohol is 1:2. More preferably, the C4-C7 alcohol is tert-butyl alcohol.

[0028] Furthermore, the 4-amino-3,5-dichlorobenzyl alcohol is prepared from 4-amino-3,5-dichlorobenzoic acid ethyl ester through a reduction reaction.

[0029] Furthermore, the reduction reaction method is: 4-bromo-3,5-dichlorobenzoic acid ethyl ester or 4-amino-3,5-dichlorobenzoic acid ethyl ester is reacted with a catalyst and / or a reducing agent to obtain the product; the catalyst is one or more of lithium chloride, calcium chloride, and magnesium chloride; the reducing agent is one or more of sodium borohydride, potassium borohydride, and lithium aluminum hydride; the molar ratio of the 4-bromo-3,5-dichlorobenzoic acid ethyl ester or 4-amino-3,5-dichlorobenzoic acid ethyl ester to the catalyst is 1:0-2.5; the molar ratio of the 4-bromo-3,5-dichlorobenzoic acid ethyl ester or 4-amino-3,5-dichlorobenzoic acid ethyl ester to the reducing agent is 1:1.5-3.8.

[0030] Preferably, the solvent for the reduction reaction is one or more of tetrahydrofuran, methyltetrahydrofuran, and isopropyl ether.

[0031] Preferably, the 4-amino-3,5-dichlorobenzoic acid ethyl ester is prepared by heating ethyl p-aminobenzoate and a chlorinating agent.

[0032] Preferably, the chlorinating agent is at least one of NCS, NaDCC, and TCCA; the molar ratio of ethyl p-aminobenzoate to the chlorinating agent is 1:0.7-2.5; and the heating reaction solvent is one or more of acetonitrile, THF, DMF, 1,4-dioxane, and dichloromethane.

[0033] Compared with the prior art, the present invention has the following beneficial effects:

[0034] The present invention can use (4-bromo-3,5-dichlorophenyl)oxy) (tert-butyl) dimethylsilane as a synthetic raw material, and does not need to use butyl lithium. The activity of isopropyl magnesium chloride and lithium chloride is much lower than that of butyl lithium, and the safety is higher. The whole reaction does not need to be carried out at an ultra-low temperature. Because the activity of isopropyl magnesium chloride and lithium chloride is lower, the small impurities generated by the coupling itself are much less than those when butyl lithium is used. When hydrochloric acid is used for deprotection, the purity of the product in the reaction solution is increased by nearly 10%, which greatly reduces the difficulty of purification and improves the product yield.

[0035] The (4-bromo-3,5-dichlorophenyl)oxy) (tert-butyl) dimethylsilane of the present invention can also be obtained by self-production. The entire process route is simple, the reaction raw materials are easy to obtain, the synthesis cost is low, the conditions are mild, and the safety is high. DETAILED DESCRIPTION

[0036] Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in the field without making any creative work shall fall within the scope of protection of the present invention.

[0037] It should be noted that if the embodiments of the present application involve directional indications (such as up, down, left, right, front, back, etc.), the directional indications are only used to explain the relative position relationship, movement status, etc. between the components in a certain specific posture. If the specific posture changes, the directional indication will also change accordingly.

[0038] In addition, if there are descriptions involving "first", "second", etc. in the embodiments of the present application, the descriptions of "first", "second", etc. are only used for descriptive purposes and cannot be understood as indicating or suggesting their relative importance or implicitly indicating the number of technical features indicated. Therefore, the features defined as "first" and "second" may explicitly or implicitly include at least one of the features. In addition, the technical solutions between the various embodiments can be combined with each other, but they must be based on the ability of ordinary technicians in the field to implement them. When the combination of technical solutions is contradictory or cannot be implemented, it should be deemed that such combination of technical solutions does not exist and is not within the scope of protection required by this application. Example 1

[0039] Examples 1 to 4 provide methods for preparing carboxyamine triazole intermediates from (4-bromo-3,5-dichlorophenyl)oxy)(tert-butyl)dimethylsilane.

[0040] Example 4 is an amplified experiment of preparing a carboxyamide triazole intermediate from (4-bromo-3,5-dichlorophenyl)oxy)(tert-butyl)dimethylsilane. The reaction formula is as follows:

[0041] Under nitrogen protection, add 7.4g (4-bromo-3,5-dichlorophenyl)oxy) (tert-butyl) dimethylsilane and 45mL tetrahydrofuran to the reaction bottle, cool to 10℃, control the temperature not higher than 17℃, drop 15mL isopropyl magnesium chloride lithium chloride solution (concentration 1.3mol / L), after the drop is complete, keep the temperature at 10℃ for 30min, control the temperature not higher than 17℃, drop 5.2g p-chlorobenzoyl chloride in 15mL tetrahydrofuran solution, after the drop is complete, keep the temperature at 10℃ for 2h, take samples for HPLC, the control meets the standard, and the main peak purity is 88.4%. After adding 70mL 4% sodium hydroxide aqueous solution, return to room temperature, stir for 1h, stand for separation, add 7.4g concentrated hydrochloric acid to the organic phase, react for 2h, take samples for HPLC, the original main peak remains 0.62%, and the target main peak purity is 95.2%. After adding 60 mL of water and 50 mL of ethyl acetate to the system and stirring at room temperature for 30 min, the system was allowed to stand for separation. The organic phase was washed with 60 mL of 4% sodium hydroxide and then with 60 mL of 0.01 mol / L dilute saline solution, dried over anhydrous sodium sulfate, concentrated to remove the solvent, and n-heptane was added for crystallization and slurrying. After the solid was dried, 4.9 g was obtained, with a yield of 77.7% and an HPLC purity of 99.7%. Example 2

