CN113735902A

CN113735902A - C15 phosphine salt isomer and preparation method and application thereof

Info

Publication number: CN113735902A
Application number: CN202111182006.1A
Authority: CN
Inventors: 罗朝辉; 冯兴磊; 郑兵; 曹娜
Original assignee: Wanhua Chemical Group Co Ltd
Current assignee: Wanhua Chemical Group Co Ltd
Priority date: 2021-10-11
Filing date: 2021-10-11
Publication date: 2021-12-03

Abstract

The invention relates to a C15 phosphine salt isomer, a preparation method and an application thereof, wherein the C15 phosphine salt isomer has a structure shown in a formula I: wherein X is selected from halogen atoms or sulfite. The isomer of the C15 phosphine salt is matched with the C15 phosphine salt to form the vitamin A acetate with high selectivity, low impurity content and high crystallization yield.

Description

C15 phosphine salt isomer and preparation method and application thereof

Technical Field

The invention relates to the technical field of materials, in particular to a C15 phosphonium salt isomer and a preparation method and application thereof.

Background

Vitamin A acetate (VA acetate) is an important substance used in the fields of medicines and cosmetics, foods and food supplements, animal nutrition feed additives and the like, and has important functions of maintaining visual function, maintaining epithelial tissue cell health, promoting immunoglobulin synthesis and the like. Various isomers of vitamin A acetate exist in nature, and mainly have structures such as all-trans, 11 cis, 9 cis and 13 cis, wherein all-trans VA acetate has the most physiological activity, and cis VA acetate has lower physiological activity and is not beneficial to crystallization and separation.

The synthesis of the vitamin A acetate generally adopts a C15+ C5 route which is characterized by a Wittig reaction, takes beta-ionone as a raw material, takes an organic phosphine compound to carry out a salt forming reaction to generate a Wittig reagent precursor, and then takes the Wittig reaction with C15 aldehyde under the action of strong alkali to generate the vitamin A acetate.

CN103044302A discloses a method for preparing vitamin A acetate by a one-pot method. The method disclosed by the method comprises the steps of utilizing C14 aldehyde and an intermediate C1 (tetraethyl methylenediphosphonate or tetramethyl methylenediphosphonate) to react under alkaline conditions to generate C15 phosphonate; the C15 phosphonate directly reacts with C5 aldehyde in a one-pot method to prepare vitamin A acetate without separation. The method disclosed by the method combines the two-step Wittig reaction in one pot, has simple process operation, reduces the use and separation of solvents, avoids the drying of C15 phosphonate, has short process flow, reacts at a set temperature, improves the reaction selectivity, avoids a cryogenic operation environment and reduces the energy consumption; meanwhile, the method reduces the waste water discharge, and is economical and environment-friendly. The obtained vitamin A acetate product has high purity, high yield and low cost, and is beneficial to industrial production. The disclosed method needs to use dangerous reagents such as sodium methoxide, sodium ethoxide, potassium tert-butoxide or sodium hydride and the like, and has high requirements on air and moisture control, and the atom utilization rate of the two-step wittig reagent is low and is 20 percent.

CN100455558C discloses a process for the production of vitamin a acetate by reacting beta-vinyl ionol with triphenylphosphine in the presence of sulfuric acid in a solvent mixture consisting of 60-80 wt.% methanol, 10-20 wt.% water and 10-20 wt.% of an aliphatic, cyclic or aromatic hydrocarbon having 5-8 carbon atoms to give beta-ionoethyl triphenyl phosphonium salt, and subsequently performing Wittig reaction with 4-acetoxy-2-methyl-but-2-enal. In the reaction process of the method, because the reaction temperature is difficult to control, a large amount of isomer impurities are generated, the product is difficult to crystallize and separate, the VA acetic ester generated as the subsequent wittig reaction raw material contains more tar, the cis-trans isomer ratio is 7:3, the trans-VA acetic ester content is very low, and the method is not beneficial to industrial production.

In conclusion, the development of the all-trans vitamin A acetate is important, wherein the all-trans vitamin A acetate has high selectivity, small impurity content and high crystallization yield.

Disclosure of Invention

Aiming at the defects of the prior art, the invention aims to provide a C15 phosphine salt isomer and a preparation method and application thereof, wherein the C15 phosphine salt isomer is matched with a C15 phosphine salt to form vitamin A acetate with high selectivity, low impurity content and high crystallization yield.

In order to achieve the purpose, the invention adopts the following technical scheme:

in a first aspect, the present invention provides a C15 isomer of a phosphine salt, wherein the C15 isomer of the phosphine salt has the structure shown in formula i:

wherein X is selected from halogen atoms or sulfite.

The C15 phosphine salt isomer is the isomer of C15 phosphine salt in the prior art, and the C15 phosphine salt isomer can be matched with C15 phosphine salt to form vitamin A acetate with high selectivity, low impurity content and high crystallization yield.

In a second aspect, the present invention provides a method for preparing the C15 phosphine salt isomer according to the first aspect, wherein the method for preparing the C15 phosphine salt isomer comprises the following steps: mixing an organic phosphorus compound, a compound shown as a formula II and a first organic solvent, and then reacting under a heating condition to obtain the C15 phosphonium salt isomer;

the X is selected from a halogen atom or sulfite.

The C15 phosphine salt isomer prepared by the method has higher yield and purity, and is beneficial to further preparing high-performance vitamin A acetate.

Preferably, the reaction temperature is 50-200 ℃, such as 60 ℃, 100 ℃, 120 ℃, 140 ℃, 160 ℃, 180 ℃, further preferably 100-.

Preferably, the pressure of the reaction is 0.05 to 2.0MPa, for example, 0.1MPa, 0.3MPa, 0.5MPa, 0.8MPa, 1MPa, 1.2MPa, 1.5MPa, 1.8MPa, etc., and more preferably 0.1 to 1.0 MPa.

Preferably, the reaction time is 1 to 10h, such as 2h, 4h, 6h, 8h, etc., further preferably 3 to 7 h.

Preferably, the reaction is carried out under stirring conditions.

Preferably, the rotation speed of the stirring is 50 to 1000rpm, 100rpm, 200rpm, 300rpm, 400rpm, 500rpm, 600rpm, 700rpm, 800rpm, 900rpm and the like, for example, further preferably 300rpm and 700 rpm.

Preferably, the organophosphorus contains an aryl group.

Preferably, the organophosphorus compound comprises any one or a combination of at least two of triphenylphosphine, benzyldiamantane-trimethylphosphine, triethylphosphine, tripropylphosphine, triisopropylphosphine, tri-n-butylphosphine, tri-tert-butylphosphine, dicyclopentylbutylphosphine, tricyclopentylphosphine, tricyclohexylphosphine, or tri-n-octylphosphine, wherein typical but non-limiting combinations include: a combination of triphenylphosphine, benzyldiadamantane phosphine trimethylphosphine and triethylphosphine, a combination of tri-n-butylphosphine, tri-t-butylphosphine, dicyclopentylbutylphosphine and tricyclopentylphosphine, a combination of tri-n-butylphosphine, tri-t-butylphosphine, dicyclopentylbutylphosphine, tricyclopentylphosphine, tricyclohexylphosphine and tri-n-octylphosphine, etc., and triphenylphosphine is more preferable.

Preferably, the first organic solvent comprises any one of methanol, ethanol, n-hexane, isopropanol, acetone, dichloromethane or n-heptane, or a combination of at least two thereof, wherein typical but non-limiting combinations include: a combination of methanol and ethanol, a combination of ethanol, n-hexane, and isopropanol, a combination of isopropanol, acetone, dichloromethane, and n-heptane, and the like, and n-heptane is more preferable.

Preferably, the molar ratio of the compound shown in the formula II to the organic phosphine compound is 1 (0.5-5), wherein 0.5-5 can be 1, 2, 3, 4 and the like, and more preferably 1 (1-3).

Preferably, the mass ratio of the organophosphorus compound to the first organic solvent is 1 (0.5-10), wherein 0.5-10 can be 1, 2, 3, 4, 5, 6, 7, 8, 9, etc., and further preferably 1 (1-5).

Preferably, after the reaction under heating condition, the operation of post-treatment is also included.

Preferably, the work-up comprises two operations, a desolventization and a crystallization.

Preferably, the crystallization is carried out in a second organic solvent.

Preferably, the crystallization temperature is 0-50 ℃, such as 5 ℃, 10 ℃, 15 ℃, 20 ℃, 25 ℃, 30 ℃, 35 ℃, 40 ℃, 45 ℃, further preferably 20-35 ℃.

Preferably, the second organic solvent comprises any one of ethyl acetate, toluene, tetrahydrofuran, isopropanol, or ethylene glycol, or a combination of at least two thereof, wherein typical but non-limiting combinations include: a combination of ethyl acetate and toluene, a combination of toluene, tetrahydrofuran and isopropanol, tetrahydrofuran, isopropanol, ethylene glycol and the like, and ethyl acetate is further preferable.

Preferably, the mass ratio of the second organic solvent to the material after solvent removal is (0.5-10):1, wherein 0.5-10 can be 1, 2, 33, 4, 5, 6, 7, 8, 9, etc., and more preferably (1-5): 1.

As a preferred technical scheme, the preparation method comprises the following steps:

step a, mixing an organic phosphorus compound and a first organic solvent according to the mass ratio of 1 (0.5-10), mixing the mixture with a compound shown in a formula II according to the molar ratio of 1 (0.5-5) of the compound shown in the formula II to the organic phosphorus compound, and then reacting for 1-10h at the rotation speed of 50-1000rpm under the conditions that the temperature is 50-200 ℃ and the pressure is 0.05-2.0MPa to obtain a C15 phosphonium salt isomer crude product;

and b, after the solvent of the C15 phosphine salt isomer crude product is removed, mixing a second organic solvent with the material after the solvent removal according to the mass ratio of (0.5-10) to 1, and then crystallizing at 0-50 ℃ to obtain the C15 phosphine salt isomer.

In a third aspect, the invention provides vitamin A acetate, wherein the raw materials for preparing the vitamin A acetate comprise a C15 phosphonium salt composition, a C5 aldehyde and a catalyst;

the C15 phosphine salt composition includes C15 phosphine salt and the C15 phosphine salt isomer described above;

the C15 phosphine salt is a compound shown as a formula III;

wherein X is selected from halogen atoms or sulfite.

The invention uses the C15 phosphine salt isomer and C15 phosphine salt to form a C15 phosphine salt composition which is used as a raw material for preparing vitamin A acetate, and can prepare the vitamin A acetate with high crystallization purity.

Preferably, the mass percentage of the C15 phosphine salt isomer is 0.1% to 10.0%, for example, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0%, etc., based on 100% of the total mass of the C15 phosphine salt composition, and more preferably 0.5% to 5.0%.

The invention takes the total mass of the C15 phosphine salt as 100 percent, the mass percent of the C15 phosphine salt isomer is 0.1 to 10.0 percent, the vitamin A acetate with high crystallization purity can be prepared by the C15 phosphine salt composition under the mixture ratio, the content of the C15 phosphine salt isomer is too low, the proportion of the all-trans C15 phosphine salt to generate 11 cis-form and all-trans VA contents cannot be adjusted, and further, the subsequent crystallization purity is lower and the crystallization yield is poorer due to the increase of the non-all-trans VA content; the content of the C15 phosphine salt isomer was too high, and the conversion of C5 aldehyde decreased and the initial reaction rate decreased for the same reaction time. In addition, the temperature change of the system is extremely large in the dropping reaction process or the heat preservation reaction process, the yield of the total VA acetic ester is reduced, and further, the subsequent crystallization purity is low and the crystallization yield is poor due to the fact that the content of the non-all-trans VA is increased.

Preferably, the molar ratio of the C15 phosphine salt composition to the C5 aldehyde is 1 (0.5-2), wherein 0.5-2 can be 0.6, 0.8, 1, 1.2, 1.4, 1.6, 1.8, etc., and more preferably 1 (1-1.5).

Preferably, the catalyst comprises a basic compound.

Preferably, the basic compound comprises any one of, or a combination of at least two of, inorganic salts of metals, metal hydroxides, aqueous ammonia, or organic salts, wherein typical but non-limiting combinations include: a combination of metal inorganic salt and metal hydroxide, a combination of metal hydroxide, aqueous ammonia and organic salt, a combination of metal inorganic salt, metal hydroxide, aqueous ammonia and organic salt, and the like.

Preferably, the metal inorganic salt comprises any one of a carbonate, bicarbonate, phosphate or hydrogen phosphate or a combination of at least two thereof, wherein typical but non-limiting combinations include: combinations of carbonates and bicarbonates, combinations of bicarbonates, phosphates and bicarbonates, combinations of carbonates, bicarbonates, phosphates and bicarbonates, and the like.

Preferably, the carbonate salt comprises any one of sodium carbonate, potassium carbonate or lithium carbonate, or a combination of at least two thereof, wherein typical but non-limiting combinations include: combinations of sodium carbonate and potassium carbonate, potassium carbonate and lithium carbonate, sodium carbonate, potassium carbonate and lithium carbonate, and the like.

Preferably, the bicarbonate comprises any one of sodium bicarbonate, potassium bicarbonate or lithium bicarbonate, or a combination of at least two of them, wherein a typical but non-limiting combination comprises: combinations of sodium and potassium carbonate, potassium and lithium bicarbonate, sodium, potassium and lithium bicarbonate, and the like.

Preferably, the metal hydroxide comprises any one of lithium hydroxide, sodium hydroxide or potassium hydroxide or a combination of at least two thereof, wherein typical but non-limiting combinations include: combinations of lithium hydroxide and sodium hydroxide, combinations of sodium hydroxide and potassium hydroxide, lithium hydroxide, combinations of sodium hydroxide and potassium hydroxide, and the like.

Preferably, the organic salt comprises sodium methoxide.

Preferably, the molar ratio of the C15 phosphine salt composition to the basic compound is 1 (0.5-5), wherein 0.5-5 can be 1, 2, 3, 4, etc., and more preferably 1 (0.5-2).

In a fourth aspect, the present invention provides a method for preparing vitamin a acetate as described in the third aspect, wherein the method comprises the following steps:

(1) mixing a C15 phosphine salt and a C15 phosphine salt isomer to form a C15 phosphine salt composition;

(2) reacting the C15 phosphonium salt composition with C15 aldehyde under the action of a catalyst to obtain the vitamin A acetate.

The vitamin A acetate crystal prepared by the preparation method has high purity and high crystal yield.

Preferably, the step (2) specifically comprises: mixing the C15 phosphonium salt composition and the C15 aldehyde with a first solvent in sequence to form a first reactant, mixing a catalyst with a second solvent to form a second reactant, dropwise adding the second reactant to the first reactant, and reacting to obtain the vitamin A acetate.

Preferably, the first solvent comprises any one of, or a combination of at least two of, water, methanol, ethanol, isopropanol, or glycerol, wherein typical but non-limiting combinations include: a combination of methanol, ethanol and isopropanol, a combination of ethanol, isopropanol and glycerol, a combination of water, methanol, ethanol, isopropanol and glycerol, and the like, with water being more preferred.

Preferably, the mass ratio of the C15 phosphine salt to the first solvent is 1 (1-20), wherein 1-20 can be 2, 4, 6, 8, 10, 12, 14, 16, 18, etc., and further preferably 1 (5-10).

Preferably, the dropping time of the second reactant is 0.5 to 5 hours, such as 1 hour, 2 hours, 3 hours, 4 hours, etc., and further preferably 1 to 2 hours.

Preferably, the temperature of the reaction is 10 to 100 ℃, such as 20 ℃, 40 ℃, 60 ℃, 80 ℃, and the like, and more preferably 35 to 65 ℃.

Preferably, the reaction time is 0.1 to 5h, such as 1h, 2h, 3h, 4h, etc., further preferably 0.5 to 2 h.

Preferably, the rotation speed of the reaction is 50-800rpm, such as 100rpm, 200rpm, 300rpm, 400rpm, 500rpm, 600rpm, 700rpm, etc., and further preferably 100-500 rpm.

Preferably, the pressure of the reaction is 0.01 to 1.0MPa, for example, 0.1MPa, 0.2MPa, 0.4MPa, 0.5MPa, 0.6MPa, 0.8MPa, etc., and more preferably 0.1 to 0.5 MPa.

Preferably, the reaction further comprises: and standing the system until layering, separating two layers, mixing the low-density first phase with a third solvent, and then carrying out post-treatment.

Preferably, the standing time is 0.1 to 4 hours, such as 0.2 hour, 0.5 hour, 1 hour, 1.5 hour, 2 hours, 2.5 hours, 3 hours, 3.5 hours and the like, and further preferably 0.5 to 2 hours.

Preferably, the third solvent comprises a non-polar solvent.

Preferably, the non-polar solvent comprises an alkane solvent.

Preferably, the non-polar solvent comprises any one of petroleum ether, n-hexane, n-heptane, benzene, toluene, or p-xylene, or a combination of at least two thereof, wherein typical but non-limiting combinations include: a combination of petroleum ether and n-hexane, a combination of n-hexane, n-heptane and benzene, a combination of n-heptane, benzene, toluene and p-xylene, etc., and n-hexane is more preferable.

Preferably, the volume of the third solvent is 10 to 1000mL, for example, 100mL, 200mL, 400mL, 600mL, 800mL, etc., and more preferably 50 to 500mL, based on 1g of the C15 phosphine salt composition.

Preferably, the work-up comprises two operations, solvent removal and crystallization.

Preferably, the solvent removal comprises in particular centrifugation and rectification.

Preferably, the rectification temperature is 10-100 ℃, such as 20 ℃, 40 ℃, 60 ℃, 80 ℃ and the like, preferably 40-80 ℃.

Preferably, the crystallization temperature is-10-50 ℃, such as 2 ℃, 10 ℃, 20 ℃, 30 ℃, 40 ℃, and the like, preferably 0-30 ℃.

Preferably, the crystallizing agent comprises any one of toluene, ethyl acetate, acetonitrile, ethanol or isopropanol, or a combination of at least two thereof, wherein typical but non-limiting combinations include: a combination of toluene and ethyl acetate, a combination of ethyl acetate, acetonitrile and ethanol, a combination of ethyl acetate, acetonitrile, ethanol and isopropanol, and the like, with ethanol being more preferred.

Preferably, the volume of the crystallization reagent is 1 to 100mL, for example, 20mL, 40mL, 60mL, 80mL, etc., more preferably 5 to 50mL, based on the mass of the centrifuged product being 1g of the reagent.

(2) sequentially mixing a C15 phosphonium salt composition and C15 aldehyde with a first solvent to form a first reactant, mixing a catalyst with a second solvent to form a second reactant, dropwise adding the second reactant to the first reactant for 0.5-5h, and reacting at the rotation speed of 50-800rpm for 0.1-5h under the conditions that the temperature is 10-100 ℃ and the pressure is 0.01-1.0 MPa;

and then standing the system for 0.1-4h until layering, separating two layers, mixing the low-density first phase with a third solvent, and then performing solvent removal and crystallization to obtain the vitamin A acetate.

Compared with the prior art, the invention has the following beneficial effects:

(1) the C15 phosphonium salt isomer with the structure has high liquid phase analysis purity of more than 99.0 percent and yield of more than 91.6 percent.

(2) The C15 phosphine salt isomer and the C15 phosphine salt are compounded to form the C15 phosphine salt composition, so that the vitamin A acetate with excellent crystallization purity and crystallization yield can be prepared, the crystallization purity is more than 99.5 percent, and the crystallization yield is more than 95.6 percent.

(3) The raw materials for preparing the vitamin A acetate are calculated by taking the total mass of the C15 phosphine salt composition as 100%, and the purity and the yield of the vitamin A acetate formed by the C15 phosphine salt isomer with the mass percent of 0.1-10.0% are higher.

Drawings

FIG. 1 is a process flow diagram of vitamin A acetate according to the present invention;

FIG. 2 is a liquid chromatogram of a C15 isomer of phosphine salt described in preparation example 1;

FIG. 3 is a nuclear magnetic spectrum of an isomer of the C15 phosphonium salt described in preparation example 1;

FIG. 4 is a liquid chromatogram of a C15 isomer of phosphine salt described in preparation example 6;

FIG. 5 is a liquid chromatogram of a C15 isomer of phosphine salt described in preparation example 7;

wherein, 1-catalyst batching tank; 2-raw material C15 phosphonium salt composition and C15 aldehyde dosing tank; 3-a flow meter; 4-a metering pump; 5-a reaction kettle; 6-a buffer tank; 7-a centrifuge; 8-product tank; 9-rectifying tower.

Detailed Description

For the purpose of facilitating an understanding of the present invention, the present invention will now be described by way of examples. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.

The reagents methanol, ethanol, inorganic carbonate and alkane solvents used in the invention are all purchased from Shanghai Tantake technology, Inc., the organic phosphine is purchased from Aladdin reagent, Inc., and the compound 1 is purchased from Hangzhou Rintai Biotechnology, Inc. The C15 aldehyde and C15 phosphonium salt crystal is purchased from Basv chemical company Limited and has a purity of more than 99 percent.

The molecular formula of the C15 phosphine salt is as follows:

x is selected from Cl, Br, I or HSO₄；

Wherein, when X is Cl, the molecular weight is 501.08 g/mol:

the molecular formula of the raw material C5 aldehyde is as follows, and the molecular weight is 142.0 g/mol:

compound 1: 2- (4-chloro-3-methyl-1, 3-butadiene) yl-1, 3, 3-trimethyl-cyclohex-1-ene having a molecular weight of 238.0g/mol and having the following formula:

compound 2 has the following formula:

compound 3 has the following formula:

preparation example 1

A C15 isomer of a phosphine salt, said C15 isomer of a phosphine salt having the formula:

the liquid chromatogram of the C15 phosphine salt isomer is shown in figure 2, and the nuclear magnetic spectrum is shown in figure 3.

The preparation method of the C15 phosphine salt isomer comprises the following steps:

step a, adding 238.0g (1mol) of compound 1, 262.3g (1mol) of triphenylphosphine and 263g of n-heptane into a reaction kettle, adjusting the pressure of the reaction kettle to be 0.145MPa, heating the reaction system to 100 ℃, reacting for 3 hours at the stirring speed of 300rpm, and sampling and analyzing the C15 phosphonium salt isomer to obtain the yield of 91.0 percent after the reaction is finished;

and step b, adding 650g of ethyl acetate into the reaction solution after the solvent is removed, crystallizing at 25 ℃, and drying to obtain C15 phosphine salt isomer solid with the liquid phase analysis purity of 99.2%.

Preparation example 2

step a, 273.7g of compound 1, 262.3g of triphenylphosphine and 514g of n-heptane are added into a reaction kettle, the pressure of the reaction kettle is adjusted to be 0.197MPa, then the reaction system is heated to 110 ℃, the reaction is carried out for 4 hours under the stirring rotating speed of 400rpm, and the yield of the C15 phosphonium salt isomer is 93.0% by sampling and analyzing after the reaction is finished.

Preparation example 3

step a, adding 285.6g of compound 1, 262.3g of triphenylphosphine and 786g of dichloromethane into a reaction kettle, adjusting the pressure of the reaction kettle to be 0.267MPa, heating the reaction system to 130 ℃, reacting for 5 hours at the stirring speed of 500rpm, and sampling to analyze that the yield of the C15 phosphonium salt isomer is 94.2%.

And step b, after the solvent is removed from the reaction liquid, adding 750g of ethyl acetate, crystallizing at 25 ℃, and drying to obtain C15 phosphine salt isomer solid with the liquid phase analysis purity of 99.0%.

Preparation example 4

step a, adding 297.5g of compound 1, 262.3g of triphenylphosphine and 1310g of n-heptane into a reaction kettle, adjusting the pressure of the reaction kettle to be 0.57MPa, heating the reaction system to 150 ℃, and sampling and analyzing the yield of the C15 phosphonium salt isomer to be 96.0% after reacting for 6 hours at the stirring speed of 500 rpm.

And step b, adding 2500g of ethyl acetate into the reaction solution after the solvent is removed, crystallizing at the temperature of 35 ℃, and drying to obtain a C15 phosphonium salt isomer solid, wherein the liquid phase analysis purity is 99.8%.

Preparation example 5

step a, adding 309.4g of compound 1, 262.3g of triphenylphosphine and 1310g of n-heptane into a reaction kettle, adjusting the pressure of the reaction kettle to be 1.0MPa, heating the reaction system to 160 ℃, and sampling and analyzing the yield of the C15 phosphonium salt isomer to be 98.5% after reacting for 7 hours at the stirring speed of 700 rpm.

And step b, adding 2500g of ethyl acetate into the reaction solution after the solvent is removed, crystallizing at 25 ℃, and drying to obtain C15 phosphine salt isomer solid with the liquid phase analysis purity of 99.6%.

Preparation example 6

the liquid chromatogram of the C15 phosphine salt isomer is shown in FIG. 4.

step a, mixing an organic phosphorus compound and a first organic solvent according to a mass ratio of 1:0.5, mixing the mixture with a compound 2 according to a molar ratio of the compound 2 to the organic phosphorus compound of 1:0.5, and reacting at a temperature of 50 ℃ and a pressure of 2.0MPa at a rotating speed of 50rpm for 10 hours to obtain a C15 phosphine salt isomer crude product, wherein the yield of the C15 phosphine salt isomer is 95.8% by sampling analysis;

and b, after the solvent of the crude product of the C15 phosphonium salt isomer is removed, mixing a second organic solvent with the material after the solvent removal according to the mass ratio of 0.5:1, then crystallizing at 0 ℃, and drying to obtain the C15 phosphonium salt isomer, wherein the liquid phase analysis purity is 99.8%.

The organophosphorus compounds are benzyl diamantane phosphine trimethyl phosphine, triethyl phosphine, tripropyl phosphine, triisopropyl phosphine and tri-n-butyl phosphine which are equal in mass.

The first organic solvent is methanol, ethanol and n-hexane with equal mass.

The second organic solvent is toluene and tetrahydrofuran with equal mass.

Preparation example 7

the liquid chromatogram of the C15 phosphine salt isomer is shown in FIG. 5.

step a, mixing an organic phosphorus compound and a first organic solvent according to a mass ratio of 1:10, mixing the organic phosphorus compound and the first organic solvent with 3 according to a molar ratio of 1:1.5 of the compound 3 to the organic phosphorus compound, and then reacting for 1h at a rotation speed of 1000rpm under the conditions that the temperature is 200 ℃ and the pressure is 0.05MPa to obtain a C15 phosphine salt isomer crude product, wherein the yield of the C15 phosphine salt isomer is 97.4% by sampling analysis;

and b, after the solvent of the crude product of the C15 phosphonium salt isomer is removed, mixing a second organic solvent with the material after the solvent removal according to the mass ratio of (10: 1), then crystallizing at 50 ℃, and drying to obtain the C15 phosphonium salt isomer, wherein the liquid phase analysis purity is 99.8%.

The organophosphorus compounds are tri-tert-butylphosphine, dicyclopentylbutylphosphine, tricyclopentylphosphine, tricyclohexylphosphine and tri-n-octylphosphine which are equal in mass.

The first organic solvent is isopropanol and acetone in a mass ratio of 2: 1.

The second organic solvent is isopropanol and ethylene glycol in a mass ratio of 3: 1.

Example 1

The preparation raw materials of the vitamin A acetate comprise a C15 phosphonium salt composition, C5 aldehyde and a catalyst;

the C15 phosphine salt composition comprises a C15 phosphine salt and a C15 phosphine salt isomer described in preparation example 1, wherein the weight percentage of the C15 phosphine salt is 99.5%, and the weight percentage of the C15 phosphine salt isomer is 0.5%.

The preparation method of the vitamin A acetate comprises the following steps, and the process flow chart is shown in figure 1:

(2) in a catalyst preparation tank 1, referred to as a raw material tank 1 for short, a 33% potassium carbonate solution (wherein the mass of potassium carbonate is 138g, and the mass of deionized water is 280.2g) is prepared, and after uniform stirring, nitrogen sealing is carried out for later use. Adding 5000mL of normal hexane into a material preparation tank 2 of the raw material C15 phosphonium salt composition and C15 aldehyde, which is called the raw material tank 2 for short, and sealing with nitrogen for later use. After nitrogen replacement is carried out on a reaction kettle 5 (with the volume of 10L) for 6 times before reaction, the rotating speed of a stirring paddle of the reaction kettle is adjusted to 200rpm, 501.08g of the C15 phosphonium salt composition, 142g of C15 aldehyde and 2500g of water are added into the reaction kettle and are uniformly stirred, the temperature of the reaction kettle is increased to 35 ℃, the system pressure is adjusted to 0.01MPa, and then alkali liquor is dropwise added into the system to carry out wittig reaction to generate a VA acetic ester product. Adjusting the metering pump 4 on the raw material tank 1, controlling the dropping time to be 0.5h, observing the temperature change of the system, and accurately controlling the temperature of the system in the dropping process to be 35.0-35.5 ℃. After the dropwise addition, the reaction was continued for 0.5h at the reaction temperature. And observing the temperature change of the system, and accurately controlling the temperature of the system to be 36.2-37.3 ℃ in the heat preservation reaction process. The initial reaction rate was calculated to be 0.0033 mol/(g.h.L) by sampling analysis after the dropwise addition reaction for 6 min. After the heat preservation reaction is finished, standing for 0.5h, and discharging the liquid phase with high density through a valve at the bottom of the reaction kettle out through a buffer tank 6. And then adding n-hexane into the reaction kettle once through a flow meter 3, pumping all materials in the reaction kettle into a buffer tank, taking a trace upper layer liquid phase, analyzing the conversion rate of the raw material C15 phosphonium salt by liquid chromatography to be 100%, the selectivity of the target product (all-trans VA acetate) to be 86.2%, the selectivity of 11 cis VA to be 12.3%, the impurity content to be 1.5%, the yield of the total VA acetate to be 98.5% and the yield of the all-trans VA acetate to be 86.2%.

After analysis, the material is fed into a centrifuge 7 for solid-liquid separation, solid triphenylphosphine oxide is retained, and the phosphine oxide compound as a byproduct is simply and completely separated. And the liquid phase containing VA acetic ester is then sent into a rectifying tower 9 to remove the solvent at normal pressure and 45 ℃, and the solvent obtained at the tower top is pumped into a raw material tank 2 for recycling. Pumping the tower bottom liquid into a product tank 8, adding 2500mL of ethanol, reducing the temperature of the system to 5 ℃, and crystallizing to obtain the high-purity VA acetic ester. The purity of the crystal obtained by liquid phase analysis was 99.8%, and the crystal yield was 98.5%.

Example 2

the C15 phosphine salt composition comprises a C15 phosphine salt and a C15 phosphine salt isomer described in preparation example 2, wherein the weight percentage of the C15 phosphine salt is 99.5%, and the weight percentage of the C15 phosphine salt isomer is 0.5%.

(2) in a catalyst preparation tank 1, referred to as a raw material tank 1 for short, 20% potassium carbonate solution (wherein the mass of potassium carbonate is 106g, and the mass of deionized water is 424.0g) is prepared, and after uniform stirring, nitrogen sealing is carried out for later use. Adding 5000mL of normal hexane into a material preparation tank 2 of the raw material C15 phosphonium salt composition and C15 aldehyde, which is called the raw material tank 2 for short, and sealing with nitrogen for later use. After nitrogen replacement is carried out on a reaction kettle 5 (with the volume of 10L) for 6 times before reaction, the rotating speed of a stirring paddle of the reaction kettle is adjusted to 200rpm, 501.08g of the C15 phosphonium salt composition, 142g of C15 aldehyde and 2500g of water are added into the reaction kettle and are uniformly stirred, the temperature of the reaction kettle is increased to 35 ℃, the system pressure is adjusted to 0.1MPa, and then alkali liquor is dropwise added into the system to carry out wittig reaction to generate a VA acetic ester product.

Adjusting the metering pump 4 on the raw material tank 1, controlling the dropping time to be 0.5h, observing the temperature change of the system, and accurately controlling the temperature of the system in the dropping process to be 34.0-36.5 ℃. After the dropwise addition, the reaction was continued for 0.5h at the reaction temperature. And observing the temperature change of the system, and accurately controlling the system temperature to be 36.5-37.5 ℃ in the heat preservation reaction process. The initial reaction rate was calculated to be 0.0029 mol/(g.h.L) by sampling analysis after 6min of dropwise addition reaction. After the heat preservation reaction is finished, standing for 0.5h, and discharging the liquid phase with high density through a valve at the bottom of the reaction kettle out through a buffer tank 6. And then adding n-hexane into the reaction kettle once through a flow meter 3, pumping all materials in the reaction kettle into a buffer tank, taking a trace upper layer liquid phase, analyzing the conversion rate of the raw material C15 phosphonium salt by liquid chromatography to be 100%, the selectivity of the target product (all-trans VA acetate) to be 85.7%, the selectivity of 11 cis VA to be 13.3%, the impurity content to be 1.0%, the yield of the total VA acetate to be 99.0% and the yield of the all-trans VA acetate to be 85.7%.

After analysis, the material is fed into a centrifuge 7 for solid-liquid separation, solid triphenylphosphine oxide is retained, and the phosphine oxide compound as a byproduct is simply and completely separated. And the liquid phase containing VA acetic ester is then sent into a rectifying tower 9 to remove the solvent at normal pressure and 45 ℃, and the solvent obtained at the tower top is pumped into a raw material tank 2 for recycling. Pumping the tower bottom liquid into a product tank 8, adding 3000mL of ethanol, reducing the system temperature to 5 ℃, and crystallizing to obtain the high-purity VA acetic ester. The purity of the crystal obtained by liquid phase analysis was 99.7%, and the crystal yield was 98.3%.

Example 3

the C15 phosphine salt composition comprises a C15 phosphine salt and a C15 phosphine salt isomer described in preparation example 3, wherein the weight percentage of the C15 phosphine salt is 97.5%, and the weight percentage of the C15 phosphine salt isomer is 2.5%.

(2) in a catalyst dosing tank 1, referred to as a raw material tank 1 for short, 10% potassium carbonate solution (wherein the mass of the potassium carbonate is 207g, and the mass of the deionized water is 1863g) is prepared, and after uniform stirring, nitrogen sealing is carried out for later use. Adding 5000mL of normal hexane into a material preparation tank 2 of the raw material C15 phosphonium salt composition and C15 aldehyde, which is called the raw material tank 2 for short, and sealing with nitrogen for later use. After nitrogen replacement is carried out on a reaction kettle 5 (with the volume of 10L) for 6 times before reaction, the rotation speed of a stirring paddle of the reaction kettle is adjusted to 300rpm, 501.08g of the composition of C15 phosphonium salt is added into the reaction kettle, wherein the content of C15 phosphonium salt is 97.5 percent, the content of C15 phosphonium salt isomer is 2.5 percent, 142g of C15 aldehyde and 4008g of water are uniformly stirred, the temperature of the reaction kettle is increased to 45 ℃, the pressure of the system is adjusted to 0.3MPa, and then alkali liquor is dripped into the system to carry out wittig reaction to generate a VA acetate product.

Adjusting the metering pump 4 on the raw material tank 1, controlling the dropping time to be 1.0h, observing the temperature change of the system, and accurately controlling the temperature of the system in the dropping process to be 45.0-46.7 ℃. After the dropwise addition, the reaction was continued for 1.0h at the reaction temperature. And observing the temperature change of the system, and accurately controlling the temperature of the system to be 36.2-37.3 ℃ in the heat preservation reaction process. The initial reaction rate was calculated to be 0.0043 mol/(g.h.L) by sampling analysis after 6min of dropwise addition reaction. After the heat preservation reaction is finished, standing for 1.0h, and discharging the liquid phase with high density through a valve at the bottom of the reaction kettle out through a buffer tank 6. And then adding n-hexane into the reaction kettle once through a flow meter 3, pumping all materials in the reaction kettle into a buffer tank, taking a trace upper layer liquid phase, analyzing the conversion rate of the raw material C15 phosphonium salt by liquid chromatography to be 100%, the selectivity of the target product (all-trans VA acetate) to be 87.6%, the selectivity of 11 cis VA to be 11.4%, the impurity content to be 2.0%, the yield of the total VA acetate to be 98.0% and the yield of the all-trans VA acetate to be 87.6%.

After analysis, the material is fed into a centrifuge 7 for solid-liquid separation, solid triphenylphosphine oxide is retained, and the phosphine oxide compound as a byproduct is simply and completely separated. And the liquid phase containing VA acetic ester is then sent into a rectifying tower 9 to remove the solvent at normal pressure and 65 ℃, and the solvent obtained at the tower top is pumped into a raw material tank 2 for recycling. Pumping the tower bottom liquid into a product tank 8, adding 7000mL of ethanol, reducing the system temperature to 10 ℃, and crystallizing to obtain the high-purity VA acetic ester. The purity of the crystal obtained by liquid phase analysis was 99.5%, and the crystal yield was 98.9%.

Example 4

the C15 phosphine salt composition comprises a C15 phosphine salt and a C15 phosphine salt isomer described in preparation example 4, wherein the weight percentage of the C15 phosphine salt is 95.0%, and the weight percentage of the C15 phosphine salt isomer is 5.0%.

(2) in a catalyst preparation tank 1, referred to as a raw material tank 1 for short, a 50% potassium carbonate solution (wherein the mass of potassium carbonate is 276g, and the mass of deionized water is 276.0g) is prepared, and after uniform stirring, nitrogen sealing is carried out for later use. Adding 4000mL of n-hexane into a material preparation tank 2 of the raw material C15 phosphonium salt composition and C15 aldehyde, which is called the raw material tank 2 for short, and sealing with nitrogen for later use. After nitrogen replacement is carried out on a reaction kettle 5 (with the volume of 10L) for 6 times before reaction, the rotating speed of a stirring paddle of the reaction kettle is adjusted to 500rpm, 501.08g of the composition of C15 phosphonium salt is added into the reaction kettle, wherein the content of C15 phosphonium salt is 95.0.5%, the content of C15 phosphonium salt isomer is 5.0%, 213g of C15 aldehyde and 5000g of water are uniformly stirred, the temperature of the reaction kettle is increased to 65 ℃, the pressure of the system is adjusted to 0.5MPa, and then alkali liquor is dripped into the system to carry out wittig reaction to generate a VA acetate product.

Adjusting the metering pump 4 on the raw material tank 1, controlling the dropping time to be 2.0h, observing the temperature change of the system, and accurately controlling the temperature of the system in the dropping process to be 35.0-35.5 ℃. After the dropwise addition, the reaction was continued for 2.0h at the reaction temperature. And observing the temperature change of the system, wherein the temperature of the system can be accurately controlled to be 64.5-67.5 ℃ in the heat preservation reaction process. The initial reaction rate was calculated to be 0.0079 mol/(g.h.L) by sampling analysis after the dropwise addition reaction for 6 min. After the heat preservation reaction is finished, standing for 2.0h, and discharging the liquid phase with high density through a valve at the bottom of the reaction kettle out through a buffer tank 6. And then adding n-hexane into the reaction kettle once through a flow meter 3, pumping all materials in the reaction kettle into a buffer tank, taking a trace upper layer liquid phase, analyzing the conversion rate of the raw material C15 phosphonium salt by liquid chromatography to be 100%, the selectivity of the target product (all-trans VA acetate) to be 85.2%, the selectivity of 11 cis VA to be 14.3%, the impurity content to be 0.5%, the yield of the total VA acetate to be 99.5% and the yield of the all-trans VA acetate to be 85.2%.

After analysis, the material is fed into a centrifuge 7 for solid-liquid separation, solid triphenylphosphine oxide is retained, and the phosphine oxide compound as a byproduct is simply and completely separated. And the liquid phase containing VA acetic ester is then sent into a rectifying tower 9 to remove the solvent at normal pressure and 80 ℃, and the solvent obtained at the tower top is pumped into a raw material tank 2 for recycling. Pumping the tower bottom liquid into a product tank 8, adding 16.0L of ethanol, reducing the system temperature to 0 ℃, and crystallizing to obtain the high-purity VA acetic ester. The purity of the crystal obtained by liquid phase analysis was 100%, and the crystal yield was 99.5%.

Example 5

the C15 phosphine salt composition comprises a C15 phosphine salt and a C15 phosphine salt isomer described in preparation example 5, wherein the weight percentage of the C15 phosphine salt is 95.0%, and the weight percentage of the C15 phosphine salt isomer is 5.0%.

(2) in a catalyst preparation tank 1, referred to as a raw material tank 1 for short, a 50% potassium carbonate solution (wherein the mass of potassium carbonate is 276g, and the mass of deionized water is 276.0g) is prepared, and after uniform stirring, nitrogen sealing is carried out for later use. Adding 4000mL of n-hexane into a material preparation tank 2 of the raw material C15 phosphonium salt composition and C15 aldehyde, which is called the raw material tank 2 for short, and sealing with nitrogen for later use. After nitrogen replacement is carried out on a reaction kettle 5 (with the volume of 10L) for 6 times before reaction, the rotating speed of a stirring paddle of the reaction kettle is adjusted to 500rpm, 501.08g of the composition of C15 phosphonium salt is added into the reaction kettle, wherein the content of the C15 phosphonium salt is 97.5 percent, the content of the C15 phosphonium salt isomer is 2.5 percent, 213g of C15 aldehyde and 5000g of water are uniformly stirred, the temperature of the reaction kettle is increased to 65 ℃, the system pressure is adjusted to 0.5MPa, and then alkali liquor is dripped into the system to carry out wittig reaction to generate a VA acetate product.

Adjusting the metering pump 4 on the raw material tank 1, controlling the dropping time to be 2.0h, observing the temperature change of the system, and accurately controlling the temperature of the system in the dropping process to be 35.0-36.5 ℃. After the dropwise addition, the reaction was continued for 2.0h at the reaction temperature. And observing the temperature change of the system, and accurately controlling the system temperature to be 62.5-69.5 ℃ in the heat preservation reaction process. The initial reaction rate was calculated to be 0.0076 mol/(g.h.L) by sampling analysis after the dropwise addition reaction for 6 min. After the heat preservation reaction is finished, standing for 2.0h, and discharging the liquid phase with high density through a valve at the bottom of the reaction kettle out through a buffer tank 6. And then adding n-hexane into the reaction kettle once through a flow meter 3, pumping all materials in the reaction kettle into a buffer tank, taking a trace upper layer liquid phase, and analyzing the conversion rate of the raw material C15 phosphonium salt by liquid chromatography, wherein the conversion rate is 99.6%, the selectivity of the target product (all-trans VA acetate) is 88.4%, the selectivity of 11 cis VA is 11.0%, the impurity content is 0.5%, the yield of the total VA acetate is 99.0%, and the yield of the all-trans VA acetate is 88.0%.

After analysis, the material is fed into a centrifuge 7 for solid-liquid separation, solid triphenylphosphine oxide is retained, and the phosphine oxide compound as a byproduct is simply and completely separated. And the liquid phase containing VA acetic ester is then sent into a rectifying tower 9 to remove the solvent at normal pressure and 80 ℃, and the solvent obtained at the tower top is pumped into a raw material tank 2 for recycling. Pumping the tower bottom liquid into a product tank 8, adding 16.0L of ethanol, reducing the system temperature to 0 ℃, and crystallizing to obtain the high-purity VA acetic ester. The purity of the crystal obtained by liquid phase analysis was 99.7%, and the crystal yield was 99.0%.

Example 6

the C15 phosphine salt composition comprises a C15 phosphine salt and a C15 phosphine salt isomer described in preparation example 6, wherein the weight percentage of the C15 phosphine salt is 90.0%, and the weight percentage of the C15 phosphine salt isomer is 10.0%.

(2) preparing 1% alkali liquor (solute is a mixture of potassium hydroxide, sodium methoxide and ammonia water with equal mass) in a raw material tank 1, uniformly stirring, and then sealing with nitrogen for later use. 4000mL of a nonpolar solvent (n-heptane, benzene, and toluene of the same volume) was added to the stock tank 2, and the mixture was purged with nitrogen. After nitrogen replacement is carried out on a reaction kettle 5 (with the volume of 10L) for 6 times before reaction, the rotation speed of a stirring paddle of the reaction kettle is adjusted to 50rpm, the C15 phosphonium salt composition is stirred uniformly in the reaction kettle, wherein the content of the C15 phosphonium salt is 95%, the content of the C15 phosphonium salt isomer is 5%, C15 aldehyde and a first solvent (methanol and ethanol with the same mass) are stirred uniformly, the mass ratio of the C15 phosphonium salt to the first solvent is 1:1, the molar ratio of the C15 phosphonium salt composition to the C5 aldehyde is 1:0.5, the reaction kettle is heated to 100 ℃, the system pressure is adjusted to 0.01MPa, and then alkali liquor is dripped into the system to carry out wittig reaction to generate a product VA acetate.

Adjusting the metering pump 4 on the raw material tank 1, controlling the dropping time to be 2.0h, observing the temperature change of the system, and accurately controlling the temperature of the system in the dropping process to be 35.0-36.5 ℃. After the dropwise addition, the reaction was continued for 2.0h at the reaction temperature. And observing the temperature change of the system, and accurately controlling the system temperature to be 62.5-69.5 ℃ in the heat preservation reaction process. The initial reaction rate was calculated to be 0.0058 mol/(g.h.L) by sampling analysis after 6min of the dropwise addition reaction. After the heat preservation reaction is finished, standing for 2.0h, and discharging the liquid phase with high density through a valve at the bottom of the reaction kettle out through a buffer tank 6. And then adding the nonpolar solvent into the reaction kettle through a flow meter 3 at one time, pumping all materials in the reaction kettle into a buffer tank, taking a trace upper layer liquid phase, and analyzing the conversion rate of the raw material C15 phosphonium salt by liquid chromatography to be 99.4%, the selectivity of the target product (all-trans VA acetate) to be 88.3%, the selectivity of 11 cis VA to be 10.7%, the impurity content to be 1.0%, the yield of the total VA acetate to be 98.4% and the yield of the all-trans VA acetate to be 87.8%.

After analysis, the material is fed into a centrifuge 7 for solid-liquid separation, solid triphenylphosphine oxide is retained, and the phosphine oxide compound as a byproduct is simply and completely separated. And the liquid phase containing VA acetic ester is then sent into a rectifying tower 9 to remove the solvent at normal pressure and 80 ℃, and the solvent obtained at the tower top is pumped into a raw material tank 2 for recycling. Pumping the tower bottom liquid into a product tank 8, adding 8.0L of acetonitrile and 8.0L of toluene, reducing the system temperature to 0 ℃, and crystallizing to obtain the high-purity VA acetic ester. The purity of the crystal obtained by liquid phase analysis was 99.6%, and the crystal yield was 95.6%.

Example 7

the C15 phosphine salt composition comprises a C15 phosphine salt and a C15 phosphine salt isomer described in preparation example 6, wherein the weight percentage of the C15 phosphine salt is 99.9%, and the weight percentage of the C15 phosphine salt isomer is 0.1%.

(2) preparing 80% alkali liquor (solute is mixture of sodium hydrogen phosphate and ammonia water with equal mass) in a raw material tank 1, stirring uniformly, and sealing with nitrogen for later use. 4000mL of a nonpolar solvent (petroleum ether and p-xylene of the same volume) was added to the feed tank 2 and nitrogen-sealed for future use. After nitrogen replacement is carried out on a reaction kettle 5 (with the volume of 10L) for 6 times before reaction, the rotation speed of a stirring paddle of the reaction kettle is adjusted to 50rpm, a C15 phosphonium salt composition is added into the reaction kettle, wherein the content of the C15 phosphonium salt is 99.9%, the content of the C15 phosphonium salt isomer is 0.1%, C15 aldehyde and a first solvent (isopropanol and glycerol with the same mass) are uniformly stirred, wherein the mass ratio of the C15 phosphonium salt to the first solvent is 1:20, the molar ratio of the C15 phosphonium salt composition to the C5 aldehyde is 1:2, the reaction kettle is heated to 10 ℃, the system pressure is adjusted to 0.01MPa, and then alkali liquor is dripped into the system to carry out wittig reaction to generate a product VA acetate.

Adjusting the metering pump 4 on the raw material tank 1, controlling the dropping time to be 2.0h, observing the temperature change of the system, and accurately controlling the temperature of the system in the dropping process to be 35.0-36.5 ℃. After the dropwise addition, the reaction was continued for 2.0h at the reaction temperature. And observing the temperature change of the system, and accurately controlling the system temperature to be 62.5-69.5 ℃ in the heat preservation reaction process. The initial reaction rate was calculated to be 0.0051 mol/(g.h.L) by sampling analysis after 6min of the dropwise addition reaction. After the heat preservation reaction is finished, standing for 2.0h, and discharging the liquid phase with high density through a valve at the bottom of the reaction kettle out through a buffer tank 6. And then adding the nonpolar solvent into the reaction kettle through a flow meter 3 at one time, pumping all materials in the reaction kettle into a buffer tank, taking a trace upper layer liquid phase, and analyzing the conversion rate of the raw material C15 phosphonium salt by liquid chromatography to be 98.5%, the selectivity of the target product (all-trans VA acetate) to be 88.8%, the selectivity of 11 cis VA to be 10.9%, the impurity content to be 0.3%, the yield of the total VA acetate to be 98.2% and the yield of the all-trans VA acetate to be 87.5%.

After analysis, the material is fed into a centrifuge 7 for solid-liquid separation, solid triphenylphosphine oxide is retained, and the phosphine oxide compound as a byproduct is simply and completely separated. And the liquid phase containing VA acetic ester is then sent into a rectifying tower 9 to remove the solvent at normal pressure and 80 ℃, and the solvent obtained at the tower top is pumped into a raw material tank 2 for recycling. Pumping the tower bottom liquid into a product tank 8, adding 8.0L of ethyl acetate and 8.0L of isopropanol, reducing the temperature of the system to 0 ℃, and crystallizing to obtain the high-purity VA acetic ester. The purity of the crystal obtained by liquid phase analysis was 99.6%, and the crystal yield was 98.5%.

Comparative example 1

A vitamin A acetate, wherein the raw materials for preparing the vitamin A acetate comprise a C15 phosphine salt (the C15 phosphine salt isomer is not contained), a C5 aldehyde and a catalyst; the total mass of the C15 phosphine salt in this comparative example is the same as the C15 phosphine salt composition in example 1.

The preparation method of the vitamin A acetate comprises the following steps:

preparing a 33% potassium carbonate solution (wherein the mass of the potassium carbonate is 138g, and the mass of the deionized water is 280.2g) in a raw material tank 1, uniformly stirring, and then carrying out nitrogen sealing for later use. 5000mL of normal hexane is added into the raw material tank 2, and nitrogen sealing is carried out for standby. After nitrogen replacement is carried out on a reaction kettle 5 (with the volume of 10L) for 6 times before reaction, the rotating speed of a stirring paddle of the reaction kettle is adjusted to 200rpm, 501.08g of the C15 phosphonium salt composition is added into the reaction kettle, wherein the content of C15 phosphonium salt is 100%, the content of C15 phosphonium salt isomer is 0%, 142g of C15 aldehyde and 2500g of water are uniformly stirred, the temperature of the reaction kettle is increased to 35 ℃, the system pressure is adjusted to 0.01MPa, and then alkali liquor is dropwise added into the system to carry out wittig reaction to generate a VA acetic ester product.

Adjusting the metering pump 4 on the raw material tank 1, controlling the dropping time to be 0.5h, observing the temperature change of the system, and accurately controlling the temperature of the system in the dropping process to be 35.0-35.5 ℃. After the dropwise addition, the reaction was continued for 0.5h at the reaction temperature. And observing the temperature change of the system, and accurately controlling the temperature of the system to be 36.0-38.1 ℃ in the heat preservation reaction process. The initial reaction rate was calculated to be 0.0025 mol/(g.h.L) by sampling analysis after 6min of dropwise addition reaction. After the heat preservation reaction is finished, standing for 0.5h, and discharging the liquid phase with high density through a valve at the bottom of the reaction kettle. And adding n-hexane into the reaction kettle at one time, pumping all materials in the reaction kettle into a buffer tank, taking a trace upper layer liquid phase, analyzing the conversion rate of the raw material C15 phosphonium salt by liquid chromatography to be 100%, and analyzing the selectivity of the target product (all-trans VA acetate) to be 77.8%, the selectivity of 11 cis VA to be 22.2% and the yield of all-trans VA acetate to be 77.8%.

After analysis, the material is fed into a centrifuge 7 for solid-liquid separation, solid triphenylphosphine oxide is retained, and the phosphine oxide compound as a byproduct is simply and completely separated. And the liquid phase containing VA acetic ester is then pumped into a rectifying tower to remove the solvent at normal pressure and 45 ℃, and the solvent obtained at the tower top is pumped into a raw material tank 2 for recycling. Pumping the tower bottom liquid into a product tank, adding 2500mL of ethanol, reducing the system temperature to 5 ℃, and crystallizing to obtain the high-purity VA acetic ester. The purity of the crystal obtained by liquid phase analysis was 95.6%, and the crystal yield was 90.1%.

Comparative example 2

The comparative example differs from example 1 only in that in the C15 phosphine salt composition, the weight percent of the C15 phosphine salt is 88.0 percent, the weight percent of the C15 phosphine salt isomer is 12.0 percent, the total mass of the comparative example is the same as that of the C15 phosphine salt composition of example 1, and the rest of the preparation process is the same as that of example 1.

In the comparative example, the temperature changes of the system in the dropping reaction process and the heat preservation reaction process are recorded to be 35.2-56.2 ℃ and 55.2-35.2 ℃, respectively, the initial reaction rate is 0.001 mol/(g.h.L) calculated by sampling analysis after 6min of dropping reaction, the reaction rate is reduced by 3 times, the conversion rate of the liquid phase analysis raw material C15 phosphonium salt is 82.9%, the selectivity of all-trans VA acetate is 51.2%, the selectivity of 11 cis VA is 23.3%, the yield of total VA acetate is 61.8%, and the yield of all-trans VA acetate is 42.4%. After the product is crystallized by the same process, the crystal purity is 91.5 percent, and the crystallization yield is 60.5 percent.

Analysis of results

(1) As is clear from preparation examples 1 to 7, the C15 phosphine salt isomer having the structure described above was successfully prepared by the method of the present invention, the yield was 91.6% or more, and the liquid phase analysis purity was 99.0% or more.

(2) As can be seen from comparative example 1, when the content of the C15 phosphine salt isomer in the raw material is 0, the content of the 11 cis-VA obtained by the reaction is as high as 22.2%, which shows that the isomer in the raw material C15 phosphine salt can adjust the proportion of the 11 cis-VA and all-trans VA generated by the all-trans C15 phosphine salt, and further, the subsequent crystallization purity is low and the crystallization yield is poor due to the increase of the non-all-trans VA.

From the results of comparative example 2, it is understood that when the content of the isomer is more than 10.0%, the conversion rate of triphenylphosphine as a raw material is decreased and the initial reaction rate is decreased for the same reaction time. In addition, the temperature change of the system is extremely large in both the dropwise addition reaction process and the heat preservation reaction process, and the total yield of the VA acetic ester is reduced. Further, the non-all-trans VA content is increased, so that the subsequent crystallization purity is low, and the crystallization yield is poor.

In summary, the raw materials for preparing the vitamin A acetate have high purity and yield of the vitamin A acetate formed by the C15 phosphine salt isomer with the mass percentage of 0.1-10.0 percent, wherein the total mass of the C15 phosphine salt composition is 100 percent.

(3) From examples 1 to 7, it is understood that the vitamin A acetate having both of excellent crystal purity and crystal yield of 99.5% or more and 95.6% or more can be prepared by compounding the C15 phosphine salt isomer of the present invention with the C15 phosphine salt to form the C15 phosphine salt composition.

The applicant states that the present invention is illustrated in detail by the above examples, but the present invention is not limited to the above detailed methods, i.e. it is not meant that the present invention must rely on the above detailed methods for its implementation. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.

Claims

1. A C15 isomer of phosphine salt, wherein said C15 isomer of phosphine salt has the structure shown in formula i:

wherein X is selected from halogen atoms or sulfite.

2. A method for preparing the C15 phosphine salt isomer as defined in claim 1, wherein the method for preparing the C15 phosphine salt isomer comprises the steps of: mixing an organic phosphorus compound, a compound shown as a formula II and a first organic solvent, and then reacting under a heating condition to obtain the C15 phosphonium salt isomer;

the X is selected from a halogen atom or sulfite.

3. The method of claim 1 or 2, wherein the reaction temperature is 50 to 200 ℃;

preferably, the pressure of the reaction is 0.05-2.0 MPa;

preferably, the reaction time is 1-10 h;

preferably, the reaction is carried out under stirring conditions;

preferably, the rotation speed of the stirring is 50-1000 rpm;

preferably, the organophosphorus contains an aryl group;

preferably, the organophosphorus compound includes any one or a combination of at least two of triphenylphosphine, benzyldiamantane phosphine trimethylphosphine, triethylphosphine, tripropylphosphine, triisopropylphosphine, tri-n-butylphosphine, tri-tert-butylphosphine, dicyclopentylbutylphosphine, tricyclopentylphosphine, tricyclohexylphosphine, or tri-n-octylphosphine;

preferably, the first organic solvent comprises any one of methanol, ethanol, n-hexane, isopropanol, acetone, dichloromethane or n-heptane or a combination of at least two thereof;

preferably, the molar ratio of the compound shown in the formula II to the organic phosphine compound is 1 (0.5-5);

preferably, the mass ratio of the organophosphorus compound to the first organic solvent is 1 (0.5-10).

4. The method according to claim 2 or 3, characterized in that it further comprises, after the reaction under heating, an operation of post-treatment;

preferably, the post-treatment comprises two operations of desolventizing and crystallizing;

preferably, the crystallization is carried out in a second organic solvent;

preferably, the temperature of the crystallization is 0 to 50 ℃;

preferably, the second organic solvent comprises any one of ethyl acetate, toluene, tetrahydrofuran, isopropanol or ethylene glycol or a combination of at least two thereof;

preferably, the mass ratio of the second organic solvent to the material after solvent removal is (0.5-10): 1.

5. The production method according to any one of claims 2 to 4, characterized by comprising the steps of:

6. The vitamin A acetate is characterized in that raw materials for preparing the vitamin A acetate comprise a C15 phosphonium salt composition, a C5 aldehyde and a catalyst;

the C15 phosphine salt composition comprises a C15 phosphine salt and the C15 phosphine salt isomer of claim 1;

the C15 phosphine salt is a compound shown as a formula III;

wherein X is selected from halogen atoms or sulfite.

7. The vitamin A acetate as claimed in claim 6, wherein the mass percentage of the C15 phosphine salt isomer is 0.1-10.0%, preferably 0.5-5.0%, based on 100% of the total mass of the C15 phosphine salt composition;

preferably, the molar ratio of the C15 phosphine salt composition to the C5 aldehyde is 1 (0.5-2);

preferably, the catalyst comprises a basic compound;

preferably, the basic compound comprises any one of metal inorganic salt, metal hydroxide, ammonia water or organic salt or a combination of at least two of the metal inorganic salt, the metal hydroxide, the ammonia water or the organic salt;

preferably, the metal inorganic salt comprises any one of carbonate, bicarbonate, phosphate or hydrogen phosphate or a combination of at least two thereof;

preferably, the carbonate salt comprises any one of sodium carbonate, potassium carbonate or lithium carbonate or a combination of at least two thereof;

preferably, the bicarbonate comprises any one or a combination of at least two of sodium bicarbonate, potassium bicarbonate, or lithium bicarbonate;

preferably, the metal hydroxide comprises any one of lithium hydroxide, sodium hydroxide or potassium hydroxide or a combination of at least two thereof;

preferably, the organic salt comprises sodium methoxide;

preferably, the molar ratio of the C15 phosphine salt composition to the basic compound is 1 (0.5-5).

8. A process for the preparation of vitamin A acetate according to claim 6 or 7, characterized in that it comprises the following steps:

9. The preparation method according to claim 8, wherein the step (2) specifically comprises: sequentially mixing a C15 phosphonium salt composition and C15 aldehyde with a first solvent to form a first reactant, mixing a catalyst with a second solvent to form a second reactant, dropwise adding the second reactant to the first reactant, and reacting to obtain the vitamin A acetate;

preferably, the first solvent comprises any one of water, methanol, ethanol, isopropanol or glycerol or a combination of at least two thereof;

preferably, the dropping time of the second reactant is 0.5-5 h;

preferably, the temperature of the reaction is 10-100 ℃;

preferably, the reaction time is 0.1-5 h;

preferably, the rotation speed of the reaction is 50-800 rpm;

preferably, the pressure of the reaction is 0.01 to 1.0 MPa;

preferably, the reaction further comprises: standing the system until layering, separating two layers, mixing the low-density first phase with a third solvent, and then carrying out post-treatment;

preferably, the standing time is 0.1-4 h;

preferably, the third solvent comprises a non-polar solvent;

preferably, the non-polar solvent comprises an alkane solvent;

preferably, the non-polar solvent comprises any one or a combination of at least two of petroleum ether, n-hexane, n-heptane, benzene, toluene or p-xylene;

preferably, the volume of the third solvent is 10-1000mL based on 1g of the C15 phosphine salt composition;

preferably, the post-treatment comprises two operations of solvent removal and crystallization;

preferably, the solvent removal specifically comprises centrifugation and rectification;

preferably, the temperature of the rectification is 10-100 ℃;

preferably, the temperature of the crystallization is-10-50 ℃;

preferably, the crystallizing agent comprises any one of toluene, ethyl acetate, acetonitrile, ethanol or isopropanol or a combination of at least two thereof;

preferably, the volume of the crystallized reagent is 1-100mL, based on the mass of the centrifuged product being 1g of reagent.

10. The method of manufacturing according to claim 8 or 9, comprising the steps of: