CN114957069B - Method for preparing all-trans vitamin A acetate - Google Patents
Method for preparing all-trans vitamin A acetate Download PDFInfo
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- C07C403/00—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone
- C07C403/06—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms
- C07C403/12—Derivatives of cyclohexane or of a cyclohexene or of cyclohexadiene, having a side-chain containing an acyclic unsaturated part of at least four carbon atoms, this part being directly attached to the cyclohexane or cyclohexene or cyclohexadiene rings, e.g. vitamin A, beta-carotene, beta-ionone having side-chains substituted by singly-bound oxygen atoms by esterified hydroxy groups
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Abstract
The invention relates to the technical field of medicines and discloses a method for preparing all-trans vitamin A acetate, which is characterized in that 11-cis isomer of vitamin A acetate raw material is subjected to isomerization reaction in the presence of an isomerization catalyst nitrogen-containing free radical catalyst, a first nitrogen-containing organic base or iodine, a second nitrogen-containing organic base and a solvent. The method can effectively improve the yield of all-trans vitamin A acetate by using a small amount of isomerization catalyst, reduce cost and environmental pollution, and can repeatedly convert the vitamin A acetate obtained by Wittig, thereby being beneficial to industrial production.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a method for preparing all-trans vitamin A acetate.
Background
Vitamin A, also called retinol, has the functions of helping growth and reproduction, maintaining normal secretion of bones, epithelial tissues, visual and mucosal epithelium and other physiological functions, has obvious promotion effect on the formation and improvement of vision, is one of nutrients necessary for human body, and is an essential micronutrient in the growth and development process of children. Vitamin A and its analogues have the effect of preventing precancerous lesions. The lack of the ability to adapt to darkness is manifested as growth retardation, and night blindness.
Vitamin A can be extracted from animal tissues, but resources are relatively dispersed, the steps are complicated, and the cost is high, so that the commercial vitamin A is a chemical synthesis product. It is widely used in medicines, nutritional health products, cosmetics, feed additives, etc. Vitamin a (VAc) currently on the market refers to vitamin a acetate.
Many chemists have therefore focused on the synthesis of vitamin a and its derivatives. There are three main processes currently available in the art for isomerising the 11-cis isomer of vitamin a acetate to all-trans vitamin a acetate: iodine catalysis, photocatalysis, and metal catalysis. However, all three methods have certain defects and shortcomings, wherein iodized salt (CN 110204471A) is used as a common iodine catalyst for iodine catalysis, or simple substance iodine is used for catalyzing vitamin A ester (US 3384633A), a large amount of iodine-containing wastewater is generated in the reaction process, and the environmental pollution is serious; the photocatalysis, namely the photoinduction method, needs to add a photosensitizer, and the photosensitizer can cause damage to VAc to a certain extent during the reaction, so that the purity of the product is reduced. And after the reaction reaches equilibrium, the difficulty of removing the photosensitizer by post-treatment is great, and the residual photosensitizer causes pollution of the product (US 03838029). Photosensitizers are typically iodine-or bromine-containing, nitro-containing luciferins that have the adverse effect of carcinogenic mutagenesis on various biological species; the metal catalysis is that the metal iodide (CN 109731612A) can only carry out isomer conversion in a Wittig reaction system, but can not carry out conversion of related vitamin A acetate isomer after the metal iodide is separated from the Wittig reaction system, and can not carry out conversion of cis-isomer in mother liquor after crystallization and separation of the vitamin A acetate. The method also has the problems of low comprehensive utilization, high cost and complex post-treatment steps, is easy to pollute the environment, and still can generate about 20-30% of 11-cis isomer when the all-trans vitamin A acetate product is produced by the Wittig method.
Disclosure of Invention
The invention aims to overcome the problems in the prior art and provide a method for preparing all-trans vitamin A acetate.
To achieve the above object, in one aspect, the present invention provides a method for preparing all-trans vitamin a acetate, the method comprising: carrying out isomerization reaction on the 11-cis isomer of the vitamin A acetate in the presence of an isomerization catalyst and a solvent; wherein the isomerization catalyst comprises a nitrogen-containing free radical catalyst and a first nitrogen-containing organic base or the isomerization catalyst comprises a weight ratio of 1:0.5-1.5 iodine and a second nitrogen-containing organic base.