[0042] Under nitrogen protection, add 7.4g (4-bromo-3,5-dichlorophenyl)oxy) (tert-butyl) dimethylsilane and 45mL isopropyl ether to the reaction bottle, cool to 10℃, control the temperature not higher than 20℃, drop 23mL of propylmagnesium chloride lithium chloride solution (concentration 1.0mol / L), after the drop is completed, keep the temperature at 10℃ for 30min, control the temperature not higher than 20℃, drop 5.6g of p-chlorobenzoyl chloride in 15mL isopropyl ether solution, after the drop is completed, keep the temperature at 10℃ for 2h, take samples for HPLC, the control meets the standard, and the main peak purity is 88.4%. After adding 70mL of 4% sodium hydroxide aqueous solution, return to room temperature, stir for 1h, stand for separation, add 3.5g of concentrated sulfuric acid to the organic phase, react for 2h, take samples for HPLC, the original main peak remains 0.62%, and the target main peak purity is 95.2%. After adding 60 mL of water and 50 mL of ethyl acetate to the system and stirring at room temperature for 30 min, the system was allowed to stand for separation. The organic phase was washed with 60 mL of 4% sodium hydroxide and then with 60 mL of 0.01 mol / L dilute saline solution, dried over anhydrous sodium sulfate, concentrated to remove the solvent, and n-heptane was added for crystallization and slurrying. After the solid was dried, 4.9 g was obtained, with a yield of 77.7% and an HPLC purity of 99.7%. Example 3

[0043] Under nitrogen protection, add 7.4g (4-bromo-3,5-dichlorophenyl)oxy) (tert-butyl) dimethylsilane and 45mL dioxane to the reaction bottle, cool to 10℃, control the temperature not higher than 15℃, drop 21mL of sec-butyl magnesium chloride lithium chloride solution (concentration 1.0mol / L), after the drop is complete, keep the temperature at 10℃ for 30min, control the temperature not higher than 17℃, drop 4.9g of p-chlorobenzoyl chloride in 15mL dioxane solution, after the drop is complete, keep the temperature at 10℃ for 2h, take samples for HPLC, the control meets the standard, and the main peak purity is 85.1%. After adding 70mL of 4% sodium hydroxide aqueous solution, return to room temperature, stir for 1h, stand for separation, add 7.4g of concentrated hydrochloric acid to the organic phase, react for 2h, take samples for HPLC, the original main peak remains 0.91%, and the target main peak purity is 94.7%. After adding 60 mL of water and 50 mL of ethyl acetate to the system and stirring at room temperature for 30 min, the system was allowed to stand for separation. The organic phase was washed with 60 mL of 4% sodium hydroxide and then with 60 mL of 0.01 mol / L dilute saline solution, dried over anhydrous sodium sulfate, concentrated to remove the solvent, and n-heptane was added for crystallization and slurrying. After the solid was dried, 5.0 g was obtained, with a yield of 79.3% and a HPLC purity of 99.5%. Example 4

[0044] Under nitrogen protection, add 74g (4-bromo-3,5-dichlorophenyl)oxy) (tert-butyl) dimethylsilane and 450mL methyltetrahydrofuran to the reaction bottle, cool to 10°C, control the temperature not higher than 17°C, drop 221mL of isopropylmagnesium chloride lithium chloride solution (concentration 1.0mol / L), after the drop is completed, keep the temperature at 10°C for 30min, control the temperature not higher than 17°C, drop 52g of p-chlorobenzoyl chloride in 150mL methyltetrahydrofuran solution, after the drop is completed, keep the temperature at 10°C for 2h, take samples and measure HPLC, the control meets the standard, and the main peak purity is 86.4%. After adding 700mL of 4% sodium hydroxide aqueous solution, return to room temperature, stir for 1h, stand for separation, add 74g of concentrated hydrochloric acid to the organic phase, react for 2h, take samples and measure HPLC, the original main peak remains 0.74%, and the target main peak purity is 94.7%. After adding 600 mL of water and 500 mL of ethyl acetate to the system and stirring at room temperature for 30 min, the system was allowed to stand for separation. The organic phase was washed with 600 mL of 4% sodium hydroxide and then with 600 mL of 0.01 mol / L dilute saline solution, dried over anhydrous sodium sulfate, concentrated to remove the solvent, and n-heptane was added for crystallization and slurrying. After the solid was dried, 51 g was obtained, with a yield of 80.4% and an HPLC purity of 99.6%. Example 5

[0045] Examples 5 to 8 are methods for preparing (4-bromo-3,5-dichlorophenyl)oxy)(tert-butyl)dimethylsilane from 4-bromo-3,5-dichlorobenzyl alcohol.

