A method for preparing cyclopropylamine

Abstract

This invention relates to a method for preparing cyclopropylamine. The method employs triphosgene and a specific catalyst in the chlorination stage, improving the ammonolysis and degradation reaction into a continuous process. Toluene / xylene solvent is removed from the main process and replaced, and excess ammonia is absorbed and reused using sodium methoxide-methanol. The preparation method of this invention exhibits high yields in each step, with an overall yield exceeding 89%, making it a promising method for the industrial-scale preparation of cyclopropylamine.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical intermediate preparation, and more specifically, to a method for preparing cyclopropylamine. Background Technology

[0002] Cyclopropylamine (CPA) is a three-membered ring aliphatic amine that was synthesized as early as 1941, but it only gained attention as an intermediate in antibacterial drugs after the advent of ciprofloxacin. With the rapid development of quinolone antibacterial drugs, new antibacterial drugs such as ciprofloxacin, sparfloxacin, barofloxacin, and tomefloxacin all use cyclopropylamine as a major intermediate or raw material, leading to a growing market demand for cyclopropylamine.

[0003] There are many methods for synthesizing cyclopropylamine, which, based on the starting materials, mainly include:

[0004] 1. Using γ-butyrolactone as a raw material. γ-Butyrolactone undergoes ring-opening with hydrogen chloride and esterification with an alcohol to produce chlorobutyrate. Then, using sodium alkoxide as a strong base, it is cyclized in toluene, followed by amidation with ammonia gas, and finally Hoffmann degradation in sodium hypochlorite solution to produce cyclopropylamine. The advantage of this route is the readily available and inexpensive raw materials, but the first and fourth steps require high-pressure equipment, demanding strict operating conditions and a long reaction cycle. In this route, the ring-opening reagent can be replaced with thionyl chloride, and catalysts such as zinc chloride and copper chloride can be further added. A simplified process has been developed based on this method, where γ-butyrolactone reacts directly with thionyl chloride and an alcohol to produce chlorobutyrate, with the remaining steps remaining the same. In this route, the ring-opening and esterification of γ-butyrolactone are completed in one step, simplifying the process and shortening the reaction cycle. Using γ-butyrolactone as a raw material is currently the method adopted by most manufacturers in China.

[0005] 2. Using ethyl acetoacetate as the starting material. Ethyl acetoacetate condenses and cyclizes with ethylene oxide to form α-acetyl-γ-butyrolactone, which is then ring-opened with hydrochloric acid and cyclized under sodium hydroxide catalysis to form methylcyclopropyl ketone. This is then oxime-treated with hydroxylamine hydrochloride, followed by a rearrangement reaction with trifluoroacetic anhydride or a reaction with phosphorus pentachloride to obtain a mixed amide, which is then degraded to yield cyclopropylamine. This route uses explosive ethylene oxide, is hazardous, and is lengthy with difficult product separation.

[0006] 3. Using 1,3-propanediol as a raw material. 1,3-propanediol is brominated, cyaninated, and cyclized to produce cyclopropanenitrile, which is then amidated and subsequently degraded by Hofmann to obtain cyclopropylamine. Alternatively, cyclopropanenitrile can be hydrolyzed to obtain cyclopropanecarboxylic acid, which is then hydrolyzed to cyclopropylamine via acylation and azide reaction. This route is simple to operate, but it requires the use of highly toxic cyanide and explosive azide, resulting in high reaction costs, strict control requirements, and low overall yield, thus limiting its practical application value.

[0007] 4. Using epoxide as a raw material. Epioxide is first converted into 2,3-dihydrofuran, and then undergoes intermediates such as cyclopropaneformaldehyde, cyclopropanecarboxylic acid, methyl cyclopropanecarboxylate, and cyclopropanecarboxamide to produce the product cyclopropaneamine. Among these, epoxide is inexpensive and readily available, giving it a certain cost advantage.

[0008] 5. Using 1-chloro-3-bromopropane as a raw material. 1-chloro-3-bromopropane reacts with sodium nitrite to produce 1-chloro-3-nitropropane, which undergoes ring closure under alkaline conditions to form nitrocyclopropane, which is then reduced with hydrogen to produce cyclopropylamine. This route has fewer steps and is simpler to operate, but the raw material cost is higher, the equipment requirements are more demanding, the reaction conditions are harsh, and the overall yield is lower.

[0009] However, there is still a need to develop more efficient, simple, and economical methods for preparing cyclopropylamine. Summary of the Invention

[0010] To address the problems existing in the prior art, the present invention provides a method for preparing cyclopropylamine, which is simpler, more environmentally friendly, and more economical.

[0011] The method for preparing cyclopropylamine according to the present invention includes:

[0012]

[0013] a. Chloride

[0014] γ-Butyrolactone and triphosgene are reacted under the catalysis of a mixed catalyst of N,N-dimethylformamide and pyridine, and then methanol is added to continue the reaction to produce methyl 4-chlorobutyrate;

[0015] b. Circulation

[0016] Methyl 4-chlorobutyrate was heated to 80–100 °C, and sodium methoxide-methanol solution was slowly added. The reaction was then continued to yield methyl cyclopropionate.

[0017] c. Ammonolysis

[0018] Methyl cyclopropionate-methanol solution and ammonia-sodium methoxide-methanol solution are mixed, preheated to 100-130°C, and then fed into a tubular reactor. The reactor pressure is maintained at 1-3 MPa, and the reaction temperature is controlled at 100-130°C to produce cyclopropionamide.

[0019] d. Degradation

[0020] Cyclopropylformamide was dissolved in water, and sodium hydroxide was dissolved in sodium hypochlorite solution under cooling. The two solutions were mixed and preheated to 90-100°C before being fed into a tubular reactor and reacted at 90-100°C to obtain cyclopropylamine.

[0021] In one embodiment, step a includes: adding a mixed catalyst of γ-butyrolactone, triphosgene, N,N-dimethylformamide and pyridine to a reaction vessel, heating to 40-70°C, and maintaining the temperature for 1-24 hours; cooling to 20-35°C and slowly adding methanol dropwise, stirring the reaction for 1-24 hours after the addition is complete; distilling the reaction solution to recover methanol, adding 1-10% sodium hydroxide solution or sodium bicarbonate solution, stirring, allowing to stand for separation, separating the oil phase, washing with water until neutral, and dehydrating to obtain methyl 4-chlorobutyrate.

[0022] In one embodiment, the molar ratio of γ-butyrolactone to triphosgene is 1:0.34 to 1; more preferably, the molar ratio of γ-butyrolactone to triphosgene is 1:0.35 to 0.5.

[0023] In one embodiment, the mass ratio of γ-butyrolactone to the mixed catalyst is 10–30:1, preferably 15–25:1, and more preferably 20–24:1.

[0024] In one embodiment, the mass ratio of N,N-dimethylformamide to pyridine is 4 to 12:1, preferably 4 to 8:1, and more preferably 5 to 7:1.

[0025] In one embodiment, the molar ratio of γ-butyrolactone to methanol is 1:1.1 to 2, preferably 1:1.2 to 1.5.

[0026] In one embodiment, the concentration of the sodium hydroxide solution or sodium bicarbonate solution is 5-10%.

[0027] In one embodiment, the mixture is heated to 55–65°C and held at that temperature for 2–12 hours; then cooled to room temperature and the reaction continues at room temperature for 2–8 hours.

[0028] In one embodiment, step b includes: adding methyl 4-chlorobutyrate to a reaction vessel, controlling the reaction vessel temperature at 80-100°C, slowly adding 20-40% sodium methoxide-methanol solution, and maintaining the temperature for 0.5-12 hours after the addition is complete; after the reaction is completed, cooling to room temperature, adjusting the pH value to 4-5 with acid, filtering to remove salt, and evaporating the mixture of methanol and water to obtain methyl cyclopropionate.

[0029] In one embodiment, the molar ratio of methyl 4-chlorobutyrate to sodium methoxide is 1:1 to 1.5, preferably 1:1 to 1.2.

[0030] In one embodiment, the concentration of the sodium methoxide-methanol solution is 25-35%, preferably 30%.

[0031] In one embodiment, the reactor temperature is controlled at 90–95°C, the sodium methoxide-methanol solution is added over a period of 2–8 hours, and the reaction is maintained at this temperature for 1–3 hours after the addition is complete.

[0032] In one embodiment, the acid is at least one of hydrochloric acid, sulfuric acid, and glacial acetic acid, preferably 1-5M hydrochloric acid, more preferably 2-3M hydrochloric acid.

[0033] In one embodiment, step c includes: dissolving methyl cyclopropionate in methanol to prepare solution A, dissolving ammonia in sodium methoxide-methanol solution to prepare solution B, mixing solutions A and B in a pipe mixer and then preheating them to 100-130°C in a preheater, and then sending them to a tubular reactor. The reactor pressure is maintained at 1-3 MPa, the reaction temperature is controlled at 100-130°C, and the residence time is 10-120 min, generating cyclopropionamide and methanol. After the reaction is completed, the reaction solution is sent to a separation tower for deammoniation, then the pH value is adjusted to 4-5 with acid, heated to reflux, filtered while hot to remove salt, and methanol is distilled off to obtain cyclopropionamide.

[0034] In one embodiment, the mass ratio of methyl cyclopropionate to methanol in solution A is 0.3 to 2:1, preferably 0.8 to 1.5:1, and more preferably 1.1 to 1.4:1.

[0035] In one embodiment, the molar ratio of methyl cyclopropionate, ammonia, and sodium methoxide is 1:2 to 4:0.03 to 0.3, preferably 1:3 to 4:0.08 to 0.25, and more preferably 1:3 to 3.6:0.18 to 0.23.

[0036] In one embodiment, the concentration of the sodium methoxide-methanol solution is 5-20%, preferably 7-15%.

[0037] In one embodiment, the feed rate of solution A is 10–60 g / min, preferably 30–40 g / min; the feed rate of solution B is 10–60 g / min, preferably 30–40 g / min. The feed rates of solutions A and B are adjusted so that methyl cyclopropionate, ammonia, and sodium methoxide meet the set ratio.

[0038] In one embodiment, the reactor is preheated to 125–130°C, and the reaction temperature is controlled at 125–130°C. The reactor pressure is maintained at 2–2.5 MPa, and the residence time is 30–80 min.

[0039] In one embodiment, the acid is at least one of hydrochloric acid, sulfuric acid, and glacial acetic acid, preferably 1-5M hydrochloric acid, more preferably 2-3M hydrochloric acid.

[0040] In one embodiment, step d includes: dissolving cyclopropylformamide in water to prepare solution C; dissolving sodium hydroxide in sodium hypochlorite solution under cooling to prepare solution D; mixing solutions C and D in a pipe mixer and then preheating them to 90–100°C in a preheater; then feeding them into a tubular reactor and reacting them at 90–100°C for a residence time of 30–300 s; after the reaction is complete, distilling the reaction solution and collecting the fraction at 75–98°C to obtain an aqueous solution of cyclopropylamine; adding sodium hydroxide to the solution and stirring evenly, then performing atmospheric distillation and collecting the fraction at 49–50.5°C to obtain cyclopropylamine.

[0041] In one embodiment, the mass ratio of cyclopropylformamide to water is 1:3 to 10, preferably 1:3 to 5.

[0042] In one embodiment, the molar ratio of sodium hydroxide to sodium hypochlorite is 1.5 to 3:1, preferably 1.8 to 2.2:1.

[0043] In one embodiment, the molar ratio of cyclopropaneformamide to sodium hypochlorite is 1:1 to 1.5, preferably 1:1 to 1.2.

[0044] In one embodiment, the feed rate of solution C is 10–100 g / min, preferably 30–40 g / min; the feed rate of solution D is 20–120 g / min, preferably 60–75 g / min. The feed rates of solutions C and D are adjusted such that the molar ratio of cyclopropylformamide to sodium hypochlorite conforms to a predetermined ratio.

[0045] In one embodiment, the reactor is preheated to 95–100°C, and the reaction temperature is controlled at 95–100°C. The reactor pressure is atmospheric pressure, and the residence time is 40–100 s.

[0046] In one embodiment, the amount of sodium hydroxide added to the aqueous solution of cyclopropylamine is 1 to 10% of the mass of cyclopropylformamide, preferably 2 to 5%.

[0047] The beneficial effects of the present invention include: 1. In the chlorination process, thionyl chloride, which generates more toxic gases, is not used, but triphosgene is used instead, which produces fewer pollutants. At the same time, the yield of methyl 4-chlorobutyrate is guaranteed by using a combination catalyst of DMF and pyridine.

[0048] 2. Based on the batch process, through improvement and optimization, in addition to transforming the ammonolysis and degradation reactions into continuous processes, the post-processing processes of some sections have also been improved and optimized, which has greatly improved production efficiency.

[0049] 3. Breakthrough improvements were made to the cyclization and ammonolysis reaction sections. Toluene / xylene solvents were removed from the main process, allowing the use of methanol as the sole organic solvent throughout the entire process, simplifying the entire system. In the cyclization section, by adding sodium methoxide-methanol solution dropwise to methyl 4-chlorobutyrate at a set temperature, the conversion rate under aromatic solvent-free conditions was ensured. Methyl cyclopropionate was obtained after desalting and evaporating low-boiling-point methanol / water, without the need for distillation. In the ammonolysis section, methyl cyclopropionate was first dissolved in methanol, and ammonia was dissolved in sodium methoxide-methanol solution, improving the conversion rate and yield of ammonolysis under aromatic solvent-free conditions without causing large amounts of solid precipitation during the reaction, thus simplifying post-processing.

[0050] 4. Through experimental verification and optimization, the use of solid sodium methoxide in the cyclization process was optimized to a sodium methoxide solution, which simplified the operation and reduced the cost to a certain extent, and also provided a certain possibility for the continuous cyclization process.

[0051] 5. Taking advantage of the good solubility of ammonia in methanol, excess ammonia is absorbed and reused using methanol or sodium methoxide-methanol, avoiding the dangers of pressurized liquefaction for ammonia recovery and making the recovery process safer and more reliable.

[0052] 6. High yields at each step, with an overall yield of over 89% and high product purity.

[0053] In summary, the cyclopropylamine preparation method of the present invention has higher environmental friendliness, a simpler system and operation, and lower cost. It can produce high-purity cyclopropylamine in high yield, and is a promising method for the industrial preparation of cyclopropylamine. Detailed Implementation

[0054] The invention is described in more detail below to aid in understanding it.

[0055] Unless otherwise specified, the experimental methods in the following embodiments are conventional methods. Where specific techniques or conditions are not specified in the embodiments, they should be performed in accordance with the techniques or conditions described in the literature in this field, or in accordance with the product instructions.

[0056] Example 1:

[0057] 1) Chlorination

[0058] A mixed catalyst consisting of 258.0 kg (3.0 kmol) γ-butyrolactone, 312 kg (1.05 kmol) triphosgene, 10.5 kg N,N-dimethylformamide (DMF), and 1.5 kg pyridine was added to a reactor. The mixture was heated to 60 °C and maintained at this temperature for 6 h. After cooling to room temperature, 115 kg (3.6 kmol) methanol was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 4 h. The reaction solution was distilled to recover methanol. 300 kg of 5% sodium hydroxide solution was added, and the mixture was stirred for 30 min. After standing and separating the layers, the oil phase was separated, washed with water until neutral, and dried to obtain 402.0 kg of methyl 4-chlorobutyrate. D 20 The yield was 1.432, with a recovery rate of 98.1%.

[0059] 2) Ring closure

[0060] 389 kg (2.85 kmol) of methyl 4-chlorobutyrate was added to a reaction vessel, and the reaction vessel temperature was controlled at 55–60 °C. 540 kg of a 30% sodium methoxide-methanol solution (containing 3 kmol of sodium methoxide) was added dropwise over approximately 6 hours. After the addition was complete, the reaction was maintained at this temperature for 1 hour. After the reaction was complete, the temperature was lowered to room temperature, and the pH was adjusted to 4–5 with 3M hydrochloric acid. The mixture was filtered to remove salts, and methanol and water were evaporated to obtain 291.3 kg of methyl cyclopropionate. D 20 The yield was 1.419, with a recovery rate of approximately 97.1%.

[0061] 3) Ammonolysis

[0062] Solution A was prepared by dissolving 226.4 kg (2.26 kmol) of methyl cyclopropionate in 181.1 kg of methanol. Solution B was prepared by dissolving 24.2 kg (0.45 kmol) of sodium methoxide in 289.8 kg of methanol and then introducing 134.9 kg (7.9 kmol) of ammonia gas. Solution A was pumped through pump A and solution B through pump B to a pipeline mixer. The feed rate of solution A was 34.0 g / min and the feed rate of solution B was 37.4 g / min, so that the molar ratio of methyl cyclopropionate, ammonia gas, and sodium methoxide was 1:3. The mixture was prepared with a ratio of 0.5:0.2, preheated to 125–130°C, and then fed into a tubular reactor. The reactor was pressurized to 2.3–2.5 MPa, the reaction temperature was 125–130°C, and the residence time was 1 h, producing cyclopropylformamide and methanol. After the reaction was completed, the reaction solution was sent to a separation tower for deammoniation (absorbed and reused with methanol or sodium methoxide-methanol), the pH was adjusted to 4–5 with 3M hydrochloric acid, and the mixture was heated under reflux for 0.5 h. The solution was filtered while hot to remove salt, and concentrated to dryness to obtain cyclopropylformamide with a mp of 119–121°C. The yield was 96.8% based on the methyl cyclopropylformate feed rate.

[0063] 4) Degradation

[0064] 150 kg of cyclopropamide was dissolved in 600 kg of water to obtain solution C. Under cooling, 148 kg of sodium hydroxide was dissolved in 1440 kg of a 10% sodium hypochlorite solution to obtain solution C with a sodium hydroxide:sodium hypochlorite molar ratio of 2.1:1.1. Solution C was pumped through pump C, and solution D was pumped through pump D to a tubular mixer. The feed rate of solution C was 31.3 g / min, and the feed rate of solution D was 66.0 g / min, resulting in a molar ratio of cyclopropamide, sodium hypochlorite, and sodium hydroxide of 1:1.1:2.1. After preheating to 95-100℃, the solution was fed to a tubular reactor. The temperature in the tubular reactor was 95-100℃, and the residence time was 1 min. After the reaction was completed, the reaction solution was distilled, and the fraction at 75-98℃ was collected to obtain an aqueous solution of cyclopropamide. 5 kg of sodium hydroxide was added to this solution, and after stirring evenly, it was subjected to atmospheric distillation, and the fraction at 49-50.5℃ was collected to obtain cyclopropamide. D 20 The concentration was 1.420, and the content was determined by gas chromatography to be 99.8%, with a yield of 97.0% based on the cyclopropionamide feed rate.

[0065] The overall yield of cyclopropylamine calculated from the four-step reaction was approximately 89.4%.

[0066] Example 2:

[0067] 1) Chlorination

[0068] A mixed catalyst consisting of 258.0 kg (3.0 kmol) γ-butyrolactone, 312 kg (1.05 kmol) triphosgene, 7.5 kg N,N-dimethylformamide (DMF), and 1.5 kg pyridine was added to a reactor. The mixture was heated to 60 °C and maintained at this temperature for 8 h. After cooling to room temperature, 115 kg (3.6 kmol) methanol was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 4 h. The reaction solution was distilled to recover methanol. 300 kg of 5% sodium hydroxide solution was added, and the mixture was stirred for 30 min. After standing and separating the layers, the oil phase was separated, washed with water until neutral, and dried to obtain 400.8 kg of methyl 4-chlorobutyrate. D 20 The yield was 1.432, with a yield of 97.8%.

[0069] 2) Ring closure

[0070] 389 kg (2.85 kmol) of methyl 4-chlorobutyrate was added to a reaction vessel, and the reaction vessel temperature was controlled at 55–60 °C. 560 kg of a 30% sodium methoxide-methanol solution (containing 3.1 kmol of sodium methoxide) was added dropwise over approximately 6 hours. After the addition was complete, the reaction was maintained at this temperature for 1 hour. After the reaction was complete, the temperature was lowered to room temperature, and the pH was adjusted to 4–5 with 3M hydrochloric acid. The mixture was filtered to remove salts, and methanol and water were evaporated to obtain 292.2 kg of methyl cyclopropionate. D 20The yield was 1.419, and the recovery rate was approximately 97.4%.

[0071] 3) Ammonolysis

[0072] Solution A was prepared by dissolving 226.4 kg (2.26 kmol) of methyl cyclopropionate in 181.1 kg of methanol. Solution B was prepared by dissolving 24.2 kg (0.45 kmol) of sodium methoxide in 289.8 kg of methanol and then introducing 115.6 kg (6.8 kmol) of ammonia gas. Solution A was pumped through pump A and solution B through pump B to a pipeline mixer. The feed rate of solution A was 34.0 g / min and the feed rate of solution B was 35.8 g / min, so that the molar ratio of methyl cyclopropionate, ammonia gas, and sodium methoxide was 1:1. The mixture was prepared at a ratio of 3:0.2, preheated to 125–130°C, and then fed into a tubular reactor. The reactor was pressurized to 2.3–2.5 MPa, the reaction temperature was 125–130°C, and the residence time was 1 h, producing cyclopropylformamide and methanol. After the reaction was completed, the reaction solution was sent to a separation tower for deammoniation (absorbed with methanol or sodium methoxide-methanol and reused). The pH was adjusted to 4–5 with 3M hydrochloric acid, and the mixture was heated under reflux for 0.5 h. The solution was filtered while hot to remove salt, and concentrated to dryness to obtain cyclopropylformamide with a mp of 119–121°C. The yield was 97.1% based on the methyl cyclopropylformate feed rate.

[0073] 4) Degradation

[0074] 150 kg of cyclopropamide was dissolved in 600 kg of water to obtain solution C. Under cooling, 155 kg of sodium hydroxide was dissolved in 1575 kg of a 10% sodium hypochlorite solution to obtain solution C with a sodium hydroxide:sodium hypochlorite molar ratio of 2.2:1.2. Solution C was pumped through pump C, and solution D was pumped through pump D to a tubular mixer. The feed rate of solution C was 31.3 g / min, and the feed rate of solution D was 72.0 g / min, resulting in a molar ratio of cyclopropamide, sodium hypochlorite, and sodium hydroxide of 1:1.2:2.2. After preheating to 95-100℃, the mixture was fed to a tubular reactor. The temperature in the tubular reactor was 95-100℃, and the residence time was 1 min. After the reaction was complete, the reaction solution was distilled, and the fraction at 75-98℃ was collected to obtain an aqueous solution of cyclopropamide. 5 kg of sodium hydroxide was added to this solution, and after stirring evenly, it was subjected to atmospheric distillation, collecting the fraction at 49-50.5℃ to obtain cyclopropamide. D 20 The concentration was 1.420, and the content was determined by gas chromatography to be 99.7%, with a yield of 97.2% based on the cyclopropionamide feed rate.

[0075] The overall yield of cyclopropylamine, calculated from the four-step reaction, is approximately 89.9%.

[0076] Comparative Example 1:

[0077] 86 g (1.0 mol) of γ-butyrolactone, 104 g (0.35 mol) of triphosgene, and 4 g of DMF were added to a reactor. The mixture was heated to 60 °C and maintained at this temperature for 8 h. After cooling to room temperature, 38.4 g (1.2 mol) of methanol was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 4 h. The methanol was removed by distillation of the reaction solution. 100 g of 5% sodium hydroxide solution was added, and the mixture was stirred for 30 min. After standing and separating the layers, the oil phase was separated, washed with water until neutral, and dried to obtain 114.6 g of methyl 4-chlorobutyrate. D 20 The yield was 1.428, with a yield of 84.2%.

[0078] Comparative Example 2:

[0079] 86 g (1.0 mol) of γ-butyrolactone, 104 g (0.35 mol) of triphosgene, and 4 g of pyridine were added to a reactor. The mixture was heated to 60 °C and maintained at this temperature for 7 h. After cooling to room temperature, 38.4 g (1.2 mol) of methanol was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 4 h. The methanol was removed by distillation of the reaction solution. 100 g of 5% sodium hydroxide solution was added, and the mixture was stirred for 30 min. After standing and separating the layers, the oil phase was separated, washed with water until neutral, and dried to obtain 119.4 g of methyl 4-chlorobutyrate. D 20 The yield was 1.429, with a yield of 87.4%.

[0080] The above description is only a preferred embodiment of the present invention. It should be noted that those skilled in the art can make several improvements and additions without departing from the method of the present invention, and these improvements and additions should also be considered within the scope of protection of the present invention.

Claims

1. A method for preparing cyclopropylamine, comprising: a. Chlorination A mixed catalyst of γ-butyrolactone, triphosgene, N,N-dimethylformamide, and pyridine was added to a reactor and heated to 40-70°C, and the reaction was maintained at this temperature for 1-24 hours. After cooling to 20-35°C, methanol was slowly added dropwise, and the reaction was stirred for 1-24 hours after the addition was complete. The reaction solution was distilled to recover methanol, and 1-10% sodium hydroxide solution or sodium bicarbonate solution was added. The mixture was stirred, allowed to stand for separation, and the oil phase was separated, washed with water until neutral, and dehydrated to obtain methyl 4-chlorobutyrate. The molar ratio of γ-butyrolactone to triphosgene was 1:0.35-0.5; the mass ratio of γ-butyrolactone to the mixed catalyst was 10-30:1; and the mass ratio of N,N-dimethylformamide to pyridine was 5-7:

1. b. Circulation Methyl 4-chlorobutyrate was heated to 80-100°C, and sodium methoxide-methanol solution was slowly added. The reaction was then continued to yield methyl cyclopropionate. c. Ammonolysis Methyl cyclopropionate-methanol solution and ammonia-sodium methoxide-methanol solution are mixed, preheated to 100~130℃, and then fed into a tubular reactor. The reactor pressure is maintained at 1~3MPa, and the reaction temperature is controlled at 100~130℃ to produce cyclopropionamide. d. Degradation Cyclopropylformamide was dissolved in water, and sodium hydroxide was dissolved in sodium hypochlorite solution under cooling. The two solutions were mixed and preheated to 90-100°C before being fed into a tubular reactor and reacted at 90-100°C to obtain cyclopropylamine.

2. The preparation method according to claim 1, characterized in that, Step b includes: adding methyl 4-chlorobutyrate to a reaction vessel, controlling the reaction vessel temperature at 80~100℃, slowly adding 20~40% sodium methoxide-methanol solution, and maintaining the temperature for 0.5~12h after the addition is complete; after the reaction is completed, cooling to room temperature, adjusting the pH value to 4~5 with acid, filtering to remove salt, and evaporating the mixture of methanol and water to obtain methyl cyclopropionate.

3. The preparation method according to claim 1 or 2, characterized in that, The molar ratio of methyl 4-chlorobutyrate to sodium methoxide is 1:1 to 1.

5.

4. The preparation method according to claim 1, characterized in that, Step c includes: dissolving methyl cyclopropionate in methanol to prepare solution A, dissolving ammonia in sodium methoxide-methanol solution to prepare solution B, mixing solutions A and B in a pipe mixer and then preheating them to 100-130°C in a preheater, and then sending them to a tubular reactor. The reactor pressure is maintained at 1-3 MPa, the reaction temperature is controlled at 100-130°C, and the residence time is 10-120 min, generating cyclopropionamide and methanol. After the reaction is completed, the reaction solution is sent to a separation tower for deammoniation, then the pH value is adjusted to 4-5 with acid, heated to reflux, filtered while hot to remove salt, and methanol is distilled off to obtain cyclopropionamide.

5. The preparation method according to claim 4, characterized in that, The molar ratio of methyl cyclopropionate, ammonia, and sodium methoxide is 1:2~4:0.03~0.

3.

6. The preparation method according to claim 1, characterized in that, Step d includes: dissolving cyclopropylformamide in water to prepare solution C; dissolving sodium hydroxide in sodium hypochlorite solution under cooling to prepare solution D; mixing solutions C and D in a pipe mixer and then preheating them to 90-100°C in a preheater; then feeding them into a tubular reactor and reacting them at 90-100°C for a residence time of 30-300s; after the reaction is complete, the reaction solution is distilled, and the fraction at 75-98°C is collected to obtain an aqueous solution of cyclopropylamine; sodium hydroxide is added to the solution and stirred evenly, and then the solution is subjected to atmospheric distillation, and the fraction at 49-50.5°C is collected to obtain cyclopropylamine.

7. The preparation method according to claim 1 or 6, characterized in that, The molar ratio of sodium hydroxide to sodium hypochlorite is 1.5 to 3:1; the molar ratio of cyclopropaneformamide to sodium hypochlorite is 1:1 to 1.5.

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