Preparation method of 1-chloroethyl chloroformate

Abstract

The invention discloses a preparation method of 1-chloroethyl chloroformate. The preparation method comprises the following steps: preparing a mixed solution A of acetaldehyde and a catalyst in a batching kettle; respectively conveying triphosgene and dichloromethane into a continuous batching kettle by using a solid conveyor and a metering pump, and mixing to obtain a mixed solution B; controlling the pre-cooling temperature range of the microchannel reactor to be-25 DEG C to-10 DEG C, adjusting the flow velocity of the mixed solution A and the mixed solution B, and respectively pumping the mixed solution A and the mixed solution B into the microchannel reactor to form reaction solutions at the reaction temperature of-25 DEG C to-10 DEG C; and distilling the reaction material out of the micro-channel reactor, and rectifying to obtain the 1-chloroethyl chloroformate. According to the preparation method, the reaction time is remarkably shortened, the reaction temperature control is good, few byproducts are produced, the yield is high, meanwhile, the instability factor of using phosgene in the amplified production process is solved, and industrial amplified production is more facilitated.

Description

Technical Field

[0001] The invention belongs to the field of chemical synthesis, and specifically relates to a method for preparing 1-chloroethyl chloroformate. Background Art

[0002] Chloroethyl chloroformate is an efficient and mild reagent for removing benzyl protecting groups, especially for compounds containing easily reduced functional groups. It is also used in the pharmaceutical synthesis of cefpodoxime axetil, candesartan cilexetil, ceftriaxone, bacampicillin, ampiroxicam and other drugs.

[0003] At present, the synthesis methods of 1-chloroethyl chloroformate include chlorination method, acyl chloride method and phosgene method. The chlorination method uses ethyl chloroformate to react with chlorine, which has poor selectivity, low purity and low yield; the acyl chloride method uses ethyl chloroformate and sulfonyl chloride to carry out chlorination reaction under reflux, which has poor selectivity and produces a large amount of waste gas; the phosgene method uses phosgene to react with acetaldehyde under the action of a catalyst, which has good selectivity, high raw material toxicity and high process safety risk.

[0004] Patent CN 113861027A discloses a method for synthesizing chloroformate compounds by continuous flow. The method uses alcohol and triphosgene as raw materials, reacts in a continuous flow reactor under the action of a catalyst to obtain chloroformate compounds. The continuous flow reactor includes a preheating module, a mixing module, a reaction module, and a quenching module. The reaction process has high energy consumption, complicated post-processing, and 1-chloroethyl chloroformate is not prepared.

[0005] In view of the shortcomings of the existing technology, the market needs a safe and efficient preparation method for producing 1-chloroethyl chloroformate. Summary of the invention

[0006] Purpose of the invention: The purpose of the present invention is to overcome the deficiencies of the above-mentioned prior art and provide a method for preparing 1-chloroethyl chloroformate. To achieve the above-mentioned purpose, the technical solution provided by the present invention is as follows:

[0007] A method for preparing 1-chloroethyl chloroformate comprises the following steps:

[0008] Step 1: preparing a mixed solution A of acetaldehyde and a catalyst in a batching kettle;

[0009] Step 2: transporting triphosgene to a continuous batching kettle by a solid conveyor, and transporting dichloromethane to a continuous batching kettle by a metering pump, and mixing to obtain a mixed solution B;

[0010] Step 3: Control the precooling temperature range of the microchannel reactor to -25 to -10°C, adjust the flow rates of the mixed solution A and the mixed solution B, and pump them into the microchannel reactor to form a reaction solution, respectively, and the reaction temperature is -25 to -10°C;

[0011] Step 4: After the reaction materials are distilled out of the microchannel reactor, the fractions at 45-55°C and 10-20 mmHg are collected by distillation to obtain 1-chloroethyl chloroformate.

[0012] In step 1, the catalyst is pyridine, N,N-dimethylaminopyridine, N,N-dimethylformamide, N,N-dimethylacetamide or N,N-dimethylaniline, preferably pyridine.

[0013] In step 1, the molar ratio of acetaldehyde to catalyst is 1:0.03-0.20, preferably 1:0.05-0.10.

[0014] In step 2, the mass ratio of triphosgene to dichloromethane is 1:3-10, preferably 1:3-8.

[0015] In step 3, the molar ratio of acetaldehyde to triphosgene in the reaction solution is 1:0.25-0.35, preferably 1:0.33-0.35.

[0016] In step 3, the flow rate of the mixed solution A is 8-16 ml / min, and the flow rate of the mixed solution B is 20-40 ml / min.

[0017] In step 3, the reaction time is 60 to 300 s, preferably 150 to 300 s.

[0018] In step 2, the metering pump is a peristaltic pump, a diaphragm pump or a plunger pump.

[0019] The material of the microchannel reactor is silicon carbide, PTFE, Hastelloy, Monel or titanium.

[0020] The inner diameter of the microchannel reactor is 0.5-5 mm.

[0021] Beneficial effects: The invention uses aldehyde and triphosgene as raw materials, and obtains 1-chloroethyl chloroformate through continuous reaction in a microchannel reactor. Since the inner diameter of the channel of the microchannel reactor reaches the millimeter level, the specific surface area of ​​contact between materials is increased, and at the same time, it has a good heat transfer effect, shortens the reaction time, avoids the generation of by-products caused by inaccurate temperature control in the kettle reaction, improves the selectivity of the product, and realizes the efficient preparation of 1-chloroethyl chloroformate; at the same time, triphosgene is used to replace the phosgene in the prior art, solves the instability factor of phosgene storage in the scale-up production, reduces the risk factor of using phosgene, and is beneficial to industrial scale-up production; various influencing factors of synthesizing 1-chloroethyl chloroformate are studied through the microchannel reactor, the optimal parameter range is found, the conversion rate of acetaldehyde is improved, the yield of 1-chloroethyl chloroformate is improved, and at the same time, the temperature is efficiently controlled and the reaction by-products are less.

[0022] The abbreviations of the reaction reagents involved in the instructions are as follows:

[0023] DCM: dichloromethane;

[0024] DMAP: N,N-dimethylaminopyridine;

[0025] DMF: N,N-dimethylformamide;

[0026] DMAC: N,N-dimethylacetamide. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 This is a process flow chart for preparing compound I in Example 1. DETAILED DESCRIPTION

[0028] The present invention is further illustrated below in conjunction with specific embodiments. The embodiments are implemented based on the technical solutions of the present invention. It should be understood that these embodiments are only used to illustrate the present invention and are not used to limit the scope of the present invention.

[0029] Example 1

[0030] Synthesis of compound I (1-chloroethyl chloroformate):

[0031]

[0032] A mixed solution A of compound III (acetaldehyde) and catalyst pyridine is prepared in a batching kettle, and the molar ratio of acetaldehyde to pyridine in the mixed solution A is 1:0.1. Triphosgene and dichloromethane are respectively conveyed to a continuous batching kettle by a solid conveyor and a metering pump to mix to obtain a mixed solution B, and the mass ratio of triphosgene to dichloromethane in the mixed solution B is 1:3. The precooling temperature range of the microchannel reactor is controlled at -25°C, the flow rate of the mixed solution A is adjusted at 8ml / min, and the flow rate of the mixed solution B is adjusted at 20ml / min. The molar ratio of acetaldehyde and triphosgene is in the range of 1:0.33, and they are pumped into the microchannel reactor for mixing and reaction. The reaction temperature range is -25°C, and the retention time is 200s. After the reaction materials are distilled out of the microchannel reactor, the 45-55°C, 10-20mmHg fractions are collected by distillation to obtain 1-chloroethyl chloroformate. The process flow is as follows Figure 1 As shown, the material of the microchannel reactor is silicon carbide, PTFE, Hastelloy, monel or titanium, and the inner diameter of the microchannel reactor is 0.5-5 mm. The selectivity is the ratio of 1-chloroethyl ethyl formate and the by-product di(2-chloroethyl) carbonate, and the results are shown in Tables 1 and 2 below:

[0033] Table 1 Examples of preparing compound I under different temperature conditions

[0034]

[0035] Table 2 Comparative Examples of Compound I Prepared under Different Temperature Conditions

[0036]

[0037] From the results in Table 1, it can be seen that when the reaction temperature is between -25°C and -10°C, the yield and selectivity of compound I are higher.

[0038] As can be seen from Table 2, as the reaction temperature increases, the yield and selectivity of compound I both decrease, and the by-product di(2-chloroethyl) carbonate increases with the increase of temperature.

[0039] Example 2

[0040] Synthesis of compound I (1-chloroethyl chloroformate):

[0041]

[0042] A mixed solution A of compound III (acetaldehyde) and catalyst pyridine is prepared in a batching kettle, and the molar ratio of acetaldehyde to pyridine in the mixed solution A is 1:0.05. Triphosgene and dichloromethane are respectively transported to a continuous batching kettle by a solid conveyor and a metering pump to mix to obtain a mixed solution B, and the mass ratio of triphosgene to dichloromethane in the mixed solution B is 1:3. The precooling temperature range of the microchannel reactor is controlled at -20°C, the flow rate of the mixed solution A is adjusted at 8ml / min, and the flow rate of the mixed solution B is adjusted at 20ml / min. The molar ratio of acetaldehyde to triphosgene is in the range of 1:0.33, and they are pumped into the microchannel reactor for mixing and reaction. The reaction temperature range is -10°C, and the retention time is 200s. After the reaction material is distilled out of the microchannel reactor, the fractions at 45-55°C and 10-20 mmHg are collected by distillation to obtain 1-chloroethyl chloroformate. The selectivity is the ratio of 1-chloroethyl ethyl formate and the by-product di(2-chloroethyl) carbonate. The catalysts in Example 2-2.4 are all pyridine. The results are shown in Table 3 below:

[0043] Table 3 Examples of preparing compound I under different catalyst and different dosage conditions

[0044]

[0045] From the results in Table 3, it can be seen that when the molar ratio of compound III: catalyst is 1:0.05-0.15, the yield and selectivity of compound I are high, and when the molar ratio of compound III: catalyst is 1:0.1, the yield is the highest. With less or more catalyst, the yield of compound I decreases. Among the different catalysts, when the catalyst is pyridine, the yield and selectivity are the best.

[0046] Example 3

[0047] Synthesis of compound I (1-chloroethyl chloroformate):

[0048]

[0049] A mixed solution A of compound III (acetaldehyde) and catalyst pyridine is prepared in a batching kettle, and the molar ratio of acetaldehyde to pyridine in the mixed solution A is 1:0.1. Triphosgene and dichloromethane are respectively transported to a continuous batching kettle by a solid conveyor and a metering pump to mix to obtain a mixed solution B, and the mass ratio of triphosgene to dichloromethane in the mixed solution B is 1:3. The precooling temperature range of the microchannel reactor is controlled at -20°C, the flow rate of the mixed solution A is adjusted at 16ml / min, and the flow rate of the mixed solution B is adjusted at 40ml / min. The molar ratio of acetaldehyde to triphosgene is in the range of 1:0.33, and they are pumped into the microchannel reactor for mixing and reaction. The reaction temperature range is -10°C, and the retention time is 200s. After the reaction material is distilled out of the microchannel reactor, the fraction at 45-55°C and 10-20 mmHg is collected by rectification to obtain 1-chloroethyl chloroformate, and the selectivity is the ratio of 1-chloroethyl ethyl formate and the by-product di(2-chloroethyl) carbonate. The results are shown in Table 4 below:

[0050] Table 4 Examples of preparing compound I under different solvent dosage conditions

[0051]

[0052] From the results in Table 4, it can be seen that when the mass ratio of compound II to dichloromethane solvent is 1:3-8, the yield of compound I is higher.

[0053] Example 4

[0054] Synthesis of compound I (1-chloroethyl chloroformate):

[0055]

[0056] A mixed solution A of compound III (acetaldehyde) and catalyst pyridine is prepared in a batching kettle, and the molar ratio of acetaldehyde to pyridine in the mixed solution A is 1:0.1. Triphosgene and dichloromethane are respectively transported to a continuous batching kettle by a solid conveyor and a metering pump to mix to obtain a mixed solution B, and the mass ratio of triphosgene to dichloromethane in the mixed solution B is 1:3. The precooling temperature range of the microchannel reactor is controlled at -20°C, the flow rate of the mixed solution A is adjusted at 8ml / min, and the flow rate of the mixed solution B is adjusted at 20ml / min. The molar ratio of acetaldehyde to triphosgene is in the range of 1:0.33, and they are pumped into the microchannel reactor for mixing and reaction. The reaction temperature range is -10°C, and the retention time is 60s. After the reaction material is distilled out of the microchannel reactor, the fraction at 45-55°C and 10-20 mmHg is collected by rectification to obtain 1-chloroethyl chloroformate, and the selectivity is the ratio of 1-chloroethyl ethyl formate and the by-product di(2-chloroethyl) carbonate. The results are shown in Table 5 below:

[0057] Table 5 Examples of preparing compound I under different reaction time conditions

[0058]

[0059] From the results in Table 5, it can be seen that when the reaction time is between 150 and 300 seconds, the conversion rate of compound III reaches 100%, and the yield and selectivity of compound I are relatively high. The shortening and prolonging of the reaction time have an effect on the conversion rate of acetaldehyde and the yield of compound I.

[0060] Example 5

[0061] Synthesis of compound I (1-chloroethyl chloroformate):

[0062]

[0063] A mixed solution A of compound III (acetaldehyde) and catalyst pyridine is prepared in a batching kettle, and the molar ratio of acetaldehyde to pyridine in the mixed solution A is 1:0.1. Triphosgene and dichloromethane are respectively transported to a continuous batching kettle by a solid conveyor and a metering pump to mix to obtain a mixed solution B, and the mass ratio of triphosgene to dichloromethane in the mixed solution B is 1:3. The precooling temperature range of the microchannel reactor is controlled at -20°C, the flow rate of the mixed solution A is adjusted at 8ml / min, and the flow rate of the mixed solution B is adjusted at 20ml / min. The molar ratio of acetaldehyde to triphosgene is in the range of 1:0.25, and they are pumped into the microchannel reactor for mixing and reaction. The reaction temperature range is -10°C, and the retention time is 200s. After the reaction material is distilled out of the microchannel reactor, the fraction at 45-55°C and 10-20 mmHg is collected by rectification to obtain 1-chloroethyl chloroformate, and the selectivity is the ratio of 1-chloroethyl ethyl formate and the by-product di(2-chloroethyl) carbonate. The results are shown in Table 6 below:

[0064] Table 6 Examples of preparing compound I under different equivalent conditions of compound II

[0065]

[0066] From the results in Table 6, it can be seen that when the molar ratio of compound III:compound II is between 0.33 and 0.35, the conversion rate of compound III reaches 100%, and the yield and selectivity of compound I are relatively high.

[0067] Comparative Example 6 (tank reactor)

[0068] Synthesis of compound I (1-chloroethyl chloroformate):

[0069]

[0070] Compound III and catalyst pyridine were added to the reaction kettle, and a dichloromethane solution of triphosgene was added dropwise at a temperature of -10°C. After the reaction, distillation was performed and the fractions at 45-55°C and 10-20 mmHg were collected to obtain compound I (1-chloroethyl chloroformate). The results are shown in Table 7 below:

[0071] Table 7 Comparative Examples of Compound I Prepared by Tank Reactor

[0072]

[0073] From the results in Table 7, it can be seen that under the conditions of optimal parameters of the autoclave reactor, the yield is only 60%, and the selectivity is not good. At the same time, due to the poor heat transfer effect, acetaldehyde deteriorates in the system for a long time to produce trimeraldehyde, which is close to the boiling point of the product, resulting in poor quality of subsequent products. At the same time, compared with the autoclave reactor, the microchannel reactor has good temperature control to avoid the generation of more by-products, and also avoids the possibility of safety accidents caused by the decomposition of a large amount of triphosgene solution stored.

[0074] The above specific implementation methods further illustrate the purpose, technical solutions and beneficial effects of the present application in detail. It should be understood that the above are only specific implementation methods of the present application and are not used to limit the protection scope of the present application. Any modifications, equivalent substitutions, improvements, etc. made on the basis of the technical solutions of the present application should be included in the protection scope of the present application.

Claims

1. A method for preparing 1-chloroethyl chloroformate, characterized in that, The following steps are involved: Step 1: preparing a mixed solution A of acetaldehyde and a catalyst in a batching kettle; Step 2: transporting triphosgene to a continuous batching kettle by a solid conveyor, and transporting dichloromethane to a continuous batching kettle by a metering pump, and mixing to obtain a mixed solution B; Step 3: Control the precooling temperature range of the microchannel reactor to -25 to -10°C, adjust the flow rates of the mixed solution A and the mixed solution B, and pump them into the microchannel reactor to form a reaction solution, respectively, and the reaction temperature is -25 to -10°C; Step 4: After the reaction materials are distilled out of the microchannel reactor, the fractions at 45-55°C and 10-20 mmHg are collected by distillation to obtain 1-chloroethyl chloroformate.

2. The preparation method according to claim 1, characterized in that: In step 1, the catalyst is pyridine, N,N-dimethylaminopyridine, N,N-dimethylformamide, N,N-dimethylacetamide or N,N-dimethylaniline.

3. The preparation method according to claim 1 or 2, characterized in that: In step 1, the molar ratio of acetaldehyde to catalyst is 1:0.03-0.

20.

4. The preparation method according to claim 1, characterized in that: In step 2, the mass ratio of triphosgene to dichloromethane is 1:3-10.

5. The preparation method according to claim 1, characterized in that: In step 3, the molar ratio of acetaldehyde to triphosgene in the reaction solution is 1:0.25-0.

35.

6. The preparation method according to claim 1, characterized in that: In step 3, the flow rate of the mixed solution A is 8-16 ml / min, and the flow rate of the mixed solution B is 20-40 ml / min.

7. The preparation method according to claim 1, characterized in that: In step 3, the reaction time is 60 to 300 seconds.

8. The preparation method according to claim 1, characterized in that: In step 2, the metering pump is a peristaltic pump, a diaphragm pump or a plunger pump.

9. The preparation method according to claim 1, characterized in that: The material of the microchannel reactor is silicon carbide, PTFE, Hastelloy, Monel or titanium.

10. The preparation method according to claim 1, characterized in that: The inner diameter of the microchannel reactor is 0.5-5 mm.

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