[0046] The reaction formula is as follows:

[0047]

[0048] Add 23.7g of 4-bromo-3,5-dichlorobenzyl alcohol, 10.1g of imidazole, and 75ml of DMF to the reaction bottle, stir and dissolve; add 19.5g of TBDMSCl to the system, stir and react at room temperature for 1.5h, take samples and test HPLC, the central control meets the standard, and the main peak purity is 99.9%. Add 120mL of n-heptane to the system, wash the system with 220mL of water, separate the phases, extract the aqueous phase with 40mL of n-heptane, combine the organic phases, wash twice with 150ml of dilute brine, dry with anhydrous sodium sulfate, and concentrate to obtain 34.3g of the product with a yield of 100.1%. The HPLC purity is 99.4%. Example 6

[0049] Add 23.7g of 4-bromo-3,5-dichlorobenzyl alcohol, 17.0g of triethylamine, and 75ml of DMF to the reaction bottle, stir and dissolve; add 25.1g of TBDMSCl to the system, stir and react at room temperature for 1.5h, take samples and test HPLC, the central control meets the standard, and the main peak purity is 99.7%. Add 120mL of n-heptane to the system, wash the system with 220mL of water, separate the phases, extract the aqueous phase with 40mL of n-heptane, combine the organic phases, wash twice with 150ml of dilute brine, dry with anhydrous sodium sulfate, and concentrate to obtain 34.2g of the product with a yield of 99.8%. The HPLC purity is 99.2%. Example 7

[0050] Add 23.7g of 4-bromo-3,5-dichlorobenzyl alcohol, 8.8g of imidazole, and 75ml of DMF to the reaction bottle, stir and dissolve; add 18.1g of TBDMSCl to the system, stir and react at room temperature for 1.5h, take samples and test HPLC, the central control meets the standard, and the main peak purity is 99.9%. Add 120mL of n-heptane to the system, wash the system with 220mL of water, separate the phases, extract the aqueous phase with 40mL of n-heptane, combine the organic phases, wash twice with 150ml of dilute brine, dry with anhydrous sodium sulfate, and concentrate to obtain 33.8g of the product with a yield of 98.7%. The HPLC purity is 99.4%. Example 8

[0051] Add 23.7g of 4-bromo-3,5-dichlorobenzyl alcohol, 11.4g of imidazole, and 75ml of DMF to the reaction bottle, stir and dissolve; add 21.0g of TBDMSCl to the system, stir and react at room temperature for 1.5h, take samples and test HPLC, the central control meets the standard, and the main peak purity is 99.9%. Add 120mL of n-heptane to the system, wash the system with 220mL of water, separate the phases, extract the aqueous phase with 40mL of n-heptane, combine the organic phases, wash twice with 150ml of dilute brine, dry with anhydrous sodium sulfate, and concentrate to obtain 34.0g of the product with a yield of 99.2%. The HPLC purity is 99.6%. Example 9

[0052] Examples 9 to 13 provide methods for preparing 4-bromo-3,5-dichlorobenzyl alcohol from ethyl 4-bromo-3,5-dichlorobenzoate.

[0053] The reaction formula is as follows:

[0054]

[0055] Add 30.0g of ethyl 4-bromo-3,5-dichlorobenzoate, 5.5g of lithium chloride, 8.14g of potassium borohydride, and 270ml of THF to the reaction bottle, stir and react, heat to reflux for 2h, take a sample and measure HPLC, the reaction is up to standard, and the main peak purity is 97.71%. After cooling the system to 30℃, add 700ml of water, cool to 5℃, stir for 1h, filter; after drying the filter cake, 23.7g is obtained, the yield is 92.0%, and the HPLC purity is: 99.72%. Example 10

[0056] Add 0.72g lithium chloride, 0.65g sodium borohydride, 10ml THF to the reaction bottle, stir at room temperature for 5min, then drop 2.00g 4-bromo-3,5-dichlorobenzoic acid ethyl ester in 10ml THF solution, stir and heat to reflux for 2h, take a sample and measure HPLC, the reaction is up to standard, the main peak purity is 97.01%. Cool the system to 30℃ and add 50ml water, after addition, cool to 5℃ and stir for 1h, filter; after drying the filter cake, 1.55g is obtained, the yield is 90.2%, and the HPLC purity is: 98.6%. Embodiment 11

[0057] Add 2.85g of calcium chloride, 1.38g of potassium borohydride, and 10ml of THF to the reaction bottle, stir at room temperature for 5min, then drop 2.00g of ethyl 4-bromo-3,5-dichlorobenzoate in 10ml of THF solution, stir and heat to reflux for 2h, take a sample and measure HPLC, the reaction is up to standard, and the main peak purity is 93.02%. Cool the system to 30℃ and add 50ml of water, after addition, cool to 5℃ and stir for 1h, filter; after drying the filter cake, 1.54g is obtained, the yield is 89.6%, and the HPLC purity is: 99.3%. Example 12

[0058] Add 1.63g of magnesium chloride, 1.38g of potassium borohydride, and 10ml of THF to the reaction bottle, stir at room temperature for 5min, then drop 2.00g of ethyl 4-bromo-3,5-dichlorobenzoate in 10ml of THF solution, stir and heat to reflux for 2h, take a sample and measure HPLC, the reaction is up to standard, and the main peak purity is 91.27%. Cool the system to 30℃ and add 50ml of water, after addition, cool to 5℃ and stir for 1h, filter; after drying the filter cake, 1.47g is obtained, the yield is 85.4%, and the HPLC purity is: 98.6%. Embodiment 13

