WO2022241669A1 - 一种维生素a醋酸酯的制备方法 - Google Patents

一种维生素a醋酸酯的制备方法 Download PDF

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WO2022241669A1
WO2022241669A1 PCT/CN2021/094550 CN2021094550W WO2022241669A1 WO 2022241669 A1 WO2022241669 A1 WO 2022241669A1 CN 2021094550 W CN2021094550 W CN 2021094550W WO 2022241669 A1 WO2022241669 A1 WO 2022241669A1
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reaction
preparation
acetate
solvent
vitamin
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PCT/CN2021/094550
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French (fr)
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罗朝辉
张涛
吕英东
林龙
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万华化学集团股份有限公司
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Priority to DE112021007675.2T priority Critical patent/DE112021007675T5/de
Priority to PCT/CN2021/094550 priority patent/WO2022241669A1/zh
Publication of WO2022241669A1 publication Critical patent/WO2022241669A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
    • C07C403/06—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms
    • C07C403/12—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms by esterified hydroxy groups

Definitions

  • the application belongs to the technical field of chemical synthesis, and in particular relates to a preparation method of vitamin A acetate.
  • Vitamin A acetate is an important substance used in medicine, cosmetics, food, food supplements, and animal feed additives. It has the functions of maintaining visual function, maintaining the health of epithelial tissue cells, and promoting immunoglobulin synthesis. . Vitamin A acetate has the following three difficulties in storage and use: first, vitamin A acetate has extremely poor antioxidant properties and is easily oxidized and decomposed when exposed to air; second, vitamin A acetate has poor thermal stability , especially in hot summer, the problem of storage is more difficult; third, most commercially available vitamin A acetates are darker in color, with yellowish or reddish crystals, and the color will gradually deepen with time, and few manufacturers can Products with good color are produced to achieve high market share. The above causes the storage of vitamin A acetate to be difficult, and a large amount of production costs are concentrated on the stable preservation of the product; therefore, the preparation of vitamin A acetate with high stability has a good market prospect.
  • the synthesis of currently commonly used vitamin A acetate includes two reaction routes: (1) the C14+C6 route characterized by Grignard reagents. This method is relatively mature in industry, but there are as many as 50 kinds of raw materials, and the fixed investment is large. (2) The C15+C5 route characterized by the Wittig reaction uses ⁇ -ionone as a raw material. After reaction conversion, it reacts with an organic phosphine compound to form a salt-forming reaction to generate a Wittig precursor. Wittig reaction with five-carbon aldehyde under the action of strong base produces vitamin A acetate. The Wittig method has a short route, simple process, and low cost, and gradually shows a mature prospect for industrial scale-up.
  • CN103044302A discloses a one-pot method for preparing vitamin A acetate, which uses C14 aldehyde and intermediate C1 ester to generate C15 phosphonate under alkaline conditions, and C15 phosphonate directly reacts with C5 aldehyde in one pot without separation , producing vitamin A acetate.
  • This method reduces the use and separation of solvents, but requires the use of highly hazardous reagents such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, or sodium hydride, which require high air and moisture control, and the atomic utilization of the two-step Wittig reagent The rates are lower, both at 20%.
  • CN101219983A discloses an improved preparation method of vitamin A acetate, through the Wittig reaction of carbon pentaphosphonic acid dialkyl ester and 4-acetoxy-2-methyl-2-butene-1 aldehyde as raw material
  • the target product is obtained, and the reaction solvent is a mixture of toluene and pyridine (or methyl-substituted pyridine), so that the reaction is carried out in an environment close to room temperature; however, the method needs to use high-risk reagents such as sodium methylate and sodium ethylate, and The isomer selectivity of the product is poor.
  • CN1894208A discloses a method for generating vitamin A acetate, which specifically includes: reacting ⁇ -vinylionol with triphenylphosphine in the presence of sulfuric acid to generate C15 phosphine salt, and then reacting with 4-acetoxy-2-methyl -But-2-enal undergoes a Wittig reaction to give vitamin A acetate.
  • the preparation reaction temperature of the C15 phosphine salt is difficult to control, a large amount of isomer impurities are generated, and the product is difficult to crystallize and separate, resulting in the vitamin A acetate generated by the C15 phosphine salt as a follow-up Wittig reaction raw material containing more tar, and along the way
  • the ratio of trans isomers is 7:3, and the content of trans vitamin A acetate is extremely small, which is not conducive to industrial production.
  • the reaction conditions of the Wittig method are relatively harsh, requiring a large amount of organic/inorganic acid-base catalysts, difficult post-treatment, low atom utilization, poor selectivity of the all-trans form in the vitamin A acetate generated after the reaction, and the reaction
  • the elimination and decomposition reaction of intermediates in the process is relatively slow, resulting in the formation of vitamin A acetate doped with more impurities that are difficult to remove due to similar compatibility, which is not conducive to product stability and subsequent crystallization operations.
  • the purpose of this application is to provide a preparation method of vitamin A acetate, the preparation method is based on the Wittig reaction, by controlling the content of ylide in the reaction system to obtain high purity, high isomerization selectivity and high-yield vitamin A acetate, and the chroma value of the product is low, the oxidation resistance and thermal stability are improved, and the deterioration rate is low, which significantly improves the quality of vitamin A acetate.
  • the application provides a method for preparing vitamin A acetate, the preparation method comprising: an addition reaction of C15 phosphonate and C5 aldehyde in the presence of a basic compound to generate an ylide; a decomposition reaction of the ylide , to obtain the vitamin A acetate; during the reaction, the content of the ylide in the reaction system is ⁇ 0.06mol/L, such as 0.055mol/L, 0.05mol/L, 0.045mol/L, 0.04mol/L , 0.035mol/L, 0.03mol/L, 0.025mol/L, 0.02mol/L, 0.015mol/L, 0.01mol/L or 0.005mol/L, etc.
  • reaction formula of the addition reaction is as follows:
  • Ph represents a phenyl group
  • the product generated by the addition reaction is an ylide, which is further decomposed to obtain the target product vitamin A acetate and by-products (triphenylphosphine oxide, triphenylphosphine oxide, );
  • said vitamin A acetate comprises all-trans vitamin A acetate 11 cis vitamin A acetate and 9-cis vitamin A acetate mixture.
  • the content of the ylide in the reaction system during the reaction means the content of the ylide in the reaction system at any point in the reaction process.
  • the content of the ylide in the reaction system during the reaction can be measured by the following methods: sampling from the reaction system, using conventional quantitative detection methods in chemistry (such as liquid chromatography, gas chromatography, gas chromatography Use, liquid chromatography-mass spectrometry, etc.) analysis test, to get final product.
  • conventional quantitative detection methods in chemistry such as liquid chromatography, gas chromatography, gas chromatography Use, liquid chromatography-mass spectrometry, etc.
  • the preparation method provided by this application is based on the Wittig reaction of C15+C5.
  • the internal onium salt can be decomposed quickly and completely to generate vitamin C.
  • the preparation method is suitable for reactions of any scale, and can be carried out in batches, semi-continuously or completely continuously.
  • the raw material utilization rate of the preparation method is high, the conversion rate of C15 phosphine salt can reach more than 99%, and the selectivity of all-trans products is high.
  • All-trans selectivity > 86% can be achieved without other optical isomerization treatment, vitamin A acetate with high purity, high stability and low chromaticity value can be obtained, and the product has good oxidation resistance and thermal stability , the rate of deterioration is low, it is beneficial to long-term stable storage, and it has very good market competitiveness.
  • the structural formula of the C15 phosphonium salt is wherein, X is selected from any one of Cl, Br, I or HSO 4 .
  • the structural formula of the C5 aldehyde is
  • the molar ratio of the C15 phosphine salt to the C5 aldehyde is 1:(0.8-2), for example, it can be 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8 or 1:1.9 etc., More preferably, it is 1:(1-1.6).
  • the molar ratio of the C15 phosphine salt to the basic compound is 1:(0.5-5), for example, it can be 1:0.6, 1:0.8, 1:1, 1:1.1, 1:1.3, 1:1.5 , 1:1.7, 1:1.9, 1:2, 1:2.2, 1:2.5, 1:2.8, 1:3, 1:3.5, 1:4, 1:4.5, 1:4.8, etc., more preferably 1 : (1 ⁇ 2).
  • the basic compound includes any one or a combination of at least two of metal inorganic salts, metal hydroxides or ammonia water.
  • the metal inorganic salt includes any one or a combination of at least two of carbonate, bicarbonate, phosphate or hydrogen phosphate, more preferably carbonate.
  • the carbonate is selected from any one or a combination of at least two of sodium carbonate, potassium carbonate or lithium carbonate.
  • the metal hydroxide includes any one or a combination of at least two of sodium hydroxide, potassium hydroxide or lithium hydroxide.
  • the temperature of the addition reaction and decomposition reaction is 10-80°C, such as 15°C, 20°C, 25°C, 30°C, 32°C, 35°C, 38°C, 40°C, 42°C, 45°C, 48°C, 50°C, 52°C, 55°C, 58°C, 60°C, 62°C, 65°C, 68°C, 70°C, 72°C, 75°C or 78°C, and specific point values between the above point values, Due to limited space and for the sake of brevity, the present application does not exhaustively list the specific point values included in the range, and is more preferably 25-75°C.
  • the content of the ylide in the reaction system during the reaction is ⁇ 0.03 mol/L, more preferably ⁇ 0.01 mol/L.
  • the process of the preparation method includes: uniformly mixing C15 phosphine salt, C5 aldehyde and the first solvent to obtain material A; uniformly mixing the basic compound with the second solvent to obtain material B; the material A and the material B enters the reaction device synchronously through different feeding channels respectively, and reacts to obtain the vitamin A acetate.
  • the method of synchronous entry is continuous dripping.
  • material A solution of C15 phosphine salt and C5 aldehyde
  • material B solution of basic compound
  • an addition reaction first occurs to form Intermediate ylide
  • ylide undergoes decomposition reaction to obtain vitamin A acetate
  • the process of simultaneous feeding is conducive to the formation and decomposition of ylide, so that the cumulative amount of ylide in the reaction system is ⁇ 0.06mol/L , quickly converted to the target product vitamin A acetate.
  • the first solvent is a mixture of polar solvents and non-polar solvents.
  • the existence of the non-polar solvent is conducive to the addition reaction of C15 phosphine salt and C5 aldehyde, impels the reaction to proceed forward, and generates the ylide;
  • the existence of the polar solvent is conducive to the decomposition of the ylide Reaction, the ylide is quickly and completely converted into vitamin A acetate, and the all-trans isomerization selectivity is improved to generate more all-trans vitamin A acetate.
  • the volume ratio of the polar solvent to the non-polar solvent is (0.5-1000):1, such as 1:1, 5:1, 8:1, 10:1, 20:1, 50:1 1, 80:1, 100:1, 200:1, 300:1, 400:1, 500:1, 600:1, 700:1, 800:1, 900:1 or 950:1, etc., more preferably (1-500):1, more preferably (10-500):1.
  • the polar solvent includes any one or a combination of at least two of water, methanol, ethanol, acetone, ethyl acetate, chloroform or dichloromethane; the combination includes: water and methanol The combination of water and ethanol, the combination of water and acetone, the combination of water and ethyl acetate, the combination of water and chloroform, the combination of methanol and acetone, the combination of methanol and ethyl acetate, etc.; more preferably water Combination with Methanol.
  • the non-polar solvent includes any one or a combination of at least two of carbon tetrachloride, cyclohexane, n-hexane, n-heptane, n-pentane or petroleum ether.
  • the volume of the first solvent is 1-30 mL, such as 2 mL, 3 mL, 5 mL, 7 mL, 9 mL, 10 mL, 11 mL, 13 mL, 15 mL, 17 mL, 19mL, 20mL, 21mL, 23mL, 25mL or 28mL, and the specific point values between the above-mentioned point values, due to space limitations and for the sake of brevity, this application no longer exhaustively lists the specific point values included in the range, and is more preferably 5 ⁇ 15mL.
  • the second solvent is a protic solvent; the protic solvent is conducive to contributing to the formation of hydrogen in the carbon-carbon double bond, reducing the steric resistance of the product in the configuration, and improving the selection of all-trans isomers Sex, forming more all-trans vitamin A acetate with high stability.
  • the second solvent includes any one or a combination of at least two of water, methanol, ethanol, isopropanol or glycerol.
  • the volume of the second solvent is 1-100 mL, for example, 5 mL, 10 mL, 15 mL, 20 mL, 25 mL, 30 mL, 35 mL, 40 mL, 45 mL, 50 mL, 60mL, 70mL, 80mL or 90mL, and the specific point values between the above point values, due to space limitations and for the sake of simplicity, this application will not exhaustively list the specific point values included in the range, and it is more preferably 10-50mL.
  • the mass percentage of the basic compound in the material B is 1-90%, for example, it can be 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45% %, 50%, 55%, 60%, 65%, 70%, 80% or 85%, and the specific point values between the above point values, due to space limitations and for the sake of brevity, this application will not exhaustively list all
  • the specific point value included in the above range is more preferably 10% to 70%.
  • the material A and material B enter the reaction device synchronously and at a uniform speed.
  • the space velocities of material A and material B are each independently 1 to 50h -1 , for example, 2h -1 , 5h -1 , 8h -1 , 10h -1 , 15h -1 , 20h -1 , 25h -1 , 30h -1 , 35h -1 , 40h -1 or 45h -1 , and the specific point values between the above point values, due to space limitations and for the sake of simplicity, this application will not exhaustively list the range including The specific point value of is more preferably 5 to 30h -1 .
  • the temperature in the reaction device before feeding is 10-50°C, such as 12°C, 15°C, 18°C, 20°C, 22°C, 25°C, 28°C, 30°C, 32°C, 35°C, 38°C, 40°C, 42°C, 45°C or 48°C, and the specific point values between the above point values, due to space limitations and for the sake of brevity, this application will not exhaustively list the specific points included in the range.
  • the point value is more preferably 20 to 40°C.
  • the reaction temperature is 10-80°C, such as 15°C, 20°C, 25°C, 30°C, 32°C, 35°C, 38°C, 40°C, 42°C, 45°C, 48°C, 50°C .
  • the present application does not exhaustively list the specific point values included in the range, and it is more preferably 25-75°C.
  • the reaction pressure is 10kPaA ⁇ 5MPaG, for example, it can be 15kPaA, 20kPaA, 30kPaA, 40kPaA, 50kPaA, 60kPaA, 70kPaA, 80kPaA, 90kPaA, 100kPaA, 0.2MPaG, 0.5MPaG, 0.8MPaG, 1MPaG, 1.5MPaG, 2MPaG, 2.5MPaG, 3MPaG, 3.5MPaG, 4MPaG, or 4.5MPaG, etc., More preferably, it is 50kPaA-1MPaG.
  • the reaction is carried out under stirring conditions.
  • the rotational speed of the stirring is 50-1000rpm, such as 100rpm, 200rpm, 300rpm, 400rpm, 500rpm, 600rpm, 700rpm, 800rpm or 900rpm, and the specific point values between the above-mentioned point values are limited by space and for the sake of brevity In consideration, the present application does not exhaustively enumerate the specific point values included in the range, more preferably 100-800rpm.
  • a post-treatment step is also included, and the post-treatment includes solid-liquid separation, precipitation and recrystallization in sequence.
  • the solid-liquid separation method is centrifugation and filtration
  • the obtained solid phase is a by-product (triphenylphosphine oxide)
  • the liquid phase enters the step of precipitation.
  • the desolvation device is a thin film evaporator.
  • the temperature of the bottom of the thin-film evaporator is 10-100°C, for example, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 70°C , 80°C, 90°C or 95°C, and the specific point values between the above-mentioned point values, due to space limitations and for the sake of brevity, this application does not exhaustively list the specific point values included in the range, and is more preferably 30 ⁇ 50°C.
  • the pressure in the thin film evaporator is 0.1-10kPaA, such as 0.2kPaA, 0.5kPaA, 0.8kPaA, 1kPaA, 2kPaA, 3kPaA, 4kPaA, 5kPaA, 6kPaA, 7kPaA, 8kPaA or 9kPaA, and between the above-mentioned point values Due to space limitations and for the sake of brevity, this application does not exhaustively list the specific point values included in the range, and is more preferably 1 to 5 kPaA.
  • the residence time in the thin-film evaporator is 1 to 60 min, for example, 5 min, 10 min, 15 min, 20 min, 25 min, 30 min, 35 min, 40 min, 45 min, 50 min or 55 min, and specific intervals between the above-mentioned point values Point value, due to space limitation and for the sake of brevity, this application will not exhaustively list the specific point value included in the range, and it is more preferably 10 to 30 minutes.
  • the recrystallization reagent comprises any one or a combination of at least two of toluene, ethyl acetate, acetonitrile, ethanol or isopropanol.
  • the amount of the reagent for recrystallization is 1-100 mL, such as 5 mL, 10 mL, 15 mL, 20 mL, 25 mL, 30 mL, 35 mL, 40 mL, 45 mL, 50 mL, 60 mL, 70mL, 80mL or 90mL, and the specific point values between the above point values, due to space limitations and for the sake of simplicity, this application will not exhaustively list the specific point values included in the range, and it is more preferably 5-30mL.
  • the recrystallization temperature is -10°C to 50°C, for example, it can be -5°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C or 45°C, and the specific point values between the above point values, due to space limitations and for the sake of brevity, this application will not exhaustively list the specific point values included in the range, and it is more preferably 0-30°C.
  • the preparation method specifically includes the following steps:
  • C15 phosphine salt, C5 aldehyde and the first solvent are mixed uniformly to obtain material A; basic compound is mixed uniformly with the second solvent to obtain material B; the mol ratio of the C15 phosphine salt to C5 aldehyde is 1: (1 ⁇ 1.6), the molar ratio of the C15 phosphine salt to the basic compound is 1:(1 ⁇ 2); the first solvent is a polar solvent and a non-polar solvent with a volume ratio of (1 ⁇ 500):1 A mixture of neutral solvents, the second solvent is a protic solvent;
  • step (1) Material A and material B obtained in step (1) are fed into the reaction device synchronously and uniformly through different feeding channels respectively, with a space velocity of 5-30h -1 , at a temperature of 25-75°C and a pressure of 50kPaA Stir the reaction under the condition of ⁇ 1MPaG to obtain the reaction solution; the content of the ylide in the reaction system during the reaction is ⁇ 0.06mol/L;
  • step (3) The reaction solution obtained in step (2) is separated from solid to liquid, and the obtained liquid phase is subjected to precipitation and recrystallization to obtain the vitamin A acetate.
  • the preparation method provided by this application is based on the Wittig reaction of C15+C5, by controlling the content of the ylide in the reaction system during the reaction, the ylide can be rapidly and completely decomposed to generate vitamin A acetate, the product Yield ⁇ 97.4%.
  • the preparation method is applicable to reactions of any scale, and can be carried out in batches, semi-continuously or completely continuously.
  • the selectivity of the all-trans product is high, which can reach 86.2-90%.
  • the obtained vitamin A acetate is light yellow to white.
  • Powder particles, chromaticity value ⁇ 50Hazen, purity ⁇ 99% has the characteristics of high purity, good stability, low chromaticity value, and the product has good oxidation resistance and thermal stability, low deterioration rate, and the average deterioration rate of the product ⁇ 0.05%/d, the chromaticity value is still lower than 50 Hazen after being stored in air for 7 days, which is conducive to long-term stable storage and has very good market competitiveness.
  • Fig. 1 is the process flow chart of preparation method described in embodiment 1;
  • the preparation method refers to the prior art, such as referring to CN109651150A, specifically as follows: after the autoclave leak detection, add (264.5g, 1.01mol) triphenylphosphine and (96.8g, 38wt% , 1.01mol) hydrochloric acid; after replacing 3 times with CO 2 , fill the autoclave with CO 2 gas and start stirring, raise the temperature so that the temperature in the autoclave is 45°C, and the pressure in the autoclave is maintained at 14MPa, (220g, 1mol) vinyl- ⁇ -ionol is pumped into the high-pressure reactor through a vertical pump to carry out a salt-forming reaction to prepare C15 phosphine salt.
  • the content and purity of each component are tested and calculated by the external standard method of high performance liquid chromatography (Shimadzu LC-20AD), and the conversion rate is calculated based on the content of the product;
  • the liquid chromatography conditions are as follows :
  • Chromatographic column Waters XSelect HSS T3, 4.6 ⁇ m ⁇ 250mm; injection volume: 2-10 ⁇ L, fine-tuned according to the sample; column temperature: 40°C; flow rate: 1mL/min; detector: ultraviolet detector (UV), detection The wavelength is 254-400nm; mobile phase: acetonitrile/0.1% phosphoric acid aqueous solution;
  • the initial mass of vitamin A acetate is m 1
  • the mass obtained by weighing after the heat test is m 2
  • the average loss rate 100% ⁇ (m 1 -m 2 )/n ⁇ m 1
  • Vitamin A acetate crystals are dissolved in n-hexane to prepare vitamin A acetate n-hexane solution with a mass fraction of 10%, and the platinum-cobalt chromaticity and chromaticity of the solution are measured on a CS-810 transmission spectrophotometer at room temperature. The lower the value, the closer it is to a colorless transparent liquid; the chromaticity value of deionized water is 5-15 Hazen.
  • reaction formula is as follows:
  • Reactor 3 is replaced with nitrogen 5 times before the reaction, adjust the rotation speed of the stirring paddle in the reactor to 100rpm, raise the temperature of the reactor to 25°C, and adjust the system pressure to 0.1MPaG, then control the first flowmeter 2 and the second Two flow meters 11, slowly drop material B and material A into the reactor simultaneously, the space velocity of material B and material A is both 14h -1 , keep the temperature and pressure for reaction, and obtain the reaction liquid; during the reaction process, every interval Take a sample every 10 minutes and analyze the content of the ylide and the product vitamin A acetate until the content of the ylide is stable, and the content is 0.02mol/L, 0.04mol/L, 0.05mol/L, 0.055mol/L, 0.059mol /L, 0.060mol/L, 0.059mol/L, 0.058mol/L, 0.060mol/L, the ylide content was basically stable at 0.06mol/L, indicating that the ylide could be rapidly decomposed into the target product during
  • the reaction solution generated is centrifuged and filtered by centrifuge 4 and is divided into solid phase and liquid phase.
  • the solid phase is injected into the by-product storage tank 9 (i.e. triphenylphosphine oxide receiving tank), and the liquid phase is extracted after sampling and analysis.
  • the thin film evaporator 5 control the residence time to be 10min, remove the solvent at 30°C and 1kPaA, put the crude product into the buffer tank 6, and inject 1650mL of ethanol in the recrystallization reagent storage tank 7 into it, and in 3 Recrystallize at °C to obtain the target product and put it into the product tank 8, take samples to analyze the purity, crystallization yield and test the product stability.
  • the conversion rate of raw material C15 phosphine salt after the reaction is stable is 99.9%
  • the conversion rate of ylide is 98.4%
  • the selectivity 86.2% of target product (all-trans) total vitamin A acetate (comprising all-trans)
  • the yield of trans, 11 cis and 9 cis) was 97.4%.
  • the purity of the obtained crystals was 99.9%, and the crystallization yield was 94.5%.
  • Stability test the vitamin A acetate crystals obtained in this example were heated and stored at 45°C for 7 days, and the average loss rate was 0.002%/d, and the vitamin A acetate crystals were stored in air atmosphere for 7 days, and the average loss rate was 0.05% %/d, measure its liquid chromaticity value as 45Hazen.
  • Reactor 3 is replaced with nitrogen 5 times before the reaction, adjust the rotating speed of the stirring paddle in the reactor to 300rpm, raise the temperature of the reactor to 25°C, and adjust the system pressure to 1.0MPaG, then control the first flowmeter 2 and the second Two flowmeters 11, slowly drop the material B and material A into the reaction kettle synchronously, the space velocity of the material B and the material A is both 10h -1 , keep the temperature and pressure for reaction, and obtain the reaction liquid; during the reaction process, every interval Take a sample every 10 minutes, analyze the content of ylide and product vitamin A acetate until the content of ylide is stable, and the content is 0.01mol/L, 0.03mol/L, 0.04mol/L, 0.035mol/L, 0.036mol /L, 0.038mol/L, 0.036mol/L, 0.035mol/L, 0.035mol/L, 0.035mol/L, the content of ylide is basically stable at 0.035mol/L, indicating that the y
  • reaction liquid that generates is divided into solid phase and liquid phase after centrifuge 4 centrifugation and filtration, and solid phase is squeezed into by-product storage tank 9, and liquid phase is squeezed into film evaporator 5 after sampling analysis, and the control residence time is After 12 minutes, the solvent was removed at 35°C and 1kPaA, the crude product was put into the buffer tank 6, and 1650mL of ethanol in the recrystallization reagent storage tank 7 was injected into it, recrystallized at 14°C, and the target product was obtained and punched. Into product tank 8, sampling analysis purity, crystallization yield and test product stability.
  • Stability test the vitamin A acetate crystals obtained in this example were heated and stored at 45°C for 7 days, with an average loss rate of 0.001%/d, and the vitamin A acetate crystals were stored in air atmosphere for 7 days, with an average loss rate of 0.03 %/d, measure its liquid chromaticity value to be 35 Hazen.
  • Reactor 3 is replaced with nitrogen 5 times before the reaction, adjust the rotating speed of the stirring paddle in the reactor to 400rpm, raise the temperature of the reactor to 35°C, and adjust the system pressure to 50kPaA, then control the first flowmeter 2 and the second Flow meter 11, slowly drop material B and material A into the reaction kettle simultaneously, the space velocity of material B and material A are both 20h -1 , keep the temperature and pressure for reaction, and obtain the reaction liquid; every 10min during the reaction process Sampling once, analyze the content of ylide and product vitamin A acetate, until the content of ylide is stable, its content is respectively 0.03mol/L, 0.023mol/L, 0.034mol/L, 0.055mol/L, 0.056mol/L L, 0.049mol/L, 0.051mol/L, 0.051mol/L, 0.050mol/L, the ylide content is basically stable at 0.050mol/L, indicating that the ylide can be rapidly decomposed into the target product during
  • reaction liquid that generates is divided into solid phase and liquid phase after centrifuge 4 centrifugation and filtration, and solid phase is squeezed into by-product storage tank 9, and liquid phase is squeezed into film evaporator 5 after sampling analysis, and the control residence time is After 20 minutes, remove the solvent at 45°C and 1kPaA, put the crude product into the buffer tank 6, inject 1650mL of ethanol from the recrystallization reagent storage tank 7 into it, and recrystallize at 20°C to obtain the target product and beat Into product tank 8, sampling analysis purity, crystallization yield and test product stability.
  • the transformation efficiency of raw material C15 phosphine salt after the reaction is stable is 99.1%
  • the transformation efficiency of ylide is 98.5%
  • the selectivity 86.5% of target product (all-trans) total vitamin A acetate (comprising all-trans)
  • the yield of trans, 11 cis and 9 cis) was 98.4%.
  • the purity of the obtained crystals was 99.9%
  • the crystallization yield was 96.5%.
  • Reactor 3 is replaced with nitrogen 5 times before the reaction, adjust the rotating speed of the stirring paddle in the reactor to 400rpm, raise the temperature of the reactor to 35°C, and adjust the system pressure to 0.1MPaG, then control the first flowmeter 2 and the second Two flowmeters 11, slowly drop material B and material A into the reactor simultaneously, the space velocity of material B and material A is both 30h -1 , keep the temperature and pressure for reaction, and obtain the reaction liquid; Take a sample every 10 minutes, analyze the content of the ylide and the product vitamin A acetate until the content of the ylide is stable, and the content is 0.02mol/L, 0.023mol/L, 0.034mol/L, 0.045mol/L, 0.036mol /L, 0.029mol/L, 0.028mol/L, 0.027mol/L, 0.027mol/L, the ylide content was basically stable at 0.027mol/L, indicating that the ylide could be rapidly decomposed into the target product during the reaction;
  • reaction liquid that generates is divided into solid phase and liquid phase after centrifuge 4 centrifugation and filtration, and solid phase is squeezed into by-product storage tank 9, and liquid phase is squeezed into film evaporator 5 after sampling analysis, and the control residence time is After removing the solvent at 50°C and 1kPaA for 30min, put the crude product into the buffer tank 6, inject 1650mL of ethanol from the recrystallization reagent storage tank 7 into it, and recrystallize at 20°C to obtain the target product and beat Into product tank 8, sampling analysis purity, crystallization yield and test product stability.
  • the conversion rate of raw material C15 phosphine salt is 100% after the reaction is stable, the conversion rate of ylide is 99.6%, the selectivity 89.4% of target product (all-trans), the total vitamin A acetate (including all-trans) The yield of trans, 11 cis and 9 cis) was 97.6%. The purity of the obtained crystals was 98.9%, and the crystallization yield was 97.2%.
  • Stability test the vitamin A acetate crystals obtained in this example were heated and stored at 45°C for 7 days, and the average loss rate was 0.0025%/d, and the vitamin A acetate crystals were stored in air atmosphere for 7 days, and the average loss rate was 0.0152% %/d, measure its liquid chromaticity value to be 25 Hazen.
  • Reactor 3 is replaced with nitrogen 5 times before the reaction, adjust the rotation speed of the stirring paddle in the reactor to 100rpm, raise the temperature of the reactor to 25°C, and adjust the system pressure to 0.1MPaG, then control the first flowmeter 2 and the second Two flowmeters 11, slowly drop material B and material A into the reaction kettle simultaneously, the space velocity of material B and material A are both 14h -1 , keep the temperature and pressure for reaction, and obtain the reaction liquid; during the reaction process, every interval Take a sample every 10 minutes, analyze the content of ylide and product vitamin A acetate, until the content of ylide is stable, the content is 0.22mol/L, 0.43mol/L, 0.84mol/L, 0.15mol/L, 0.26mol /L, 0.30mol/L, 0.35mol/L, 0.34mol/L, 0.32mol/L, the ylide content is basically stable at 0.33mol/L;
  • the reaction solution generated is centrifuged and filtered by centrifuge 4 and is divided into solid phase and liquid phase.
  • the solid phase is injected into the by-product storage tank 9 (i.e. triphenylphosphine oxide receiving tank), and the liquid phase is extracted after sampling and analysis.
  • the thin film evaporator 5 control the residence time to be 10min, remove the solvent at 30°C and 1kPaA, put the crude product into the buffer tank 6, and inject 1650mL of ethanol in the recrystallization reagent storage tank 7 into it, and in 3 Recrystallize at °C to obtain the target product and put it into the product tank 8, take samples to analyze the purity, crystallization yield and test the product stability.
  • Example 1 Compared with Example 1, water is used as the solvent (the first solvent) of C15 phosphine salt and C5 aldehyde in Comparative Example 1, causes the rate of the decomposition reaction of ylide to be slower, and the excessive of ylide intermediate in the reaction system More accumulation, vitamin A acetate and by-product triphenylphosphine oxide generated by the decomposition reaction cannot be separated in time, and the mass transfer effect is poor, resulting in a decrease in its selectivity, increased impurity content in vitamin A acetate, crystallization purity and crystallization yield. The rate is poor, and the oxidation resistance and thermal stability are greatly reduced.
  • Reactor 3 is replaced with nitrogen 5 times before the reaction, adjust the rotation speed of the stirring paddle in the reactor to 100rpm, raise the temperature of the reactor to 25°C, and adjust the system pressure to 0.1MPaG, then control the first flowmeter 2 and the second Two flowmeters 11, slowly drop material B and material A into the reaction kettle simultaneously, the space velocity of material B and material A are both 14h -1 , keep the temperature and pressure for reaction, and obtain the reaction liquid; during the reaction process, every interval Take a sample every 10 minutes, analyze the content of ylide and product vitamin A acetate, until the content of ylide is stable, the content is 0.12mol/L, 0.13mol/L, 0.16mol/L, 0.18mol/L, 0.19mol /L, 0.20mol/L, 0.21mol/L, 0.20mol/L, 0.19mol/L, the ylide content is basically stable at 0.20mol/L;
  • the reaction solution generated is centrifuged and filtered by centrifuge 4 and is divided into solid phase and liquid phase.
  • the solid phase is injected into the by-product storage tank 9 (i.e. triphenylphosphine oxide receiving tank), and the liquid phase is extracted after sampling and analysis.
  • the thin film evaporator 5 control the residence time to be 10min, remove the solvent at 30°C and 1kPaA, put the crude product into the buffer tank 6, and inject 1650mL of ethanol in the recrystallization reagent storage tank 7 into it, and in 3 Recrystallize at °C to obtain the target product and put it into the product tank 8, take samples to analyze the purity, crystallization yield and test the product stability.
  • the conversion rate of the raw material C15 phosphine salt after the reaction is stable is 93.9%, and the conversion rate of the ylide is 67.5%.
  • the ylide cannot be rapidly decomposed into the target product; the selectivity of the target product (all-trans) is 70.7%, and the yield of total vitamin A acetate (including all-trans, 11-cis and 9-cis) is 56.3%.
  • the purity of the obtained crystals was 91.9%, and the crystallization yield was 75.4%.
  • Example 2 Compared with Example 1, in Comparative Example 2, a large amount of non-polar solvent is used as the solvent of C15 phosphine salt and C5 aldehyde, and there is a large amount of ylide transfer to the process of organic phase in the reaction process, one is to bring extremely slow The mass transfer resistance of the phase interface, the second is that the concentration of the ylide is low, the rate of the decomposition reaction is slow, the excessive accumulation of the ylide intermediate in the reaction system, the impurity content in the vitamin A acetate increases, the crystallization purity and crystallization The yield is poor, and the antioxidant performance and thermal stability are greatly reduced.

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Abstract

本文公布一种维生素A醋酸酯的制备方法，所述制备方法包括：C15膦盐与C5醛在碱性化合物的存在下进行加成反应，生成内鎓盐；所述内鎓盐发生分解反应，得到所述维生素A醋酸酯；反应过程中所述内鎓盐在反应体系的含量≤0.06mol/L。所述制备方法以C15+C5的Wittig反应为基础，通过控制反应过程中的内鎓盐在反应体系的含量，得到高纯度、高反式异构选择性和高收率的维生素A醋酸酯。所述制备方法适用于任何规模的反应，可以分批、半连续或完全连续进行，得到的维生素A醋酸酯色度值低，抗氧化性和热稳定性好，变质速率低，有利于长期稳定的储存，具有很好的市场竞争力。

Description

一种维生素A醋酸酯的制备方法 技术领域
本申请属于化学合成技术领域，具体涉及一种维生素A醋酸酯的制备方法。
背景技术
维生素A醋酸酯(VA醋酸酯)是一种应用于药物、化妆品、食品、食品补充剂、动物饲料添加剂中的重要物质，具有维持视觉功能、维护上皮组织细胞健康和促进免疫球蛋白合成等作用。维生素A醋酸酯在存储和使用上存在以下三方面的难点：第一，维生素A醋酸酯的抗氧化性能极差，暴露在空气中极易氧化分解；第二，维生素A醋酸酯的热稳定性差，尤其在炎热夏季的储存问题更加棘手；第三，大部分市售的维生素A醋酸酯的颜色较深，晶体偏黄或偏红，且颜色会随着时间延长逐渐加深，鲜有生产厂商能够制得具有良好色泽的产品以达到高的市场份额。以上造成维生素A醋酸酯的存储较难，大量的生产成本集中在产品的稳定性保存上；因此，制备具有高稳定性的维生素A醋酸酯具有良好的市场前景。
目前常用的维生素A醋酸酯的合成包括两种反应路线：(1)以格式试剂为特征的C14+C6路线，该方法在工业上相对成熟，但原料多达50种，固定投资大，反应步骤多，工艺繁琐；(2)以Wittig反应为特征的C15+C5路线，以β-紫罗兰酮为原料，经反应转化后，再与有机膦化合物发生成盐反应，生成Wittig前驱体，该前驱体与五碳醛在强碱作用下发生Wittig反应，生成维生素A醋酸酯。Wittig方法的路线短、工艺简单、成本较低，逐渐展现出成熟的工业化放大前景。
CN103044302A公开了一锅法制备维生素A醋酸酯的方法，其利用C14醛和中间体C1酯在碱性条件下生成C15膦酸酯，C15膦酸酯不经过分离，直接与C5醛一锅法反应，生成维生素A醋酸酯。该方法减少了溶剂的使用和分离，但是需要使用甲醇钠、乙醇钠、叔丁醇钾或氢化钠等危险性高、对空气和湿气控制要求高的试剂，且两步Wittig试剂的原子利用率较低，均为20％。
CN101219983A公开了一种改进的维生素A乙酸酯的制备方法，通过碳十五膦酸二烷基酯和4-乙酰氧基-2-甲基-2-丁烯-1醛为原料的Wittig反应制得目标产物，反应溶剂为甲苯和吡啶(或甲基取代的吡啶)的混合物，使反应在接近室温的环境下进行；但是，该方法需使用甲醇钠、乙醇钠等高危险性试剂，且产物的异构选择性较差。
CN1894208A公开了一种生成维生素A乙酸酯的方法，具体包括：β-乙烯基紫罗兰醇与三苯基膦在硫酸存在下反应生成C15膦盐，再与4-乙酰氧基-2-甲基-丁-2-烯醛进行Wittig反应，得到维生素A乙酸酯。该方法中，C15膦盐的制备反应温度难以控制，生成大量异构体杂质，产物难以结晶分离，导致C15膦盐作为后续Wittig反应原料生成的维生素A乙酸酯中含有较多焦油，且顺反异构体的比例为7:3，反式维生素A乙酸酯的含量极少，不利于工业化生产。
整体而言，Wittig方法的反应条件相对苛刻，需要大量有机/无机酸碱催化剂，后处理困难，原子利用率低，反应后生成的维生素A醋酸酯中全反式的选择性较差，而且反应过程中中间体的消除分解反应较慢，导致生成的维生素A醋酸酯中因相似相溶而掺杂了较多难以除去的杂质，不利于产品的稳定性和后续结晶操作。
因此，开发一种产物稳定性高、色值低、异构选择性好的维生素A醋酸酯的制备方法，是本领域的研究重点。
发明内容
以下是对本文详细描述的主题的概述。本概述并非是为了限制权利要求的保护范围。
针对现有技术的不足，本申请的目的在于提供一种维生素A醋酸酯的制备方法，所述制备方法以Wittig反应为基础，通过控制反应体系中内鎓盐的含量得到高纯度、高异构选择性和高收率的维生素A醋酸酯，且产物的色度值低，抗氧化性和热稳定性得以改善，变质速率低，显著提升了维生素A醋酸酯的品质。
为达到此发明目的，本申请采用以下技术方案：
本申请提供一种维生素A醋酸酯的制备方法，所述制备方法包括：C15膦盐与C5醛在碱性化合物的存在下进行加成反应，生成内鎓盐；所述内鎓盐发生分解反应，得到所述维生素A醋酸酯；反应过程中所述内鎓盐在反应体系的含量≤0.06mol/L，例如可以为0.055mol/L、0.05mol/L、0.045mol/L、0.04mol/L、0.035mol/L、0.03mol/L、0.025mol/L、0.02mol/L、0.015mol/L、0.01mol/L或0.005mol/L等。
本申请中，所述加成反应的反应式如下：
Figure PCTCN2021094550-appb-000001
其中，Ph代表苯基；加成反应生成的产物为内鎓盐，其进一步分解，得到目标产物维生素A醋酸酯和副产物(三苯基氧膦，
Figure PCTCN2021094550-appb-000002
)；所述维生 素A醋酸酯包括全反式维生素A醋酸酯
Figure PCTCN2021094550-appb-000003
11顺式维生素A醋酸酯
Figure PCTCN2021094550-appb-000004
和9顺式维生素A醋酸酯
Figure PCTCN2021094550-appb-000005
的混合物。
本申请中，“反应过程中所述内鎓盐在反应体系的含量”意指反应过程中的任意时间节点下，反应体系中所述内鎓盐的含量。
示例性地，反应过程中所述内鎓盐在反应体系中的含量可通过如下方法测得：从反应体系中取样，采用化学中常规的定量检测方法(如液相色谱、气相色谱、气质联用、液质联用等)分析测试，即得。
本申请提供的制备方法以C15+C5的Wittig反应为基础，通过控制反应过程中的中间体内鎓盐在反应体系的含量(累积量)，使内鎓盐快速、完全地发生分解反应，生成维生素A醋酸酯。所述制备方法适用于任何规模的反应，可以分批、半连续或完全连续进行，制备方法的原料利用率高，C15膦盐的转化率可达99％以上，全反式产物选择性高，无需其他的光学异构化处理即可使全反式选择性＞86％，可以得到高纯度、高稳定性、低色度值的维生素A醋酸酯，且产物的抗氧化性和热稳定性好，变质速率低，有利于长期稳定的储存，具有很好的市场竞争力。
优选地，所述C15膦盐的结构式为
Figure PCTCN2021094550-appb-000006
其中，X选自Cl、Br、I或HSO 4中的任意一种。
优选地，所述C5醛的结构式为
Figure PCTCN2021094550-appb-000007
优选地，所述C15膦盐与C5醛的摩尔比为1:(0.8～2)，例如可以为1:0.9、1:1、1:1.1、1:1.2、1:1.3、1:1.4、1:1.5、1:1.6、1:1.7、1:1.8或1:1.9等，进一步优选为1:(1～1.6)。
优选地，所述C15膦盐与碱性化合物的摩尔比为1:(0.5～5)，例如可以为1:0.6、1:0.8、1:1、1:1.1、1:1.3、1:1.5、1:1.7、1:1.9、1:2、1:2.2、1:2.5、1:2.8、1:3、1:3.5、1:4、1:4.5、1:4.8等，进一步优选为1:(1～2)。
优选地，所述碱性化合物包括金属无机盐、金属氢氧化物或氨水中的任意一种或至少两种的组合。
优选地，所述金属无机盐包括碳酸盐、碳酸氢盐、磷酸盐或磷酸氢盐中的任意一种或至少两种的组合，进一步优选为碳酸盐。
优选地，所述碳酸盐选自碳酸钠、碳酸钾或碳酸锂中的任意一种或至少两种的组合。
优选地，所述金属氢氧化物包括氢氧化钠、氢氧化钾或氢氧化锂中的任意一种或至少两种的组合。
优选地，所述加成反应、分解反应的温度为10～80℃，例如15℃、20℃、25℃、30℃、32℃、35℃、38℃、40℃、42℃、45℃、48℃、50℃、52℃、55℃、58℃、60℃、62℃、65℃、68℃、70℃、72℃、75℃或78℃，以及上述点值之 间的具体点值，限于篇幅及出于简明的考虑，本申请不再穷尽列举所述范围包括的具体点值，进一步优选为25～75℃。
优选地，反应过程中所述内鎓盐在反应体系的含量≤0.03mol/L，进一步优选为≤0.01mol/L。
优选地，所述制备方法的工艺包括：将C15膦盐、C5醛和第一溶剂混合均匀，得到物料A；将碱性化合物与第二溶剂混合均匀，得到物料B；所述物料A与物料B分别通过不同的进料通道同步进入反应装置，反应，得到所述维生素A醋酸酯。
优选地，所述同步进入的方法为持续滴加。
作为本申请的优选技术方案，所述制备方法中，物料A(C15膦盐与C5醛的溶液)与物料B(碱性化合物的溶液)同步进入反应装置，混合后首先发生加成反应，生成中间体内鎓盐；内鎓盐再进行分解反应，得到维生素A醋酸酯；同步入料的工艺有助于内鎓盐的生成和分解，使反应体系中内鎓盐的累积量≤0.06mol/L，快速转化为目标产物维生素A醋酸酯。
优选地，所述第一溶剂为极性溶剂与非极性溶剂的混合物。
其中，所述非极性溶剂的存在有利于C15膦盐与C5醛的加成反应，促使反应正向进行，生成内鎓盐；所述极性溶剂的存在有利于所述内鎓盐的分解反应，使内鎓盐快速、完全地转化为维生素A醋酸酯，并提高全反式的异构选择性，生成更多的全反式维生素A醋酸酯。
优选地，所述极性溶剂与非极性溶剂的体积比为(0.5～1000):1，例如可以为1:1、5:1、8:1、10:1、20:1、50:1、80:1、100:1、200:1、300:1、400:1、500:1、600:1、700:1、800:1、900:1或950:1等，进一步优选为(1～500):1，更进一步优选为(10～500):1。
优选地，所述极性溶剂包括水、甲醇、乙醇、丙酮、乙酸乙酯、三氯甲烷或二氯甲烷中的任意一种或至少两种的组合；所述组合的方式包括：水与甲醇的组合，水与乙醇的组合，水与丙酮的组合，水与乙酸乙酯的组合，水与三氯甲烷的组合，甲醇与丙酮的组合，甲醇与乙酸乙酯的组合等；进一步优选为水与甲醇的组合。
优选地，所述非极性溶剂包括四氯化碳、环己烷、正己烷、正庚烷、正戊烷或石油醚中的任意一种或至少两种的组合。
优选地，以所述C15膦盐的质量为1g计，所述第一溶剂的体积为1～30mL，例如可以为2mL、3mL、5mL、7mL、9mL、10mL、11mL、13mL、15mL、17mL、19mL、20mL、21mL、23mL、25mL或28mL，以及上述点值之间的具体点值，限于篇幅及出于简明的考虑，本申请不再穷尽列举所述范围包括的具体点值，进一步优选为5～15mL。
优选地，所述第二溶剂为质子型溶剂；所述质子型溶剂有利于贡献形成碳碳双键中的氢，降低产物在构型中的空间位阻力，提升全反式异构体的选择性，形成更多高稳定性的全反式维生素A醋酸酯。
优选地，所述第二溶剂包括水、甲醇、乙醇、异丙醇或丙三醇中的任意一种或至少两种的组合。
优选地，以所述碱性化合物的质量为1g计，所述第二溶剂的体积为1～100mL，例如可以为5mL、10mL、15mL、20mL、25mL、30mL、35mL、40mL、45mL、50mL、60mL、70mL、80mL或90mL，以及上述点值之间的具体点值，限于篇幅及出于简明的考虑，本申请不再穷尽列举所述范围包括的具体点值，进一步优选为10～50mL。
优选地，所述物料B中碱性化合物的质量百分含量为1～90％，例如可以为 5％、10％、15％、20％、25％、30％、35％、40％、45％、50％、55％、60％、65％、70％、80％或85％，以及上述点值之间的具体点值，限于篇幅及出于简明的考虑，本申请不再穷尽列举所述范围包括的具体点值，进一步优选为10～70％。
优选地，所述物料A与物料B同步匀速地进入反应装置。
优选地，所述物料A与物料B的空速各自独立地为1～50h -1，例如可以为2h -1、5h -1、8h -1、10h -1、15h -1、20h -1、25h -1、30h -1、35h -1、40h -1或45h -1，以及上述点值之间的具体点值，限于篇幅及出于简明的考虑，本申请不再穷尽列举所述范围包括的具体点值，进一步优选为5～30h -1。
优选地，在入料之前所述反应装置中的温度为10～50℃，例如可以为12℃、15℃、18℃、20℃、22℃、25℃、28℃、30℃、32℃、35℃、38℃、40℃、42℃、45℃或48℃，以及上述点值之间的具体点值，限于篇幅及出于简明的考虑，本申请不再穷尽列举所述范围包括的具体点值，进一步优选为20～40℃。
优选地，所述反应的温度为10～80℃，例如15℃、20℃、25℃、30℃、32℃、35℃、38℃、40℃、42℃、45℃、48℃、50℃、52℃、55℃、58℃、60℃、62℃、65℃、68℃、70℃、72℃、75℃或78℃，以及上述点值之间的具体点值，限于篇幅及出于简明的考虑，本申请不再穷尽列举所述范围包括的具体点值，进一步优选为25～75℃。
优选地，所述反应的压力为10kPaA～5MPaG，例如可以为15kPaA、20kPaA、30kPaA、40kPaA、50kPaA、60kPaA、70kPaA、80kPaA、90kPaA、100kPaA、0.2MPaG、0.5MPaG、0.8MPaG、1MPaG、1.5MPaG、2MPaG、2.5MPaG、3MPaG、3.5MPaG、4MPaG或4.5MPaG等，进一步优选为50kPaA～1MPaG。
本申请中，“A”表示绝对压力，“G”表示表压。
优选地，所述反应在搅拌条件下进行。
优选地，所述搅拌的转速为50～1000rpm，例如100rpm、200rpm、300rpm、400rpm、500rpm、600rpm、700rpm、800rpm或900rpm，以及上述点值之间的具体点值，限于篇幅及出于简明的考虑，本申请不再穷尽列举所述范围包括的具体点值，进一步优选100～800rpm。
优选地，所述反应完成后还包括后处理的步骤，所述后处理依次包括固液分离、脱溶和重结晶。
优选地，所述固液分离的方法为离心和过滤，得到的固相为副产物(三苯基氧膦)，液相进入脱溶的步骤。
优选地，所述脱溶的装置为薄膜蒸发器。
优选地，所述薄膜蒸发器的塔釜温度为10～100℃，例如可以为20℃、25℃、30℃、35℃、40℃、45℃、50℃、55℃、60℃、70℃、80℃、90℃或95℃，以及上述点值之间的具体点值，限于篇幅及出于简明的考虑，本申请不再穷尽列举所述范围包括的具体点值，进一步优选为30～50℃。
优选地，所述薄膜蒸发器中的压力为0.1～10kPaA，例如0.2kPaA、0.5kPaA、0.8kPaA、1kPaA、2kPaA、3kPaA、4kPaA、5kPaA、6kPaA、7kPaA、8kPaA或9kPaA，以及上述点值之间的具体点值，限于篇幅及出于简明的考虑，本申请不再穷尽列举所述范围包括的具体点值，进一步优选为1～5kPaA。
优选地，所述薄膜蒸发器中的停留时间为1～60min，例如可以为5min、10min、15min、20min、25min、30min、35min、40min、45min、50min或55min，以及上述点值之间的具体点值，限于篇幅及出于简明的考虑，本申请不再穷尽列举所述范围包括的具体点值，进一步优选为10～30min。
优选地，所述重结晶的试剂包括甲苯、乙酸乙酯、乙腈、乙醇或异丙醇中 的任意一种或至少两种的组合。
优选地，以粗产物的质量为1g计，所述重结晶的试剂的用量为1～100mL，例如可以为5mL、10mL、15mL、20mL、25mL、30mL、35mL、40mL、45mL、50mL、60mL、70mL、80mL或90mL，以及上述点值之间的具体点值，限于篇幅及出于简明的考虑，本申请不再穷尽列举所述范围包括的具体点值，进一步优选为5～30mL。
优选地，所述重结晶的温度为-10～50℃，例如可以为-5℃、0℃、5℃、10℃、15℃、20℃、25℃、30℃、35℃、40℃或45℃，以及上述点值之间的具体点值，限于篇幅及出于简明的考虑，本申请不再穷尽列举所述范围包括的具体点值，进一步优选为0～30℃。
优选地，所述制备方法具体包括如下步骤：
(1)将C15膦盐、C5醛和第一溶剂混合均匀，得到物料A；将碱性化合物与第二溶剂混合均匀，得到物料B；所述C15膦盐与C5醛的摩尔比为1:(1～1.6)，所述C15膦盐与碱性化合物的摩尔比为1:(1～2)；所述第一溶剂为体积比为(1～500):1的极性溶剂与非极性溶剂的混合物，所述第二溶剂为质子型溶剂；
(2)将步骤(1)得到的物料A与物料B分别通过不同的进料通道同步、匀速地进入反应装置，空速为5～30h -1，在温度为25～75℃、压力为50kPaA～1MPaG的条件下搅拌反应，得到反应液；反应过程中所述内鎓盐在反应体系的含量≤0.06mol/L；
(3)将步骤(2)得到的反应液固液分离，得到的液相经脱溶、重结晶，得到所述维生素A醋酸酯。
相对于现有技术，本申请具有以下有益效果：
本申请提供的制备方法以C15+C5的Wittig反应为基础，通过控制反应过程中的内鎓盐在反应体系的含量，使内鎓盐快速、完全地发生分解反应，生成维生素A醋酸酯，产物收率≥97.4％。所述制备方法适用于任何规模的反应，可以分批、半连续或完全连续进行，全反式产物选择性高，可达到86.2～90％，得到的维生素A醋酸酯为淡黄色至白色体的粉末颗粒，色度值＜50Hazen，纯度≥99％，具有纯度高、稳定性好、色度值低的特点，且产物的抗氧化性和热稳定性好，变质速率低，产品的平均变质速率≤0.05％/d，空气中储存7天后的色度值仍低于50Hazen，有利于长期稳定的储存，具有很好的市场竞争力。
在阅读并理解了详细描述后，可以明白其他方面。
附图说明
图1为实施例1所述制备方法的工艺流程图；
其中，1-第一原料罐，2-第一流量计，3-反应釜，4-离心机，5-薄膜蒸发器，6-缓冲罐，7-重结晶试剂储罐，8-产品罐，9-副产物储罐，10-第二原料罐，11-第二流量计。
具体实施方式
下面通过具体实施方式来进一步说明本申请的技术方案。本领域技术人员应该明了，所述实施例仅仅是帮助理解本申请，不应视为对本申请的具体限制。
本申请以下实施例中的甲醇、乙醇、碳酸盐、烷烃溶剂均购自上海泰坦科技有限公司；C5醛
Figure PCTCN2021094550-appb-000008
购自巴斯夫化工有限公司；C15膦盐
Figure PCTCN2021094550-appb-000009
为自制原料，制备方法参考现有技术，例如参考 CN109651150A，具体地如下所示：在高压反应釜检漏后，往其中加入(264.5g，1.01mol)三苯基膦和(96.8g，38wt％，1.01mol)盐酸；用CO 2置换3次后，往高压反应釜充入CO 2气体并开启搅拌，升温使得高压反应釜内温度为45℃，并且通过调压阀使釜内的压力维持在14MPa，通过平流泵将(220g，1mol)乙烯基-β-紫罗兰醇泵入高压反应釜进行成盐反应，制取C15膦盐。
本申请以下实施例中，各组分的含量和纯度通过高效液相色谱仪(岛津LC-20AD)的外标法测试和计算得到，转化率基于产物的含量计算得到；液相色谱条件如下：
色谱柱：Waters XSelect HSS T3，4.6μm×250mm；进样量：2～10μL，根据样品情况进行微调；柱温：40℃；流速：1mL/min；检测器：紫外检测器(UV)，检测波长为254～400nm；流动相：乙腈/0.1％磷酸水溶液；
测样时，先以纯品建立液相外标曲线，以浓度和液相峰面积的线性关系计算各检测物质的质量分数(含量)。
本申请以下实施例中产物的平均损失率(受热时的分解速率)采用如下方法进行测试：
维生素A醋酸酯的初始质量为m 1，受热测试后的称量得到的质量为m 2，平均损失率＝100％×(m 1-m 2)/n×m 1，n表示存储的天数，以下实施例中n＝7。
本申请以下实施例中产物的变质速率采用如下方法进行测试：
称取质量为1g(以实际称量数据为准，记作m 1)的分散均匀的维生素A醋酸酯(纯度99.9％)于室温下空气氛围中储存7天，将存储7天后的全部固体以溶剂稀释，以高效液相分析其中维生素A醋酸酯的含量(记作m 2)，变质速率＝100％×(m 1-m 2)/n×m 1，其中n表示存储的天数，以下实施例中n＝7。
本申请以下实施例中产物的色度值采用如下方法进行测试：
将维生素A醋酸酯晶体溶解在正己烷中，配制成质量分数10％的维生素A醋酸酯正己烷溶液，在室温下于CS-810透射分光测色仪上测量溶液的铂钴色度，色度值越低，越接近于无色透明液体；去离子水的色度值为5～15Hazen。
本申请的维生素A醋酸酯的制备方法中，反应式如下：
Figure PCTCN2021094550-appb-000010
本申请以下实施例中仅将全反式维生素A醋酸酯记为目标产物。
实施例1
一种维生素A醋酸酯的制备方法，工艺流程图如图1所示，具体步骤如下：
(1)在第一原料罐1中加入106g碳酸钠固体粉末，搅拌状态下加入1060mL水，混合均匀得到物料B；在第二原料罐10中加入501.08g C15膦盐、142g C5醛，搅拌状态下加入2500mL混合溶剂(水、甲醇与正己烷的体积比为100:1:10)，混合均匀得到物料A，并氮封待用；
(2)反应釜3在反应前进行氮气置换5次后，将反应釜搅拌桨转速调至100rpm，将反应釜升温至25℃，调节体系压力至0.1MPaG后，控制第一流量计2和第二流量计11，同步将物料B和物料A缓慢滴加至反应釜中，物料B 和物料A的空速均为14h -1，保持温度和压力进行反应，得到反应液；反应过程中每间隔10min取样一次，分析内鎓盐和产物维生素A醋酸酯的含量，直至内鎓盐含量平稳，其含量分别为0.02mol/L、0.04mol/L、0.05mol/L、0.055mol/L、0.059mol/L、0.060mol/L、0.059mol/L、0.058mol/L、0.060mol/L，内鎓盐含量基本稳定在0.06mol/L，说明在反应过程中内鎓盐能快速分解为目标产物；
(3)生成的反应液经离心机4离心并过滤后分为固相和液相，固相打入副产物储罐9(即三苯基氧膦接收罐)，液相经取样分析后打入薄膜蒸发器5，控制停留时间为10min，于30℃、1kPaA下脱除溶剂后，将粗产物打入缓冲罐6中，并将重结晶试剂储罐7中的1650mL乙醇注入其中，于3℃下重结晶，得到目标产物并打入产品罐8中，取样分析纯度、结晶收率以及测试产品稳定性。
通过分析测试可知，反应稳定后原料C15膦盐的转化率为99.9％，内鎓盐的转化率为98.4％，目标产物(全反式)的选择性86.2％，总维生素A醋酸酯(包括全反式、11顺式和9顺式)的收率为97.4％。所得晶体的纯度为99.9％，结晶收率为94.5％。
稳定性测试：本实施例得到的维生素A醋酸酯晶体在45℃加热存储7天，平均损失率为0.002％/d，维生素A醋酸酯晶体置于空气氛围中存储7天，平均损失率为0.05％/d，测量其液体色度值为45Hazen。
实施例2
一种维生素A醋酸酯的制备方法，工艺流程图如图1所示，具体步骤如下：
(1)在第一原料罐1中加入138g碳酸钾固体粉末，搅拌状态下加入280mL水，混合均匀得到物料B；在第二原料罐10中加入501.08g C15膦盐、156.2g C5醛，搅拌状态下加入2500mL混合溶剂(水、甲醇与正己烷的体积比为200:1:5)，混合均匀得到物料A，并氮封待用；
(2)反应釜3在反应前进行氮气置换5次后，将反应釜搅拌桨转速调至300rpm，将反应釜升温至25℃，调节体系压力至1.0MPaG后，控制第一流量计2和第二流量计11，同步将物料B和物料A缓慢滴加至反应釜中，物料B和物料A的空速均为10h -1，保持温度和压力进行反应，得到反应液；反应过程中每间隔10min取样一次，分析内鎓盐和产物维生素A醋酸酯的含量，直至内鎓盐含量平稳，其含量分别为0.01mol/L，0.03mol/L，0.04mol/L，0.035mol/L，0.036mol/L，0.038mol/L，0.036mol/L，0.035mol/L，0.035mol/L，内鎓盐含量基本稳定在0.035mol/L，说明在反应过程中内鎓盐能快速分解为目标产物；
(3)生成的反应液经离心机4离心并过滤后分为固相和液相，固相打入副产物储罐9，液相经取样分析后打入薄膜蒸发器5，控制停留时间为12min，于35℃、1kPaA下脱除溶剂后，将粗产物打入缓冲罐6中，并将重结晶试剂储罐7中的1650mL乙醇注入其中，于14℃下重结晶，得到目标产物并打入产品罐8中，取样分析纯度、结晶收率以及测试产品稳定性。
通过分析测试可知，反应稳定后原料C15膦盐的转化率为100％，内鎓盐的转化率为99.5％，目标产物(全反式)的选择性87.6％，总维生素A醋酸酯(包括全反式、11顺式和9顺式)的收率为98.4％。所得晶体的纯度为99.9％，结晶收率为97.5％。
稳定性测试：本实施例得到的维生素A醋酸酯晶体在45℃加热存储7天，平均损失率为0.001％/d，维生素A醋酸酯晶体置于空气氛围中存储7天，平均损失率为0.03％/d，测量其液体色度值为35Hazen。
实施例3
一种维生素A醋酸酯的制备方法，工艺流程图如图1所示，具体步骤如下：
(1)在第一原料罐1中加入276g碳酸钾固体粉末，搅拌状态下加入5520 mL水，混合均匀得到物料B；在第二原料罐10中加入501.08g C15膦盐、227.2g C5醛，搅拌状态下加入1302.5mL混合溶剂(水、甲醇与正己烷的体积比为200:1:2)，混合均匀得到物料A，并氮封待用；
(2)反应釜3在反应前进行氮气置换5次后，将反应釜搅拌桨转速调至400rpm，将反应釜升温至35℃，调节体系压力至50kPaA后，控制第一流量计2和第二流量计11，同步将物料B和物料A缓慢滴加至反应釜中，物料B和物料A的空速均为20h -1，保持温度和压力进行反应，得到反应液；反应过程中每间隔10min取样一次，分析内鎓盐和产物维生素A醋酸酯的含量，直至内鎓盐含量平稳，其含量分别为0.03mol/L，0.023mol/L，0.034mol/L，0.055mol/L，0.056mol/L，0.049mol/L，0.051mol/L，0.051mol/L，0.050mol/L，内鎓盐含量基本稳定在0.050mol/L，说明在反应过程中内鎓盐能快速分解为目标产物；
(3)生成的反应液经离心机4离心并过滤后分为固相和液相，固相打入副产物储罐9，液相经取样分析后打入薄膜蒸发器5，控制停留时间为20min，于45℃、1kPaA下脱除溶剂后，将粗产物打入缓冲罐6中，并将重结晶试剂储罐7中的1650mL乙醇注入其中，于20℃下重结晶，得到目标产物并打入产品罐8中，取样分析纯度、结晶收率以及测试产品稳定性。
通过分析测试可知，反应稳定后原料C15膦盐的转化率为99.1％，内鎓盐的转化率为98.5％，目标产物(全反式)的选择性86.5％，总维生素A醋酸酯(包括全反式、11顺式和9顺式)的收率为98.4％。所得晶体的纯度为99.9％，结晶收率为96.5％。
稳定性测试：本实施例得到的维生素A醋酸酯晶体在45℃加热存储7天，平均损失率为0.003％/d，维生素A醋酸酯晶体置于空气氛围中存储7天，平均损失率为0.02％/d，测量其液体色度值为31Hazen。
实施例4
一种维生素A醋酸酯的制备方法，工艺流程图如图1所示，具体步骤如下：
(1)在第一原料罐1中加入88.8g碳酸锂固体粉末，搅拌状态下加入1780mL水，混合均匀得到物料B；在第二原料罐10中加入501.08g C15膦盐、213g C5醛，搅拌状态下加入7500mL混合溶剂(水、甲醇与正己烷的体积比为300:1:1)，混合均匀得到物料A，并氮封待用；
(2)反应釜3在反应前进行氮气置换5次后，将反应釜搅拌桨转速调至400rpm，将反应釜升温至35℃，调节体系压力至0.1MPaG后，控制第一流量计2和第二流量计11，同步将物料B和物料A缓慢滴加至反应釜中，物料B和物料A的空速均为30h -1，保持温度和压力进行反应，得到反应液；反应过程中每间隔10min取样一次，分析内鎓盐和产物维生素A醋酸酯的含量，直至内鎓盐含量平稳，其含量分别为0.02mol/L，0.023mol/L，0.034mol/L，0.045mol/L，0.036mol/L，0.029mol/L，0.028mol/L，0.027mol/L，0.027mol/L，内鎓盐含量基本稳定在0.027mol/L，说明在反应过程中内鎓盐能快速分解为目标产物；
(3)生成的反应液经离心机4离心并过滤后分为固相和液相，固相打入副产物储罐9，液相经取样分析后打入薄膜蒸发器5，控制停留时间为30min，于50℃、1kPaA下脱除溶剂后，将粗产物打入缓冲罐6中，并将重结晶试剂储罐7中的1650mL乙醇注入其中，于20℃下重结晶，得到目标产物并打入产品罐8中，取样分析纯度、结晶收率以及测试产品稳定性。
通过分析测试可知，反应稳定后原料C15膦盐的转化率为100％，内鎓盐的转化率为99.6％，目标产物(全反式)的选择性89.4％，总维生素A醋酸酯(包括全反式、11顺式和9顺式)的收率为97.6％。所得晶体的纯度为98.9％， 结晶收率为97.2％。
稳定性测试：本实施例得到的维生素A醋酸酯晶体在45℃加热存储7天，平均损失率为0.0025％/d，维生素A醋酸酯晶体置于空气氛围中存储7天，平均损失率为0.0152％/d，测量其液体色度值为25Hazen。
对比例1
一种维生素A醋酸酯的制备方法，工艺流程图如图1所示，具体步骤如下：
(1)在第一原料罐1中加入106g碳酸钠固体粉末，搅拌状态下加入1060mL水，混合均匀得到物料B；在第二原料罐10中加入501.08g C15膦盐、142g C5醛，搅拌状态下加入2500mL去离子水，混合均匀得到物料A，并氮封待用；
(2)反应釜3在反应前进行氮气置换5次后，将反应釜搅拌桨转速调至100rpm，将反应釜升温至25℃，调节体系压力至0.1MPaG后，控制第一流量计2和第二流量计11，同步将物料B和物料A缓慢滴加至反应釜中，物料B和物料A的空速均为14h -1，保持温度和压力进行反应，得到反应液；反应过程中每间隔10min取样一次，分析内鎓盐和产物维生素A醋酸酯的含量，直至内鎓盐含量平稳，其含量分别为0.22mol/L，0.43mol/L，0.84mol/L，0.15mol/L，0.26mol/L，0.30mol/L，0.35mol/L，0.34mol/L，0.32mol/L，内鎓盐含量基本稳定在0.33mol/L；
(3)生成的反应液经离心机4离心并过滤后分为固相和液相，固相打入副产物储罐9(即三苯基氧膦接收罐)，液相经取样分析后打入薄膜蒸发器5，控制停留时间为10min，于30℃、1kPaA下脱除溶剂后，将粗产物打入缓冲罐6中，并将重结晶试剂储罐7中的1650mL乙醇注入其中，于3℃下重结晶，得到目标产物并打入产品罐8中，取样分析纯度、结晶收率以及测试产品稳定性。
通过分析测试可知，反应稳定后原料C15膦盐的转化率为96.9％，内鎓盐的转化率为59.5％，反应过程中内鎓盐的最大累积量为0.33mol/L，说明在反应体系里内鎓盐不能快速分解为目标产物；目标产物(全反式)的选择性56.2％，总维生素A醋酸酯(包括全反式、11顺式和9顺式)的收率为77.3％。所得晶体的纯度为94.6％，结晶收率为72.9％。
稳定性测试：本对比例得到的维生素A醋酸酯晶体在45℃加热存储7天，平均损失率为0.012％/d，维生素A醋酸酯晶体置于空气氛围中存储7天，平均损失率为0.04％/d，测量其液体色度值为100Hazen。与实施例1相比，对比例1中以水作为C15膦盐和C5醛的溶剂(第一溶剂)，导致内鎓盐的分解反应的速率较慢，反应体系中内鎓盐中间体的过多累积，分解反应生成的维生素A醋酸酯和副产三苯基氧膦也不能及时分离，传质效果较差，导致其选择性降低，维生素A醋酸酯中杂质含量增多，结晶纯度和结晶收率差，抗氧化性能和热稳定性大幅度降低。
对比例2
一种维生素A醋酸酯的制备方法，工艺流程图如图1所示，具体步骤如下：
(1)在第一原料罐1中加入106g碳酸钠固体粉末，搅拌状态下加入1060mL水，混合均匀得到物料B；在第二原料罐10中加入501.08g C15膦盐、142g C5醛，搅拌状态下加入2500mL混合溶剂(水、甲醇与正己烷的体积比为3:1:10)，混合均匀得到物料A，并氮封待用；
(2)反应釜3在反应前进行氮气置换5次后，将反应釜搅拌桨转速调至100rpm，将反应釜升温至25℃，调节体系压力至0.1MPaG后，控制第一流量计2和第二流量计11，同步将物料B和物料A缓慢滴加至反应釜中，物料B和物料A的空速均为14h -1，保持温度和压力进行反应，得到反应液；反应过 程中每间隔10min取样一次，分析内鎓盐和产物维生素A醋酸酯的含量，直至内鎓盐含量平稳，其含量分别为0.12mol/L，0.13mol/L，0.16mol/L，0.18mol/L，0.19mol/L，0.20mol/L，0.21mol/L，0.20mol/L，0.19mol/L，内鎓盐含量基本稳定在0.20mol/L；
(3)生成的反应液经离心机4离心并过滤后分为固相和液相，固相打入副产物储罐9(即三苯基氧膦接收罐)，液相经取样分析后打入薄膜蒸发器5，控制停留时间为10min，于30℃、1kPaA下脱除溶剂后，将粗产物打入缓冲罐6中，并将重结晶试剂储罐7中的1650mL乙醇注入其中，于3℃下重结晶，得到目标产物并打入产品罐8中，取样分析纯度、结晶收率以及测试产品稳定性。
通过分析测试可知，反应稳定后原料C15膦盐的转化率为93.9％，内鎓盐的转化率为67.5％，反应过程中内鎓盐的最大累积量为0.20mol/L，说明在反应体系里内鎓盐不能快速分解为目标产物；目标产物(全反式)的选择性70.7％，总维生素A醋酸酯(包括全反式、11顺式和9顺式)的收率为56.3％。所得晶体的纯度为91.9％，结晶收率为75.4％。
稳定性测试：本对比例得到的维生素A醋酸酯晶体在45℃加热存储7天，平均损失率为0.021％/d，维生素A醋酸酯晶体置于空气氛围中存储7天，平均损失率为0.07％/d，测量其液体色度值为123Hazen。与实施例1相比，对比例2中以大量非极性溶剂作为C15膦盐和C5醛的溶剂，在反应过程中存在大量的内鎓盐转移至有机相的过程，一是带来极慢的相界面传质阻力，二是导致内鎓盐浓度较低，分解反应的速率较慢，反应体系中内鎓盐中间体的过多累积，维生素A醋酸酯中杂质含量增多，结晶纯度和结晶收率差，抗氧化性能和热稳定性大幅度降低。

Claims (11)

  1. 一种维生素A醋酸酯的制备方法，其特征在于，所述制备方法包括：C15膦盐与C5醛在碱性化合物的存在下进行加成反应，生成内鎓盐；所述内鎓盐发生分解反应，得到所述维生素A醋酸酯；反应过程中所述内鎓盐在反应体系的含量≤0.06mol/L。
  2. 根据权利要求1所述的制备方法，其特征在于，所述C15膦盐的结构式为
    Figure PCTCN2021094550-appb-100001
    其中，X选自Cl、Br、I或HSO 4中的任意一种。
  3. 根据权利要求1或2所述的制备方法，其特征在于，所述C15膦盐与C5醛的摩尔比为1:(0.8～2)，进一步优选为1:(1～1.6)。
  4. 根据权利要求1～3任一项所述的制备方法，其特征在于，所述C15膦盐与碱性化合物的摩尔比为1:(0.5～5)，优选为1:(1～2)；
    优选地，所述碱性化合物包括金属无机盐、金属氢氧化物或氨水中的任意一种或至少两种的组合；
    优选地，所述金属无机盐包括碳酸盐、碳酸氢盐、磷酸盐或磷酸氢盐中的任意一种或至少两种的组合，进一步优选为碳酸盐；
    优选地，所述碳酸盐选自碳酸钠、碳酸钾或碳酸锂中的任意一种或至少两种的组合；
    优选地，所述金属氢氧化物包括氢氧化钠、氢氧化钾或氢氧化锂中的任意一种或至少两种的组合。
  5. 根据权利要求1～4任一项所述的制备方法，其特征在于，所述加成反应、分解反应的温度为10～80℃，优选为25～75℃；
    优选地，反应过程中所述内鎓盐在反应体系的含量≤0.03mol/L，进一步优选为≤0.01mol/L。
  6. 根据权利要求1～5任一项所述的制备方法，其特征在于，所述制备方法的工艺包括：将C15膦盐、C5醛和第一溶剂混合均匀，得到物料A；将碱性化合物与第二溶剂混合均匀，得到物料B；所述物料A与物料B分别通过不同的进料通道同步进入反应装置，反应，得到所述维生素A醋酸酯。
  7. 根据权利要求6所述的制备方法，其特征在于，所述第一溶剂为极性溶剂与非极性溶剂的混合物；
    优选地，所述极性溶剂与非极性溶剂的体积比为(0.5～1000):1，进一步优选为(1～500):1，更进一步优选为(10～500):1；
    优选地，所述极性溶剂包括水、甲醇、乙醇、丙酮、乙酸乙酯、三氯甲烷或二氯甲烷中的任意一种或至少两种的组合，进一步优选为水与甲醇的组合；
    优选地，所述非极性溶剂包括四氯化碳、环己烷、正己烷、正庚烷、正戊烷或石油醚中的任意一种或至少两种的组合；
    优选地，以所述C15膦盐的质量为1g计，所述第一溶剂的体积为1～30mL，进一步优选为5～15mL。
  8. 根据权利要求6或7所述的制备方法，其特征在于，所述第二溶剂为质子型溶剂；
    优选地，所述第二溶剂包括水、甲醇、乙醇、异丙醇或丙三醇中的任意一种或至少两种的组合；
    优选地，以所述碱性化合物的质量为1g计，所述第二溶剂的体积为1～100mL，进一步优选为10～50mL；
    优选地，所述物料B中碱性化合物的质量百分含量为1～90％，进一步优选为10～70％。
  9. 根据权利要求6～8任一项所述的制备方法，其特征在于，所述物料A 与物料B同步匀速地进入反应装置；
    优选地，所述物料A与物料B的空速各自独立地为1～50h -1，进一步优选为5～30h -1；
    优选地，在入料之前所述反应装置中的温度为10～50℃，进一步优选为20～40℃；
    优选地，所述反应的温度为10～80℃，进一步优选为25～75℃；
    优选地，所述反应的压力为10kPaA～5MPaG，进一步优选为50kPaA～1MPaG；
    优选地，所述反应在搅拌条件下进行；
    优选地，所述搅拌的转速为50～1000rpm，进一步优选100～800rpm。
  10. 根据权利要求6～9任一项所述的制备方法，其特征在于，所述反应完成后还包括后处理的步骤，所述后处理依次包括固液分离、脱溶和重结晶；
    优选地，所述固液分离的方法为离心和过滤，得到的固相为副产物，液相进入脱溶的步骤；
    优选地，所述脱溶的装置为薄膜蒸发器；
    优选地，所述薄膜蒸发器的塔釜温度为10～100℃，进一步优选为30～50℃；
    优选地，所述薄膜蒸发器中的压力为0.1～10kPaA，进一步优选为1～5kPaA；
    优选地，所述薄膜蒸发器中的停留时间为1～60min，进一步优选为10～30min；
    优选地，所述重结晶的试剂包括甲苯、乙酸乙酯、乙腈、乙醇或异丙醇中的任意一种或至少两种的组合；
    优选地，以粗产物的质量为1g计，所述重结晶的试剂的用量为1～100mL，进一步优选为5～30mL；
    优选地，所述重结晶的温度为-10～50℃，进一步优选为0～30℃。
  11. 根据权利要求1～10任一项所述的制备方法，其特征在于，所述制备方法具体包括如下步骤：
    (1)将C15膦盐、C5醛和第一溶剂混合均匀，得到物料A；将碱性化合物与第二溶剂混合均匀，得到物料B；所述C15膦盐与C5醛的摩尔比为1:(1～1.6)，所述C15膦盐与碱性化合物的摩尔比为1:(1～2)；所述第一溶剂为体积比为(1～500):1的极性溶剂与非极性溶剂的混合物，所述第二溶剂为质子型溶剂；
    (2)将步骤(1)得到的物料A与物料B分别通过不同的进料通道同步、匀速地进入反应装置，空速为5～30h -1，在温度为25～75℃、压力为50kPaA～1MPaG的条件下搅拌反应，得到反应液；反应过程中所述内鎓盐在反应体系的含量≤0.06mol/L；
    (3)将步骤(2)得到的反应液固液分离，得到的液相经脱溶、重结晶，得到所述维生素A醋酸酯。
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