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CN-121991004-A - Synthesis method of high-purity benzothiazole

CN121991004ACN 121991004 ACN121991004 ACN 121991004ACN-121991004-A

Abstract

The invention discloses a synthesis method of high-purity benzothiazole, and relates to the field of chemical synthesis. The invention discloses a method for synthesizing high-purity benzothiazole, which takes o-amino thiophenol and carboxylic acid as raw materials, promotes cyclization reaction through a hydrogen bond activation mechanism under a neutral to weak alkaline deep eutectic solvent or an acidic deep eutectic solvent and low-power density ultrasonic synergistic system, and combines molecular sieve dehydration, MIPs auxiliary purification and suspension melting technology to prepare the high-purity benzothiazole compound. The method has mild reaction conditions, no heavy metal residue and the deep eutectic solvent which can be recycled for 5-8 times after purification, and is suitable for industrial production of pharmaceutical benzothiazole.

Inventors

  • WANG RUIFENG
  • LI YU
  • WANG YUEMEI
  • ZHANG YANAN

Assignees

  • 鄂尔多斯应用技术学院

Dates

Publication Date
20260508
Application Date
20260331

Claims (9)

  1. 1. The synthesis method of the high-purity benzothiazole is characterized by comprising the following steps of: Uniformly mixing o-amino thiophenol and carboxylic acid compounds according to a molar ratio of 1 (1.0-1.2) to prepare a reactant, and uniformly mixing the reactant and deep eutectic solvent according to a mass ratio of 1 (1.2-1.4); Adding a 3A molecular sieve accounting for 10-15% of the mass of the deep eutectic solvent in the reaction process; adding a reducing agent with the molar quantity of the reactant of 0.5% -1.0%, and carrying out ultrasonic reaction for 50-70 min at 60-80 ℃ under the protection of inert gas to obtain a reaction solution; Mixing and extracting the reaction liquid and ethyl acetate according to the volume ratio of 1 (1.1-1.3), separating a solvent phase and an organic phase, adsorbing the solvent phase by active carbon, drying in vacuum and recycling, performing alkaline washing pretreatment on the organic phase, concentrating under reduced pressure to obtain a crude product, removing the crude product by using MIPs solid phase extraction, and performing suspension melting crystallization to obtain the product.
  2. 2. The synthetic method of benzothiazole according to claim 1 is characterized in that the deep eutectic solvent in the step (1) is divided into neutral to weak alkaline solvent and acid solvent, the preparation method of the neutral to weak alkaline solvent comprises the steps of uniformly mixing choline chloride and urea according to a molar ratio of 1:2, stirring at 600rpm for 2h at 80 ℃, heating at 80 ℃ for 30min again, and the preparation method of the acid solvent comprises the steps of uniformly mixing choline chloride and p-toluenesulfonic acid according to a molar ratio of 1:1, and stirring at 600rpm for 2h at 90 ℃.
  3. 3. The method for producing benzothiazole according to claim 1, wherein said carboxylic acid compound in step (1) is an aromatic carboxylic acid, a heteroaromatic carboxylic acid or a C1-C6 aliphatic carboxylic acid.
  4. 4. The method for preparing benzothiazole according to claim 1, wherein said reducing agent in step (3) is triphenylphosphine or sodium bisulphite.
  5. 5. The method for preparing benzothiazole according to claim 1, wherein the power density of the ultrasound in the step (3) is 0.5-1.5W/mL, the pulse mode is adopted, and the frequency is 30-40 kHz.
  6. 6. The method for preparing benzothiazole according to claim 1, characterized in that the alkaline solution used in the alkaline washing pretreatment in the step (4) is sodium bicarbonate aqueous solution with a mass concentration of 5%, and the number of alkaline washing is 2.
  7. 7. The method for preparing benzothiazole according to claim 1, wherein in the solid phase extraction of MIPs in the step (4), the mass ratio of crude product to MIPs is 1 (1-2), the solvent is methanol, the concentration of the crude methanol solution is 0.3-0.5 g/mL, the flow rate is 2 mL/min, the washing phase is methanol: water=8:2, and the eluting phase is methanol: acetic acid=9:1.
  8. 8. The method for preparing benzothiazole according to claim 1, wherein the suspension melting crystallization cooling rate in the step (4) is 0.3-0.5 ℃ per hour, the crystallization final temperature is-5~0 ℃, and the mother liquor is recycled for 2-3 times.
  9. 9. The preparation method of benzothiazole according to claim 1, wherein the specific method of solvent phase activated carbon adsorption and vacuum drying in the step (4) is that activated carbon with the mass of 5% of the solvent phase is added into the solvent phase, stirred for 1h at 80 ℃, filtered and vacuum dried for 2h at 80 ℃ to prepare the regenerated deep eutectic solvent.

Description

Synthesis method of high-purity benzothiazole Technical Field The invention relates to the field of chemical synthesis, in particular to a synthesis method of benzothiazole. Background Benzothiazole and its derivatives are important nitrogen-sulfur-containing heterocyclic compounds, and their structural skeletons are widely existing in natural products, drug molecules and functional materials. The compound has unique biological activities of anti-infection, anti-tumor, anti-oxidation, neuroprotection and the like, and has important application value in the industrial fields of rubber vulcanization accelerators, dye intermediates, photosensitive materials, fluorescent probes and the like. At present, the synthesis of benzothiazole compounds mainly depends on the following technical routes: (1) The traditional condensation cyclization method is to take o-amino thiophenol and carboxylic acid, acyl chloride or aldehyde compounds as raw materials, and carry out high-temperature condensation cyclization reaction under the catalysis of strong acid or heavy metal salt. The method has the problems of harsh reaction conditions, serious equipment corrosion, more byproducts, deep color of products, difficult removal of heavy metal residues and the like. (2) The oxidation cyclization method is to take thiobenzanilide compounds as raw materials and realize intramolecular carbon-sulfur bond formation through chemical oxidant or photocatalytic oxidation. The method needs a large amount of oxidant to produce a large amount of salt-containing wastewater, and the oxidant has high cost and is not suitable for industrial production. (3) The transition metal catalysis method adopts transition metal complexes such as copper, palladium, ruthenium and the like to catalyze the coupling cyclization reaction of o-halogenated aniline and sulfur source. Although the reaction condition of the method is relatively mild, the catalyst preparation process is complex, the catalyst is expensive and difficult to recycle, and the purity of the product is difficult to meet the medical grade standard due to metal residues. (4) The catalyst-free hot melting method is partially researched and reported to be solvent free reaction under the condition of no catalyst, but has the problems of long reaction time, low conversion rate, poor selectivity, serious tar formation of products and the like. Therefore, a high-purity benzothiazole synthesis method which is simple and convenient to operate, mild in condition, capable of recycling a catalytic system and capable of achieving the pharmaceutical grade standard in product purity is developed, and the method has important industrial application value and academic significance. Disclosure of Invention The invention aims to provide a synthesis method of benzothiazole, which aims to solve the problems in the prior art. In order to solve the technical problems, the invention provides the following technical scheme: a synthetic method of high-purity benzothiazole comprises the following steps: (1) Uniformly mixing o-amino thiophenol and carboxylic acid compounds according to a molar ratio of 1 (1.0-1.2) to prepare a reactant, and uniformly mixing the reactant and deep eutectic solvent according to a mass ratio of 1 (1.2-1.4); (2) Adding a 3A molecular sieve accounting for 10-15% of the mass of the deep eutectic solvent in the reaction process; (3) Adding a reducing agent with the molar quantity of the reactant of 0.5% -1.0%, and carrying out ultrasonic reaction for 50-70 min at 60-80 ℃ under the protection of inert gas to obtain a reaction solution; (4) Mixing and extracting the reaction liquid and ethyl acetate according to the volume ratio of 1 (1.1-1.3), separating a solvent phase and an organic phase, adsorbing the solvent phase by active carbon, drying in vacuum and recycling, performing alkaline washing pretreatment on the organic phase, concentrating under reduced pressure to obtain a crude product, removing the crude product by using MIPs solid phase extraction, and performing suspension melting crystallization to obtain the product. The deep eutectic solvent in the step (1) is divided into neutral to weakly alkaline solvent and acid solvent, the preparation method of the neutral to weakly alkaline solvent comprises the steps of uniformly mixing choline chloride and urea according to a molar ratio of 1:2, stirring at 600rpm for 2 hours at 80 ℃, heating at 80 ℃ for 30 minutes again when the deep eutectic solvent is used, and the preparation method of the acid solvent comprises the steps of uniformly mixing choline chloride and p-toluenesulfonic acid according to a molar ratio of 1:1, and stirring at 600rpm for 2 hours at 90 ℃. Preferably, the carboxylic acid compound in the step (1) is aromatic carboxylic acid, heteroaromatic carboxylic acid or C1-C6 aliphatic carboxylic acid. Preferably, the reducing agent in the step (3) is triphenylphosphine or sodium bisulphite. And (3) optimizing, wherein the power