阅读说明：本技术 一种医药中间体氰胺基甲酸甲酯的生产方法 (Production method of medicine intermediate methyl cyanamide formate ) 是由 过学军 袁树林 金斐 丁锐 马军 于 2020-07-28 设计创作，主要内容包括：本发明涉及一种医药中间体氰胺基甲酸甲酯的生产方法,包括有以下步骤：配置乙醇的乙醇钠溶液,纳米γ-Al2O3研磨,加入乙醇钠溶液制备悬浮液；石灰氮水解并过滤,将悬浮液转入到酯化釜,加入碳酸甲乙酯和石灰氮滤液,反应后得到水解酯化液；用酸调pH后回收催化剂和溶剂,电渗析得到高纯度氰胺基甲酸甲酯；本发明将常规使用的氯甲酸甲酯替换为更加安全、更加环保的碳酸甲乙酯,不需要液氯和光气,石灰氮水解后先进行过滤,避免引入杂质,选用乙醇钠和纳米级γ-Al2O3作为催化剂,能够显著地提升反应速率,催化剂回收后可循环再利用,得到的氰胺基甲酸甲酯的纯度可达95％以上,收率可达90％以上,显著降低生产成本,提高经济效益。(The invention relates to a production method of a medical intermediate methyl cyanamide formate, which comprises the following steps: preparing a sodium ethoxide solution of ethanol, grinding the nano gamma-Al 2O3, and adding the sodium ethoxide solution to prepare a suspension; hydrolyzing and filtering lime nitrogen, transferring the suspension into an esterification kettle, adding methyl ethyl carbonate and lime nitrogen filtrate, and reacting to obtain hydrolyzed esterification liquid; adjusting pH with acid, recovering catalyst and solvent, and performing electrodialysis to obtain high-purity methyl cyanocarbamate; according to the invention, conventionally used methyl chloroformate is replaced by safer and more environment-friendly ethyl methyl carbonate, liquid chlorine and phosgene are not needed, lime nitrogen is firstly filtered after hydrolysis, impurities are avoided from being introduced, sodium ethoxide and nano-scale gamma-Al 2O3 are selected as catalysts, the reaction rate can be remarkably improved, the catalysts can be recycled after recovery, the purity of the obtained cyanamide methyl formate can reach more than 95%, the yield can reach more than 90%, the production cost is remarkably reduced, and the economic benefit is improved.)

1. A production method of a medical intermediate methyl cyanamide formate is characterized by comprising the following steps: the production method comprises the following steps:

1) dissolving metal sodium in ethanol to prepare a sodium ethoxide solution with ethanol with proper concentration, introducing nitrogen to remove the gas for 10-30 min, and refrigerating for later use;

grinding the nano-scale gamma-Al 2O3 into powder, adding the powder into a sodium ethoxide solution of ethanol, and uniformly mixing the materials at a stirring speed of 500-1000 r/min to prepare a suspension;

2) adding lime nitrogen into cold water at the temperature of 10-20 ℃ for hydrolysis, filtering the mixture after the hydrolysis is complete, heating the filtrate to the temperature of 80-90 ℃, filtering the filtrate while the filtrate is hot, and storing the filtrate at constant temperature;

3) firstly transferring the sodium ethoxide solution of ethanol into an esterification kettle, heating to 80-90 ℃, adding methyl ethyl carbonate into the esterification kettle, uniformly mixing the solution at a stirring speed of 500-1000 r/min, dropwise adding the filtrate obtained in the step 2 into the mixed solution, condensing and recovering the evaporated ethanol steam, and keeping the temperature at constant temperature for 2-5 hours to obtain hydrolysis esterification liquid;

4) dripping a pH regulator into the obtained hydrolysis esterification solution, uniformly mixing the solution at a stirring speed of 500-1000 r/min while adding, and after regulating the pH to 1-4, generating a methyl cyanamide formate mixed solution with a byproduct calcium salt;

5) pumping and filtering the mixed material, recovering gamma-Al 2O3, putting the filtrate on the filter cake again for pumping and filtering, repeatedly washing the filter cake with ethanol, and mixing the filtrate with the washed ethanol;

6) adding excessive deionized water into the filtered mixed solution, uniformly mixing the solution at a stirring speed of 500-1000 r/min while adding, standing and layering for 30-90 min, and separating out an organic phase solution;

7) transferring the organic phase solution into a rectifying kettle, heating to 80-85 ℃, evaporating and recovering ethanol in the solution, heating to 100-102 ℃ to evaporate water in the organic phase, keeping the high-boiling-point solution at the bottom of the kettle, and cooling to normal temperature;

8) cooling the rectified organic phase solution to 5-15 ℃, introducing the organic phase solution into a dilute chamber of an electrodialyzer, introducing ethanol into a dense chamber of the electrodialyzer, circulating the organic phase solution in the electrodialyzer respectively, and turning on and adjusting a direct-current power supply to enable the electrodialyzer to work; when the calcium ion content in the dilute esterification solution is reduced to 500-1500 ppm, the sodium ion content is reduced to 500-1500 ppm, and the aluminum ion content is reduced to 500-1000 ppm, the final high-purity methyl cyanamide formate is obtained.

2. The method for producing a pharmaceutical intermediate, methyl cyanamide formate, according to claim 1, wherein the method comprises the steps of: the mixing molar ratio of the sodium ethoxide to the ethanol in the step 1 of the production method is 1: 100-150.

3. The method for producing a pharmaceutical intermediate, methyl cyanamide formate, according to claim 1, wherein the method comprises the steps of: in the production method, the mixing molar ratio of sodium ethoxide to gamma-Al 2O3 in the step 1 is 2-5: 1.

4. The method for producing a pharmaceutical intermediate, methyl cyanamide formate, according to claim 1, wherein the method comprises the steps of: the mixing molar ratio of the lime nitrogen to the cold water in the step 2 of the production method is 1: 10-20.

5. The method for producing a pharmaceutical intermediate, methyl cyanamide formate, according to claim 1, wherein the method comprises the steps of: the mixing molar ratio of the lime nitrogen and the ethanol in the step 2 of the production method is 2-3: 6-10.

6. The method for producing a pharmaceutical intermediate, methyl cyanamide formate, according to claim 1, wherein the method comprises the steps of: the mixing molar ratio of the methyl ethyl carbonate to the lime nitrogen in the production method step 3 is 1: 1-1.15.

7. The method for producing a pharmaceutical intermediate, methyl cyanamide formate, according to claim 1, wherein the method comprises the steps of: the pH regulator in step 4 of the production method is one or a mixture of more of dilute hydrochloric acid, dilute sulfuric acid and dilute nitric acid.

Technical Field

The invention relates to the technical field of drug synthesis, in particular to a production method of a medical intermediate methyl cyanamide formate.

Background

Methyl cyanamide formate is an intermediate for producing bactericide carbendazim. The present post-filtering process is obtained through lime nitrogen hydrolysis, amination of methyl chloroformate and filtering. The method has high consumption of methyl chloroformate, and the raw materials of liquid chlorine and methanol needed for synthesizing the methyl chloroformate are relatively tense, thereby bringing certain difficulty to the production of carbendazim.

In addition, the methyl cyanocarbamate is colorless or has a little light blue aqueous solution, is alkalescent and has odor, and is also an important intermediate for synthesizing the carbendazim.

Disclosure of Invention

The invention aims to provide a method for producing a pharmaceutical intermediate methyl cyanamide formate, which aims to replace methyl chloroformate, further reduce the use of liquid chlorine and phosgene, avoid environmental pollution and improve the safety of reaction.

The invention is realized by the following technical scheme:

a production method of a medical intermediate methyl cyanamide formate comprises the following steps:

1) dissolving metal sodium in ethanol to prepare a sodium ethoxide solution with ethanol with proper concentration, introducing nitrogen to remove the gas for 10-30 min, and refrigerating for later use;

grinding the nano-scale gamma-Al 2O3 into powder, adding the powder into a sodium ethoxide solution of ethanol, and uniformly mixing the materials at a stirring speed of 500-1000 r/min to prepare a suspension;

2) adding lime nitrogen into cold water at the temperature of 10-20 ℃ for hydrolysis, filtering the mixture after the hydrolysis is complete, heating the filtrate to the temperature of 80-90 ℃, filtering the filtrate while the filtrate is hot, and storing the filtrate at constant temperature;

3) firstly transferring the sodium ethoxide solution of ethanol into an esterification kettle, heating to 80-90 ℃, adding methyl ethyl carbonate into the esterification kettle, uniformly mixing the solution at a stirring speed of 500-1000 r/min, dropwise adding the filtrate obtained in the step 2 into the mixed solution, condensing and recovering the evaporated ethanol steam, and keeping the temperature at constant temperature for 2-5 hours to obtain hydrolysis esterification liquid;

4) dripping a pH regulator into the obtained hydrolysis esterification solution, uniformly mixing the solution at a stirring speed of 500-1000 r/min while adding, and after regulating the pH to 1-4, generating a methyl cyanamide formate mixed solution with a byproduct calcium salt;

5) pumping and filtering the mixed material, recovering gamma-Al 2O3, putting the filtrate on the filter cake again for pumping and filtering, repeatedly washing the filter cake with ethanol, and mixing the filtrate with the washed ethanol;

6) adding excessive deionized water into the filtered mixed solution, uniformly mixing the solution at a stirring speed of 500-1000 r/min while adding, standing and layering for 30-90 min, and separating out an organic phase solution;

7) transferring the organic phase solution into a rectifying kettle, heating to 80-85 ℃, evaporating and recovering ethanol in the solution, heating to 100-102 ℃ to evaporate water in the organic phase, keeping the high-boiling-point solution at the bottom of the kettle, and cooling to normal temperature;

8) cooling the rectified organic phase solution to 5-15 ℃, introducing the organic phase solution into a dilute chamber of an electrodialyzer, introducing ethanol into a dense chamber of the electrodialyzer, circulating the organic phase solution in the electrodialyzer respectively, and turning on and adjusting a direct-current power supply to enable the electrodialyzer to work; when the calcium ion content in the dilute esterification solution is reduced to 500-1500 ppm, the sodium ion content is reduced to 500-1500 ppm, and the aluminum ion content is reduced to 500-1000 ppm, the final high-purity methyl cyanamide formate is obtained.

As a preferable technical scheme, the mixing molar ratio of the sodium ethoxide and the ethanol in the step 1 of the production method is 1: 100-150.

As a preferable technical scheme, the mixing molar ratio of the sodium ethoxide to the gamma-Al 2O3 in the step 1 of the production method is 2-5: 1.

According to the preferable technical scheme, the mixing molar ratio of the lime nitrogen and the cold water in the step 2 of the production method is 1: 10-20.

According to the preferable technical scheme, the mixing molar ratio of the lime nitrogen to the ethanol in the step 2 of the production method is 2-3: 6-10.

As a preferable technical scheme, the mixing molar ratio of the methyl ethyl carbonate and the lime nitrogen in the step 3 of the production method is 1: 1-1.15.

As a preferable technical scheme, the pH regulator in the step 4 of the production method is one or a mixture of more of dilute hydrochloric acid, dilute sulfuric acid and dilute nitric acid.

The invention has the beneficial effects that: according to the method for producing the cyanamide methyl formate, the conventionally used methyl chloroformate is replaced by safer and more environment-friendly ethyl methyl carbonate, a large amount of liquid chlorine and phosgene are not required to be consumed in the whole process, the lime nitrogen is hydrolyzed and then filtered, impurities are prevented from being introduced, sodium ethoxide and nano-scale gamma-Al 2O3 powder are selected as double catalysts, the reaction rate can be remarkably improved, the catalysts are easy to recover and can be recycled, the purity of the finally obtained cyanamide methyl formate can reach more than 95%, the yield can reach more than 90%, the production cost can be remarkably reduced, the economic benefit is improved, and the method is environment-friendly, safe, economical and practical.

Detailed Description

The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the technical solutions in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.