[0059] Add 2.00g of ethyl 4-bromo-3,5-dichlorobenzoate and 10ml of THF to the reaction bottle, stir evenly at room temperature, add 0.42g of lithium aluminum hydride to the system in batches, heat to 30°C, react for 2h, take samples for HPLC, the reaction is up to standard, and the main peak purity is 90.87%. Filter and rinse the filter cake with 10mL of THF, add the filtrate to 50ml of water, keep warm at 5°C after stirring and crystallizing for 1h, and filter to obtain the filter cake; dry the product under reduced pressure at 55°C for 16h to obtain 1.44g of the product, with a yield of 83.82% and a HPLC purity of 98.51%. Embodiment 14

[0060] Examples 14 to 17 provide a method for preparing 4-bromo-3,5-dichlorobenzoic acid ethyl ester from 4-amino-3,5-dichlorobenzoic acid ethyl ester. The reaction formula is as follows:

[0061]

[0062] Add 12.7 g of tert-butanol, 50 ml of water, and 13.0 g of sodium nitrite to the reaction bottle, stir and cool to -5°C; add 34.6 g of 40% hydrobromic acid dropwise while controlling the temperature of the reaction solution to no higher than 5°C, and after the addition, keep warm at 0±5°C and stir; after 2 hours, add 100 ml of acetonitrile and 9.5 g of copper bromide to the reaction solution, stir well, then add 20.0 g of 4-amino-3,5-dichlorobenzoic acid ethyl ester in 100 ml of acetonitrile solution, after the addition, slowly heat to room temperature and continue to heat the reaction to 80°C, keep warm for reaction, and detect after 2 hours that the reaction is complete; the purity of the main peak is 94.6%.

[0063] The system was cooled to room temperature, diluted with 200 mL of ethyl acetate, washed with 500 mL of water and separated into phases, the aqueous phase was back-extracted with ethyl acetate, the two organic phases were combined, washed twice with 300 mL of dilute brine, dried over anhydrous sodium sulfate, concentrated to remove the solvent, and purified by recrystallization from acetonitrile water. After drying, 24.1 g of the product was obtained with a yield of 94.7%. The HPLC purity of the product was 99.26%. Embodiment 15

[0064] Add 15.1g of tert-amyl alcohol, 50ml of water, and 13.0g of sodium nitrite to the reaction bottle, stir and cool to -5°C; add 51.8g of concentrated hydrobromic acid dropwise while controlling the temperature of the reaction solution to no higher than 5°C, and after addition, keep warm at 0±5°C and stir; after 1h, add 100ml of acetonitrile and 3.4g of copper oxide to the reaction solution, stir well, and then add 20.0g of ethyl 4-amino-3,5-dichlorobenzoate in 100ml of dioxane solution, after addition, slowly heat to room temperature and continue to heat the reaction to 60°C, keep warm for reaction, and detect the reaction completion after 2h; the main peak purity is 93.4%;

[0065] The system was cooled to room temperature, diluted with 200 mL of ethyl acetate, washed with 500 mL of water and separated into phases, the aqueous phase was back-extracted with ethyl acetate, the two organic phases were combined, washed twice with 300 mL of dilute brine, dried over anhydrous sodium sulfate, concentrated to remove the solvent, and purified by recrystallization from acetonitrile water. After drying, 23.9 g of the product was obtained with a yield of 93.9%. The HPLC purity of the product was 99.01%. Example 16

[0066] Add 10.6g of n-butanol, 35ml of water, and 16.0g of potassium nitrite to the reaction bottle, stir and cool to -5°C; add 52.0g of concentrated hydrobromic acid dropwise while controlling the temperature of the reaction solution to not exceed 5°C, and after addition, keep warm at 0±5°C and stir; after 1h, add 100ml of dimethyl sulfoxide and 4.2g of copper hydroxide to the reaction solution, stir well, and then add 20.0g of 4-amino-3,5-dichlorobenzoic acid ethyl ester in 100ml of dimethyl sulfoxide solution, after addition, slowly heat to room temperature and continue to heat the reaction to 60°C, keep warm for reaction, and detect the reaction completion after 2h; the main peak purity is 82.3%;

[0067] The system was cooled to room temperature, diluted with 200 mL of ethyl acetate, washed with 500 mL of water and separated into phases, the aqueous phase was back-extracted with ethyl acetate, the two organic phases were combined, washed twice with 300 mL of dilute brine, dried over anhydrous sodium sulfate, concentrated to remove the solvent, and purified by recrystallization from acetonitrile water. After drying, 20.5 g of the product was obtained with a yield of 80.5%. The HPLC purity of the product was 98.6%. Embodiment 17

[0068] Add 5 ml of water and 1.6 g of sodium nitrite to the reaction bottle, stir and cool to 0°C; add 5.2 g of concentrated hydrobromic acid dropwise while controlling the temperature of the reaction solution to no higher than 5°C, and keep it warm at 0°C and stir after completion; add 15 ml of acetonitrile and 0.4 g of copper bromide to the reaction solution after 1 hour, stir well and add 2.0 g of 4-amino-3,5-dichlorobenzoic acid ethyl ester in 15 ml of acetonitrile solution, and slowly heat to room temperature and continue to heat the reaction to 60°C, keep warm and react, and detect the reaction completion after 2 hours; the main peak purity is 80.3%;

