Method for preparing triethyl phosphonoacetate by using microchannel reactor

Abstract

The invention provides a method for preparing triethyl phosphonoacetate by using micro-channel reactors based on Michael Arbuzov rearrangement reaction, triethyl phosphite and halogenated ethyl acetate are used as initial raw materials, the reaction system is effectively optimized by using the micro-channel reactors which are sequentially connected in series under the conditions of no catalyst and no solvent, and the yield of triethyl phosphonoacetate is increased. And the continuous flow process of the target product triethyl phosphonoacetate is completed. Compared with the existing synthesis process, the method has the advantages that continuous feeding is adopted, so that the reaction flux is increased, the loss of raw material dripping feeding in the reaction process and the risk accompanying reaction heat release are reduced, the reaction temperature is effectively reduced, the reaction time is shortened, and the reaction safety is improved.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing triethyl phosphonoacetate by utilizing a microchannel reactor. Background Art

[0002] As an important chemical substance, triethyl phosphonoacetate is widely used in medicine, pesticide and other chemical production due to its excellent structural characteristics and pharmacological activity. Among them, in many classic organic reactions, triethyl phosphonoacetate not only serves as an important reaction intermediate, but also a key link in the synthesis of common drugs. The construction of the CP bond in phosphonate compounds is often prepared by Michael Arbuzov rearrangement reaction using triethyl phosphite and ethyl halide as raw materials, but traditional kettle reactions often require the addition of catalysts and reaction solvents and post-treatment, and have disadvantages such as high reaction temperature, long reaction time, low reaction yield, and high environmental pollution.

[0003] The microchannel reactor is composed of a number of reaction modules. Among them, the size of the microchannel is only at the micron level and the specific surface area is very large. It is composed of a heat transfer layer-reaction layer-heat transfer layer arranged alternately. It not only greatly enhances mixing, mass transfer, reaction rate, shortens reaction time, improves reaction efficiency, and improves selectivity, but also has extremely high heat exchange efficiency, which is ten times, a hundred times, or even a thousand times higher than conventional reaction vessels. It can quickly remove a large amount of reaction heat released instantly, maintain the reaction temperature, reduce the traditional process cycle volume, and improve reaction safety. In addition, the microchannel reactor can achieve precise control of the reaction through metering pump feeding, reduce raw material consumption, especially reduce the amount of expensive, toxic, and harmful reactants, inhibit the occurrence of side reactions, and improve the purity and yield of the product. It can meet many chemical reaction process requirements, especially liquid-liquid and gas-liquid reactions.

[0004] The invention utilizes a microreactor to solve the technical problems that cannot or are difficult to solve in the traditional autoclave reaction of triethyl phosphonoacetate, optimizes the high mass transfer and heat transfer performance, improves the reaction temperature and the reaction time, completes the continuous flow process of triethyl phosphonoacetate under the condition of no catalyst and no solvent, effectively reduces the loss of raw materials and the amount of toxic and harmful reactants in the reaction process, and greatly improves the purity and yield of the product. Summary of the invention

[0005] The main purpose of the present invention is to provide a method for preparing triethyl phosphonoacetate using a microchannel reactor. The microchannel reactor is used to realize the catalyst-free and solvent-free production of triethyl phosphonoacetate, which not only solves the problems of high reaction temperature and long reaction time, but also correspondingly improves the yield of the product and improves the product quality.

[0006] A method for preparing triethyl phosphonoacetate using a microchannel reactor, characterized in that it comprises the following steps: (1) pumping raw materials triethyl phosphite and ethyl halide into the first premixing module in the continuous flow microreactor respectively for cooling and premixing; (2) The mixed materials flow through the first reaction module, the second reaction module, and the third reaction module in sequence to undergo a gradient temperature increase reaction; (3) After the reaction is completed, the product is cooled by a cooling module, and then degassed and purified by distillation from the outlet of the continuous flow microreactor to obtain triethyl phosphonoacetate.

[0007] In the above technical solution, the flow rates of triethyl phosphite and ethyl halide in the micro-reactor are 1.0-10.0 mL / min and 0.5-5.0 mL / min, respectively.

[0008] In the above technical scheme, the ethyl halide includes one or more of ethyl chloroacetate, ethyl bromoacetate and ethyl iodoacetate.

[0009] In the above technical solution, the plate temperature of the first premixing module in the microchannel reactor is 10~30℃, the plate temperature of the first reaction module is 40~50℃, the plate temperature of the second reaction module is 50~70℃, the plate temperature of the third reaction module is 70~100℃, and the plate temperature of the cooling module is 20~30℃.

[0010] In the above technical solution, the residence time of the mixed materials in step (2) in each reaction module is 2 to 4 minutes.

[0011] In the above technical solution, the molar ratio of triethyl phosphite to ethyl halide is 1:0.8-1.1.

[0012] In the above technical solution, the end of the microreactor is equipped with a back pressure valve, wherein the reaction pressure is controlled at 1.1-5.0 bar.

[0013] Compared with the traditional autoclave synthesis, the present invention provides a method for preparing triethyl phosphonoacetate using a microchannel reactor. The excellent mass transfer and heat transfer performance of the microreactor is used to improve some problems in the traditional synthesis of triethyl phosphonoacetate, such as long reaction time, high reaction temperature, and cumbersome reaction operation. It is found through experiments that the use of a microreactor to accurately control the material ratio not only reduces the loss during the raw material addition process, but also improves the ease of operation and the safety of the reaction. More importantly, it also solves the problems of high reaction temperature and long reaction time that have always existed, and realizes a catalyst-free, solvent-free continuous flow process for triethyl phosphonoacetate. DETAILED DESCRIPTION

[0014] The present invention is further described below with reference to embodiments, but the scope of protection claimed by the present invention is not limited to the scope described in the embodiments.

[0015] First, the solvent cyclohexane was pumped in to clean the reaction module and check for leaks in the line connections, and the plunger pump used was calibrated. After the leak detection calibration was completed, the corresponding microchannel reaction conditions were optimized.

[0016] Example 1 The raw materials ethyl chloroacetate and triethyl phosphite were simultaneously pumped into the microchannel reactor at flow rates of 1.54 mL / min and 0.95 mL / min, respectively, by a high-throughput plunger pump for reaction. The plate temperature of each reaction module was set at 30 °C, the reaction pressure was about 1 bar, and after the reaction was completed for 16.4 min, the product triethyl phosphonoacetate was obtained by discharging liquid at the outlet with a yield of 25.4%.

[0017] Example 2 The raw materials triethyl phosphite (Feed A) and ethyl chloroacetate (Feed B) were simultaneously pumped into the microchannel reactor for reaction according to the corresponding reaction molar ratio (as shown in the following table) by a high-throughput plunger pump. The plate temperature of each reaction module was set to 80 °C, the reaction pressure was about 1 bar, and the plunger pump flow of triethyl phosphite and ethyl chloroacetate was continuously adjusted (as shown in the following table). After the reaction was completed for 16.4 min, the liquid was discharged from the discharge port, and the yield of triethyl phosphonoacetate under different reaction molar ratios and different feed flow rates could be compared when the plate temperature was constant, the reaction residence time was constant, and the yield of triethyl phosphonoacetate under different reaction molar ratios and different feed flow rates could be obtained.

[0018]

[0019] Example 3 The raw materials ethyl chloroacetate and triethyl phosphite were simultaneously pumped into the microchannel reactor at flow rates of 1.54 mL / min and 0.95 mL / min, respectively, by a high-throughput plunger pump for reaction. The reaction mixture was first fully premixed in a premixing module at 30 °C. Then, it flowed through the first reaction module, the second reaction module, and the third reaction module in sequence for gradient temperature increase reaction. Among them, the plate temperature of the first reaction module was 40 °C, the plate temperature of the second reaction module was 50 °C, the plate temperature of the third reaction module was 70 °C, and the plate temperature of the cooling module was 30 °C. The pressure of each reaction module was controlled at about 2 bar. After the reaction system stayed in the premixing module and the first reaction module, the second reaction module, the third reaction module, and the cooling module for 16.4 min, the liquid was discharged at the discharge port to obtain the product triethyl phosphonoacetate with a yield of 85.4%.

[0020] Example 4 The raw materials ethyl chloroacetate and triethyl phosphite were simultaneously pumped into the microchannel reactor at flow rates of 1.54 mL / min and 0.95 mL / min, respectively, by a high-throughput plunger pump for reaction. The reaction mixture was first fully premixed in the premixing module at 30 °C. Then, it flowed through the first reaction module, the second reaction module, and the third reaction module in sequence for gradient temperature increase reaction. Among them, the plate temperature of the first reaction module was 40 °C, the plate temperature of the second reaction module was 60 °C, the plate temperature of the third reaction module was 80 °C, and the plate temperature of the cooling module was 30 °C. The reaction pressure was controlled at about 3 bar. After the reaction system stayed in the premixing module and the first reaction module, the second reaction module, the third reaction module, and the cooling module for 16.4 min, the liquid was discharged at the discharge port to obtain the product triethyl phosphonoacetate with a yield of 94.5%.

[0021] Example 5 The raw materials ethyl bromoacetate and triethyl phosphite were pumped into the microchannel reactor at a reaction molar ratio of 1:1 by a high-throughput plunger pump for reaction. The reaction mixture was first fully premixed in the premixing module at 30 °C. Then, it flowed through the first reaction module, the second reaction module, and the third reaction module in sequence for gradient temperature reaction. Among them, the plate temperature of the first reaction module was 40 °C, the plate temperature of the second reaction module was 60 °C, the plate temperature of the third reaction module was 80 °C, and the plate temperature of the cooling module was 30 °C. The reaction pressure was controlled at about 3 bar. After the reaction system stayed in the premixing module and the first reaction module, the second reaction module, the third reaction module, and the cooling module for 16.4 min, the liquid was discharged at the discharge port to obtain the product triethyl phosphonoacetate with a yield of 95.7%.

[0022] Example 6 The raw materials ethyl iodide and triethyl phosphite were pumped into the microchannel reactor at a reaction molar ratio of 1:1 by a high-throughput plunger pump for reaction. The reaction mixture was first fully premixed in the premixing module at 30 °C. Then, it flowed through the first reaction module, the second reaction module, and the third reaction module in sequence for gradient temperature increase reaction. Among them, the plate temperature of the first reaction module was 40 °C, the plate temperature of the second reaction module was 60 °C, the plate temperature of the third reaction module was 80 °C, and the plate temperature of the cooling module was 30 °C. The reaction pressure was controlled at about 3 bar. After the reaction system stayed in the premixing module and the first reaction module, the second reaction module, the third reaction module, and the cooling module for 16.4 min, the liquid was discharged at the discharge port to obtain the product triethyl phosphonoacetate with a yield of 98.2%.

[0023] It can be seen from the above embodiments that the above description of the present invention is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for preparing triethyl phosphonoacetate using a microchannel reactor, characterized in that: The steps include: (1) pumping raw materials triethyl phosphite and ethyl halide into the first premixing module in the continuous flow microreactor respectively for cooling and premixing; (2) The mixed materials flow through the first reaction module, the second reaction module, and the third reaction module in sequence to undergo a gradient temperature increase reaction; (3) After the reaction is completed, the product is cooled by a cooling module, and then degassed and purified by distillation from the outlet of the continuous flow microreactor to obtain triethyl phosphonoacetate.

2. The method for preparing triethyl phosphonoacetate using a microchannel reactor according to claim 1, characterized in that: The flow rates of triethyl phosphite and ethyl halide in the micro-reactor are 1.0-10.0 mL / min and 0.5-5.0 mL / min respectively.

3. The method for preparing triethyl phosphonoacetate by using a microchannel reactor according to claim 2, characterized in that: The ethyl halide includes one or more of ethyl chloroacetate, ethyl bromoacetate and ethyl iodoacetate.

4. The method for preparing triethyl phosphonoacetate using a microchannel reactor according to claim 1, characterized in that: The plate temperature of the first premixing module in the microchannel reactor is 10~30°C, the plate temperature of the first reaction module is 40~50°C, the plate temperature of the second reaction module is 50~70°C, the plate temperature of the third reaction module is 70~100°C, and the plate temperature of the cooling module is 20~30°C.

5. The method for preparing triethyl phosphonoacetate using a microchannel reactor according to claim 1, characterized in that: The residence time of the mixed materials in step (2) in each reaction module is 2 to 4 minutes.

6. The method for preparing triethyl phosphonoacetate using a microchannel reactor according to claim 1, characterized in that: The molar ratio of triethyl phosphite to ethyl halide is 1:0.8-1.

1.

7. The method for preparing triethyl phosphonoacetate using a microchannel reactor according to claim 1, characterized in that: The end of the microreactor is equipped with a back pressure valve, wherein the reaction pressure is controlled at 1.1-5.0 bar.

Images