CN111205209B - Device and method for preparing vitamin A acetate through multistage continuous series reaction extraction - Google Patents
Device and method for preparing vitamin A acetate through multistage continuous series reaction extraction Download PDFInfo
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Abstract
The invention relates to a method for preparing vitamin A acetate by multistage continuous series reaction extractionA pump, a hydrocyclone separator and an oil-water separator. The process comprises the following steps: feeding a raw material F1Alkali liquor F2And an extractant E0Continuously introducing the mixture into a multistage continuous series reaction extraction device for wittig reaction synthesis to obtain the vitamin A acetic ester. The invention has the advantages that the reaction and extraction processes can be simultaneously carried out in the multistage continuous series reaction extraction device, and the solid phase generated in the reaction process can be separated in time, thereby being beneficial to reducing the occurrence of side reaction and improving the yield of vitamin A acetate; compared with the traditional intermittent production process, the process realizes continuous production, shortens the production period and can reduce the production cost.
Description
Technical Field
The invention relates to a device and a method for preparing vitamin A acetate through multistage continuous series reaction extraction, and belongs to the technical field of production of vitamin A and derivatives thereof.
Background
Vitamin A, which is known as retinol in chemical name, is a fat-soluble vitamin which is discovered at the earliest time and is one of essential nutrients for human body. However, vitamin a is very unstable, easily destroyed by acids, air, oxidizing substances, high temperature or ultraviolet rays, and the like, and is irritating to the skin. Ester derivatives of vitamin a are more stable and non-irritating than vitamin a, and therefore the commercial forms of vitamin a are all provided in the form of esters, the most common commercial form being vitamin a acetate. Vitamin A acetate is one of the most important series of vitamin A products, and due to better stability and better pharmacological action, the demand of vitamin A acetate is increasing, so that the vitamin A acetate is widely applied to cosmetics, medicines, feeds and the like.
In recent years, people mainly focus on batch processes for the synthesis research of vitamin A acetate, and the continuous synthesis process of vitamin A acetate is rarely researched.
WO2005058811A, DE10164041A and Chinese patents CN101318975A, CN101219983A and CN102190565A all report that C14 aldehyde and C1 are used for Wittig reaction, and after the steps are complicated, C15 phosphonate is obtained, the reported yield is 80-92%, but actually is lower than 80%, and the C15 phosphonate can be used for the next Wittig reaction after being completely dried or processed, such as CN 1097414A.
Patent CN103044302A reports a one-pot method for preparing vitamin a acetate, which utilizes C14 aldehyde and intermediate C1 (tetraethyl methylenediphosphonate or tetramethyl methylenediphosphonate) to react under alkaline conditions to produce C15 phosphonate, and the C15 phosphonate directly reacts with C5 aldehyde in one-pot method without separation to prepare vitamin a acetate, which has been improved greatly, but still avoids the need of using dangerous and high air and moisture control reagents such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or sodium hydride.
Patent CN109731612A reports that in the presence of inorganic base and functionalized ionic liquid, C15 phosphonium salt reacts with C5 aldehyde to produce all-trans vitamin a acetate, using water as reaction medium, the production is safer and easier to control, but is still only suitable for batch production.
The production of vitamin A acetate by using C15 phosphonium salt and C5 aldehyde as raw materials is a hotspot of research in the field of vitamin A acetate synthesis in recent years, but continuous production cannot be realized.
The reactive extraction is used as a process strengthening technology, and by coupling the reaction process with the extraction process, compared with the traditional unit operation and other chemical process strengthening technologies, the reactive extraction technology has the advantages of simple process, mild conditions, economy, practicability, strong designability and the like. The application of the reactive extraction technology in liquid-liquid reaction is related to, a great deal of research is carried out by a plurality of scholars at home and abroad, but the application of the reactive extraction technology is relatively less when the reactive extraction technology relates to the reaction containing solids in a system. The reaction system contains solid reaction, the solid in the system can be deposited at the bottom of equipment and is not easy to clean in the long-term operation process, the risk of blocking a pipeline is easy to occur, and the solid cannot be removed from the reaction system in time, so that products, raw materials, intermediates and byproduct solid can be wrapped mutually under the stirring condition, the reaction rate is reduced, the conversion rate and the yield are influenced, and the occurrence of side reactions is increased. In the reactive extraction process, the problems are difficult to solve by conventional methods such as stirring and the like, and the continuity is difficult to realize, so the continuous reactive extraction process of liquid and solid phases is rarely reported.
According to the preparation process of the vitamin A acetate by taking the C15 phosphonium salt and the C5 aldehyde as reaction raw materials and taking water as a reaction solvent, by-product solid particles such as triphenylphosphine oxide and the like are generated in the reaction process, and the continuously generated solid particles are difficult to realize continuous production of reaction extraction, so that side reactions are increased to influence the synthesis yield of the vitamin A acetate. The production process for preparing vitamin A acetate by the chemical synthesis method reported at present is an intermittent process, and has the defects of high labor intensity, low production efficiency, large influence on environment and the like, so that the problem of seeking a proper green production process with high competitiveness is urgent to solve.
Disclosure of Invention
Aiming at the problems in the prior art, the invention improves the method for synthesizing the vitamin A acetate by a chemical synthesis method. The invention discloses a method and a device for preparing vitamin A acetate by multistage continuous series reaction extraction. The method has mild reaction conditions, realizes continuous production, is safe and easy to control, is environment-friendly, can remove generated byproducts out of a reaction system in time, reduces the occurrence of side reactions, and has high reaction yield.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a method for preparing vitamin A acetate by multistage continuous series reaction extraction is provided, which is to use raw material F1Alkali liquor F2And an extractant E0Continuously introducing the mixture into a multistage continuous series reaction extraction device for wittig reaction, and synthesizing to obtain the vitamin A acetic ester.
In the process of the present invention, the starting material F1Is a mixed solution of C15 phosphine salt, water and C5 aldehyde.
Preferably, the feedstock F1The amount of water is 1.5-6 times, preferably 2-5 times of the mass of the C15 phosphonium salt; the molar ratio of the C5 aldehyde to the C15 phosphine salt is 1/1-1.6/1, preferably 1.03/1-1.2/1.
Further, the general structural formula of the C15 phosphonium salt is
Wherein X is halogen, preferably Cl or Br, more preferably Cl, namely C15 chloride phosphonium salt with the structural formula
Further, the C5 aldehyde is 3-formyl but-2-alkenyl acetate, and the structural formula is shown in the specification
In the process of the invention, the lye F2Selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, carbonic acidOne or more of an aqueous solution of sodium, ammonium carbonate and aqueous ammonia, preferably an aqueous solution of sodium carbonate and/or potassium carbonate; preferably, the lye F2The alkali concentration of (A) is 10 to 45 wt%, preferably 15 to 35 wt%.
Further, the alkali liquor F2The phase transfer assistant is quaternary ammonium salt phase transfer assistant, which is selected from one or more of triethylbenzylammonium chloride, triethylbenzylammonium bromide, trioctylmethylammonium chloride, dodecyltrimethylammonium bromide, hexadecyltrimethylammonium chloride, hexadecyltrimethylammonium bromide and tetrabutylammonium hydrogen sulfate, and is preferably one or more of dodecyltrimethylammonium chloride, dodecyltrimethylammonium bromide, hexadecyltrimethylammonium chloride and hexadecyltrimethylammonium bromide; preferably, the molar ratio of the phase transfer aid to the base (calculated by the compound) is 1/8-1/50, preferably 1/15-1/36. According to the invention, the quaternary ammonium salt phase transfer assistant is added into the reaction system, so that on one hand, the anion in the aqueous phase alkali liquor can be promoted to be fully contacted with the C15 phosphonium salt, the generation of intermediate ylide is facilitated, and simultaneously, the ylide can be continuously promoted to react with the C5 aldehyde to generate the vitamin A acetate, so that the effects of shortening the reaction time and improving the conversion rate can be achieved; on the other hand, adverse effects caused by the mutual wrapping problem among products, raw materials, intermediates and byproduct solids in a reaction system can be avoided, side reactions are inhibited, and the effect of improving selectivity is achieved.
In the process of the invention, the extractant E is0Is selected from one or more of petroleum ether, n-hexane, n-heptane, n-pentane, cyclohexane and methylcyclohexane, preferably one or more of petroleum ether, n-hexane and n-heptane.
In the process of the present invention, the starting material F1With alkali liquor F2The feeding mass flow ratio is (2-20): 1; the raw material F1With an extractant E0The feeding mass flow ratio is (2-4): 1.
in the method, the wittig reaction mechanism is as follows:
in the method, the multistage continuous series reaction extraction device comprises a reaction extraction repeating structural unit and an oil-water separator which are connected in multistage series, wherein each stage of reaction extraction repeating structural unit comprises a set of reaction extraction stirring kettle, a pump and a hydrocyclone separator which are connected in sequence;
and a high-speed shearing mixer is arranged at the bottom of the reaction extraction stirring kettle. The high-speed shearing mixer is added at the bottom of each stage of reaction extraction stirring kettle, so that each phase of a reaction system can be more fully contacted, the reaction is facilitated, a byproduct solid phase of triphenylphosphine oxide generated in the reaction process can be dispersed in a liquid phase, the risk of pipeline blockage is reduced, and conditions are created for continuous production.
Preferably, the extraction stages of the multistage continuous series reaction extraction device are 2-6 stages, and preferably 3-5 stages.
Preferably, the rotating speed of the high-speed shearing mixer in the reaction extraction stirring kettle is 3000-12000 rpm, and preferably 5000-9000 rpm.
In the method of the present invention, the stirring in the reaction extraction stirred tank is not particularly limited, and conventional stirring may be employed. Experiments show that the stirring speed of the stirring kettle is only adjusted in the process of continuously producing vitamin A acetate by the reaction extraction method, so that no special effect is provided for solving solid deposition, improving reaction speed and the like, and the high-speed shearing mixer is arranged at the bottom of the reaction extraction stirring kettle, so that the rotating speed of the high-speed shearing mixer has a remarkable influence on the reaction effect and the product quality and needs to be controlled within a specific range. If the rotating speed is not properly controlled, if the reaction system is easy to be in an emulsified state at an excessively high rotating speed, solid-phase by-products such as triphenylphosphine oxide (TPPO) and the like are excessively stopped in a liquid phase, materials are mutually wrapped to prevent the smooth reaction, and the difficulty is increased for subsequent separation; if the rotating speed is too low, the solid phase is easy to agglomerate, the system is easy to increase the blocking risk when entering a pipeline, the effect of dispersing the solid cannot be achieved, and the continuous operation cannot be realized.
In the method, the retention time of the materials in each stage of reaction extraction stirring kettle is 2-8 min, preferably 3-6 min.
In the method, the reaction temperature in each stage of reaction extraction stirring kettle is 35-70 ℃, and preferably 40-55 ℃.
In some methods of the invention, the specific steps employed are: feeding a raw material F1Alkali liquor F2And an extractant E0Introducing the mixture into a reaction extraction stirring kettle from the top, stirring and mixing, simultaneously starting a high-speed shearing mixer to perform wittig reaction, simultaneously discharging reaction liquid from the bottom, pumping the reaction liquid into a hydrocyclone separator to separate out solids, then entering a next-stage extraction repeated structural unit to repeat the operation, and finally entering an oil-water separator to separate to obtain a vitamin A acetate product.
In the method, the materials are fully contacted under the synergistic action of the high-speed shearing mixer and the quaternary ammonium salt phase transfer assistant, the reaction time is shortened, the solid-phase by-product generated in the reaction process can be timely removed from the reaction system under the combined action of the high-speed shearing mixer and the hydrocyclone arranged in the multistage continuous series reaction extraction device, the mutual wrapping among the product, the raw material, the intermediate and the by-product solid is avoided, the occurrence of side reaction is favorably reduced, meanwhile, the hydrocyclone provides a continuous liquid phase for the multistage continuous series reaction extraction device, the multistage reaction is smoothly carried out backwards, and the continuous production under a solid-liquid system is realized.
The invention also provides a multistage continuous series reaction extraction device, which comprises a reaction extraction repeating structural unit and an oil-water separator which are connected in multistage series, wherein each stage of reaction extraction repeating structural unit comprises a set of reaction extraction stirring kettle, a pump and a hydrocyclone separator which are connected in sequence;
and a high-speed shearing mixer is arranged at the bottom of the reaction extraction stirring kettle.
Preferably, in the extraction repeating structural unit, a feed inlet is arranged at the top of the reaction extraction stirring kettle, a discharge outlet is arranged at the bottom of the reaction extraction stirring kettle, and the discharge outlet is connected with an inlet of the hydrocyclone separator through a pipeline via a pump.
Preferably, the extraction stages of the multistage continuous series reaction extraction device are 2-6 stages.
The multistage continuous series reaction extraction device has universal applicability, can be used for a liquid-liquid reaction system extraction process, can also be used for a liquid-solid reaction system extraction process, and is particularly suitable for the synthesis method of the vitamin A acetate with solid-phase by-products.
The technical scheme of the invention has the beneficial effects that:
(1) the method realizes the continuous production of the vitamin A acetate, can greatly improve the production efficiency, shorten the production period, reduce the production cost and essentially reduce the labor intensity of the process operation;
(2) the reaction process and the extraction process are coupled together, and a solid phase generated in the reaction process can be timely removed out of a reaction system, so that the side reaction is favorably reduced, and the reaction extraction continuous process production related to the solid contained in the system is realized;
(3) the method has the advantages of high yield of the vitamin A acetic ester, mild reaction conditions, environmental friendliness, suitability for large-scale industrial production and great significance for improving the industrial production level of the vitamin A acetic ester in China.
Drawings
FIG. 1 is a schematic diagram of a three-stage continuous series reactive extraction apparatus used in example 1 of the present invention;
in the figure: 1-1, 1-2 and 1-3 are reaction extraction stirring kettles of each stage; 2-1, 2-2 and 2-3 are material conveying pumps of each stage; 3-1, 3-2 and 3-3 are each stage of hydrocyclone separator for solid-liquid separation; 4 is an oil-water separator for oil-water phase separation; 5-1, 5-2 and 5-3 are high-speed shearing mixers arranged at the bottom of each stage of the reaction extraction stirring kettle;
F1as raw material (mixed liquor); f2Is alkali liquor; e0Is an extracting agent; e1、E2And E3Each stage is a liquid phase separated by a hydrocyclone; s1、S2And S3Each stage is a solid phase separated by a hydrocyclone; n is an oil phase (extractant phase) separated by an oil-water separator; w is water phase separated by an oil-water separator.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention in any way.
The final product obtained in the examples was analyzed for purity by high performance liquid chromatography, and standard samples were used to establish an external standard curve, and the measured purity was that of the liquid external standard method.
Analysis conditions were as follows:
high performance liquid chromatograph: shimadzu LC-20A model, CTO-10ASvp column incubator, SPD-M20A detector, chromatographic column ODS C18 column (250 mm. times.4.6 mm. times.5 μ M). The temperature of the column oven is 40 ℃; the mobile phase is methanol water solution (the volume ratio of methanol to water is equal to 3: 2); the flow rate is 0.4 ml/min; the UV detection wavelength was 328 nm.
The main raw material sources of the embodiment of the invention are shown in table 1:
TABLE 1 sources of reagents involved in the examples and comparative examples
| Reagent | Source | Purity specification |
| Chlorinated C15 phosphonium salts | Self-made | 99.5％ |
| Brominated C15 phosphonium salts | Self-made | 99.5％ |
| Pyridine compound | SHANDONG KUNDA BIOTECHNOLOGY Co.,Ltd. | 99.9％ |
| Vinyl-beta ionol | ZHEJIANG NHU Co.,Ltd. | 94％ |
| Methanol | SHANDONG LIANMENG CHEMICAL Co.,Ltd. | 99.9％ |
| Triphenylphosphine | Chat for chemical industry Co Ltd | 99.9％ |
| Hydrochloric acid | Yantai Far East Fine Chemical Co.,Ltd. | 36～38％ |
| Hydrobromic acid | Yantai Far East Fine Chemical Co.,Ltd. | 33～35％ |
| C5 aldehyde (3-formylbut-2-enylacetate) | Linyi Ezilas Biotechnology Ltd | 99％ |
| Sodium carbonate | Yantai Far East Fine Chemical Co.,Ltd. | 99.5％ |
| Potassium carbonate | The far east fine chemical industry of cigarette end isLimited company | 99％ |
| Potassium hydroxide | Yantai Far East Fine Chemical Co.,Ltd. | 99％ |
| Sodium hydroxide | Yantai Far East Fine Chemical Co.,Ltd. | 99％ |
| Lithium hydroxide | Tai an Ying Li chemical materials Co Ltd | 99％ |
| Ammonium carbonate | Yantai Far East Fine Chemical Co.,Ltd. | 99％ |
| Aqueous ammonia | Yantai Far East Fine Chemical Co.,Ltd. | 25～28％ |
| Petroleum ether | Yantai Far East Fine Chemical Co.,Ltd. | Boiling range of 60-90 DEG C |
| N-hexane | Yantai Far East Fine Chemical Co.,Ltd. | 99％ |
| N-pentane | Yantai Far East Fine Chemical Co.,Ltd. | 99％ |
| N-heptane | Yantai Far East Fine Chemical Co.,Ltd. | 99％ |
| Cyclohexane | Yantai Far East Fine Chemical Co.,Ltd. | 99％ |
| Methylcyclohexane | Jinan Gurui speciality chemical Co., Ltd | 99％ |
| Hexadecyl trimethyl ammonium chloride | Zhouhai chemical industries, Ltd | 99％ |
| Dodecyl trimethyl ammonium chloride | Zhouhai chemical industries, Ltd | 99％ |
| Cetyl trimethyl ammonium Bromide | Zhouhai chemical industries, Ltd | 99％ |
| Triethyl benzyl ammonium chloride | Linyi Ezilas Biotechnology Ltd | 99％ |
| Dodecyl trimethyl ammonium bromide | Zhouhai chemical industries, Ltd | 99％ |
| Trioctyl methyl ammonium chloride | Zhouhai chemical industries, Ltd | 99％ |
| Tetrabutylammonium hydrogen sulfate | Zhouhai chemical industries, Ltd | 99％ |
| 18-crown-6-ethers | Linyi Ezilas Biotechnology Ltd | 99％ |
The preparation method of the C15 phosphine salt can be carried out according to journal literature 'New Process research on vitamin A synthesis by Wittig method [ D ]. Lu Guofeng. Zhejiang industry university 2007'.
