阅读说明：本技术 一种合成盐酸阿比朵尔中间体的方法 (Method for synthesizing arbidol hydrochloride intermediate ) 是由 方典军 魏克思 孙庆发 高峰 于 2020-05-13 设计创作，主要内容包括：一种合成盐酸阿比朵尔中间体的方法,其属于医药中间体技术领域。该方法采用5-羟基-1,2-二甲基吲哚-3-羧酸乙酯为原料,经酯化、溴代、苯硫酚化和脱保护、Mannich反应、成盐得到盐酸阿比朵尔。在溴代反应生成最重要的中间体5-乙酰氧基-6-溴-2-溴甲基-1-甲基吲哚-3-羧酸过程中,以(对甲基异丙基苯)-二氯化钌二聚体为催化剂,NBS为溴代试剂,DMA为溶剂代替传统溴素溴代试剂,反应条件温和,反应选择性高以及原料来源方便,同时可以避免溴素对环境的污染,并且新型催化剂不受反应环境影响导致催化活性降低。因此该方法具有副产物少,产率高,生产成本低,安全性高,节省能源等诸多优点,符合绿色反应的现代化工生产要求。(A method for synthesizing arbidol hydrochloride intermediate, which belongs to the technical field of medical intermediate. The method adopts 5-hydroxy-1, 2-dimethyl indole-3-carboxylic acid ethyl ester as a raw material, and prepares arbidol hydrochloride through esterification, bromination, thiophenol, deprotection, Mannich reaction and salification. In the process of generating the most important intermediate 5-acetoxyl-6-bromo-2-bromomethyl-1-methylindole-3-carboxylic acid through bromination reaction, the (p-cymene) -ruthenium dichloride dimer is used as a catalyst, NBS is used as a bromination reagent, DMA is used as a solvent to replace the traditional bromine bromination reagent, the reaction condition is mild, the reaction selectivity is high, the raw material source is convenient, meanwhile, the pollution of bromine to the environment can be avoided, and the novel catalyst is not influenced by the reaction environment to cause the reduction of the catalytic activity. Therefore, the method has the advantages of few byproducts, high yield, low production cost, high safety, energy conservation and the like, and meets the modern chemical production requirement of green reaction.)

1. A method for synthesizing an arbidol hydrochloride intermediate is characterized by comprising the following steps:

adding an acetic anhydride solvent into a three-neck flask, adding solid 5-hydroxy-1, 2-dimethyl indole-3-carboxylic acid ethyl ester while stirring, heating and refluxing for 4 hours after complete dissolution, cooling, filtering, washing and drying to obtain a crude product; recrystallizing with methanol to obtain brown crystal 5-acetoxyl-1, 2-dimethyl indole-3-carboxylic acid ethyl ester; washing the solid with water for 4 times, and finally performing suction filtration to obtain a solid;

sequentially adding 5-acetoxyl-1, 2-dimethyl indole-3-carboxylic acid ethyl ester, a catalyst (p-cymene) -ruthenium dichloride dimer, N-bromosuccinimide NBS and Dimethylacetamide (DMA) into a three-neck flask, heating to 90 ℃ under the protection of nitrogen, reacting for 24 hours, and after the reaction is finished; cooling to room temperature, extracting with ethyl acetate, and spin-drying the solvent to obtain a solid; recrystallizing with acetone to obtain white powdery solid, and vacuum drying to obtain 5-acetoxyl-6-bromo-2-bromomethyl-1-methylindole-3-carboxylic acid ethyl ester;

the 5-acetoxyl-1, 2-dimethyl indole-3-carboxylic acid ethyl ester: (p-cymene) -ruthenium dichloride dimer: the mol ratio of the N-bromosuccinimide is 1:0.1-0.12: 4-5;

adding methanol solvent into a three-neck flask, adding solid potassium hydroxide under stirring, cooling to room temperature after dissolving, adding thiophenol for reacting for 15 min, adding 5-acetoxyl-6-bromo-2-bromomethyl-1-methylindole-3-carboxylic acid ethyl ester, and stirring to react for 4h at room temperature; dropwise adding 10% acetic acid into the reaction liquid to adjust the pH =3-4, separating out yellow solid, and performing suction filtration, washing and drying to obtain a crude product; recrystallizing with ethyl acetate to obtain yellow white crystal 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethyl indole-3-carboxylic acid ethyl ester;

the 5-acetoxy-6-bromo-2-bromomethyl-1-methylindole-3-carboxylic acid ethyl ester: the molar ratio of thiophenol is 1: 1-1.2;

adding a glacial acetic acid solution into a three-neck flask, cooling to 0 ℃, adding a dimethylamine aqueous solution with the mass fraction of 40% while stirring, adding a formaldehyde aqueous solution with the mass fraction of 37%, reacting and stirring for 15 min, adding 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethyl indole-3-carboxylic acid ethyl ester, heating to 80 ℃, reacting for 4h, and pouring a reaction solution into water after the reaction is finished; adding 20% potassium hydroxide solution for neutralization under stirring, adjusting the pH of the solution to be =7.0, separating out solids, and performing suction filtration, washing and drying to obtain a crude product; recrystallizing with acetonitrile, adding active carbon for refluxing, thermally filtering, and cooling to separate out brown solid arbidol;

adding an acetone solvent into a three-neck flask, adding arbidol under stirring, heating to reflux, dropwise adding concentrated hydrochloric acid, refluxing for 30 min, cooling the reaction solution to room temperature after the reaction is finished, performing suction filtration, and drying to obtain a crude arbidol hydrochloride product; the preparation method comprises the following steps of: 2, recrystallizing with acetone and ethanol solvent, cooling at room temperature for 10 h, freezing in a refrigerator for 10 h, filtering, and washing to obtain refined arbidol hydrochloride.

Technical Field

The invention relates to a method for synthesizing an arbidol hydrochloride intermediate, belonging to the technical field of medical intermediates.

Background

The arbidol hydrochloride is used as a medical intermediate with the chemical name of 6-bromo-4- (dimethylaminomethyl) -5-hydroxy-1-methyl-2- (phenylthiomethyl) -1H-indole-3-carboxylic acid ethyl ester hydrochloride, wherein the hydrochloric acid is used as a stabilizer of the arbidol hydrochloride, is mainly used for preventing and treating influenza A and B and other respiratory virus infection diseases, has the advantages of convenience in oral administration, high safety, good compliance, no cytotoxicity and the like, is a research hotspot of scholars at home and abroad in recent years, and has wide application prospect.

However, in the traditional process method, some problems exist, bromine is used as a bromination reagent in the process of generating the most important intermediate 5-acetoxyl-6-bromo-2-bromomethyl-1-methylindole-3-carboxylic acid through bromination reaction, the reaction environment is greatly influenced, the bromination activity is low, the selectivity is poor, a large amount of bromine reagent is required to be added, meanwhile, the reaction conditions are harsh, the time is long, the temperature is high, the yield is poor, a strong acid solvent is generated in the reaction process, a large amount of residual organic solvents and other pollutants are generated, and the final product is difficult to purify; the cost is increased, and inevitable disasters are brought to people and the environment. The bromination reaction step therefore needs to be improved and optimized.

Disclosure of Invention

In order to solve the problems in the prior art, the invention provides a method for synthesizing an arbidol hydrochloride intermediate, which adopts a (p-cymene) -ruthenium dichloride dimer catalyst, NBS as a bromization reagent and DMA as a solvent, improves the yield of the product and meets the requirement of green process production. The method is optimized to simplify the process, reduce the production cost and improve the experimental safety.

The technical scheme adopted by the invention is as follows:

a method for efficiently and environmentally synthesizing an arbidol hydrochloride intermediate is developed, wherein the arbidol hydrochloride intermediate has a structural formula as follows:

the method comprises the following steps:

(1) the method comprises the steps of loading a device, adding an acetic anhydride solvent into a three-neck flask, adding solid 5-hydroxy-1, 2-dimethyl indole-3-carboxylic acid ethyl ester while stirring, heating and refluxing for 4 hours after all the materials are dissolved, cooling reaction liquid after the reaction is finished, and performing suction filtration to obtain a solid. And (3) washing the solid with water for 4 times, slowly dropwise adding 0.15 mol/L ammonia water into the solution at the 3 rd time to control the pH of the mixed system of the solid and the water to be 8-9, finally performing suction filtration to obtain the solid, and drying the solid in an oven at 70 ℃ for 5 hours to obtain a crude product. Recrystallizing with methanol to obtain brown crystal 5-acetoxyl-1, 2-dimethyl indole-3-carboxylic acid ethyl ester.

(2) The method comprises the following steps of (1) installing a device, sequentially adding 5-acetoxyl-1, 2-dimethylindole-3-carboxylic acid ethyl ester, a catalyst (p-cymene) -ruthenium dichloride dimer and DMA into a three-neck flask, slowly heating to 90 ℃ in an oil bath under the protection of nitrogen, maintaining the reaction temperature for reaction for 24 hours, and after the reaction is finished; cooling the reaction liquid to room temperature, adding a proper amount of water into the reaction liquid, extracting with ethyl acetate for 5 times, combining organic phases, drying, spin-drying the solvent to obtain a solid, recrystallizing with acetone to separate out a white powdery solid, and drying in vacuum to obtain the 5-acetoxyl-6-bromo-2-bromomethyl-1-methylindole-3-carboxylic acid ethyl ester.

(3) The preparation method comprises the steps of loading a device, adding a proper amount of methanol solvent into a three-neck flask, slowly adding solid potassium hydroxide under stirring, cooling to room temperature after all the solid potassium hydroxide is dissolved, then adding thiophenol under stirring, adding 5-acetoxyl-6-bromo-2-bromomethyl-1-methylindole-3-carboxylic acid ethyl ester after about 15 min, stirring at room temperature for reacting for 4h, and after the reaction is finished. And (3) dropwise adding 10% acetic acid into the reaction liquid until the pH of the reaction liquid is =3-4, after a large amount of yellow solid is separated out, performing suction filtration to obtain a solid, washing the solid for 1 time with water, performing suction filtration, and drying the solid for 5 hours in a drying oven at the temperature of 7O ℃ to obtain a crude product. Ethyl acetate is used for recrystallization to obtain a yellow white crystal 6-bromo-5-hydroxy-1-methyl-2-thiophenylmethylindole-3-carboxylic acid ethyl ester.

(4) The method comprises the steps of loading a device, adding a glacial acetic acid solution into a three-neck flask, cooling to 0 ℃, stirring, slowly adding a 40% methylamine aqueous solution, adding a 37% formaldehyde aqueous solution, stirring for 15 min after reaction, adding 6-bromo-5-hydroxy-1-methyl-2-thiophenylmethylindole-3-carboxylic acid ethyl ester, stirring uniformly for 10 min, then heating to 80 ℃, maintaining the reaction temperature, reacting for 4h after complete dissolution, pouring the reaction liquid into water after the reaction is finished, adding a 20% potassium hydroxide solution for neutralization under stirring, adjusting the pH =7.0 of the solution, separating out a solid, performing suction filtration, washing for 1 time with water, performing suction filtration to obtain a solid, and drying for 5h at 70 ℃ in a drying box to obtain a crude product. Recrystallizing with acetonitrile, dissolving completely, adding active carbon, refluxing for 30 min, heat filtering, cooling, and separating out brown solid arbidol.

(5) Loading the device, adding a proper amount of acetone solvent into a three-neck flask, adding arbidol under stirring, heating to reflux, dropwise adding concentrated hydrochloric acid, refluxing for 30 min, cooling the reaction solution to room temperature after the reaction is finished, performing suction filtration to obtain a crude arbidol hydrochloride product, and drying for 3 h at the temperature of 5O in an oven. Using acetone: recrystallizing with ethanol (3: 2) solvent, cooling at room temperature for 10 h, freezing in refrigerator for 10 h, vacuum filtering, and washing the solid with small amount of acetone to obtain refined arbidol hydrochloride.

The invention has the beneficial effects that: abidol hydrochloride is used as a very important medical intermediate, has a plurality of medical applications and has very large demand. The method adopts 5-hydroxy-1, 2-dimethyl indole-3-carboxylic acid ethyl ester as a raw material, and prepares arbidol hydrochloride through esterification, bromination, thiophenol, deprotection, Mannich reaction and salification. In the process of generating the most important intermediate 5-acetoxyl-6-bromo-2-bromomethyl-1-methylindole-3-carboxylic acid through bromination reaction, a (p-cymene) -ruthenium dichloride dimer catalyst is selected, NBS is used as a bromination reagent, DMA is used as a solvent to replace bromine as the bromination reagent, and the reaction yield of the step can be improved to 80%. The method can avoid the excessive use of bromine, and reduce the problems of environmental pollution, post-treatment difficulty, operation danger and the like caused by strong acid and organic solvent. The method optimizes the reaction scheme, and greatly improves the selectivity and yield of the reaction. And the NBS is used as a bromination reagent, so that the problems of harm and operation danger of residual bromine in the reaction to people are reduced. The optimized reaction scheme has the advantages of improved yield, reduced cost, environmental friendliness and accordance with the requirements of green modern production.

Detailed Description

The invention is further illustrated by the following examples, which are intended to provide a better understanding of the contents of the invention. The examples given therefore do not limit the scope of protection of the invention.