CN111925340A

CN111925340A - Preparation process of methyl mercapto thiadiazole

Info

Publication number: CN111925340A
Application number: CN201911287812.8A
Authority: CN
Inventors: 李家全; 张�林; 宋广慧; 邱化齐
Original assignee: Shandong Jincheng Courage Chemical Co ltd
Current assignee: Shandong Jincheng Courage Chemical Co ltd
Priority date: 2019-12-16
Filing date: 2019-12-16
Publication date: 2020-11-13

Abstract

The invention discloses a preparation process of methyl mercapto thiadiazole, which relates to the technical field of pharmaceutical chemicals, and comprises the following steps of (1) preparing hydrazino dithioformic acid (HDF) by taking hydrazine hydrate as a raw material and reacting with carbon disulfide; (2) the HDF and acetic acid are cyclized under the action of an acid catalyst to generate a crude product of methylmercaptothiadiazole (MMTD); (3) refining to obtain the MMTD product. Compared with the traditional process, the process greatly reduces or even avoids the use of concentrated sulfuric acid, is green and pollution-free, has simple process steps, greatly improves the cyclization reaction rate and the cyclization reaction conversion rate, saves time and energy, and is suitable for industrial production.

Description

Preparation process of methyl mercapto thiadiazole

Technical Field

The invention relates to the technical field of pharmaceutical chemicals, and particularly relates to a preparation process of methylmercaptothiadiazole.

Background

The methylmercaptothiadiazole is an important intermediate for producing cefazolin, cefkaempferia, cefazedone, azone cephalosporin, cefprozil, cephalosporin BL-S339, furbenconazole cephalosporin and the like, and is clinically and widely used because the medicaments have the characteristics of broad antibacterial spectrum, good absorption, small side effect, particular suitability for oral absorption and the like.

The prior preparation process of the methyl mercapto thiadiazole is to obtain ethyl acetate through hydrazine, addition and cyclization, and comprises the following specific steps: carrying out reflux reaction on hydrazine hydrate and ethyl acetate for 5 hours to obtain acethydrazide; adding acethydrazide into an ethanol solution of potassium hydroxide or ammonia gas, dropwise adding carbon disulfide at low temperature, reacting for 3h, filtering, and leaching to obtain potassium acethydrazide dithioformate or ammonium salt; adding the dried potassium salt or ammonium salt into low-temperature concentrated sulfuric acid for cyclization, adding the cyclization mother liquor into a large amount of ice water, separating out a crude product of the methylmercaptothiadiazole, and refining to obtain a finished product.

The most important defects of the reaction are that a large amount of concentrated sulfuric acid is used in the cyclization reaction, a large amount of waste acid is generated, great pressure is generated on equipment and environment protection, and the relevant patents do not describe how the generated waste acid is treated, which is a great leak.

Disclosure of Invention

Aiming at the defects of the prior art, the invention aims to provide a preparation process of methylmercaptothiadiazole, which bypasses the traditional route of using a large amount of concentrated sulfuric acid, greatly reduces or even avoids the use of the concentrated sulfuric acid, is green and pollution-free, has simple process steps, greatly improves the cyclization reaction rate, improves the cyclization reaction conversion rate, saves time and energy, and is suitable for industrial production.

The preparation process of the methylmercaptothiadiazole comprises the following steps:

1. adding 1mol of hydrazine hydrate into a reaction bottle, dropwise adding carbon disulfide with the molar weight 1-1.05 times of that of the hydrazine hydrate at the temperature of 20-25 ℃, wherein the dropwise adding time is 2-3 hours, after the dropwise adding is finished, preserving the heat at the temperature of 20-25 ℃ for 1-2 hours, filtering to obtain hydrazino dithioformic acid (HDF), and performing vacuum drying on the HDF at the temperature of 55-75 ℃ for more than 3 hours to control the water content to be less than 0.1% to obtain white or light yellow crystalline powder;

2. controlling the temperature to be 25-30 ℃, adding dried HDF into a reaction bottle, adding 1-1.1mol of glacial acetic acid, dropwise adding an acid catalyst for 1-2h, heating to react for 3-5 h, cooling to 0-5 ℃, adjusting the pH of a 30% sodium hydroxide solution to 8-9, and filtering to obtain a crude product of the methylmercaptothiadiazole (MMTD);

3. adding the MMTD crude product into distilled water with the weight ratio of 5-7 times, heating and refluxing for 0.5-1 h, slowly cooling to 45-50 ℃, stirring for 1-2h, continuously cooling to 0-5 ℃, stirring for 0.5-1 h, filtering to obtain an MMTD wet product, vacuum drying for 2h at 55-60 ℃, heating to 70-75 ℃ for more than 2h, and controlling the water content to be less than 0.1% to obtain white crystalline powder.

In the step 1, the mass fraction of hydrazine hydrate is 80%.

In the step 1, the vacuum degree is 0.09-0.1 MPa.

In the step 2, the acid catalyst may be one of concentrated hydrochloric acid, concentrated sulfuric acid, and phosphorus oxychloride.

In the step 2, the amount of the acid catalyst is 1-1.5 times of the molar weight of hydrazine hydrate.

In the step 2, the temperature rise reaction temperature is 50-70 ℃.

In the step 3, the reflux temperature is 90-95 ℃.

In the step 3, the vacuum degree is 0.09-0.1 MPa.

Compared with the prior art, the invention has the following beneficial effects:

1. the raw materials are wide in source, the reaction condition is mild, the selectivity is high, the industrial production is easy, and the production advantage is achieved;

2. the operation steps are simple, various cheap and easily available raw materials are used, and the cost advantage is achieved;

3. the acid catalyst is used in the cyclization step, so that the selectivity is high, the yield can reach over 95 percent, and the selectivity advantage is achieved;

4. the process avoids a reaction system in which a large amount of concentrated sulfuric acid is used for cyclization in the traditional process, greatly reduces the use amount of the concentrated sulfuric acid, even can avoid the use of the concentrated sulfuric acid, further reduces and avoids the generation of waste acid, is a green synthesis route, and has the advantage of environmental protection.

In conclusion, the research has stronger innovation and practicability.

Detailed Description

The present invention will be further described with reference to the following examples.

Example 1

A preparation process of methylmercaptothiadiazole comprises the following steps:

(1) putting 62.5g of 80% hydrazine hydrate into a three-neck flask, controlling the reaction temperature to be 25 ℃, dropwise adding 80g of carbon disulfide for 2 hours, keeping the temperature at 25 ℃ for 1 hour, filtering, and vacuum drying HDF wet products at 55 ℃ for 4 hours to obtain white crystalline powder;

(2) controlling the temperature to be 30 ℃, adding dried HDF into a reaction bottle, adding 61.2g of glacial acetic acid, dropwise adding 122g of 36% concentrated hydrochloric acid for 2h, heating to 50 ℃, reacting for 3h, cooling to 0-5 ℃, adjusting the pH value to 8.5 by using 30% sodium hydroxide solution, and filtering to obtain a crude product of the methylmercaptothiadiazole (MMTD);

(3) adding the MMTD crude product into 750g of distilled water, heating to 90 ℃, refluxing for 1h, slowly cooling to 45 ℃, stirring for 1h, continuously cooling to 0-5 ℃, stirring for 1h, filtering to obtain an MMTD wet product, vacuum drying for 2h at 55 ℃, heating to 70 ℃ for 3h, controlling the water content to be less than 0.1%, and obtaining 125.8g of white crystalline powder, the yield is 95.3%, and the purity is 99.2%.

Example 2

(2) controlling the temperature to be 25 ℃, adding dried HDF into a reaction bottle, adding 61.2g of glacial acetic acid, dropwise adding 199g of phosphorus oxychloride for 2h, heating to 60 ℃, reacting for 3h, cooling to 0-5 ℃, adjusting the pH value to 8.5 by using 30% sodium hydroxide solution, and filtering to obtain a crude product of methylmercaptothiadiazole (MMTD);

(3) adding the MMTD crude product into 800g of distilled water, heating to 95 ℃, refluxing for 1h, slowly cooling to 45 ℃, stirring for 1h, continuously cooling to 0-5 ℃, stirring for 1h, filtering to obtain an MMTD wet product, vacuum drying for 2h at 55 ℃, heating to 70 ℃ for 3h, controlling the water content to be less than 0.1%, and obtaining 122.1g of white crystalline powder, wherein the yield is 92.5%, and the purity is 99.5%.

Example 3

(2) controlling the temperature to be 25 ℃, adding dried HDF into a reaction bottle, adding 61.2g of glacial acetic acid, dropwise adding 107.8g of 98% concentrated sulfuric acid, wherein the dropwise adding time is 1.5h, heating to 60 ℃, reacting for 3h, cooling to 0-5 ℃, adjusting the pH value to 8.5 by using 30% sodium hydroxide solution, and filtering to obtain a crude product of the methylmercaptothiadiazole (MMTD);

(3) adding the MMTD crude product into 800g of distilled water, heating to 95 ℃, refluxing for 1h, slowly cooling to 45 ℃, stirring for 1h, continuously cooling to 0-5 ℃, stirring for 1h, filtering to obtain an MMTD wet product, vacuum drying for 2h at 55 ℃, heating to 70 ℃ for 3h, controlling the water content to be less than 0.1%, and obtaining 123.4g of white crystalline powder, wherein the yield is 93.5%, and the purity is 99.3%.

The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims

1. A preparation process of methylmercaptothiadiazole is characterized by comprising the following steps:

1) adding hydrazine hydrate into a reaction container, dropwise adding carbon disulfide with the molar weight 1-1.05 times that of the hydrazine hydrate, preserving the heat at 20-25 ℃ for 1-2h, filtering to obtain hydrazino dithioformic acid (HDF), and drying the HDF in vacuum to control the water content of the HDF to be less than 0.1%;

2) controlling the temperature to be 25-30 ℃, adding dried HDF into a reaction bottle, adding glacial acetic acid with the molar weight 1-1.1 times that of hydrazine hydrate, dropwise adding an acid catalyst, heating for reaction, cooling to 0-5 ℃, adjusting the pH to 8-9, and filtering to obtain a crude product of methylmercaptothiadiazole (MMTD);

3) adding the MMTD crude product into distilled water in an amount which is 5-7 times the weight of the MMTD crude product, heating and refluxing, then slowly cooling to 45-50 ℃, stirring for 1-2 hours, continuously cooling to 0-5 ℃, stirring for 0.5-1 hour, filtering to obtain an MMTD wet product, and drying in vacuum to control the water content to be less than 0.1% to obtain white crystalline powder.

2. The method of claim 1, wherein: the mass fraction of the hydrazine hydrate is 80%.

3. The method of claim 1, wherein: the dripping time of the carbon disulfide is 2-3h, and the dripping temperature is 20-25 ℃.

4. The method of claim 1, wherein: the vacuum degree of the vacuum drying in the step 1) is 0.09-0.1MPa, the drying temperature is 55-75 ℃, and the drying time is more than 3 h.

5. The method of claim 1, wherein: the vacuum drying in the step 3) is specifically that the drying is carried out for more than 2 hours at the temperature of 55-60 ℃ and then for more than 2 hours at the temperature of 70-75 ℃ under the condition that the vacuum degree is 0.09-0.1MPa

The method of claim 1, wherein: the acid catalyst comprises more than one of concentrated hydrochloric acid, concentrated sulfuric acid and phosphorus oxychloride.

6. The method of claim 1, wherein: the molar weight of the acid catalyst is 1-1.5 times of that of hydrazine hydrate, and the dripping time of the acid catalyst is 1-2 h.

7. The method of claim 1, wherein: the temperature rise temperature of the step 2) and the step 3) is 50-70 ℃.

8. The method of claim 1, wherein: the reflux temperature is 90-95 ℃.

9. The method of claim 1, wherein: the pH adjusting solution was a 30% sodium hydroxide solution.