CN110437069B - Continuous synthesis method of 2-fluoro-malonic diester compound - Google Patents
Continuous synthesis method of 2-fluoro-malonic diester compound Download PDFInfo
- Publication number
- CN110437069B CN110437069B CN201910775355.0A CN201910775355A CN110437069B CN 110437069 B CN110437069 B CN 110437069B CN 201910775355 A CN201910775355 A CN 201910775355A CN 110437069 B CN110437069 B CN 110437069B
- Authority
- CN
- China
- Prior art keywords
- continuous
- reaction
- equipment
- temperature
- fluoro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
- C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
Abstract
The invention discloses a continuous synthesis method of 2-fluoro-malonic diester compounds. The continuous synthesis method comprises the following steps: to be provided with
Taking the raw materials as raw materials, carrying out continuous decarbonylation reaction in continuous reaction equipment to obtain 2-fluoro-malonic diester compounds
Description
Technical Field
The invention relates to the field of pharmaceutical chemicals, and particularly relates to a continuous synthesis method of 2-fluoro-malonic diester compounds.
Background
2-fluoro-malonic diester is an important fluorine-containing organic intermediate, can perform a series of reactions such as alkylation, alkoxylation, hydroxyalkylation and the like, is widely applied to the production of organic synthesis, medicines, pesticides, perfumes, dyes and the like, can also be used for preparing amino acid, and is widely applied to biochemical research. Therefore, the 2-fluoro-malonic diester derivative has extremely wide fields and very wide development prospects, and the development of a high-benefit and low-cost 2-fluoro-malonic diester synthesis process is of great significance.
At present, the method for preparing 2-fluoro-malonic diester mainly comprises the following steps: carbonyl elimination, esterification, cracking, and fluorination.
At present, most of domestic manufacturers adopt a hydrogen fluoride salt fluorination method, namely, a target product is prepared by using malonic diester as a raw material and performing two-step reactions of chlorination and triethylamine hydrogen fluoride salt fluorination. The method has the main defects of high raw material toxicity, strong corrosion to equipment, higher requirement on reaction equipment, and influence on product quality and yield due to dichloromalonate and dichloromalonate diester generated in the reaction process. In addition, triethylamine is difficult to recover and generates a large amount of nitrogen-containing wastewater in the post-treatment process, the treatment is troublesome, and the environment is greatly polluted.
Chinese patent (CN 102531897) provides a method for preparing 2-fluoro diethyl malonate, wherein the method takes fluoro ethyl acetate and diethyl oxalate as initial raw materials, and the 2-fluoro diethyl malonate is synthesized by condensation and oxidation steps, the total yield is 32.5%, and the method still has the problems of low yield and more three wastes.
Chinese patent (CN 107935853) provides a new method for preparing diethyl 2-fluoromalonate, which uses ethyl fluoroacetate, diethyl carbonate and sodium hydride as initial raw materials to synthesize diethyl 2-fluoromalonate with a total yield of 52.3%, and in contrast, the method has a higher yield, but the main disadvantage of the process is that sodium hydride is used, a large amount of hydrogen is generated during the production process, the process is more dangerous, the process does not have the capacity of industrial production, a large amount of diethyl carbonate is needed, and the diethyl carbonate is difficult to recover during the post-treatment process.
In addition, most of the traditional processes adopt a kettle type reactor, if high-temperature and high-pressure reaction is required, the traditional kettle type reaction has great safety risk, has high requirements on equipment, and is not suitable for industrial mass production. Meanwhile, the reaction time of the traditional kettle type process is long, often tens of hours or even days are needed, and the production efficiency is low.
Disclosure of Invention
The invention aims to provide a continuous synthesis method of 2-fluoro-malonic diester compounds, so as to improve the production efficiency.
In order to achieve the above object, according to one aspect of the present invention, a continuous synthesis method of 2-fluoro malonic acid diester compounds is provided. The continuous synthesis method comprises the following steps: to be provided with
Taking the raw materials as raw materials, carrying out continuous decarbonylation reaction in continuous reaction equipment to obtain 2-fluoro-malonic diester compounds
Wherein R and R 'independently represent a linear or branched alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic ring or a cyclic alkyl group, and R' are the same or different.
Further, decarbonylation reaction is high-temperature decarbonylation reaction, and the high temperature is 200-500 ℃; preferably 250 to 450 ℃.
Further, the decarbonylation reaction is carried out under the condition of no solvent or with solvent, and when the solvent is available, the solvent is one or more selected from the group consisting of water, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, benzene, toluene, xylene, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, methanol, ethanol, isopropanol, dichloromethane, biphenyl, ethylene glycol, hexamethylphosphoric triamide, phenol, pyridine, m-xylene, o-xylene, diphenyl ether, cyclohexanone, cyclohexanol, o-cresol, diethyl carbonate, diethyl oxalate morpholine, N-octadecane, N-eicosane, silicone oil, diethyl malonate, diethylene glycol diethyl ether, and chloroform; preferably, the solvent is selected from
The amount of the surfactant is 1-50 mL/g.
Further, the continuous reaction apparatus includes a tubular continuous reactor or a column reactor.
Furthermore, the residence time of the raw materials in the continuous reaction equipment is 5-50 min, preferably 10-30 min.
Further, will
Dissolving in a solvent to form
A solution; then will be
Continuously pumping the solution into continuous reaction equipment for reaction; or directly will
Continuously pumping into a continuous reaction device for reaction.
Further, the air conditioner is provided with a fan,
solutions or
The pumping speed of (A) is 0.5 to 50mL/min, preferably 25 to 35 mL/min.
Further, a continuous reaction apparatus is provided comprising: the heat exchange equipment is used for adjusting the temperature of the continuous reaction equipment; temperature detection equipment for monitoring the reaction temperature in the continuous reaction equipment; a pressure detection device for monitoring the reaction pressure in the continuous reaction device; the online PAT equipment is used for detecting the product composition of the continuous reaction equipment; and the automatic control system is electrically connected with the liquid pump, the heat exchange equipment, the temperature detection equipment, the pressure detection equipment and the online PAT equipment.
Further, the pressure of the continuous reaction equipment is 0.5-10 MPa.
Further, a rectifying device is arranged at the downstream of the continuous reaction equipment.
The invention adopts continuous reaction equipment to realize the high-temperature carbonyl elimination reaction of 2-fluoro-3-oxosuccinic acid diester. Compare in traditional kettle-type reaction, because the material volume that participates in the reaction in the unit interval significantly reduces, high temperature danger area reduces, and the safety risk obtains greatly reducing, can heat the raw materials to reaction temperature in the twinkling of an eye through continuous reactor, avoids long-time intensification process to cause the raw materials to decompose, can more accurate control to process parameter, and the yield has obtained the improvement. Furthermore, an automatic control system is adopted, so that the relevant parameters of the reaction, such as temperature, pressure, flow rate and the like, can be accurately controlled and fed back in real time.
Detailed Description
It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict. The present invention will be described in detail with reference to examples.
Aiming at the technical problems in the prior art, the invention provides the following technical scheme.
According to a typical embodiment of the invention, a continuous synthesis method of 2-fluoro-malonic acid diester compounds is provided. The continuous synthesis method comprises the following steps: to be provided with
Taking the raw materials as raw materials, carrying out continuous decarbonylation reaction in continuous reaction equipment to obtain 2-fluoro-malonic diester compounds
Wherein R and R 'respectively represent a linear or branched alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic ring or a cyclic alkyl group, and R' may be the same or different.
The invention adopts continuous reaction equipment to realize the high-temperature carbonyl elimination reaction of 2-fluoro-3-oxosuccinic acid diester. Compare in traditional kettle-type reaction, because the material volume that participates in the reaction in the unit interval significantly reduces, high temperature danger area reduces, and the safety risk obtains greatly reducing, can heat the raw materials to reaction temperature in the twinkling of an eye through continuous reactor, avoids long-time intensification process to cause the raw materials to decompose, can more accurate control to process parameter, and the yield has obtained the improvement. Furthermore, an automatic control system is adopted, so that the relevant parameters of the reaction, such as temperature, pressure, flow rate and the like, can be accurately controlled and fed back in real time.
The invention adopts continuous reaction equipment, and the raw material solution flows through the continuous reactor, thereby greatly shortening the reaction time and obviously improving the production efficiency.
In addition, the invention successfully avoids the use of highly toxic hydrogen fluoride salts, the materials in the process have little corrosion to equipment and lower requirements on the equipment, and the high-temperature carbonyl elimination method is a self-reaction of the raw materials, so that other reagents or solvents are not needed in the reaction and the post-treatment, the cost is lower, and the three wastes are less.
Therefore, the technical scheme of the invention solves the problems of high safety risk, low production efficiency, high raw material toxicity, higher requirement on reaction equipment, large amount of three wastes, larger pollution to the environment and the like of the traditional kettle type process.
The decarbonylation reaction is a high-temperature decarbonylation reaction, and the high temperature is 200-500 ℃; preferably 250 to 450 ℃.
The decarbonylation reaction can be carried out under the condition of no solvent or with solvent, and when the solvent is adopted, the solvent is selected from water, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, glycol dimethyl ether, diethylene glycol dimethyl ether, benzene, toluene, xylene, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide and N, one or more selected from the group consisting of N-diethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, methanol, ethanol, isopropanol, dichloromethane, biphenyl, ethylene glycol, hexamethylphosphoric triamide, phenol, pyridine, m-xylene, o-xylene, diphenyl ether, cyclohexanone, cyclohexanol, o-cresol, diethyl carbonate, diethyl oxalate, morpholine, N-octadecane, N-eicosane, silicone oil, diethyl malonate, diethylene glycol diethyl ether and chloroform; the solvents have no special functional groups, are stable, are not easy to react, have relatively low price and are beneficial to the control of industrial production cost. Preferred solvents are those relative to
The amount of (A) is 1 to 50mL/g。
In a typical embodiment of the present invention, the continuous reaction apparatus comprises a tubular continuous reactor or a column reactor, and the internal special structure of the coil reactor can increase the reaction effect, such as: glass beads are added into the coil pipe, so that the heating area of the raw materials can be increased. In order to fully react and not to reduce the production efficiency, the retention time of the raw materials in the continuous reaction equipment is 5-50 min, preferably 10-30 min.
In a typical embodiment of the present invention, the decarbonylation reaction is carried out in the absence of a solvent, with the advantages of: a solvent is not used, so that the cost is saved, and three wastes are reduced; the product can be directly rectified by post-treatment, and the step of distilling to remove the solvent is saved.
In an exemplary embodiment of the invention, the invention will be described
Dissolving in a solvent to form
A solution; then will be
Continuously pumping the solution into continuous reaction equipment for reaction; or directly will
Continuously pumping into a continuous reaction device for reaction. Preferably, the first and second liquid crystal materials are,
solutions or
The pumping speed is 0.5-50 mL/min, preferably 25-35 mL/min, and the pumping speed can improve the unit time yield of continuous reaction under the condition of ensuring sufficient reaction time.
According to a typical embodiment of the invention, the continuous reaction equipment is provided with heat exchange equipment, temperature detection equipment, pressure detection equipment, online PAT equipment and an automatic control system, wherein the heat exchange equipment is used for adjusting the temperature of the continuous reaction equipment; the temperature detection equipment is used for monitoring the reaction temperature in the continuous reaction equipment; the pressure detection equipment is used for monitoring the reaction pressure in the continuous reaction equipment; an online PAT apparatus (Process Analytical Technology) for detecting the product composition of a continuous reaction apparatus; the automatic control system is electrically connected with the liquid pump, the heat exchange equipment, the temperature detection equipment, the pressure detection equipment and the online PAT equipment.
Preferably, the pressure of the continuous reaction equipment is 0.5-10 MPa, and the pressure is controlled within the range, so that the material is in a liquid state at the temperature, and sufficient retention time of the material in the continuous reactor is ensured.
According to a typical embodiment of the present invention, a rectification device is also provided downstream of the continuous reaction apparatus.
After the synthesis reaction is finished, the product can be obtained by removing impurities through simple rectification, the purity is up to more than 98%, and the post-treatment operation is simple.
The following examples are provided to further illustrate the advantageous effects of the present invention.
Example 1
Referring to chinese patent (CN 102531897), 614.0kg of tetrahydrofuran (1kg/6L) is added into a 1000L reaction kettle at one time, 156.3kg of sodium tert-butoxide (1.5eq) and 136.5kg of diethyl oxalate (1.3eq) are added in batches, the temperature is controlled to 25 ± 2 ℃, 115kg of main raw material ethyl fluoroacetate (1.0eq) is added into the system dropwise, the reaction is kept at a constant temperature, after the reaction is completed, the temperature is controlled to 25 ± 2 ℃ for post-treatment, 690kg of 10% hydrochloric acid solution (1kg/6kg) is used for adjusting the pH to 2, then extraction and washing are carried out, in addition, 17.3kg of silica gel (1g/0.15g) is added to remove tar, and finally, drying, pressure filtration and concentration are carried out to obtain 217.2kg of 2-fluoro-3-oxodiethyl succinate with the yield of 72.9%, and the external standard (Wt%): 75%, liquid chromatography purity (HPLC): 91.2 percent.
Example 2
The charge of compound I was 1.0kg (3.64mol) and compound I was pumped at a rate of 1.2g/min to a continuous coil reactor (15 mL volume) with a retention time of: 15min, controlling the temperature to 350 ℃, keeping the pressure at the outlet of the continuous reactor to be 2.5-3.0 MPa, sampling at the outlet, carrying out GC analysis, wherein the residual raw material is 0.5-3.0%, and rectifying the effluent system to obtain 595.0g of product 2-fluoro diethyl malonate (II), wherein the gas phase purity is as follows: 98.1%, yield 90%, correct NMR.
The rectification parameters are as follows: the column temperature is 90 ℃, the still temperature is 106.9-142 ℃, the vacuum degree is 9mmHg, and the overhead temperature is as follows: 84-78.4, reflux ratio: 12/4, respectively;
example 3
Uniformly mixing a compound I (30.00g, 109.13mmol) and diphenyl ether (60mL, 2V) to obtain a reaction raw material, pumping the raw material into a continuous coil reactor (with the volume of 15mL) at the speed of 0.4g/min, controlling the temperature at 350 ℃, keeping the pressure at the outlet of the continuous reactor at 2.5-3.0 MPa, and rectifying an effluent system to obtain 12.0g of a product 2-diethyl fluoromalonate (II), wherein the gas phase purity is as follows: 97.2%, yield 60.0%, correct NMR.
The rectification parameters are as follows: the column temperature is 90 ℃, the still temperature is 106.9-142 ℃, the vacuum degree is 9mmHg, and the overhead temperature is as follows: 84-78.4, reflux ratio: 12/4, respectively;
the differences from example 2 are: diphenyl ether was used as a solvent.
Example 4
Pumping a compound I (30.00g, 109.13mmol) into a continuous coil reactor (with the volume of 15mL) at the speed of 1.2g/min, controlling the temperature at 500 ℃, keeping the pressure at the outlet of the continuous reactor at 2.5-3.0 MPa, and rectifying an effluent system to obtain 10.6g of a product 2-diethyl fluoromalonate (II), wherein the gas phase purity is as follows: 95.2% and yield 51.90%.
The rectification parameters are as follows: the column temperature is 90 ℃, the still temperature is 106.9-142 ℃, the vacuum degree is 9mmHg, and the overhead temperature is as follows: 84-78.4, reflux ratio: 12/4, respectively;
the differences from example 2 are: the reaction temperature for decarbonylation was 500 ℃.
Example 5
Pumping a compound I (30.00g, 109.13mmol) into a continuous coil reactor (with the volume of 15mL) at the speed of 1.2g/min, controlling the temperature at 200 ℃, keeping the pressure at the outlet of the continuous reactor at 2.5-3.0 MPa, and rectifying an effluent system to obtain 9.4g of a product 2-diethyl fluoromalonate (II), wherein the gas phase purity is as follows: 96.1% and yield 46.46%.
The rectification parameters are as follows: the column temperature is 90 ℃, the still temperature is 106.9-142 ℃, the vacuum degree is 9mmHg, and the overhead temperature is as follows: 84-78.4, reflux ratio: 12/4, respectively;
the differences from example 2 are: the reaction temperature for decarbonylation was 200 ℃.
Example 6
Pumping a compound I (30.00g, 109.13mmol) into a continuous coil reactor (with the volume of 15mL) at the speed of 1.2g/min, controlling the temperature at 250 ℃, keeping the pressure at the outlet of the continuous reactor at 2.5-3.0 MPa, and rectifying an effluent system to obtain 17.9g of a product 2-diethyl fluoromalonate (II), wherein the gas phase purity is as follows: 98.2% and yield 90.41%.
The rectification parameters are as follows: the column temperature is 90 ℃, the still temperature is 106.9-142 ℃, the vacuum degree is 9mmHg, and the overhead temperature is as follows: 84-78.4, reflux ratio: 12/4, respectively;
the differences from example 2 are: the reaction temperature for decarbonylation was 250 ℃.
Example 7
Pumping a compound I (30.00g, 109.13mmol) into a continuous coil reactor (with the volume of 15mL) at the speed of 1.2g/min, controlling the temperature at 450 ℃, keeping the pressure at the outlet of the continuous reactor at 2.5-3.0 MPa, and rectifying an effluent system to obtain 18.0g of a product 2-diethyl fluoromalonate (II), wherein the gas phase purity is as follows: 98.0% and yield 90.73%.
The rectification parameters are as follows: the column temperature is 90 ℃, the still temperature is 106.9-142 ℃, the vacuum degree is 9mmHg, and the overhead temperature is as follows: 84-78.4, reflux ratio: 12/4, respectively;
the differences from example 2 are: the reaction temperature for decarbonylation was 450 ℃.
Example 8
The compound I (30.00g, 109.13mmol) is pumped into a continuous coil reactor (with the volume of 15mL) at the speed of 1.2g/min, the temperature is controlled at 350 ℃, the back pressure at the outlet of the continuous reactor is 0.4MPa, and the effluent system is rectified to obtain 11.1g of the product diethyl 2-fluoro malonate (II), the gas phase purity: 96.4% and yield 8.62%.
The rectification parameters are as follows: the column temperature is 90 ℃, the still temperature is 106.9-142 ℃, the vacuum degree is 9mmHg, and the overhead temperature is as follows: 84-78.4, reflux ratio: 12/4, respectively;
the differences from example 2 are: the reaction pressure for decarbonylation was 0.4 MPa.
Example 9
The feeding amount of the compound III is 30g (151.59mmol), the compound I is pumped into a continuous coil reactor (the volume is 15mL) at the speed of 1.2g/min, the temperature is controlled to be 350 ℃, the pressure at the outlet of the continuous reactor is 2.5-3.0 MPa, the sample at the outlet is subjected to GC analysis, the remainder of the raw material is 0.5-3.0%, the effluent system is rectified to obtain 20.9g of the product dimethyl 2-fluoro-malonate (IV), and the gas phase purity: 98.0%, yield 90.01%, correct NMR.
The rectification parameters are as follows: the column temperature is 90 ℃, the kettle liquid temperature is 100.9-132 ℃, the vacuum degree is 9mmHg, and the tower top temperature is as follows: 80-76.4, reflux ratio: 12/4, respectively;
the differences from example 2 are: the product is dimethyl 2-fluoro malonate.
Example 10
Preparation of 2-Fluoromalonic acid diphenyl ester
The feeding amount of the compound V is 30g (84.37mmol), the compound I is pumped into a continuous coil reactor (the volume is 15mL) at the speed of 1.2g/min, the temperature is controlled to be 350 ℃, the pressure at the outlet of the continuous reactor is 2.5-3.0 MPa, the sample at the outlet is sampled and analyzed by GC, the residual amount of the raw material is 0.5-3.0%, the effluent system is rectified to obtain 20.4g of the product 2-diphenyl fluoromalonate (VI), and the gas phase purity: 97.6%, yield 86.05%, correct NMR.
The rectification parameters are as follows: the column temperature is 90 ℃, the kettle liquid temperature is 120.9-162 ℃, the vacuum degree is 9mmHg, and the tower top temperature is as follows: 100-86.7.4, reflux ratio: 12/4, respectively;
the differences from example 2 are: the product is 2-fluoro diphenyl malonate.
Example 11
The charge of compound I was (30.00g, 109.13mmol) and compound I was pumped at a rate of 1.2g/min to a continuous coil reactor (50 mL volume) with a retention time of: controlling the temperature to be 350 ℃ and the pressure of the outlet of the continuous reactor to be 2.5-3.0 MPa for 50min, rectifying the effluent system to obtain 11.8g of the product 2-fluoro diethyl malonate (II), wherein the gas phase purity is as follows: 94.7%, yield 57.47%, correct NMR identification.
The rectification parameters are as follows: the column temperature is 90 ℃, the still temperature is 106.9-142 ℃, the vacuum degree is 9mmHg, and the overhead temperature is as follows: 84-78.4, reflux ratio: 12/4, respectively;
the differences from example 2 are: retention time 50 min.
Example 12
The charge of compound I was (30.00g, 109.13mmol) and compound I was pumped at a rate of 1.2g/min to a continuous coil reactor (volume 5mL) with a retention time of: 5min, controlling the temperature to 350 ℃, keeping the pressure at the outlet of the continuous reactor to be 2.5-3.0 MPa, rectifying the effluent system to obtain 10.17g of product 2-fluoro diethyl malonate (II), wherein the gas phase purity is as follows: 95.6%, yield 50.00%, correct NMR.
The rectification parameters are as follows: the column temperature is 90 ℃, the still temperature is 106.9-142 ℃, the vacuum degree is 9mmHg, and the overhead temperature is as follows: 84-78.4, reflux ratio: 12/4, respectively;
the differences from example 2 are: retention time 5 min.
Example 13
The charge of compound I was (30.00g, 109.13mmol) and compound I was pumped at a rate of 1.2g/min to a continuous coil reactor (10 mL volume) with a retention time of: for 10min, controlling the temperature to 350 ℃, keeping the pressure at the outlet of the continuous reactor to be 2.5-3.0 MPa, rectifying the effluent system to obtain 17.8g of product 2-diethyl fluoromalonate (II), wherein the gas phase purity is as follows: 98.2%, yield 89.90%, correct NMR.
The rectification parameters are as follows: the column temperature is 90 ℃, the still temperature is 106.9-142 ℃, the vacuum degree is 9mmHg, and the overhead temperature is as follows: 84-78.4, reflux ratio: 12/4, respectively;
the differences from example 2 are: the retention time is 10 min.
Example 14
The charge of compound I was (30.00g, 109.13mmol) and compound I was pumped at a rate of 1.2g/min to a continuous coil reactor (30 mL volume) with a retention time of: controlling the temperature to be 350 ℃ and the pressure of the outlet of the continuous reactor to be 2.5-3.0 MPa for 30min, rectifying the effluent system to obtain 17.9g of product 2-diethyl fluoromalonate (II), wherein the gas phase purity is as follows: 98.1%, yield 90.31%, correct NMR.
The rectification parameters are as follows: the column temperature is 90 ℃, the still temperature is 106.9-142 ℃, the vacuum degree is 9mmHg, and the overhead temperature is as follows: 84-78.4, reflux ratio: 12/4, respectively;
the differences from example 2 are: retention time 30 min.
Comparative example 1
Adding a compound I (30.00g, 109.13mmol) into a 250mL autoclave, heating the system to 350 ℃, keeping the temperature for reaction for 15min, then keeping the system pressure at 2.5-3.0 MPa, releasing the pressure of the system, and tracking the reaction by using GC. After the reaction is finished, the system is rectified to obtain 8.3g of product 2-diethyl fluoromalonate (II), and the gas phase purity is as follows: 92.4%, yield 39.44%.
The rectification parameters are as follows: the column temperature is 90 ℃, the still temperature is 106.9-142 ℃, the vacuum degree is 9mmHg, and the overhead temperature is as follows: 84-78.4, reflux ratio: 12/4, respectively;
the differences from example 2 are: the decarbonylation reaction is carried out in a reaction kettle.
Comparative example 2
Pumping a compound I (30.00g, 109.13mmol) into a continuous coil reactor (with the volume of 15mL) at the speed of 1.2g/min, controlling the temperature at 150 ℃, keeping the pressure at the outlet of the continuous reactor at 2.5-3.0 MPa, and rectifying an effluent system to obtain 2.1g of a product 2-diethyl fluoromalonate (II), wherein the gas phase purity is as follows: 95.1% and a yield of 10.27%.
The rectification parameters are as follows: the column temperature is 90 ℃, the still temperature is 106.9-142 ℃, the vacuum degree is 9mmHg, and the overhead temperature is as follows: 84-78.4, reflux ratio: 12/4, respectively;
the differences from example 2 are: the reaction temperature for decarbonylation was 150 ℃.
With reference to examples 1 and 2, a raw material conversion experiment on a 1.0kg scale has been performed using the above optimum conditions, and in the synthesis of compound ii, the gas phase purity was 98.1% and the yield was 90%; and the continuous reaction equipment continuously runs for 24x7 h and is provided with corresponding standby equipment and parts, so that the equipment can be replaced on line without stopping, and uninterrupted continuous reaction in the whole process is realized.
From the above description, it can be seen that the above-described embodiments of the present invention achieve the following technical effects:
1) the method avoids the use of hydrogen fluoride, reduces the danger of the process, does not need other reagents for the decarboxylation reaction, and can carry out post-treatment rectification, so that the amount of three wastes is small, the environmental pollution is low, and materials which seriously corrode equipment are involved in the process of the process, so the requirement on reaction equipment is not high;
2) the invention adopts a continuous reaction process and continuous reaction equipment, the reaction scale can not be limited by the size of the reactor, and the large-scale production is easy to realize;
3) most of the traditional processes adopt a kettle type reactor, if high-temperature and high-pressure reaction is required, the traditional kettle type reaction has great safety risk, has high requirements on equipment and is not suitable for industrial mass production. Meanwhile, the reaction time of the traditional kettle type process is long, often tens of hours or even days are needed, and the production efficiency is low. This patent adopts continuous reaction equipment, flows through the continuous reactor with raw materials solution, has avoided the time of heating and cooling, has shortened reaction time greatly, is showing and has improved production efficiency.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (13)
1. A continuous synthesis method of 2-fluoro-malonic diester compounds is characterized by comprising the following steps: to be provided with
Taking the raw materials as raw materials, carrying out continuous decarbonylation reaction in continuous reaction equipment to obtain 2-fluoro-malonic diester compounds
Wherein R and R 'independently represent a linear or branched alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heterocyclic ring or a cyclic alkyl group, and R' are the same or different; the decarbonylation reaction is a high-temperature decarbonylation reaction, and the high temperature is 200-500 ℃.
2. The continuous synthesis method according to claim 1, wherein the decarbonylation reaction is a high temperature decarbonylation reaction, and the high temperature is 250-450 ℃.
3. The continuous synthesis process according to claim 1, wherein the decarbonylation reaction is carried out in the absence of a solvent or in the presence of a solvent selected from the group consisting of water, tetrahydrofuran, 2-methyltetrahydrofuran, 1, 4-dioxane, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether, benzene, toluene, xylene, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-diethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, methanol, ethanol, isopropanol, dichloromethane, biphenyl, ethylene glycol, hexamethylphosphoric triamide, phenol, pyridine, m-xylene, o-xylene, diphenyl ether, cyclohexanone, cyclohexanol, o-cresol, diethyl carbonate, diethyl oxalate morpholine, N-octadecane hydrocarbon, One or more of the group consisting of n-eicosane, silicone oil, diethyl malonate, diethylene glycol diethyl ether and chloroform.
4. The continuous synthesis process according to claim 3, characterized in that the solvent is relative to
The amount of the surfactant is 1-50 mL/g.
5. The continuous synthesis process of claim 1, wherein the continuous reaction apparatus comprises a tubular continuous reactor or a column reactor.
6. The continuous synthesis method according to claim 1, wherein the residence time of the raw materials in the continuous reaction equipment is 5-50 min.
7. The continuous synthesis method according to claim 6, wherein the residence time of the raw materials in the continuous reaction equipment is 10-30 min.
8. The continuous synthesis process according to claim 3, characterized in that
Dissolving in said solvent to form
A solution; then the said
Continuously pumping the solution into the continuous reaction equipment for reaction; or directly will
Continuously pumping into the continuous reaction equipment for reaction.
9. The continuous synthesis process according to claim 8, characterized in that said
Solutions or
The pumping speed of (A) is 0.5 to 50 mL/min.
10. The continuous synthesis process according to claim 9, characterized in that said
Solutions or
The pumping speed of the pump is 25 to 35 mL/min.
11. The continuous synthesis process according to claim 1, characterized in that the continuous reaction equipment is equipped with:
the heat exchange equipment is used for adjusting the temperature of the continuous reaction equipment;
temperature detection means for monitoring the reaction temperature in the continuous reaction means;
a pressure detection device for monitoring the reaction pressure in the continuous reaction device;
the online PAT equipment is used for detecting the product composition of the continuous reaction equipment;
and the automatic control system is electrically connected with the liquid pump, the heat exchange equipment, the temperature detection equipment, the pressure detection equipment and the online PAT equipment.
12. The continuous synthesis method according to claim 1, wherein the pressure of the continuous reaction equipment is 0.5-10 MPa.
13. The continuous synthesis method according to claim 1, characterized in that a rectifying device is further arranged downstream of the continuous reaction equipment.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910775355.0A CN110437069B (en) | 2019-08-21 | 2019-08-21 | Continuous synthesis method of 2-fluoro-malonic diester compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910775355.0A CN110437069B (en) | 2019-08-21 | 2019-08-21 | Continuous synthesis method of 2-fluoro-malonic diester compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110437069A CN110437069A (en) | 2019-11-12 |
| CN110437069B true CN110437069B (en) | 2022-04-01 |
Family
ID=68437014
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910775355.0A Active CN110437069B (en) | 2019-08-21 | 2019-08-21 | Continuous synthesis method of 2-fluoro-malonic diester compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110437069B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110683999B (en) * | 2019-12-11 | 2020-05-26 | 凯莱英生命科学技术(天津)有限公司 | Preparation method of trifluorohydrocarbyl sulfone compound |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102531897A (en) * | 2011-12-28 | 2012-07-04 | 凯莱英医药集团（天津）股份有限公司 | Method for preparing alpha-replacing malonic acid diacetoxyiodo derivative |
| CN107935853A (en) * | 2017-11-17 | 2018-04-20 | 滨海康杰化学有限公司 | A kind of preparation method of fluoromalonic acid diester |
| CN109794215A (en) * | 2019-02-18 | 2019-05-24 | 凯莱英医药集团（天津）股份有限公司 | The method of continuous device and continuous chlorination pyridone substance for chlorination pyridone substance |
-
2019
- 2019-08-21 CN CN201910775355.0A patent/CN110437069B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102531897A (en) * | 2011-12-28 | 2012-07-04 | 凯莱英医药集团（天津）股份有限公司 | Method for preparing alpha-replacing malonic acid diacetoxyiodo derivative |
| CN107935853A (en) * | 2017-11-17 | 2018-04-20 | 滨海康杰化学有限公司 | A kind of preparation method of fluoromalonic acid diester |
| CN109794215A (en) * | 2019-02-18 | 2019-05-24 | 凯莱英医药集团（天津）股份有限公司 | The method of continuous device and continuous chlorination pyridone substance for chlorination pyridone substance |
Non-Patent Citations (1)
| Title |
|---|
| Simple preparation of fluoromalonic acid esters;Bergmann, E. D.等;《Chemistry & Industry (London, United Kingdom)》;1961;591 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110437069A (en) | 2019-11-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102584582B (en) | Preparing technology of hydroxyethyl acrylate | |
| CN105384707B (en) | A kind of preparation method of α amino acetophenones light trigger | |
| CN110437069B (en) | Continuous synthesis method of 2-fluoro-malonic diester compound | |
| CN107892654B (en) | Isolongifolane-based fluorescent acid-base indicator and synthetic method and application thereof | |
| CN112544621B (en) | Method for preparing 2- (4-chlorophenoxy) -propoxyamine | |
| CN105985258B (en) | A kind of Preparation Method And Their Intermediate of benzamide compounds | |
| CN108997305A (en) | A kind of new compound 3- methyl -4,5- dichloro-thiophene -2- carboxylic acid and preparation method thereof | |
| CN104860833A (en) | Purification method of dobutamine hydrochloride | |
| CN108947800B (en) | Synthesis method of (1S) -4, 5-dimethoxy-1- (carbonylaminomethyl) benzocyclobutane | |
| CN113957461B (en) | Electrochemical synthesis method of 1,1' -binaphthyl compound | |
| WO2021031168A1 (en) | Continuous synthesis method for 2-fluoromalonic acid diester compound | |
| CN103664940A (en) | Preparation method of moxifloxacin impurity | |
| CN113896675A (en) | Organic luminescent material based on carbazole-triphenylamine derivative and preparation method thereof | |
| CN107867992A (en) | A kind of method for synthesizing Phenoxiacetic acid derivatives | |
| CN105985348B (en) | A kind of preparation method of methylnaltrexone bromide | |
| CN114181139B (en) | Synthesis method of 5-halogenated nicotinic acid | |
| CN108822060B (en) | 3-aryl substituted oxetane and preparation method thereof | |
| CN104030906A (en) | Method for preparing 9-fluorenone by liquid-phase oxidation | |
| CN112225657B (en) | Preparation method of flurbiprofen | |
| CN102993116A (en) | Preparation method of benzoxazine excitant | |
| CN108299239A (en) | One kind 1,6-（To carbamimido-phenyl）The new synthetic method of own diether | |
| CN108299169B (en) | Synthesis method of 6-chloro-3, 4-dihydro-2H-1-naphthalenone | |
| CN114181028B (en) | Preparation method of phenylacetylene | |
| CN111072518B (en) | Continuous synthesis method of ethoxymethylene malononitrile | |
| CN111440059B (en) | Synthetic method of loxoprofen |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |