WO2021108999A1 - 一种4-乙氧基-1,1,1-三氟-3-丁烯-2-酮的连续化合成方法 - Google Patents

一种4-乙氧基-1,1,1-三氟-3-丁烯-2-酮的连续化合成方法 Download PDF

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WO2021108999A1
WO2021108999A1 PCT/CN2019/122788 CN2019122788W WO2021108999A1 WO 2021108999 A1 WO2021108999 A1 WO 2021108999A1 CN 2019122788 W CN2019122788 W CN 2019122788W WO 2021108999 A1 WO2021108999 A1 WO 2021108999A1
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reaction
continuous
solution
polar solvent
acid
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PCT/CN2019/122788
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English (en)
French (fr)
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洪浩
张恩选
卢江平
申慰
闫红磊
刘云鹏
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辽宁凯莱英医药化学有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/78—Separation; Purification; Stabilisation; Use of additives
    • C07C45/80—Separation; Purification; Stabilisation; Use of additives by liquid-liquid treatment
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
    • C07C49/255—Unsaturated compounds containing keto groups bound to acyclic carbon atoms containing ether groups, groups, groups, or groups

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  • the present invention relates to the technical field of organic synthesis, in particular to a continuous synthesis method of 4-ethoxy-1,1,1-trifluoro-3-buten-2-one.
  • 4-Ethoxy-1,1,1-trifluoro-3-butene-2-one is an important chemical synthesis intermediate, which is widely used in the organic synthesis industry, but its chemical properties are unstable and traditional synthesis The thinking operation is relatively cumbersome, and there are many inconveniences when applied to the scale-up production process.
  • the existing synthetic processes of 4-ethoxy-1,1,1-trifluoro-3-buten-2-one include the following:
  • Trifluoroacetic acid and vinyl ethyl ether as raw materials mix 10V of dichloromethane and 2.0eq of pyridine at room temperature, then control the temperature of the system to -5°C, slowly add trifluoroacetic acid dropwise to the system, and mix After stirring for 10 minutes, after adding 1.0 eq of ethyl vinyl ether to the system, keeping the low temperature, then slowly adding 1.0 eq of methylsulfonyl chloride dropwise. After the addition, the temperature of the system was naturally raised to 20°C and then stirred overnight.
  • the following post-treatments are performed: first, after the reaction is completed, a large amount of solids will precipitate out, the filter cake is washed with dichloromethane to remove the products that may be carried away by the filter cake, and then the filtrate is concentrated at 58°C under normal pressure. The solvent is taken away, and finally the system is distilled under reduced pressure. The product will be evaporated at about 48°C/10mmHg.
  • the yield of this process is as high as 99.5%.
  • the advantages of this process are obvious: the yield is very high, but its shortcomings are also clear to us.
  • the entire process is controlled twice to control the low temperature and slowly drop the raw materials, which is very time-consuming and not easy to operate. It also uses more raw materials and relatively costs. High, and in the subsequent scale-up production process, there may be scale-up effects that may usually occur in batch reactions.
  • Trifluoroacetyl chloride and vinyl ethyl ether as raw materials Dissolve 1.0 eq of vinyl ethyl ether and 1.5 eq of pyridine in 10V dichloromethane, and then add 1.5 eq of trifluoroacetyl chloride dropwise under the protection of nitrogen at 30°C. In the system, after the dropwise addition, the system was stirred at room temperature for 1.5 hours. Post-treatment: Add 6.7V ice droplets to the reaction system, stir and extract, and then wash the organic phase with water and saturated aqueous sodium chloride solution, then dry the organic phase with anhydrous sodium sulfate, and collect the organic phase at 60°C.
  • the main purpose of the present invention is to provide a continuous synthesis method of 4-ethoxy-1,1,1-trifluoro-3-butene-2-one to solve the problem of 4-ethoxy-
  • the synthesis method of 1,1,1-trifluoro-3-buten-2-one is difficult to adapt to the problem of industrial scale-up production.
  • a continuous synthesis method of 4-ethoxy-1,1,1-trifluoro-3-buten-2-one includes: The raw materials of ethyl ether, triethylamine and trifluoroacetic anhydride continuously enter the continuous reactor for reaction to obtain a product containing 4-ethoxy-1,1,1-trifluoro-3-buten-2-one System; continuous extraction of the product system to obtain 4-ethoxy-1,1,1-trifluoro-3-buten-2-one.
  • the molar ratio of the vinyl ether and trifluoroacetic anhydride is 1:1 to 1.5:1, preferably 1.1:1 to 1.3:1, and the molar ratio of triethylamine and trifluoroacetic anhydride is 1:1 to 1.5:1, preferably 1.2:1 to 1.3:1.
  • the above-mentioned vinyl ethyl ether, triethylamine and trifluoroacetic anhydride are continuously fed into the continuous reactor in the form of a solution, and the solvent in the solution is preferably a polar solvent.
  • the reaction temperature of the above-mentioned reaction is -40 to 100°C, preferably the reaction includes a first-stage reaction and a second-stage reaction that are carried out successively, and the reaction temperature T1 of the first-stage reaction is -40 to 40°C, preferably the first stage reaction.
  • the retention time of the stage reaction is 40-80 min, and the reaction temperature T2 of the second stage reaction is 0-100° C., preferably the retention time of the second stage reaction is 40-80 min, and more preferably the reaction temperature T1 is less than or equal to the reaction temperature T2.
  • the above-mentioned continuous reactor includes a first continuous reactor and a second continuous reactor arranged in series, and the process of continuously entering the raw material into the continuous reactor for reaction includes: dissolving vinyl ethyl ether and triethylamine In the first polar solvent, the mixed solution is obtained; the trifluoroacetic anhydride is dissolved in the second polar solvent to obtain the acid anhydride solution; the mixed solution and the acid anhydride solution are continuously fed into the first continuous reactor for the second
  • the one-stage reaction obtains the initial reaction system; the initial reaction system is continuously fed into the second continuous reactor for the second stage reaction to obtain the product system.
  • the above-mentioned continuous reactor has a first reaction section and a second reaction section connected in communication, and the first reaction section and the second reaction section each have a temperature control structure, so that the raw materials continuously enter the continuous reactor for the process of reaction.
  • the volume of the first polar solvent used per gram of the above vinyl ether is 0.95 to 1.1 mL
  • the volume of the second polar solvent used per gram of trifluoroacetic anhydride is 0.95 to 1.1 mL
  • the first polar solvent and the second polar solvent are each independently selected from any one of the group consisting of chloroform, dichloromethane, and carbon tetrachloride, and it is more preferable that the first polar solvent and the second polar solvent are the same.
  • the above process of continuously extracting the product system includes: continuously entering the product system and the acidic solution into the first extraction column to continuously perform acid extraction to obtain a separated first organic phase and an acid aqueous phase; making the first organic phase
  • the continuous and alkaline solution continuously enters the second extraction column for continuous alkaline extraction to obtain a separated second organic phase and alkaline aqueous phase; remove the solvent in the second organic phase to obtain 4-ethoxy-1,1,1 -Trifluoro-3-butene-2-one.
  • the above-mentioned acidic solution is hydrochloric acid, citric acid, or trifluoroacetic acid
  • the alkaline solution is any one of sodium bicarbonate aqueous solution, potassium bicarbonate aqueous solution, sodium carbonate aqueous solution, and potassium carbonate aqueous solution.
  • the retention time of the acid extraction is 10 to 80 min, and the retention time of the alkali extraction is 10 to 80 min.
  • the above-mentioned raw materials can be fed into the continuous reactor conveniently and accurately.
  • continuous extraction is also used for post-processing.
  • the whole process is fast, simple and efficient, and greatly improves The efficiency of the entire synthesis process, because the product is continuously extracted and separated in time with the continuous output, thereby reducing the loss of product damage; and the reactor can be reused, reducing the use cost.
  • a large amount of heat generated during the reaction process can be exchanged in a timely and efficient manner through a continuous reactor, avoiding the safety hazards of batch production.
  • the continuous synthesis method of the present application has no amplification effect after amplification, and can still maintain safety and high synthesis efficiency.
  • Fig. 1 shows a 1 HNMR spectrum of the intermediate product at a certain time during the reaction process of Example 1 of the present invention.
  • Figure 2 shows the 1 HNMR spectrum of the final product of Example 1 according to the present invention.
