Synthesis method of high-purity benzothiazole

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 comprises the following steps: by taking o-aminothiophenol and carboxylic acid as raw materials, promoting cyclization reaction through a hydrogen bond activation mechanism in a neutral to weakly alkaline deep eutectic solvent or acidic deep eutectic solvent and low-power-density ultrasonic synergistic system, thereby obtaining the high-purity benzothiazole. The high-purity benzothiazole compound is prepared by combining molecular sieve dehydration, MIPs-assisted purification and suspension melting technologies. The method is mild in reaction condition and free of heavy metal residues, the deep eutectic solvent can be recycled for 5-8 times after being purified, and the method is suitable for industrial production of pharmaceutical-grade benzothiazole.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis, specifically to a method for synthesizing benzothiazole. Background Technology

[0002] Benzothiazoles and their derivatives are an important class of nitrogen- and sulfur-containing heterocyclic compounds, whose structural skeletons are widely found in natural products, drug molecules, and functional materials. These compounds possess unique biological activities such as anti-infection, anti-tumor, antioxidant, and neuroprotective effects, and have significant application value in industrial fields such as rubber vulcanization accelerators, dye intermediates, photosensitive materials, and fluorescent probes.

[0003] Currently, the synthesis of benzothiazole compounds mainly relies on the following technical routes:

[0004] (1) Traditional condensation cyclization method: using o-aminothiophenol and carboxylic acids, acyl chlorides or aldehydes as raw materials, a high-temperature condensation cyclization reaction is carried out under the catalysis of strong acids or heavy metal salts. This method has problems such as harsh reaction conditions, severe equipment corrosion, many by-products, dark product color, and difficulty in removing heavy metal residues.

[0005] (2) Oxidative cyclization method: Using thiobenzoylaniline compounds as raw materials, intramolecular carbon-sulfur bonds are formed through chemical oxidants or photocatalytic oxidation. This method requires a large amount of oxidant, generates a large amount of saline wastewater, and the cost of oxidants is high, making it unsuitable for industrial production.

[0006] (3) Transition metal catalysis: The coupling cyclization reaction of o-halogenated aniline with sulfur source is catalyzed by transition metal complexes such as copper, palladium, and ruthenium. Although the reaction conditions of this method are relatively mild, the catalyst preparation process is complicated, expensive, and difficult to recover, and the metal residue makes it difficult for the product purity to meet pharmaceutical grade standards.

[0007] (4) Catalyst-free hot melting method: Some studies have reported solvent-free reaction under catalyst-free conditions, but there are problems such as long reaction time, low conversion rate, poor selectivity and serious tar formation of products.

[0008] Therefore, developing a high-purity benzothiazole synthesis method that is simple to operate, has mild conditions, allows for the recycling of the catalytic system, and produces products with purity up to pharmaceutical grade standards has significant industrial application value and academic significance. Summary of the Invention

[0009] The purpose of this invention is to provide a method for synthesizing benzothiazole to solve the problems existing in the prior art.

[0010] To solve the above-mentioned technical problems, the present invention provides the following technical solution:

[0011] A method for synthesizing high-purity benzothiazole includes the following steps:

[0012] (1) Prepare a reactant by mixing o-aminothiophenol and a carboxylic acid compound at a molar ratio of 1: (1.0~1.2), and then mix the reactant with a deep eutectic solvent at a mass ratio of 1: (1.2~1.4);

[0013] (2) 10% to 15% by mass of 3A molecular sieve is added to the deep eutectic solvent during the reaction process;

[0014] (3) Add 0.5%~1.0% of the molar amount of the reactants to a reducing agent, and under the protection of an inert gas, sonicate at 60~80℃ for 50~70 min to obtain a reaction solution;

[0015] (4) The reaction solution and ethyl acetate are mixed and extracted at a volume ratio of 1: (1.1~1.3) to separate the solvent phase and the organic phase. The solvent phase is recycled after being adsorbed by activated carbon and dried under vacuum. The organic phase is pretreated by alkaline washing and concentrated under reduced pressure to obtain crude product. The crude product is removed by solid phase extraction with MIPs and then obtained by suspension melt crystallization.

[0016] As an optimization, the deep eutectic solvent in step (1) is divided into neutral to weakly basic solvent and acidic solvent. The neutral to weakly basic solvent is prepared by mixing choline chloride and urea in a molar ratio of 1:2 and stirring at 600 rpm for 2 hours at 80°C. When using it, it needs to be heated at 80°C for 30 minutes again. The acidic solvent is prepared by mixing choline chloride and p-toluenesulfonic acid in a molar ratio of 1:1 and stirring at 600 rpm for 2 hours at 90°C.

