DE112021007675T5 - PRODUCTION PROCESS FOR VITAMIN A ACETATE - Google Patents

Abstract

A process for producing vitamin A acetate is disclosed here. The production process includes: an addition reaction is performed on C15 phosphonium salt with C5 aldehyde in the presence of an alkali compound to form ylide; the ylide undergoes a decomposition reaction to obtain vitamin A acetate; and the content of the ylide in a reaction system during the reaction is ≤ 0.06 mol%/L. The production process is based on a Wittig reaction of C15+C5, and by controlling the content of the ylide in the reaction system during the reaction, vitamin A acetate is obtained, which has high purity, high trans-isomerization selectivity and high yield. The production process is suitable for the reaction on any scale and can be carried out in batch, semi-continuous or fully continuous, so that the obtained vitamin A acetate has a low chromaticity value, good oxidation resistance and thermal stability, a low deterioration rate, suitability for stable Long-term storage and good market competitiveness.

Description

TECHNICAL FIELD

The present application belongs to the technical field of chemical synthesis and relates in particular to a production process for vitamin A acetate.

BACKGROUND

Vitamin A acetate (VA acetate) is an important substance used in pharmaceuticals, cosmetics, foods, dietary supplements and animal feed additives, which has the effects of maintaining visual function, maintaining the health of epithelial tissue cells and increasing immunoglobulin synthesis stimulate. The storage and use of vitamin A acetate is problematic in three ways: first, vitamin A acetate has extremely poor oxidation resistance and is easily oxidized and decomposed when exposed to air; secondly, vitamin A acetate has extremely poor thermal stability, and its storage is a tricky problem, especially in hot summer; and thirdly, most commercially available vitamin A acetates are dark in color, the crystals are yellowish or reddish in color, and the color will gradually deepen over time, and few manufacturers are able to produce products with good color, to achieve a high market share. Therefore, the production of vitamin A acetate with high stability has good market prospects.

At present, the synthesis of vitamin A acetate involves two common reaction routes: (1) the C14+C6 route, which is characterized by the Grignard reagent, which is relatively mature in the industry, but requires up to 50 types of raw materials, large fixed investments, has multiple reaction steps and a cumbersome process; and (2) the C15+C5 route, characterized by the Wittig reaction, where β-ionone is used as a raw material and then, after reaction conversion, reacts with an organic phosphonium compound to produce a Wittig precursor through a salt formation reaction produce, and the precursor and a C5 aldehyde are subjected to a Wittig reaction with strong alkali to produce vitamin A acetate. The Wittig process, with its short route, simple process and low costs, is gradually showing the prospect of large-scale implementation.

CN103044302A discloses a one-pot process for preparing vitamin A acetate, wherein a C14 aldehyde and an intermediate C1 ester are used to produce a C15 phosphonate under alkaline conditions, and the C15 phosphonate is directly reacted with a C5 aldehyde without separation reacted through a one-pot process to produce vitamin A acetate. This method reduces the use of solvents and separation, but requires reagents such as sodium methanol, sodium ethanol, potassium tert-butoxide or sodium hydride, which are very dangerous and very sensitive to air and moisture, and the two-stage Wittig reagent has a low atom utilization of 20% for both levels.

CN101219983A discloses an improved production process for vitamin A acetate, wherein the target product is prepared by a Wittig reaction with raw materials of a C15 dialkylphosphonate and 4-acetyloxy-2-methyl-2-butene-1-aldehyde and the solvent for the reaction is a mixture of toluene and pyridine (or pyridine with methyl) so that the reaction is carried out at near room temperature; however, the process requires very hazardous reagents such as sodium methanol and sodium ethanol, and the isomerization selectivity of the product is low.

CN1894208A discloses a process for producing vitamin A acetate, particularly comprising: reacting vinyl-β-ionol with triphenylphosphine in the presence of sulfuric acid to produce a C15 phosphonium salt and then performing a Wittig reaction on the C15 phosphonium salt and 4-acetoxy-2-methyl-but-2-enal to obtain vitamin A acetate. In this process, the reaction temperature is difficult to control during the preparation of the C15 phosphonium salt, a large number of isomeric impurities are generated, and the product is difficult to crystallize and separate, resulting in the resulting from the Wittig reaction using the Vitamin A acetate produced using C15 phosphonium salt as raw material contains a lot of tar and the ratio of cis to trans isomers is 7:3; the trans-vitamin A acetate content is very low, which is not conducive to industrial production.

Overall, the reaction conditions of the Wittig process are relatively harsh and require a large number of organic/inorganic acid or base catalysts, the post-treatment is difficult, the atom utilization is low, the vitamin A acetate produced after the reaction has a poor selection tivity of the all-trans form, and during the reaction process, the elimination and decomposition of intermediates is slow, resulting in the vitamin A acetate produced being doped with many impurities due to the fact that like is like dissolves, are difficult to remove, which is not beneficial to the product stability and the subsequent crystallization process.

The development of a production process for vitamin A acetate with high product stability, low chromaticity value and good isomerization selectivity is therefore a priority research goal in this area.

SUMMARY

What follows is a summary of the subject matter described in detail here. This summary is not intended to limit the scope of the claims.

In view of the shortcomings of the prior art, the present application aims to provide a production process for vitamin A acetate, which is based on the Wittig reaction and, by controlling the ylide content of the reaction system, vitamin A acetate with high purity, high isomerization selectivity and high yield, and in addition, the chromaticity value of the product is low, the oxidation resistance and thermal stability are improved, the deterioration rate is low, and the quality of vitamin A acetate is significantly improved.

In order to achieve this goal, the following technical solutions are applied in the present application.

The present application provides a production process for vitamin A acetate, and the production process includes: subjecting a C15 phosphonium salt and a C5 aldehyde to an addition reaction in the presence of an alkaline compound to produce an ylide; and subjecting the ylide to a decomposition reaction to obtain the vitamin A acetate; wherein during the reaction process a content of the ylide in the reaction system is less than or equal to 0.06 mol%, which is, for example, 0.055 mol%, 0.05 mol%, 0.045 mol%, 0.04 mol%, 0.035 mol% , 0.03 mol%, 0.025 mol%, 0.02 mol%, 0.015 mol%, 0.01 mol% or 0.005 mol% etc. can be.

wobei Ph Phenyl darstellt; das aus der Additionsreaktion erhaltene Produkt ist ein Ylid, das weiter zersetzt wird, um das Zielprodukt Vitamin-A-Acetat und ein Nebenprodukt (Triphenylphosphinoxid,

zu erhalten; das Vitamin-A-Acetat beinhaltet eine Mischung aus all-trans-Vitamin-A-Acetat

11 -cis-Vitamin-A-Acetat

und 9-cis-Vitamin-A-Acetat

In the present application, the reaction formula of the addition reaction is as follows:

where Ph represents phenyl; the product obtained from the addition reaction is an ylide, which is further decomposed to produce the target product vitamin A acetate and a by-product (triphenylphosphine oxide,

to obtain; The vitamin A acetate contains a mixture of all-trans vitamin A acetate

11 -cis-vitamin A acetate

and 9-cis-vitamin A acetate

In the present application, the “content of the ylide in the reaction system during the reaction process” refers to the content of the ylide in the reaction system at any point in the reaction process.

By way of example, the content of the ylide in the reaction system can be detected during the reaction process by the following method: analyzing and testing a sample from the reaction system by the usual quantitative detection methods in chemistry (e.g. liquid chromatography, gas chromatography, gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry, etc. ) to receive the salary.

The production process described in the present application is based on the Wittig reaction of C15+C5, and by controlling the content (cumulative amount) of the ylide intermediates in the reaction system during the reaction process, the ylide is rapidly and completely decomposed to produce vitamin A acetate to produce. The manufacturing process is applicable at any reaction scale and can be carried out in batches, semi-continuously or continuously; the manufacturing process has a high utilization rate of raw materials, and the conversion rate of C15 phosphonium salt can reach 99% or more; the selectivity of the all-trans product is high and can be more than 86% without any optical isomerization treatment; the vitamin A acetate with high purity, high stability and low chromaticity value is obtained, and the product has good oxidation resistance, good thermal stability and low deterioration rate, which is conducive to long-term stable storage and has good market competitiveness .

wobei X ausgewählt ist aus irgendeinem von Cl, Br, I oder HSO₄.The C15 phosphonium salt preferably has the structural formula

where X is selected from any of Cl, Br, I or HSO ₄ .

The C5 aldehyde preferably has the structural formula

The molar ratio of the C15 phosphonium salt to the C5 aldehyde is preferably 1:(0.8-2), which is, for example, 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., and more preferably 1:(1 -1.6).

A molar ratio of the C15 phosphonium salt to the alkaline compound is preferably 1:(0.5-5), which is, for example, 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, or 1:4.8, etc, more preferably 1:(1-2).

Preferably the alkaline compound includes any or a combination of at least two of an inorganic metal salt, a metal hydroxide or ammonia.

Preferably, the inorganic metal salt includes any or a combination of at least two of a carbonate salt, a bicarbonate salt, a phosphate salt or a hydrogen phosphate salt, more preferably the carbonate salt.

