阅读说明：本技术 一种连续流合成氯甲酸酯类化合物的方法 (Method for continuous flow synthesis of chloroformate compound ) 是由 张华东 王银 刘波 王鑫 郭鹏 于 2021-09-17 设计创作，主要内容包括：本发明提供了一种连续流合成氯甲酸酯类化合物的方法,属于合成工艺领域。所述方法包括以下步骤：以化合物X和三光气为原料,在催化剂的作用下于连续流反应器中进行反应,得到氯甲酸酯类化合物；其中,化合物X的结构为氯甲酸酯类化合物的结构为：利用本发明的连续流合成方法实现了氯甲酸酯类化合物的高效、绿色制备。另外,本发明的连续流合成方法将反应时间显著缩短,同时解决了放大生产过程中使用光气的不稳定性因素,更有益于工业化放大生产。(The invention provides a method for continuously synthesizing chloroformate compounds, belonging to the field of synthesis processes. The method comprises the following steps: reacting a compound X and triphosgene serving as raw materials in a continuous flow reactor under the action of a catalyst to obtain a chloroformate compound; wherein the compound X has the structure The structure of the chloroformate compound is as follows: the continuous flow synthesis method of the invention realizes the high-efficiency and green preparation of chloroformate compounds. In addition, the continuous flow synthesis method of the invention obviously shortens the reaction time, solves the instability factor of phosgene used in the amplification production process, and is more beneficial to industrial amplification production.)

1. A method for continuous flow synthesis of chloroformate compounds, characterized in that: the method comprises the following steps: reacting a compound X and triphosgene serving as raw materials in a continuous flow reactor under the action of a catalyst to obtain a chloroformate compound;

the structure of compound X isThe structure of the chloroformate compound is as follows:R₁selected from the following unsubstituted or substituted by a substituent: c_1～12Alkyl radical, C_1～12Alkoxy, aryl and heteroaryl, wherein the substituent is selected from nitro, amino, halogen and cyano.

2. The method of claim 1, wherein: the continuous flow reactor comprises a preheating module, a mixing module, a reaction module and a quenching module; the method comprises the following steps:

(1) uniformly mixing the compound X with a catalyst to obtain a material A;

(2) uniformly mixing triphosgene and a solvent to obtain a material B;

(3) inputting the material A and the material B into a preheating module to obtain a material 1; inputting the material 1 into a mixing module to obtain a material 2; inputting the material 2 into a reaction module to obtain a material 3; inputting the material 3 into a quenching module, and inputting a quenching agent into the quenching module to quench and react to obtain the chloroformate compound.

3. The method of claim 2, wherein: the continuous flow reactor is a microchannel reactor;

and/or, in the step (1), the catalyst is alkali; the equivalent ratio of the catalyst to the compound X is (0.05 to 0.50) eq: 1 eq;

and/or in the step (2), the solvent is an organic solvent, and the equivalent ratio of the triphosgene to the compound X is (0.20-0.50) eq: 1eq, and the molar concentration of triphosgene in the material B is 0.35-1.5 mol/L;

and/or, in step (3), the quenching agent is water.

4. The method of claim 3, wherein: in the step (1), the alkali is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, triethylamine, pyridine, aniline, N-dimethylaniline, N-diethylaniline and N, N-dimethylaminopyridine; the equivalent ratio of the catalyst to the compound X is (0.20 to 0.35) eq: 1 eq;

and/or in the step (2), the organic solvent is selected from tetrahydrofuran, dichloromethane, 1, 2-dichloroethane and toluene, and the equivalent ratio of triphosgene to the compound X is (0.33-0.35) eq: 1eq, and the molar concentration of triphosgene in the material B is 0.35-1.5 mol/L;

and/or in the step (3), the flow rate ratio of the material A to the material B is 1: (2.5-3.5), the ratio of the flow rate of the quenching agent to the sum of the flow rates of the material A and the material B is 1: (0.5-2.0).

5. The method of claim 4, wherein: in the step (1), the base is triethylamine, and the equivalent ratio of the catalyst to the compound X is 0.34 eq: 1 eq;

and/or, in the step (2), the organic solvent is 1, 2-dichloroethane, and the equivalent ratio of triphosgene to the compound X is 0.34 eq: 1eq, and the molar concentration of triphosgene in the material B is 1.0 mol/L;

and/or in the step (3), the flow rate ratio of the material A to the material B is 1: 2.75, the ratio of the flow rate of the quenching agent to the sum of the flow rates of feed A and feed B was 1: 1.

6. the method of claim 1, wherein: in the step (3), the temperature of the preheating module is set to be 40-55 ℃, and the material retention time is 0.1-4 min;

and/or setting the temperature of the mixing module to be 45-65 ℃ and the retention time of the materials to be 0.1-2 min;

and/or the reaction setting temperature of the reaction module is 45-65 ℃, and the material retention time is 0.1-10 min;

and/or setting the temperature of the quenching module to be 0-30 ℃ and the quenching reaction time to be 0.1-2 min.

7. The method of claim 6, wherein: in the step (3), the temperature of the preheating module is set to be 45 ℃, and the material retention time is 1 min;

and/or the temperature of the mixing module is set to be 50 ℃, and the material retention time is 0.3 min;

and/or the reaction setting temperature of the reaction module is 55 ℃, and the material retention time is 1.1 min;

and/or the temperature of the quenching module is set to be 10 ℃, and the time of quenching reaction is 0.3 min.

8. The method of claim 1, wherein: after the quenching reaction is finished, the method further comprises the following operations: and (3) standing and separating the system after the quenching reaction, and concentrating and distilling the organic phase to obtain the chloroformate compound.

9. The method according to any one of claims 1 to 8, wherein: r₁Selected from the following unsubstituted or substituted by a substituent: c_1～6Alkyl radical, C_1～6Alkoxy and phenyl, wherein the substituent is selected from nitro, amino, halogen and cyano.

10. The method according to any one of claims 9, wherein: r₁Is selected from Preferably, R₁Is composed of

Technical Field

The invention belongs to the field of synthesis processes, and particularly relates to a method for continuously synthesizing chloroformate compounds.

Background

Chloroformate compounds are intermediates with increasingly wide application, and are commonly used intermediates for synthesizing medical compounds, pesticide compounds and the like. Chloroformate compounds are in various types and include n-butyl chloroformate, n-hexyl chloroformate and the like. Wherein, chloroformic acid n-butyl ester is also called butyl chloromethyl ester, CAS number: 592-34-7, which is a key intermediate in the synthesis of efavirenz.

Efavirenz (English: Efavirenz) is a specific drug against HIV, belongs to the class of non-nucleoside reverse transcriptase inhibitors (NNRTI) and can be used in highly active antiretroviral therapy for the treatment of human immune virus A (HIV type 1). N-butyl chloroformate is a key intermediate for synthesizing efavirenz (the synthetic route is as follows).

The existing method for synthesizing the chloroformic acid n-butyl ester mainly comprises the following steps: 1580g of n-butanol (M ═ 74) was preheated to 100 ℃, fed from the upper inlet of the reactive distillation column by means of an advection pump, and fully contacted with phosgene (0.5MPa, M ═ 98.9) fed from the lower inlet in the reaction zone, at a temperature of 100 ℃. The generated hydrogen chloride and excessive phosgene enter a subsequent recovery device through the top of the tower, the hydrogen chloride and the excessive phosgene are separated in a deep condensation chemical book mode at the temperature of minus 40 ℃, liquid phosgene enters a reaction rectifying tower through a heat exchanger for reuse, and hydrogen chloride gas is introduced into 1.0 wt% of NaOH aqueous solution for absorption. The chloroformic acid n-butyl ester as a single product flow enters a storage tank through a tower kettle for subsequent use. The composition of the reaction solution is analyzed by gas chromatography, and the result shows that the conversion rate of the butanol is more than 99.9 percent and the selectivity of the chloroformate is more than 99.9 percent. However, the synthesis method adopts phosgene as a raw material, and the phosgene has instability factors in the storage process and the amplification production process, so that the method is suitable for small-batch production in a laboratory and is not suitable for industrial amplification production.

The continuous flow micro-channel reactor technology is one of the most popular technologies in the international pharmaceutical and chemical fields at present. The continuous flow microchannel reactor has the characteristics of fast mass transfer and fast heat transfer, and is beneficial to the fine control of the reaction process. More importantly, the implementation of continuous flow can also avoid the danger brought to the reaction process due to the rapid accumulation of heat in the reaction process. Due to the small volume of the reactor, the safety risk of the whole process is greatly reduced even if a harsh reaction process is adopted. Therefore, the technology has the advantages of high-efficiency mass and heat transfer, accurate temperature and time control, intrinsic safety, no amplification effect and the like. However, the continuous flow microchannel reactor technology is not suitable for synthesis of all substances, and the purpose can be achieved by simply applying the process in the traditional reaction kettle to the reaction in the continuous flow microchannel reactor. The microstructure of the continuous flow microchannel reactor causes that the method is not suitable for the reaction in which a large amount of solid is generated in the reaction, otherwise, the microchannel is easy to block, and the production cannot be continuously carried out; in the continuous flow microchannel reactor, the raw material flow, the equivalent ratio of reactants and the setting parameters of each module in the continuous flow microchannel reactor need to be strictly controlled according to the characteristics of target products. The processes for synthesis using continuous flow microchannel reactors are generally not the same for different target products.

At present, no report is found for preparing the butyl chloroformate by using a continuous flow microchannel reactor. In order to synthesize n-butyl chloroformate safely, efficiently and rapidly, a process for synthesizing n-butyl chloroformate by using a continuous flow microchannel reactor is urgently needed to be developed.

Disclosure of Invention

The invention aims to provide a continuous flow synthesis method which is efficient, rapid, safe and environment-friendly and can obviously improve the yield and purity of chloroformate compounds.

The invention provides a method for continuous flow synthesis of chloroformate compounds, which comprises the following steps: reacting a compound X and triphosgene serving as raw materials in a continuous flow reactor under the action of a catalyst to obtain a chloroformate compound;

the structure of compound X isThe structure of the chloroformate compound is as follows:R₁selected from the following unsubstituted or substituted by a substituent: c_1～12Alkyl radical, C_1～12Alkoxy, aryl and heteroaryl, wherein the substituent is selected from nitro, amino, halogen and cyano.

Further, the continuous flow reactor comprises a preheating module, a mixing module, a reaction module and a quenching module; the method comprises the following steps:

(1) uniformly mixing the compound X with a catalyst to obtain a material A;

(2) uniformly mixing triphosgene and a solvent to obtain a material B;

(3) inputting the material A and the material B into a preheating module to obtain a material 1; inputting the material 1 into a mixing module to obtain a material 2; inputting the material 2 into a reaction module to obtain a material 3; inputting the material 3 into a quenching module, and inputting a quenching agent into the quenching module to quench and react to obtain the chloroformate compound.

Further, the continuous flow reactor is a microchannel reactor;

and/or, in the step (1), the catalyst is alkali; the equivalent ratio of the catalyst to the compound X is (0.05 to 0.50) eq: 1 eq;

and/or in the step (2), the solvent is an organic solvent, and the equivalent ratio of the triphosgene to the compound X is (0.20-0.50) eq: 1eq, and the molar concentration of triphosgene in the material B is 0.35-1.5 mol/L;

and/or, in step (3), the quenching agent is water.

Further, in the step (1), the base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, triethylamine, pyridine, aniline, N-dimethylaniline, N-diethylaniline, N-dimethylaminopyridine; the equivalent ratio of the catalyst to the compound X is (0.20 to 0.35) eq: 1 eq;

and/or in the step (2), the organic solvent is selected from tetrahydrofuran, dichloromethane, 1, 2-dichloroethane and toluene, and the equivalent ratio of triphosgene to the compound X is (0.33-0.35) eq: 1eq, and the molar concentration of triphosgene in the material B is 0.35-1.5 mol/L;

and/or in the step (3), the flow rate ratio of the material A to the material B is 1: (2.5-3.5), the ratio of the flow rate of the quenching agent to the sum of the flow rates of the material A and the material B is 1: (0.5-2.0).

Further, in step (1), the base is triethylamine, and the equivalent ratio of the catalyst to the compound X is 0.34 eq: 1 eq;

and/or, in the step (2), the organic solvent is 1, 2-dichloroethane, and the equivalent ratio of triphosgene to the compound X is 0.34 eq: 1eq, and the molar concentration of triphosgene in the material B is 1.0 mol/L;

and/or in the step (3), the flow rate ratio of the material A to the material B is 1: 2.75, the ratio of the flow rate of the quenching agent to the sum of the flow rates of feed A and feed B was 1: 1.

further, in the step (3), the temperature of the preheating module is set to be 40-55 ℃, and the material retention time is 0.1-4 min;

and/or setting the temperature of the mixing module to be 45-65 ℃ and the retention time of the materials to be 0.1-2 min;

and/or the reaction setting temperature of the reaction module is 45-65 ℃, and the material retention time is 0.1-10 min;

and/or setting the temperature of the quenching module to be 0-30 ℃ and the quenching reaction time to be 0.1-2 min.

Further, in the step (3), the temperature of the preheating module is set to be 45 ℃, and the material retention time is 1 min;

and/or the temperature of the mixing module is set to be 50 ℃, and the material retention time is 0.3 min;

and/or the reaction setting temperature of the reaction module is 55 ℃, and the material retention time is 1.1 min;

and/or the temperature of the quenching module is set to be 10 ℃, and the time of quenching reaction is 0.3 min.

Further, after the quenching reaction is finished, the method further comprises the following operations: and (3) standing and separating the system after the quenching reaction, and concentrating and distilling the organic phase to obtain the chloroformate compound.

Further, R₁Selected from the following unsubstituted or substituted by a substituent: c_1～6Alkyl radical, C_1～6Alkoxy and phenyl, wherein the substituent is selected from nitro, amino, halogen and cyano.

Further, R₁Is selected fromPreferably, R₁Is composed of

Compared with the prior art, the method for synthesizing chloroformate compounds has the following advantages:

1) the invention uses continuous flow reactor for the first time, uses alcohol or phenol as raw material, and prepares various chloroformate compounds through continuous reaction with triphosgene; by applying the method, continuous feeding, continuous reaction and continuous quenching are realized, and the high-efficiency preparation of the chloroformate compound is realized;

2) the method of the invention obviously shortens the unit reaction time, enables the chloroformate compound to be continuously and efficiently produced in an enlarged scale, and enables the industrialized mass production of the chloroformate compound to be safer and more green;

3) in the method, triphosgene is used for replacing phosgene in the prior art, so that the instability factor of phosgene storage in amplification production is solved, the risk coefficient of phosgene usage is reduced, the labor cost is saved, and the industrial amplification production is facilitated;

4) compared with the existing traditional reaction, the method of the invention can stop the reaction or terminate the reaction at any time according to the actual situation, and the post-treatment can be carried out in batch or combined according to the requirement, thus being convenient and simple.

5) The method of the invention can obtain the chloroformate compound with high purity and high yield.

Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.

The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.

Drawings

FIG. 1 is a schematic diagram of the process for synthesizing chloroformate compounds using a microchannel reactor according to the present invention.

Detailed Description

The raw materials and equipment used in the invention are known products and are obtained by purchasing commercial products.

EXAMPLE 1 Synthesis of n-butyl chloroformate Using Microchannel reactor

The microchannel reactor comprises a preheating module (also called a first-stage module), a mixing module (also called a second-stage module), a reaction module (also called a third-stage module) and a quenching module which are connected in sequence.

1. Preparing raw materials:

solution A: 350g (1.00eq) of n-butanol and 162.1g (0.34eq) of triethylamine were mixed homogeneouslyObtaining a solution A; the n-butanol structure:R₁＝C₄H₉；

solution B: 476g (0.34eq) of triphosgene and 1.6L of 1, 2-dichloroethane were mixed well to give solution B; in the solution B, the concentration of triphosgene is 1.0 mol/L;

solution C: tap water.

2. The module parameters are set as follows:

preheating module temperature control 45 ℃, module volume: 50 mL;

temperature control of the mixing module was 50 ℃, module volume: 20 mL;

temperature control of the reaction module was 55 ℃, module volume: 140 mL;

quench module temperature control 10 ℃, module volume: 20 mL;

the total volume of the microchannel reactor was 230mL, and the total time was 2.7 minutes.

The total volume of the microchannel reactor is equal to the volume of a preheating module, the volume of a mixing module, the volume of a reaction module and the volume of a quenching module;

the total time is preheating module residence time, mixing module residence time, reaction module residence time and quenching module residence time.

3. The specific operation is as follows:

starting an automatic feeding system, respectively conveying and feeding the solution A and the solution B by a metering pump, wherein the flow rate of the solution A is 40mL/min, the flow rate of the solution B is 110mL/min, preheating the two materials by a preheating module for 1min, then feeding the materials into a mixing module, staying for 0.3min, feeding the materials into a reaction module, and staying for 1.1min, and then feeding the materials into a quenching module; the feed system was then turned on and the reaction was quenched by continuously feeding tap water (flow rate 150mL/min) for 0.3 min. And (3) carrying out post-treatment on the system after the quenching reaction: standing for phase separation, taking the organic phase, concentrating and distilling under reduced pressure (10mmHg, 50-55 ℃) to obtain 458.4g of the target product n-butyl chloroformate, wherein the yield is 99.5%, and the GC purity is 99.3%.

Example 2 Synthesis of 2-ethyl-1-butyl chloroformate using a microchannel reactor

1. Preparing raw materials:

solution A: uniformly mixing 0.35kg (1.00eq) of 2-ethyl-1-butanol and 117.8g (0.34eq) of triethylamine to obtain a solution A; 2-ethyl-1-butanol structure:R₁＝C₆H₁₃，

solution B: uniformly mixing 0.34eq of triphosgene and a 1, 2-dichloroethane solution to obtain a solution B; in the solution B, the concentration of triphosgene is 1.0 mol/L;

solution C: tap water.

2. The module parameters are set as follows:

preheating module temperature control 45 ℃, module volume: 150 mL;

temperature control of the mixing module was 50 ℃, module volume: 75 mL;

temperature control of the reaction module was 55 ℃, module volume: 300 mL;

the temperature of the quenching module was controlled at 10 ℃ and the volume of the module was 20 mL.

3. The specific operation is as follows:

starting an automatic feeding system, respectively conveying and feeding the solution A and the solution B by a metering pump, wherein the flow rate of the solution A is 40mL/min, the flow rate of the solution B is 110mL/min, preheating the two materials by a preheating module for 1min, then feeding the materials into a mixing module, staying for 0.5min, feeding the materials into a reaction module, and staying for 2min, and then feeding the materials into a quenching module; the feed system was then turned on and the reaction was quenched by continuously feeding tap water (flow rate 150mL/min) for 0.1 min. And (3) carrying out post-treatment on the system after the quenching reaction: standing for phase separation, taking the organic phase, concentrating and distilling under reduced pressure to obtain 441.2g of the target product 2-ethyl-1-butyl chloroformate, wherein the GC purity is 99.0 percent, and the yield is 94.5 percent.

Example 3 Synthesis of p-nitrophenyl chloroformate Using a Microchannel reactor

1. Preparing raw materials:

solution A: 0.35kg (1.00eq) of p-nitrophenol, 1750mL of toluene and86.5g (0.34eq) of triethylamine are mixed uniformly to obtain a solution A; p-nitrophenol structure:R₁＝C₆H₆O₃N，

solution B: uniformly mixing 0.34eq of triphosgene and a 1, 2-dichloroethane solution to obtain a solution B; in the solution B, the concentration of triphosgene is 1.0 mol/L; (ii) a

Solution C: tap water.

2. The module parameters are set as follows:

preheating module temperature control 45 ℃, module volume: 115 mL;

temperature control of the mixing module was 50 ℃, module volume: 100 mL;

temperature control of the reaction module was 55 ℃, module volume: 140 mL;

the temperature of the quenching module was controlled at 10 ℃ and the volume of the module was 20 mL.

3. The specific operation is as follows:

starting an automatic feeding system, respectively conveying and feeding the solution A and the solution B by a metering pump, wherein the flow rate of the solution A is 120mL/min, the flow rate of the solution B is 110mL/min, preheating the two materials by a preheating module for 30s, then feeding the materials into a mixing module, staying for 0.4min, feeding the materials into a reaction module, and staying for 2.5min, and then feeding the materials into a quenching module; the feed system was then turned on and the reaction was quenched by continuously feeding tap water (230 mL/min), 0.1 min. And (3) carrying out post-treatment on the system after the quenching reaction: standing for phase separation, taking the organic phase, concentrating under reduced pressure, and crystallizing at 25 ℃ to obtain 384.50g of the target product p-nitrophenyl chloroformate, wherein the GC purity is 99.4% and the yield is 95.8%.

Example 4 Synthesis of n-butyl chloroformate Using Microchannel reactor

The base used in this example is different from that used in example 1.

1. Preparing raw materials:

solution A: 0.35kg (1.00eq) of n-butanol and 27.1g (0.34eq) of pyridine were mixed well to give solution A; (ii) a

Solution B: 0.34eq of triphosgene and 1, 2-dichloroethane are mixed uniformly to obtain a solution B; in the solution B, the concentration of triphosgene is 1.0 mol/L;

solution C: tap water;

2. the module parameters are set as follows:

preheating module temperature control 45 ℃, module volume: 50 mL;

temperature control of the mixing module was 50 ℃, module volume: 20 mL;

temperature control of the reaction module was 55 ℃, module volume: 140 mL;

quench module temperature control 10 ℃, module volume: 20 mL.

3. The specific operation is as follows:

starting an automatic feeding system, respectively conveying and feeding the solution A and the solution B by a metering pump, wherein the flow rate of the solution A is 40mL/min, the flow rate of the solution B is 110mL/min, the two materials are preheated by a preheating module for 0.3min, then the materials enter a mixing module, stay for 0.13min, then the materials enter a reaction module, and stay for 0.9min, then the materials enter a quenching module; the feed system was then turned on and the reaction was quenched by continuously feeding tap water (flow rate 150mL/min) for 0.13 min. And (3) carrying out post-treatment on the system after the quenching reaction: standing for phase separation, taking the organic phase, concentrating and distilling under reduced pressure to obtain 422.7g of target product n-butyl chloroformate, wherein the GC purity is 99.6 percent, and the yield is 94.2 percent.

Example 5 Synthesis of n-butyl chloroformate Using Microchannel reactor

The temperature of the preheating module of this embodiment is different from that of embodiment 1.

1. Preparing raw materials:

solution A: uniformly mixing 0.35kg (1.00eq) of n-butanol with 162.0g (0.34eq) of triethylamine to obtain a solution A;

solution B: 0.34eq of triphosgene and 1, 2-dichloroethane are mixed uniformly to obtain a solution B; in the solution B, the concentration of triphosgene is 1.0 mol/L;

solution C: tap water.

2. The module parameters are set as follows:

preheating module temperature control 55 ℃, module volume: 50 mL;

temperature control of the mixing module was 50 ℃, module volume: 20 mL;

temperature control of the reaction module was 55 ℃, module volume: 400 mL;

quench module temperature control 10 ℃, module volume: 20 mL.

3. The specific operation is as follows:

starting an automatic feeding system, respectively conveying and feeding the solution A and the solution B by a metering pump, wherein the flow rate of the solution A is 40mL/min, the flow rate of the solution B is 110mL/min, preheating the two materials by a preheating module for 0.33min, then feeding the materials into a mixing module, staying for 0.13min, feeding the materials into a reaction module, and staying for 2.67min, and then feeding the materials into a quenching module; the feed system was then turned on and the reaction was quenched by continuously feeding tap water (flow rate 150mL/min) for 0.1 min. And (3) carrying out post-treatment on the system after the quenching reaction: standing for phase separation, taking the organic phase, concentrating and distilling under reduced pressure to obtain 411.2g of target product n-butyl chloroformate, wherein the GC purity is 99.1 percent, and the yield is 95.3 percent.

Example 6 Synthesis of n-butyl chloroformate Using Microchannel reactor

The quench module of this example was fed at a different flow rate of tap water than in example 1.

1. Preparing raw materials:

solution A: uniformly mixing 0.35kg (1.00eq) of n-butanol with 162.0g (0.34eq) of triethylamine to obtain a solution A;

solution B: 0.34eq of triphosgene and 1, 2-dichloroethane are mixed uniformly to obtain a solution B; in the solution B, the concentration of triphosgene is 1.0 mol/L;

solution C: tap water.

2. The module parameters are set as follows:

preheating module temperature control 45 ℃, module volume: 50 mL;

temperature control of the mixing module was 50 ℃, module volume: 20 mL;

temperature control of the reaction module was 55 ℃, module volume: 260 mL;

quench module temperature control 10 ℃, module volume: 20 mL.

3. The specific operation is as follows:

starting an automatic feeding system, respectively conveying and feeding the solution A and the solution B by a metering pump, wherein the flow rate of the solution A is 40mL/min, the flow rate of the solution B is 110mL/min, preheating the two materials by a preheating module for 0.33min, then feeding the materials into a mixing module, staying for 0.13min, feeding the materials into a reaction module, and staying for 1.73min, and then feeding the materials into a quenching module; the feed system was then turned on and the reaction was quenched by continuously feeding tap water (flow rate 300mL/min) for 0.13 min. And (3) carrying out post-treatment on the system after the quenching reaction: standing for phase separation, taking the organic phase, concentrating and distilling under reduced pressure to obtain 387.4g of target product n-butyl chloroformate, wherein the GC purity is 99.4 percent, and the yield is 95.9 percent.

Example 7 Synthesis of n-butyl chloroformate Using Microchannel reactor

The solvent of this example is different from example 1.

1. Preparing raw materials:

solution A: uniformly mixing 0.35kg (1.00eq) of n-butanol with 162.0g (0.34eq) of triethylamine to obtain a solution A;

solution B: 0.34eq of triphosgene and toluene are mixed uniformly to obtain a solution B; in the solution B, the concentration of triphosgene is 1.0 mol/L;

solution C: tap water.

2. The module parameters are set as follows:

preheating module temperature control 45 ℃, module volume: 50 mL;

temperature control of the mixing module was 50 ℃, module volume: 20 mL;

temperature control of the reaction module was 55 ℃, module volume: 300 mL;

quench module temperature control 10 ℃, module volume: 20 mL.

3. The specific operation is as follows:

starting an automatic feeding system, respectively conveying and feeding the solution A and the solution B by a metering pump, wherein the flow rate of the solution A is 40mL/min, the flow rate of the solution B is 110mL/min, the two materials are preheated by a preheating module for 0.33min, then the materials enter a mixing module, stay for 0.13min, then the materials enter a reaction module, and stay for 2.0min, then the materials enter a quenching module; the feed system was then turned on and the reaction was quenched by continuously feeding tap water (flow rate 150mL/min) for 0.13 min. And (3) carrying out post-treatment on the system after the quenching reaction: standing for phase separation, taking the organic phase, concentrating and distilling under reduced pressure to obtain 466.6g of target product n-butyl chloroformate, wherein the GC purity is 99.1 percent, and the yield is 92.0 percent.

Example 8 Synthesis of n-butyl chloroformate Using Microchannel reactor

The amount of triphosgene used in this example was different from that of example 1.

1. Preparing raw materials:

solution A: uniformly mixing 0.35kg (1.00eq) of n-butanol with 162.0g (0.34eq) of triethylamine to obtain a solution A;

solution B: 0.35eq triphosgene and 1, 2-dichloroethane are mixed uniformly to obtain a solution B; in the solution B, the concentration of triphosgene is 1.0 mol/L;

solution C: tap water.

2. The module parameters are set as follows:

preheating module temperature control 45 ℃, module volume: 50 mL;

temperature control of the mixing module was 50 ℃, module volume: 20 mL;

temperature control of the reaction module was 55 ℃, module volume: 700 mL;

quench module temperature control 10 ℃, module volume: 20 mL.

3. The specific operation is as follows:

starting an automatic feeding system, respectively conveying and feeding the solution A and the solution B by a metering pump, wherein the flow rate of the solution A is 40mL/min, the flow rate of the solution B is 110mL/min, preheating the two materials by a preheating module for 0.33min, then feeding the materials into a mixing module, staying for 0.33min, feeding the materials into a reaction module, and staying for 4.67min, and then feeding the materials into a quenching module; the feed system was then turned on and the reaction was quenched by continuously feeding tap water (flow rate 150mL/min) for 0.13 min. And (3) carrying out post-treatment on the system after the quenching reaction: standing for phase separation, taking the organic phase, concentrating and distilling under reduced pressure to obtain 439.3g of target product n-butyl chloroformate, wherein the GC purity is 98.4 percent, and the yield is 94.2 percent.

Example 9 Synthesis of n-butyl chloroformate Using Microchannel reactor

The module parameter setting of this embodiment is different from that of embodiment 1.

1. Preparing raw materials:

solution A: uniformly mixing 0.35kg (1.00eq) of n-butanol with 162.0g (0.34eq) of triethylamine to obtain a solution A;

solution B: 0.34eq of triphosgene and 1, 2-dichloroethane are mixed uniformly to obtain a solution B; in the solution B, the concentration of triphosgene is 1.0 mol/L;

solution C: tap water.

2. The module parameters are set as follows:

preheating module temperature control 45 ℃, module volume: 100 mL;

temperature control of the mixing module was 50 ℃, module volume: 30 mL;

temperature control of the reaction module was 55 ℃, module volume: 400 mL;

quench module temperature control 10 ℃, module volume: 20 mL.

3. The specific operation is as follows:

starting an automatic feeding system, respectively conveying and feeding the solution A and the solution B by a metering pump, wherein the flow rate of the solution A is 40mL/min, the flow rate of the solution B is 110mL/min, preheating the two materials by a preheating module for 0.67min, then feeding the materials into a mixing module, staying for 0.2min, feeding the materials into a reaction module, and staying for 2.67min, and then feeding the materials into a quenching module; the feed system was then turned on and the reaction was quenched by continuously feeding tap water (flow rate 150mL/min) for 0.13 min. And (3) carrying out post-treatment on the system after the quenching reaction: standing for phase separation, taking the organic phase, concentrating and distilling under reduced pressure to obtain 468.8g of target product n-butyl chloroformate, wherein the GC purity is 98.6 percent, and the yield is 95.3 percent.

Example 10 Synthesis of n-butyl chloroformate Using Microchannel reactor

The module temperature setting of this example is different from that of example 1.

1. Preparing raw materials:

solution A: uniformly mixing 0.35kg (1.00eq) of n-butanol with 162.0g (0.34eq) of triethylamine to obtain a solution A;

solution B: 0.34eq of triphosgene and 1, 2-dichloroethane are mixed uniformly to obtain a solution B; in the solution B, the concentration of triphosgene is 1.0 mol/L;

solution C: tap water.

2. The module parameters are set as follows:

preheating module temperature control 50 ℃, module volume: 50 mL;

temperature control of the mixing module was 45 ℃, module volume: 20 mL;

temperature control of the reaction module is 60 ℃, volume of the module: 140 mL;

quench module temperature control 10 ℃, module volume: 20 mL.

3. The specific operation is as follows:

starting an automatic feeding system, respectively conveying and feeding the solution A and the solution B by a metering pump, wherein the flow rate of the solution A is 40mL/min, the flow rate of the solution B is 110mL/min, the two materials are preheated by a preheating module for 0.3min, then the materials enter a mixing module, stay for 0.13min, then the materials enter a reaction module, and stay for 0.93min, then the materials enter a quenching module; the feed system was then turned on and the reaction was quenched by continuously feeding tap water (flow rate 150mL/min) for 0.13 min. And (3) carrying out post-treatment on the system after the quenching reaction: standing for phase separation, taking the organic phase, concentrating and distilling under reduced pressure to obtain 418.1g of target product n-butyl chloroformate, wherein the GC purity is 99.0 percent, and the yield is 95.4 percent.

Example 11 Synthesis of n-butyl chloroformate Using Microchannel reactor

The equipment specification, material parameters and the like are the same as those in example 1, and the difference from example 1 is only that the temperature of a mixing module is controlled to be 55 ℃, the GC purity of the target product, namely the n-butyl chloroformate, is 98.6 percent, and the yield is 79.1 percent.

Example 12 Synthesis of n-butyl chloroformate Using Microchannel reactor

The equipment specification, material parameters and the like are the same as those in example 1, and the difference from example 1 is only that the temperature of a reaction module is controlled to 65 ℃, the GC purity of the target product, namely n-butyl chloroformate, is 98.4%, and the yield is 82.5%.

Example 13 Synthesis of n-butyl chloroformate Using Microchannel reactor

The equipment specification, material parameters and the like are the same as those in example 1, and the difference from example 1 is only that the equivalent weight of triethylamine is 0.2eq, the GC purity of the target product n-butyl chloroformate is 95.4%, and the yield is 80.2%.

Example 14 Synthesis of n-butyl chloroformate Using Microchannel reactor

The equipment specification, material parameters and the like are the same as those in example 1, and the difference from example 1 is only that the equivalent weight of triethylamine is 0.35eq, the GC purity of the target product n-butyl chloroformate is 97.4%, and the yield is 73.6%.

Example 15 Synthesis of n-butyl chloroformate Using Microchannel reactor

The equipment specification, material parameters and the like are the same as those of the example 1, and the difference from the example 1 is only that triphosgene is changed into phosgene, the GC purity of the target product n-butyl chloroformate is 99.1 percent, and the yield is 68.4 percent.

Example 16 Synthesis of n-butyl chloroformate Using Microchannel reactor

The equipment specification, material parameters and the like are the same as those of example 15, and the difference from example 15 is only that the equivalent weight of phosgene is 0.5eq, the GC purity of the target product, n-butyl chloroformate, is 99.2%, and the yield is 73.2%.

Compared with the traditional method, the method for synthesizing the chloroformic acid n-butyl ester by continuous flow obviously shortens the time consumption and obviously improves the efficiency.

In conclusion, the invention provides a continuous flow synthesis method of chloroformate compounds. The continuous flow synthesis method of the invention realizes the high-efficiency and green preparation of chloroformate compounds. In addition, the continuous flow synthesis method of the invention obviously shortens the reaction time, solves the instability factor of phosgene used in the amplification production process, and is more beneficial to industrial amplification production.