In a second aspect, the present invention provides a method for preparing all-trans vitamin a acetate, the method comprising: firstly, the quaternary phosphonium salt and the five-carbon aldehyde are contacted to generate a Wittig reaction, the obtained Wittig reaction product is crystallized to obtain a refined all-trans vitamin A acetate and a liquid phase containing 11-cis isomer of the vitamin A acetate, and the liquid phase is treated according to the method to obtain the other part of all-trans vitamin A acetate.
Through the technical scheme, the invention greatly improves the yield of all-trans vitamin A acetate through the use of a small amount of isomerization catalyst, reduces the cost and environmental pollution, can recycle the crystallization filtrate of the Wittig method, improves the content of the all-trans vitamin A acetate finally obtained by the Wittig reaction, can carry out repeated conversion, improves the comprehensive utilization rate, and is beneficial to industrial production.
Detailed Description
The endpoints and any values of the ranges disclosed herein are not limited to the precise range or value, and are understood to encompass values approaching those ranges or values. For numerical ranges, one or more new numerical ranges may be found between the endpoints of each range, between the endpoint of each range and the individual point value, and between the individual point value, in combination with each other, and are to be considered as specifically disclosed herein.
In the present invention, VAc used refers to vitamin A acetate unless otherwise stated.
In a first aspect, the present invention provides a method for preparing all-trans vitamin a acetate, comprising: carrying out isomerization reaction on the 11-cis isomer of the vitamin A acetate in the presence of an isomerization catalyst and a solvent; wherein the isomerization catalyst comprises a nitrogen-containing free radical catalyst and a first nitrogen-containing organic base or the isomerization catalyst comprises a weight ratio of 1:0.5-1.5 iodine and a second nitrogen-containing organic base.
According to the method of the invention, the weight ratio of iodine to the second nitrogen-containing organic base is, for example, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5 or any value between the above values.
According to the process of the present invention, a more preferred mode of isomerising the weight ratio of the nitrogen containing free radical catalyst to the first nitrogen containing organic base in the catalyst is from 1:0.5 to 1.5, such as 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5 or any value between the above values.
According to a more preferred embodiment of the present invention, the nitrogen-containing radical catalyst is azobisisobutyronitrile.
According to a more preferred embodiment of the present invention, the first nitrogen-containing organic base is the same or different from the second nitrogen-containing organic base, preferably the first nitrogen-containing organic base is triethylamine and the second nitrogen-containing organic base is pyridine and N-methylpiperidine.
According to a more preferred embodiment, the amount of the nitrogen-containing free radical catalyst and the first nitrogen-containing organic base or the iodine and second nitrogen-containing organic base isomerization catalyst composition is from 0.1 to 1mg per gram of 11-cis isomer of vitamin a acetate.
The solvent according to the method of the present invention may be various solvents commonly used in the art, for example, a C1-C8 organic solvent, preferably at least one of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tetrahydrofuran, ethylene glycol dimethyl ether, benzene, toluene, xylene, 1, 4-dioxane, cyclohexane, more preferably at least one of ethylene glycol dimethyl ether, cyclohexane and toluene.
According to a preferred embodiment of the present invention, the solvent is used in an amount of 10 to 80% by weight, preferably 60 to 75% by weight, of the isomerization reaction system formed by the isomerization catalyst, the solvent and the 11-cis isomer of vitamin A acetate.
According to the method of the invention, the 11-cis isomer of the vitamin A acetate is provided by a raw material containing the 11-cis isomer of the vitamin A acetate, and the raw material can be an organic phase obtained by diluting a vitamin A acetate crystallization filtrate with water, adding an extracting agent, extracting and separating.
According to the method of the invention, the 11-cis isomer of the vitamin A acetate with a specific content can be used together to obtain higher comprehensive utilization, and according to a preferred embodiment of the invention, the weight content ratio of the 11-cis isomer to the all-trans vitamin A acetate in the raw material containing the 11-cis isomer of the vitamin A acetate is 1:0.1 to 9, preferably 1:0.5-1.5.
According to the method of the invention, the weight content of the water added after the dilution by water is 10-30% of that of the mother liquor.
According to the method of the invention, the extractant is an extractant common in the art, preferably an organic solvent of C4-C8, more preferably at least one of tetrahydrofuran, ethylene glycol dimethyl ether, benzene, toluene, xylene, 1, 4-dioxane and cyclohexane.
According to the process of the present invention, the weight ratio of the amount of the isomerization catalyst to the content of the 11-cis isomer of vitamin a acetate may be 1:500-100000, such as 1:600, 1:700, 1: 800. 1: 1000. 1: 2000. 1: 3000. 1: 4000. 1: 5000. 1: 5500. 1: 6000. 1: 6500. 1: 7000. 1: 7500. 1: 8000. 1: 8500. 1: 9000. 1: 9100. 1: 9200. 1: 9300. 1: 9400. 1: 9500. 1: 9600. 1: 9700. 1: 9800. 1:9900 or any value between the above values, preferably 1:1000-10000. The method can obtain better isomerization effect under the condition of lower isomerization catalyst dosage.
According to the method of the invention, the isomerization conditions include: the reaction temperature is 10-80 ℃ and the reaction time is 0.5-8h.
According to a more preferred embodiment of the invention, the reaction temperature is 30-50℃and the reaction time is 1-5h.
According to the process of the invention, the isomerisation reaction is generally carried out in the absence of light.
According to the method of the invention, the method further comprises: and washing, reduced pressure distillation and crystallization are sequentially carried out on the product obtained by the isomerization reaction.
According to the method of the present invention, the solvent used for washing and crystallization is water or a 30-80% lower alcohol aqueous solution. The lower alcohol may be a lower alcohol commonly used in the art, for example a monohydric alcohol selected from C1-C3, preferably at least one of methanol, ethanol, isopropanol, more preferably the crystallization solvent is isopropanol. The inventors of the present invention have found that the use of a preferred crystallization solvent further increases the molar ratio of 11-cis-VAc to all-trans-VAc in the final VAc solid.
According to the method of the present invention, the solvent is used in an amount of 10% to 30% by weight based on the total weight of the reaction solution in order to reduce the loss caused by washing, and the washing may be performed 1 to 2 times.
According to the process of the invention, the temperature of the reduced pressure distillation is from 0 to 80 ℃, preferably from 20 to 60 ℃. Distillation was stopped when the reduced pressure distilled to a solvent content of less than 3% by volume (tracked using gas chromatography).
According to the method of the present invention, the crystallization is carried out at a temperature of-50 to 0 ℃ for a time of 2 to 8 hours, preferably at a temperature of-30 to-5 ℃ for a time of 3 to 5 hours.
In addition, the invention also provides a method for preparing all-trans vitamin A acetate, which comprises the following steps: firstly, the quaternary phosphonium salt and the five-carbon aldehyde are contacted to generate a Wittig reaction, and the obtained Wittig reaction product is crystallized to obtain a refined all-trans vitamin A acetate and a liquid phase containing 11-cis isomer of the vitamin A acetate, and the liquid phase is treated according to the method to obtain the other part of all-trans vitamin A acetate.
According to the method of the invention, the molar ratio of all-trans-VAc to 11-cis-VAc in the reaction product after the Wittig reaction is finished is 1:0.2-0.4.
According to the method of the invention, the ratio of VAc to cis-trans in the residual solution after crystallization of the reaction product obtained by the Wittig reaction is preferably 1:0.5-1.
According to the method of the invention, the reaction process of the Wittig reaction is as follows:
according to the method of the present invention, the temperature at which the Wittig reaction product is crystallized may be from-30 ℃ to-40 ℃, and the solvent for crystallization may be a C1-C8 organic solvent, preferably at least one of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tetrahydrofuran, ethylene glycol dimethyl ether, benzene, toluene, xylene, 1, 4-dioxane, cyclohexane, more preferably methanol and ethanol.
According to the method of the invention, the solution can be recovered and reused, and the final crystallized product can be reused in the method of the invention.
According to the invention, the 11-cis isomer and all-trans VAc of vitamin A acetate are qualitatively tested by nuclear magnetic resonance and quantitatively tested by high performance liquid chromatograph. The 11-cis isomer of vitamin A acetate and all-trans VAc are subjected to silica gel column chromatography purification and then are detected by a machine. In 400MHz nuclear magnetic resonance hydrogen spectrum, the 11-cis isomer of vitamin a acetate shows d peak at 6.43PPM, calculated j=12.0 Hz; while the dd peak appears at 6.64PPM in all-trans VAc, and J is calculated 1 ＝15.0Hz，J 2 =11.4 Hz, and the nuclear magnetic solvent for detection was deuterated chloroform.
According to a particularly preferred embodiment of the invention, water is added to a VAc crystallization methanol mother liquor having a VAc cis-trans molar ratio of 1:0.5-1 in an amount of 10% to 30% of the mother liquor to precipitate VAc solids to form an emulsion. Then cyclohexane is added for extraction, and an ether phase is separated. Extracting the water phase with cyclohexane once again, and combining the organic phases of the two times; after the organic phase is transferred and replaced by nitrogen, cyclohexane solution of azodiisobutyronitrile and triethylamine (the concentration of azodiisobutyronitrile is 0.3-0.4mol/L, the dosage of the mixed solution is 0.3-0.7mL relative to each milliliter of the organic phase) is rapidly injected, wherein the weight ratio of the azodiisobutyronitrile to the triethylamine is 1:0.8-1.2. The reaction solution is shaded and reacts for 2 to 4 hours at the temperature of 30 to 50 ℃ to obtain the 11-cis-vitamin A acetate and trans-VAc mixed solution.
In the present invention, the VAc refers to vitamin a acetate, unless otherwise stated.
The present invention will be described in detail by examples. In the following examples, the 11-cis isomer and trans VAc parameters of vitamin A acetate were measured by nuclear magnetic resonance and HPLC methods, respectively, after purification and separation; the nuclear magnetic resonance system is Bruker 400MHz, and the HPLC detection system is Ultimate 3000; the 11-cis isomer of vitamin A acetate is obtained by crystallizing and filtering the filtrate after the reaction of quaternary phosphonium salt and pentacarbon aldehyde.
Nuclear magnetic resonance testing method
Purifying 11-cis isomer and all-trans VAc of vitamin A acetate by column chromatography, eluting with commercially available yellow sea 200-300 mesh silica gel with normal hexane as mobile phase, and distilling the obtained pure mobile phase under reduced pressure to obtain all-trans vitamin A acetate and 11-cis vitamin A acetate. Taking 5mg of each of the two pure products, adding solvent deuterated chloroform, performing nuclear magnetic resonance hydrogen spectrum detection at 400MHz, performing qualitative analysis, and calculating J=12.0 Hz when d peak appears at 6.43PPM of 11-cis isomer of vitamin A acetate; the dd peak appears at 6.64PPM of all-trans VAc, and J is calculated 1 ＝15.0Hz，J 2 =11.4 Hz. The structures of the 11-cis isomer and the all-trans VAc of the vitamin A acetate are determined by the peak position of the hydrogen spectrum and the calculated coupling constant, which shows that the sample does contain the 11-cis VAc and the all-trans VAc.
HPLC test method:
the obtained all-trans vitamin A acetate and 11-cis vitamin A acetate were scaled by HPLC and added with acetonitrile as a solvent, and quantitatively analyzed on a high performance liquid chromatograph by a high performance chromatographic column, and retention times of the two were 21.1 minutes and 22.0 minutes, respectively. The 11-cis isomer of the vitamin A acetate and the all-trans VAc are obtained according to the separation and the distinction of the retention time to obtain the molar ratio.
Retention time calculation formula: rt=t0 (1+kvs/Vm), where Rt represents the retention time of a substance, and t0 is the dead time of the chromatographic system, i.e. the time from the mobile phase entering the chromatographic column to the mobile phase exiting the chromatographic column, which is determined by factors such as the pore of the chromatographic column, the flow rate of the mobile phase, etc. K is the partition coefficient, vs, vm represents the volumes of the stationary phase and the mobile phase.
Example 1
(1) The VAc crystallization methanol mother liquor (500 g, total VAc content 7.05 wt%) was placed in a 1000ml separatory funnel.
(2) 100g of water was added to the separatory funnel of step (1) and the VAc solids separated out to form an emulsion. 150g of ethylene glycol dimethyl ether was then added to extract the mixture, and an ether phase was separated. The aqueous phase was again extracted once with 50g of ethylene glycol dimethyl ether and the organic phases of the two were combined.
(3) The VAc cis-trans ratio in the organic phase was determined by HPLC, wherein the weight ratio of 11-cis-VAc to all-trans-VAc was 1:0.62. the total amount of external VAc measured by external standard method was 29.96g. The organic phase was transferred to a 500mL three-port reaction flask, equipped with a stirrer and thermometer and a nitrogen exchange valve. After 3 nitrogen substitutions, 0.5mL of ethylene glycol dimethyl ether solution of iodine and pyridine was rapidly injected, wherein iodine was 30mg and pyridine was 30mg. After shading the reaction solution, reacting for 3 hours at 42 ℃ to obtain a mixed solution of 11-cis-vitamin A acetate and trans-VAc, and retesting the cis-trans ratio of the VAc, wherein the weight content ratio of the 11-cis-VAc to the all-trans-VAc is 1:3.99. the total amount of external standard VAc was 53.22g, and the conversion (= (amount of all-trans VAc after isomerization-amount of all-trans VAc before isomerization)/total amount of 11-cis VAc and all-trans VAc after isomerization) was 67.4%.
Example 2
The procedure of example 1 was followed, except that the type of extractant was changed in step (2), cyclohexane was used, and isomerization was also performed in cyclohexane. The variety of the catalyst in the step (3) is changed to azodiisobutyronitrile and triethylamine which are used as isomerization catalysts, wherein the azodiisobutyronitrile is 30mg, and the triethylamine is 30mg. The VAc cis-trans ratio in the organic phase prior to isomerisation was determined, wherein the weight content ratio of 11-cis-VAc to all trans-VAc was 1:0.98. the total amount of external standard VAc was 32.21g. After isomerization, the conversion of VAc in the organic phase into 11-cis-VAc and all-trans-VAc was measured in a cis-trans ratio of 1:6.08. the total amount of external VAc was 58.78g and the conversion was 94.5%.
Example 3
The procedure of example 1 was followed except that the type of extractant was changed in step (2), toluene was used, and the isomerization was also carried out in toluene. The catalyst species in step (3) was changed to iodine and N-methylpiperidine as isomerization catalyst, wherein iodine was 30mg and N-methylpiperidine was 30mg. The VAc cis-trans ratio in the organic phase prior to isomerisation was determined, wherein the weight content ratio of 11-cis-VAc to all trans-VAc was 1:0.78. the total amount of external standard VAc was 31.19g. After isomerization, the conversion of VAc in the organic phase into 11-cis-VAc and all-trans-VAc was measured in a cis-trans ratio of 1:3.44. the total amount of external VAc was 55.12g and the conversion was 59.9%.
Example 4
(1) 250g of the 11-cis-vitamin A acetate and trans-VAc mixed solution obtained after isomerization in example 1 (total VAc external standard content: 15.2%,38 g) was placed in a 500mL separating funnel, 30mL of 70 vol% aqueous methanol solution was added thereto, and after washing, the mixture was allowed to stand for separation, and after separation of the supernatant, the mixture was washed once again with 30mL of the same aqueous lower alcohol solution, and the supernatant was separated. And (5) discarding the lower layer liquid.
(2) The supernatant of (1) was dried over anhydrous sodium sulfate and distilled under reduced pressure, whereby 55.4g of a crude VAc oil was obtained.