Preferably the carbonate salt is selected from any or a combination of at least two of sodium carbonate, potassium carbonate or lithium carbonate.

Preferably, the metal hydroxide includes any or a combination of at least two of sodium hydroxide, potassium hydroxide or lithium hydroxide.

Preferred are the addition reaction and the decomposition reaction at 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, or at any specific point values between two of the above point values; For reasons of space and brevity, the specific point values included in the range are not exhaustively listed here; the temperature is still preferably 25-75°C.

During the reaction process, the content of the ylide in the reaction system is preferably less than or equal to 0.03 mol%/L, more preferably less or equal to 0.01 mol%/L.

Preferably, the production method includes the following processes: uniformly mixing the C15 phosphonium salt, the C5 aldehyde and a first solvent to obtain material A; uniformly mixing the alkaline compound with a second solvent to obtain material B; synchronously introducing the material A and the material B into a reaction unit through different feed channels and carrying out a reaction to obtain the vitamin A acetate.

The synchronous addition preferably takes place in the form of a continuous dropwise addition.

In a preferred technical solution of the present application, in the production process, substance A (a solution of the C15 phosphonium salt and the C5 aldehyde) and substance B (a solution of the alkaline compound) are introduced synchronously into the reaction unit, and after mixing takes place an addition reaction first takes place to produce the intermediate ylide; the ylide then undergoes a decomposition reaction to produce vitamin A acetate; the synchronous material introduction process facilitates the generation and decomposition of ylide, quickly converts the ylide into the target product vitamin A acetate, and maintains the cumulative amount of ylide in the reaction system at less than or equal to 0.06 mol%/L.

The first solvent is preferably a mixture of a polar and a non-polar solvent.

The presence of the nonpolar solvent facilitates the addition reaction between the C15 phosphonium salt and the C5 aldehyde, favoring the reaction to proceed in a forward direction to produce the ylide; the presence of the polar solvent facilitates the decomposition reaction of the ylide, resulting in rapid and complete conversion of the ylide to vitamin A acetate, and improves the isomerization selectivity of the all-trans form, producing more all-trans-vitamin A acetate here.

A volume ratio of the polar solvent to the non-polar solvent is preferably (0.5-1000):1, which is, for example, 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 or 950:1 etc., more preferably (1-500): 1 and even more preferably (10-500): 1.

Preferably the polar solvent includes any or a combination of at least two of water, methanol, ethanol, acetone, ethyl acetate, trichloromethane or dichloromethane; the combination includes: a combination of water and methanol, a combination of water and ethanol, a combination of water and acetone, a combination of water and ethyl acetate, a combination of water and trichloromethane, a combination of methanol and acetone, a combination of methanol and ethyl acetate, etc., and more preferably a combination of water and methanol;.

Preferably, the non-polar solvent includes any or a combination of at least two of carbon tetrachloride, cyclohexane, n-hexane, n-heptane, n-pentane or petroleum ether.

Preferably, based on a mass of the C15 phosphonium salt, which is 1 g, the first solvent has a volume of 1-30 mL, which is, for example, 2 mL, 3 mL, 5 mL, 7 mL, 9 mL, 10 mL, 11 mL , 13 mL, 15 mL, 17 mL, 19 mL, 20 mL, 21 mL, 23 mL, 25 mL or 28 mL or any specific point value between any two of the above point values; For reasons of space and brevity, the specific point values included in the range are not exhaustively listed here; and the volume is more preferably 5-15 mL.

Preferably the second solvent is a protic solvent; the protic solvent facilitates the formation of hydrogen between the carbon-carbon double bonds, reduces the steric hindrance of the product in terms of configuration and improves the selectivity of the all-trans isomers, allowing more all-trans vitamin A acetate is formed with high stability.

Preferably, the second solvent includes any or a combination of at least two of water, methanol, ethanol, isopropanol or glycerin.

The second solvent preferably has a volume of 1-100 mL, based on a mass of the alkaline compound, which is 1 g, which is, for example, 5 mL, 10 mL, 15 mL, 20 mL, 25 mL, 30 mL, 35 mL, 40 mL, 45 mL, 50 mL, 60 mL, 70 mL, 80 mL or 90 mL or any specific point value between two of the above point values; For reasons of space and brevity, the specific point values included in the range are not exhaustively listed here; the volume is also preferably 10-50 mL.

The alkaline compound preferably has a mass percentage of 1%-90% in material B, which is, for example, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55 %, 60%, 65%, 70%, 80% or 85% or any specific point values between any two of the above point values; For reasons of space and brevity, the specific point values included in the range are not exhaustively listed here; the mass percentage is more preferably 10%-70%.

The material A and the material B are preferably introduced into the reaction unit synchronously at a constant speed.

Preferably, the material A and the material B independently have a space velocity of 1-50 h ^-1 , for example 2 h ^-1 , 5 h ^-1 , 8 h ^-1 , 10 h ^-1 , 15 h ^-1 , 20 h ^-1 , 25 hrs ^-1 , 30 hrs ^-1 , 35 hrs ^-1 , 40 hrs ^-1 or 45 hrs ^-1 or any specific point values between two of the above mentioned point values; For reasons of space and brevity, the specific point values included in the range are not exhaustively listed here; the space velocity is more preferably 5-30 h ^-1 .

Before introducing the material, the reaction unit preferably has a temperature of 10-50°C, which is, for example, 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 or any specific point values between any two of the above point values; For reasons of space and brevity, the specific point values included in the range are not exhaustively listed here; the temperature is also preferably 20-40° C.

The reaction is preferably carried out at 10-80°C, for example at 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 or for any specific points between two of the above points; For reasons of space and brevity, the specific point values included in the range are not exhaustively listed here; the temperature is most preferably 25-75°C.

The reaction is preferably carried out at a pressure of 10 kPaA-5 MPaG, which is, for example, 15 kPaA, 20 kPaA, 30 kPaA, 40 kPaA, 50 kPaA, 60 kPaA, 70 kPaA, 80 kPaA, 90 kPaA, 100 kPaA, 0.2 MPaG, 0.5 MPaG, 0.8 MPaG, 1 MPaG, 1.5 MPaG, 2 MPaG, 2.5 MPaG, 3 MPaG, 3.5 MPaG, 4 MPaG, or 4.5 MPaG, etc., and more preferably 50 kPaA-1 MpaG can be.

In the present application, “A” denotes the absolute pressure and “G” the gauge pressure.

The reaction is preferably carried out with stirring.

Stirring is preferably carried out at a speed of 50-1000 rpm, for example 100 rpm, 200 rpm, 300 rpm, 400 rpm, 500 rpm, 600 rpm, 700 rpm. min, 800 rpm or 900 rpm, or with any specific point values between two of the above point values; For reasons of space and brevity, the specific point values included in the range are not exhaustively listed here; the speed is also preferably 100-800 rpm.

Preferably, the production method further includes a step of post-treatment after completion of the reaction, and the post-treatment successively includes solid-liquid separation, solvent removal and recrystallization.

The solid-liquid separation is preferably carried out by centrifugation and filtration, with a solid phase being produced as a by-product (triphenylphosphine oxide) and a liquid phase being subjected to solvent removal.

A device in the form of a thin-film evaporator is preferably used for solvent removal.

The thin-film evaporator preferably has a boiler temperature of 10-100°C, which is, 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 or any specific point values between two of the abovementioned point values; For reasons of space and brevity, the specific point values included in the range are not exhaustively listed here; the boiler temperature is also preferably 30-50° C.

The thin film evaporator preferably has a pressure of 0.1-10 kPaA, for example 0.2 kPaA, 0.5 kPaA, 0.8 kPaA, 1 kPaA, 2 kPaA, 3 kPaA, 4 kPaA, 5 kPaA, 6 kPaA, 7 kPaA, 8 kPaA or 9 kPaA or any specific point value between two of the above point values; For reasons of space and brevity, the specific point values included in the range are not exhaustively listed here; the pressure is also preferably 1-5 kPaA.

The thin film evaporator preferably has a residence time of 1-60 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 or any specific point values can be between two of the above point values; For reasons of space and brevity, the specific point values included in the range are not exhaustively listed here; the residence time is also preferably 10-30 minutes.

Preferably, the reagent for recrystallization includes any or a combination of at least two of toluene, ethyl acetate, acetonitrile, ethanol or isopropanol.

Preferably, the reagent used for recrystallization has an amount of 1-100 mL, based on a mass of the raw product which is 1 g, which is for example 5 mL, 10 mL, 15 mL, 20 mL, 25 mL, 30 mL, 35 mL, 40 mL, 45 mL, 50 mL, 60 mL, 70 mL, 80 mL or 90 mL or any specific point value between any two of the above point values; For reasons of space and brevity, the specific point values included in the range are not exhaustively listed here; the amount is also preferably 5-30 mL.

The recrystallization is preferably carried out at -10 to 50°C, which is, for example, -5°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35° C, 40°C or 45°C or any specific point values between any two of the above point values; For reasons of space and brevity, the specific point values included in the range are not exhaustively listed here; the temperature is also preferably 0-30°C.

• (1) gleichmäßiges Mischen des C15-Phosphoniumsalzes, des C5-Aldehyds und eines ersten Lösungsmittels, um Material A zu erhalten; gleichmäßiges Mischen der alkalischen Verbindung mit einem zweiten Lösungsmittel, um Material B zu erhalten; wobei ein Molverhältnis des C15-Phosphoniumsalzes zu dem C5-Aldehyd 1:(1-1.6) beträgt und ein molares Verhältnis des C15-Phosphoniumsalzes zu der alkalischen Verbindung 1:(1-2) beträgt; das erste Lösungsmittel eine Mischung aus einem polaren Lösungsmittel und einem unpolaren Lösungsmittel in einem Volumenverhältnis von (1-500): 1 beträgt und das zweite Lösungsmittel ein protisches Lösungsmittel ist;
• (2) synchrones Einführen des Materials A und des Materials B, die in Schritt (1) erhalten wurden, in eine Reaktionseinheit mit einer konstanten Geschwindigkeit durch jeweils verschiedene Zuführungskanäle, wobei eine Raumgeschwindigkeit 5-30 Std^-1beträgt, und Durchführen einer Reaktion unter Rühren bei 25-75°C und bei 50 kPaA-1 MPaG, um eine Reaktionsflüssigkeit zu erhalten; wobei während des Reaktionsprozesses ein Gehalt des Ylids in dem Reaktionssystem weniger als oder gleich 0,06 Mol-%/L beträgt; und
• (3) Durchführen einer Fest-Flüssig-Trennung an der in Schritt (2) erhaltenen Reaktionsflüssigkeit und Durchführen einer Lösungsmittelentfernung und Rekristallisation an einer erhaltenen flüssigen Phase, um das Vitamin-A-Acetat zu erhalten.

The manufacturing process preferably includes in particular the following steps:

• (1) uniformly mixing the C15 phosphonium salt, the C5 aldehyde and a first solvent to obtain material A; uniformly mixing the alkaline compound with a second solvent to obtain material B; wherein a molar ratio of the C15 phosphonium salt to the C5 aldehyde is 1:(1-1.6) and a molar ratio of the C15 phosphonium salt to the alkaline compound is 1:(1-2); the first solvent is a mixture of a polar solvent and a non-polar solvent in a volume ratio of (1-500): 1 and the second solvent is a protic solvent;
• (2) synchronously introducing the material A and the material B obtained in step (1) into a reaction unit at a constant speed through different feed channels, respectively, with a space velocity of 5-30 h ^-1 , and performing a reaction under Stir at 25-75°C and at 50 kPaA-1 MPaG to obtain a reaction liquid; wherein during the reaction process, a content of the ylide in the reaction system is less than or equal to 0.06 mol%/L; and
• (3) Performing solid-liquid separation on the reaction liquid obtained in step (2), and performing solvent removal and recrystallization on a resulting liquid phase to obtain the vitamin A acetate.

Compared with the prior art, the present application has the following advantageous effects.

The production process described in the present application is based on the Wittig reaction of C15+C5, and by controlling the ylide content in the reaction system during the reaction process, the ylide is rapidly and completely decomposed to produce vitamin A acetate, and the product yield is more than or equal to 97.4%. The manufacturing process is applicable to any reaction scale and can be carried out in batch, semi-continuous or continuous manner; the selectivity of the all-trans product is high, reaching 86.2-90%, the obtained vitamin A acetate is a light yellow or white powder, which has a chromaticity value of less than 50 Hazen and a purity of 99% or more as well has characteristics of high purity, high stability and low chromaticity value, and in addition, the product has good oxidation resistance, good thermal stability and a low deterioration rate, the average deterioration rate of the product being less than or equal to 0.05%/d and the chromaticity value after 7 days of storage in air is still less than 50 Hazen. The product is suitable for long-term stable storage and has good competitiveness in the market.

Further points of view become clear when reading and understanding the detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

• 1 shows a flowchart of a manufacturing process in Example 1;

in the figure: 1. first raw material tank, 2. first flow meter, 3. reactor, 4. centrifuge, 5. thin film evaporator, 6. buffer tank, 7. recrystallizer storage tank, 8. product tank, 9. by-product storage tank, 10. second raw material tank and 11. second flow meter.

DETAILED DESCRIPTION

The technical solutions of the present application are described in more detail below using specific embodiments. It should be clear to those skilled in the art that the examples are merely for the purpose of better understanding the present application and should not be considered as a specific limitation of the present application.

wird von BASF bezogen; das C15-Phosphoniumsalz

ist ein selbst hergestelltes Rohmaterial, und siehe den Stand der Technik für sein Herstellungsverfahren, beispielsweise CN109651150A , und zwar wie folgt: nach Durchführung einer Leckageerkennung an einem Hochdruckreaktor werden Triphenylphosphin (264,5 g, 1,01 Mol-%) und Salzsäure (96,8 g, 38 Gew.-%, 1,01 Mol) in den Hochdruckreaktor gegeben; nach dreimaligem Spülen mit CO₂ wird der Hochdruckreaktor mit CO₂ beschickt und unter Rühren auf eine Innentemperatur von 45°C erwärmt und über ein Druckregelventil auf einem Innendruck von 14 MPa gehalten; Vinyl-β-Ionol (220 g, 1 Mol) wird über eine Advektionspumpe in den Hochdruckreaktor gepumpt und einer Salzbildungsreaktion unterzogen, um das C15-Phosphoniumsalz herzustellen.In the following examples of the present application, methanol, ethanol, carbonate salts and alkane solvents are available from Shanghai Titan Technology Co, Ltd. based; the C5 aldehyde

is purchased from BASF; the C15 phosphonium salt

is a home-made raw material, and see the prior art for its manufacturing process, for example CN109651150A , as follows: after carrying out leakage detection on a high-pressure reactor, triphenylphosphine (264.5 g, 1.01 mol%) and hydrochloric acid (96.8 g, 38% by weight, 1.01 mol) are added to the high-pressure reactor given; after flushing three times with CO ₂ , the high-pressure reactor is charged with CO ₂ and heated with stirring to an internal temperature of 45 ° C and maintained at an internal pressure of 14 MPa via a pressure control valve; Vinyl-β-ionol (220 g, 1 mol) is pumped into the high pressure reactor via an advection pump and subjected to a salt formation reaction to produce the C15 phosphonium salt.

• Chromatographische Säule: Waters XSelectHSS T3, 4,6 µm×250 mm; Injektionsvolumen: 2-10 µL, das nach den Probenbedingungen fein eingestellt werden kann; Säulentemperatur: 40°C; Flussrate: 1 mL/min; Detektor: Ultraviolett-Detektor (UV), Detektionswellenlängen: 254-400 nm; und mobile Phase: Acetonitril/0,1%ige wässrige Phosphorsäurelösung;

In the following examples of the present application, the content and purity of each component are tested and calculated by external standardization with a high performance liquid chromatograph (Shimadzu LC-20AD), and a conversion rate is calculated based on the content of the product; the conditions for liquid chromatography are as follows:

• Chromatographic column: Waters XSelectHSS T3, 4.6 µm×250 mm; Injection volume: 2-10 µL, which can be fine-tuned according to sample conditions; Column temperature: 40°C; Flow rate: 1 mL/min; Detector: Ultraviolet detector (UV), detection wavelengths: 254-400 nm; and mobile phase: acetonitrile/0.1% aqueous phosphoric acid solution;

For the detection process, an external liquid phase standard curve is first constructed with a pure sample, and the mass fraction (content) of each detected substance is calculated based on the linear relationship between the concentration and the liquid phase peak area.

• eine anfängliche Masse des Vitamin-A-Acetats ist m₁, und eine nach dem Erwärmen und Wiegen erhaltene Masse ist m₂; die durchschnittliche Verlustrate = 100% × (m₁ - m₂) / n × m₁, wobei n die Anzahl der Lagertage bezeichnet und in den folgenden Beispielen n=7 ist.

In the following examples of the present application, an average loss rate (rate of decomposition upon heating) of the product is tested using the following method:

• an initial mass of the vitamin A acetate is m ₁ , and a mass obtained after heating and weighing is m ₂ ; the average loss rate = 100% × (m ₁ - m ₂ ) / n × m ₁ , where n denotes the number of storage days and in the following examples n = 7.

• 1 g (basierend auf den tatsächlichen Wägedaten, bezeichnet als m₁) gleichmäßig dispergiertes Vitamin-A-Acetat (99.9% Reinheit) wird eingewogen und 7 Tage lang bei Raumtemperatur an der Luft gelagert, und der gesamte Feststoff wird nach 7 Tagen Lagerung mit einem Lösungsmittel verdünnt und einer Hochleistungsflüssigkeitschromatographie unterzogen, um den Gehalt an Vitamin-A-Acetat (bezeichnet als m₂) darin zu bestimmen; eine Verschlechterungsrate = 100% × (m₁ - m₂) / n × m₁, wobei n die Anzahl der Tage der Lagerung bezeichnet und in den folgenden Beispielen n=7 ist.

In the following examples of the present application, a deterioration rate of the product is tested according to the following method:

• 1 g (based on the actual weighing data, denoted as m ₁ ) of uniformly dispersed vitamin A acetate (99.9% purity) is weighed and stored in air at room temperature for 7 days, and the entire solid is separated after 7 days of storage with a solvent diluted and subjected to high performance liquid chromatography to determine the content of vitamin A acetate (denoted as m ₂ ) therein; a deterioration rate = 100% × (m ₁ - m ₂ ) / n × m ₁ , where n denotes the number of days of storage and in the following examples n = 7.

• Vitamin-A-Acetat-Kristalle werden in n-Hexan gelöst, um eine Vitamin-A-Acetat-n-Hexan-Lösung mit einem Massenanteil von 10% zu bilden, und die Lösung wird mit einem CS-810-Transmissionsspektralphotometer bei Raumtemperatur auf ihre Platin-Kobalt-Chromatizität geprüft; je niedriger der Chromatizitätswert ist, desto näher ist die Lösung an einer farblosen und transparenten Flüssigkeit; und der Chromatizitätswert von deionisiertem Wasser beträgt 5-15 Hazen.

In the following examples of the present application, the color value of the product is checked using the following method:

• Vitamin A acetate crystals are dissolved in n-hexane to form a 10% mass fraction vitamin A acetate n-hexane solution, and the solution is measured using a CS-810 transmission spectrophotometer at room temperature their platinum-cobalt chromaticity tested; the lower the chromaticity value, the closer the solution is to a colorless and transparent liquid; and the chromaticity value of deionized water is 5-15 Hazen.

In a production process for vitamin A acetate in the context of the present application, the reaction formula is as follows:

In the following examples of the present application, only all-trans vitamin A acetate is considered as the target product.

example 1

• (1) 106 g festes Natriumcarbonatpulver wurden in einen ersten Rohmaterialtank 1 gegeben, unter Rühren mit 1060 mL Wasser versetzt und gleichmäßig gemischt, um Material B zu erhalten; 501,08 g C15-Phosphoniumsalz und 142 g C5-Aldehyd wurden in einen zweiten Rohmaterialtank 10 gegeben, unter Rühren mit 2500 mL Lösungsmittelgemisch (ein Volumenverhältnis von Wasser, Methanol und n-Hexan war 100:1:10) versetzt und gleichmäßig gemischt, um Material A zu erhalten, und das Material A wurde für die spätere Verwendung mit Stickstoff versiegelt;
• (2) ein Reaktor 3 wurde vor der Reaktion fünfmal mit Stickstoff gespült, ein Rührwerk des Reaktors wurde auf eine Rotationsgeschwindigkeit von 100 U/min eingestellt, der Reaktor wurde auf 25°C erwärmt, und ein Druck des Systems wurde auf 0,1 MPaG eingestellt; anschließend wurden durch Steuern eines ersten Durchflussmessers 2 und eines zweiten Durchflussmessers 11 das Material B und das Material A langsam und synchron tropfenweise in den Reaktor zugegeben, wobei die Raumgeschwindigkeit sowohl des Materials B als auch des Materials A 14 Std^-1 betrug, und einer Reaktion unterworfen, wobei die Temperatur und der Druck beibehalten wurden, um eine Reaktionsflüssigkeit zu erhalten; während des Reaktionsprozesses wurden alle 10 Minuten Proben aus dem Reaktionssystem entnommen, um die Ylidgehalte und die Gehalte an Vitamin-A-Acetat-Produkt zu analysieren, bis die Ylidgehalte stabil waren und die Ylidgehalte betrugen 0,02 Mol/L, 0,04 Mol/L, 0,05 Mol/L, 0,055 Mol/L, 0,059 Mol/L, 0,060 Mol/L, 0,059 Mol/L, 0,058 Mol/L und 0,060 Mol/L, die Ylidgehalte blieben im Wesentlichen bei 0,06 Mol/L, was darauf hinweist, dass das Ylid während der Reaktion schnell in das Zielprodukt zersetzt werden konnte; und
• (3) die erhaltene Reaktionsflüssigkeit wurde in einer Zentrifuge 4 zentrifugiert und filtriert, um in eine feste und eine flüssige Phase getrennt zu werden, die feste Phase wurde in einen Nebenprodukt-Lagertank 9 (d.h., Triphenylphosphinoxid-Aufnahmetank) eingeleitet, und die flüssige Phase wurde nach der Entnahme von Proben und der Analyse in einen Dünnschichtverdampfer 5 eingeleitet und einer Lösungsmittelentfernung bei 30°C und 1 kPaA mit einer auf 10 min gesteuerten Verweilzeit unterzogen; dann wurde ein Rohprodukt in einen Puffertank 6 eingeführt, 1650 mL Ethanol aus einem Rekristallisationsreagenzvorratstank 7 zugeben und einer Rekristallisation bei 3°C unterzogen; ein erhaltenes Zielprodukt wurde in einen Produkttank 8 eingeführt, eine Probe entnommen und auf Reinheit, Kristallisationsausbeute und Stabilität analysiert.

Manufacturing process for vitamin A acetate, its process flow diagram in 1 is shown, the manufacturing process having the following specific steps:

• (1) 106 g of solid sodium carbonate powder was placed in a first raw material tank 1, added with 1060 mL of water while stirring, and mixed uniformly to obtain material B; 501.08 g of C15 phosphonium salt and 142 g of C5 aldehyde were placed in a second raw material tank 10, added with stirring with 2500 mL of solvent mixture (a volume ratio of water, methanol and n-hexane was 100:1:10) and mixed evenly, to obtain material A, and the material A was sealed with nitrogen for later use;
• (2) a reactor 3 was purged with nitrogen five times before reaction, an agitator of the reactor was set at a rotation speed of 100 rpm, the reactor was heated to 25 ° C, and a pressure of the system was set to 0.1 MPaG set; subsequently, by controlling a first flow meter 2 and a second flow meter 11, the material B and the material A were slowly and synchronously added dropwise into the reactor, the space velocity of both the material B and the material A being 14 hr ^-1 , and a reaction subjected while maintaining the temperature and pressure to obtain a reaction liquid; During the reaction process, samples were taken from the reaction system every 10 minutes to analyze the ylide levels and the vitamin A acetate product levels until the ylide levels were stable and the ylide levels were 0.02 mol/L, 0.04 mol /L, 0.05 mol/L, 0.055 mol/L, 0.059 mol/L, 0.060 mol/L, 0.059 mol/L, 0.058 mol/L and 0.060 mol/L, the ylide contents essentially remained at 0.06 mol /L, indicating that the ylide could be rapidly decomposed into the target product during the reaction; and
• (3) the obtained reaction liquid was centrifuged in a centrifuge 4 and filtered to be separated into a solid and a liquid phase, the solid phase was introduced into a by-product storage tank 9 (ie, triphenylphosphine oxide receiving tank), and the liquid phase after sampling and analysis, was introduced into a thin film evaporator 5 and subjected to solvent removal at 30 ° C and 1 kPaA with a residence time controlled at 10 min; then a crude product was introduced into a buffer tank 6, added 1650 mL of ethanol from a recrystallization reagent storage tank 7 and subjected to recrystallization at 3°C; a target product obtained was introduced into a product tank 8, a sample was taken and analyzed for purity, crystallization yield and stability.

Based on the sample, it can be found that after the reaction was stable, the conversion rate of the raw material C15 phosphonium salt was 99.9%, the conversion rate of the ylide was 98.4%, the selectivity of the target product (all-trans) was 86.2 % and the yield of total vitamin A acetate (including all-trans, 11-cis and 9-cis) was 97.4%. The crystals obtained had a purity of 99.9% and a crystallization yield of 94.5%.

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 0.002%/d, and the vitamin A acetate crystals were stored for 7 days Air was stored at an average loss rate of 0.05%/d and the chromaticity value of the liquid was tested at 45 Hazen.

Example 2

• (1) 138 g festes Kaliumcarbonatpulver wurden in einen ersten Rohmaterialtank 1 gegeben, unter Rühren mit 280 mL Wasser versetzt und gleichmäßig gemischt, um Material B zu erhalten; 501,08 g C15-Phosphoniumsalz und 156,2 g C5-Aldehyd wurden in einen zweiten Rohmaterialtank 10 gegeben, mit 2500 mL Lösungsmittelgemisch (das Volumenverhältnis von Wasser, Methanol und n-Hexan betrug 200:1:5) unter Rühren versetzt und gleichmäßig gemischt, um Material A zu erhalten, und das Material A wurde für die spätere Verwendung mit Stickstoff versiegelt;
• (2) ein Reaktor 3 wurde vor der Reaktion fünfmal mit Stickstoff gespült, ein Rührwerk des Reaktors wurde auf eine Rotationsgeschwindigkeit von 300 U/min eingestellt, der Reaktor wurde auf 25°C erwärmt, und ein Druck des Systems wurde auf 1,0 MPaG eingestellt; anschließend wurden durch Steuerung eines ersten Durchflussmessers 2 und eines zweiten Durchflussmessers 11 das Material B und das Material A langsam und synchron tropfenweise in den Reaktor gegeben, wobei die Raumgeschwindigkeit des Materials B und des Materials A jeweils 10 Std^-1 betrug, und einer Reaktion unterzogen, wobei die Temperatur und der Druck beibehalten wurden, um eine Reaktionsflüssigkeit zu erhalten; während des Reaktionsprozesses wurden alle 10 Minuten Proben aus dem Reaktionssystem entnommen, um die Ylidgehalte und die Gehalte an Vitamin-A-Acetat-Produkt zu analysieren, bis die Ylidgehalte stabil waren und die Ylidgehalte betrugen 0,01 Mol/L, 0,03 Mol/L, 0,04 Mol/L, 0,035 Mol/L, 0,036 Mol/L, 0,038 Mol/L, 0,036 Mol/L, 0,035 Mol/L und 0,035 Mol/L, die Ylidgehalte blieben im Wesentlichen bei 0,035 Mol/L, was darauf hinweist, dass das Ylid während der Reaktion schnell in das Zielprodukt zersetzt werden konnte; und
• (3) die erhaltene Reaktionsflüssigkeit wurde durch eine Zentrifuge 4 zentrifugiert und filtriert, um in eine feste und eine flüssige Phase getrennt zu werden, die feste Phase wurde in einen Nebenprodukt-Vorratstank 9 eingeleitet, und die flüssige Phase wurde nach der Probenahme und Analyse in einen Dünnschichtverdampfer 5 eingeleitet und einer Lösungsmittelentfernung bei 35°C und 1 kPaA mit einer auf 12 min gesteuerten Verweilzeit unterzogen; dann wurde ein Rohprodukt in einen Puffertank 6 eingeführt, 1650 mL Ethanol aus einem Rekristallisationsreagenzvorratstank 7 zugeben und einer Rekristallisation bei 14°C unterzogen; ein erhaltenes Zielprodukt wurde in einen Produkttank 8 eingeführt, eine Probe entnommen und auf Reinheit, Kristallisationsausbeute und Stabilität analysiert.

Manufacturing process for vitamin A acetate, its process flow diagram in 1 is shown, the manufacturing process having the following specific steps:

• (1) 138 g of solid potassium carbonate powder was placed in a first raw material tank 1, added with 280 mL of water while stirring, and mixed uniformly to obtain material B; 501.08 g of C15 phosphonium salt and 156.2 g of C5 aldehyde were placed in a second raw material tank 10, added with 2500 mL of solvent mixture (the volume ratio of water, methanol and n-hexane was 200:1:5) with stirring and uniform mixed to obtain material A, and the material A was sealed with nitrogen for later use;
• (2) a reactor 3 was purged with nitrogen five times before the reaction, an agitator of the reactor was set at a rotation speed of 300 rpm, the reactor was heated to 25 ° C, and a pressure of the system was set to 1.0 MPaG set; Subsequently, by controlling a first flow meter 2 and a second flow meter 11, the material B and the material A were slowly and synchronously added dropwise into the reactor, the space velocity of the material B and the material A each being 10 hours ^-1 , and subjected to a reaction , maintaining the temperature and pressure to obtain a reaction liquid; During the reaction process, samples were taken from the reaction system every 10 minutes to analyze the ylide levels and the vitamin A acetate product levels until the ylide levels were stable and the ylide levels were 0.01 mol/L, 0.03 mol /L, 0.04 mol/L, 0.035 mol/L, 0.036 mol/L, 0.038 mol/L, 0.036 mol/L, 0.035 mol/L and 0.035 mol/L, the ylide contents essentially remained at 0.035 mol/L , indicating that the ylide could be rapidly decomposed into the target product during the reaction; and
• (3) the obtained reaction liquid was centrifuged by a centrifuge 4 and filtered to be separated into a solid and a liquid phase, the solid phase was introduced into a by-product storage tank 9, and the liquid phase was discharged after sampling and analysis introduced into a thin film evaporator 5 and subjected to solvent removal at 35°C and 1 kPaA with a residence time controlled at 12 min; then a crude product was introduced into a buffer tank 6, 1650 mL of ethanol was added from a recrystallization reagent storage tank 7, and subjected to recrystallization at 14°C; a target product obtained was introduced into a product tank 8, a sample was taken and analyzed for purity, crystallization yield and stability.

Based on the sample, it can be found that after the reaction was stable, the conversion rate of the raw material C15 phosphonium salt was 100%, the conversion rate of the ylide was 99.5%, the selectivity of the target product (all-trans) was 87.6% and the yield of total vitamin A acetate (including all-trans, 11-cis and 9-cis) was 98.4%. The crystals obtained had a purity of 99.9% and a crystallization yield of 97.5%.

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 for 7 days Air was stored at an average loss rate of 0.03%/d and the chromaticity value of the liquid was tested at 35 Hazen.

Example 3

• (1) 276 g festes Kaliumcarbonatpulver wurden in einen ersten Rohmaterialtank 1 gegeben, mit 5520 mL Wasser unter Rühren versetzt und gleichmäßig gemischt, um Material B zu erhalten; 501,08 g C15-Phosphoniumsalz und 227,2 g C5-Aldehyd wurden in einen zweiten Rohmaterialtank 10 gegeben, mit 1302,5 mL Lösungsmittelgemisch (das Volumenverhältnis von Wasser, Methanol und n-Hexan betrug 200:1:2) unter Rühren zugegeben und gleichmäßig gemischt, um Material A zu erhalten, und das Material A wurde zur späteren Verwendung mit Stickstoff versiegelt;
• (2) ein Reaktor 3 wurde vor der Reaktion fünfmal mit Stickstoff gespült, ein Rührwerk des Reaktors wurde auf eine Rotationsgeschwindigkeit von 400 U/min eingestellt, der Reaktor wurde auf 35°C erwärmt, und ein Druck des Systems wurde auf 50 MPaG eingestellt; Anschließend wurden durch Steuern eines ersten Durchflussmessers 2 und eines zweiten Durchflussmessers 11 das Material B und das Material A langsam und synchron tropfenweise in den Reaktor zugegeben, wobei eine Raumgeschwindigkeit sowohl des Materials B als auch des Materials A 20 Std^-1 betrug, und einer Reaktion unterworfen, wobei die Temperatur und der Druck beibehalten wurden, um eine Reaktionsflüssigkeit zu erhalten; während des Reaktionsprozesses wurden alle 10 Minuten Proben aus dem Reaktionssystem entnommen, um die Ylidgehalte und die Gehalte an Vitamin-A-Acetat-Produkt zu analysieren, bis die Ylidgehalte stabil waren und die Ylidgehalte betrugen 0,03 Mol/L, 0,023 Mol/L, 0,034 Mol/L, 0,055 Mol/L, 0,056 Mol/L, 0,049 Mol/L, 0,051 Mol/L, 0,051 Mol/L und 0,050 Mol/L, die Ylidgehalte blieben im Wesentlichen bei 0,050 Mol/L, was darauf hinweist, dass das Ylid während der Reaktion schnell in das Zielprodukt zersetzt werden konnte; und
• (3) die erhaltene Reaktionsflüssigkeit wurde durch eine Zentrifuge 4 zentrifugiert und filtriert, um in eine feste und eine flüssige Phase getrennt zu werden, die feste Phase wurde in einen Nebenprodukt-Vorratstank 9 eingeleitet, und die flüssige Phase wurde nach der Probenahme und Analyse in einen Dünnschichtverdampfer 5 eingeleitet und einer Lösungsmittelentfernung bei 45°C und 1 kPaA mit einer auf 20 min gesteuerten Verweilzeit unterzogen; anschließend wurde ein Rohprodukt in einen Puffertank 6 eingeleitet, 1650 mL Ethanol aus einem Rekristallisationsreagenz-Lagertank 7 zugeben und einer Rekristallisation bei 20°C unterzogen; ein erhaltenes Zielprodukt wurde in einen Produkttank 8 eingeleitet, eine Probe entnommen und auf Reinheit, Kristallisationsausbeute und Stabilität analysiert.

Manufacturing process for vitamin A acetate, its process flow diagram in 1 is shown, the manufacturing process having the following specific steps:

• (1) 276 g of solid potassium carbonate powder was placed in a first raw material tank 1, added with 5520 mL of water with stirring and mixed uniformly to obtain material B; 501.08 g of C15 phosphonium salt and 227.2 g of C5 aldehyde were placed in a second raw material tank 10, with 1302.5 mL of solvent mixture (the volume ratio of water, methanol and n-hexane was 200:1:2) added with stirring and mixed evenly to obtain material A, and the material A was sealed with nitrogen for later use;
• (2) a reactor 3 was purged with nitrogen five times before reaction, an agitator of the reactor was set at a rotation speed of 400 rpm, the reactor was heated to 35 ° C, and a pressure of the system was set to 50 MPaG; Subsequently, by controlling a first flow meter 2 and a second flow meter 11, the material B and the material A were slowly and synchronously added dropwise into the reactor, with a space velocity of both the material B and the material A being 20 hr ^-1 , and a reaction subjected while maintaining the temperature and pressure to obtain a reaction liquid; During the reaction process, samples were taken from the reaction system every 10 minutes to analyze the ylide levels and the vitamin A acetate product levels until the ylide levels were stable and the ylide levels were 0.03 mol/L, 0.023 mol/L , 0.034 mol/L, 0.055 mol/L, 0.056 mol/L, 0.049 mol/L, 0.051 mol/L, 0.051 mol/L and 0.050 mol/L, the ylide contents remained essentially at 0.050 mol/L, indicating this , that the ylide could be rapidly decomposed into the target product during the reaction; and
• (3) the obtained reaction liquid was centrifuged by a centrifuge 4 and filtered to be separated into a solid and a liquid phase, the solid phase was introduced into a by-product storage tank 9, and the liquid phase was discharged after sampling and analysis introduced into a thin film evaporator 5 and subjected to solvent removal at 45°C and 1 kPaA with a residence time controlled at 20 min; then a crude product was introduced into a buffer tank 6, 1650 mL of ethanol from a recrystallization reagent storage tank 7 was added and subjected to recrystallization at 20 ° C; A target product obtained was introduced into a product tank 8, a sample was taken and analyzed for purity, crystallization yield and stability.

Based on the sample, it can be found that after the reaction was stable, the conversion rate of the raw material C15 phosphonium salt was 99.1%, the conversion rate of the ylide was 98.5%, the selectivity of the target product (all-trans) was 86.5 % and the yield of total vitamin A acetate (including all-trans, 11-cis and 9-cis) was 98.4%. The crystals obtained had a purity of 99.9% and a crystallization yield of 96.5%.

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 0.003%/d, and the vitamin A acetate crystals were stored for 7 days Air was stored at an average loss rate of 0.02%/d and the chromaticity value of the liquid was tested at 31 Hazen.

Example 4

• (1) 88,8 g festes Lithiumcarbonatpulver wurden in einen ersten Rohmaterialtank 1 gegeben, mit 1780 mL Wasser unter Rühren versetzt und gleichmäßig gemischt, um Material B zu erhalten; 501,08 g C15-Phosphoniumsalz und 213 g C5-Aldehyd wurden in einen zweiten Rohmaterialtank 10 gegeben, mit 7500 mL Lösungsmittelgemisch (ein Volumenverhältnis von Wasser, Methanol und n-Hexan war 300:1:1) unter Rühren zugegeben und gleichmäßig gemischt, um Material A zu erhalten, und das Material A wurde zur späteren Verwendung mit Stickstoff versiegelt;
• (2) ein Reaktor 3 wurde vor der Reaktion fünfmal mit Stickstoff gespült, ein Rührwerk des Reaktors wurde auf eine Rotationsgeschwindigkeit von 400 U/min eingestellt, der Reaktor wurde auf 35°C erwärmt, und ein Druck des Systems wurde auf 0,1 MPaG eingestellt; anschließend wurden durch Steuern eines ersten Durchflussmessers 2 und eines zweiten Durchflussmessers 11 das Material B und das Material A langsam und synchron tropfenweise in den Reaktor zugegeben, wobei eine Raumgeschwindigkeit sowohl des Materials B als auch des Materials A 30 Std^-1 betrug, und einer Reaktion unterzogen, wobei die Temperatur und der Druck beibehalten wurden, um eine Reaktionsflüssigkeit zu erhalten; während des Reaktionsprozesses wurden alle 10 Minuten Proben aus dem Reaktionssystem entnommen, um die Ylidgehalte und die Gehalte an Vitamin-A-Acetat-Produkt zu analysieren, bis die Ylidgehalte stabil waren und die Ylidgehalte betrugen 0,02 Mol/L, 0,023 Mol/L, 0,034 Mol/L, 0,045 Mol/L, 0,036 Mol/L, 0,029 Mol/L, 0,028 Mol/L, 0,027 Mol/L und 0,027 Mol/L, die Ylidgehalte blieben im Wesentlichen bei 0,027 Mol/L, was darauf hinweist, dass das Ylid während der Reaktion schnell in das Zielprodukt zersetzt werden konnte; und
• (3) die erhaltene Reaktionsflüssigkeit wurde durch eine Zentrifuge 4 zentrifugiert und filtriert, um in eine feste und eine flüssige Phase getrennt zu werden, die feste Phase wurde in einen Nebenprodukt-Vorratstank 9 eingeleitet, und die flüssige Phase wurde nach der Probenahme und Analyse in einen Dünnschichtverdampfer 5 eingeleitet und einer Lösungsmittelentfernung bei 50°C und 1 kPaA mit einer auf 30 min gesteuerten Verweilzeit unterzogen; dann wurde ein Rohprodukt in einen Puffertank 6 eingeführt, 1650 mL Ethanol aus einem Rekristallisationsreagenzvorratstank 7 zugeben und einer Rekristallisation bei 20°C unterzogen; ein erhaltenes Zielprodukt wurde in einen Produkttank 8 eingeführt, eine Probe entnommen und auf Reinheit, Kristallisationsausbeute und Stabilität analysiert.

Manufacturing process for vitamin A acetate, its process flow diagram in 1 is shown, the manufacturing process having the following specific steps:

• (1) 88.8 g of solid lithium carbonate powder was placed in a first raw material tank 1, added with 1780 mL of water with stirring and mixed uniformly to obtain material B; 501.08 g of C15 phosphonium salt and 213 g of C5 aldehyde were placed in a second raw material tank 10, added with 7500 mL of solvent mixture (a volume ratio of water, methanol and n-hexane was 300:1:1) with stirring and mixed evenly, to obtain material A, and the material A was sealed with nitrogen for later use;
• (2) a reactor 3 was purged with nitrogen five times before the reaction, an agitator of the reactor was set at a rotation speed of 400 rpm, the reactor was heated to 35 ° C, and a pressure of the system was set to 0.1 MPaG set; subsequently, by controlling a first flow meter 2 and a second flow meter 11, the material B and the material A were slowly and synchronously added dropwise into the reactor, with a space velocity of both the material B and the material A being 30 hr ^-1 , and a reaction subjected to maintaining the temperature and pressure to obtain a reaction liquid; During the reaction process, samples were taken from the reaction system every 10 minutes to analyze the ylide levels and the vitamin A acetate product levels until the ylide levels were stable and the ylide levels were 0.02 mol/L, 0.023 mol/L , 0.034 mol/L, 0.045 mol/L, 0.036 mol/L, 0.029 mol/L, 0.028 mol/L, 0.027 mol/L and 0.027 mol/L, the ylide contents remained essentially at 0.027 mol/L, indicating this , that the ylide could be rapidly decomposed into the target product during the reaction; and
• (3) the obtained reaction liquid was centrifuged by a centrifuge 4 and filtered to be separated into a solid and a liquid phase, the solid phase was introduced into a by-product storage tank 9, and the liquid phase was discharged after sampling and analysis introduced into a thin film evaporator 5 and subjected to solvent removal at 50°C and 1 kPaA with a residence time controlled at 30 min; then a crude product was introduced into a buffer tank 6, 1650 mL of ethanol was added from a recrystallization reagent storage tank 7, and subjected to recrystallization at 20°C; a target product obtained was introduced into a product tank 8, a sample was taken and analyzed for purity, crystallization yield and stability.

Based on the sample, it can be found that after the reaction was stable, the conversion rate of the raw material C15 phosphonium salt was 100%, the conversion rate of the ylide was 99.6%, the selectivity of the target product (all-trans) was 89.4% and the yield of total vitamin A acetate (including all-trans, 11-cis and 9-cis) was 97.6%. The crystals obtained had a purity of 98.9% and a crystallization yield of 97.2%.

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 0.0025%/d, and the vitamin A acetate crystals were stored for 7 days stored in air with an average loss rate of 0.0152%/d, and the chromaticity value of the liquid was tested at 25 Hazen.

Comparative example 1

• (1) 106 g festes Natriumcarbonatpulver wurden in einen ersten Rohmaterialtank 1 gegeben, mit 1060 mL Wasser unter Rühren versetzt und gleichmäßig gemischt, um Material B zu erhalten; 501,08 g C15-Phosphoniumsalz und 142 g C5-Aldehyd wurden in einen zweiten Rohmaterialtank 10 gegeben, mit 2500 mL entionisiertem Wasser unter Rühren versetzt und gleichmäßig gemischt, um Material A zu erhalten, und das Material A wurde zur späteren Verwendung mit Stickstoff versiegelt;
• (2) ein Reaktor 3 wurde vor der Reaktion fünfmal mit Stickstoff gespült, ein Rührwerk des Reaktors wurde auf eine Rotationsgeschwindigkeit von 100 U/min eingestellt, der Reaktor wurde auf 25°C erwärmt, und ein Druck des Systems wurde auf 0,1 MPaG eingestellt; anschließend wurden durch Steuern eines ersten Durchflussmessers 2 und eines zweiten Durchflussmessers 11 das Material B und das Material A langsam und synchron tropfenweise in den Reaktor zugegeben, wobei eine Raumgeschwindigkeit sowohl des Materials B als auch des Materials A 14 Std^-1 betrug, und einer Reaktion unterworfen, wobei die Temperatur und der Druck beibehalten wurden, um eine Reaktionsflüssigkeit zu erhalten; während des Reaktionsprozesses wurden alle 10 Minuten Proben aus dem Reaktionssystem entnommen, um die Ylidgehalte und die Gehalte an Vitamin-A-Acetat-Produkt zu analysieren, bis die Ylidgehalte stabil waren und die Ylidgehalte betrugen 0,22 Mol/L, 0,43 Mol/L, 0,84 Mol/L, 0,15 Mol/L, 0,26 Mol/L, 0,30 Mol/L, 0,35 Mol/L, 0,34 Mol/L und 0,32 Mol/L, der Ylidgehalt blieb im Wesentlichen bei 0,33 Mol/L, und
• (3) die erhaltene Reaktionsflüssigkeit wurde in einer Zentrifuge 4 zentrifugiert und filtriert, um in eine feste und eine flüssige Phase getrennt zu werden, die feste Phase wurde in einen Nebenprodukt-Lagertank 9 (d.h., Triphenylphosphinoxid-Aufnahmetank) eingeleitet, und die flüssige Phase wurde nach der Entnahme von Proben und der Analyse in einen Dünnschichtverdampfer 5 eingeleitet und einer Lösungsmittelentfernung bei 30°C und 1 kPaA mit einer auf 10 min gesteuerten Verweilzeit unterzogen; dann wurde ein Rohprodukt in einen Puffertank 6 eingeführt, 1650 mL Ethanol aus einem Rekristallisationsreagenz-Lagertank 7 zugeben und einer Rekristallisation bei 3°C unterzogen; ein erhaltenes Zielprodukt wurde in einen Produkttank 8 eingeführt, eine Probe entnommen und auf Reinheit, Kristallisationsausbeute und Stabilität analysiert.

Manufacturing process for vitamin A acetate, its process flow diagram in 1 is shown, the manufacturing process having the following specific steps:

• (1) 106 g of solid sodium carbonate powder was placed in a first raw material tank 1, added with 1060 mL of water with stirring and mixed uniformly to obtain material B; 501.08 g of C15 phosphonium salt and 142 g of C5 aldehyde were placed in a second raw material tank 10, added with 2500 mL of deionized water with stirring and mixed uniformly to obtain material A, and the material A was sealed with nitrogen for later use ;
• (2) a reactor 3 was purged with nitrogen five times before reaction, an agitator of the reactor was set at a rotation speed of 100 rpm, the reactor was heated to 25 ° C, and a pressure of the system was set to 0.1 MPaG set; then, by controlling a first flow meter 2 and a second flow meter 11, the material B and the material A were slowly and synchronously added dropwise into the reactor, with a space velocity of both the material B and the material A being 14 hr ^-1 , and a reaction subjected while maintaining the temperature and pressure to obtain a reaction liquid; During the reaction process, samples were taken from the reaction system every 10 minutes to analyze the ylide levels and the vitamin A acetate product levels until the ylide levels were stable and the ylide levels were 0.22 mol/L, 0.43 mol /L, 0.84 mol/L, 0.15 mol/L, 0.26 mol/L, 0.30 mol/L, 0.35 mol/L, 0.34 mol/L and 0.32 mol/ L, the ylide content remained essentially at 0.33 mol/L, and
• (3) the obtained reaction liquid was centrifuged in a centrifuge 4 and filtered to be separated into a solid and a liquid phase, the solid phase was introduced into a by-product storage tank 9 (ie, triphenylphosphine oxide receiving tank), and the liquid phase was introduced into a thin film evaporator 5 after taking samples and analysis and one subjected to solvent removal at 30°C and 1 kPaA with a residence time controlled at 10 min; then a crude product was introduced into a buffer tank 6, added 1650 mL of ethanol from a recrystallization reagent storage tank 7, and subjected to recrystallization at 3°C; a target product obtained was introduced into a product tank 8, a sample was taken and analyzed for purity, crystallization yield and stability.

Based on the sample, it can be found that after the reaction was stable, a conversion rate of the raw material C15 phosphonium salt was 96.9%, a conversion rate of the ylide was 59.5%, and during the reaction, a maximum accumulated amount of the Yield was 0.33 mol%/L, indicating that the yield cannot be quickly decomposed into the target product in the reaction system; the selectivity of the target product (all-trans) was 56.2%, and the yield of total vitamin A acetate (including all-trans, 11-cis and 9-cis) was 77.3%. The crystals obtained had a purity of 94.6% and a crystallization yield of 72.9%.

Stability test: The vitamin A acetate crystals obtained in this comparative example were heated and stored at 45°C for 7 days with an average loss rate of 0.012%/d, and the vitamin A acetate crystals were stored for 7 days Air was stored at an average loss rate of 0.04%/d and the chromaticity value of the liquid was tested to 100 Hazen. Unlike Example 1, in Comparative Example 1, water is used as the solvent (first solvent) for the C15 phosphonium salt and the C5 aldehyde, resulting in a slower rate of the decomposition reaction of the ylide and thus excessive enrichment of the ylide intermediate in the reaction system leads; the vitamin A acetate and the by-product triphenylphosphine oxide produced by the decomposition reaction cannot be separated in time and the mass transfer effect is poor; accordingly, the selectivity is reduced, the content of impurities in vitamin A acetate is increased, the crystallization purity and crystallization yield are poor, and the oxidation resistance and thermal stability are drastically reduced.

Comparative example 2

• (1) 106 g festes Natriumcarbonatpulver wurden in einen ersten Rohmaterialtank 1 gegeben, unter Rühren mit 1060 mL Wasser versetzt und gleichmäßig gemischt, um Material B zu erhalten; 501,08 g C15-Phosphoniumsalz und 142 g C5-Aldehyd wurden in einen zweiten Rohmaterialtank 10 gegeben, unter Rühren mit 2500 mL Lösungsmittelgemisch (ein Volumenverhältnis von Wasser, Methanol und n-Hexan war 3:1:10) versetzt und gleichmäßig gemischt, um Material A zu erhalten, und das Material A wurde für die spätere Verwendung mit Stickstoff versiegelt;
• (2) ein Reaktor 3 wurde vor der Reaktion fünfmal mit Stickstoff gespült, ein Rührwerk des Reaktors wurde auf eine Rotationsgeschwindigkeit von 100 U/min eingestellt, der Reaktor wurde auf 25°C erwärmt, und ein Druck des Systems wurde auf 0,1 MPaG eingestellt; anschließend wurden durch Steuern eines ersten Durchflussmessers 2 und eines zweiten Durchflussmessers 11 das Material B und das Material A langsam und synchron tropfenweise in den Reaktor zugegeben, wobei eine Raumgeschwindigkeit sowohl des Materials B als auch des Materials A 14 Std^-1 betrug, und einer Reaktion unterworfen, wobei die Temperatur und der Druck beibehalten wurden, um eine Reaktionsflüssigkeit zu erhalten; während des Reaktionsprozesses wurden alle 10 Minuten Proben aus dem Reaktionssystem entnommen, um die Ylidgehalte und die Gehalte an Vitamin-A-Acetat-Produkt zu analysieren, bis die Ylidgehalte stabil waren und die Ylidgehalte betrugen 0,12 mol/L, 0,13 mol/L, 0,16 mol/L, 0,18 mol/L, 0,19 mol/L, 0,20 mol/L, 0,21 mol/L, 0,20 mol/L und 0,19 mol/L; die Ylidgehalte blieben im Wesentlichen bei 0,20 mol/L; und
• (3) die erhaltene Reaktionsflüssigkeit wurde in einer Zentrifuge 4 zentrifugiert und filtriert, um in eine feste und eine flüssige Phase getrennt zu werden, die feste Phase wurde in einen Nebenprodukt-Lagertank 9 (d.h., Triphenylphosphinoxid-Aufnahmetank) eingeleitet, und die flüssige Phase wurde nach der Entnahme von Proben und der Analyse in einen Dünnschichtverdampfer 5 eingeleitet und einer Lösungsmittelentfernung bei 30°C und 1 kPaA mit einer auf 10 min gesteuerten Verweilzeit unterzogen; dann wurde ein Rohprodukt in einen Puffertank 6 eingeführt, 1650 mL Ethanol aus einem Rekristallisationsreagenz-Lagertank 7 zugeben und einer Rekristallisation bei 3°C unterzogen; ein erhaltenes Zielprodukt wurde in einen Produkttank 8 eingeführt, eine Probe entnommen und auf Reinheit, Kristallisationsausbeute und Stabilität analysiert.

Manufacturing process for vitamin A acetate, its process flow diagram in 1 is shown, the manufacturing process having the following specific steps:

• (1) 106 g of solid sodium carbonate powder was placed in a first raw material tank 1, added with 1060 mL of water while stirring, and mixed uniformly to obtain material B; 501.08 g of C15 phosphonium salt and 142 g of C5 aldehyde were placed in a second raw material tank 10, added with stirring with 2500 mL of solvent mixture (a volume ratio of water, methanol and n-hexane was 3:1:10) and mixed evenly, to obtain material A, and the material A was sealed with nitrogen for later use;
• (2) a reactor 3 was purged with nitrogen five times before reaction, an agitator of the reactor was set at a rotation speed of 100 rpm, the reactor was heated to 25 ° C, and a pressure of the system was set to 0.1 MPaG set; then, by controlling a first flow meter 2 and a second flow meter 11, the material B and the material A were slowly and synchronously added dropwise into the reactor, with a space velocity of both the material B and the material A being 14 hr ^-1 , and a reaction subjected while maintaining the temperature and pressure to obtain a reaction liquid; During the reaction process, samples were taken from the reaction system every 10 minutes to analyze the ylide levels and the vitamin A acetate product levels until the ylide levels were stable and the ylide levels were 0.12 mol/L, 0.13 mol /L, 0.16 mol/L, 0.18 mol/L, 0.19 mol/L, 0.20 mol/L, 0.21 mol/L, 0.20 mol/L and 0.19 mol/ L; the ylide levels essentially remained at 0.20 mol/L; and
• (3) the obtained reaction liquid was centrifuged in a centrifuge 4 and filtered to be separated into a solid and a liquid phase, the solid phase was introduced into a by-product storage tank 9 (ie, triphenylphosphine oxide receiving tank), and the liquid phase after sampling and analysis, was introduced into a thin film evaporator 5 and subjected to solvent removal at 30 ° C and 1 kPaA with a residence time controlled at 10 min; then a crude product was introduced into a buffer tank 6, added 1650 mL of ethanol from a recrystallization reagent storage tank 7, and subjected to recrystallization at 3°C; a target product obtained was introduced into a product tank 8, a sample was taken and analyzed for purity, crystallization yield and stability.

Based on the sample, it can be found that after the reaction was stable, a conversion rate of the raw material C15 phosphonium salt was 93.9%, a conversion rate of the ylide was 67.5%, and during the reaction, a maximum accumulated amount of the Yield was 0.20 mol%/L, indicating that the yield cannot be quickly decomposed into the target product in the reaction system; the selectivity of the target product (all-trans) was 70.7%, and the yield of total vitamin A acetate (including all-trans, 11-cis and 9-cis) was 56.3%. The crystals obtained had a purity of 91.9% and a crystallization yield of 75.4%.

Stability test: The vitamin A acetate crystals obtained in this comparative example were heated and stored at 45°C for 7 days with an average loss rate of 0.012%/d, and the vitamin A acetate crystals were stored for 7 days Air was stored at an average loss rate of 0.07%/d and the chromaticity value of the liquid was tested at 123 Hazen. Different from Example 1, in Comparative Example 2, a large amount of non-polar solvent is used as a solvent for the C15 phosphonium salt and the C5 aldehyde, and a large amount of ylide passes into the organic phase during the reaction process; accordingly, on the one hand, the phase interface has a large mass transfer resistance, and on the other hand, the ylide concentration is low, and the rate of decomposition reaction is low; the ylide intermediates accumulate excessively in the reaction system, the content of impurities in vitamin A acetate is increased, the crystallization purity and crystallization yield are poor, and the oxidation resistance and thermal stability are drastically reduced.

QUOTES INCLUDED IN THE DESCRIPTION

This list of documents listed by the applicant was generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• CN 103044302 A [0004]
• CN 101219983 A [0005]
• CN 1894208 A [0006]
• CN 109651150 A [0063]

Claims (11)

A method of producing vitamin A acetate, comprising: subjecting a C15 phosphonium salt and a C5 aldehyde to an addition reaction in the presence of an alkaline compound to produce an ylide; and subjecting the ylide to a decomposition reaction to obtain the vitamin A acetate; wherein during the reaction process, a content of the ylide in the reaction system is less than or equal to 0.06 mol%/L. Manufacturing process according to Claim 1 , where the C15 phosphonium salt has the structural formula

wherein X is selected from any of Cl, Br, I or HSO ₄ . Manufacturing process according to Claim 1 or 2 , where the molar ratio of the C15 phosphonium salt to the C5 aldehyde is 1: (0.8-2), more preferably 1: (1-1.6). Manufacturing process according to one of the Claims 1 until 3 , wherein the molar ratio of the C15 phosphonium salt to the alkaline compound is 1:(0.5-5), preferably 1:(1-2); preferably the alkaline compound comprises any or a combination of at least two of an inorganic metal salt, a metal hydroxide or ammonia; preferably the inorganic metal salt comprises any or a combination of at least two of a carbonate salt, a bicarbonate salt, a phosphate salt or a hydrogen phosphate salt, more preferably the carbonate salt; preferably the carbonate salt is selected from any one or a combination of at least two of sodium carbonate, potassium carbonate or lithium carbonate; preferably the metal hydroxide comprises any or a combination of at least two of sodium hydroxide, potassium hydroxide or lithium hydroxide. Manufacturing process according to one of the Claims 1 until 4 , wherein the addition reaction and the decomposition reaction are carried out at 10-80°C, preferably 25-75°C; During the reaction process, a content of the ylide in the reaction system is preferably less than or equal to 0.03 mol%/L, more preferably less than or equal to 0.01 mol%/L. Manufacturing process according to one of the Claims 1 until 5 , wherein the manufacturing method comprises the following processes: uniformly mixing the C15 phosphonium salt, the C5 aldehyde and a first solvent to obtain material A; uniformly mixing the alkaline compound with a second solvent to obtain material B; synchronously introducing the material A and the material B into a reaction unit through respective different feed channels and performing a reaction to obtain the vitamin A acetate. Manufacturing process according to Claim 6 , wherein the first solvent is a mixture of a polar solvent and a non-polar solvent; The volume ratio of the polar solvent to the non-polar solvent is preferably (0.5-1000): 1, more preferably (1-500): 1 and even more preferably (10-500): 1; preferably the polar solvent comprises any or a combination of at least two of water, methanol, ethanol, acetone, ethyl acetate, trichloromethane or dichloromethane, more preferably a combination of water and methanol; preferably the non-polar solvent comprises any or a combination of at least two of carbon tetrachloride, cyclohexane, n-hexane, n-heptane, n-pentane or petroleum ether; preferably, based on a mass of the C15 phosphonium salt which is 1 g, the first solvent has a volume of 1-30 mL, more preferably 5-15 mL. Manufacturing process according to Claim 6 or 7 , wherein the second solvent is a protic solvent; preferably the second solvent comprises any or a combination of at least two of water, methanol, ethanol, isopropanol or glycerin; preferably, based on a mass of the alkaline compound which is 1 g, the second solvent has a volume of 1-100 mL, more preferably 10-50 mL; The alkaline compound preferably has a mass % of 1%-90% in material B, more preferably 10%-70%. Manufacturing process according to one of the Claims 6 until 8th , wherein the material A and the material B are introduced into the reaction unit synchronously at a constant speed; preferably the material A and the material B independently of one another have a space velocity of 1-50 h ^-1 , more preferably 5-30 h ^-1 ; The reaction unit preferably has a temperature of 10-50° C., more preferably 20-40° C., before the material is introduced; the reaction is preferably carried out at 10-80° C., more preferably at 25-75° C.; the reaction is preferably carried out at a pressure of 10 kPaA-5 MPaG, more preferably at 50 kPaA-1 MPaG; the reaction is preferably carried out with stirring; Stirring is preferably carried out at a speed of 50-1000 rpm, more preferably 100-800 rpm. Manufacturing process according to one of the Claims 6 until 9 , wherein the production method further comprises a step of post-treatment after completion of the reaction, and the post-treatment successively comprises solid-liquid separation, solvent removal and recrystallization; preferably the solid-liquid separation is carried out by centrifugation and filtration, obtaining a solid phase as a by-product and a liquid phase undergoing solvent removal; The device for solvent removal is preferably a thin-film evaporator; The thin-film evaporator preferably has a boiler temperature of 10-100° C., more preferably 30-50° C.; The thin film evaporator preferably has a pressure of 0.1-10 kPaA, more preferably 1-5 kPaA; The thin film evaporator preferably has a residence time of 1-60 minutes, more preferably 10-30 minutes; preferably the reagent used for recrystallization comprises any or a combination of at least two of toluene, ethyl acetate, acetonitrile, ethanol or isopropanol; based on a mass of the raw product which is 1 g, an amount of 1-100 mL, preferably 5-30 mL, of reagent is preferably used for the recrystallization; Recrystallization is preferably carried out at -10 to 50°C, more preferably at 0 to 30°C. Manufacturing process according to one of the Claims 1 until 10 , wherein the production method particularly comprises the following steps: (1) uniformly mixing the C15 phosphonium salt, the C5 aldehyde and a first solvent to obtain material A; uniformly mixing the alkaline compound with a second solvent to obtain material B; wherein a molar ratio of the C15 phosphonium salt to the C5 aldehyde is 1:(1-1.6) and a molar ratio of the C15 phosphonium salt to the alkaline compound is 1:(1-2); the first solvent is a mixture of a polar solvent and a non-polar solvent in a volume ratio of (1-500):1 and the second solvent is a protic solvent; (2) synchronously introducing the material A and the material B obtained in step (1) into a reaction unit at a constant speed through different feed channels, respectively, with a space velocity of 5-30 h ^-1 , and carrying out a reaction Stir at 25-75°C and at 50 kPaA-1 MPaG to obtain a reaction liquid; wherein during the reaction process, a content of the ylide in the reaction system is less than or equal to 0.06 mol%/L; and (3) performing solid-liquid separation on the reaction liquid obtained in step (2), and performing solvent removal and recrystallization on a resulting liquid phase to obtain the vitamin A acetate.

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