Preparation method and application of 2-acetamido-5-chlorosulfonyl-1, 3, 4-thiadiazole

Abstract

The invention discloses a preparation method of 2-acetamido-5-chlorosulfonyl-1, 3, 4-thiadiazole and application of the 2-acetamido-5-chlorosulfonyl-1, 3, 4-thiadiazole, and belongs to the field of medicine synthesis. The preparation method comprises the following steps that 2-acetamido-5-sulfydryl-1, 3, 4-thiadiazole, sodium nitrate, dichloromethane and trimethylchlorosilane are mixed for a chlorine oxidation reaction, the 2-acetamido-5-chlorosulfonyl-1, 3, 4-thiadiazole is prepared, and the molar ratio of the 2-acetamido-5-sulfydryl-1, 3, 4-thiadiazole to the trimethylchlorosilane is 1: (2-12). According to the method, sodium nitrate is adopted to replace chlorine to serve as an oxidizing agent of the oxychlorination reaction, dichloromethane serves as a reaction medium, trimethylchlorosilane serves as a catalyst, selectivity is good, side reactions are few, the reaction is easy to control, high production efficiency can be achieved under the mild reaction condition, safety is good, the requirement for equipment is low, and the method is suitable for industrial production.

Description

Technical Field

[0001] The present application relates to the field of pharmaceutical synthesis, and in particular to a preparation method and application of 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole. Background Art

[0002] Acetazolamide, scientific name N-(5-sulfamoyl-1,3,4-thiadiazole-2-yl)acetamide, has the following chemical structure:

[0003] .

[0004] Acetazolamide is a carbonic anhydrase inhibitor that can inhibit the activity of carbonic anhydrase in the ciliary epithelium and reduce the production of carbonate ions, thereby reducing the production of aqueous humor by about 50% to 60%, ultimately achieving the goal of reducing intraocular pressure in patients with glaucoma. Recent studies have found that acetazolamide has a broad-spectrum inhibitory effect on carbonic anhydrase in many tissue cells, blocking the forward pathway of CO2 hydration reaction in cells, thereby correcting the biochemical metabolic disorders of many pathological conditions, thereby expanding its application in acute mountain sickness, chronic mountain sickness, cerebrovascular disease, tumors, intractable hiccups, epilepsy, metabolic bone disease, oxygen convulsions, etc.

[0005] Acetazolamide was first synthesized by Roblin and Clapp in 1950. The synthesis route is as follows:

[0006] .

[0007] The method comprises the following steps: subjecting 2-amino-5-mercapto-1,3,4-thiadiazole to an acetylation reaction with acetic anhydride to obtain 2-acetylamino-5-mercapto-1,3,4-thiadiazole; and then subjecting the chlorine gas to a chlorine oxidation reaction to obtain 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole; and finally subjecting the chlorine gas to an ammonolysis reaction with ammonia water to obtain acetazolamide.

[0008] The above method uses the chlorine method to prepare 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole, which requires a large amount of chlorine. Chlorine is a toxic gas. When it enters the human body through the respiratory tract, it will cause damage to the upper respiratory tract mucosa, such as stimulating the mucosa to inflammatory swelling, causing edema of the respiratory tract mucosa, and secreting a large amount of mucus, causing difficulty in breathing and severe coughing. When the symptoms are severe, pulmonary edema will occur, and circulation will be difficult and cause death; when it enters the human body through the esophagus, it will cause nausea, vomiting, chest pain and diarrhea. The maximum amount of chlorine allowed in 1L of air is 0.001mg. Exceeding the limit will cause human poisoning.

[0009] At the same time, the industrial production of acetazolamide uses liquid chlorine, which needs to be stored in steel cylinders. The requirements for plant equipment and worker operation are very strict. Once leaked, it will cause serious consequences, and the pressure on safety and environmental protection work is huge. In addition, the reaction rate of the gas-liquid reaction is difficult to control, and the amount of chlorine involved in the reaction is also difficult to accurately control. Insufficient chlorine will cause incomplete reaction and generate some reaction transition state impurities, and excessive chlorine will cause environmental pollution.

[0010] Therefore, the chlorine method for preparing 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole has problems such as poor safety, high process cost, difficult reaction control, and low reaction efficiency, and cannot meet the needs of industrial production. Summary of the invention

[0011] Based on this, it is necessary to provide a preparation method and application of 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole, which uses sodium nitrate instead of chlorine as an oxidant for the chlorination reaction, dichloromethane as a reaction medium, and trimethylsilyl chloride as a catalyst. The method has good selectivity, few side reactions, and easy control of the reaction. It can achieve higher production efficiency under mild reaction conditions, and does not require the use of raw materials with safety hazards such as chlorine. It has good safety, low equipment requirements, and is suitable for industrial production.

[0012] In a first aspect of the present application, a method for preparing 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole is provided, comprising the following steps:

[0013] 2-acetylamino-5-mercapto-1,3,4-thiadiazole, sodium nitrate, dichloromethane and trimethylsilyl chloride are mixed for chlorination oxidation reaction to prepare 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole, wherein the molar ratio of the 2-acetylamino-5-mercapto-1,3,4-thiadiazole to the trimethylsilyl chloride is 1:(2-12).

[0014] In some embodiments, the molar ratio of the 2-acetylamino-5-mercapto-1,3,4-thiadiazole to the trimethylsilyl chloride is 1:(2-4).

[0015] In some embodiments, the molar ratio of the 2-acetylamino-5-mercapto-1,3,4-thiadiazole to the sodium nitrate is 1:(1-12); optionally, the molar ratio of the 2-acetylamino-5-mercapto-1,3,4-thiadiazole to the sodium nitrate is 1:(1-5).

[0016] In some embodiments, the weight ratio of the 2-acetylamino-5-mercapto-1,3,4-thiadiazole to the dichloromethane is 1:(5-50); optionally, the weight ratio of the 2-acetylamino-5-mercapto-1,3,4-thiadiazole to the dichloromethane is 1:(10-50).

[0017] In some embodiments, the conditions of the chlorine oxidation reaction include: the reaction temperature is 30°C~50°C, and the reaction time is 2h~4h; optionally, the reaction temperature is 40°C~50°C, and the reaction time is 2h~3h.

[0018] The second aspect of the present application provides the use of the aforementioned preparation method of 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole in the preparation of acetazolamide.

[0019] The beneficial effects of this application are:

[0020] 1. The present invention adopts sodium nitrate instead of chlorine as the oxidant of the chlorination reaction, which has good selectivity and reduces side reactions. In the reaction process, dichloromethane is used as the reaction medium, and the chlorine oxide generated by the reaction has low solubility in dichloromethane, which is more conducive to centrifugation and avoids the material from reacting with water and hydrolyzing into the corresponding sulfonic acid. Trimethylchlorosilane is used as a catalyst to make the chlorination reaction milder, the reaction time is significantly shortened, and the chlorination reaction is more thorough. The selection of the above oxidant, reaction medium and catalyst can ensure the yield and purity of the product under mild reaction conditions, thereby improving the production efficiency of acetazolamide.

[0021] 2. The preparation conditions of the present application are relatively stable and mild, more environmentally friendly, have low requirements on reaction equipment, have strong reaction operability, ensure production safety, and are a route suitable for industrial production. DETAILED DESCRIPTION

[0022] In order to facilitate the understanding of the present application, the present application will be described more comprehensively below in conjunction with specific embodiments. Preferred embodiments of the present application are provided hereinafter. However, the present application can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosure of the present application more thorough and comprehensive.

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this application belongs. The terms used herein in the specification of this application are only for the purpose of describing specific embodiments and are not intended to limit this application. The term "and / or" used herein includes any and all combinations of one or more of the related listed items.

[0024] In this article, the terms "first" and "second" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Therefore, a feature defined as "first" or "second" may explicitly or implicitly include at least one of the features. In the description of the invention, the meaning of "multiple" is at least two, such as two, three, etc., unless otherwise clearly and specifically defined. In the description of this application, the meaning of "several" is at least one, such as one, two, etc., unless otherwise clearly and specifically defined.

[0025] The words "optional", "preferable", "preferably", "more preferably", etc. in this application refer to embodiments of the present application that may provide certain beneficial effects in certain circumstances. However, other embodiments may also be preferred under the same or other circumstances. In addition, the statement of one or more preferred embodiments does not imply that other embodiments are not applicable, nor is it intended to exclude other embodiments from the scope of this application.

[0026] Herein, when it comes to numerical ranges, unless otherwise specified, the numerical ranges are deemed to be continuous and include the minimum and maximum values ​​of the range, as well as every value between such minimum and maximum values. Further, when a range refers to an integer, every integer between the minimum and maximum values ​​of the range is included. In addition, when multiple ranges are provided to describe features or characteristics, the ranges can be merged. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all subranges included therein.

[0027] Unless otherwise specified, all percentages, fractions and ratios are calculated by the total mass of the composition of the present application. Unless otherwise specified, all masses of the listed ingredients are given to the content of active substances, so they do not include solvents or by-products that may be contained in commercially available materials. The term "mass percentage content" herein can be represented by the symbol "%". Unless otherwise specified, all molecular weights in this article are weight average molecular weights expressed in Daltons. Unless otherwise specified, all formulations and tests in this article occur in an environment of 25°C. "Including", "including", "containing", "containing", "having" or other variants herein are intended to cover non-closed inclusions, and these terms are not distinguished. The term "comprising" means that other steps and ingredients that do not affect the final result can be added. The composition and method / process of the present application include, consist of and are basically composed of the necessary elements and restrictions described herein and any additional or optional ingredients, components, steps or restrictions described herein. The terms "efficacy", "performance", "effect" and "efficacy" are not distinguished herein.

[0028] In the present application, the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.

[0029] The temperature parameters in this application, unless otherwise specified, allow for both constant temperature treatment and treatment within a certain temperature range. The constant temperature treatment allows the temperature to fluctuate within the accuracy range of instrument control.

[0030] In this article, when referring to the unit of a data range, if there is a unit only after the right endpoint, it means that the units of the left and right endpoints are the same. For example, 500-600rpm means that the units of the left endpoint "500" and the right endpoint "600" are both rpm (revolutions per minute).

[0031] In a first aspect of the present application, a method for preparing 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole is provided, comprising the following steps:

[0032] 2-acetylamino-5-mercapto-1,3,4-thiadiazole, sodium nitrate, dichloromethane and trimethylsilyl chloride are mixed for chlorination oxidation reaction to prepare 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole, wherein the molar ratio of the 2-acetylamino-5-mercapto-1,3,4-thiadiazole to the trimethylsilyl chloride is 1:(2-12).

[0033] The present application adopts sodium nitrate instead of chlorine as the oxidant of the chlorination reaction, which has good selectivity and reduces side reactions; dichloromethane is used as the reaction medium in the reaction process, and the chlorine oxide generated by the reaction has low solubility in dichloromethane, which is more conducive to centrifugation and avoids the material from reacting with water and hydrolyzing into corresponding sulfonic acid; trimethylchlorosilane is used as a catalyst, so that the chlorination reaction is milder, the reaction time is significantly shortened, and the chlorination reaction is more thorough. The selection of the above oxidant, reaction medium and catalyst can ensure the yield and purity of the product under mild reaction conditions, thereby improving the production efficiency of acetazolamide.

[0034] In some embodiments, the purity of 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole can reach more than 95%, and the yield can reach more than 80%. After further aminolysis, the purity of the crude acetazolamide obtained can reach more than 95%, and the total yield can reach more than 80% (the starting material is calculated as 2-acetylamino-5-mercapto-1,3,4-thiadiazole).

[0035] In some embodiments, the molar ratio of the 2-acetylamino-5-mercapto-1,3,4-thiadiazole to the trimethylchlorosilane is 1:(2-4); optionally, the molar ratio of the 2-acetylamino-5-mercapto-1,3,4-thiadiazole to the trimethylchlorosilane is 1:(2-3). It can be understood that in the present application, the molar ratio of 2-acetylamino-5-mercapto-1,3,4-thiadiazole to trimethylchlorosilane includes but is not limited to 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, etc.

[0036] In some embodiments, the molar ratio of the 2-acetylamino-5-mercapto-1,3,4-thiadiazole to the sodium nitrate is 1:(1-12); optionally, the 2-acetylamino-5-mercapto-1,3,4-thiadiazole to the sodium nitrate is 1:(1-5); further optionally, the 2-acetylamino-5-mercapto-1,3,4-thiadiazole to the sodium nitrate is 1:(2-4). It can be understood that in the present application, the molar ratio of 2-acetylamino-5-mercapto-1,3,4-thiadiazole to sodium nitrate includes but is not limited to 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, etc.

[0037] In some embodiments, the weight ratio of the 2-acetylamino-5-mercapto-1,3,4-thiadiazole to the dichloromethane is 1:(5-50); optionally, the weight ratio of the 2-acetylamino-5-mercapto-1,3,4-thiadiazole to the dichloromethane is 1:(10-50). It is understood that in the present application, the weight ratio of 2-acetylamino-5-mercapto-1,3,4-thiadiazole to dichloromethane includes but is not limited to 1:5, 1:10, 1:15, 1:20, 1:25, 1:30, 1:35, 1:40, 1:45, 1:50, etc.

[0038] In some embodiments, the conditions of the chlorine oxidation reaction include: a reaction temperature of 30°C to 50°C, and a reaction time of 2h-4h; optionally, the reaction temperature is 40°C to 50°C, and the reaction time is 2h to 3h. It can be understood that in the present application, the temperature of the chlorine oxidation reaction includes but is not limited to 30°C, 31°C, 32°C, 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, 50°C, etc.; the time of the chlorine oxidation reaction includes but is not limited to 2h, 3h, 4h, 5h, etc.

[0039] In some embodiments, the step of mixing 2-acetylamino-5-mercapto-1,3,4-thiadiazole, sodium nitrate, dichloromethane, and trimethylsilyl chloride to perform chlorination oxidation reaction comprises:

[0040] 2-Acetylamino-5-mercapto-1,3,4-thiadiazole, dichloromethane, trimethylsilyl chloride and sodium nitrate were mixed and heated to carry out chlorination oxidation reaction.

[0041] It is understandable that after the chlorination reaction is completed, the steps of solid-liquid separation, washing, and drying may also be included. The conditions for the solid-liquid separation, drying, and washing are not particularly limited, and common solid-liquid separation methods (centrifugation, filtration, etc.), common drying methods (such as heating drying, vacuum drying, freeze drying, natural drying, etc.), and common washing methods may be used.

[0042] The second aspect of the present application provides the use of the aforementioned preparation method of 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole in the preparation of acetazolamide.

[0043] It is understandable that the selection of the oxidant, reaction medium and catalyst in the present application can ensure the yield and purity of 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole under mild reaction conditions, thereby improving the production efficiency of acetazolamide and ensuring the production quality of acetazolamide.

[0044] The preparation method of 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole of the present application is further described in detail below in conjunction with specific examples. The raw materials used in the following examples, unless otherwise specified, are all commercially available products.

[0045] The following are specific embodiments.

[0046] The following examples use liquid chromatography to determine 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole, and the determination conditions are: the chromatographic column is a Phenyl-Hexyl column, 4.6×150 mm, and the flow rate is controlled at 0.8 mL / min; the detector is an ultraviolet detector; the wavelength is 265 nm; the injection volume is 20 μL; the mobile phase is 6.8 g / L potassium dihydrogen phosphate aqueous solution: acetonitrile = 90:10 (v / v); the sample solution preparation steps are: weigh 10 mg of the sample, i.e. the obtained intermediate, to 0.0001 g, and dilute to a 25 mg volumetric flask with the mobile phase to obtain a sample solution to be tested.

[0047] Example 1

[0048] This embodiment provides a method for preparing 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole and acetazolamide, which is as follows:

[0049] 1. Preparation of 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole: 10.0g 2-acetylamino-5-thiol-1,3,4-thiadiazole, 13.6g trimethylsilyl chloride, 100.0g dichloromethane, 10.5g sodium nitrate were added to a 500ml reaction bottle in sequence, stirring was started, the temperature was raised to 40-50°C, and the reaction was stirred for 2h. After the reaction was completed, suction filtration was started, and the filter cake was rinsed once with 30.0g dichloromethane and dried to obtain an off-white solid powder. After drying, 12.8g of 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole was obtained, with a molar yield of 93.2% and a purity of 99.3%.

[0050] 2. Preparation of acetazolamide: Add 20.0g of ammonia water to a 250ml three-necked flask, start stirring, cool to -15~-10℃ and control the internal temperature to -10~-0℃, add 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole wet powder in batches, after addition, control the internal temperature to -10~0℃ and react for 30min, control the internal temperature below 20℃ and add 6mol / L hydrochloric acid dropwise until the pH is 4~5, a large amount of solid precipitates, raise the internal temperature to 25±5℃ and stir for 1h. Filter by suction, rinse the filter cake with 50.0g of purified water, drain, and air dry at 60℃ to obtain 10.6g of off-white acetazolamide solid, with a total molar yield of 83.6% (calculated as 2-acetylamino-5-thiol-1,3,4-thiadiazole); the liquid phase purity is 99.4%, and the structure is correct as identified by NMR.

[0051] Example 2

[0052] This embodiment provides a method for preparing 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole, which is as follows:

[0053] 10.0g 2-acetylamino-5-thiol-1,3,4-thiadiazole, 62.0g trimethylsilyl chloride (10 times equivalent), 100.0g dichloromethane, 10.5g sodium nitrate were added to a 500ml reaction bottle in sequence, stirring was started, the temperature was raised to 40-50°C, and the reaction was stirred for 2h. After the reaction was completed, suction filtration was started, and the filter cake was rinsed once with 30.0g dichloromethane and dried to obtain an off-white solid powder. After drying, 12.0g of 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole was obtained, with a molar yield of 87.6% and a purity of 98.6%.

[0054] Example 3

[0055] This embodiment provides a method for preparing 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole, which is as follows:

[0056] 10.0g 2-acetylamino-5-thiol-1,3,4-thiadiazole, 13.6g trimethylsilyl chloride, 100.0g dichloromethane, 48.5g sodium nitrate (10 times equivalent) were added to a 500ml reaction bottle in sequence, stirring was started, the temperature was raised to 40-50°C, and the reaction was stirred for 2h. After the reaction was completed, suction filtration was started, and the filter cake was rinsed once with 30.0g dichloromethane and dried to obtain an off-white solid powder. After drying, 11.9g of 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole was obtained, with a molar yield of 86.3% and a purity of 98.7%.

[0057] Example 4

[0058] This embodiment provides a method for preparing 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole, which is as follows:

[0059] 10.0g 2-acetylamino-5-thiol-1,3,4-thiadiazole, 13.6g trimethylsilyl chloride, 500g dichloromethane (10V), 10.5g sodium nitrate were added to a 1000ml reaction bottle in sequence, stirring was started, the temperature was raised to 40-50°C, and the reaction was stirred for 2h. After the reaction was completed, suction filtration was started, and the filter cake was rinsed once with 30.0g dichloromethane and dried to obtain an off-white solid powder. After drying, 11.7g of 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole was obtained, with a molar yield of 85.3% and a purity of 99.43%.

[0060] Example 5

[0061] This embodiment provides a method for preparing 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole, which is as follows:

[0062] 10.0g 2-acetylamino-5-thiol-1,3,4-thiadiazole, 13.6g trimethylsilyl chloride, 100.0g dichloromethane, 10.5g sodium nitrate were added to a 500ml reaction bottle in sequence, stirring was started, the temperature was raised to 30-40°C, the reaction was stirred for 2h, and after the reaction was completed, suction filtration was started, the filter cake was rinsed once with 30.0g dichloromethane, and dried to obtain an off-white solid powder. After drying, 12.0g 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole was obtained, with a molar yield of 87.4% and a purity of 96.9%.

[0063] Example 6

[0064] This embodiment provides a method for preparing 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole, which is as follows:

[0065] 10.0g 2-acetylamino-5-thiol-1,3,4-thiadiazole, 13.6g trimethylsilyl chloride, 100.0g dichloromethane, 10.5g sodium nitrate were added to a 500ml reaction bottle in sequence, stirring was started, the temperature was raised to 40-50°C, and the reaction was stirred for 4h. After the reaction was completed, suction filtration was started, and the filter cake was rinsed once with 30.0g dichloromethane and dried to obtain an off-white solid powder. After drying, 12.1g of 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole was obtained, with a molar yield of 87.9% and a purity of 98.6%.

[0066] Comparative Example 1

[0067] This comparative example provides a method for preparing 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole, which is as follows:

[0068] 10.0g 2-acetylamino-5-mercapto-1,3,4-thiadiazole, 13.6g trimethylsilyl chloride, 100.0g acetonitrile, and 10.5g sodium nitrate were added to a 500ml reaction bottle in sequence, stirred, and heated to 40-50°C. The reaction was stirred for 2h at room temperature. After the reaction was completed, suction filtration was started. The filter cake was rinsed once with 30.0g acetonitrile and dried to obtain an off-white solid powder. After drying, 7.4g of 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole was obtained, with a molar yield of 54.3% and a purity of 75.4%.

[0069] Comparative Example 2

[0070] This comparative example provides a method for preparing 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole, which is as follows:

[0071] 10.0g 2-acetylamino-5-thiol-1,3,4-thiadiazole, 13.6g trimethylsilyl chloride, 100.0g dichloromethane, and 10.5g potassium nitrate were added to a 500ml reaction bottle in sequence, stirred, and heated to 40-50°C. The reaction was stirred for 2h at room temperature. After the reaction was completed, suction filtration was started. The filter cake was rinsed once with 30.0g dichloromethane and dried to obtain an off-white solid powder. After drying, 5.3g of 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole was obtained, with a molar yield of 38.5% and a purity of 62.3%.

[0072] It can be seen that Examples 1-6 efficiently prepared 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole under mild reaction conditions (reaction at 30-50°C for 2-4h). Comparative Example 1 replaced dichloromethane with acetonitrile and Comparative Example 2 replaced sodium nitrate with potassium nitrate, both of which resulted in a decrease in the yield and purity of 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole.

[0073] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0074] The above-described embodiments only express several implementation methods of the present application, which is convenient for understanding the technical solution of the present application in detail, but it cannot be understood as limiting the scope of protection of the invention patent. It should be pointed out that for ordinary technicians in this field, without departing from the concept of the present application, several modifications and improvements can be made, which all belong to the scope of protection of the present application. It should be understood that the technical solutions obtained by those skilled in the art through logical analysis, reasoning or limited experiments on the basis of the technical solutions provided in the present application are all within the scope of protection of the claims attached to the present application. Therefore, the scope of protection of the patent of this application shall be based on the content of the attached claims, and the description can be used to interpret the content of the claims.

Claims

1. A method for preparing 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole, characterized in that: The steps include: 2-acetylamino-5-mercapto-1,3,4-thiadiazole, sodium nitrate, dichloromethane and trimethylsilyl chloride are mixed for chlorination oxidation reaction to prepare 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole, wherein the molar ratio of the 2-acetylamino-5-mercapto-1,3,4-thiadiazole to the trimethylsilyl chloride is 1:(2-12).

2. The preparation method according to claim 1, characterized in that The molar ratio of the 2-acetylamino-5-mercapto-1,3,4-thiadiazole to the trimethylchlorosilane is 1:(2-4).

3. The preparation method according to claim 2, characterized in that: The molar ratio of the 2-acetylamino-5-mercapto-1,3,4-thiadiazole to the trimethylchlorosilane is 1:(2-3).

4. The preparation method according to any one of claims 1 to 3, characterized in that: The molar ratio of the 2-acetylamino-5-mercapto-1,3,4-thiadiazole to the sodium nitrate is 1:(1-12).

5. The preparation method according to claim 4, characterized in that: The molar ratio of the 2-acetylamino-5-mercapto-1,3,4-thiadiazole to the sodium nitrate is 1:(1-5).

6. The preparation method according to any one of claims 1 to 3, characterized in that: The weight ratio of the 2-acetylamino-5-mercapto-1,3,4-thiadiazole to the dichloromethane is 1:(5-50).

7. The preparation method according to claim 6, characterized in that: The weight ratio of the 2-acetylamino-5-mercapto-1,3,4-thiadiazole to the dichloromethane is 1:(10-50).

8. The preparation method according to any one of claims 1 to 3, characterized in that: The conditions of the chlorine oxidation reaction include: reaction temperature of 30° C. to 50° C., and reaction time of 2 h to 4 h.

9. The preparation method according to claim 8, characterized in that: The reaction temperature is 40°C to 50°C, and the reaction time is 2h to 3h.

10. Use of the preparation method of 2-acetylamino-5-chlorosulfonyl-1,3,4-thiadiazole according to any one of claims 1 to 9 in the preparation of acetazolamide.