Synthesis Methods of 2,5 - Dichlorobenzoic Acid

2,5-dichlorobenzoic acid is a chlorobenzoic acid that is benzoic acid in which the ring hydrogens at positions 2 and 5 are substituted by chloro groups.It is a chlorobenzoic acid and a dichlorobenzene. Here we'll introduce two synthesis methods.

Synthesis from 2,5-dichlorotoluene

In order to solve the problems of 5-chloro-2-aminobenzoic acid in the prior art, such as nitration reaction and reduction reaction in the preparation process, the danger is high, and the sewage treatment is difficult. The invention provides a preparation method of 5-chloro-2-aminobenzoic acid, which has simple preparation process, low cost, and is environmentally friendly. The present invention is realized through the following technical solutions: In the present invention, a preparation method of 5-chloro-2-aminobenzoic acid includes the following steps:（1）Dissolve 2,5-dichlorotoluene in the solvent, add oxidant under stirring, heat to 50~80℃, keep the reaction temperature for 3~6h, recover the organic solvent after the reaction, add water and filter while hot, and adjust the filtrate to pH with hydrochloric acid =2, 2,5-dichlorobenzoic acid is obtained by cooling, crystallization and filtration;（2）Add the 2,5-dichlorobenzoic acid obtained in step (1) to the organic solvent to dissolve, add the metal catalyst, alkali and ammonia source, heat to 70~150℃, keep the temperature for 8~15 hours, and distill under reduced pressure after the reaction is over , To give 5-chloro-2-aminobenzoic acid;[1]

Further, step (2) also includes adding N,N-dimethylglycine. Further, the mass ratio of the added amount of N,N-dimethylglycine to 2,5-dichlorobenzoic acid in step (2) is 1:0.5-5.0. Further, the solvent in step (1) is an aqueous pyridine solution, and the oxidizing agent is potassium permanganate. Further, in step (1), the mass ratio of 2,5-dichlorotoluene and pyridine aqueous solution is 1:12.0~16.0; the mass ratio of 2,5-dichlorotoluene to potassium permanganate is 1: 1.0~3.0. Further, the catalyst described in step (2) is a copper salt catalyst, which is one or more of cuprous chloride, cuprous iodide, and cuprous bromide. Further, the alkali in step (2) is more than one of potassium phosphate, potassium carbonate, sodium carbonate, sodium phosphate, and sodium bicarbonate; the ammonia source is ammonia gas, aqueous ammonia solution and methanol amine One or more; the organic solvent is more than one of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, acetonitrile and the like. Further, the added amount of the catalyst in step (2) is 0.5-3.0% of the mass of 2,5-dichlorobenzoic acid; the ratio of the added amount of alkali to the mass of 2,5-dichlorobenzoic acid is 0.1~3.0:1; the molar ratio of the 2,5-dichlorobenzoic acid to the amount of ammonia added is 1:1.0~10.0; the organic solvent is added to 1.0 per millimole of the 2,5-dichlorobenzoic acid -2.0 ml. Further, the percent mass concentration of the pyridine aqueous solution in step (1) is 55%. 

The present invention designs a new route for synthesizing 5-chloro-2-aminobenzoic acid. It takes 2,5-dichlorotoluene as a raw material to produce 2,5-dichlorobenzoic acid through oxidation, and finally undergoes ammoniation to produce 5-Chloro-2-aminobenzoic acid, the preparation method of the present invention is simple, easy to operate, low cost and environmentally friendly, and adding N,N-dimethylglycine during the amination reaction process can reduce the temperature of the amination reaction , Shorten the reaction time and increase the reaction yield.

Synthesis from 2,5-dichloro-6-aminobenzoic acid

2,5-Dichlorobenzoic acid is mainly used as a pesticide, a pharmaceutical intermediate and an organic synthesis intermediate for the synthesis of herbicides such as kekewei and grasses. However, most of the existing synthetic methods use a reaction of p-dichlorobenzene with phosgene. 2,5-dichlorobenzoyl chloride is obtained by hydrolysis, the process is complicated, and the final yield is not very high. Therefore, it is necessary to propose a new synthesis method, which further improves the quality and collection of the product. The rate and reduction of by-product content have important economic significance.[2]

The object of the present invention is to provide a method for synthesizing a pharmaceutical intermediate 2,5-dichlorobenzoic acid, comprising the following steps:(i) adding 2 mol of 2,5-dichloro-6-aminobenzoic acid, 3-5 mol of diisobutyl adipate solution to the reaction vessel, raising the temperature of the solution to 70-78 ° C, and controlling the stirring speed 130 -160rpm, add 3-4mol of cobalt naphthenate in 3-5 times, each time interval is 30-40min, continue to react for 90-120min, add 1200ml potassium chloride solution, layer the solution, reduce the solution temperature to 10- At 15 ° C, add oxalic acid solution to adjust the pH to 4-5, wash with potassium sulfate solution, wash with methyl tert-butyl ether solution, wash with 2-methyltetrahydrofuran solution, distill under reduced pressure, collect fractions at 110-120 ° C, dehydrate the dehydrating agent. The finished product 2,5-dichlorobenzoic acid; wherein the mass fraction of the diisobutyl adipate solution in the step (i) is 70-76%, and the mass fraction of the potassium chloride solution described in the step (i) 15-22%, the mass fraction of the oxalic acid solution described in the step (i) is 20-25%, the mass fraction of the potassium sulfate solution described in the step (i) is 10-18%, and the methyl group described in the step (i) The mass fraction of the tert-butyl ether solution is 80-85%, the mass fraction of the 2-methyltetrahydrofuran solution described in the step (i) is 90-96%, and the pressure of the vacuum distillation described in the step (i) is 15-15. 20kPa.

References

[1]SHANGHAI JIAO TONG UNIVERSITY - CN113233990, 2021, A

[2]CHENGDU DONG DIAN AI ER TECHNOLOGY - CN108238900, 2018, A