A one-pot method for preparing methyl chloroformate and 2-amino-4,6-dimethoxypyrimidine

Abstract

The invention belongs to the technical field of organic chemical synthesis, and specifically relates to a synthetic method for preparing methyl chloroformate and 2-amino-4,6-dimethoxypyrimidine by a one-pot method, specifically comprising the following steps: S1, the preparation of methyl chloroformate and 1,3-dimethoxy-propanediimide dihydrochloride; S2, the preparation of 3-amino-3-methoxy-N-cyano-2-propanediimide; S3, the preparation of 2-amino-4,6-dimethoxypyrimidine. In the present invention, the preparation of methyl chloroformate is combined with the preparation of 2-amino-4,6-dimethoxypyrimidine by a one-pot method, and the hydrogen chloride generated in the preparation process of methyl chloroformate is directly used as a reactant in the preparation process of 1,3-dimethylpropanediimide dihydrochloride, so that the effective utilization of hydrogen chloride is achieved, and the production efficiency is improved, and the obtained methyl chloroformate and 2-amino-4,6-dimethoxypyrimidine have high yield and high purity.

Description

Technical Field

[0001] The invention belongs to the technical field of organic chemical synthesis, and specifically relates to a one-pot method for preparing methyl chloroformate and 2-amino-4,6-dimethoxypyrimidine. Background Art

[0002] There are many varieties of sulfonylurea herbicides, such as nicosulfuron, benzylsulfuron-methyl, pyrazosulfuron-methyl, cyprosulfuron-methyl, pyrimidosulfuron-methyl, rimidosulfuron-methyl, mesosulfuron-methyl, etc. This type of herbicide is a broad-spectrum and highly effective field herbicide for corn, rice, soybean, etc. It has the characteristics of wide application range, high activity, low drug residue, low dosage, no volatility and low toxicity. Therefore, it is recognized as a highly effective and environmentally friendly green pesticide in the world. my country is a major producer and user of sulfonylurea herbicides, and has broad market prospects.

[0003] 2-amino-4,6-dimethoxypyrimidine is an important intermediate in the synthesis of sulfonylurea herbicides, commonly known as dimethoxypyrimidine or pyrimidineamine, and its English name is 2-amino-4,6-dimethoxypyrimidine (abbreviated as ADMP or ADM). There are currently two industrialized synthetic routes for 2-amino-4,6-dimethoxypyrimidine:

[0004] Method 1: Guanidine nitrate is reacted with diethyl malonate to obtain 2-amino-4,6-dihydroxypyrimidine, which is then reacted with sodium methoxide and phosphorus oxychloride to generate 2-amino-4,6-dichloropyrimidine, which is then reacted with a methanol solution containing sodium methoxide to obtain 2-amino-4,6-dimethoxypyrimidine. This process route uses a large amount of phosphorus oxychloride as a chlorination agent, produces a large amount of phosphorus-containing solid waste and wastewater, and brings serious environmental problems.

[0005] Method 2: 1,3-dimethylmalonamidine dihydrochloride is obtained by reacting malononitrile with methanol and hydrogen chloride, and then reacting with alkali and monocyanamide to obtain 3-amino-3-methoxy-N-nitrile-2-propionamidine, which is then subjected to thermal cyclization to obtain ADM. The process for preparing 2-amino-4,6-dimethoxypyrimidine using malononitrile as the main raw material has the advantages of cheap and easy raw materials, simple route, relatively mild reaction conditions in each step, and high purity of the obtained product. In the synthesis of 2-amino-4,6-dimethoxypyrimidine, the optimal reaction temperature is 60-65°C, the reaction time is 4-5 h, the yield is 90.2%, the total yield is 80.9%, and the product content is greater than 99.0%. However, this method requires the preparation of anhydrous hydrogen chloride, and in order to ensure the dryness of anhydrous hydrogen chloride, complex drying equipment is required, which not only increases the investment cost of the equipment, but also has high operating costs. If the quality of the prepared anhydrous hydrogen chloride is poor, such as containing water or other impurities, this will directly affect the yield and purity of the product. In addition, in the step of reacting malononitrile with hydrogen chloride and methanol, methanol is often used in excess, and the excess methanol cannot be recovered, which brings cost problems. Summary of the invention

[0006] In order to solve the problems existing in the prior art, the purpose of the present invention is to provide a one-pot method for preparing methyl chloroformate and 2-amino-4,6-dimethoxypyrimidine. In the present invention, the preparation of methyl chloroformate and the preparation of 2-amino-4,6-dimethoxypyrimidine are combined by a one-pot method, and the hydrogen chloride generated in the preparation process of methyl chloroformate is directly used as a reactant in the preparation process of 1,3-dimethylmalonamidine dihydrochloride, so that the effective utilization of hydrogen chloride is achieved, the production efficiency is improved, and the prepared methyl chloroformate and 2-amino-4,6-dimethoxypyrimidine have high yield and high purity.

[0007] The technical solution of the present invention is:

[0008] A one-pot method for preparing methyl chloroformate and 2-amino-4,6-dimethoxypyrimidine comprises the following preparation steps:

[0009] S1, preparation of methyl chloroformate and 1,3-dimethoxypropylenediimide dihydrochloride:

[0010] Methanol and malononitrile are added to a reaction kettle, and after cooling, phosgene is introduced in two stages for reaction. After the reaction is completed, nitrogen is introduced into the reaction system to purge the residual phosgene and hydrogen chloride in the system to obtain methyl chloroformate and 1,3-dimethoxypropylenediimide dihydrochloride;

[0011] S2, Preparation of 3-amino-3-methoxy-N-cyano-2-propionamidine:

[0012] Adding a solvent and an organic amine to the reaction kettle of step S1, then adding cyanamide solid and keeping the temperature to react, when the content of 1,3-dimethoxypropylenediimide dihydrochloride in the system is less than 0.3%, the reaction is terminated to obtain 3-amino-3-methoxy-N-cyano-2-propionamidine;

[0013] S3. Preparation of 2-amino-4,6-dimethoxypyrimidine:

[0014] The temperature of the reaction system is raised to a certain range and kept warm for reaction. When the content of 3-amino-3-methoxy-N-cyano-2-propionamidine in the system is less than 0.3%, the reaction is terminated and cooled to room temperature. A hydrochloric acid solution is added to the system to adjust the pH value of the system. Water is then added and stirred evenly, and then allowed to stand for stratification to obtain an aqueous layer and an organic layer. The organic layer is washed with water again, and an organic solvent is added to the aqueous layer, stirred, allowed to stand, and stratified. The obtained organic layer and the organic layer after washing are combined and concentrated until no solvent is evaporated. Methanol is then added to the solid for recrystallization, followed by filtration, distillation to remove methanol, and drying to obtain white crystalline 2-amino-4,6-dimethoxypyrimidine.

[0015] Furthermore, in step S1, the molar ratio of the added amounts of methanol and malononitrile is 6-40:1.

[0016] Furthermore, in the step S1, methanol and malononitrile are added to the reactor, the temperature is lowered to -10~10°C and kept warm, and the first stage of phosgene reaction is carried out. When the content of malononitrile in the system is less than 0.3%, the second stage of phosgene reaction is carried out, and the reaction temperature of the system is continued to be controlled at -10~10°C. The central control sampling is carried out for detection, and the phosgene is stopped when the methanol content in the reaction system is less than 0.3%.

[0017] Furthermore, in the first stage of step S1, the molar ratio of phosgene to malononitrile is ≥ 2:1, preferably {2.5~(M 甲醇 / M 丙二腈 -2.5)}: 1, where M 甲醇 represents the molar amount of methanol in step S1, M 丙二腈 represents the molar amount of malononitrile in step S1.

[0018] Furthermore, in the step S1, after the two-stage light reaction, nitrogen is introduced into the reaction system to purge the residual phosgene and hydrogen chloride in the system, and then the pipeline suction filtration device in the reactor is used for pressure filtration, the methyl chloroformate is transferred to another place and the material is discharged and packaged, and then nitrogen at a certain temperature is introduced into the reactor through the coil in the reactor to take out the residual methyl chloroformate and condense and recover it. The white solid obtained in the reactor is 1,3-dimethoxypropylenediimide dihydrochloride.

[0019] Furthermore, in step S1, nitrogen gas at a temperature of 20-90° C., preferably 40-70° C., is introduced into the reactor through the coil in the reactor.

[0020] Furthermore, the solvent in step S2 is one of aromatic hydrocarbon compounds or alkane compounds.

[0021] Furthermore, the solvent in step S2 is one of toluene or chlorobenzene; and the amount of the solvent added is 3 to 30 times the weight of malononitrile in step S1.

[0022] Furthermore, the organic amine in step S2 is a tertiary amine.

[0023] Furthermore, the organic amine in step S2 is one or a combination of triethylamine, tripropylamine, tributylamine, trimethylamine, dodecyldimethylamine, hexadecyldimethylamine, dodecylbenzylmethylamine, N-methyldicyclohexylamine, N,N-dimethylaniline, N,N-diethylaniline, and N,N-dimethyl-p-toluidine, preferably triethylamine.

[0024] Furthermore, in step S2, after the organic amine is added, the pH value of the reaction system is greater than 4, and then solid cyanamide is added and the reaction is carried out at a temperature less than 35°C.

[0025] Furthermore, in step S2, after the addition of the organic amine, the pH value of the reaction system is 7-9, and then solid cyanamide is added and the reaction is carried out at a temperature of 5-25°C.

[0026] Furthermore, the reaction system in step S3 is heated to less than 135°C, preferably 70-100°C.

[0027] Furthermore, the concentration of the hydrochloric acid solution in step S3 is 2-5%. After adding the hydrochloric acid solution, the pH value of the system is less than 7, preferably less than 4.

[0028] Furthermore, in step S3, the amount of organic solvent added is 3% to 30% of the weight of the water layer; the organic solvent is toluene.

[0029] Furthermore, the molar ratio of malononitrile in step S1, cyanamide in step S2, organic amine in step S2 and HCl in the hydrochloric acid solution in step S3 is 1:1.05-1.20:1.05-1.40:0.10-0.60, preferably 1:1.05-1.10:1.10-1.20:0.20-0.35.

[0030] Furthermore, the water layer obtained in step S3 is treated with alkaline water to recover the triethylamine therein and use it in the next batch.

[0031] The present invention combines the preparation of methyl chloroformate with the preparation of 2-amino-4,6-dimethoxypyrimidine by a one-pot method. First, in the first step of preparing methyl chloroformate and 1,3-dimethoxymalonimidamine dihydrochloride, the hydrogen chloride produced in the preparation of methyl chloroformate is directly used as a reactant in the preparation of 1,3-dimethylmalonimidamine dihydrochloride.

[0032] The existing preparation process of methyl chloroformate mainly utilizes phosgene and methanol to react, and a large amount of hydrogen chloride gas is produced during the synthesis process. For this part of hydrogen chloride, the factory is usually treated in the form of by-product hydrochloric acid, which not only causes a waste of resources, but also increases the processing cost. In the one-pot method for preparing methyl chloroformate and 2-amino-4,6-dimethoxypyrimidine provided by the present invention, phosgene is introduced into the reactor in two stages in step S1, phosgene is introduced in the first stage, and the molar ratio of the addition amount of phosgene and malononitrile in the first stage is limited, and the temperature of the entire reaction process is optimized to be -10~10°C. During the entire step S1 process, it is carried out in the reactor, phosgene only reacts with methanol, therefore, phosgene is introduced in the first stage, phosgene and methanol are reacted to generate methyl chloroformate and enough hydrogen chloride. In general industrial production, hydrogen chloride is discharged as a by-product, but in the present invention, hydrogen chloride can be used as a raw material for reacting with malononitrile, and the water content of the hydrogen chloride generated in the system can be ensured to be extremely low, thereby ensuring a high yield of 1,3-dimethoxypropylenediimine dihydrochloride.

[0033] At the same time, in the first stage, by controlling the molar amount of phosgene introduced, it is possible to control that there is enough methanol remaining in the system, and at this time there are methyl chloroformate, methanol, hydrogen chloride and malononitrile in the reaction system; methyl chloroformate does not participate in the reaction, and malononitrile, methanol and hydrogen chloride in the system continue to react, and it is ensured that the unreacted methanol in the system is sufficient to complete the reaction of malononitrile; then when the content of malononitrile in the system is less than 0.3%, the second stage of light-passing reaction is continued to complete the reaction of the remaining methanol in the system.

[0034] In the whole process, methanol is both a reaction solvent and a reaction raw material. And by accurately controlling the temperature during the overall reaction process, the reaction rate of the raw materials can be effectively increased, and the yield and purity of the product can be increased. Controlling the temperature in the two-stage reaction is crucial to ensure the smooth progress of the reaction and improve the purity and yield of the product. Appropriate temperature control can increase the reaction rate, reduce the generation of by-products, ensure the completion of the reaction, and ensure the safety of the operation.

[0035] Furthermore, the process of the present invention can also adopt a continuous production method. In this case, the molar ratio of the added amount of methanol and malononitrile in step S1 is maintained at ≥6:1, and the molar ratio of phosgene and malononitrile introduced in the first stage of step S1 is ≥2:1 to ensure that the process of the present invention can be continuously produced.

[0036] Compared with the prior art, the one-pot synthesis method for preparing methyl chloroformate and 2-amino-4,6-dimethoxypyrimidine provided by the present invention has the following advantages:

[0037] (1) The present invention combines the preparation of methyl chloroformate with the preparation of 2-amino-4,6-dimethoxypyrimidine by a one-pot method, and directly utilizes the hydrogen chloride generated in the preparation of methyl chloroformate as a reactant in the preparation of 1,3-dimethylmalonamidine dihydrochloride, thereby achieving effective utilization of hydrogen chloride, reducing the cost of processing by-products, reducing the number of reaction steps, simplifying the production process, and improving production efficiency, thereby effectively solving the problems of difficulty in preparing anhydrous hydrogen chloride, complex drying equipment, and high operating cost in the preparation of 1,3-dimethylmalonamidine dihydrochloride by the reaction of malononitrile with methanol and hydrogen chloride.

[0038] (2) In the one-pot method for preparing methyl chloroformate and 2-amino-4,6-dimethoxypyrimidine provided by the present invention, the reaction efficiency is improved by optimizing the addition ratio of the reactants, the reaction temperature, the time and other conditions, the reaction process can be effectively controlled, the reaction efficiency and the yield of the product can be improved, the utilization rate of methanol is increased, the unit consumption is reduced, and the one-pot method for preparing two materials is effectively realized. The prepared methyl chloroformate and 2-amino-4,6-dimethoxypyrimidine have high yield and high purity. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 The synthetic route diagram of the one-pot method for preparing methyl chloroformate and 2-amino-4,6-dimethoxypyrimidine in Example 1 of the present invention is shown in FIG. DETAILED DESCRIPTION

[0040] The present invention is further illustrated below through the description of specific implementation methods, but this is not a limitation of the present invention. Those skilled in the art can make various modifications or improvements based on the basic idea of ​​the present invention, but as long as they do not deviate from the basic idea of ​​the present invention, they are all within the protection scope of the present invention.

[0041] In the following examples and comparative examples, reagents not otherwise specified are conventional reagents and can be purchased from conventional reagent production and sales companies. The methods used are all prior art unless otherwise specified.

[0042] Embodiment 1:

[0043] A one-pot method for preparing methyl chloroformate and 2-amino-4,6-dimethoxypyrimidine comprises the following preparation steps:

[0044] S1, preparation of methyl chloroformate and 1,3-dimethoxypropylenediimide dihydrochloride:

[0045] 165 kg of malononitrile and 800 kg of methanol were added to the reactor, and the temperature was lowered to 0°C. 630 kg of phosgene was introduced in the first stage for heat preservation reaction. The temperature of the reaction system was controlled to be 0-5°C. When the malononitrile content was less than 0.3% by central control sampling, phosgene was introduced in the second stage for reaction, and the reaction temperature was kept at 0-5°C. The methanol content was detected by central control sampling. When the methanol content was less than 0.3%, the phosgene was stopped. Then nitrogen was introduced into the reactor to purge the residual phosgene and hydrogen chloride in the system. After that, the pipeline filter device in the reactor was used for pressure filtration to press methyl chloroformate out of the reactor to obtain 1540.85 kg of methyl chloroformate, which was transferred to another place and discharged and packaged. After that, the reactor was heated to 40-50°C, and nitrogen was introduced into the reactor through the coil in the reactor to take out the residual methyl chloroformate and condense and recover it to obtain 245.2 kg methyl chloroformate, the total yield of methyl chloroformate was 94.5%, the content was 99.2%, and the white solid obtained in the reactor was 498.12 kg of 1,3-dimethoxypropylenediimide dihydrochloride, with a yield of 98.2%;

[0046] The specific reaction route is as follows:

[0047] ;

[0048] S2, Preparation of 3-amino-3-methoxy-N-cyano-2-propionamidine:

[0049] Add 2390 kg of toluene and 278.0 kg of triethylamine to the reactor of step S1, adjust the pH of the system to 7-8, then add 110.25 kg of cyanamide solid and control the temperature to 5°C for insulation reaction; the content of 1,3-dimethoxypropylenediimine dihydrochloride in the central control detection system is less than 0.3%, the reaction is terminated to obtain 3-amino-3-methoxy-N-cyano-2-propionamidine;

[0050] The specific reaction route is as follows:

[0051] ;

[0052] S3. Preparation of 2-amino-4,6-dimethoxypyrimidine:

[0053] The temperature of the reaction system was raised to 90°C and kept warm for reaction. When the content of 3-amino-3-methoxy-N-cyano-2-propionamidine in the system was less than 0.3%, the reaction was terminated and cooled to room temperature. 1138.3 kg of 2% hydrochloric acid solution was added to the system to adjust the pH value of the system to 3. Then 165 kg of water was added and stirred evenly, and then allowed to stand for stratification to obtain an aqueous layer and an organic layer. The organic layer was washed with water again, and 8% toluene by weight of the aqueous layer was added to the aqueous layer, stirred, allowed to stand, and stratified. The obtained toluene layer and the organic layer after washing were combined and concentrated until no toluene was evaporated. Then 495 kg of methanol was added to the solid for recrystallization, filtered, distilled to remove methanol, and dried to obtain 350.12 kg of white crystalline 2-amino-4,6-dimethoxypyrimidine with a content of 99.3% and a yield of 90.4%.

[0054] 13 C NMR spectrum data:

[0055] 13 C NMR (125 MHz, d6-DMSO): δ=53.2 (4-OMe, 6-OMe), 77.9 (5-C), 162.8(2-C), 171.7 (6-C, 4-C);

[0056] The obtained water layer is treated with alkaline water to recover the triethylamine therein and use it for the next batch.

[0057] The specific reaction route is as follows:

[0058] .

[0059] Embodiment 2:

[0060] A one-pot method for preparing methyl chloroformate and 2-amino-4,6-dimethoxypyrimidine comprises the following preparation steps:

[0061] S1, preparation of methyl chloroformate and 1,3-dimethoxypropylenediimide dihydrochloride:

[0062] 165 kg of malononitrile and 480 kg of methanol were added to the reactor, and the temperature was lowered to -10°C. 625 kg of phosgene was introduced in the first stage for heat preservation reaction. The temperature of the reaction system was controlled to be -5~0°C. When the malononitrile content was less than 0.3% by central control sampling, phosgene was introduced in the second stage for reaction, and the reaction temperature was continued to be -5~0°C. The methanol content was detected by central control sampling. When the methanol content was less than 0.3%, the phosgene was stopped. Then nitrogen was introduced into the reactor to purge the residual phosgene and hydrogen chloride in the system. After that, the pipeline filter device in the reactor was used for pressure filtration to press methyl chloroformate out of the reactor to obtain 661.5 kg of methyl chloroformate, which was transferred to another place and discharged and packaged. After that, the reactor was heated to 50~60°C and nitrogen was introduced into the reactor through the coil in the reactor to take out the residual methyl chloroformate and condense and recover it to obtain 228.69 kg methyl chloroformate, the total yield of methyl chloroformate was 94.2%, the content was 99.3%, and the white solid obtained in the reactor was 497.11 kg of 1,3-dimethoxypropylenediimide dihydrochloride, with a yield of 98.0%;

[0063] S2, Preparation of 3-amino-3-methoxy-N-cyano-2-propionamidine:

[0064] Add 2390 kg of toluene and 278.0 kg of triethylamine to the reactor of step S1, adjust the pH of the system to 7-8, then add 110.25 kg of cyanamide solid and control the temperature to 10°C for insulation reaction; the content of 1,3-dimethoxypropylenediimine dihydrochloride in the central control detection system is less than 0.3%, the reaction is terminated to obtain 3-amino-3-methoxy-N-cyano-2-propionamidine;

[0065] S3. Preparation of 2-amino-4,6-dimethoxypyrimidine:

[0066] The temperature of the reaction system was raised to 70°C and kept warm for reaction. When the content of 3-amino-3-methoxy-N-cyano-2-propionamidine in the system was less than 0.3%, the reaction was terminated and cooled to room temperature. 912.5 kg of 3% hydrochloric acid solution was added to the system to adjust the pH value of the system to 3. Then 165 kg of water was added and stirred evenly, and then allowed to stand for stratification to obtain an aqueous layer and an organic layer. The organic layer was washed with water again, and 15% toluene by weight of the water layer was added to the water layer, stirred, allowed to stand, and stratified. The obtained toluene layer and the organic layer after washing were combined and concentrated until no toluene was evaporated. Then 495 kg of methanol was added to the solid for recrystallization, filtered, distilled to remove methanol, and dried to obtain 349.34 kg of white crystalline 2-amino-4,6-dimethoxypyrimidine with a content of 99.2% and a yield of 90.2%.

[0067] The obtained water layer is treated with alkaline water to recover the triethylamine therein and use it for the next batch.

[0068] Embodiment 3:

[0069] A one-pot method for preparing methyl chloroformate and 2-amino-4,6-dimethoxypyrimidine comprises the following preparation steps:

[0070] S1, preparation of methyl chloroformate and 1,3-dimethoxypropylenediimide dihydrochloride:

[0071] 165 kg of malononitrile and 3200 kg of methanol were added to the reactor, and the temperature was lowered to 5°C. 990 kg of phosgene was introduced in the first stage for heat preservation reaction. The temperature of the reaction system was controlled to be 5-10°C. When the malononitrile content was less than 0.3% by central control sampling, phosgene was introduced in the second stage for reaction, and the reaction temperature was kept at 5-10°C. The methanol content was detected by central control sampling. When the methanol content was less than 0.3%, the phosgene was stopped. Then nitrogen was introduced into the reactor to purge the residual phosgene and hydrogen chloride in the system. After that, the pipeline filter device in the reactor was used for pressure filtration to press methyl chloroformate out of the reactor to obtain 8302.9 kg of methyl chloroformate, which was transferred to another place and discharged and packaged. After that, the reactor was heated to 60-70°C, and nitrogen was introduced into the reactor through the coil in the reactor to take out the residual methyl chloroformate and condense and recover it to obtain 234.7 kg methyl chloroformate, the total yield of methyl chloroformate was 95.1%, the content was 99.5%, and the white solid obtained in the reactor was 1,3-dimethoxypropylenediimide dihydrochloride 500.65 kg, with a yield of 98.7%;

[0072] S2, Preparation of 3-amino-3-methoxy-N-cyano-2-propionamidine:

[0073] Add 2390 kg of toluene and 278.0 kg of triethylamine to the reactor of step S1, adjust the pH of the system to 7-9, then add 110.25 kg of cyanamide solid and control the temperature to 25°C for insulation reaction; the content of 1,3-dimethoxypropylenediimine dihydrochloride in the central control detection system is less than 0.3%, the reaction is terminated to obtain 3-amino-3-methoxy-N-cyano-2-propionamidine;

[0074] S3. Preparation of 2-amino-4,6-dimethoxypyrimidine:

[0075] The temperature of the reaction system was raised to 100°C and kept warm for reaction. When the content of 3-amino-3-methoxy-N-cyano-2-propionamidine in the system was less than 0.3%, the reaction was terminated and cooled to room temperature. 638.75 kg of 5% hydrochloric acid solution was added to the system to adjust the pH value of the system to 3. Then 165 kg of water was added, stirred evenly, and allowed to stand for stratification to obtain an aqueous layer and an organic layer. The organic layer was washed with water again, and 20% of the weight of the water layer was added to the water layer for stirring, standing, and stratification. The obtained toluene layer and the washed organic layer were combined and concentrated until no toluene was evaporated. Then 495 kg of methanol was added to the solid for recrystallization, filtered, distilled to remove methanol, and dried to obtain 350.89 kg of white crystalline 2-amino-4,6-dimethoxypyrimidine with a content of 99.6% and a yield of 90.6%.

[0076] The obtained water layer is treated with alkaline water to recover the triethylamine therein and use it for the next batch.

[0077] Embodiment 4:

[0078] A one-pot method for preparing methyl chloroformate and 2-amino-4,6-dimethoxypyrimidine comprises the following preparation steps:

[0079] S1, preparation of methyl chloroformate and 1,3-dimethoxypropylenediimide dihydrochloride:

[0080] 165 kg of malononitrile and 800 kg of methanol were added to the reactor, and the temperature was lowered to 0°C. 630 kg of phosgene was introduced in the first stage for heat preservation reaction. The temperature of the reaction system was controlled to be 0-5°C. When the malononitrile content was less than 0.3% by central control sampling, phosgene was introduced in the second stage for reaction, and the reaction temperature was kept at 0-5°C. The methanol content was detected by central control sampling. When the methanol content was less than 0.3%, the phosgene was stopped. Then nitrogen was introduced into the reactor to purge the residual phosgene and hydrogen chloride in the system. After that, the pipeline filter device in the reactor was used for pressure filtration to press methyl chloroformate out of the reactor to obtain 1556.5 kg of methyl chloroformate, which was transferred to another place and discharged and packaged. After that, the reactor was heated to 40-50°C, and nitrogen was introduced into the reactor through the coil in the reactor to take out the residual methyl chloroformate and condense and recover it to obtain 231.4 kg methyl chloroformate, the total yield of methyl chloroformate was 94.6%, the content was 99.3%, and the white solid obtained in the reactor was 498.63 kg of 1,3-dimethoxypropylenediimide dihydrochloride, with a yield of 98.3%;

[0081] S2, Preparation of 3-amino-3-methoxy-N-cyano-2-propionamidine:

[0082] Add 2390 kg of toluene and 303.6 kg of triethylamine to the reactor of step S1, adjust the pH of the system to 8-9, then add 126 kg of cyanamide solid and control the temperature to 5°C for insulation reaction; the content of 1,3-dimethoxypropylenediimine dihydrochloride in the central control detection system is less than 0.3%, the reaction is terminated to obtain 3-amino-3-methoxy-N-cyano-2-propionamidine;

[0083] S3. Preparation of 2-amino-4,6-dimethoxypyrimidine:

[0084] The temperature of the reaction system was raised to 90°C and kept warm for reaction. When the content of 3-amino-3-methoxy-N-cyano-2-propionamidine in the system was less than 0.3%, the reaction was terminated and cooled to room temperature. 2281.25 kg of 2% hydrochloric acid solution was added to the system to adjust the pH value of the system to 3. Then 165 kg of water was added and stirred evenly, and then allowed to stand for stratification to obtain an aqueous layer and an organic layer. The organic layer was washed with water again, and 30% of the weight of the water layer was added to the water layer for stirring, standing, and stratification. The obtained toluene layer and the washed organic layer were combined and concentrated until no toluene was evaporated. Then 495 kg of methanol was added to the solid for recrystallization, filtered, distilled to remove methanol, and dried to obtain 348.56 kg of white crystalline 2-amino-4,6-dimethoxypyrimidine with a content of 99.1% and a yield of 90.0%.

[0085] The obtained water layer is treated with alkaline water to recover the triethylamine therein and use it for the next batch.

[0086] Comparative Example 1:

[0087] Compared with Example 1, the difference is that in step S1, the amount of methanol added is 400 kg, that is, the molar ratio of the amount of methanol and malononitrile added is 5:1, and other parameters and operations are the same as those in Example 1.

[0088] In step S1 of comparative example 1, 489.7 kg of methyl chloroformate was obtained, transferred to another place and discharged and packaged, and then the reactor was heated to 40-50 ° C, nitrogen was introduced into the reactor through the coil in the reactor, and the residual methyl chloroformate was taken out and condensed and recovered to obtain 233.5 kg of methyl chloroformate, the total yield of methyl chloroformate was 92.2%, the content was 97.5%, and the white solid obtained in the reactor was 423.55 kg of 1,3-dimethoxypropylenediimide dihydrochloride, with a yield of 83.5%.

[0089] After drying in step S3, 279.04 kg of 2-amino-4,6-dimethoxypyrimidine was obtained, with a content of 99.3% and a yield of 72.0%.

[0090] It can be seen that the reduction in the amount of methanol used in step S1 leads to a decrease in the total yield and content of methyl chloroformate, a decrease in the yield of 1,3-dimethoxypropylenediimide dihydrochloride, and a significant decrease in the yield of the final product 2-amino-4,6-dimethoxypyrimidine.

[0091] Comparative Example 2:

[0092] Compared with Example 1, the difference is that in step S1, the amount of phosgene introduced in the first stage of light-passing reaction is 2227.5 kg, and other parameters and operations are the same as those in Example 1.

[0093] In step S1 of comparative example 2, 1646.8 kg of methyl chloroformate was obtained, transferred to another place and discharged and packaged, and then the reactor was heated to 40-50 ° C and nitrogen was introduced into the reactor through the coil in the reactor to remove the residual methyl chloroformate and condense and recover 236.2 kg of methyl chloroformate, the total yield of methyl chloroformate was 97.2%, the content was 96.5%, and the white solid obtained in the reactor was 432.18 kg of 1,3-dimethoxypropylene diimide dihydrochloride, with a yield of 85.2%.

[0094] In step S3, 290.66 kg of 2-amino-4,6-dimethoxypyrimidine was obtained by drying, with a content of 99.2% and a yield of 75.0%.

[0095] It can be seen that increasing the amount of phosgene added in the first-stage light-transmitting reaction of step S1 leads to a decrease in the yield of 1,3-dimethoxypropylenediimine dihydrochloride, and a significant decrease in the yield of the final product 2-amino-4,6-dimethoxypyrimidine.

[0096] Comparative Example 3:

[0097] Compared with Example 1, the difference is that in step S1, the light-transmitting reaction temperature of the two stages is controlled at -15 to -10°C, and other parameters and operations are the same as those of Example 1.

[0098] In step S1 of comparative example 3, 1558.5 kg of methyl chloroformate was obtained, transferred to another place and discharged and packaged, and then the reactor was heated to 40-50 ° C and nitrogen was introduced into the reactor through the coil in the reactor to remove the residual methyl chloroformate and condense and recover 235.1 kg of methyl chloroformate, the total yield of methyl chloroformate was 94.6%, the content was 96.5%, and the white solid obtained in the reactor was 416.96 kg of 1,3-dimethoxypropylene diimide dihydrochloride, with a yield of 82.2%.

[0099] After drying in step S3, 273.61 kg of 2-amino-4,6-dimethoxypyrimidine was obtained, with a content of 98.3% and a yield of 70.6%.

[0100] It can be seen that when the temperature of the light-passing reaction is lowered in step S1, the yield of 1,3-dimethoxypropylenediimide dihydrochloride is reduced, and the yield of the final product 2-amino-4,6-dimethoxypyrimidine is significantly reduced.

[0101] Comparative Example 4:

[0102] Compared with Example 1, the difference is that in step S1, the reaction temperature in the two-stage light-transmitting reaction is 25-30° C., and other parameters and operations are the same as those in Example 1.

[0103] In step S1 of comparative example 4, 1280.3 kg of methyl chloroformate was obtained, which was transferred to another place and discharged and packaged, and then the reactor was heated to 40-50 ° C, nitrogen was introduced into the reactor through the coil in the reactor, and the residual methyl chloroformate was taken out and condensed and recovered to obtain 233.6 kg of methyl chloroformate, the total yield of methyl chloroformate was 80.1%, the content was 90.2%, and the white solid obtained in the reactor was 415.95 kg of 1,3-dimethoxypropylenediimide dihydrochloride, with a yield of 82.0%.

[0104] In step S3, 273.23 kg of 2-amino-4,6-dimethoxypyrimidine was obtained by drying, with a content of 99.4% and a yield of 70.5%.

[0105] It can be seen that when the temperature of the light-passing reaction is increased in step S1, the total yield and content of methyl chloroformate are reduced, the yield of 1,3-dimethoxypropylenediimide dihydrochloride is reduced, and the yield of the final product 2-amino-4,6-dimethoxypyrimidine is significantly reduced.

[0106] Comparative Example 5:

[0107] Compared with Example 1, the difference is that in step S1, no staged light-passing reaction is carried out, the temperature is lowered to -10°C, phosgene is directly introduced for light-passing reaction, the temperature of the reaction system is controlled to be -5~0°C, and the central control sampling is used to detect the content of malononitrile and methanol. When the methanol content is less than 0.3%, the light passing is stopped, and other parameters and operations are the same as those in Example 1.

[0108] In step S1 of comparative example 5, 1594.7 kg of methyl chloroformate was obtained, which was transferred to another place and discharged and packaged, and then the reactor was heated to 40-50 ° C, nitrogen was introduced into the reactor through the coil in the reactor, and the residual methyl chloroformate was taken out and condensed and recovered to obtain 234.8 kg of methyl chloroformate, the total yield of methyl chloroformate was 96.8%, the content was 88.2%, and the white solid obtained in the reactor was 380.44 kg of 1,3-dimethoxypropylenediimide dihydrochloride, with a yield of 75.0%.

[0109] In step S3, 251.91 kg of 2-amino-4,6-dimethoxypyrimidine is obtained by drying, with a content of 99.3% and a yield of 65.0%.

[0110] It can be seen that in step S1, the step-by-step light-passing reaction is not performed, resulting in a significant decrease in the content of methyl chloroformate, a decrease in the yield of 1,3-dimethoxypropylenediimide dihydrochloride, and a significant decrease in the yield of the final product 2-amino-4,6-dimethoxypyrimidine.

[0111] Based on the weight, content, yield and other data of the products in the above embodiments and comparative examples, Table 1 is obtained.

[0112] Table 1:

[0113]

[0114] The above embodiments are merely illustrative of the principles and effects of the present invention, and are not intended to limit the present invention. Anyone familiar with the art may modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by a person of ordinary skill in the art without departing from the spirit and technical concept disclosed by the present invention shall still be covered by the claims of the present invention.

Claims

1. A one-pot method for preparing methyl chloroformate and 2-amino-4,6-dimethoxypyrimidine, characterized in that: The method comprises the following preparation steps: S1, preparation of methyl chloroformate and 1,3-dimethoxypropylenediimide dihydrochloride: Methanol and malononitrile are added to a reaction kettle, and after cooling, phosgene is introduced in two stages for reaction. After the reaction is completed, nitrogen is introduced into the reaction system to purge the residual phosgene and hydrogen chloride in the system to obtain methyl chloroformate and 1,3-dimethoxypropylenediimide dihydrochloride; S2, Preparation of 3-amino-3-methoxy-N-cyano-2-propionamidine: Adding a solvent and an organic amine to the reaction kettle of step S1, then adding cyanamide solid and keeping the temperature to react, when the content of 1,3-dimethoxypropylenediimide dihydrochloride in the system is less than 0.3%, the reaction is terminated to obtain 3-amino-3-methoxy-N-cyano-2-propionamidine; S3. Preparation of 2-amino-4,6-dimethoxypyrimidine: The temperature of the reaction system is raised to a certain range and kept warm for reaction. When the content of 3-amino-3-methoxy-N-cyano-2-propionamidine in the system is less than 0.3%, the reaction is terminated, and the temperature is cooled to room temperature. A hydrochloric acid solution is added to the system to adjust the pH value of the system, and then water is added, stirred evenly, and allowed to stand for stratification to obtain a water layer and an organic layer. The organic layer is washed with water again, and an organic solvent is added to the water layer, stirred, allowed to stand, and stratified. The obtained organic layer is combined with the organic layer after washing with water, and concentrated until no solvent is evaporated, and then methanol is added to the solid for recrystallization, followed by filtering, distilling to remove methanol, and drying to obtain white crystalline 2-amino-4,6-dimethoxypyrimidine; The molar ratio of the added amount of methanol and malononitrile in step S1 is 6-40:1; In the step S1, methanol and malononitrile are added to the reactor, the temperature is lowered to -10-10°C and kept warm, and a first-stage phosgene reaction is performed. When the content of malononitrile in the system is less than 0.3%, a second-stage phosgene reaction is performed, and the system reaction temperature is continuously controlled to be -10-10°C. When the content of methanol in the reaction system is less than 0.3%, the phosgene is stopped from being introduced. The molar ratio of phosgene to malononitrile introduced in the first stage of step S1 is {2.5~(M 甲醇 / M 丙二腈 -2.5)}: 1, where M 甲醇 represents the molar amount of methanol in step S1, M 丙二腈 represents the molar amount of malononitrile in step S1.

2. The one-pot method for preparing methyl chloroformate and 2-amino-4,6-dimethoxypyrimidine according to claim 1, characterized in that: In the step S1, after the two-stage light-passing reaction, nitrogen is introduced into the reaction system to purge the residual phosgene and hydrogen chloride in the system, and then the pipeline suction filtration device in the reactor is used for pressure filtration, the methyl chloroformate is transferred to another place and the material is discharged and packaged, and then nitrogen at a certain temperature is introduced into the reactor through the coil in the reactor to take out the residual methyl chloroformate and condense and recover it. The white solid obtained in the reactor is 1,3-dimethoxypropylenediimide dihydrochloride.

3. The one-pot method for preparing methyl chloroformate and 2-amino-4,6-dimethoxypyrimidine according to claim 2, characterized in that: In the step S1, nitrogen gas at a temperature of 40-70° C. is introduced into the reactor through the coil in the reactor.

4. The one-pot method for preparing methyl chloroformate and 2-amino-4,6-dimethoxypyrimidine according to claim 1, characterized in that: The solvent in step S2 is toluene or chlorobenzene, and the organic amine in step S2 is triethylamine.

5. The one-pot method for preparing methyl chloroformate and 2-amino-4,6-dimethoxypyrimidine according to claim 1, characterized in that: In the step S2, after the organic amine is added, the pH value of the system is 7-9, and then solid cyanamide is added and the reaction is carried out at a temperature of 5-25°C.

6. The one-pot method for preparing methyl chloroformate and 2-amino-4,6-dimethoxypyrimidine according to claim 1, characterized in that: The temperature of the reaction system in step S3 is raised to 70-100° C.; the concentration of the hydrochloric acid solution in step S3 is 2-5%. After the hydrochloric acid solution is added, the pH value of the system is less than 4.

7. The one-pot method for preparing methyl chloroformate and 2-amino-4,6-dimethoxypyrimidine according to claim 1, characterized in that: The molar ratio of malononitrile in step S1, cyanamide in step S2, organic amine in step S2 and HCl in the hydrochloric acid solution in step S3 is 1:1.05-1.20:1.05-1.40:0.10-0.60.

Images