[0069] The system was cooled to room temperature, diluted with ethyl acetate, washed with water and then separated into phases, the aqueous phase was back-extracted with ethyl acetate, the two organic phases were combined, washed twice with dilute brine, dried over anhydrous sodium sulfate, concentrated to remove the solvent, and purified by recrystallization with acetonitrile water. After drying, 2.0 g of the product was obtained with a yield of 78.6%. The HPLC purity of the product was 98.1%. Embodiment 18

[0070] Examples 18 to 23 provide methods for preparing 4-amino-3,5-dichlorobenzoic acid ethyl ester from ethyl p-aminobenzoate, and the reaction formula is as follows:

[0071] Add 20.0g of ethyl p-aminobenzoate and 100ml of acetonitrile to reaction flask 1, stir until dissolved, add 34.0g of NCS, heat to 80℃ and reflux, react for 2h, and the control reaches the standard; add 400mL of water to reaction flask 2 and precool to 0℃. Add the reaction solution dropwise to the precooled water under stirring to precipitate solid, maintain stirring at 0℃ for 1h; filter by suction, wash the filter cake with water; dry under reduced pressure at 55℃ to obtain 28.8g of product, with a yield of 101.6% and a HPLC purity of 99.9%. Embodiment 19

[0072] Add 20.0g of ethyl p-aminobenzoate and 100ml of THF to reaction flask 1, stir until dissolved, add 34.0g of NCS, heat to 65°C and reflux, react for 6h, and the control reaches the standard; add 400mL of water to reaction flask 2 and precool to 0°C. Add the reaction solution dropwise to the precooled water under stirring to precipitate solid, maintain stirring at 0°C for 1h; filter by suction, wash the filter cake with water; dry under reduced pressure at 55°C to obtain 26.6g of product, with a yield of 93.9% and a HPLC purity of 99.8%. Embodiment 20

[0073] Add 20.0g of ethyl p-aminobenzoate and 100ml of DMF to reaction flask 1, stir until dissolved, then add 34.0g of NCS, heat to 65°C, react for 2h, and the control reaches the standard; add 400mL of water to reaction flask 2, and precool to 0°C. Add the reaction solution dropwise to the precooled water under stirring, precipitate solid, and stir at 0°C for 1h; filter by suction, wash the filter cake with water; dry under reduced pressure at 55°C to obtain 23.9g of product, with a yield of 84.3% and a HPLC purity of 98.9%. Embodiment 21

[0074] Add 20.0g of ethyl p-aminobenzoate and 100ml of 1,4-dioxane to reaction flask 1, stir until dissolved, then add 27.0g of NaDCC, heat to 85°C, react for 4h, and the control reaches the standard; add 400mL of water to reaction flask 2 and precool to 0°C. Add the reaction solution dropwise to the precooled water under stirring to precipitate solids, and stir at 0°C for 1h; filter by suction, wash the filter cake with water; dry under reduced pressure at 55°C to obtain 27.0g of the product, with a yield of 95.3% and a HPLC purity of 99.8%. Embodiment 22

[0075] Add 20.0g of ethyl p-aminobenzoate and 100ml of dichloromethane to reaction flask 1, stir until dissolved, then add 20.0g of TCCA, heat to 75°C, react for 2h, and the control reaches the standard; add 400mL of water to reaction flask 2, and precool to 0°C. Add the reaction solution dropwise to the precooled water under stirring, precipitate solid, and stir at 0°C for 1h; filter by suction, wash the filter cake with water; dry under reduced pressure at 55°C to obtain 20.9g of product, with a yield of 73.8% and an HPLC purity of 92.9%. Embodiment 23

[0076] Add 200.0g of ethyl p-aminobenzoate and 1l of acetonitrile to the reaction bottle, stir until dissolved, then add 340.0g of NCS, heat to 80°C, react for 2h, and the central control meets the standard; add 4L of water to the reactor and precool to 0°C. Add the reaction solution dropwise to the precooled water under stirring to precipitate solids, and stir at 0°C for 1h; filter by suction, wash the filter cake with water; dry under reduced pressure at 55°C to obtain 290.0g of the product, with a yield of 102.3% and a HPLC purity of 99.9%. Embodiment 24

[0077] This embodiment provides a process for reducing 4-amino-3,5-dichlorobenzoic acid ethyl ester to 4-amino-3,5-dichlorobenzyl alcohol, and the reaction formula is as follows:

[0078]

[0079] Add 10.00g of ethyl 4-amino-3,5-dichlorobenzoate and 150ml of THF to the reaction bottle, stir evenly, cool to 0°C, add 0.42g of lithium aluminum hydride to the system in batches, warm to room temperature, react for 3 hours, take samples for HPLC, the reaction meets the standard, and the main peak purity is 87.82%. Cool the reaction to 30°C, filter and rinse the filter cake with 10mL of THF, add the filtrate to 50ml of water, extract with ethyl acetate, dry with anhydrous sodium sulfate, concentrate to remove the solvent, crystallize and slurry with n-heptane; after the product is dried under reduced pressure at 55°C, 7.3g of the product is obtained, with a yield of 88.98% and a HPLC purity of 98.26%. Embodiment 25

