CN116082206A - Preparation method of vitamin A - Google Patents

Preparation method of vitamin A Download PDF

Info

Publication number
CN116082206A
CN116082206A CN202310000390.1A CN202310000390A CN116082206A CN 116082206 A CN116082206 A CN 116082206A CN 202310000390 A CN202310000390 A CN 202310000390A CN 116082206 A CN116082206 A CN 116082206A
Authority
CN
China
Prior art keywords
methyl
reaction
acetoxy
vitamin
butenal
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202310000390.1A
Other languages
Chinese (zh)
Inventor
吕英东
翟文超
罗朝辉
张涛
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wanhua Chemical Group Co Ltd
Original Assignee
Wanhua Chemical Group Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Wanhua Chemical Group Co Ltd filed Critical Wanhua Chemical Group Co Ltd
Priority to CN202310000390.1A priority Critical patent/CN116082206A/en
Publication of CN116082206A publication Critical patent/CN116082206A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
    • C07C403/06—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms
    • C07C403/08—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms by hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/09—Geometrical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/584—Recycling of catalysts

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention provides a preparation method of vitamin A, wherein pentadecyl phosphonate or pentadecyl phosphonate reacts with 2-methyl-4-acetoxy-2-butenal and alkali to prepare the vitamin A, and the sum of the contents of 2-methyl-3, 4-diacetoxy butyraldehyde and 2-methyl-3-acetoxy-3-butene-1-aldehyde in the 2-methyl-4-acetoxy-2-butenal is 0.02% -0.8%. According to the invention, the content of all-trans vitamin A in the obtained vitamin A crude product is improved by controlling the content of 2-methyl-3, 4-diacetoxy butyraldehyde and 2-methyl-3-acetoxy-3-butene-1-aldehyde in 2-methyl-4-acetoxy-2-butenal.

Description

Preparation method of vitamin A
Technical Field
The invention belongs to the field of fine chemical synthesis, and particularly relates to a method for preparing vitamin A.
Background
Vitamin A is an important nutritional chemical, has the effects of promoting the growth and development of human bodies, and can enhance the resistance to diseases. Simultaneously, the vitamin A is also an important feed additive, and has various physiological functions of promoting the synthesis of immunoglobulin of animals, promoting growth, reproduction and the like. Wherein the physiological activity of the all-trans vitamin A is the highest.
The vitamin A crude product obtained by chemical synthesis contains a plurality of vitamin A isomers, the content of all-trans-vitamin A is usually only 60% -70%, and the high-purity all-trans-vitamin A can be obtained only by crystallization and purification. The vitamin A isomer has solubilization effect on vitamin A, and reduces crystallization yield, and single crystallization yield is not higher than 80%. A large amount of vitamin a and its isomers remain in the crystallization mother liquor, resulting in product loss.
In order to overcome the defects in the existing production process, a preparation method for producing high content of all-trans vitamin A must be found.
Disclosure of Invention
The invention aims to provide a preparation method of vitamin A, which improves the selectivity of all-trans structure of vitamin A by controlling the content of 2-methyl-3, 4-diacetoxy butyraldehyde and 2-methyl-3-acetoxy-3-butene-1-aldehyde in raw material 2-methyl-4-acetoxy-2-butenal.
In order to achieve the above purpose, the invention adopts the following technical scheme:
a preparation method of vitamin A comprises the steps of reacting pentadecaphosphonate or pentadecaphosphonate with 2-methyl-4-acetoxy-2-butenal and alkali to prepare the vitamin A, wherein the sum of the contents of 2-methyl-3, 4-diacetoxy butyraldehyde and 2-methyl-3-acetoxy-3-butene-1-aldehyde in the 2-methyl-4-acetoxy-2-butenal is 0.02% -0.8%, and preferably 0.1% -0.5%.
The structure of the 2-methyl-4-acetoxyl-2-butenal is
Figure BDA0004034239900000021
The structure of the 2-methyl-3, 4-diacetoxy butyraldehyde is
Figure BDA0004034239900000022
The structure of the 2-methyl-3-acetoxyl-3-butene-1-aldehyde is
Figure BDA0004034239900000023
In the invention, 2-methyl-4-acetoxy-2-butenal is synthesized by the following method: (a) 3, 4-diacetyl-1-butene is subjected to hydroformylation reaction under the action of rhodium catalyst to generate 2-methyl-3, 4-diacetoxy butyraldehyde; (b) 2-methyl-3, 4-diacetoxy butyraldehyde reacts under the action of acetic acid and sodium acetate to generate 2-methyl-4-acetoxy-2-butenal.
Wherein, the rhodium catalyst which is preferable in the hydroformylation reaction in the step (a) is rhodium acetylacetonate carbonyl, and the consumption of the rhodium catalyst is 0.01-0.1% of the molar amount of 3, 4-diacetoxy-1-butene calculated by rhodium atoms; the reaction pressure is 2-4 Mpa, the reaction temperature is 60-100 ℃ and the reaction time is 2-4 hours; in the step (b), the dosage of acetic acid is 1-5% of the molar quantity of 2-methyl-3, 4-diacetoxy butyraldehyde, the dosage of sodium acetate is 1-5% of the molar quantity of 2-methyl-3, 4-diacetoxy butyraldehyde, the molar ratio of acetic acid to sodium acetate is 0.5:1-2:1, the reaction temperature is 100-120 ℃, and the reaction time is 2-4 h.
In the reaction of the step (b), controlling the content of 2-methyl-3-acetoxy-3-butene-1-aldehyde in 2-methyl-4-acetoxy-2-butenal by regulating the ratio of acetic acid to sodium acetate; the content of 2-methyl-3, 4-diacetoxybutyraldehyde in 2-methyl-4-acetoxy-2-butenal is controlled by controlling the reaction temperature and the reaction time.
The mechanism for preparing vitamin A by reacting pentadecaphosphonate with 2-methyl-4-acetoxy-2-butenal and alkali is as follows:
Figure BDA0004034239900000031
the mechanism for preparing vitamin A by reacting pentadecaphosphonate with 2-methyl-4-acetoxy-2-butenal and alkali is as follows:
Figure BDA0004034239900000041
wherein the reaction (1) is that pentadecyl phosphonate or pentadecyl phosphonate reacts with alkali to generate ylide; (2) The ylide reacts with 2-methyl-4-acetoxy-2-butenal to generate a four-membered ring intermediate; (3) The four-membered ring intermediate reacts in a reverse 2+2 reaction to form VA and VA isomer.
In the reaction process of step (3) 2+2, a c=c double bond is formed, producing all-trans VA and cis isomers. In the process, 2-methyl-3, 4-diacetoxybutyraldehyde or 2-methyl-3-acetoxy-3-butene-1-aldehyde remotely interacts with the four-membered ring intermediate by using two C=O with similar spatial positions, so that the selectivity of all-trans VA is improved; at the same time, the aldehyde group of 2-methyl-3, 4-diacetoxy butyraldehyde or 2-methyl-3-acetoxy-3-butene-1-aldehyde can react with ylide by 2+2 and subsequent inverse 2+2 to generate non-VA substance. Therefore, the total amount of 2-methyl-3, 4-diacetoxybutyraldehyde or 2-methyl-3-acetoxy-3-butene-1-aldehyde needs to be controlled within a certain range, so that the content of all-trans structure is improved, more byproducts are avoided, and the overall selectivity and yield are improved.
In the present invention, pentadecanophosphonate is
Figure BDA0004034239900000051
R is alkyl of 1 to 6 carbon atoms, preferably pentadeca ethyl phosphonate +.>
Figure BDA0004034239900000052
In the invention, pentadecyl phosphine salt is hydrochloride
Figure BDA0004034239900000053
Hydrobromide->
Figure BDA0004034239900000054
Acetate->
Figure BDA0004034239900000055
Dihydrogen phosphate salt
Figure BDA0004034239900000056
Bisulfate salt->
Figure BDA0004034239900000057
One or more of the following.
In the invention, the molar ratio of pentadecaphosphonate or phosphine salt to 2-methyl-4-acetoxy-2-butenal is 1:1-1:1.1.
In the invention, the alkali is one or more of alkali metal hydride, alkali metal amide, alkali metal alkyl, alkali metal hydroxide, alkali metal alkoxide and alkali metal carbonate; preferably one or more of sodium hydroxide, sodium methoxide, sodium carbonate.
In the invention, the molar ratio of the alkali to the pentadecyl phosphonate or the phosphonate is 1.1:1-1.3:1.
In the present invention, the reaction temperature is 30 to 60 ℃.
In the invention, the solvent is one or more of water, methanol, tetrahydrofuran, dioxane, dimethoxyethane and N, N-dimethylformamide.
In the invention, the solvent dosage is 2-3 times of the mass of pentadecaphosphonate or phosphonate.
In the invention, the reaction time is 0.5-2 h.
In the invention, one of hexane, heptane or petroleum ether (boiling range 60-90 ℃) is used for extraction after the reaction is finished, and the solvent is removed after the extraction liquid is washed to obtain a vitamin A crude product; crystallizing the vitamin A crude product by using methanol or ethanol to obtain a vitamin A product.
Compared with the prior art, the method has the following positive effects:
1. the content of all-trans-vitamin A substances in the vitamin A crude product is higher than 85 percent;
2. the single crystallization yield of vitamin A is higher than 90%.
Detailed Description
The process according to the invention is further illustrated by the following specific examples, but the invention is not limited to the examples listed but encompasses any other known modifications within the scope of the claims.
Major reagent specification and source
Reagent name Reagent specification Manufacturing factories
Pentadecyl carbonPhosphonic acid esters ≥99.5％ Medicine Mingkang De
Pentadeca-phosphine salt ≥98％ Rentai biology
3, 4-diacetoxy-1-butene ≥95％ Sigma of
Sodium methoxide solution 5mol/L methanol solution "Bailingwei
Sodium hydroxide ≥97％ "Bailingwei
Sodium carbonate ≥99.5％ "Bailingwei
Gas Chromatography (GC): model Agilent WAX 1701.42249; the carrier gas is high-purity nitrogen; the sample injection mode is an automatic sample injector; the nitrogen flow is 64.5ml/min; the temperature of the vaporization chamber is 280 ℃; split sample introduction, wherein the split ratio is 1:40; the sample injection amount is 0.2 mu l; the column flow rate was 1.5ml/min; the column temperature is first-order programmed temperature, the initial temperature is 100 ℃, the temperature is kept for 2 minutes, then the temperature is increased to 230 ℃ at the speed of 15 ℃/min, and the temperature is kept for 15 minutes; the total running time is 25.67min; the detector temperature was 300 ℃; and (3) quantifying by an external standard method, wherein the external standard method is used for quantifying 2-methyl-4-acetoxyl-2-butenal by a quantitative analysis method.
High performance liquid analysis (HPLC): shimadzu LC-20A, a SIL-20A autosampler, a CTO-10ASvp column incubator, an SPD-M20A detector, or an instrument with the same performance. Liquid chromatography conditions: sample injection amount is 1 mu L, UV detection wavelength is 328nm, column temperature box: 40 ℃, flow rate: 0.4ml/min. And the external standard method is selected for quantification and is used for quantitative and qualitative analysis of vitamin A.
Nuclear magnetic analysis: bruck Fourier 300 for qualitative analysis.
Example 1
Rhodium acetylacetonate (0.2 mmol) and 3, 4-diacetoxy-1-butene (2 mol) were added to the reaction vessel, the temperature was raised to 100℃and synthesis gas was charged to a pressure of 4MPaG, and the reaction pressure and temperature were maintained for 4 hours. And after the reaction is finished, cooling to room temperature and releasing pressure. To the crude 2-methyl-3, 4-diacetoxybutyraldehyde obtained by distillation was added acetic acid (0.02 mol) and sodium acetate (0.04 mol) under reduced pressure and distilled under 100PaA, and the temperature was raised to 100℃for 2 hours. After the reaction, the reaction mixture was sampled and analyzed, and the sum of the contents of 2-methyl-3, 4-diacetoxybutyraldehyde and 2-methyl-3-acetoxy-3-butene-1-aldehyde in 2-methyl-4-acetoxy-2-butenal was 0.78%.
And (3) separating 2-methyl-4-acetoxyl-2-butenal containing 2-methyl-3, 4-diacetoxybutyraldehyde and 2-methyl-3-acetoxyl-3-butenal by column chromatography to obtain pure products (purity more than or equal to 98%) of the 2-methyl-3, 4-diacetoxybutyraldehyde and the 2-methyl-3-acetoxyl-3-butenal-1-aldehyde respectively, and determining the structure through nuclear magnetism and then using the pure products as a standard product for GC quantitative analysis.
2-methyl-3, 4-diacetoxybutyraldehyde 1 H NMR(300MHz,CDCl3)：δ＝9.68(d,J H-H ＝4.8Hz,1H),4.73(m,1H),4.38(m,2H),3.15(m,1H),2.28(s,3H),2.27(s,3H),1.18(d,J H-H ＝4.5Hz,3H)。
2-methyl-3-acetoxy-3-butene-1-aldehyde 1 H NMR(300MHz,CDCl3)：δ＝9.74(d,J H-H ＝4.8Hz,1H),4.85(d,J H-H ＝6.6Hz,1H),4.41(d,J H-H ＝6.6Hz,1H),3.25(m,1H),2.05(s,3H),0.98(d, 2 J H-H ＝4.5Hz,3H)。
3492 g of 1, 3-double bond pentadecyl phosphonate (1.00 mol), 144g of 2-methyl-4-acetoxy-2-butenal are dissolved in 685g of methanol and the temperature is raised to 30 ℃. 220mL of sodium methoxide solution (5 mol/L) was added dropwise thereto, and the dropping speed was controlled so that the reaction temperature did not exceed 20 ℃. After the completion of the dropwise addition, the temperature was kept at 30℃and the reaction was continued for 2 hours. After the completion of the reaction, 1L of n-hexane was added to the reaction mixture to extract. After the hexane extract was washed with 0.5L of water, the solvent was removed to obtain a yellow oil having a vitamin A content of 95.5% by mass and an all-trans vitamin A content of 89.5% by mass. 0.5L of methanol is added into the solution, the temperature of the methanol solution is gradually reduced to minus 20 ℃ for crystallization, and 290g of VA crystal is obtained after filtration and drying, and the purity is more than or equal to 98 percent.
Example 2
Rhodium acetylacetonate (2 mmol) and 3, 4-diacetoxy-1-butene (2 mol) were added to the reaction vessel, the temperature was raised to 60℃and synthesis gas was charged to a pressure of 2MPaG, and the reaction pressure and temperature were maintained for 3 hours. And after the reaction is finished, cooling to room temperature and releasing pressure. To the crude 2-methyl-3, 4-diacetoxybutyraldehyde obtained by distillation was added acetic acid (0.06 mol) and sodium acetate (0.06 mol) under reduced pressure and distilled 100PaA, and the temperature was raised to 120℃for 3 hours. At the end of the reaction, the sample analysis was performed, and the sum of the contents of 2-methyl-3, 4-diacetoxybutyraldehyde and 2-methyl-3-acetoxy-3-butene-1-aldehyde in 2-methyl-4-acetoxy-2-butenal was 0.49%.
3492 g of 2, 4-two-bond pentadecaphosphonate (1.00 mol), 151g of 2-methyl-4-acetoxy-2-butenal were dissolved in 1000g of DMF and warmed to 30 ℃. 240mL of sodium methoxide solution (5 mol/L) was added dropwise thereto, and the dropping speed was controlled so that the reaction temperature did not exceed 30 ℃. After the completion of the dropwise addition, the temperature was kept at 30℃and the reaction was continued for 1 hour. After the completion of the reaction, 1L of n-hexane was added to the reaction mixture to extract. After washing the hexane extract with 0.5L of water, the solvent was removed to obtain a yellow oil, wherein the mass content of vitamin A and its isomer was 96.8% and the mass content of all-trans vitamin A was 91.3%. 0.5L of ethanol is added into the mixture, the ethanol solution is gradually cooled to the temperature of minus 20 ℃ for crystallization, and then 300g of VA crystal is obtained after filtration and drying, and the purity is more than or equal to 98 percent.
Example 3
Rhodium acetylacetonate (1 mmol) and 3, 4-diacetoxy-1-butene (2 mol) were added to the reaction vessel, the temperature was raised to 80 ℃, synthesis gas was charged to a pressure of 4MPaG, and the reaction pressure and temperature were maintained for reaction for 4 hours. And after the reaction is finished, cooling to room temperature and releasing pressure. To the crude 2-methyl-3, 4-diacetoxybutyraldehyde obtained by distillation was added acetic acid (0.1 mol) and sodium acetate (0.05 mol) under reduced pressure and distilled 100PaA, and the temperature was raised to 120℃for 4 hours. At the end of the reaction, the sample analysis was carried out, and the sum of the contents of 2-methyl-3, 4-diacetoxy butyraldehyde and 2-methyl-3-acetoxy-3-butene-1-aldehyde in 2-methyl-4-acetoxy-2-butenal was 0.023%.
504g pentadecaphosphine hydrochloride (1.00 mol), 148g 2-methyl-4-acetoxy-2-butenal are dissolved in 1000g water and warmed to 60 ℃. 480g of aqueous sodium hydroxide solution (10 wt%) was added dropwise thereto, and the dropping speed was controlled so that the reaction temperature did not exceed 60 ℃. After the completion of the dropwise addition, the temperature was kept at 60℃and the reaction was continued for 0.5h. After the completion of the reaction, 2L of n-heptane was added to the reaction mixture to extract. After washing the extract with 1L of water, the solvent was removed to obtain a yellow oil, wherein the mass content of vitamin A and its isomer was 97.2% and the mass content of all-trans vitamin A was 88.8%. Adding 1L of ethanol into the mixture, gradually cooling the ethanol solution to the temperature of minus 20 ℃ for crystallization, filtering and drying to obtain 295g of VA crystal with the purity of more than or equal to 98 percent.
Example 4
Rhodium acetylacetonate (1 mmol) and 3, 4-diacetoxy-1-butene (2 mol) were added to the reaction vessel, the temperature was raised to 100℃and synthesis gas was charged to a pressure of 4MPaG, and the reaction pressure and temperature were maintained for 3 hours. And after the reaction is finished, cooling to room temperature and releasing pressure. To the crude 2-methyl-3, 4-diacetoxybutyraldehyde obtained by distillation was added acetic acid (0.08 mol) and sodium acetate (0.04 mol) under reduced pressure and distilled at 100PaA, and the temperature was raised to 120℃for 3 hours. After the reaction, the reaction mixture was sampled and analyzed, and the sum of the contents of 2-methyl-3, 4-diacetoxybutyraldehyde and 2-methyl-3-acetoxy-3-butene-1-aldehyde in 2-methyl-4-acetoxy-2-butenal was 0.11%.
546g pentadecaphosphine hydrobromide (1.00 mol), 148g 2-methyl-4-acetoxy-2-butenal were dissolved in 1000g water and warmed to 40 ℃. 680g of an aqueous sodium carbonate solution (1.2 mol) was added dropwise thereto, and the dropping speed was controlled so that the reaction temperature did not exceed 40 ℃. After the completion of the dropwise addition, the temperature was kept at 40℃and the reaction was continued for 2 hours. After the completion of the reaction, 2L of n-heptane was added to the reaction mixture to extract. After washing the extract with 1L of water, the solvent is removed to obtain yellow oily matter, wherein the mass content of vitamin A and isomers thereof is 96.2%, and the mass content of all-trans vitamin A is 90.9%. 1L of methanol is added into the solution, the temperature of the methanol solution is gradually reduced to minus 20 ℃ for crystallization, 298.5g of VA crystal is obtained after filtration and drying, and the purity is more than or equal to 98%.
Example 5
Rhodium acetylacetonate (1 mmol) and 3, 4-diacetoxy-1-butene (2 mol) were added to the reaction vessel, the temperature was raised to 80 ℃, synthesis gas was charged to a pressure of 4MPaG, and the reaction pressure and temperature were maintained for reaction for 4 hours. And after the reaction is finished, cooling to room temperature and releasing pressure. To the crude 2-methyl-3, 4-diacetoxybutyraldehyde obtained by distillation was added acetic acid (0.04 mol) and sodium acetate (0.02 mol) under reduced pressure and distilled 100PaA, and the temperature was raised to 110℃for 3 hours. After the reaction, the reaction mixture was sampled and analyzed, and the sum of the contents of 2-methyl-3, 4-diacetoxybutyraldehyde and 2-methyl-3-acetoxy-3-butene-1-aldehyde in 2-methyl-4-acetoxy-2-butenal was 0.66%.
525g of pentadecaphosphonate acetate (1.00 mol), 152g of 2-methyl-4-acetoxy-2-butenal are dissolved in 1000g of methanol and the temperature is raised to 50 ℃. 560g of aqueous sodium hydroxide solution (1.3 mol) was added dropwise thereto, and the dropping speed was controlled so that the reaction temperature did not exceed 50 ℃. After the completion of the dropwise addition, the temperature was kept at 50℃and the reaction was continued for 1 hour. After the completion of the reaction, 2L of petroleum ether was added to the reaction mixture to extract. After the extract was washed with 1L of water, the solvent was removed to obtain a yellow oil containing 96% by mass of vitamin A and its isomer and 90.3% by mass of all-trans vitamin A. 1L of ethanol is added into the mixture, the ethanol solution is gradually cooled to the temperature of minus 20 ℃ for crystallization, and then the VA crystal 297g is obtained after filtration and drying, and the purity is more than or equal to 98 percent.
Example 6
Rhodium acetylacetonate (1 mmol) and 3, 4-diacetoxy-1-butene (2 mol) were added to the reaction vessel, the temperature was raised to 80 ℃, synthesis gas was charged to a pressure of 4MPaG, and the reaction pressure and temperature were maintained for reaction for 4 hours. And after the reaction is finished, cooling to room temperature and releasing pressure. To the crude 2-methyl-3, 4-diacetoxybutyraldehyde obtained by distillation was added acetic acid (0.02 mol) and sodium acetate (0.04 mol) under reduced pressure and distilled under 100PaA, and the temperature was raised to 120℃to react for 3 hours. After the reaction, the reaction mixture was sampled and analyzed, and the sum of the contents of 2-methyl-3, 4-diacetoxybutyraldehyde and 2-methyl-3-acetoxy-3-butene-1-aldehyde in 2-methyl-4-acetoxy-2-butenal was 0.52%.
567g of pentadecaphosphine bisulfate (1.00 mol), 150g of 2-methyl-4-acetoxy-2-butenal were dissolved in 1000g of tetrahydrofuran, and the temperature was raised to 45 ℃. 560g of aqueous sodium hydroxide solution (1.3 mol) was added dropwise thereto, and the dropping speed was controlled so that the reaction temperature did not exceed 45 ℃. After the completion of the dropwise addition, the temperature was kept at 45℃and the reaction was continued for 2 hours. After the completion of the reaction, 2L of hexane was added to the reaction mixture to extract. After the extract was washed with 1L of water, the solvent was removed to obtain a yellow oil containing vitamin A and its isomer in an amount of 95.9% by mass and all-trans vitamin A in an amount of 89.8% by mass. 1L of methanol is added into the solution, the temperature of the methanol solution is gradually reduced to minus 20 ℃ for crystallization, 294g of VA crystal is obtained after filtration and drying, and the purity is more than or equal to 98 percent.
Comparative example 1
Rhodium acetylacetonate (1 mmol) and 3, 4-diacetoxy-1-butene (2 mol) were added to the reaction vessel, the temperature was raised to 80 ℃, synthesis gas was charged to a pressure of 4MPaG, and the reaction pressure and temperature were maintained for reaction for 4 hours. And after the reaction is finished, cooling to room temperature and releasing pressure. To the crude 2-methyl-3, 4-diacetoxybutyraldehyde obtained by distillation was added acetic acid (0.1 mol) and the temperature was raised to 120℃under reduced pressure, and the reaction was carried out for 6 hours. After the reaction, sampling and analyzing, wherein the sum of the 2-methyl-3, 4-diacetoxy butyraldehyde and the 2-methyl-3-acetoxy-3-butene-1-aldehyde content in the 2-methyl-4-acetoxy-2-butenal is 0.35 percent, and the sum of the 2-methyl-3, 4-diacetoxy butyraldehyde and the 2-methyl-3-acetoxy-3-butene-1-aldehyde content after refining is less than 0.01 percent
565g pentadecaphosphine dihydrogen phosphate (1.00 mol), 148g 2-methyl-4-acetoxy-2-butenal were dissolved in 1000g water and the temperature was raised to 40 ℃. 1378g of an aqueous sodium carbonate solution (10 wt%) was added dropwise thereto, and the dropping speed was controlled so that the reaction temperature did not exceed 40 ℃. After the completion of the dropwise addition, the temperature was kept at 40℃and the reaction was continued for 0.5h. After the completion of the reaction, 2L of petroleum ether was added to the reaction mixture to extract. After washing the extract with 1L of water, the solvent was removed to obtain a yellow oil, wherein the mass content of vitamin A and its isomer was 98.8% and the mass content of all-trans vitamin A was 78.9%. Adding 1L of ethanol into the mixture, gradually cooling the ethanol solution to the temperature of minus 20 ℃ for crystallization, filtering and drying to obtain 238g of VA crystals with the purity of more than or equal to 97 percent.
Comparative example 2
Rhodium acetylacetonate (1 mmol) and 3, 4-diacetoxy-1-butene (2 mol) were added to the reaction vessel, the temperature was raised to 80 ℃, synthesis gas was charged to a pressure of 4MPaG, and the reaction pressure and temperature were maintained for reaction for 4 hours. And after the reaction is finished, cooling to room temperature and releasing pressure. To the crude 2-methyl-3, 4-diacetoxybutyraldehyde obtained by distillation was added acetic acid (0.02 mol) and sodium acetate (0.1 mol) under reduced pressure and distilled under 100PaA, and the temperature was raised to 100℃for 2 hours. After the reaction, the reaction mixture was sampled and analyzed, and the sum of the contents of 2-methyl-3, 4-diacetoxybutyraldehyde and 2-methyl-3-acetoxy-3-butene-1-aldehyde in 2-methyl-4-acetoxy-2-butenal was 2.02%.
349 g of 1, 3-two-bond pentadecyl phosphonate (1.00 mol), 148g of 2-methyl-4-acetoxy-2-butenal are dissolved in 685g of methanol and the temperature is raised to 30 ℃. 220mL of sodium methoxide solution (5 mol/L) was added dropwise thereto, and the dropping speed was controlled so that the reaction temperature did not exceed 30 ℃. After the completion of the dropwise addition, the temperature was kept at 30℃and the reaction was continued for 2 hours. After the completion of the reaction, 1L of n-hexane was added to the reaction mixture to extract. After the hexane extract was washed with 0.5L of water, the solvent was removed to obtain a brown yellow oil having a vitamin A and its isomer mass content of 82.6% and an all-trans vitamin A mass content of 98%. 0.5L of methanol is added into the solution, the temperature of the methanol solution is gradually reduced to minus 20 ℃ for crystallization, and the VA crystal 206g is obtained after filtration and drying, and the purity is more than or equal to 96 percent.
All modifications and equivalent substitutions to the technical proposal of the invention are included in the protection scope of the invention without departing from the scope of the technical proposal of the invention.

Claims (6)

1. A preparation method of vitamin A is characterized in that pentadecyl phosphonate or pentadecyl phosphonate reacts with 2-methyl-4-acetoxy-2-butenal and alkali to prepare vitamin A, wherein the sum of the contents of 2-methyl-3, 4-diacetoxy butyraldehyde and 2-methyl-3-acetoxy-3-butene-1-aldehyde in 2-methyl-4-acetoxy-2-butenal is 0.02% -0.8%, preferably 0.1% -0.5%;
wherein the structure of the 2-methyl-4-acetoxyl-2-butenal is
Figure FDA0004034239890000011
The structure of the 2-methyl-3, 4-diacetoxy butyraldehyde is
Figure FDA0004034239890000012
The structure of the 2-methyl-3-acetoxyl-3-butene-1-aldehyde is
Figure FDA0004034239890000013
2. The preparation method according to claim 1, wherein 2-methyl-4-acetoxy-2-butenal is synthesized by the following method: (a) 3, 4-diacetyl-1-butene is subjected to hydroformylation reaction under the action of rhodium catalyst to generate 2-methyl-3, 4-diacetoxy butyraldehyde; (b) 2-methyl-3, 4-diacetoxy butyraldehyde reacts under the action of acetic acid and sodium acetate to generate 2-methyl-4-acetoxy-2-butenal;
preferably, the rhodium catalyst is rhodium acetylacetonate carbonyl, and the dosage of the rhodium catalyst is 0.01-0.1% of the molar quantity of 3, 4-diacetoxy-1-butene calculated by rhodium atoms;
preferably, in the step (a), the reaction pressure is 2-4 Mpa, the reaction temperature is 60-100 ℃ and the reaction time is 2-4 hours;
preferably, in the step (b), the amount of acetic acid is 1-5% of the molar amount of 2-methyl-3, 4-diacetoxy butyraldehyde, the amount of sodium acetate is 1-5% of the molar amount of 2-methyl-3, 4-diacetoxy butyraldehyde, the molar ratio of acetic acid to sodium acetate is 0.5:1-2:1, the reaction temperature is 100-120 ℃, and the reaction time is 2-4 h.
3. The method according to claim 1, wherein,
preferably, pentadecanophosphonate is
Figure FDA0004034239890000021
R is an alkyl radical of 1 to 6 carbon atoms, preferably +.>
Figure FDA0004034239890000022
Preferably, pentadecylphosphine salt is
Figure FDA0004034239890000023
/>
Figure FDA0004034239890000024
One or more of the following.
4. A process according to any one of claims 1 to 3, wherein the molar ratio of pentadecanophosphonate or phosphonate to 2-methyl-4-acetoxy-2-butenal is from 1:1 to 1:1.1;
preferably, the base is one or more of alkali metal hydride, alkali metal amide, alkali metal alkyl, alkali metal hydroxide, alkali metal alkoxide, alkali metal carbonate; preferably one or more of sodium hydroxide, sodium methoxide, sodium carbonate.
5. The process according to any one of claims 1 to 4, wherein the molar ratio of base to pentadecaphosphonate or phosphonate is from 1.1:1 to 1.3:1;
preferably, the reaction temperature is 30-60 ℃;
preferably, the solvent is one or more of water, methanol, tetrahydrofuran, dioxane, dimethoxyethane and N, N-dimethylformamide;
preferably, the solvent is 2-3 times of the pentadecaphosphonate or phosphonate in mass;
preferably, the reaction time is 0.5 to 2 hours.
6. The preparation method according to any one of claims 1 to 5, wherein the reaction is finished by using hexane, heptane or petroleum ether for extraction, and the solvent is removed after the extraction liquid is washed with water to obtain a crude vitamin A product; crystallizing the vitamin A crude product by using methanol or ethanol to obtain a vitamin A product.
CN202310000390.1A 2023-01-03 2023-01-03 Preparation method of vitamin A Pending CN116082206A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202310000390.1A CN116082206A (en) 2023-01-03 2023-01-03 Preparation method of vitamin A

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202310000390.1A CN116082206A (en) 2023-01-03 2023-01-03 Preparation method of vitamin A

Publications (1)

Publication Number Publication Date
CN116082206A true CN116082206A (en) 2023-05-09

Family

ID=86187854

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202310000390.1A Pending CN116082206A (en) 2023-01-03 2023-01-03 Preparation method of vitamin A

Country Status (1)

Country Link
CN (1) CN116082206A (en)

Similar Documents

Publication Publication Date Title
EP1858903B1 (en) Diarylphenoxy aluminum compounds
US10246430B2 (en) Methods for producing Beraprost and its derivatives
EP2225192B1 (en) Method for producing optically active, racemic menthol
CN105254603B (en) The synthesis technique of SMIA
BR112018015531B1 (en) Process for the preparation of a terpene alcohol mixture and use of a carboxylic acid ester
DE102005061472A1 (en) Process for the preparation of enantiomerically enriched 2-alkoxy-3-phenylpropionic acids
CN112020498A (en) Buvalracetam intermediate, preparation method thereof and preparation method of Buvalracetam
CN115490697B (en) Asymmetric synthesis method of chiral azaspiro [4,5] -decylamine
CN107266294B (en) Method for purifying guaiacol primary product for catalytic synthesis of catechol and methanol
EA021061B1 (en) Process for the production of artemisinin intermediates
JP2019532070A (en) Process for producing 2-alkylalkanols
CN116082206A (en) Preparation method of vitamin A
CN112457229B (en) Preparation method of vitamin A acetate
CH623584A5 (en)
FR2658187A1 (en) NOVEL ALPHA-HYDROXYL ACIDS, PREPARATION METHOD AND USE THEREOF
CN111978195B (en) Method for synthesizing oseltamivir
CN108997117B (en) Novel method for preparing 4-acetoxyl-2-methyl-2-butenal
JP2002121160A (en) Method for producing isopropyl alcohol
CN111377850B (en) Chiral N-substituted-3,3-difluoro-4-hydroxypiperidine derivative and preparation method thereof
RU2529996C2 (en) Method for enantioselective synthesis of (s)-pregabalin
LEONARD et al. Synthesis of 2-Hydroxymethylquinolizidine (dl-2-Lupinine)
WO2023108327A1 (en) Preparation method for light-colored vitamin a
CN112250567A (en) Synthetic method of AMG837 and chiral gamma-methyl phenylpentanol
US2688038A (en) Hydrolysis of methionine nitrile
US2753366A (en) Production of isobutyl alcohol

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination