Method for safely producing amidine compound with high yield
By introducing thioether catalysts into the production of amidine compounds, the problem of heat control in addition reactions has been solved, achieving safe, efficient, and high-yield production, which is suitable for industrial production of amidine compounds.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- XINFA PHARMA
- Filing Date
- 2025-12-31
- Publication Date
- 2026-05-01
AI Technical Summary
Existing technologies for producing amidine compounds have safety hazards, high energy consumption, and low yields, mainly due to the difficulty in controlling heat during the addition reaction, which leads to a sharp rise in reactor temperature and difficulties in heat transfer.
By introducing thioether catalysts and controlling the reaction conversion rate and exothermic rate, the addition reaction can proceed smoothly, avoiding heat accumulation. Inexpensive and readily available thioether catalysts such as dimethyl sulfide can be used to optimize the neutralization reaction conditions and improve the reaction stability and selectivity.
This method enables safe and reliable high-yield production of amidine compounds, significantly reducing energy consumption, increasing the yield of the target product, and shortening the reaction time, making it suitable for industrial production.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of chemical synthesis and relates to a safe and high-yield method for producing amidine compounds. Background Technology
[0002] Amidine compounds are important pharmaceutical intermediates and also crucial monomers in organic synthesis, such as acetamidine hydrochloride, propamidine hydrochloride, and butylamidine hydrochloride; acetamidine hydrochloride is used in the synthesis of vitamin B1. The traditional production method for amidine compounds involves preparing the intermediate imino ether hydrochloride (commonly known as amidine compounds) using nitrile compounds, methanol, and hydrogen chloride, followed by neutralization with a prepared ammonia-methanol solution to finally obtain the amidine hydrochloride compound. The specific reaction equations are as follows:
[0003]
[0004] Where R is methyl, ethyl or propyl.
[0005] The synthesis of amidine compounds involves low reaction temperatures, high exothermic reactions, and produces solid products, which are highly corrosive to hydrogen chloride. Therefore, enamel-lined batch reactors are commonly used, employing a dropwise addition method where acetonitrile is added to acidic methanol. Experiments have shown that acetonitrile does not completely convert to the product upon addition; a period of heat preservation is required for the solid to precipitate as amidine. This precipitation involves both reaction and crystallization processes, releasing a large amount of heat instantaneously. Due to the limited heat exchange area and low efficiency of the enamel-lined reactor, the reactor temperature rises rapidly and becomes uncontrollable, posing significant safety hazards and reducing yield. Secondly, the addition reaction requires low temperatures, and as the amidine compounds gradually become viscous in the later stages, the low solid-state heat transfer coefficient makes cooling difficult, requiring even lower-temperature refrigerants and larger heat exchange areas, increasing energy consumption and leading to significant safety risks during scale-up production. Furthermore, the low yield of the target product and long reaction time further increase energy consumption. Summary of the Invention
[0006] To address the shortcomings of existing technologies in terms of safety, energy efficiency, and yield, this invention provides a safe and high-yield method for producing amidine compounds. By introducing a thioether catalyst into the addition reaction, this invention effectively controls the reaction conversion rate and exothermic rate, ensuring a stable addition reaction, avoiding heat accumulation, effectively solving the problem of temperature surge during precipitation, improving system stability, and addressing the issue of intense exothermic reactions during industrial production. This method is energy-efficient, environmentally friendly, safe, and reliable. The use of the thioether catalyst in this invention enables the high-yield production of the target product.
[0007] The technical solution of this invention is as follows:
[0008] A method for safely and in high yield producing amidine compounds, comprising the steps of:
[0009] (1) Under the catalysis of sulfide catalyst, nitriles and hydrogen chloride methanol solution undergo an addition reaction to generate amidine compounds;
[0010] (2) In the solvent methanol, amidine compounds and ammonia undergo a neutralization reaction to generate amidine compounds.
[0011] According to a preferred embodiment of the present invention, in step (1), the sulfide catalyst is one or more of dimethyl sulfide, methyl ethyl sulfide, chloromethyl methyl sulfide, benzyl sulfide, 4-nitrobenzene sulfide, dimethyl disulfide or diethyl sulfide, preferably dimethyl sulfide or dimethyl disulfide, and especially preferably dimethyl sulfide.
[0012] According to a preferred embodiment of the present invention, in step (1), the molar ratio of the sulfide catalyst to the nitrile compound is 0.01-0.20:1, preferably 0.016-0.05:1, and more preferably 0.05:1.
[0013] According to a preferred embodiment of the present invention, in step (1), the nitrile compound is acetonitrile, propionitrile, or n-butyronitrile, preferably acetonitrile.
[0014] According to a preferred embodiment of the present invention, in step (1), the mass concentration of the hydrogen chloride methanol solution is 44-70%, preferably 45-61%. The hydrogen chloride methanol solution is prepared by passing dried hydrogen chloride into methanol.
[0015] According to a preferred embodiment of the present invention, in step (1), the molar ratio of hydrogen chloride to nitrile compound in the hydrogen chloride methanol solution is 1.20-1.30:1, preferably 1.27-1.29:1.
[0016] According to a preferred embodiment of the present invention, in step (1), the nitrile compound is added dropwise to the mixture of sulfide catalyst and hydrogen chloride methanol solution.
[0017] According to a preferred embodiment of the present invention, in step (1), the addition reaction temperature is 0-30°C, preferably 10-20°C. The addition reaction time is 1-12 h, and the addition reaction is carried out under stirring conditions.
[0018] According to a preferred embodiment of the present invention, in step (1), the reaction solution obtained by the addition reaction is directly carried out in the next step without further treatment.
[0019] According to a preferred embodiment of the present invention, in step (2), the mass of ammonia accounts for 8-34% of the total mass of ammonia and solvent methanol, preferably 8-15%.
[0020] According to a preferred embodiment of the present invention, the molar ratio of the nitrile compound in step (1) to the ammonia in step (2) is 1:1.28-1.3.
[0021] According to a preferred embodiment of the present invention, in step (2), the neutralization reaction temperature is 0-50°C, preferably 40-50°C. The neutralization reaction time is 1-6 hours, preferably 2-3 hours, and the neutralization reaction is carried out under stirring conditions.
[0022] According to a preferred embodiment of the present invention, in step (2), the reaction solution obtained from the neutralization reaction is filtered to obtain filter residue and filtrate; the filter residue is washed and dried to obtain ammonium chloride solid; and the filtrate is distilled, filtered, and dried to obtain amidine compounds.
[0023] According to a preferred embodiment of the present invention, the preparation method of amidine compounds includes the following steps:
[0024] (1) Stir the hydrogen chloride methanol solution and cool it to 0-5℃, add sulfide catalyst, and add nitrile compound dropwise. During the dropwise addition, the temperature is kept stable between 0-30℃. After stirring the reaction, a reaction solution containing amidine compounds is obtained.
[0025] (2) Dilute the reaction solution containing amidine compounds with methanol, then mix it with ammonia methanol solution, keep it warm, and filter it under pressure to obtain a solution containing amidine compounds.
[0026] Taking dimethyl sulfide as an example, the specific mechanism of the addition reaction is as follows:
[0027]
[0028]
[0029] Wherein, the substituent R is methyl, ethyl or propyl.
[0030] The technical features and beneficial effects of this invention are as follows:
[0031] 1. The use of sulfide catalyst in this invention improves the reaction rate and conversion rate. During the slow dropwise addition of nitrile compounds, the nitrile compounds react rapidly without heat accumulation, thus avoiding heat superposition. The entire reaction rate is uniform, and there is no problem of rapid exothermic reaction. This effectively solves the problem of temperature surge in addition reaction, improves system stability, ensures smooth and reliable reaction, and helps to guarantee product quality. Moreover, refrigeration is no longer difficult, energy consumption is greatly reduced, and the energy-saving effect is obvious.
[0032] 2. The use of sulfide catalyst in this invention makes the "C" on the cyano group more active, which is more conducive to the attack of the lone pair electrons of the "O" on methanol, thereby improving the reaction selectivity, increasing the atom utilization rate, reducing the generated methyl acetate and acetamide impurities, increasing the yield of the target product by more than 8%, and shortening the reaction time, thus improving production efficiency.
[0033] 3. The catalyst used in this invention is inexpensive and readily available, requires a small amount, and has low cost, making the method of this invention suitable for industrial production. Detailed Implementation
[0034] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.
[0035] Unless otherwise specified, all reagents or materials used in the examples are commercially available or prepared by existing methods; unless otherwise specified, all methods are existing methods.
[0036] Example 1
[0037] A method for safely and in high yield producing amidine compounds, comprising the steps of:
[0038] A hydrogen chloride methanol solution with a mass concentration of 49.25 wt% (water content < 0.5 wt%) was prepared by passing dry hydrogen chloride into methanol.
[0039] Add 229.56 kg of hydrogen chloride methanol solution (containing 3097.5 mol of hydrogen chloride) to the reaction vessel, stir and cool to 0-5℃, add 7.5 kg (120.7 mol) of dimethyl sulfide, and then slowly add 168 kg (2430.9 mol) of nitrile butadiene. The addition is completed in about 5 hours. During the addition, the temperature rises slowly. Use chilled water at around -5℃ to control the temperature and stabilize it between 10-20℃. The solution is a white suspension. Stir and keep warm at 10-20℃ for 1 hour until the reaction is complete. The solution is a white turbid liquid. After the warming is completed, the reaction solution of butylamine hydrochloride is obtained. Cool it to below 5℃ for later use.
[0040] The reaction solution of butamidine hydrochloride was diluted with 100 kg of methanol and then mixed with 451.6 kg of an ammonia methanol solution with a mass concentration of 11.8 wt% (ammonia content of 3128.9 mol) (moisture content <0.5%) at a temperature below 5°C. The reaction temperature was controlled between 40-50°C, and the pH was measured to be 7.0-8.0. The mixture was stirred for 2 h, filtered, and the filter cake was washed and dried to obtain 35.14 kg of ammonium chloride solid. The filtrate was butamidine hydrochloride filtrate with a content of 23.15% and a yield of 90.15%.
[0041] The filtrate of butamidine hydrochloride can be concentrated using general techniques to obtain high-content butamidine hydrochloride solid. For example, distillation at 70°C under normal pressure, followed by vacuum distillation, filtration, and drying, yields the butamidine hydrochloride product with a content of 93.28% and a yield of 90.06%.
[0042] Example 2
[0043] A method for safely and in high yield producing amidine compounds, comprising the steps of:
[0044] A hydrogen chloride methanol solution with a mass concentration of 49.25 wt% (water content < 0.5 wt%) was prepared by passing dry hydrogen chloride into methanol.
[0045] Add 229.56 kg of hydrogen chloride methanol solution (containing 3097.5 mol of hydrogen chloride) to the reaction vessel, stir and cool to 0-5℃, add 7.5 kg (120.7 mol) of dimethyl sulfide, and then slowly add 132.51 kg (2405.8 mol) of propionitrile. The addition is completed in about 5 hours. During the addition, the temperature rises slowly. Use chilled water at around -5℃ to control the temperature and stabilize it between 10-20℃. The solution is a white suspension. Keep it at 10-20℃ for 1 hour until the reaction is complete. The solution is a white turbid liquid. After the temperature is maintained, the reaction solution of propanediamine hydrochloride is obtained. Cool it to below 5℃ for later use.
[0046] The above-mentioned propanediamine hydrochloride reaction solution was diluted with 100 kg of methanol, and then mixed with 451.6 kg of an ammonia methanol solution with a mass concentration of 11.8 wt% (ammonia content of 3128.9 mol) (moisture content <0.5%) at 5℃. The temperature was controlled at 40-50℃, the pH was measured to be 7.0-8.0, and the reaction was stirred for 2 h. The mixture was then filtered, and the filter cake was washed and dried to obtain 30.02 kg of ammonium chloride solid. The filtrate was a propanediamine hydrochloride solution with a content of 23.92% and a yield of 90.86%.
[0047] Propaneamine hydrochloride solution can be concentrated using general techniques to obtain high-content propaneamine hydrochloride solid. For example, distillation at 70°C under normal pressure, followed by vacuum distillation, filtration, and drying yields the final propaneamine hydrochloride product with a purity of 92.59% and a yield of 90.68%.
[0048] Example 3
[0049] A method for safely and in high yield producing amidine compounds, comprising the steps of:
[0050] A hydrogen chloride methanol solution with a mass concentration of 60.02 wt% (water content < 0.5 wt%) was prepared by passing dry hydrogen chloride into methanol.
[0051] Add 188.43 kg of hydrogen chloride methanol solution (containing 3097.5 mol of hydrogen chloride) to the reaction vessel, stir and cool to 0-5℃, add 7.5 kg (120.7 mol) of dimethyl sulfide, and then slowly add 100 kg (2439 mol) of acetonitrile dropwise. The addition is completed in about 5 hours. During the addition, the temperature rises slowly. Use chilled water at around -5℃ to control the temperature and stabilize it between 5-20℃. The solution is a white suspension. Stir and keep warm at 10-20℃ for 1 hour until the reaction is complete. The solution is a white turbid liquid. After the warming is completed, the reaction solution of ethylene amidine hydrochloride is obtained. Cool it to below 5℃ for later use.
[0052] The above acetamiprid hydrochloride reaction solution was diluted with 100 kg of methanol, and then mixed with 451.6 kg of an 11.8 wt% ammonia-methanol solution (containing 3128.9 mol of ammonia) (water content <0.5%) at a temperature below 5°C. The reaction temperature was controlled between 40-50°C, and the pH was measured to be 7.0-8.0. The mixture was stirred for 2 hours, filtered under pressure, and the filter cake was washed and dried to obtain 31.87 kg of ammonium chloride solid. The filtrate was acetamiprid hydrochloride filtrate with a purity of 27.98% and a yield of 97.08%.
[0053] The acetamidine hydrochloride filtrate can be concentrated using general techniques to obtain high-content acetamidine hydrochloride solid. For example, distillation at 70°C under normal pressure, followed by vacuum distillation, filtration, and drying, yields the final acetamidine hydrochloride product with a content of 95.26% and a yield of 97.10%.
[0054] Example 4
[0055] A method for safely and in high yield producing amidine compounds, comprising the steps of:
[0056] A hydrogen chloride methanol solution with a mass concentration of 45.26 wt% (water content < 0.5 wt%) was prepared by passing dry hydrogen chloride into methanol.
[0057] Add 249.8 kg of hydrogen chloride methanol solution (containing 3097.5 mol of hydrogen chloride) to the reaction vessel, stir and cool to 0-5℃, add 2.5 kg (40.2 mol) of dimethyl sulfide, and then slowly add 100 kg (2439 mol) of acetonitrile dropwise. The addition is completed in about 5 hours. During the addition, the temperature rises slowly. Use chilled water at around -5℃ to control the temperature and stabilize it between 10-20℃. The solution is a white suspension. Keep it at 10-20℃ for 4 hours until the reaction is complete. After the temperature is maintained, the reaction solution of ethylene amidine hydrochloride is obtained. Cool it to below 5℃ for later use.
[0058] The above acetamiprid hydrochloride reaction solution was diluted with 100 kg of methanol, and then mixed with 451.6 kg of an 11.8 wt% ammonia-methanol solution (containing 3128.9 mol of ammonia) (water content <0.5%) at a temperature below 5°C. The reaction temperature was controlled between 40-50°C, and the pH was measured to be 7.0-8.0. The mixture was stirred for 2 hours, filtered under pressure, and the filter cake was washed and dried to obtain 33.27 kg of ammonium chloride solid. The filtrate was acetamiprid hydrochloride filtrate with a purity of 25.80% and a yield of 95.05%.
[0059] The acetamidine hydrochloride filtrate can be concentrated using general techniques to obtain high-content acetamidine hydrochloride solid. For example, distillation at 70°C under normal pressure, followed by vacuum distillation, filtration, and drying, yields the final acetamidine hydrochloride product with a content of 95.03% and a yield of 97.01%.
[0060] Example 5
[0061] A method for safely and in high yield producing amidine compounds, comprising the steps of:
[0062] A hydrogen chloride methanol solution with a mass concentration of 49.25 wt% (water content < 0.5 wt%) was prepared by passing dry hydrogen chloride into methanol.
[0063] Add 229.56 kg of hydrogen chloride methanol solution (containing 3097.5 mol of hydrogen chloride) to the reaction vessel, stir and cool to 0-5℃, add 7.5 kg (120.7 mol) of dimethyl sulfide, and then slowly add 100 kg (2439 mol) of acetonitrile dropwise. The addition is completed in about 5 hours. During the addition, the temperature rises slowly. Use chilled water at around -5℃ to control the temperature and stabilize it between 10-20℃. The solution is a white suspension. Keep it at 10-20℃ for 1 hour until the reaction is complete. The solution is a white turbid liquid. After the heat preservation is completed, the reaction solution of ethylene amidine hydrochloride is obtained. Cool it to below 5℃ for later use.
[0064] The above acetamiprid hydrochloride reaction solution was diluted with 100 kg of methanol, and then mixed with 451.6 kg of an 11.8 wt% ammonia-methanol solution (containing 3128.9 mol of ammonia) (water content <0.5%) at a temperature below 5°C. The reaction temperature was controlled between 40-50°C, and the pH was measured to be 7.0-8.0. The mixture was stirred for 2 hours, filtered under pressure, and the filter cake was washed and dried to obtain 29.65 kg of ammonium chloride solid. The filtrate was an acetamiprid hydrochloride solution with a purity of 26.32% and a yield of 97.24%.
[0065] Ethamidinium hydrochloride solution can be concentrated using common techniques to obtain high-content acetamidine hydrochloride solid. For example, distillation at 70°C under normal pressure, followed by vacuum distillation, filtration, and drying yields the final acetamidine hydrochloride product with a content of 94.50% and a yield of 95.03%.
[0066] Example 6
[0067] A safe and high-yield method for producing amidine compounds, as described in Example 5, except that dimethyl sulfide is replaced with the same molar amount of chloromethyl methyl sulfide (120.70 mol); other steps and conditions are the same as in Example 5. An acetamidine hydrochloride filtrate is obtained with a purity of 23.73% and a yield of 89.56%.
[0068] High-content acetamidine hydrochloride solid was obtained using a general concentration technique. For example, it was distilled at 70°C under normal pressure, followed by vacuum distillation, filtration, and drying to obtain the final acetamidine hydrochloride product with a content of 91.16% and a yield of 89.60%.
[0069] Example 7
[0070] A safe and high-yield method for producing amidine compounds, as described in Example 5, except that dimethyl sulfide is replaced with the same molar amount of anisole (120.70 mol); other steps and conditions are the same as in Example 5. An acetamidine hydrochloride filtrate is obtained with a purity of 24.11% and a yield of 91.56%.
[0071] High-content acetamidine hydrochloride solid was obtained using a general concentration technique. For example, distillation at 70°C under normal pressure, followed by vacuum distillation, filtration, and drying yielded an acetamidine hydrochloride product with a content of 92.82% and a yield of 91.43%.
[0072] Example 8
[0073] A safe and high-yield method for producing amidine compounds is provided, as described in Example 5, except that dimethyl sulfide is replaced with the same molar amount of 4-nitrobenzyl sulfide (120.70 mol); other steps and conditions are the same as in Example 5. An acetamidine hydrochloride filtrate is obtained with a purity of 23.33% and a yield of 90.25%.
[0074] High-content acetamidine hydrochloride solid was obtained using a general concentration technique. For example, it was distilled at 70°C under normal pressure, followed by vacuum distillation, filtration, and drying to obtain the final acetamidine hydrochloride product with a content of 91.27% and a yield of 90.21%.
[0075] Example 9
[0076] A safe and high-yield method for producing amidine compounds is provided, as described in Example 5, except that dimethyl sulfide is replaced with the same molar amount of dimethyl disulfide, 120.70 mol; other steps and conditions are the same as in Example 5. An acetamidine hydrochloride filtrate is obtained with a purity of 24.84% and a yield of 94.28%.
[0077] High-content acetamidine hydrochloride solid was obtained using a general concentration technique. For example, it was distilled at 70°C under normal pressure, followed by vacuum distillation, filtration, and drying to obtain the final acetamidine hydrochloride product with a content of 94.95% and a yield of 94.20%.
[0078] Example 10
[0079] A safe and high-yield method for producing amidine compounds is provided, as described in Example 5, except that the amount of dimethyl sulfide used is 104.62 mol; other steps and conditions are the same as in Example 5. An acetamidine hydrochloride filtrate is obtained with a purity of 24.62% and a yield of 93.26%.
[0080] High-content acetamidine hydrochloride solid was obtained using a general concentration technique. For example, distillation at 70°C under normal pressure, followed by vacuum distillation, filtration, and drying yielded an acetamidine hydrochloride product with a content of 92.68% and a yield of 93.21%.
[0081] Comparative Example 1
[0082] A method for safely and in high yield producing amidine compounds, comprising the steps of:
[0083] A hydrogen chloride methanol solution with a mass concentration of 49.25 wt% (water content < 0.5 wt%) was prepared by passing dry hydrogen chloride into methanol.
[0084] Add 229.56 kg of hydrogen chloride methanol solution to the reaction vessel, stir and cool to 0-5℃; then slowly add 100 kg (2439 mol) of acetonitrile dropwise, which is completed in about 12 hours. During the dropwise addition, the temperature rises sharply and is prone to overheating. It is necessary to control the temperature with a -40℃ refrigerant and stabilize the temperature at 10-30℃. The solution is a white suspension. Stir and keep warm for 2 hours at 10-30℃ until the reaction is complete. The solution is a white viscous turbid liquid. After the warming is completed, the reaction solution of ethylene amidine hydrochloride is obtained and cooled to below 5℃ for later use.
[0085] The above acetamiprid hydrochloride reaction solution was diluted with 100 kg of methanol, and then mixed with 451.6 kg of an 11.8 wt% ammonia-methanol solution (containing 3128.9 mol of ammonia) (water content <0.5%) at a temperature below 5°C. The reaction temperature was controlled between 40-50°C, and the pH was measured to be 7.0-8.0. The mixture was stirred for 2 hours, filtered under pressure, and the filter cake was washed and dried to obtain 34.57 kg of ammonium chloride solid. The filtrate was an acetamiprid hydrochloride solution with a purity of 23.77% and a yield of 87.02%.
[0086] High-content acetamidine hydrochloride solid was obtained using a general concentration technique. For example, it was distilled at 70°C under normal pressure, followed by vacuum distillation, filtration, and drying to obtain the final acetamidine hydrochloride product with a content of 87.89% and a yield of 87.61%.
Claims
1. A method for the safe and high-yield production of amidine compounds, comprising the steps of: (1) Under the catalysis of sulfide catalyst, nitriles and hydrogen chloride methanol solution undergo an addition reaction to generate amidine compounds; (2) In the solvent methanol, amidine compounds and ammonia undergo a neutralization reaction to generate amidine compounds.
2. The method for safe and high-yield production of amidine compounds according to claim 1, characterized in that, In step (1), the sulfide catalyst is one or a combination of two or more of dimethyl sulfide, methyl ethyl sulfide, chloromethyl methyl sulfide, benzyl sulfide, 4-nitrobenzyl sulfide, dimethyl disulfide or diethyl sulfide, preferably dimethyl sulfide or dimethyl disulfide, and especially preferably dimethyl sulfide.
3. The method for safe and high-yield production of amidine compounds according to claim 1, characterized in that, In step (1), the molar ratio of the sulfide catalyst to the nitrile compound is 0.01-0.20:1, preferably 0.016-0.05:1, and more preferably 0.05:
1.
4. The method for safe and high-yield production of amidine compounds according to claim 1, characterized in that, In step (1), the nitrile compound is acetonitrile, propionitrile or n-butyronitrile, preferably acetonitrile.
5. The method for safe and high-yield production of amidine compounds according to claim 1, characterized in that, In step (1), the mass concentration of the hydrogen chloride methanol solution is 44-70%, preferably 45-61%; the hydrogen chloride methanol solution is prepared by passing dry hydrogen chloride into methanol.
6. The method for safe and high-yield production of amidine compounds according to claim 1, characterized in that, In step (1), the molar ratio of hydrogen chloride to nitrile compounds in the hydrogen chloride methanol solution is 1.20-1.30:1, preferably 1.27-1.29:
1.
7. The method for producing amidine compounds with safe and high yield according to claim 1, characterized in that, In step (1), the nitrile compound is added dropwise to the mixture of sulfide catalyst and hydrogen chloride methanol solution.
8. The method for safe and high-yield production of amidine compounds according to claim 1, characterized in that, In step (1), the addition reaction temperature is 0-30℃, preferably 10-20℃; preferably, in step (1), the reaction solution obtained by the addition reaction is directly carried out in the next step without further treatment.
9. The method for safe and high-yield production of amidine compounds according to claim 1, characterized in that, Includes one or more of the following conditions: i. In step (2), the mass of ammonia accounts for 8-34% of the total mass of ammonia and solvent methanol, preferably 8-15%; ii. The molar ratio of the nitrile compound in step (1) to the ammonia in step (2) is 1:1.28-1.3; iii. In step (2), the neutralization reaction temperature is 0-50℃, preferably 40-50℃.
10. The method for producing amidine compounds with safe and high yield according to claim 1, characterized in that, The preparation method of amidine compounds includes the following steps: (1) Stir the hydrogen chloride methanol solution and cool it to 0-5℃, add sulfide catalyst, and add nitrile compound dropwise. During the dropwise addition, the temperature is kept stable between 0-30℃. After stirring the reaction, a reaction solution containing amidine compounds is obtained. (2) Dilute the reaction solution containing amidine compounds with methanol, then mix it with ammonia methanol solution, keep it warm, and filter it under pressure to obtain a solution containing amidine compounds.