[0080] This example provides a process for generating 4-bromo-3,5-dichlorobenzyl alcohol by bromination reaction of 4-amino-3,5-dichlorobenzyl alcohol prepared in Example 24; the reaction formula is as follows:

[0081]

[0082] Add 3.9g of tert-butyl alcohol, 15ml of water, and 4.0g of sodium nitrite to the reaction bottle, stir and cool to -5℃; add 8.8g of concentrated hydrobromic acid dropwise while the reaction solution is controlled to be not higher than 5℃, and after addition, keep warm at 0±5℃ and stir; after 2h, add 25ml of acetonitrile and 2.9g of copper bromide to the reaction solution, stir well and add 5.0g of 4-amino-3,5-dichlorobenzyl alcohol in 25ml of acetonitrile solution, after addition, slowly heat to room temperature and continue to heat the reaction to 80℃, keep warm and react, and after 2h, the control reaches the standard, and the main peak purity is 89.6%. The system is cooled to room temperature, the system is diluted with ethyl acetate, washed with sodium carbonate aqueous solution, the aqueous phase is back-extracted with ethyl acetate, the two organic phases are combined, dried over anhydrous sodium sulfate, concentrated to remove the solvent, and purified by recrystallization from acetonitrile / water, and 5.9g of the product is obtained after drying, with a yield of 88.4%, and the HPLC purity of the product is 99.16%. Comparative Example 1

[0083] Under nitrogen protection, add 7.4g (4-bromo-3,5-dichlorophenyl)oxy) (tert-butyl) dimethylsilane and 45mL THF to the reaction bottle, cool to 10℃, control the temperature not higher than 17℃, drop 16mL isopropyl magnesium chloride lithium chloride solution (concentration 1.3mol / L), after the drop is complete, keep the temperature at 10℃ for 30min, control the temperature not higher than 17℃, drop 4.6g p-chlorobenzoyl chloride in 15mL THF solution, after the drop is complete, keep the temperature at 10℃ for 2h, take a sample and control it by HPLC, the raw material remains 0.26%, and the main peak purity is 73.4%. After adding 70mL 4% sodium hydroxide aqueous solution, return to room temperature, stir for 1h, stand and separate, add 7.4g concentrated hydrochloric acid to the organic phase, react for 2h, take a sample and measure HPLC, the original main peak remains 0.84%, and the target main peak purity is 70.9%. By comparison, it was found that when the feeding amount of 4-chlorobenzoyl chloride was reduced to 1.3eq, the impurities increased significantly. Comparative Example 2

[0084] Under nitrogen protection, add 7.4g (4-bromo-3,5-dichlorophenyl)oxy) (tert-butyl) dimethylsilane and 45mL THF to the reaction bottle, cool to 25℃, control the temperature not higher than 30℃, drop 16mL of isopropyl magnesium chloride lithium chloride solution (concentration 1.3mol / L), after the drop is completed, keep the temperature at 25℃ for 30min, control the temperature not higher than 30℃, drop 4.6g of p-chlorobenzoyl chloride in 15mL THF solution, after the drop is completed, keep the temperature at 25℃ for 2h, sample HPLC control, the raw material remains 0.21%, the main peak purity is 65.9%. After adding 70mL of 4% sodium hydroxide aqueous solution, return to room temperature, stir for 1h, stand and separate, add 7.4g of concentrated hydrochloric acid to the organic phase, react for 2h, sample and measure HPLC, the original main peak remains 0.58%, and the target main peak purity is 62.3%. By comparison, it is found that the impurities increase significantly when the reaction temperature increases. Comparative Example 3

[0085] Add 23.7g of 4-bromo-3,5-dichlorobenzyl alcohol, 8.2g of imidazole, and 75ml of DMF to the reaction bottle, stir and dissolve; add 19.6g of TBDMSCl to the system, stir and react at room temperature for 1.5h, take a sample and measure HPLC, the raw material remains 15.7%, the main peak purity is 83.6%, after continuing to react for 2h, the raw material remains 14.3%, the main peak purity is 84.2%, heat to 60℃, react for 1h, the raw material remains 12.1%, the main peak purity is 72.8%. The reaction will hardly continue to react if the reaction time is prolonged at room temperature, and the heating reaction will become worse. Comparative Example 4

[0086] Add 23.7g of 4-bromo-3,5-dichlorobenzyl alcohol, 10.1g of imidazole, and 75ml of DMF to the reaction bottle, stir and dissolve; add 15.4g of TBDMSCl to the system, stir and react at room temperature for 1.5h, take a sample and measure HPLC, the raw material remains 32.7%, the main peak purity is 67.0%, continue to react for 2h, the raw material remains 32.1%, the main peak purity is 67.1%, heat to 60℃, react for 1h, the raw material remains 21.9%, the main peak purity is 61.9%. The reaction will hardly continue to react if the reaction is prolonged at room temperature, and the heating reaction will become worse. Comparative Example 5

[0087] Add 1.37g zinc chloride, 1.38g potassium borohydride, and 10ml THF to the reaction flask, stir at room temperature for 5min, then drop 2.00g of ethyl 4-bromo-3,5-dichlorobenzoate in 10ml THF solution, stir and heat to reflux for 2h, take a sample and measure HPLC, the raw material remains 88.8%, continue to react for 2 hours, the raw material remains 88.5%, and the product is 5.25%. The reaction hardly occurs under this condition. Comparative Example 6

[0088] Add 1.37g zinc chloride, 1.38g potassium borohydride, and 10ml ethanol to the reaction bottle, stir at room temperature for 5min, then drop 2.00g ethyl 4-bromo-3,5-dichlorobenzoate in 10ml ethanol solution, stir and heat to reflux for 2h, take a sample and measure HPLC, the raw material remains 90.3%, continue to react for 2 hours, the raw material remains 90.3%, the product is 3.5%. The reaction hardly occurs under this condition. Comparative Example 7

[0089] Add 106 mg of ethylene glycol, 0.5 ml of water, and 130 mg of sodium nitrite to the reaction bottle, stir and cool to -5°C; add 382 mg of 40% hydrobromic acid dropwise while controlling the temperature of the reaction solution to no higher than 5°C, and after the addition, keep warm at 0±5°C and stir; after 1 hour, add 2 ml of acetonitrile and 382 mg of copper bromide to the reaction solution, stir thoroughly and then add 200 mg of ethyl 4-amino-3,5-dichlorobenzoate, after the addition, slowly heat to 65°C, keep warm for reaction, and detect after 2 hours that the reaction is complete; the purity of the main peak is only 43.2%. Comparative Example 8

[0090] Add 200 mg of ethyl 4-amino-3,5-dichlorobenzoate, 2 ml of acetonitrile, 126 mg of tert-butanol, and 632 mg of 40% hydrobromic acid into a test tube, and stir evenly at -5°C; add 0.5 ml of an aqueous solution of 79 mg of sodium nitrite dropwise into the system, stir and react at 0°C for 1 h, add 60 mg of cuprous bromide to the reaction solution, stir and react at 65°C for 2 h, take a sample and measure HPLC, no raw material is found, and the purity of the product is only 62.3%, indicating that a considerable portion of the raw material is converted into impurities under this condition.

[0091] The above embodiments are only used to illustrate the technical solution of the present invention and are not intended to limit it. Although the present invention is described in detail with reference to the above preferred embodiments, it should be understood by those skilled in the art that the technical solution of the present invention can be modified or replaced by equivalents without departing from the spirit and scope of the technical solution of the present invention. Those skilled in the art may also make other changes within the spirit of the present invention and apply them to the design of the present invention, as long as they do not deviate from the technical effects of the present invention. These changes made according to the spirit of the present invention should be included in the scope of protection claimed by the present invention.

Claims

1. A method for preparing a carboxyamide triazole intermediate, characterized in that: The preparation method comprises: reacting (4-bromo-3,5-dichlorophenyl)oxy)(tert-butyl)dimethylsilane with p-chlorobenzoyl chloride under the catalysis of a metal organic magnesium lithium complex, and then removing the hydroxyl protecting group to obtain a carboxyamine triazole intermediate; the structure of the carboxyamine triazole intermediate is shown below:

2. The preparation method according to claim 1, characterized in that: The molar ratio of the (4-bromo-3,5-dichlorophenyl)oxy)(tert-butyl)dimethylsilane to p-chlorobenzoyl chloride is 1:1.4-1.

6.

3. The preparation method according to claim 1, characterized in that: The molar ratio of the (4-bromo-3,5-dichlorophenyl)oxy) (tert-butyl) dimethylsilane to the metal organic magnesium lithium complex is 1:1.0-1.

2.

4. The preparation method according to any one of claims 1 to 3, characterized in that: The metal organic magnesium lithium complex is one or more of propylmagnesium chloride lithium chloride, sec-butylmagnesium chloride lithium chloride, and isopropylmagnesium chloride lithium chloride.

5. The preparation method according to claim 1, characterized in that: The reaction temperature is ≤20°C; the reaction solvent is one or more of tetrahydrofuran, methyltetrahydrofuran, isopropyl ether, and dioxane; the method for removing the hydroxyl protecting group is: removing the tert-butyldimethylsilyl group under acidic conditions at room temperature to obtain a carboxyamine triazole intermediate; the acidic conditions are adjusted by adding a protonic acid.

6. The preparation method according to claim 1, characterized in that: The invention also includes a method for synthesizing (4-bromo-3,5-dichlorophenyl)oxy) (tert-butyl) dimethylsilane, wherein the (4-bromo-3,5-dichlorophenyl)oxy) (tert-butyl) dimethylsilane is prepared by reacting 4-bromo-3,5-dichlorobenzyl alcohol with TBDMSCl.

7. The preparation method according to claim 5, characterized in that: The 4-bromo-3,5-dichlorobenzyl alcohol reacts with TBDMSCl under alkaline conditions, wherein the alkaline conditions are adding an organic base to the reaction solution; the organic base is imidazole and / or triethylamine.

8. The preparation method according to claim 6, characterized in that: The molar ratio of the 4-bromo-3,5-dichlorobenzyl alcohol to TBDMSCl is 1:1.3-1.8; the molar ratio of the TBDMSCl to the organic base is 1:1.0-1.

2.

