CN114380770B - Synthesis process of methyl mercapto thiadiazole catalyzed by solid superacid - Google Patents
Synthesis process of methyl mercapto thiadiazole catalyzed by solid superacid Download PDFInfo
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Abstract
The invention relates to the technical field of organic synthesis, in particular to a synthesis process of methylmercapto thiadiazole catalyzed by solid superacid. The synthesis process of the methylmercaptothiadiazole catalyzed by the solid superacid comprises the steps of taking an intermediate N-acetylhydrazino ammonium dithioformate as a raw material, taking the solid superacid and sulfuric acid as catalysts, and adding ammonium salt to react to obtain the methylmercaptothiadiazole. The invention has scientific and reasonable design, improves the cyclization reaction rate, has high selectivity, reduces the generation of waste acid, and is energy-saving and environment-friendly.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a synthesis process of methylmercapto thiadiazole catalyzed by solid superacid.
Background
The drugs such as cefazolin, cefkaempferia, cefazedone, azolin cephalosporin, cefprozil, cephalosporin BL-S339, furbenconazole cephalosporin and the like have the characteristics of broad antibacterial spectrum, good absorption and small side effect, and are particularly suitable for oral absorption, so the drugs are widely used clinically. Methylmercaptothiadiazoles are important intermediates for such pharmaceuticals.
At present, the preparation process of the methyl mercapto thiadiazole involves a cyclization step, concentrated sulfuric acid is mainly used as a catalyst, a large amount of waste acid is generated in the reaction process, great pressure is formed on equipment and environmental protection, and how to reduce the concentrated sulfuric acid and even avoid the use of the concentrated sulfuric acid is an important problem to be solved urgently in the process at present. Although catalytic esterification, cyclization and other reactions of solid super acid instead of concentrated sulfuric acid are also reported, the solid super acid is often unstable and has lower activity density than concentrated sulfuric acid, so that the industrial application of the solid super acid is limited due to the defects.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: the method overcomes the defects of the prior art, provides a synthesis process of methylmercaptothiadiazole by utilizing solid superacid catalysis, has scientific and reasonable design, improves the cyclization reaction rate, has high selectivity, reduces the generation of waste acid, and is energy-saving and environment-friendly.
The synthesis process of the methylmercaptothiadiazole catalyzed by the solid superacid comprises the steps of taking an intermediate N-acetylhydrazino ammonium dithioformate as a raw material, taking the solid superacid and sulfuric acid as catalysts, and adding ammonium salt to react to obtain the methylmercaptothiadiazole.
The synthesis process of the intermediate ammonium N-acetylhydrazinodithioformate is any one of the following processes:
(1) Hydrazine hydrate and ammonia water are used as raw materials, carbon disulfide is added to react to obtain hydrazino dithioammonium formate, and then ethyl acetate is added to react to obtain the N-acetylhydrazino dithioammonium formate;
(2) Hydrazine hydrate and ethyl acetate are used as raw materials to react to obtain acethydrazide, then carbon disulfide is added to react to obtain the N-acethydrazide ammonium dithioformate.
The solid super acid is SO 4 2- MxOy, mxOy preferably being ZrO 2 、TiO 2 、Fe 3 O 4 Or Al 2 O 3 One or two of them.
The mass fraction of the sulfuric acid is 10-98%.
Preferably, the addition amount of the solid super acid is 1-80% of the mass of the hydrazine hydrate, and the addition amount of the sulfuric acid is 0.1-1.1 times of the molar amount of the hydrazine hydrate.
Specifically, the invention comprises the following two process routes:
the first route comprises the following steps:
(1) Adding 1mol of hydrazine hydrate (the mass fraction of the hydrazine hydrate is 80%) and ammonia water containing 1-1.05mol of ammonia and having the mass concentration of 18-25% into a reaction bottle, dropwise adding carbon disulfide with the molar quantity 1-1.05 times that of the hydrazine hydrate at 10-15 ℃, wherein the dropwise adding time is 2-3h, after the dropwise adding is finished, preserving the temperature at 10-15 ℃ for 1-2h, and filtering to obtain hydrazinodithioammonium formate;
(2) Controlling the temperature to be 25-30 ℃, dropwise adding ethyl acetate with the molar weight 1-1.1 times of that of hydrazine hydrate, and heating and carrying out reflux reaction for 2-8h;
(3) Cooling to 0 ℃, discharging, filtering, and spin-drying to obtain the N-acethydrazide ammonium dithioformate;
(4) Cooling the reaction kettle to 0-5 ℃, adding solid superacid and sulfuric acid, controlling the temperature at 15-17 ℃, uniformly scattering the N-acetylhydrazino ammonium dithioformate obtained by the reaction into the reaction kettle, continuing the reaction for 2 hours after the ammonia salt is added to obtain viscous white cyclization liquid, adjusting the pH value to 8-9 after the reaction is finished, filtering the solid superacid for recycling, further adjusting the pH value to 1-2, and filtering to obtain a crude product of the methylmercaptothiadiazole (MMTD).
Refining the crude product, wherein the refining process comprises the following steps:
(1) Adding 50mL of primary water to the alkali dissolution kettle, adding 30mL of liquid alkali (30%; wt%), and adding about 130g;
(2) Adjusting pH =14 with liquid caustic soda, stirring for 10 min, measuring pH more than 13, stirring for 1h, observing the phenomenon in the kettle, and ensuring that no insoluble substances and foams exist in the feed liquid;
(3) Adding 2g of active carbon, and decoloring for 1 hour; centrifuging, drying, and removing the active carbon.
(4) Slowly adding sulfuric acid into the solution, wherein the adding speed of the sulfuric acid is required to be controlled, and the adding is finished in 20 minutes. Adding amount L = adding amount L of alkali 0.3; after the acid is added, stirring for 30 minutes, re-measuring the pH value, and if the pH value is more than 1, adding sulfuric acid until the pH value is =1;
(5) And when the temperature of the reaction kettle is reduced to 15 ℃, starting centrifugation, not rinsing with water, centrifuging for 15-20 minutes, and reducing the speed and discharging to obtain a white MMTD refined product.
The second route comprises the following steps:
(1) Adding ethyl acetate and hydrazine hydrate into a closed reaction kettle, starting stirring, slowly heating to 100 ℃ within 1 hour after the temperature is constant, keeping the temperature for 2 hours, and cooling to obtain a viscous acethydrazide solution;
(2) Under the condition of stirring, when the temperature of the acethydrazide solution is reduced to 10 ℃, liquid ammonia is added, the liquid ammonia is required to be added for 30min, the temperature is continuously reduced to-10 ℃, and CS is added dropwise 2 When the reaction temperature is raised to 25 ℃, the reaction temperature is maintained at 25-35 DEG CWhen light yellow ammonium salt crystals are precipitated, the dripping speed is reduced, the reaction is continued for 1 hour after the dripping is finished, the temperature is reduced to 0 ℃, and the N-acetylhydrazino ammonium dithioformate is obtained by discharging, filtering and spin-drying;
(3) Cooling the reaction kettle to 0-5 ℃, adding solid superacid and sulfuric acid, controlling the temperature at 15-17 ℃, uniformly scattering the N-acetylhydrazino ammonium dithioformate obtained by the reaction into the reaction kettle, after the ammonia salt is added, continuing the reaction for 2 hours to obtain viscous white cyclization liquid, adjusting the pH value to 8-9 after the reaction is finished, filtering the solid superacid for retreatment, recycling, further adjusting the pH value to 1-2, and filtering to obtain the MMTD crude product.
The crude product is refined according to the refining process provided in the first route.
The invention adopts the synergistic effect of the solid super acid and the sulfuric acid, reduces the dosage of the sulfuric acid, improves the activity and the stability of the solid super acid, and can greatly improve the reaction efficiency. The solid super acid mainly adopts metal oxide loaded sulfate radicals, sulfate radicals are easy to fall off in the using process to cause acid loss, but the loss of the sulfate radicals can be prevented through the compounding of the solid super acid and sulfuric acid, and the stability of the solid acid is improved; meanwhile, if the sulfuric acid is used as a catalyst, water is generated in the reaction process, and the concentration of the sulfuric acid is reduced, so that the reaction efficiency is influenced. The presence of sulfuric acid can thus increase the stability of the solid acid and the catalytic efficiency through the equilibrium of the adsorption of sulfate ions on the solid acid surface and in the solution. In addition, the solid super acid can be recycled, and the process cost is low.
Compared with the prior art, the invention has the following beneficial effects:
(1) The solid super acid and the sulfuric acid catalyst are used in the cyclization step, and the solid super acid and the sulfuric acid have a synergistic catalytic action, so that the cyclization reaction rate can be greatly improved, the selectivity is high, the yield can reach over 90 percent, and the selectivity advantage is achieved;
(2) The invention avoids the reaction system of the traditional process which uses a large amount of concentrated sulfuric acid for cyclization, greatly reduces the using amount of the concentrated sulfuric acid, and reduces the generation of waste acid, thereby being a green synthetic route and having the advantage of environmental protection;
(3) The solid super acid can be recycled, has low cost, simple operation steps, time and energy conservation, and is suitable for industrial production.
Detailed Description
The present invention is further illustrated by the following examples.
Example 1
The synthesis of the methylmercaptothiadiazole catalyzed by the synergy of the solid superacid and the sulfuric acid comprises the following steps:
(1) Putting 80% hydrazine hydrate containing 1mol of hydrazine hydrate and 18% ammonia water containing 1.05mol of ammonia and having mass concentration of 18% into a three-neck flask, controlling the reaction temperature to be 12 +/-2 ℃, dropwise adding 1.05mol of carbon disulfide for 2 hours, heating to 25 ℃, preserving heat for 1 hour, filtering to obtain hydrazino ammonium dithioformate, and vacuum drying for 4 hours at 55 ℃ to obtain white crystalline powder;
(2) Controlling the temperature to be 28 +/-2 ℃, dropwise adding ethyl acetate with the molar weight of 1.10mol, and heating for reflux reaction for 6 hours;
(3) Cooling to 0 ℃, discharging, carrying out suction filtration and spin-drying to obtain N-acethydrazide ammonium dithioformate, and carrying out vacuum drying for 4 hours at 55 ℃ to obtain white crystalline powder;
(4) The temperature of the reaction kettle is reduced to 0 ℃, and 30.0g of solid super acidic SO is added 4 2- /ZrO 2 30.0g of concentrated sulfuric acid with the mass fraction of 98 percent, controlling the temperature at 16 +/-1 ℃, uniformly scattering the N-acetylhydrazino ammonium dithioformate obtained by the reaction into a reaction kettle, after the ammonia salt is added, continuing the reaction for 2 hours to obtain viscous white cyclization liquid, adjusting the pH value to 8 after the reaction is finished, filtering the solid super acid, drying the solid super acid in vacuum at 55 ℃ for 4 hours, wherein the mass of the recovered solid super acid is 28.8g, and the recovery rate is 96%;
(5) Further adjusting the pH value of the solution to 1, and filtering to obtain a crude MMTD product;
(6) The crude product was refined according to the refining procedure mentioned in the summary of the invention to obtain 125.3g of MMTD white powder with a yield of 94.8% based on hydrazine hydrate and a purity of 99.4%.
Example 2
The synthesis of the methyl mercapto thiadiazole catalyzed by the recovered solid superacid and the sulfuric acid is carried out according to the following steps:
(1) Putting 80% hydrazine hydrate containing 1mol of hydrazine hydrate and 25% ammonia water containing 1.05mol of ammonia by mass concentration into a three-neck flask, controlling the reaction temperature to be 12 +/-2 ℃, dropwise adding 1.05mol of carbon disulfide for 2 hours, heating to 25 ℃, preserving heat for 1 hour, filtering to obtain hydrazino ammonium dithioformate, and performing vacuum drying for 4 hours at 55 ℃ to obtain white crystalline powder;
(2) Controlling the temperature to be 27 +/-2 ℃, dropwise adding ethyl acetate with the molar weight of 1.10mol, and heating and carrying out reflux reaction for 6 hours;
(3) Cooling to 0 ℃, discharging, carrying out suction filtration and spin-drying to obtain N-acethydrazide ammonium dithioformate, and carrying out vacuum drying for 4 hours at 55 ℃ to obtain white crystalline powder;
(4) The reaction kettle was cooled to 5 ℃ and 28.8g of solid super acidic SO recovered in example 1 was added 4 2- /ZrO 2 30.0g of concentrated sulfuric acid with the mass fraction of 98 percent is added, the temperature is controlled to be 16 +/-1 ℃, the N-acetylhydrazino ammonium dithioformate obtained by the reaction is uniformly scattered into a reaction kettle, the reaction is continued for 2 hours after the ammonia salt is added, a sticky white cyclization solution is obtained, the pH value is adjusted to 9 after the reaction is finished, the solid super acid is filtered, the solid super acid is dried for 4 hours in vacuum at the temperature of 55 ℃, the mass of the recovered solid super acid is 27.1g, and the recovery rate is 94 percent;
(5) Further adjusting the pH value of the solution to 2, and filtering to obtain a crude MMTD product;
(6) The crude product was refined according to the refining procedure mentioned in the summary of the invention to obtain 124.3g of MMTD white powder with a yield of 94.0% based on hydrazine hydrate and a purity of 99.3%.
Comparative example 1
The synthesis of the methyl mercapto thiadiazole catalyzed by concentrated sulfuric acid comprises the following steps:
(1) Putting 80% hydrazine hydrate containing 1mol of hydrazine hydrate and 18-25% ammonia water containing 1.05mol of ammonia by mass concentration into a three-neck flask, controlling the reaction temperature to be 12 +/-2 ℃, dropwise adding 1.05mol of carbon disulfide for 2 hours, heating to 25 ℃, preserving heat for 1 hour, filtering to obtain hydrazino ammonium dithioformate, and carrying out vacuum drying for 4 hours at 55 ℃ to obtain white crystalline powder;
(2) Controlling the temperature to be 28 +/-2 ℃, dropwise adding ethyl acetate with the molar weight of 1.10mol, and heating up and carrying out reflux reaction for 6 hours;
(3) Cooling to 0 ℃, discharging, carrying out suction filtration and spin-drying to obtain N-acetylhydrazino ammonium dithioformate, and carrying out vacuum drying for 4h at 55 ℃ to obtain white crystalline powder;
(4) Cooling the reaction kettle to 0 ℃, adding 30g of sulfuric acid with the mass fraction of 98%, controlling the temperature to be 16 +/-1 ℃, uniformly scattering the N-acetylhydrazino ammonium dithioformate obtained by the reaction into the reaction kettle, and after the ammonia salt is added, continuing the reaction for 2 hours to obtain a viscous white cyclization liquid;
(5) Further adjusting the pH value of the solution to 1, and filtering to obtain a crude MMTD product;
(6) The crude product was refined according to the refining procedure mentioned in the summary of the invention to give 118.7g of MMTD white powder with a yield of 89.8% based on hydrazine hydrate and a purity of 99.2%.
Comparative example 2
The synthesis of the solid superacid catalyzed methylmercaptothiadiazole comprises the following steps:
(1) Putting 80% hydrazine hydrate containing 1mol of hydrazine hydrate and 18-25% ammonia water containing 1.05mol of ammonia by mass concentration into a three-neck flask, controlling the reaction temperature to be 12 +/-2 ℃, dropwise adding 1.05mol of carbon disulfide for 2 hours, heating to 25 ℃, preserving heat for 1 hour, filtering to obtain hydrazino ammonium dithioformate, and carrying out vacuum drying for 4 hours at 55 ℃ to obtain white crystalline powder;
(2) Controlling the temperature to be 28 +/-2 ℃, dropwise adding ethyl acetate with the molar weight of 1.10mol, and heating for reflux reaction for 6 hours;
(3) Cooling to 0 ℃, discharging, carrying out suction filtration and spin-drying to obtain N-acetylhydrazino ammonium dithioformate, and carrying out vacuum drying for 4h at 55 ℃ to obtain white crystalline powder;
(4) The temperature of the reaction kettle is reduced to 5 ℃, and 30.0g of solid super acidic SO is added 4 2- /ZrO 2 Uniformly scattering the N-acetylhydrazino ammonium dithioformate obtained by the reaction into a reaction kettle at the temperature of 16 +/-1 ℃, and continuing the reaction for 2 hours after the ammonia salt is added to obtain the ammonium dithioformateAdjusting the pH value to 9 after the reaction is finished, filtering the solid super acid, and carrying out vacuum drying at 55 ℃ for 4h to obtain the recovered solid super acid with the mass of 28.5g and the recovery rate of 95%;
(5) Further adjusting the pH value of the solution to 1, and filtering to obtain a crude MMTD product;
(6) The crude product was refined according to the refining procedure mentioned in the summary of the invention to give 120.0g of MMTD white powder with a yield of 90.8% based on hydrazine hydrate and a purity of 99.3%.
Example 3
The synthesis of the methylmercaptothiadiazole by the concerted catalysis of the recovered solid superacid and sulfuric acid comprises the following steps:
(1) Putting 80% hydrazine hydrate containing 1mol of hydrazine hydrate and 18-25% ammonia water containing 1.05mol of ammonia by mass concentration into a three-neck flask, controlling the reaction temperature to be 12 +/-2 ℃, dropwise adding 1.05mol of carbon disulfide for 2 hours, heating to 25 ℃, preserving heat for 1 hour, filtering to obtain hydrazino ammonium dithioformate, and carrying out vacuum drying for 4 hours at 55 ℃ to obtain white crystalline powder;
(2) Controlling the temperature to be 28 +/-2 ℃, dropwise adding ethyl acetate with the molar weight of 1.10mol, and heating up and carrying out reflux reaction for 6 hours.
(3) And (3) cooling to 0 ℃, discharging, carrying out suction filtration and spin-drying to obtain the N-acethydrazide ammonium dithioate, and carrying out vacuum drying for 4 hours at the temperature of 55 ℃ to obtain white crystalline powder.
(4) The reaction kettle was cooled to 5 ℃ and 28.5g of the solid superacid SO recovered in example 4 was added 4 2- /ZrO 2 And 30.0g of concentrated sulfuric acid with the mass fraction of 98%, controlling the temperature at 16 +/-1 ℃, uniformly scattering the N-acetylhydrazino ammonium dithioformate obtained by the reaction into a reaction kettle, after the ammonia salt is added, continuing the reaction for 2 hours to obtain a viscous white cyclization liquid, adjusting the pH value to 8 after the reaction is finished, filtering the solid superacid, and drying the solid superacid in vacuum at 55 ℃ for 4 hours, wherein the mass of the recovered solid superacid is 27.1g, and the recovery rate is 95%.
(5) Further adjusting the pH value of the solution to 2, and filtering to obtain a crude MMTD product.
(6) The crude product was refined according to the refining procedure mentioned in the summary of the invention to yield 121.6g of MMTD white powder with a yield of 92.0% based on hydrazine hydrate and a purity of 99.2%.
As can be seen from the above experimental results of examples 1-3 and comparative examples 1-2, the synergistic effect of the solid super acid and sulfuric acid greatly improves the yield of the cyclization reaction, and the stability of the solid super acid is enhanced in the presence of sulfuric acid, and the yield can still reach 94.0% after being recovered once. But only after the solid super acid is reacted once, the yield is still reduced even if sulfuric acid is added for recycling.
Example 4
The synthesis of the methylmercaptothiadiazole catalyzed by the synergy of the solid superacid and the sulfuric acid comprises the following steps:
(1) Adding 1mol of hydrazine hydrate and 1mol of ethyl acetate into a closed reaction kettle, starting stirring, slowly heating to 100 ℃ within 1 hour after the temperature is constant, keeping the temperature for 2 hours, and cooling to obtain a viscous acethydrazide solution;
(2) Under the condition of stirring, when the temperature of an acethydrazide solution is reduced to 10 ℃, adding 1.05mol of liquid ammonia, finishing adding within 30min, continuously reducing the temperature to-10 ℃, dropwise adding 1.05mol of carbon disulfide, when the reaction temperature is increased to 25 ℃, keeping the reaction temperature between 30 +/-5 ℃, slowing down the dropwise adding speed after precipitating light yellow ammonium salt and crystallizing, continuously reacting for 1h after dropwise adding, cooling to 0 ℃, discharging, filtering and spin-drying to obtain the N-acethydrazide ammonium dithiocarbamate;
(3) The temperature of the reaction kettle is reduced to 5 ℃, and 30.0g of solid super acidic SO is added 4 2- /ZrO 2 30.0g \ sulfuric acid with the mass fraction of 98 percent, controlling the temperature at 16 +/-1 ℃, uniformly scattering the N-acetylhydrazino ammonium dithioformate obtained by the reaction into a reaction kettle, after the ammonia salt is added, continuing the reaction for 2 hours to obtain viscous white cyclization liquid, adjusting the pH value to 8 after the reaction is finished, filtering the solid super acid, drying in vacuum at 55 ℃ for 4 hours, wherein the mass of the recovered solid super acid is 28.8g, and the recovery rate is 96%;
(4) Further adjusting the pH value of the solution to 1, and filtering to obtain a crude MMTD product;
(5) The crude product was refined according to the refining procedure mentioned in the summary of the invention to obtain MMTD white powder 125.6g, yield 95.0% based on hydrazine hydrate and purity 99.3%.
Example 5
The synthesis of the methyl mercapto thiadiazole catalyzed by the recovered solid superacid and the sulfuric acid is carried out according to the following steps:
(1) Adding 1mol of hydrazine hydrate and 1mol of ethyl acetate into a closed reaction kettle, starting stirring, slowly heating to 100 ℃ within 1 hour after the temperature is constant, keeping the temperature for 2 hours, and cooling to obtain a viscous acethydrazide solution;
(2) Under the condition of stirring, when the temperature of the acethydrazide solution is reduced to 10 ℃, 1.05mol of liquid ammonia is added, the addition is required to be completed within 30min, the temperature is continuously reduced to-10 ℃, 1.05mol of carbon disulfide is added dropwise, when the reaction temperature is increased to 25 ℃, the reaction temperature is kept between 30 +/-5 ℃, the dropping speed is slowed down after light yellow ammonium salt is precipitated and crystallized, the reaction is continued for 1h after the dropping is completed, and after the temperature is reduced to 0 ℃, the N-acethydrazide-based ammonium dithiocarbamate is obtained by discharging, pumping filtration and spin-drying;
(3) The reaction kettle was cooled to 5 ℃ and 28.8g of solid super acidic SO recovered in example 4 was added 4 2- /ZrO 2 30.0g of sulfuric acid with the mass fraction of 98 percent, controlling the temperature at 16 +/-1 ℃, uniformly scattering the N-acetylhydrazino ammonium dithioformate obtained by the reaction into a reaction kettle, after the ammonia salt is added, continuing the reaction for 2 hours to obtain viscous white cyclization liquid, adjusting the pH value to 8 after the reaction is finished, filtering the solid super acid, and drying the solid super acid in vacuum at 55 ℃ for 4 hours, wherein the mass of the recovered solid super acid is 27.4g, and the recovery rate is 95%;
(4) Further adjusting the pH value of the solution to 1, and filtering to obtain a crude MMTD product;
(5) The crude product was refined according to the refining procedure mentioned in the summary of the invention to give 124.7g of MMTD white powder with a yield of 94.3% based on hydrazine hydrate and a purity of 99.3%.
Comparative example 3
The synthesis of the methyl mercapto thiadiazole catalyzed by sulfuric acid is carried out according to the following steps:
(1) Adding 1mol of hydrazine hydrate and 1mol of ethyl acetate into a closed reaction kettle, starting stirring, slowly heating to 100 ℃ within 1 hour after the temperature is constant, keeping the temperature for 2 hours, and cooling to obtain a viscous acethydrazide solution;
(2) Under the condition of stirring, when the temperature of the acethydrazide solution is reduced to 10 ℃, 1.05mol of liquid ammonia is added, the addition is required to be completed within 30min, the temperature is continuously reduced to-10 ℃, 1.05mol of carbon disulfide is added dropwise, when the reaction temperature is increased to 25 ℃, the reaction temperature is kept at 30 +/-5 ℃, the dropping speed is reduced after light yellow ammonium salt is precipitated and crystallized, the reaction is continuously carried out for 1h after the dropping is completed, and after the temperature is reduced to 0 ℃, the N-acethydrazide-based ammonium dithiocarbamate is obtained by discharging, pumping filtration and spin-drying;
(3) Cooling the reaction kettle to 5 ℃, adding 300g of concentrated sulfuric acid with the mass fraction of 98%, controlling the temperature at 16 +/-1 ℃, uniformly scattering the N-acetylhydrazino ammonium dithioformate obtained by the reaction into the reaction kettle, and after the ammonia salt is added, continuing the reaction for 2 hours to obtain a viscous white cyclization liquid;
(4) Further adjusting the pH value of the solution to 1, and filtering to obtain a crude MMTD product;
(5) The crude product was refined according to the refining procedure mentioned in the summary of the invention to obtain 119.0g of MMTD white powder with a yield of 90% based on hydrazine hydrate and a purity of 99.1%.
Comparative example 4
The synthesis of the solid superacid catalyzed methylmercaptothiadiazole comprises the following steps:
(1) Adding 1mol of hydrazine hydrate and 1mol of ethyl acetate into a closed reaction kettle, starting stirring, slowly heating to 100 ℃ within 1 hour after the temperature is constant, keeping the temperature for 2 hours, and cooling to obtain a viscous acethydrazide solution;
(2) Under the condition of stirring, when the temperature of an acethydrazide solution is reduced to 10 ℃, adding 1.05mol of liquid ammonia, finishing adding within 30min, continuously reducing the temperature to-10 ℃, dropwise adding 1.05mol of carbon disulfide, when the reaction temperature is increased to 25 ℃, keeping the reaction temperature between 30 +/-5 ℃, slowing down the dropwise adding speed after precipitating light yellow ammonium salt and crystallizing, continuously reacting for 1h after dropwise adding, cooling to 0 ℃, discharging, filtering and spin-drying to obtain the N-acethydrazide ammonium dithiocarbamate;
(3) The temperature of the reaction kettle is reduced to 0 ℃, and 30.0g of solid super acidic SO is added 4 2- /ZrO 2 Uniformly scattering the ammonium N-acetylhydrazinodithioformate obtained by the reaction at the temperature of 16 +/-1 DEG CPutting the mixture into a reaction kettle, after adding ammonia salt, continuing the reaction for 2 hours to obtain viscous white cyclization liquid, adjusting the pH value to 9 after the reaction is finished, filtering the solid super acid, and drying the solid super acid at 55 ℃ for 4 hours in vacuum, wherein the mass of the recovered solid super acid is 28.5g, and the recovery rate is 95%;
(4) Further adjusting the pH value of the solution to 1, and filtering to obtain a crude MMTD product;
(5) The crude product was refined according to the refining procedure mentioned in the summary of the invention to give 120.3g of MMTD white powder with a yield of 91.0% based on hydrazine hydrate and a purity of 99.3%.
Example 6
The synthesis of the methyl mercapto thiadiazole catalyzed by the recovered solid superacid and the sulfuric acid is carried out according to the following steps:
(1) Adding 1mol of hydrazine hydrate and 1mol of ethyl acetate into a closed reaction kettle, starting stirring, slowly heating to 100 ℃ within 1 hour after the temperature is constant, keeping the temperature for 2 hours, and cooling to obtain a viscous acethydrazide solution;
(2) Under the condition of stirring, when the temperature of an acethydrazide solution is reduced to 10 ℃, adding 1.05mol of liquid ammonia, finishing adding within 30min, continuously reducing the temperature to-10 ℃, dropwise adding 1.05mol of carbon disulfide, when the reaction temperature is increased to 25 ℃, keeping the reaction temperature between 30 +/-5 ℃, slowing down the dropwise adding speed after precipitating light yellow ammonium salt and crystallizing, continuously reacting for 1h after dropwise adding, cooling to 0 ℃, discharging, filtering and spin-drying to obtain the N-acethydrazide ammonium dithiocarbamate;
(3) The temperature of the reaction kettle is reduced to 0 to 5 ℃, and 28.5g of solid super acidic SO recovered in example 5 is added 4 2- /ZrO 2 30.0g of sulfuric acid with the mass fraction of 98 percent is added, the temperature is controlled to be 16 +/-1 ℃, the N-acetylhydrazino ammonium dithioformate obtained by the reaction is uniformly scattered into a reaction kettle, the reaction is continued for 2 hours after the ammonia salt is added, a sticky white cyclization solution is obtained, the pH value is adjusted to 8 after the reaction is finished, the solid super acid is filtered, the solid super acid is dried for 4 hours in vacuum at the temperature of 55 ℃, the mass of the recovered solid super acid is 27.1g, and the recovery rate is 95 percent;
(4) Further adjusting the pH value of the solution to 1, and filtering to obtain a crude MMTD product;
(5) The crude product was refined according to the refining procedure mentioned in the summary of the invention to yield 121.8g of MMTD white powder with a yield of 92.1% based on hydrazine hydrate and a purity of 99.2%.
The advantage of the synergy of the solid superacid with sulfuric acid can also be seen from the experimental results of examples 4 to 6 and comparative examples 3 to 4 above. Therefore, the research of promoting the synthesis of MMTD by utilizing the synergistic effect of the solid super acid and the sulfuric acid to catalyze the cyclization step has strong innovation and use value, can greatly reduce the cost and the use of the sulfuric acid, reduces the generation of wastewater in the reaction process, and is a green and practical reaction route.
The above description is of the preferred embodiment of the invention and should not be taken as limiting the scope of the embodiments of the invention. The present invention is not limited to the above examples, and equivalent changes and modifications made by those skilled in the art within the spirit and scope of the present invention should be construed as being included in the scope of the present invention.
Claims (2)
1. A synthesis process of methylmercaptothiadiazole catalyzed by solid superacid is characterized in that: taking an intermediate N-acetylhydrazino ammonium dithioformate as a raw material, taking solid superacid and sulfuric acid as catalysts, and adding ammonium salt to react to obtain the methylmercaptothiadiazole;
the synthesis process of the intermediate N-acetylhydrazino ammonium dithioformate is any one of the following processes:
(1) Hydrazine hydrate and ammonia water are used as raw materials, carbon disulfide is added to react to obtain hydrazino dithioammonium formate, and then ethyl acetate is added to react to obtain the N-acetylhydrazino dithioammonium formate;
(2) Hydrazine hydrate and ethyl acetate are used as raw materials to react to obtain acethydrazide, then carbon disulfide is added to react to obtain the N-acethydrazide ammonium dithioformate;
in the process (1), the molar ratio of hydrazine hydrate to ammonia water to carbon disulfide to ethyl acetate is 1:1.0-1.1:1-1.05:1-1.1;
in the process (1), the mass concentration of ammonia water is 18-25%; the solid superacid is SO4 2- /MxOy，MxOy is ZrO 2 、TiO 2 、Fe 3 O 4 Or Al 2 O 3 One or two of (a) and (b); the mass fraction of the sulfuric acid is 98 percent;
the adding amount of the solid superacid is 1 to 80 percent of the mass of the hydrazine hydrate, and the adding amount of the sulfuric acid is 0.1 to 1.1 times of the molar amount of the hydrazine hydrate.
2. The process for synthesizing methylmercaptothiadiazole using solid superacid as claimed in claim 1, wherein said process comprises the steps of: adding solid superacid and sulfuric acid at 0-5 ℃, controlling the temperature at 15-17 ℃, scattering the N-acetylhydrazino ammonium dithioformate into the reaction kettle, and continuing to react for 2-3h after the ammonium salt is added.
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| US3798229A (en) * | 1970-12-30 | 1974-03-19 | Fujisawa Pharmaceutical Co | Process for preparing 1,3,4-thiadiazole-2-thiol compounds |
| CN102219758B (en) * | 2011-08-01 | 2012-06-27 | 山东济宁裕鑫精细材料有限公司 | Synthesis method of 2-methyl-5-sulfydryl-1,3,4-thiadiazole |
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