  • the present application provides a continuous synthesis method of 4-ethoxy-1,1,1-trifluoro-3-buten-2-one.
  • the continuous synthesis method includes: The raw materials of diethyl ether, triethylamine and trifluoroacetic anhydride continuously enter the continuous reactor for reaction to obtain a product system containing 4-ethoxy-1,1,1-trifluoro-3-buten-2-one ; Continuous extraction of the product system to obtain 4-ethoxy-1,1,1-trifluoro-3-buten-2-one.
  • the above-mentioned raw materials can be fed into the continuous reactor conveniently and accurately.
  • continuous extraction is also used for post-processing.
  • the whole process is fast, simple and efficient, which greatly improves the efficiency of the entire synthesis process.
  • the product is continuously extracted and separated in time with the continuous output, thus reducing the loss of product damage; and the reactor can be reused, reducing the use cost.
  • a large amount of heat generated during the reaction process can be exchanged in a timely and efficient manner through a continuous reactor, avoiding the safety hazards of batch production.
  • the continuous synthesis method of the present application has no amplification effect after amplification, and can still maintain safety and high synthesis efficiency.
  • the molar ratio of the above vinyl ethyl ether and trifluoroacetic anhydride is 1.0:1 to 1.5:1, preferably 1.1:1 to 1.3:1, and to ensure the catalytic efficiency of triethylamine at the same time
  • the molar ratio of the above-mentioned triethylamine and trifluoroacetic anhydride is preferably 1.0:1 to 1.5:1, preferably 1.2:1 to 1.3:1.
  • the above-mentioned vinyl ether, triethylamine and trifluoroacetic anhydride are continuously fed into the continuous reactor in the form of solution, and the above-mentioned substances are conveyed in the form of solution, and the solvent is used for transportation. Dilution effectively controls the materials involved in the reaction within a unit time, thereby effectively controlling the output of reaction heat.
  • the solvent in the solution is preferably a polar solvent.
  • the reaction temperature of the above reaction is preferably -40 to 100°C, and the reaction temperature is used to control the reaction rate.
  • the reaction includes a first-stage reaction and a second-stage reaction that are carried out successively.
  • the reaction temperature T1 of the first-stage reaction is -40 to 40°C, preferably the first stage reaction.
  • the retention time of the stage reaction is 40-80 min, and the reaction temperature T1 of the second stage reaction is 0-100° C., preferably the retention time of the second stage reaction is 40-80 min, and more preferably the reaction temperature T1 is less than or equal to the reaction temperature T2.
  • the first-stage reaction is carried out at a relatively low temperature so that the substrate gradually reacts. As the reaction proceeds, the concentration of the substrate in the system decreases, and then the reaction temperature is increased to enter the second-stage reaction to ensure the reaction rate.
  • the above-mentioned continuous reactor includes a first continuous reactor and a second continuous reactor arranged in series, and the process of continuously entering the raw material into the continuous reactor for reaction includes: Ether and triethylamine are dissolved in the first polar solvent to obtain a mixed solution; trifluoroacetic anhydride is dissolved in the second polar solvent to obtain an acid anhydride solution; the mixed solution and the acid anhydride solution are continuously fed into the first continuous
  • the first-stage reaction is carried out in the chemical reactor to obtain the initial reaction system; the initial reaction system is continuously fed into the second continuous chemical reactor for the second-stage reaction to obtain the product system.
  • the ethyl vinyl ether and the triethylamine are mixed to form a mixed solution, and then the mixed solution and the acid anhydride solution are sent to the first continuous reactor to avoid the premature contact of the triethylamine and the trifluoroacetic anhydride to generate heat.
  • two continuous reactors connected in series are used for continuous reaction, which effectively controls the temperature of the first-stage reaction and the second-stage reaction, ensuring high-efficiency production efficiency.
  • the above-mentioned continuous reactor has a first reaction section and a second reaction section connected in communication, and the first reaction section and the second reaction section each have a temperature control structure, so that the raw materials continuously enter the continuous reaction section.
  • the reaction process in the reactor includes: dissolving vinyl ethyl ether and triethylamine in a first polar solvent to obtain a mixed solution; dissolving trifluoroacetic anhydride in a second polar solvent to obtain an acid anhydride solution; The solution and the acid anhydride solution are continuously fed into the first reaction section respectively, and the first stage reaction is performed in the first reaction section and the second stage reaction is performed in the second reaction section to obtain a product system.
  • the first-stage reaction and the second-stage reaction are integrated in the same continuous reactor, which simplifies the device structure and reduces the device cost.
  • the above-mentioned continuous reactor can be a continuous reactor commonly used in the prior art, preferably a continuous coil reactor or a continuous column reactor.
  • the first continuous reactor and the second continuous reactor are both provided with temperature control structures, such as temperature control jackets.
  • the temperature control structures of the first reaction section and the second reaction section can also be temperature control jackets.
  • the volume of the first polar solvent used per gram of vinyl ethyl ether is 0.95 to 1.1 mL
  • the volume of the second polar solvent used per gram of trifluoroacetic anhydride is 0.95 to 1.1 mL.
  • the first polar solvent and the second polar solvent used in the present application can be polar solvents commonly used in the prior art.
  • the first polar solvent and the second polar solvent are independently selected from chloroform and dichloromethane. Any one of the group consisting of methane and carbon tetrachloride.
  • the first polar solvent and the second polar solvent are the same.
  • the above-mentioned process of continuously extracting the product system includes: continuously entering the product system and the acidic solution into the first extraction column for continuous acid extraction to obtain a separated first organic phase and acid water Phase; continuously enter the first organic phase and the alkaline solution into the second extraction column for continuous alkaline extraction to obtain a separated second organic phase and alkaline aqueous phase; remove the solvent in the second organic phase to obtain 4-ethoxy Group-1,1,1-trifluoro-3-buten-2-one.
  • the above acidic solution is used to remove the alkaline catalyst in the reaction, and then the alkaline solution is used to wash away the acidic impurities in the system, so as to achieve the effect of 4-ethoxy-1,1,1-trifluoro-3-butene in the product system.
  • Efficient extraction of 2-ketones Due to the short contact time between acidic solution and alkaline solution and 4-ethoxy-1,1,1-trifluoro-3-buten-2-one in continuous extraction, 4-ethoxy is effectively controlled.
  • -1,1,1-Trifluoro-3-buten-2-one easily deteriorates when it comes in contact with water.
  • the acidic solution is preferably hydrochloric acid, citric acid, or trifluoroacetic acid
  • the alkaline solution is preferably any one of sodium bicarbonate aqueous solution, potassium bicarbonate aqueous solution, sodium carbonate aqueous solution, and potassium carbonate aqueous solution.
  • the retention time of the above acid extraction is preferably 10 ⁇ 80min, preferably 40 ⁇ 80min
  • the retention time of alkaline extraction is 10 ⁇ 80min, preferably 40 ⁇ 80min.
  • the first reaction section is kept at -10°C, and the retention time is 60min; the second reaction stage is kept at 40°C, the retention time is 60min, and the internal pressure is controlled at 0.02 ⁇ 0.60MPa; after the raw materials are finished, chloroform is used for topping, and the plunger
  • the feed rate of pump A is set to 3.0 g/min, and the feed rate of plunger pump B is set to 3.0 g/min.
  • the discharge port of the coil reactor is directly connected to the extraction column 1.
  • the plunger pump C pumps 6V 2% hydrochloric acid solution into the extraction column 1.
  • the feed rate of the plunger pump C is set to: 5.75g/min, and the extraction column 1
  • the retention time is 51min.
  • plunger pump D After the organic phase of the lower layer of extraction column 1 is released, connect to plunger pump D.
  • the feed rate of plunger pump D is set to 2.8g/min.
  • diaphragm pump E uses 4V 8% sodium bicarbonate solution (matching The plunger pump D) drives into the extraction column 2, the feed rate of the diaphragm pump E is set to 3.83 g/min, and the retention time of the extraction column 2 is 64 min.
  • use a 3L four-necked flask to receive the organic phase released from the lower layer of the extraction column 2
  • two 3L conical flasks to receive the acid-water phase and alkaline water overflowing from the upper layer of the extraction column 1 and the extraction column 2 during the whole process.
  • the organic phase was concentrated to 327 g under the conditions of 35° C. and 0.1 MPa, followed by vacuum distillation. When the temperature at the bottom of the tower was 50-55° C. and the temperature at the top of the tower was 40-48° C., 141 g of the product was evaporated, and the yield was 83.2%.
  • Example 2 The difference from Example 1 is that the first reaction section is kept at -10°C, and the second reaction stage is kept at -10°C.
  • the distilled product was 88.7g, and the yield was 52.3%.
  • Example 2 The difference from Example 1 is that the first reaction section is kept at 0°C and the second reaction stage is kept at 0°C.
  • the distilled product was 94.6 g, and the yield was 55.8%.
  • the equipment preparation is the same as in Example 1.
  • the first reaction section is kept at -40°C and the retention time is 80min; the second reaction stage is kept at 0°C, the retention time is 80min, and the internal pressure is controlled at 0.02 ⁇ 0.60MPa; after the raw materials are finished, chloroform is used for topping, and the plunger
  • the feed rate of pump A is set to 2.25 g/min, and the feed rate of plunger pump B is set to 2.25 g/min.
  • the discharge port of the coil reactor is directly connected to the extraction column 1.
  • the plunger pump C pumps 6V 2% hydrochloric acid solution into the extraction column 1.
  • the feed rate of the plunger pump C is set to: 5.75g/min, and the extraction column 1
  • the retention time is 51min.
  • plunger pump D After the organic phase of the lower layer of extraction column 1 is released, connect to plunger pump D.
  • the feed rate of plunger pump D is set to 2.8g/min.
  • diaphragm pump E uses 4V 8% sodium bicarbonate solution (matching The plunger pump D) drives into the extraction column 2, the feed rate of the diaphragm pump E is set to 3.83 g/min, and the retention time of the extraction column 2 is 64 min.
  • use a 3L four-necked flask to receive the organic phase released from the lower layer of the extraction column 2
  • two 3L conical flasks to receive the acid-water phase and alkaline water overflowing from the upper layer of the extraction column 1 and the extraction column 2 during the whole process.
  • the equipment preparation is the same as in Example 1.
  • the first reaction section is kept at 0°C and the retention time is 50min; the second reaction section is kept at 40°C, the retention time is 50min, and the internal pressure is controlled at 0.02 ⁇ 0.60MPa; after the raw materials are finished, chloroform is used for topping, plunger pump
  • the feed rate of A is set to 3.6g/min, and the feed rate of plunger pump B is set to 3.6g/min.
  • the discharge port of the coil reactor is directly connected to the extraction column 1.
  • the plunger pump C pumps 6V 2% hydrochloric acid solution into the extraction column 1.
  • the feed rate of the plunger pump C is set to: 5.75g/min, and the extraction column 1
  • the retention time is 51min. After the organic phase of the lower layer of extraction column 1 is released, connect to plunger pump D.
  • the feed rate of plunger pump D is set to 2.8g/min.
  • diaphragm pump E uses 4V 8% sodium bicarbonate solution (matching The plunger pump D) drives into the extraction column 2, the feed rate of the diaphragm pump E is set to 3.83 g/min, and the retention time of the extraction column 2 is 64 min.
  • After feeding use a 3L four-necked flask to receive the organic phase released from the lower layer of the extraction column 2, and at the same time use two 3L conical flasks to receive the acid-water phase and alkaline water overflowing from the upper layer of the extraction column 1 and the extraction column 2 during the whole process. phase.
  • the equipment preparation is the same as in Example 1.
  • the first reaction section is kept at 40°C and the retention time is 40min; the second reaction section is kept at 100°C, the retention time is 40min, and the internal pressure is controlled at 0.02 ⁇ 0.60MPa; after the raw materials are finished, chloroform is used for topping, plunger pump
  • the feed rate of A is set to 4.5g/min, and the feed rate of plunger pump B is set to 4.5g/min.
  • the discharge port of the coil reactor is directly connected to the extraction column 1.
  • the plunger pump C pumps 6V 2% hydrochloric acid solution into the extraction column 1.
  • the feed rate of the plunger pump C is set to: 5.75g/min, and the extraction column 1
  • the retention time is 51min. After the organic phase of the lower layer of extraction column 1 is released, connect to plunger pump D.
  • the feed rate of plunger pump D is set to 2.8g/min.
  • diaphragm pump E uses 4V 8% sodium bicarbonate solution (matching The plunger pump D) drives into the extraction column 2, the feed rate of the diaphragm pump E is set to 3.83 g/min, and the retention time of the extraction column 2 is 64 min.
  • After feeding use a 3L four-necked flask to receive the organic phase released from the lower layer of the extraction column 2, and at the same time use two 3L conical flasks to receive the acid-water phase and alkaline water overflowing from the upper layer of the extraction column 1 and the extraction column 2 during the whole process. phase.
  • the equipment preparation is the same as in Example 1.
  • the first reaction section is kept at -10°C, and the retention time is 60min; the second reaction stage is kept at 40°C, the retention time is 60min, and the internal pressure is controlled at 0.02 ⁇ 0.60MPa; after the raw materials are finished, chloroform is used for topping, and the plunger
  • the feed rate of pump A is set to 3.0 g/min, and the feed rate of plunger pump B is set to 3.0 g/min.
  • the discharge port of the coil reactor is directly connected to extraction column 1, plunger pump C pumps 6V 2% hydrochloric acid solution into extraction column 1, the feed rate of plunger pump C is set to: 7.34g/min, extraction column 1
  • the retention time is 40min; after the organic phase of the lower layer of the extraction column 1 is released, connect to the plunger pump D, the feed rate of the plunger pump D is set to 2.8g/min, and the diaphragm pump E will 4V 8% sodium bicarbonate solution (matching
  • the plunger pump D) drives into the extraction column 2, the feed rate of the diaphragm pump E is set to 6.12 g/min, and the retention time of the extraction column 2 is 40 min.
  • the equipment preparation is the same as in Example 1.
  • the first reaction section is kept at -10°C, and the retention time is 60min; the second reaction stage is kept at 40°C, the retention time is 60min, and the internal pressure is controlled at 0.02 ⁇ 0.60MPa; after the raw materials are finished, chloroform is used for topping, and the plunger
  • the feed rate of pump A is set to 3.0 g/min, and the feed rate of plunger pump B is set to 3.0 g/min.
  • the discharge port of the coil reactor is directly connected to extraction column 1, plunger pump C pumps 6V 2% hydrochloric acid solution into extraction column 1, the feed rate of plunger pump C is set to: 3.67g/min, extraction column 1
  • the retention time is 80min; after the organic phase of the lower layer of the extraction column 1 is released, connect to the plunger pump D.
  • the feed rate of the plunger pump D is set to 2.8g/min.
  • the diaphragm pump E uses 4V 8% sodium bicarbonate solution (matching The plunger pump D) is driven into the extraction column 2, the feed rate of the diaphragm pump E is set to 3.06 g/min, and the retention time of the extraction column 2 is 80 min.
  • After feeding use a 3L four-necked flask to receive the organic phase released from the lower layer of the extraction column 2, and at the same time use two 3L conical flasks to receive the acid-water phase and alkaline water overflowing from the upper layer of the extraction column 1 and the extraction column 2 during the whole process. phase.
  • the equipment preparation is the same as in Example 1.
  • the first reaction section is kept at -10°C and the retention time is 60min; the second reaction stage is kept at 40°C, the retention time is 60min, and the internal pressure is controlled at 0.02 ⁇ 0.60MPa; after the raw materials are finished, methylene chloride is used for topping.
  • the feed rate of plunger pump A is set to 3.0 g/min, and the feed rate of plunger pump B is set to 3.0 g/min.
  • the discharge port of the coil reactor is directly connected to extraction column 1, plunger pump C pumps 6V 2% hydrochloric acid solution into extraction column 1, the feed rate of plunger pump C is set to: 3.67g/min, extraction column 1
  • the retention time is 80min; after the organic phase of the lower layer of the extraction column 1 is released, connect to the plunger pump D.
  • the feed rate of the plunger pump D is set to 2.8g/min.
  • the diaphragm pump E uses 4V 8% sodium bicarbonate solution (matching The plunger pump D) is driven into the extraction column 2, the feed rate of the diaphragm pump E is set to 3.06 g/min, and the retention time of the extraction column 2 is 80 min.
  • After feeding use a 3L four-necked flask to receive the organic phase released from the lower layer of the extraction column 2, and at the same time use two 3L conical flasks to receive the acid-water phase and alkaline water overflowing from the upper layer of the extraction column 1 and the extraction column 2 during the whole process. phase.
  • the equipment preparation is the same as in Example 1. The difference lies in the raw materials.
  • the raw materials of Example 10 are as follows: Take 79.0g of vinyl ethyl ether, 110.8g of triethylamine and 230ml of chloroform to make a mixed solution and place it in the bottle A; take 230g of trifluoroacetic anhydride and 230ml of chloroform was made into acid anhydride solution and placed in the bottle B.
  • the feed rate of the plunger pump A was set to 2.3 g/min, and the feed rate of the plunger pump B was set to 2.5 g/min.
  • the final product was 114 g, and the calculated yield was 67.3%.
  • the equipment preparation is the same as in Example 1. The difference lies in the raw materials.
  • the raw materials of Example 11 are as follows: Take 1180.4g of vinyl ethyl ether, 166.2g of triethylamine and 230ml of chloroform to make a mixed solution and place it in the bottle A; take 230g of trifluoroacetic anhydride and 230ml of chloroform was made into acid anhydride solution and placed in the bottle B.
  • the feed rate of the plunger pump A was set to 2.5 g/min, and the feed rate of the plunger pump B was set to 2.3 g/min.
  • the final product was 123 g, and the calculated yield was 72.6%.
  • the equipment preparation is the same as in Example 1. The difference lies in the raw materials.
  • the raw materials of Example 12 are as follows: Take 86.9g of vinyl ether, 133.0g of triethylamine and 230ml of chloroform to make a mixed solution and place it in the bottle A; take 230g of trifluoroacetic anhydride and 230ml of chloroform was made into acid anhydride solution and placed in the bottle B.
  • the feed rate of the plunger pump A was set to 2.4 g/min, and the feed rate of the plunger pump B was set to 2.4 g/min.
  • the final product was 138 g, and the calculated yield was 81.4%.
  • the equipment preparation is the same as in Example 1. The difference lies in the raw materials.
  • the raw materials of Example 13 are as follows: Take 102.7g of vinyl ethyl ether, 144.0g of triethylamine and 230ml of chloroform to make a mixed solution and place it in the bottle A; take 230g of trifluoroacetic anhydride and 230ml of chloroform was made into acid anhydride solution and placed in the bottle B.
  • the feed rate of the plunger pump A was set to 2.4 g/min, and the feed rate of the plunger pump B was set to 2.4 g/min.
  • the final product was 139 g, and the calculated yield was 82.0%.
  • the equipment preparation is the same as in Example 1. The difference lies in the raw materials.
  • the raw materials of Example 14 are as follows: Take 103 g of vinyl ethyl ether, 144 g of triethylamine and 219 ml of chloroform to make a mixed solution and place it in the bottle A; take 230 g of trifluoroacetic anhydride and 219 ml of chloroform. Dichloromethane is made into acid anhydride solution and placed in the feed bottle B.
  • the feed rate of the plunger pump A was set to 2.4 g/min
  • the feed rate of the plunger pump B was set to 2.4 g/min
  • the final product was 130 g
  • the calculated yield was 76.7%.
  • the equipment preparation is the same as in Example 1. The difference lies in the raw materials.
  • the raw materials of Example 15 are as follows: Take 71.1g of vinyl ethyl ether, 105.3g of triethylamine and 230ml of chloroform to make a mixed solution and place it in the bottle A; take 230g of trifluoroacetic anhydride and 230ml of chloroform was made into acid anhydride solution and placed in the bottle B.
  • the feed rate of the plunger pump A was set to 2.3 g/min, and the feed rate of the plunger pump B was set to 2.5 g/min.
  • the final product was 71.9 g, and the calculated yield was 42.4%.
  • the above-mentioned raw materials can be fed into the continuous reactor conveniently and accurately.
  • continuous extraction is also used for post-processing.
  • the whole process is fast, simple and efficient, which greatly improves the efficiency of the entire synthesis process.
  • the product is continuously extracted and separated in time with the continuous output, thus reducing the loss of product damage; and the reactor can be reused, reducing the use cost.
  • a large amount of heat generated during the reaction process can be exchanged in a timely and efficient manner through a continuous reactor, avoiding the safety hazards of batch production.
  • the continuous synthesis method of the present application has no amplification effect after amplification, and can still maintain safety and high synthesis efficiency.

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Abstract

一种4-乙氧基-1,1,1-三氟-3-丁烯-2-酮的连续化合成方法。该连续化合成方法包括：使包含乙烯基乙醚、三乙胺和三氟乙酸酐的原料连续进入连续化反应器中进行反应，得到含有4-乙氧基-1,1,1-三氟-3-丁烯-2-酮的产物体系；对产物体系进行连续化萃取，得到4-乙氧基-1,1,1-三氟-3-丁烯-2-酮。使用连续化工艺，可将上述各原料便捷、精确地打入连续化反应器中，反应结束后同样利用连续萃取进行后处理，整个过程快速、简单高效，大大提高了整个合成工艺的效率，降低了产物破坏的损失；避免了批次生产的安全隐患。在放大后不存在放大效应，依然可以保持安全性和较高的合成效率。

Description

一种4-乙氧基-1,1,1-三氟-3-丁烯-2-酮的连续化合成方法 技术领域
本发明涉及有机合成技术领域，具体而言，涉及一种4-乙氧基-1,1,1-三氟-3-丁烯-2-酮的连续化合成方法。
背景技术
4-乙氧基-1,1,1-三氟-3-丁烯-2-酮是一种重要的化学合成中间体，广泛应用于有机合成行业，但其化学性质不稳定，传统的合成思路操作较为繁琐，应用于放大生产工艺中有诸多不便之处。目前现有的4-乙氧基-1,1,1-三氟-3-丁烯-2-酮的合成工艺包括以下几种：
三氟乙酸和乙烯基乙醚为原料：将10V的二氯甲烷和2.0eq的吡啶常温下混溶，然后将体系温度控制到-5℃，把三氟乙酸慢慢地滴加到体系中，混合搅拌10分钟，将1.0eq的乙烯基乙醚加入体系后，保持这个低温，再将1.0eq的甲基磺酰氯缓慢滴加进去，滴加结束后，将体系温度自然升至20℃然后搅拌过夜。反应结束后，进行以下后处理：首先反应结束后会有大量的固体析出，将滤饼用二氯甲烷洗涤，洗掉滤饼可能带走的产物，之后滤液在58℃、常压进行浓缩，带走溶剂，最后将体系进行减压蒸馏，产品大约会在48℃/10mmHg蒸出，此工艺的收率高达99.5％。此工艺的优点很明显：收率非常高，但是它的缺点我们也一目了然，整个过程两次控制低温缓慢滴加原料，非常耗时而且操作不简便，用到的原料也较多，成本相对较高，而且在后续的放大生产工艺中可能会有批次反应通常可能出现的放大效应。
三氟乙酰氯和乙烯基乙醚为原料：将1.0eq的乙烯基乙醚和1.5eq的吡啶溶于10V的二氯甲烷中，然后将1.5eq的三氟乙酰氯在30℃氮气保护下滴加到体系中，滴加结束后体系在室温下搅拌1.5小时结束。后处理：将6.7V的冰水滴加到反应体系中，搅拌后进行萃取，有机相再用水和饱和氯化钠水溶液进行洗涤，之后有机相用无水硫酸钠干燥，收集的有机相在60度进行浓缩带走溶剂，最后进行减压蒸馏，在10mbar，85℃得到产品，收率81％。该方法虽然相对上一个工艺操作简化了许多，反应时间更短，但是收率却不是很高，而且三氟乙酰氯性质活泼，不稳定，在操作过程中需要用惰性气体保护体系，否则容易失效。
同时现有技术中还存在其他方法，比如4-乙氧基-1,1,1-三氟-3-丁烯-2-酮的合成方法还有以乙烯基乙醚为基准物料，三氟乙酸、五氯化磷体系；三氟乙酸酐、DMAP体系；三氟乙酸、三乙胺体系等等。但是，这些合成路线都无法满足经济的、有效的、安全的合成4-乙氧基-1,1,1-三氟-3-丁烯-2-酮的要求。
上述的合成方法大多以批次反应为主要反应方式，这种方式操作较为繁杂，效率较低，不是非常经济和便捷，而且批次都具有共性的弊病，那就是可能存在放大效应，不能解决产品遇水容易变质的问题，产能低，不适于商业生产等实际应用。
发明内容
本发明的主要目的在于提供一种4-乙氧基-1,1,1-三氟-3-丁烯-2-酮的连续化合成方法，以解决现有技术中4-乙氧基-1,1,1-三氟-3-丁烯-2-酮的合成方法难以适应工业化放大生产的问题。
为了实现上述目的，根据本发明的一个方面，提供了一种4-乙氧基-1,1,1-三氟-3-丁烯-2-酮的连续化合成方法，包括：使包含乙烯基乙醚、三乙胺和三氟乙酸酐的原料连续进入连续化反应器中进行反应，得到含有4-乙氧基-1,1,1-三氟-3-丁烯-2-酮的产物体系；对产物体系进行连续化萃取，得到4-乙氧基-1,1,1-三氟-3-丁烯-2-酮。
进一步地，上述乙烯基乙醚和三氟乙酸酐的摩尔比为1:1～1.5:1，优选为1.1：1～1.3：1，三乙胺和三氟乙酸酐的摩尔比为1:1～1.5:1，优选为1.2：1～1.3：1。
进一步地，上述乙烯基乙醚、三乙胺和三氟乙酸酐以溶液的方式连续进入连续化反应器中，优选溶液中的溶剂为极性溶剂。
进一步地，上述反应的反应温度为-40～100℃，优选反应包括依次连续进行的第一阶段反应和第二阶段反应，第一阶段反应的反应温度T1为-40～40℃，优选第一阶段反应的保留时间为40～80min，第二阶段反应的反应温度T2为0～100℃，优选第二阶段反应的保留时间为40～80min，更优选反应温度T1小于或等于反应温度T2。
进一步地，上述连续化反应器包括串联设置的第一连续化反应器和第二连续化反应器，使原料连续进入连续化反应器中进行反应的过程包括：将乙烯基乙醚和三乙胺溶解于第一极性溶剂中，得到混合溶液；将三氟乙酸酐溶解于第二极性溶剂中，得到酸酐溶液；将混合溶液和酸酐溶液分别连续地送入第一连续化反应器中进行第一阶段反应，得到初反应体系；将初反应体系连续地送入第二连续化反应器中进行第二阶段反应，得到产物体系。
进一步地，上述连续化反应器具有连通设置的第一反应段和第二反应段，第一反应段和第二反应段各自具有控温结构，使原料连续进入连续化反应器中进行反应的过程包括：将乙烯基乙醚和三乙胺溶解于第一极性溶剂中，得到混合溶液；将三氟乙酸酐溶解于第二极性溶剂中，得到酸酐溶液；将混合溶液和酸酐溶液分别连续地送入第一反应段中，并在第一反应段中进行第一阶段反应、在第二反应段中进行第二阶段反应，得到产物体系。
进一步地，每克上述乙烯基乙醚所采用的第一极性溶剂的体积为0.95～1.1mL，每克三氟乙酸酐所采用的第二极性溶剂的体积为0.95～1.1mL，优选第一极性溶剂和第二极性溶剂各自独立地选自氯仿、二氯甲烷、四氯化碳组成的组中的任意一种，更优选第一极性溶剂和第二极性溶剂相同。
进一步地，上述对产物体系进行连续化萃取的过程包括：使产物体系和酸性溶液连续进入第一萃取柱以连续进行酸萃取，得到分离的第一有机相和酸水相；使第一有机相连续和碱性溶液连续进入第二萃取柱以连续进行碱萃取，得到分离的第二有机相和碱水相；去除第二有机相中的溶剂，得到4-乙氧基-1,1,1-三氟-3-丁烯-2-酮。
进一步地，上述酸性溶液为盐酸、柠檬酸、或三氟乙酸，优选碱性溶液为碳酸氢钠水溶液、碳酸氢钾水溶液、碳酸钠水溶液、碳酸钾水溶液中的任意一种。
进一步地，上述酸萃取的保留时间为10～80min，碱萃取的保留时间为10～80min。
应用本发明的技术方案，使用连续化工艺，可将上述各原料便捷、精确地打入连续化反应器中，反应结束后同样利用连续萃取进行后处理，整个过程快速、简单高效，大大提高了整个合成工艺的效率，由于产物随着连续产出被及时连续地萃取分离，因此降低了产物破坏的损失；而且反应器可以重复利用，降低了使用成本。同时反应过程产生的大量热量放出可以通过连续反应器及时高效的交换掉，避免了批次生产的安全隐患。而且，本申请的连续化合成方法在放大后不存在放大效应，依然可以保持安全性和较高的合成效率。
附图说明
构成本申请的一部分的说明书附图用来提供对本发明的进一步理解，本发明的示意性实施例及其说明用于解释本发明，并不构成对本发明的不当限定。在附图中：
图1示出了根据本发明的实施例1的反应过程中某一时刻的中间产物的 1HNMR谱图；以及
图2示出了根据本发明的实施例1的终产物的 1HNMR谱图。
具体实施方式
需要说明的是，在不冲突的情况下，本申请中的实施例及实施例中的特征可以相互组合。下面将参考附图并结合实施例来详细说明本发明。
如本申请背景技术所分析的，现有技术的4-乙氧基-1,1,1-三氟-3-丁烯-2-酮的合成方法难以适应工业化放大生产，为了解决该问题，申请人试图对现有技术中的各合成方法以连续化的方式进行，但是，受限于反应条件的特殊控制，无法通过连续化精准控制反应而廉价合成4-乙氧基-1,1,1-三氟-3-丁烯-2-酮。为此申请人通过深入的化学机理研究和试验验证，提出了采用三乙胺催化乙烯基乙醚和三氟乙酸酐的反应，并且实现了该反应的连续化进行。
基于上述研究，本申请提供了一种4-乙氧基-1,1,1-三氟-3-丁烯-2-酮的连续化合成方法，该连续化合成方法包括：使包含乙烯基乙醚、三乙胺和三氟乙酸酐的原料连续进入连续化反应器中进行反应，得到含有4-乙氧基-1,1,1-三氟-3-丁烯-2-酮的产物体系；对产物体系进行连续化萃取，得到4-乙氧基-1,1,1-三氟-3-丁烯-2-酮。
上述反应的反应路线如下：
Figure PCTCN2019122788-appb-000001
使用连续化工艺，可将上述各原料便捷、精确地打入连续化反应器中，反应结束后同样利用连续萃取进行后处理，整个过程快速、简单高效，大大提高了整个合成工艺的效率，由于产物随着连续产出被及时连续地萃取分离，因此降低了产物破坏的损失；而且反应器可以重复利用，降低了使用成本。同时反应过程产生的大量热量放出可以通过连续反应器及时高效的交换掉，避免了批次生产的安全隐患。而且，本申请的连续化合成方法在放大后不存在放大效应，依然可以保持安全性和较高的合成效率。
为提高反应物转化率，优选上述乙烯基乙醚和三氟乙酸酐的摩尔比为1.0：1～1.5：1，优选为1.1：1～1.3：1，同时为了在保证三乙胺催化效率的同时，控制热量产出量，优选上述三乙胺和三氟乙酸酐的摩尔比为1.0：1～1.5：1，优选为1.2：1～1.3：1。
为了提高各物料的输送效率以及控制反应速率，优选上述乙烯基乙醚、三乙胺和三氟乙酸酐以溶液的方式连续进入连续化反应器中，上述各物质采用溶液的方式输送，利用溶剂进行稀释，有效地控制了单位时间内参与反应的物料，进而有效控制了反应热的产出。为了提高各物质的溶解性，优选溶液中的溶剂为极性溶剂。
由于上述反应为放热反应，且物料之间的反应效率较高，为了避免瞬时产热量激增以保证安全性，优选上述反应的反应温度为-40～100℃，利用反应温度控制反应速率。在保证安全性的前提下，为了尽可能提高生产效率，优选反应包括依次连续进行的第一阶段反应和第二阶段反应，第一阶段反应的反应温度T1为-40～40℃，优选第一阶段反应的保留时间为40～80min，第二阶段反应的反应温度T1为0～100℃，优选第二阶段反应的保留时间为40～80min，更优选反应温度T1小于或等于反应温度T2。第一阶段反应在相对较低的温度下进行，以使底物逐渐反应，随着反应进行体系中的底物浓度降低，然后升高反应温度以进入第二阶段反应，以保证反应速率。
在本申请一种实施例中，上述连续化反应器包括串联设置的第一连续化反应器和第二连续化反应器，使原料连续进入连续化反应器中进行反应的过程包括：将乙烯基乙醚和三乙胺溶解于第一极性溶剂中，得到混合溶液；将三氟乙酸酐溶解于第二极性溶剂中，得到酸酐溶液；将混合溶液和酸酐溶液分别连续地送入第一连续化反应器中进行第一阶段反应，得到初反应体系；将初反应体系连续地送入第二连续化反应器中进行第二阶段反应，得到产物体系。
将乙烯基乙醚和三乙胺混合形成混合溶液，然后再将混合溶液和酸酐溶液送入第一连续化反应器中，避免了三乙胺和三氟乙酸酐提前接触产热。而且利用两个串联的连续化反应器进行连续化反应，有效地控制第一阶段反应和第二阶段反应的温度，保证了高效的生产效率。
在本申请另一种实施例中，上述连续化反应器具有连通设置的第一反应段和第二反应段，第一反应段和第二反应段各自具有控温结构，使原料连续进入连续化反应器中进行反应的过程包括：将乙烯基乙醚和三乙胺溶解于第一极性溶剂中，得到混合溶液；将三氟乙酸酐溶解于第二极性溶剂中，得到酸酐溶液；将混合溶液和酸酐溶液分别连续地送入第一反应段中，并在第一反应段中进行第一阶段反应、在第二反应段中进行第二阶段反应，得到产物体系。将第一阶段反应和第二阶段反应集成在同一个连续化反应器中，简化了装置结构，减少了装置成本。
上述连续化反应器可以采用现有技术中常用的连续化反应器，优选连续盘管反应器或连续柱式反应器。且第一连续化反应器和第二连续化反应器均设置有控温结构，比如控温夹套，第一反应段和第二反应段的控温结构也可以为控温夹套，具体的设置方式在此不再赘述，本领域技术人员可以参考现有技术。
为了精确控制反应进程，优选每克乙烯基乙醚所采用的第一极性溶剂的体积为0.95～1.1mL，每克三氟乙酸酐所采用的第二极性溶剂的体积为0.95～1.1mL。用于本申请的第一极性溶剂和第二极性溶剂可以选用现有技术中常用的极性溶剂，优选上述第一极性溶剂和第二极性溶剂各自独立地选自氯仿、二氯甲烷、四氯化碳组成的组中的任意一种。为了进一步增加后处理的方便性，优选第一极性溶剂和第二极性溶剂相同。
在本申请另一种实施例中，上述对产物体系进行连续化萃取的过程包括：使产物体系和酸性溶液连续进入第一萃取柱以连续进行酸萃取，得到分离的第一有机相和酸水相；使第一有机相连续和碱性溶液连续进入第二萃取柱以连续进行碱萃取，得到分离的第二有机相和碱水相；去除第二有机相中的溶剂，得到4-乙氧基-1,1,1-三氟-3-丁烯-2-酮。利用上述酸性溶液除去反应中碱性催化剂，然后利用碱性溶液洗去体系的酸性杂质，实现了对产物体系中的4-乙氧基-1,1,1-三氟-3-丁烯-2-酮的高效萃取。由于连续化萃取中酸性溶液和碱性溶液与4-乙氧基-1,1,1-三氟-3-丁烯-2-酮的接触时间较短，因此有效控制了4-乙氧基-1,1,1-三氟-3-丁烯-2-酮与水接触容易变质的问题发生。
为了节约成本，优选上述酸性溶液为盐酸、柠檬酸、或三氟乙酸，优选碱性溶液为碳酸氢钠水溶液、碳酸氢钾水溶液、碳酸钠水溶液、碳酸钾水溶液中的任意一种。
在保证较高的萃取分离效率基础上，为了尽可能控制4-乙氧基-1,1,1-三氟-3-丁烯-2-酮的变质，优选上述酸萃取的保留时间为10～80min，优选为40～80min，碱萃取的保留时间为10～80min，优选为40～80min。
以下将结合实施例和对比例，进一步说明本申请的有益效果。
实施例1
设备准备：四台柱塞泵；一根盘管反应器，分成相互连通的两段，且各段外部设置有控温夹套，采用循环水控温；一台隔膜泵：两根萃取柱，均为500ml持液量，萃取柱1为2％盐酸萃取柱RT＝0.85hr，T＝0℃，萃取柱2为8％NaHCO 3萃取柱RT＝1.06hr，T＝0℃。
取95.19g乙烯基乙醚、139.66g的三乙胺和230ml的氯仿制成混合溶液，置于打料瓶A中；取230g三氟乙酸酐和230ml的氯仿制成酸酐溶液，置于打料瓶B中。通过柱塞泵A、柱塞泵B开始向盘管反应器中打料，柱塞泵A的进料速度设定为2.4g/min，柱塞泵B的进料速度设定为2.4g/min。第一反应段在-10℃保温，保留时间为60min；第二反应段在40℃保温，保留时间为60min，内压控制在0.02～0.60MPa；原料打完之后用氯仿进行顶料，柱塞泵A进料速度设定为3.0g/min，柱塞泵B进料速度设定为3.0g/min。盘管反应器的出料口直接连萃取柱1，柱塞泵C将6V 2％盐酸溶液打入萃取柱1，柱塞泵C的进料速度设定为：5.75g/min，萃取柱1保留时间为51min；萃取柱1下层的有机相放出后连接柱塞泵D，柱塞泵D的进料速度设定为2.8g/min，同时隔膜泵E将4V 8％碳酸氢钠溶液(匹配柱塞泵D)打入萃取柱2，隔膜泵E的进料速度设定为3.83g/min，萃取柱2的保留时间为64min。打料完毕，用3L四口瓶接收萃取柱2下层放出的有机相，同时在整个过程中用两个3L的锥形瓶分别接收萃取柱1、萃取柱2上层溢出的酸水相、碱水相。将有机相在35℃，0.1MPa条件下浓缩至327g，进行减压蒸溜，在塔底温度50～55℃，塔顶温度40～48℃时，蒸出产品141g，收率为83.2％。
在反应过程中，采用核磁共振对反应进行跟踪，某一时刻的 1HNMR谱图见图1，终产物的 1HNMR谱图见图2。
实施例2
与实施例1的区别在于，第一反应段在-10℃保温，第二反应段在-10℃保温。蒸出产品88.7g，收率为52.3％。
实施例3
与实施例1的区别在于，第一反应段在0℃保温，第二反应段在0℃保温。蒸出产品94.6g，收率为55.8％。
实施例4
设备准备同实施例1。
取95.19g乙烯基乙醚、139.66g的三乙胺和230ml的氯仿制成混合溶液，置于打料瓶A中；取230g三氟乙酸酐和230ml的氯仿制成酸酐溶液，置于打料瓶B中。通过柱塞泵A、柱塞泵B开始向盘管反应器中打料，柱塞泵A的进料速度设定为1.8g/min，柱塞泵B的进料速度设定为1.8g/min。第一反应段在-40℃保温，保留时间为80min；第二反应段在0℃保温，保留时间为80min，内压控制在0.02～0.60MPa；原料打完之后用氯仿进行顶料，柱塞泵A进料速度设定为2.25g/min，柱塞泵B进料速度设定为2.25g/min。盘管反应器的出料口直接连萃取柱1，柱塞泵C将6V 2％盐酸溶液打入萃取柱1，柱塞泵C的进料速度设定为：5.75g/min，萃取柱1保留时间为51min；萃取柱1下层的有机相放出后连接柱塞泵D，柱塞泵D的进料速度设定为2.8g/min，同时隔膜泵E将4V 8％碳酸氢钠溶液(匹配柱塞泵D)打入萃取柱2，隔膜泵E的进料速度设定为3.83g/min，萃取柱2的保留时间为64min。打料完毕，用3L四口瓶接收萃取柱2下层放出的有机相，同时在整个过程中用两个3L的锥形瓶分别接收萃取柱 1、萃取柱2上层溢出的酸水相、碱水相。将有机相在35℃，0.1MPa条件下浓缩308g，进行减压蒸溜，在塔底温度50～55℃，塔顶温度40～48℃时，蒸出产品86g，收率为65.1％。
实施例5
设备准备同实施例1。
取95.19g乙烯基乙醚、139.66g的三乙胺和230ml的氯仿制成混合溶液，置于打料瓶A中；取230g三氟乙酸酐和230ml的氯仿制成酸酐溶液，置于打料瓶B中。通过柱塞泵A、柱塞泵B开始向盘管反应器中打料，柱塞泵A的进料速度设定为2.88g/min，柱塞泵B的进料速度设定为2.88g/min。第一反应段在0℃保温，保留时间为50min；第二反应段在40℃保温，保留时间为50min，内压控制在0.02～0.60MPa；原料打完之后用氯仿进行顶料，柱塞泵A进料速度设定为3.6g/min，柱塞泵B进料速度设定为3.6g/min。盘管反应器的出料口直接连萃取柱1，柱塞泵C将6V 2％盐酸溶液打入萃取柱1，柱塞泵C的进料速度设定为：5.75g/min，萃取柱1保留时间为51min；萃取柱1下层的有机相放出后连接柱塞泵D，柱塞泵D的进料速度设定为2.8g/min，同时隔膜泵E将4V 8％碳酸氢钠溶液(匹配柱塞泵D)打入萃取柱2，隔膜泵E的进料速度设定为3.83g/min，萃取柱2的保留时间为64min。打料完毕，用3L四口瓶接收萃取柱2下层放出的有机相，同时在整个过程中用两个3L的锥形瓶分别接收萃取柱1、萃取柱2上层溢出的酸水相、碱水相。将有机相在35℃，0.1MPa条件下浓缩至321.7g，进行减压蒸溜，在塔底温度50～55℃，塔顶温度40～48℃时，蒸出产品130.1g，收率为78.2％。
实施例6
设备准备同实施例1。
取95.19g乙烯基乙醚、139.66g的三乙胺和230ml的氯仿制成混合溶液，置于打料瓶A中；取230g三氟乙酸酐和230ml的氯仿制成酸酐溶液，置于打料瓶B中。通过柱塞泵A、柱塞泵B开始向盘管反应器中打料，柱塞泵A的进料速度设定为3.6g/min，柱塞泵B的进料速度设定为3.6g/min。第一反应段在40℃保温，保留时间为40min；第二反应段在100℃保温，保留时间为40min，内压控制在0.02～0.60MPa；原料打完之后用氯仿进行顶料，柱塞泵A进料速度设定为4.5g/min，柱塞泵B进料速度设定为4.5g/min。盘管反应器的出料口直接连萃取柱1，柱塞泵C将6V 2％盐酸溶液打入萃取柱1，柱塞泵C的进料速度设定为：5.75g/min，萃取柱1保留时间为51min；萃取柱1下层的有机相放出后连接柱塞泵D，柱塞泵D的进料速度设定为2.8g/min，同时隔膜泵E将4V 8％碳酸氢钠溶液(匹配柱塞泵D)打入萃取柱2，隔膜泵E的进料速度设定为3.83g/min，萃取柱2的保留时间为64min。打料完毕，用3L四口瓶接收萃取柱2下层放出的有机相，同时在整个过程中用两个3L的锥形瓶分别接收萃取柱1、萃取柱2上层溢出的酸水相、碱水相。将有机相在35℃，0.1MPa条件下浓缩330g，进行减压蒸溜，在塔底温度50～55℃，塔顶温度40～48℃时，蒸出产品123..5g，收率为75％。
实施例7
设备准备同实施例1。
取95.19g乙烯基乙醚、139.66g的三乙胺和230ml的氯仿制成混合溶液，置于打料瓶A中；取230g三氟乙酸酐和230ml的氯仿制成酸酐溶液，置于打料瓶B中。通过柱塞泵A、柱塞泵B开始向盘管反应器中打料，柱塞泵A的进料速度设定为2.4g/min，柱塞泵B的进料速度设定为2.4g/min。第一反应段在-10℃保温，保留时间为60min；第二反应段在40℃保温，保留时间为60min，内压控制在0.02～0.60MPa；原料打完之后用氯仿进行顶料，柱塞泵A进料速度设定为3.0g/min，柱塞泵B进料速度设定为3.0g/min。盘管反应器的出料口直接连萃取柱1，柱塞泵C将6V 2％盐酸溶液打入萃取柱1，柱塞泵C的进料速度设定为：7.34g/min，萃取柱1保留时间为40min；萃取柱1下层的有机相放出后连接柱塞泵D，柱塞泵D的进料速度设定为2.8g/min，同时隔膜泵E将4V 8％碳酸氢钠溶液(匹配柱塞泵D)打入萃取柱2，隔膜泵E的进料速度设定为6.12g/min，萃取柱2的保留时间为40min。打料完毕，用3L四口瓶接收萃取柱2下层放出的有机相，同时在整个过程中用两个3L的锥形瓶分别接收萃取柱1、萃取柱2上层溢出的酸水相、碱水相。将有机相在35℃，0.1MPa条件下浓缩至292.8g，进行减压蒸溜，在塔底温度50～55℃，塔顶温度40～48℃时，蒸出产品121.7g，收率为80.2％。
实施例8
设备准备同实施例1。
取95.19g乙烯基乙醚、139.66g的三乙胺和230ml的氯仿制成混合溶液，置于打料瓶A中；取230g三氟乙酸酐和230ml的氯仿制成酸酐溶液，置于打料瓶B中。通过柱塞泵A、柱塞泵B开始向盘管反应器中打料，柱塞泵A的进料速度设定为2.4g/min，柱塞泵B的进料速度设定为2.4g/min。第一反应段在-10℃保温，保留时间为60min；第二反应段在40℃保温，保留时间为60min，内压控制在0.02～0.60MPa；原料打完之后用氯仿进行顶料，柱塞泵A进料速度设定为3.0g/min，柱塞泵B进料速度设定为3.0g/min。盘管反应器的出料口直接连萃取柱1，柱塞泵C将6V 2％盐酸溶液打入萃取柱1，柱塞泵C的进料速度设定为：3.67g/min，萃取柱1保留时间为80min；萃取柱1下层的有机相放出后连接柱塞泵D，柱塞泵D的进料速度设定为2.8g/min，同时隔膜泵E将4V 8％碳酸氢钠溶液(匹配柱塞泵D)打入萃取柱2，隔膜泵E的进料速度设定为3.06g/min，萃取柱2的保留时间为80min。打料完毕，用3L四口瓶接收萃取柱2下层放出的有机相，同时在整个过程中用两个3L的锥形瓶分别接收萃取柱1、萃取柱2上层溢出的酸水相、碱水相。将有机相在35℃，0.1MPa条件下浓缩280g，进行减压蒸溜，在塔底温度50～55℃，塔顶温度40～48℃时，蒸出产118.5g，收率为73.5％。
实施例9
设备准备同实施例1。
取95.19g乙烯基乙醚、139.66g的三乙胺和230ml的二氯甲烷制成混合溶液，置于打料瓶A中；取230g三氟乙酸酐和230ml的二氯甲烷制成酸酐溶液，置于打料瓶B中。通过柱塞泵A、柱塞泵B开始向盘管反应器中打料，柱塞泵A的进料速度设定为2.4g/min，柱塞泵B的进料速度设定为2.4g/min。第一反应段在-10℃保温，保留时间为60min；第二反应段在40℃保温，保留时间为60min，内压控制在0.02～0.60MPa；原料打完之后用二氯甲烷进行顶料， 柱塞泵A进料速度设定为3.0g/min，柱塞泵B进料速度设定为3.0g/min。盘管反应器的出料口直接连萃取柱1，柱塞泵C将6V 2％盐酸溶液打入萃取柱1，柱塞泵C的进料速度设定为：3.67g/min，萃取柱1保留时间为80min；萃取柱1下层的有机相放出后连接柱塞泵D，柱塞泵D的进料速度设定为2.8g/min，同时隔膜泵E将4V 8％碳酸氢钠溶液(匹配柱塞泵D)打入萃取柱2，隔膜泵E的进料速度设定为3.06g/min，萃取柱2的保留时间为80min。打料完毕，用3L四口瓶接收萃取柱2下层放出的有机相，同时在整个过程中用两个3L的锥形瓶分别接收萃取柱1、萃取柱2上层溢出的酸水相、碱水相。将有机相在35℃，0.1MPa条件下浓缩277.6g，进行减压蒸溜，在塔底温度50～55℃，塔顶温度40～48℃时，蒸出产102g，收率为68.3％。
实施例10
设备准备同实施例1。不同之处在于原料，实施例10的原料如下：取79.0g乙烯基乙醚、110.8g的三乙胺和230ml的氯仿制成混合溶液，置于打料瓶A中；取230g三氟乙酸酐和230ml的氯仿制成酸酐溶液，置于打料瓶B中。柱塞泵A的进料速度设定为2.3g/min，柱塞泵B的进料速度设定为2.5g/min，最终的产物114g，计算收率为67.3％。
实施例11
设备准备同实施例1。不同之处在于原料，实施例11的原料如下：取1180.4g乙烯基乙醚、166.2g的三乙胺和230ml的氯仿制成混合溶液，置于打料瓶A中；取230g三氟乙酸酐和230ml的氯仿制成酸酐溶液，置于打料瓶B中。柱塞泵A的进料速度设定为2.5g/min，柱塞泵B的进料速度设定为2.3g/min，最终的产物123g，计算收率为72.6％。
实施例12
设备准备同实施例1。不同之处在于原料，实施例12的原料如下：取86.9g乙烯基乙醚、133.0g的三乙胺和230ml的氯仿制成混合溶液，置于打料瓶A中；取230g三氟乙酸酐和230ml的氯仿制成酸酐溶液，置于打料瓶B中。柱塞泵A的进料速度设定为2.4g/min，柱塞泵B的进料速度设定为2.4g/min，最终的产物138g，计算收率为81.4％。
实施例13
设备准备同实施例1。不同之处在于原料，实施例13的原料如下：取102.7g乙烯基乙醚、144.0g的三乙胺和230ml的氯仿制成混合溶液，置于打料瓶A中；取230g三氟乙酸酐和230ml的氯仿制成酸酐溶液，置于打料瓶B中。柱塞泵A的进料速度设定为2.4g/min，柱塞泵B的进料速度设定为2.4g/min，最终的产物139g，计算收率为82.0％。
实施例14
设备准备同实施例1。不同之处在于原料，实施例14的原料如下：取103g乙烯基乙醚、144g的三乙胺和219ml的氯仿制成混合溶液，置于打料瓶A中；取230g三氟乙酸酐和219ml 的二氯甲烷制成酸酐溶液，置于打料瓶B中。柱塞泵A的进料速度设定为2.4g/min，柱塞泵B的进料速度设定为2.4g/min，最终的产物130g，计算收率为76.7％。
实施例15
设备准备同实施例1。不同之处在于原料，实施例15的原料如下：取71.1g乙烯基乙醚、105.3g的三乙胺和230ml的氯仿制成混合溶液，置于打料瓶A中；取230g三氟乙酸酐和230ml的氯仿制成酸酐溶液，置于打料瓶B中。柱塞泵A的进料速度设定为2.3g/min，柱塞泵B的进料速度设定为2.5g/min，最终的产物71.9g，计算收率为42.4％。
从以上的描述中，可以看出，本发明上述的实施例实现了如下技术效果：
使用连续化工艺，可将上述各原料便捷、精确地打入连续化反应器中，反应结束后同样利用连续萃取进行后处理，整个过程快速、简单高效，大大提高了整个合成工艺的效率，由于产物随着连续产出被及时连续地萃取分离，因此降低了产物破坏的损失；而且反应器可以重复利用，降低了使用成本。同时反应过程产生的大量热量放出可以通过连续反应器及时高效的交换掉，避免了批次生产的安全隐患。而且，本申请的连续化合成方法在放大后不存在放大效应，依然可以保持安全性和较高的合成效率。
以上所述仅为本发明的优选实施例而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种4-乙氧基-1,1,1-三氟-3-丁烯-2-酮的连续化合成方法，其特征在于，包括：
    使包含乙烯基乙醚、三乙胺和三氟乙酸酐的原料连续进入连续化反应器中进行反应，得到含有4-乙氧基-1,1,1-三氟-3-丁烯-2-酮的产物体系；
    对所述产物体系进行连续化萃取，得到所述4-乙氧基-1,1,1-三氟-3-丁烯-2-酮。
  2. 根据权利要求1所述的连续化合成方法，其特征在于，所述乙烯基乙醚和所述三氟乙酸酐的摩尔比为1:1～1.5:1，优选为1.1：1～1.3：1，所述三乙胺和所述三氟乙酸酐的摩尔比为1:1～1.5:1，优选为1.2：1～1.3：1。
  3. 根据权利要求1所述的连续化合成方法，其特征在于，所述乙烯基乙醚、所述三乙胺和所述三氟乙酸酐以溶液的方式连续进入所述连续化反应器中，优选所述溶液中的溶剂为极性溶剂。
  4. 根据权利要求1所述的连续化合成方法，其特征在于，所述反应的反应温度为-40～100℃，优选所述反应包括依次连续进行的第一阶段反应和第二阶段反应，所述第一阶段反应的反应温度T1为-40～40℃，优选所述第一阶段反应的保留时间为40～80min，所述第二阶段反应的反应温度T2为0～100℃，优选所述第二阶段反应的保留时间为40～80min，更优选所述反应温度T1小于或等于所述反应温度T2。
  5. 根据权利要求4所述的连续化合成方法，其特征在于，所述连续化反应器包括串联设置的第一连续化反应器和第二连续化反应器，使所述原料连续进入连续化反应器中进行反应的过程包括：
    将所述乙烯基乙醚和所述三乙胺溶解于第一极性溶剂中，得到混合溶液；
    将所述三氟乙酸酐溶解于第二极性溶剂中，得到酸酐溶液；
    将所述混合溶液和所述酸酐溶液分别连续地送入所述第一连续化反应器中进行所述第一阶段反应，得到初反应体系；
    将所述初反应体系连续地送入所述第二连续化反应器中进行所述第二阶段反应，得到所述产物体系。
  6. 根据权利要求4所述的连续化合成方法，其特征在于，所述连续化反应器具有连通设置的第一反应段和第二反应段，所述第一反应段和所述第二反应段各自具有控温结构，使所述原料连续进入连续化反应器中进行反应的过程包括：
    将所述乙烯基乙醚和所述三乙胺溶解于第一极性溶剂中，得到混合溶液；
    将所述三氟乙酸酐溶解于第二极性溶剂中，得到酸酐溶液；
    将所述混合溶液和所述酸酐溶液分别连续地送入所述第一反应段中，并在所述第一反应段中进行所述第一阶段反应、在所述第二反应段中进行所述第二阶段反应，得到所 述产物体系。
  7. 根据权利要求5或6所述的连续化合成方法，其特征在于，每克所述乙烯基乙醚所采用的所述第一极性溶剂的体积为0.95～1.1mL，每克所述三氟乙酸酐所采用的所述第二极性溶剂的体积为0.95～1.1mL，优选所述第一极性溶剂和所述第二极性溶剂各自独立地选自氯仿、二氯甲烷、四氯化碳组成的组中的任意一种，更优选所述第一极性溶剂和所述第二极性溶剂相同。
  8. 根据权利要求1所述的连续化合成方法，其特征在于，所述对所述产物体系进行连续化萃取的过程包括：
    使所述产物体系和酸性溶液连续进入第一萃取柱以连续进行酸萃取，得到分离的第一有机相和酸水相；
    使所述第一有机相连续和碱性溶液连续进入第二萃取柱以连续进行碱萃取，得到分离的第二有机相和碱水相；
    去除所述第二有机相中的溶剂，得到所述4-乙氧基-1,1,1-三氟-3-丁烯-2-酮。
  9. 根据权利要求8所述的连续化合成方法，其特征在于，所述酸性溶液为盐酸、柠檬酸、或三氟乙酸，优选所述碱性溶液为碳酸氢钠水溶液、碳酸氢钾水溶液、碳酸钠水溶液、碳酸钾水溶液中的任意一种。
  10. 根据权利要求8所述的连续化合成方法，其特征在于，所述酸萃取的保留时间为10～80min，所述碱萃取的保留时间为10～80min。
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