9. The preparation method according to claim 7, characterized in that: The invention also includes a method for synthesizing 4-bromo-3,5-dichlorobenzyl alcohol; the 4-bromo-3,5-dichlorobenzyl alcohol is prepared by a reduction reaction of ethyl 4-bromo-3,5-dichlorobenzoate; or by a bromine substitution reaction of 4-amino-3,5-dichlorobenzyl alcohol with nitrite, hydrobromic acid and a copper-containing catalyst.

10. The preparation method according to claim 8, characterized in that: The 4-bromo-3,5-dichlorobenzoic acid ethyl ester is prepared by a bromine substitution reaction of 4-amino-3,5-dichlorobenzoic acid ethyl ester with nitrite, hydrobromic acid and a copper-containing catalyst.

11. The preparation method according to claim 8 or 9, characterized in that: The bromine substitution reaction method comprises the following steps: adding hydrobromic acid dropwise to a nitrite aqueous solution under stirring at low temperature; then adding a solvent and a copper-containing catalyst to the reaction solution, adding 4-amino-3,5-dichlorobenzyl alcohol or 4-amino-3,5-dichlorobenzoic acid ethyl ester after sufficient stirring, and heating for reaction to obtain the nitrite; the nitrite is one or more of sodium nitrite and potassium nitrite; the solvent is one or more of acetonitrile, dioxane or dimethyl sulfoxide; and the copper-containing catalyst is one of copper bromide, copper oxide and copper hydroxide.

12. The preparation method according to claim 10, characterized in that: The low temperature is no higher than 10°C; the temperature of the heating reaction is 50-80°C.

13. The preparation method according to claim 11, characterized in that: The molar ratio of the 4-amino-3,5-dichlorobenzyl alcohol or 4-amino-3,5-dichlorobenzoic acid ethyl ester to the nitrite is 1:2-2.5; the mass volume ratio of nitrite to water in the aqueous solution of nitrite is 1g:2-5ml; the molar ratio of the 4-amino-3,5-dichlorobenzyl alcohol or 4-amino-3,5-dichlorobenzoic acid ethyl ester to hydrobromic acid is 1:2.0-2.5; the molar ratio of the 4-amino-3,5-dichlorobenzyl alcohol or 4-amino-3,5-dichlorobenzoic acid ethyl ester to the copper-containing catalyst is 1:0.2-1.0; the mass volume ratio of the 4-amino-3,5-dichlorobenzyl alcohol or 4-amino-3,5-dichlorobenzoic acid ethyl ester to the solvent is 1g:5-15ml.

14. The preparation method according to claim 12, characterized in that: The molar ratio of the 4-amino-3,5-dichlorobenzyl alcohol or 4-amino-3,5-dichlorobenzoic acid ethyl ester to the nitrite is 1:2.2; the mass volume ratio of nitrite to water in the aqueous solution of nitrite is 1g:3-4ml; the molar ratio of the 4-amino-3,5-dichlorobenzyl alcohol or 4-amino-3,5-dichlorobenzoic acid ethyl ester to the copper-containing catalyst is 1:0.5; the mass volume ratio of the 4-amino-3,5-dichlorobenzyl alcohol or 4-amino-3,5-dichlorobenzoic acid ethyl ester to the solvent is 1g:10ml.

15. The preparation method according to claim 13, characterized in that: The bromine substitution reaction also includes the step of adding alcohol while adding nitrite, wherein the alcohol is a C4-C7 alcohol; the C4-C7 alcohol is one of tert-butyl alcohol, n-butyl alcohol, and tert-pentyl alcohol; the molar ratio of the 4-amino-3,5-dichlorobenzyl alcohol or 4-amino-3,5-dichlorobenzoic acid ethyl ester to the C4-C7 alcohol is 1:

2.

16. The preparation method according to claim 8, characterized in that: The 4-amino-3,5-dichlorobenzyl alcohol is prepared from 4-amino-3,5-dichlorobenzoic acid ethyl ester through a reduction reaction.

17. The preparation method according to claim 8 or 15, characterized in that: The reduction reaction method is as follows: 4-bromo-3,5-dichlorobenzoic acid ethyl ester or 4-amino-3,5-dichlorobenzoic acid ethyl ester is reacted with a catalyst and / or a reducing agent to obtain the product; the catalyst is one or more of lithium chloride, calcium chloride and magnesium chloride; the reducing agent is one or more of sodium borohydride, potassium borohydride and lithium aluminum hydride; the molar ratio of the 4-bromo-3,5-dichlorobenzoic acid ethyl ester or 4-amino-3,5-dichlorobenzoic acid ethyl ester to the catalyst is 1:0-2.5; the molar ratio of the 4-bromo-3,5-dichlorobenzoic acid ethyl ester or 4-amino-3,5-dichlorobenzoic acid ethyl ester to the reducing agent is 1:1.5-4; the solvent for the reduction reaction is one or more of tetrahydrofuran, methyltetrahydrofuran and isopropyl ether.

18. The preparation method according to claim 9 or 15, characterized in that: The 4-amino-3,5-dichlorobenzoic acid ethyl ester is prepared by heating reaction of ethyl p-aminobenzoate and a chlorinating agent; the chlorinating agent is at least one of NCS, NaDCC, and TCCA; the molar ratio of ethyl p-aminobenzoate to the chlorinating agent is 1:0.7-2.5; and the heating reaction solvent is one or more of acetonitrile, THF, DMF, 1,4-dioxane, and dichloromethane.

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