The preparation process of the chlorinated C15 phosphine salt comprises the following steps: adding 10.5kg of vinyl-beta-ionol (with the purity of 94 wt%), 2.5L of pyridine and 25L of methanol into a stirring kettle, and stirring to prepare a mixed solution; 100L of methanol, 1.5kg of triphenylphosphine and 10L of 38.0 wt% hydrochloric acid aqueous solution are added into an enamel kettle equipped with a condensation reflux device; starting stirring, starting heating after nitrogen replacement of the enamel kettle, pumping the mixed solution in the stirring kettle into the enamel kettle for reaction by a pump when the temperature of the system reaches 50 ℃, controlling the feeding time to be about 2 hours, and keeping the temperature for 5 hours after the feeding is finished; and after the heat preservation is finished, recovering the solvent methanol under reduced pressure, adding ethyl acetate after the recovery is finished, and recovering the ethyl acetate after the stirring is uniform. And after the recovery is finished, adding ethyl acetate again to cool and crystallize the product, and then performing suction filtration and drying to obtain chlorinated C15 phosphonium salt (with the molar mass of 501.08), wherein the liquid chromatography purity of the chlorinated C15 phosphonium salt is more than 99.5 wt%.
The preparation process of the brominated C15 phosphonium salt comprises the following steps: referring to the preparation process of chlorinated C15 phosphine salt, the difference is only that the raw material "10L hydrochloric acid aqueous solution with concentration of 38.0 wt%" is replaced by "20.6L hydrobromic acid aqueous solution with concentration of 35.0 wt%" to prepare brominated C15 phosphine salt (with molar mass of 545.53) with liquid chromatography purity of more than 99.5 wt%.
The embodiment of the invention adopts a three-stage continuous series reaction extraction device (as shown in figure 1): the device comprises three stages of reactive extraction repeating structural units and an oil-water separator 4 which are connected in series, wherein each stage of reactive extraction repeating structural unit comprises a set of reactive extraction stirring kettles 1 (1-3 stages are 1-1, 1-2 and 1-3 respectively), pumps 2 (1-3 stages are 2-1, 2-2 and 2-3 respectively) and hydrocyclones 3 (1-3 stages are 3-1, 3-2 and 3-3 respectively) which are connected in sequence; the bottom of the reaction extraction stirring kettle 1 is provided with a high-speed shearing mixer 5 (1-3 levels are 5-1, 5-2 and 5-3 respectively).
In each stage of extraction repeating structural unit, a feed inlet is arranged at the top of the reaction extraction stirring kettle 1, a discharge outlet is arranged at the bottom of the reaction extraction stirring kettle, and the discharge outlet is connected with an inlet of a hydrocyclone 3 through a pipeline via a pump 2.
In FIG. 1F1Is taken as a raw material (mixed solution of C15 phosphonium salt, C5 aldehyde and water); f2Is alkali liquor; e0Is an extracting agent; e1、E2And E3The liquid phase after each stage of separation by the hydrocyclone 3; s1、S2And S3Each stage is a solid phase separated by the hydrocyclone 3; n is an oil phase (extractant phase) separated by the oil-water separator 5; w is water phase separated by an oil-water separator.
Example 1
Preparation of raw Material F1Wherein the mass content of the chlorinated C15 phosphine salt is 30.37 percent, the mass content of the C5 aldehyde is 8.88 percent, and the mass content of the water is 60.75 percent (the molar ratio of the C5 aldehyde to the chlorinated C15 phosphine salt is 1.03). Starting material F1Preheating to 40 ℃.
Preparing an alkali liquor F2Wherein the mass concentration of the sodium carbonate is 15%, the mass concentration of the phase transfer auxiliary agent hexadecyl trimethyl ammonium chloride is 3% (the molar ratio of the sodium carbonate to the hexadecyl trimethyl ammonium chloride is 15), and the balance is pure water. Lye F2Preheating to 40 ℃.
Petroleum ether is selected as an extracting agent E0. Extractant E0Preheating to 40 ℃.
As shown in FIG. 1, the reaction apparatus is configured to mix raw material F1Alkali liquor F2And an extractant E0Respectively introducing into a first-stage reaction extraction stirring kettle 1-1 at mass flow rates of 14.8kg/min, 7.0kg/min and 7.4kg/min at the same time, maintaining at 40 deg.C for reaction extraction, and starting a first-stage material delivery pump 2-1 (the flow rate is controlled to be equal to that of the raw material F) when the liquid holdup in the kettle is 175kg (the material retention time is controlled to be 6min)1Alkali liquor F2And an extractant E0The sum of the flow rates) and a hydrocyclone 3-1, the separated liquid phase enters a next-stage reaction extraction stirring kettle to continue the reaction extraction process until a liquid phase E separated by the hydrocyclone at the third stage is obtained3. The reaction temperature and the material residence time of the reaction extraction process in the second and third stage reaction extraction stirred tanks are the same as the first stage. The speed of each high speed shear mixer was 5000 rpm. Liquid phase E3Separating in an oil-water separator to obtain an oil phase N (petroleum ether phase). After the device runs stably, performing high performance liquid chromatography analysis on the obtained oil phase N, wherein the yield of the vitamin A acetate is 94.44%; after the device runs stably, 12.2kg of byproduct solid (the TPPO content is 96.62 wt%; the theoretical TPPO production amount is 11.8 kg; and the solid separation rate can reach 99.9% by calculation of TPPO) is collected from the device within 5 min.
Example 2
Preparation of raw Material F1Wherein the mass content of the chlorinated C15 phosphine salt is 15.77 percent, the mass content of the C5 aldehyde is 5.37 percent, and the mass content of the water is 78.86 percent (the molar ratio of the C5 aldehyde to the chlorinated C15 phosphine salt is 1.2). Starting material F1Pre-heating to 55 ℃.
Preparing an alkali liquor F2Wherein the mass concentration of the sodium hydroxide is 35 percent, the mass concentration of the phase transfer auxiliary agent dodecyl trimethyl ammonium chloride is 6.4 percent, and the balance is pure water (the molar ratio of the sodium hydroxide to the dodecyl trimethyl ammonium chloride is 36). Lye F2Pre-heating to 55 ℃.
N-heptane is selected as extractant E0. Extractant E0Pre-heating to 55 ℃.
As shown in the attached figure, raw material F1Alkali liquor F2And an extractant E0Respectively introducing into a first-stage reaction extraction stirring kettle 1-1 at mass flow rates of 38.0kg/min, 1.9kg/min and 9.4kg/min at the same time, maintaining at 55 deg.C for reaction extraction, and starting a first-stage material transfer pump 2-1 (flow rate is controlled to be equal to that of raw material F) when the liquid holdup in the kettle is 148kg (material retention time is controlled to be 3min)1Alkali liquor F2And an extractant E0The sum of the flow rates) and a hydrocyclone 3-1, the separated liquid phase enters a next-stage reaction extraction stirring kettle to continue the reaction extraction process until a liquid phase E separated by the hydrocyclone at the third stage is obtained3. The reaction temperature and the material residence time of the reaction extraction process in the second and third stage reaction extraction stirred tanks are the same as the first stage. The speed of each stage of the high speed shear mixer was 9000 rpm. Liquid phase E3Separating in an oil-water separator to obtain an oil phase N (N-heptane phase). After the device runs stably, performing high performance liquid chromatography analysis on the obtained oil phase N, wherein the yield of the vitamin A acetate is 94.31%; after the device runs stably, 16.2kg of byproduct solid is collected from the device within 5min (wherein the TPPO content is 96.81 wt%; the theoretical TPPO production amount is 15.7kg, and the solid separation rate can reach more than 99.9% by calculation of TPPO).
Example 3
Preparation of raw Material F1Wherein, the mass content of the chlorinated C15 phosphine salt is 23.19 percent, the mass content of the C5 aldehyde is 7.24 percent (the molar ratio of the C5 aldehyde to the chlorinated C15 phosphine salt is 1.1), and the mass content of the water is 69.57 percent. Starting material F1Pre-heating to 50 ℃.
Preparing an alkali liquor F2Wherein the mass concentration of the potassium carbonate is 30 percent, the mass concentration of the phase transfer auxiliary agent cetyl trimethyl ammonium bromide is 3.2 percent, and the balance is pure water (the molar ratio of the potassium carbonate to the cetyl trimethyl ammonium bromide is 25). Lye F2Pre-heating to 50 ℃.
N-hexane is selected as an extracting agent E0. Extractant E0Pre-heating to 50 ℃.
As shown in the attached figure, raw material F1Alkali liquor F2And an extractant E0At 21.6kg/min, 5.5kg/min andintroducing mass flow of 8.7kg/min into the first-stage reaction extraction stirring kettle 1-1 at the same time, maintaining at 50 deg.C for reaction extraction, and starting the first-stage material delivery pump 2-1 (controlling flow equal to raw material F) when liquid holdup in the kettle is 179kg (controlling material retention time to be 5min)1Alkali liquor F2And an extractant E0The sum of the flow rates) and a hydrocyclone 3-1, the separated liquid phase enters a next-stage reaction extraction stirring kettle to continue the reaction extraction process until a liquid phase E separated by the hydrocyclone at the third stage is obtained3. The reaction temperature and the material residence time of the reaction extraction process in the second and third stage reaction extraction stirred tanks are the same as the first stage. The rotational speed of each high-speed shear mixer was 7000 rpm. Liquid phase E3Separating in an oil-water separator to obtain an oil phase N (normal hexane phase). After the device runs stably, performing high performance liquid chromatography analysis on the obtained oil phase N, wherein the yield of the vitamin A acetate is 95.12%; after the device runs stably, 13.8kg of byproduct solid (wherein the TPPO content is 95.55 wt%; the theoretical TPPO production amount is 13.2 kg; and the solid separation rate can reach 99.9% calculated by TPPO) is collected from the device within 5 min.
Example 4
Preparation of raw Material F1Wherein, the mass content of the chlorinated C15 phosphine salt is 35.92 percent, the mass content of the C5 aldehyde is 10.19 percent, and the mass content of the water is 53.89 percent (the molar ratio of the C5 aldehyde to the chlorinated C15 phosphine salt is 1). Starting material F1Pre-heating to 35 ℃.
Preparing an alkali liquor F2Wherein the mass concentration of the lithium hydroxide is 10%, the mass concentration of the phase transfer additive, namely, the triethylbenzylammonium chloride is 11.9%, and the balance is pure water (the molar ratio of the lithium hydroxide to the triethylbenzylammonium chloride is 8). Lye F2Pre-heating to 35 ℃.
Selecting n-pentane as an extracting agent E0. Extractant E0Pre-heating to 35 ℃.
As shown in the attached figure, raw material F1Alkali liquor F2And an extractant E0Respectively introducing into a first-stage reaction extraction stirring kettle 1-1 at mass flow rates of 16.7kg/min, 3.0kg/min and 4.9kg/min at the same time to maintain 35 deg.C for reaction extraction process, and keeping the liquid holdup in the kettle at 197kg (while controlling the material to stay)For 8min), starting the first-stage material conveying pump 2-1 (the flow is controlled to be equal to the raw material F)1Alkali liquor F2And an extractant E0The sum of the flow rates) and a hydrocyclone 3-1, the separated liquid phase enters a next-stage reaction extraction stirring kettle to continue the reaction extraction process until a liquid phase E separated by the hydrocyclone at the third stage is obtained3. The reaction temperature and the material residence time of the reaction extraction process in the second and third stage reaction extraction stirred tanks are the same as the first stage. The speed of each high speed shear mixer was 3000 rpm. Liquid phase E3Separating in an oil-water separator to obtain an oil phase N (N-pentane phase). After the device runs stably, performing high performance liquid chromatography analysis on the obtained oil phase N, wherein the yield of the vitamin A acetate is 93.84%; after the device runs stably, 16.2kg of byproduct solid is collected from the device within 5min (wherein the TPPO content is 95.91 wt%; the theoretical TPPO production amount is 15.6kg, and the solid separation rate can reach 99.6% by calculation of TPPO).
Example 5
Preparation of raw Material F1Wherein, the mass content of the chlorinated C15 phosphine salt is 13.42 percent, the mass content of the C5 aldehyde is 6.09 percent, and the mass content of the water is 80.49 percent (the molar ratio of the C5 aldehyde to the chlorinated C15 phosphine salt is 1.6). Starting material F1Pre-heating to 70 ℃.
Preparing an alkali liquor F2Wherein the mass concentration of ammonium carbonate is 45%, the mass concentration of dodecyl trimethyl ammonium bromide serving as a phase transfer additive is 2.9%, and the balance is pure water (the molar ratio of ammonium carbonate to dodecyl trimethyl ammonium bromide is 50). Lye F2Pre-heating to 70 ℃.
Methylcyclohexane is selected as an extracting agent E0. Extractant E0Pre-heating to 70 ℃.
As shown in the attached figure, raw material F1Alkali liquor F2And an extractant E0Respectively introducing the materials into a first-stage reaction extraction stirring kettle 1-1 at mass flow rates of 52.2kg/min, 6.0kg/min and 21.8kg/min at the same time, maintaining the temperature at 70 ℃ for reaction extraction, and starting a first-stage material conveying pump 2-1 (the flow rate is controlled to be equal to that of the raw material F) when the liquid holdup in the kettle is 160kg (the material retention time is controlled to be 2min)1Alkali liquor F2And an extractant E0Sum of flow rates) and3-1 hydrocyclone separator, the separated liquid phase enters the next stage of reaction extraction stirring kettle to continue the reaction extraction process until a third stage of liquid phase E separated by hydrocyclone separator is obtained3. The reaction temperature and the material residence time of the reaction extraction process in the second and third stage reaction extraction stirred tanks are the same as the first stage. The speed of each high speed shear mixer was 12000 rpm. Liquid phase E3Separating in an oil-water separator to obtain an oil phase N (methyl cyclohexane phase). After the device runs stably, performing high performance liquid chromatography analysis on the obtained oil phase N, wherein the yield of the vitamin A acetate is 93.18%; after the device runs stably, 18.8kg of byproduct solid (wherein the TPPO content is 95.99 wt%; the theoretical amount of TPPO produced is 18.1 kg; and the solid separation rate can reach 99.7% calculated by TPPO) is collected from the device within 5 min.
Example 6
Preparation of raw Material F1Wherein, the mass content of the chlorinated C15 phosphine salt is 18.63 percent, the mass content of the C5 aldehyde is 6.87 percent, and the mass content of the water is 74.50 percent (the molar ratio of the C5 aldehyde to the chlorinated C15 phosphine salt is 1.3). Starting material F1Preheating to 60 ℃.
Preparing an alkali liquor F2Wherein the mass concentration of the ammonia water is 25 percent, the mass concentration of the phase transfer additive, namely the trioctylmethylammonium chloride is 10.7 percent, and the balance is pure water (the molar ratio of the ammonia water to the trioctylmethylammonium chloride is 27). Lye F2Preheating to 60 ℃.
Cyclohexane is selected as an extracting agent E0. Extractant E0Preheating to 60 ℃.
As shown in the attached figure, raw material F1Alkali liquor F2And an extractant E0Respectively introducing into a first-stage reaction extraction stirring kettle 1-1 at mass flow rates of 24.2kg/min, 1.9kg/min and 9.2kg/min at the same time, maintaining at 60 deg.C for reaction extraction, and starting a first-stage material delivery pump 2-1 (the flow rate is controlled to be equal to that of the raw material F) when the liquid holdup in the kettle is 141kg (the material retention time is controlled to be 4min)1Alkali liquor F2And an extractant E0The sum of the flow rates) and a hydrocyclone 3-1, the separated liquid phase enters a next-stage reaction extraction stirring kettle to continue the reaction extraction process until a liquid phase E separated by the hydrocyclone at the third stage is obtained3. The reaction temperature and the material residence time of the reaction extraction process in the second and third stage reaction extraction stirred tanks are the same as the first stage. The rotational speed of each high-speed shear mixer was 6000 rpm. Liquid phase E3Separating in an oil-water separator to obtain an oil phase N (cyclohexane phase). After the device runs stably, performing high performance liquid chromatography analysis on the obtained oil phase N, wherein the yield of the vitamin A acetate is 93.92%; after the device runs stably, 12.3kg of byproduct solid is collected from the device within 5min (wherein the TPPO content is 95.02 wt%; the theoretical TPPO production amount is 11.7kg, and the solid separation rate calculated by TPPO is more than 99.9%).
Example 7
Preparation of raw Material F1Wherein the mass content of the brominated C15 phosphine salt is 23.33 percent, the mass content of the C5 aldehyde is 6.69 percent, and the mass content of the water is 69.99 percent (the molar ratio of the C5 aldehyde to the brominated C15 phosphine salt is 1.1). Starting material F1Pre-heating to 50 ℃.
Preparing an alkali liquor F2Wherein the mass concentration of the potassium hydroxide is 30 percent, the mass concentration of the phase transfer assistant tetrabutylammonium hydrogen sulfate is 7.3 percent, and the balance is pure water (the molar ratio of the potassium hydroxide to the tetrabutylammonium hydrogen sulfate is 25). Lye F2Pre-heating to 50 ℃.
N-hexane is selected as an extracting agent E0. Extractant E0Pre-heating to 50 ℃.
As shown in the attached figure, raw material F1Alkali liquor F2And an extractant E0Respectively introducing the materials into a first-stage reaction extraction stirring kettle 1-1 at mass flow rates of 23.6kg/min, 2.3kg/min and 8.7kg/min at the same time, maintaining the temperature at 50 ℃ for reaction extraction, and starting a first-stage material conveying pump 2-1 (the flow rate is controlled to be equal to that of the raw material F) when the liquid holdup in the kettle is 173kg (the material retention time is controlled to be 5min)1Alkali liquor F2And an extractant E0The sum of the flow rates) and a hydrocyclone 3-1, the separated liquid phase enters a next-stage reaction extraction stirring kettle to continue the reaction extraction process until a liquid phase E separated by the hydrocyclone at the third stage is obtained3. The reaction temperature and the material residence time of the reaction extraction process in the second and third stage reaction extraction stirred tanks are the same as the first stage. Rotational speed of per-stage high speed shear mixerAt 7000 rpm. Liquid phase E3Separating in an oil-water separator to obtain an oil phase N (normal hexane phase). After the device runs stably, the high performance liquid chromatography analysis is carried out on the obtained oil phase N, and the yield of the vitamin A acetate is 94.24%; after the device runs stably, 13.6kg of byproduct solid (the TPPO content is 96.86 wt%; the theoretical TPPO production amount is 13.2 kg; and the solid separation rate can reach 99.8% by calculation of TPPO) is collected from the device within 5 min.
Example 8
The process is as in example 3, except that: the rotation speed of each high-speed shear mixer was adjusted to 2500 rpm. The yield of the vitamin A acetate is 85.95 percent; after the operation of the apparatus was stabilized, 12.4kg of by-produced solids (TPPO content: 93.28 wt%; theoretical amount of TPPO produced: 11.9 kg; solid separation yield: about 97.2% in terms of TPPO) were collected from the apparatus in a total amount of 5 min.
Example 9
The process is as in example 3, except that: the rotational speed of each high-speed shear mixer was adjusted to 12500 rpm. The yield of the vitamin A acetate is 87.37 percent; after the operation of the apparatus was stabilized, 12.1kg of by-produced solids (TPPO content: 96.90 wt%; theoretical amount of TPPO produced: 12.1 kg; solid separation rate: 96.9% by calculation of TPPO) were collected from the apparatus within 5 min.
Comparative example 1
The process is as in example 3, except that: lye F2The composition is not added with a phase transfer assistant cetyl trimethyl ammonium bromide, wherein the mass concentration of potassium carbonate is 30 percent, and the balance is pure water. The yield of the vitamin A acetate is 83.24 percent; after the operation of the apparatus was stabilized, 11.7kg of by-produced solids (of which the TPPO content was 98.25 wt%; the theoretical amount of TPPO produced was 11.6 kg; and the solid separation rate was 99.1% by calculation of TPPO) were collected from the apparatus within 5 min.
Comparative example 2
The process is as in example 3, except that: lye F2The phase transfer aid was replaced with "18-crown-6". The yield of the vitamin A acetate is 84.34 percent; after the operation of the apparatus was stabilized, 12.0kg of by-produced solids (wherein the TPPO content was 97.40 wt%; theoretical TPPO production amount was 11.7kg,the solids separation was 99.9% calculated as TPPO).
Comparative example 3
The process is as in example 3, except that: in the device shown in figure 1, a high-speed shearing mixer is not arranged at the bottom of a reaction extraction stirring kettle, and a raw material F is added1Alkali liquor F2And an extractant E0Respectively introducing into a first-stage reaction extraction stirring kettle 1-1 at mass flow rates of 21.6kg/min, 5.5kg/min and 8.7kg/min at the same time, maintaining at 50 deg.C for reaction extraction, and starting a first-stage material delivery pump 2-1 (the flow rate is controlled to be equal to that of the raw material F) when the liquid holdup in the kettle is 179kg (the material retention time is controlled to be 5min)1Alkali liquor F2And an extractant E0The sum of the flow rates) and a hydrocyclone 3-1, and the inlet of the pump 2-1 is blocked after the device operates for 3min, so that continuous production cannot be carried out.
Comparative example 4
The process is as in example 3, except that: the device shown in figure 1 is a batch reaction extraction device, namely a set of reaction extraction stirring kettle, pump and hydrocyclone separator are adopted. Feeding a raw material F1Alkali liquor F2And an extractant E0Respectively introducing into a first-stage reaction extraction stirring kettle 1-1 at mass flow rates of 21.6kg/min, 5.5kg/min and 8.7kg/min, stopping feeding when the liquid holdup in the kettle is 179kg, maintaining 50 deg.C in the kettle for reaction extraction for 15min (the rotation speed of high-speed shear mixer 5-1 is 7000rpm), starting material delivery pump 2-1 and hydrocyclone 3-1, and collecting liquid phase E1Directly entering an oil-water separator 4 for separation to obtain an oil phase N (normal hexane phase), and performing high performance liquid chromatography analysis on the oil phase N (normal hexane phase) to obtain the vitamin A acetate yield of 61.33%; after the completion of the reaction, 1.8kg of by-produced solids (TPPO content: 87.27 wt%; theoretical amount of TPPO produced: 1.7 kg; solid separation rate: 92.4% based on TPPO) were collected from the apparatus altogether.
Comparative example 5
The process is as in example 3, except that: the device shown in figure 1 is a one-stage continuous reactive extraction device, namely, only one set of reactive extraction stirring kettle, pump and hydrocyclone is adopted. Feeding a raw material F1Alkali liquor F2And an extractant E0At a mass of 7.3kg/min, 1.9kg/min and 2.9kg/min, respectivelyIntroducing the flow into a first-stage reaction extraction stirring kettle 1-1 at the same time, maintaining the temperature at 50 ℃ to perform a reaction extraction process (the rotating speed of a high-speed shearing mixer 5-1 is 7000rpm), and when the liquid holdup in the kettle is 182kg (the retention time of the materials is controlled to be 15min), starting a first-stage material delivery pump 2-1 (the flow is controlled to be equal to that of the raw material F)1Alkali liquor F2And an extractant E0Sum of flow rates) and a hydrocyclone 3-1, the separated liquid phase E1Directly entering an oil-water separator for separation to obtain an oil phase N (normal hexane phase). After the device runs stably, performing high performance liquid chromatography analysis on the obtained oil phase N, wherein the yield of the vitamin A acetate is 68.57%; after the device runs stably, 3.4kg of byproduct solid (the TPPO content is 89.32 wt%; the theoretical amount of TPPO produced is 3.2 kg; and the solid separation rate can reach 94.9% calculated by TPPO) is collected from the device within 5 min.
Claims (25)
1. A method for preparing vitamin A acetate by multistage continuous series reaction extraction is characterized in that a raw material F1Alkali liquor F2And an extractant E0Continuously introducing the mixture into a multistage continuous series reaction extraction device for wittig reaction to synthesize and obtain vitamin A acetate;
the multistage continuous series reactive extraction device comprises multistage series-connected reactive extraction repeating structural units and an oil-water separator, wherein each stage of reactive extraction repeating structural unit comprises a set of reactive extraction stirring kettle, a pump and a hydrocyclone separator which are connected in sequence; and a high-speed shearing mixer is arranged at the bottom of the reaction extraction stirring kettle.
2. The method according to claim 1, characterized in that said feedstock F1Is a mixed solution of C15 phosphine salt, water and C5 aldehyde.
3. Method according to claim 2, characterized in that said feedstock F1In the method, the using amount of water is 1.5-6 times of the mass of the C15 phosphonium salt; the molar ratio of the C5 aldehyde to the C15 phosphine salt is 1/1-1.6/1.
4. The method according to claim 3, wherein the amount of the water is 2 to 5 times of the mass of the C15 phosphonium salt; the molar ratio of the C5 aldehyde to the C15 phosphine salt is 1.03/1-1.2/1.
5. The method as claimed in claim 2, wherein the C15 phosphonium salt has the structural formula
Wherein X is halogen.
6. The method of claim 5, wherein X is Cl or Br.
7. The process of claim 2, wherein the C5 aldehyde is 3-formylbut-2-enylacetate.
8. The method according to claim 1, characterized in that the lye F is2One or more selected from aqueous solution of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, ammonium carbonate and ammonia water.
9. The method according to claim 8, characterized in that the lye F is2Selected from aqueous solutions of sodium carbonate and/or potassium carbonate.
10. The method according to claim 1, characterized in that the lye F is2The alkali concentration of (A) is 10-45 wt%.
11. The method according to claim 10, characterized in that the lye F is2The alkali concentration of (A) is 15-35 wt%.
12. The method according to claim 1, characterized in that the lye F is2Adding a phase transfer assistant selected from triethylbenzylammonium chloride, triethylbenzylammonium bromide, trioctylmethylammonium chloride, decaOne or more of dialkyl trimethyl ammonium chloride, dodecyl trimethyl ammonium bromide, hexadecyl trimethyl ammonium chloride, hexadecyl trimethyl ammonium bromide and tetrabutyl ammonium hydrogen sulfate.
13. The method according to claim 12, wherein the phase transfer aid is selected from one or more of preferably dodecyl trimethyl ammonium chloride, dodecyl trimethyl ammonium bromide, hexadecyl trimethyl ammonium chloride, hexadecyl trimethyl ammonium bromide.
14. The method of claim 12, wherein the molar ratio of the phase transfer aid to the base is 1/8-1/50.
15. The method of claim 14, wherein the molar ratio of the phase transfer aid to the base is 1/15-1/36.
16. The process according to claim 1, characterized in that the extractant E is an extractant E0Is selected from one or more of petroleum ether, n-hexane, n-heptane, n-pentane, cyclohexane and methylcyclohexane.
17. The process of claim 16, wherein the extractant E is0One or more selected from petroleum ether, n-hexane and n-heptane.
18. The method according to claim 1, characterized in that said feedstock F1With alkali liquor F2The feeding mass flow ratio is (2-20): 1; the raw material F1With an extractant E0The feeding mass flow ratio is (2-4): 1.
19. the method of claim 1, wherein the extraction stages of the multistage continuous series reactive extraction unit are 2-6 stages.
20. The method according to claim 1, wherein the rotating speed of the high-speed shearing mixer in the reaction extraction stirring kettle is 3000-12000 rpm.
21. The method of claim 20, wherein the rotation speed of the high-speed shear mixer in the reaction extraction stirred tank is 5000-9000 rpm.
22. The method according to claim 1, wherein the retention time of the materials in each stage of the reaction extraction stirring kettle is 2-8 min; the reaction temperature in each stage of reaction extraction stirring kettle is 35-70 ℃.
23. The method as claimed in claim 22, wherein the retention time of the materials in each stage of the reactive extraction stirred tank is 3-6 min; the reaction temperature in each stage of reaction extraction stirring kettle is 40-55 ℃.
24. The utility model provides a multistage continuous series reaction extraction device, includes multistage series connection's reactive extraction repetitive structure unit and oil water separator, and every level reactive extraction repetitive structure unit contains a set of reactive extraction stirred tank, pump and hydrocyclone that connects gradually.
25. The multistage continuous series reactive extraction apparatus of claim 24, wherein a high speed shear mixer is disposed at the bottom of the reactive extraction stirred tank.
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