[0017] As an optimization, the carboxylic acid compound in step (1) is an aromatic carboxylic acid, a heteroaromatic carboxylic acid, or a C1-C6 aliphatic carboxylic acid.

[0018] As an optimization, the reducing agent in step (3) is triphenylphosphine or sodium bisulfite.

[0019] As an optimization, the power density of the ultrasound in step (3) is 0.5~1.5 W / mL, pulse mode, and frequency 30~40kHz.

[0020] As an optimization, the alkaline solution used in the alkaline washing pretreatment in step (4) is a 5% sodium bicarbonate aqueous solution, and the alkaline washing is performed twice.

[0021] As an optimization, during the solid-phase extraction of MIPs in step (4), the mass ratio of crude product to MIPs is 1:(1~2), the solvent is methanol, the concentration of the crude product 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 elution phase is methanol:acetic acid = 9:1.

[0022] As an optimization, the cooling rate of the suspension melting crystallization in step (4) is 0.3~0.5℃ / h, the final crystallization temperature is -5~0℃, and the mother liquor is recycled 2~3 times.

[0023] As an optimization, the specific method for solvent phase activated carbon adsorption and vacuum drying in step (4) is as follows: add 5% of activated carbon by mass of solvent phase to solvent phase, stir at 80°C for 1 hour, filter, and vacuum dry at 80°C for 2 hours to obtain regenerated deep eutectic solvent.

[0024] Compared with the prior art, the beneficial effects achieved by the present invention are:

[0025] A method for synthesizing high-purity benzothiazoles is disclosed. This method uses o-aminothiophenol and carboxylic acid as raw materials, and promotes cyclization via hydrogen bonding activation in a neutral to weakly basic eutectic solvent or an acidic eutectic solvent combined with low-power-density ultrasound. This is achieved by combining molecular sieve dehydration, MIP-assisted purification, and suspension melting technology to prepare high-purity benzothiazole compounds. The reaction conditions are mild, there are no heavy metal residues, and the eutectic solvent can be recycled 5-8 times after purification, making it suitable for the industrial production of pharmaceutical-grade benzothiazoles.

[0026] First, in a neutral to weakly basic eutectic solvent, the choline chloride and urea system effectively activates the carbonyl carbon of the carboxylic acid substrate through a hydrogen bond network formed by chloride ions and urea carbonyl groups, while simultaneously stabilizing the amino nucleophile, thus lowering the energy barrier of the cyclization reaction. During the collapse of gentle microbubbles generated by low-power-density ultrasound, local microjets promote a 3-5 fold increase in the collision frequency between reactant molecules, and strict control of power density avoids local overheating. This invention reduces the temperature of the benzothiazole cyclization reaction from 150-250°C in traditional methods to 60-80°C, and shortens the reaction time from 6-12 hours to 30-90 minutes. Compared to the traditional polyphosphoric acid catalytic method requiring high-temperature, long-duration heating, this invention reduces energy consumption by approximately 75%, avoids raw material oxidation and product tarring caused by high temperatures, and changes the color of the crude product from dark brown to light yellow, laying a good foundation for subsequent purification.

[0027] Secondly, the deep eutectic solvent has the dual function of solvent and catalyst, and can be regenerated and recycled through simple activated carbon adsorption and vacuum drying. Compared with the heavy metal catalysis method, it also fundamentally eliminates the risk of heavy metal residue in the product and meets the stringent standards of pharmaceutical grade benzothiazole. At the same time, the 3A molecular sieve dehydrating agent can be regenerated by microwave drying, and the ethyl acetate extractant can also be recovered by vacuum distillation, making it more green and environmentally friendly. Detailed Implementation

[0028] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0029] Example 1:

[0030] A method for synthesizing benzothiazole includes the following preparation steps:

[0031] (1) Mix choline chloride and urea at a molar ratio of 1:2 and stir at 600 rpm for 2 h at 80°C to obtain a deep eutectic solvent. Mix o-aminothiophenol and benzoic acid at a molar ratio of 1:1.0 to obtain a reactant. Mix the reactant and the deep eutectic solvent at a mass ratio of 1:1.2.

[0032] (2) 10% by mass of 3A molecular sieve is added as a deep eutectic solvent during the reaction;

[0033] (3) Add 0.5% of triphenylphosphine by molar amount of reactants, and sonicate at 60°C for 50 min under inert gas protection, with a power density of 0.5 W / mL, pulse mode, and a frequency of 30 kHz to obtain the reaction solution;

[0034] The reaction solution and ethyl acetate were mixed and extracted at a volume ratio of 1:1.1 to separate the solvent phase and the organic phase. The solvent phase was adsorbed by activated carbon, dried under vacuum, and then recycled. The organic phase was pretreated by alkaline washing and concentrated under reduced pressure to obtain a crude product. The alkaline solution used for alkaline washing pretreatment was a 5% sodium bicarbonate aqueous solution, and the alkaline washing was performed twice. The crude product was then removed by MIPs solid-phase extraction. During MIPs solid-phase extraction, the mass ratio of crude product to MIPs was 1:1, the solvent was methanol, the concentration of the crude product methanol solution was 0.3 g / mL, the flow rate was 2 mL / min, the washing phase was methanol:water = 8:2, and the eluent phase was methanol:acetic acid = 9:1. The product was then subjected to suspension melt crystallization. The suspension melt crystallization cooling rate was 0.3℃ / h, and the final crystallization temperature was -5℃. The mother liquor was recycled twice to obtain the final product.

[0035] Example 2:

[0036] A method for synthesizing benzothiazole includes the following preparation steps:

[0037] (1) Mix choline chloride and urea at a molar ratio of 1:2 and stir at 600 rpm for 2 h at 80°C to obtain a deep eutectic solvent. Mix o-aminothiophenol and benzoic acid at a molar ratio of 1:1.1 to obtain a reactant. Mix the reactant and the deep eutectic solvent at a mass ratio of 1:1.1.

[0038] (2) 12.5% ​​by mass of 3A molecular sieve was added as a deep eutectic solvent during the reaction;

[0039] (3) Add 0.75% of triphenylphosphine as reactant, and sonicate at 70°C for 60 min under inert gas protection, with a power density of 1 W / mL, pulse mode, and a frequency of 35 kHz to obtain the reaction solution.

[0040] (4) The reaction solution and ethyl acetate were mixed and extracted at a volume ratio of 1:1.2 to separate the solvent phase and the organic phase. The solvent phase was adsorbed by activated carbon, dried under vacuum and then recycled. The organic phase was pretreated by alkaline washing and concentrated under reduced pressure to obtain the crude product. The alkaline solution used for alkaline washing pretreatment was a 5% sodium bicarbonate aqueous solution. The alkaline washing was performed twice. The crude product was removed by MIPs solid-phase extraction. During MIPs solid-phase extraction, the mass ratio of crude product to MIPs was 1:1.5. The solvent was methanol. The concentration of the crude product methanol solution was 0.4 g / mL. The flow rate was 2 mL / min. The washing phase was methanol:water = 8:2. The elution phase was methanol:acetic acid = 9:1. Then, the product was subjected to suspension melt crystallization. The cooling rate of suspension melt crystallization was 0.4℃ / h. The final crystallization temperature was -2.5℃. The mother liquor was recycled twice to obtain the product.

[0041] Example 3:

[0042] A method for synthesizing benzothiazole includes the following preparation steps:

[0043] (1) Mix choline chloride and urea at a molar ratio of 1:2 and stir at 600 rpm for 2 h at 80°C to obtain a deep eutectic solvent. Mix o-aminothiophenol and benzoic acid at a molar ratio of 1:1.2 to obtain a reactant. Mix the reactant and the deep eutectic solvent at a mass ratio of 1:1.4.

[0044] (2) 15% by mass of 3A molecular sieve is added as a deep eutectic solvent during the reaction;

[0045] (3) Add 1.0% of triphenylphosphine as reactant, and sonicate at 80°C for 70 min under inert gas protection, with a power density of 1.5 W / mL, pulse mode, and a frequency of 40 kHz to obtain the reaction solution;

[0046] (4) The reaction solution and ethyl acetate were mixed and extracted at a volume ratio of 1:1.3 to separate the solvent phase and the organic phase. The solvent phase was adsorbed by activated carbon and dried under vacuum before being recycled. The organic phase was pretreated by alkaline washing and concentrated under reduced pressure to obtain the crude product. The alkaline solution used for alkaline washing pretreatment was a 5% sodium bicarbonate aqueous solution. The alkaline washing was performed twice. The crude product was removed by MIPs solid-phase extraction. During MIPs solid-phase extraction, the mass ratio of crude product to MIPs was 1:2. The solvent was methanol. The concentration of the crude product methanol solution was 0.5 g / mL. The flow rate was 2 mL / min. The washing phase was methanol:water = 8:2. The elution phase was methanol:acetic acid = 9:1. The product was then subjected to suspension melt crystallization. The cooling rate of suspension melt crystallization was 0.5℃ / h. The final crystallization temperature was 0℃. The mother liquor was recycled 3 times to obtain the product.

[0047] Comparative Example 1:

[0048] A method for synthesizing benzothiazole includes the following preparation steps:

[0049] (1) Heat the polyphosphoric acid oil bath to 150°C, add benzoic acid all at once until completely dissolved, slowly add o-aminothiophenol within 5 min, the mass ratio of o-aminothiophenol, benzoic acid and polyphosphoric acid is 1:1.1:60, stir at 600 rpm for 6 h, cool to 60°C, add crushed ice 2.5 times the mass of polyphosphoric acid, then add a mixture of ice and water 2.5 times the mass of polyphosphoric acid, adjust the pH to 8~9 with 30% sodium hydroxide solution, and filter;

[0050] (2) The filtrate was extracted three times with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate, and the crude product was obtained by concentration under reduced pressure at 40°C.

[0051] (3) The crude product was prepared by silica gel column chromatography with a ratio of petroleum ether to ethyl acetate of 20:1.

[0052] Comparative Example 2:

[0053] A method for synthesizing benzothiazole includes the following preparation steps:

[0054] (1) Mix choline chloride and urea at a molar ratio of 1:2 and stir at 600 rpm for 2 h at 80°C to obtain a deep eutectic solvent. Mix o-aminothiophenol and benzoic acid at a molar ratio of 1:1.1 to obtain a reactant. Mix the reactant and the deep eutectic solvent at a mass ratio of 1:1.1.

[0055] (2) 12.5% ​​by mass of 3A molecular sieve was added as a deep eutectic solvent during the reaction;

[0056] (3) Add 0.75% of triphenylphosphine as reactant, and sonicate at 70°C for 60 min under inert gas protection, with a power density of 3 W / mL, pulse mode, and a frequency of 35 kHz to obtain the reaction solution.

[0057] (4) The reaction solution and ethyl acetate were mixed and extracted at a volume ratio of 1:1.2 to separate the solvent phase and the organic phase. The solvent phase was adsorbed by activated carbon, dried under vacuum and then recycled. The organic phase was pretreated by alkaline washing and concentrated under reduced pressure to obtain the crude product. The alkaline solution used for alkaline washing pretreatment was a 5% sodium bicarbonate aqueous solution. The alkaline washing was performed twice. The crude product was removed by MIPs solid-phase extraction. During MIPs solid-phase extraction, the mass ratio of crude product to MIPs was 1:1.5. The solvent was methanol. The concentration of the crude product methanol solution was 0.4 g / mL. The flow rate was 2 mL / min. The washing phase was methanol:water = 8:2. The elution phase was methanol:acetic acid = 9:1. Then, the product was subjected to suspension melt crystallization. The cooling rate of suspension melt crystallization was 0.4℃ / h. The final crystallization temperature was -2.5℃. The mother liquor was recycled twice to obtain the product.

[0058] Comparative Example 3:

[0059] A method for synthesizing benzothiazole includes the following preparation steps:

[0060] (1) 5% of activated carbon by mass of solvent phase was added to the solvent phase in Example 2, stirred at 80°C for 1 h, filtered, and vacuum dried at 80°C for 2 h to obtain regenerated deep eutectic solvent 1.

[0061] (2) Prepare the reactant by mixing o-aminothiophenol and benzoic acid in a molar ratio of 1:1.1, and mix the reactant with the regenerated deep eutectic solvent 1 in a mass ratio of 1:1.1;

[0062] (3) 12.5% ​​by mass of 3A molecular sieve was added as a deep eutectic solvent during the reaction;

[0063] (4) Add 0.75% of triphenylphosphine as reactant, and sonicate at 70°C for 60 min under inert gas protection, with a power density of 1 W / mL, pulse mode, and a frequency of 35 kHz to obtain the reaction solution.

[0064] (5) The reaction solution and ethyl acetate were mixed and extracted at a volume ratio of 1:1.2 to separate the solvent phase and the organic phase. The solvent phase was adsorbed by activated carbon, dried under vacuum and then recycled. The organic phase was pretreated by alkaline washing and concentrated under reduced pressure to obtain the crude product. The alkaline solution used for alkaline washing pretreatment was a 5% sodium bicarbonate aqueous solution. The alkaline washing was performed twice. The crude product was removed by MIPs solid-phase extraction. During MIPs solid-phase extraction, the mass ratio of crude product to MIPs was 1:1.5. The solvent was methanol. The concentration of the crude product methanol solution was 0.4 g / mL. The flow rate was 2 mL / min. The washing phase was methanol:water = 8:2. The elution phase was methanol:acetic acid = 9:1. Then, the product was subjected to suspension melt crystallization. The cooling rate of suspension melt crystallization was 0.4℃ / h. The final crystallization temperature was -2.5℃. The mother liquor was recycled twice to obtain the product.

[0065] Comparative Example 4:

[0066] A method for synthesizing benzothiazole includes the following preparation steps:

[0067] (1) 5% of activated carbon by mass of solvent phase was added to the solvent phase in Comparative Example 3, stirred at 80°C for 1 h, filtered, and vacuum dried at 80°C for 2 h to obtain regenerated deep eutectic solvent 2.

[0068] (2) Prepare the reactant by mixing o-aminothiophenol and benzoic acid in a molar ratio of 1:1.1, and mix the reactant with the regenerated deep eutectic solvent 2 in a mass ratio of 1:1.1;

[0069] (3) 12.5% ​​by mass of 3A molecular sieve was added as a deep eutectic solvent during the reaction;

[0070] (4) Add 0.75% of triphenylphosphine as reactant, and sonicate at 70°C for 60 min under inert gas protection, with a power density of 1 W / mL, pulse mode, and a frequency of 35 kHz to obtain the reaction solution.

[0071] (5) The reaction solution and ethyl acetate were mixed and extracted at a volume ratio of 1:1.2 to separate the solvent phase and the organic phase. The solvent phase was adsorbed by activated carbon, dried under vacuum and then recycled. The organic phase was pretreated by alkaline washing and concentrated under reduced pressure to obtain the crude product. The alkaline solution used for alkaline washing pretreatment was a 5% sodium bicarbonate aqueous solution. The alkaline washing was performed twice. The crude product was removed by MIPs solid-phase extraction. During MIPs solid-phase extraction, the mass ratio of crude product to MIPs was 1:1.5. The solvent was methanol. The concentration of the crude product methanol solution was 0.4 g / mL. The flow rate was 2 mL / min. The washing phase was methanol:water = 8:2. The elution phase was methanol:acetic acid = 9:1. Then, the product was subjected to suspension melt crystallization. The cooling rate of suspension melt crystallization was 0.4℃ / h. The final crystallization temperature was -2.5℃. The mother liquor was recycled twice to obtain the product.

[0072] Comparative Example 5:

[0073] A method for synthesizing benzothiazole includes the following preparation steps:

[0074] (1) 5% of activated carbon by mass of solvent phase was added to the solvent phase in Comparative Example 4, stirred at 80°C for 1 h, filtered, and vacuum dried at 80°C for 2 h to obtain regenerated deep eutectic solvent 3.

[0075] (2) Prepare the reactant by mixing o-aminothiophenol and benzoic acid in a molar ratio of 1:1.1, and mix the reactant with the regenerated deep eutectic solvent 3 in a mass ratio of 1:1.1;

[0076] (3) 12.5% ​​by mass of 3A molecular sieve was added as a deep eutectic solvent during the reaction;

[0077] (4) Add 0.75% of triphenylphosphine as reactant, and sonicate at 70°C for 60 min under inert gas protection, with a power density of 1 W / mL, pulse mode, and a frequency of 35 kHz to obtain the reaction solution.

[0078] (5) The reaction solution and ethyl acetate were mixed and extracted at a volume ratio of 1:1.2 to separate the solvent phase and the organic phase. The solvent phase was adsorbed by activated carbon, dried under vacuum and then recycled. The organic phase was pretreated by alkaline washing and concentrated under reduced pressure to obtain the crude product. The alkaline solution used for alkaline washing pretreatment was a 5% sodium bicarbonate aqueous solution. The alkaline washing was performed twice. The crude product was removed by MIPs solid-phase extraction. During MIPs solid-phase extraction, the mass ratio of crude product to MIPs was 1:1.5. The solvent was methanol. The concentration of the crude product methanol solution was 0.4 g / mL. The flow rate was 2 mL / min. The washing phase was methanol:water = 8:2. The elution phase was methanol:acetic acid = 9:1. Then, the product was subjected to suspension melt crystallization. The cooling rate of suspension melt crystallization was 0.4℃ / h. The final crystallization temperature was -2.5℃. The mother liquor was recycled twice to obtain the product.

[0079] Comparative Example 6:

[0080] A method for synthesizing benzothiazole includes the following preparation steps:

[0081] (1) 5% of activated carbon by mass of solvent phase was added to the solvent phase in Comparative Example 5, stirred at 80°C for 1 h, filtered, and vacuum dried at 80°C for 2 h to obtain regenerated deep eutectic solvent 4.

[0082] (2) Prepare the reactant by mixing o-aminothiophenol and benzoic acid in a molar ratio of 1:1.1, and mix the reactant with the regenerated deep eutectic solvent 2 in a mass ratio of 1:1.1;

[0083] (3) 12.5% ​​by mass of 3A molecular sieve was added as a deep eutectic solvent during the reaction;

[0084] (4) Add 0.75% of triphenylphosphine as reactant, and sonicate at 70°C for 60 min under inert gas protection, with a power density of 1 W / mL, pulse mode, and a frequency of 35 kHz to obtain the reaction solution.

[0085] (5) The reaction solution and ethyl acetate were mixed and extracted at a volume ratio of 1:1.2 to separate the solvent phase and the organic phase. The solvent phase was adsorbed by activated carbon, dried under vacuum and then recycled. The organic phase was pretreated by alkaline washing and concentrated under reduced pressure to obtain the crude product. The alkaline solution used for alkaline washing pretreatment was a 5% sodium bicarbonate aqueous solution. The alkaline washing was performed twice. The crude product was removed by MIPs solid-phase extraction. During MIPs solid-phase extraction, the mass ratio of crude product to MIPs was 1:1.5. The solvent was methanol. The concentration of the crude product methanol solution was 0.4 g / mL. The flow rate was 2 mL / min. The washing phase was methanol:water = 8:2. The elution phase was methanol:acetic acid = 9:1. Then, the product was subjected to suspension melt crystallization. The cooling rate of suspension melt crystallization was 0.4℃ / h. The final crystallization temperature was -2.5℃. The mother liquor was recycled twice to obtain the product.

[0086] Comparative Example 7:

[0087] A method for synthesizing benzothiazole includes the following preparation steps:

[0088] (1) 5% of activated carbon by mass of solvent phase was added to the solvent phase in Comparative Example 6, stirred at 80°C for 1 h, filtered, and vacuum dried at 80°C for 2 h to obtain regenerated deep eutectic solvent 5.

[0089] (2) Prepare the reactant by mixing o-aminothiophenol and benzoic acid at a molar ratio of 1:1.1, and mix the reactant with the regenerated deep eutectic solvent 5 at a mass ratio of 1:1.1;

[0090] (3) 12.5% ​​by mass of 3A molecular sieve was added as a deep eutectic solvent during the reaction;

[0091] (4) Add 0.75% of triphenylphosphine as reactant, and sonicate at 70°C for 60 min under inert gas protection, with a power density of 1 W / mL, pulse mode, and a frequency of 35 kHz to obtain the reaction solution.

[0092] (5) The reaction solution and ethyl acetate were mixed and extracted at a volume ratio of 1:1.2 to separate the solvent phase and the organic phase. The solvent phase was adsorbed by activated carbon, dried under vacuum and then recycled. The organic phase was pretreated by alkaline washing and concentrated under reduced pressure to obtain the crude product. The alkaline solution used for alkaline washing pretreatment was a 5% sodium bicarbonate aqueous solution. The alkaline washing was performed twice. The crude product was removed by MIPs solid-phase extraction. During MIPs solid-phase extraction, the mass ratio of crude product to MIPs was 1:1.5. The solvent was methanol. The concentration of the crude product methanol solution was 0.4 g / mL. The flow rate was 2 mL / min. The washing phase was methanol:water = 8:2. The elution phase was methanol:acetic acid = 9:1. Then, the product was subjected to suspension melt crystallization. The cooling rate of suspension melt crystallization was 0.4℃ / h. The final crystallization temperature was -2.5℃. The mother liquor was recycled twice to obtain the product.

[0093] Comparative Example 8:

[0094] A method for synthesizing benzothiazole includes the following preparation steps:

[0095] (1) 5% of activated carbon by mass of solvent phase was added to the solvent phase in Comparative Example 7, stirred at 80°C for 1 h, filtered, and vacuum dried at 80°C for 2 h to obtain regenerated deep eutectic solvent 6.

[0096] (2) Prepare the reactant by mixing o-aminothiophenol and benzoic acid in a molar ratio of 1:1.1, and mix the reactant with the regenerated deep eutectic solvent 6 in a mass ratio of 1:1.1;

[0097] (3) 12.5% ​​by mass of 3A molecular sieve was added as a deep eutectic solvent during the reaction;

[0098] (4) Add 0.75% of triphenylphosphine as reactant, and sonicate at 70°C for 60 min under inert gas protection, with a power density of 1 W / mL, pulse mode, and a frequency of 35 kHz to obtain the reaction solution.

[0099] (5) The reaction solution and ethyl acetate were mixed and extracted at a volume ratio of 1:1.2 to separate the solvent phase and the organic phase. The solvent phase was adsorbed by activated carbon, dried under vacuum and then recycled. The organic phase was pretreated by alkaline washing and concentrated under reduced pressure to obtain the crude product. The alkaline solution used for alkaline washing pretreatment was a 5% sodium bicarbonate aqueous solution. The alkaline washing was performed twice. The crude product was removed by MIPs solid-phase extraction. During MIPs solid-phase extraction, the mass ratio of crude product to MIPs was 1:1.5. The solvent was methanol. The concentration of the crude product methanol solution was 0.4 g / mL. The flow rate was 2 mL / min. The washing phase was methanol:water = 8:2. The elution phase was methanol:acetic acid = 9:1. Then, the product was subjected to suspension melt crystallization. The cooling rate of suspension melt crystallization was 0.4℃ / h. The final crystallization temperature was -2.5℃. The mother liquor was recycled twice to obtain the product.

[0100] Comparative Example 9:

[0101] A method for synthesizing benzothiazole includes the following preparation steps:

[0102] (1) 5% of activated carbon by mass of solvent phase was added to the solvent phase in Comparative Example 8, stirred at 80°C for 1 h, filtered, and vacuum dried at 80°C for 2 h to obtain regenerated deep eutectic solvent 7.

[0103] (2) Prepare the reactant by mixing o-aminothiophenol and benzoic acid in a molar ratio of 1:1.1, and mix the reactant with the regenerated deep eutectic solvent 7 in a mass ratio of 1:1.1;

[0104] (3) 12.5% ​​by mass of 3A molecular sieve was added as a deep eutectic solvent during the reaction;

[0105] (4) Add 0.75% of triphenylphosphine as reactant, and sonicate at 70°C for 60 min under inert gas protection, with a power density of 1 W / mL, pulse mode, and a frequency of 35 kHz to obtain the reaction solution.

[0106] (5) The reaction solution and ethyl acetate were mixed and extracted at a volume ratio of 1:1.2 to separate the solvent phase and the organic phase. The solvent phase was adsorbed by activated carbon, dried under vacuum and then recycled. The organic phase was pretreated by alkaline washing and concentrated under reduced pressure to obtain the crude product. The alkaline solution used for alkaline washing pretreatment was a 5% sodium bicarbonate aqueous solution. The alkaline washing was performed twice. The crude product was removed by MIPs solid-phase extraction. During MIPs solid-phase extraction, the mass ratio of crude product to MIPs was 1:1.5. The solvent was methanol. The concentration of the crude product methanol solution was 0.4 g / mL. The flow rate was 2 mL / min. The washing phase was methanol:water = 8:2. The elution phase was methanol:acetic acid = 9:1. Then, the product was subjected to suspension melt crystallization. The cooling rate of suspension melt crystallization was 0.4℃ / h. The final crystallization temperature was -2.5℃. The mother liquor was recycled twice to obtain the product.

[0107] Test Example 1:

[0108] Benzothiazole purity test: The purity of each example and comparative example was tested using high performance liquid chromatography. The results are shown in Table 1.

[0109] Table 1

[0110] purity(%) purity(%) Example 1 99.85 Comparative Example 1 96.5 Example 2 99.82 Comparative Example 2 94.1 Example 3 99.86 Comparative Example 3 99.91 Comparative Example 4 99.88 Comparative Example 5 99.85 Comparative Example 7 99.79 Comparative Example 9 99.72

[0111] A comparison of the experimental data from Examples 1-3 and Comparative Examples 1 and 2 in Table 1 reveals that the benzothiazole synthesized in this invention has high purity.

[0112] By comparison, the purity of Examples 1-3 is greater than that of Comparative Example 1, indicating that the synthesis method of benzothiazole of the present invention can synthesize benzothiazole with higher purity than the traditional acid catalysis method.

[0113] By comparison, the purity of Examples 1-3 is greater than that of Comparative Example 2, indicating that the excessively high power density of the high-power microwave method can lead to thermal decomposition side reactions, thereby affecting the purity of benzothiazole.

[0114] Test Example 2:

[0115] Eutectic solvent recovery rate test: The recovery rate was calculated as follows: Recovery rate = (Mass after recovery / Mass before recovery) * 100%. The results are shown in Table 2.

[0116] Table 2

[0117] Recovery rate (%) Comparative Example 3 91.0 Comparative Example 4 90.5 Comparative Example 5 89.8 Comparative Example 7 87.2 Comparative Example 9 84.5

[0118] A comparison of the experimental data from the comparative examples in Table 2 reveals that the eutectic solvent used in the synthesis method of benzothiazole in this invention can be regenerated and recycled through activated carbon adsorption and vacuum drying. The recovery rate of Comparative Example 9 is lower than that of Comparative Examples 3-5, indicating that with increasing cycle number, byproduct accumulation leads to increased viscosity, decreased mass transfer efficiency, and the need for appropriately extended reaction time, resulting in a decreasing yield. The eutectic solvent can be recycled multiple times, effectively reducing costs and meeting the requirements of green development.

[0119] The specific embodiments described above further illustrate the purpose, technical solution, and beneficial effects of the present invention. It should be understood that the above description is only a specific embodiment of the present invention and is not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for synthesizing high-purity benzothiazole, characterized in that, Includes the following steps: The reactant was prepared by mixing o-aminothiophenol with a carboxylic acid compound at a molar ratio of 1:(1.0~1.2), and the reactant was mixed with a deep eutectic solvent at a mass ratio of 1:(1.2~1.4). During the reaction, 10%~15% by mass of 3A molecular sieve is added as a deep eutectic solvent; Add 0.5% to 1.0% of the molar amount of the reactants to a reducing agent, and sonicate at 60 to 80°C for 50 to 70 minutes under inert gas protection to obtain a reaction solution. The reaction solution and ethyl acetate were mixed and extracted at a volume ratio of 1:(1.1~1.3) to separate the solvent phase and the organic phase. The solvent phase was adsorbed by activated carbon, dried under vacuum and then recycled. The organic phase was pretreated by alkaline washing and concentrated under reduced pressure to obtain a crude product. The crude product was removed by solid-phase extraction with MIPs and then obtained by suspension melt crystallization.

2. The method for synthesizing benzothiazole according to claim 1, characterized in that, The deep eutectic solvent mentioned in step (1) is divided into neutral to weakly basic solvent and acidic solvent. The neutral to weakly basic solvent is prepared by mixing choline chloride and urea in a molar ratio of 1:2 and stirring at 600 rpm for 2 hours at 80°C. When using it, it needs to be heated again at 80°C for 30 minutes. The acidic solvent is prepared by mixing choline chloride and p-toluenesulfonic acid in a molar ratio of 1:1 and stirring at 600 rpm for 2 hours at 90°C.

3. The method for preparing benzothiazole according to claim 1, characterized in that, The carboxylic acid compound mentioned in step (1) is an aromatic carboxylic acid, a heteroaromatic carboxylic acid, or a C1-C6 aliphatic carboxylic acid.

4. The method for preparing benzothiazole according to claim 1, characterized in that, The reducing agent in step (3) is triphenylphosphine or sodium bisulfite.

5. The method for preparing benzothiazole according to claim 1, characterized in that, The power density of the ultrasound in step (3) is 0.5~1.5 W / mL, pulse mode, and frequency 30~40 kHz.

6. The method for preparing benzothiazole according to claim 1, characterized in that, The alkaline solution used in step (4) for alkaline washing pretreatment is a 5% sodium bicarbonate aqueous solution, and the alkaline washing is performed twice.

7. The method for preparing benzothiazole according to claim 1, characterized in that, In step (4), during solid-phase extraction of MIPs, the mass ratio of crude product to MIPs is 1:(1~2), the solvent is methanol, the concentration of the crude product 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 elution phase is methanol:acetic acid = 9:

1.

8. The method for preparing benzothiazole according to claim 1, characterized in that, The cooling rate of the suspension melting crystallization in step (4) is 0.3~0.5℃ / h, the final crystallization temperature is -5~0℃, and the mother liquor is recycled 2~3 times.

9. The method for preparing benzothiazole according to claim 1, characterized in that, The specific method for solvent phase activated carbon adsorption and vacuum drying in step (4) is as follows: add 5% of activated carbon by mass of solvent phase to solvent phase, stir at 80℃ for 1 hour, filter, and vacuum dry at 80℃ for 2 hours to obtain regenerated deep eutectic solvent.