(3) The crude oil in (2) was mixed with 70g of methanol at 0℃and placed in-30℃for pre-cooling. When the temperature no longer changes, 1mg of VAc seed is added and crystallization continues at that temperature. VAc solids precipitated within 3 hours.
(4) And (3) filtering the suspension to obtain a VAc solid, weighing 14.55g, and ensuring that the HPLC purity is 92.5%, wherein the weight ratio of 11-cis-VAc to all-trans is 7:93.
Example 5
The procedure of example 4 was followed, except that the crystallization solvent in steps (1) and (3) was changed to ethanol, to give 16.47g of VAc solid with an HPLC purity of 94.3% and a weight ratio of 11-cis-VAc to all-trans of 6:94.
Example 6
The procedure of example 4 was followed, except that the crystallization solvent in steps (1) and (3) was changed to isopropanol, to give a VAc solid of 15.73g, a HPLC purity of 91.1% and a 11-cis-VAc to all-trans weight content ratio of 9:91.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, a number of simple variants of the technical solution of the invention are possible, including combinations of the individual technical features in any other suitable way, which simple variants and combinations should likewise be regarded as being disclosed by the invention, all falling within the scope of protection of the invention.
Claims (20)
1. A method for preparing all-trans vitamin a acetate, comprising: carrying out isomerization reaction on the 11-cis isomer of the vitamin A acetate in the presence of an isomerization catalyst and a solvent; wherein the isomerization catalyst is azodiisobutyronitrile and triethylamine.
2. The process according to claim 1, wherein the weight ratio of azobisisobutyronitrile to triethylamine is 1:0.5-1.5.
3. The method of claim 1, wherein the solvent is selected from the group consisting of C1-C8 organic solvents.
4. The method according to claim 3, wherein the solvent is at least one of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tetrahydrofuran, ethylene glycol dimethyl ether, benzene, toluene, xylene, 1, 4-dioxane, and cyclohexane.
5. The method of claim 4, wherein the solvent is at least one of ethylene glycol dimethyl ether, cyclohexane, and toluene.
6. The method of claim 1, wherein the solvent comprises 10-80% by weight of the total weight of the isomerization reaction system formed by the isomerization catalyst, the solvent, and the 11-cis isomer of vitamin a acetate.
7. The method of claim 6, wherein the solvent comprises 60-75% by weight of the total weight of the isomerization reaction system formed by the isomerization catalyst, the solvent, and the 11-cis isomer of vitamin a acetate.
8. The method of claim 1, wherein the 11-cis isomer of vitamin a acetate is provided from a starting material comprising the 11-cis isomer of vitamin a acetate, wherein the weight ratio of 11-cis isomer to all-trans vitamin a acetate in the starting material comprising the 11-cis isomer of vitamin a acetate is 1:0.1-9.
9. The method of claim 8, wherein the weight ratio of 11-cis isomer to all-trans vitamin a acetate in the 11-cis isomer containing feedstock of vitamin a acetate is 1:0.5-1.5.
10. A process according to claim 1 or 3, wherein the weight ratio of the isomerisation catalyst to the 11-cis isomer of vitamin a acetate is from 1:500 to 100000.
11. The method of claim 10, wherein the weight ratio of the isomerization catalyst to the 11-cis isomer of vitamin a acetate is 1:1000-10000.
12. The method of claim 1, wherein the isomerization reaction conditions comprise: the reaction temperature is 10-80 ℃ and the reaction time is 0.5-8h.
13. The method of claim 1, wherein the isomerization reaction conditions comprise: the reaction temperature is 30-50 ℃ and the reaction time is 1-5h.
14. The method of claim 1, wherein the method further comprises: and washing, reduced pressure distillation and crystallization are sequentially carried out on the product obtained by the isomerization reaction.
15. The method according to claim 14, wherein the washing solvent used for the washing is water or 30-80 vol.% lower alcohol aqueous solution; the lower alcohol is selected from C1-C3 monohydric alcohols; the weight of the washing solvent is 10-30% of the total weight of the reaction solution.
16. The method of claim 14, wherein the reduced pressure distillation is at a temperature of 0-80 ℃.
17. The method of claim 16, wherein the reduced pressure distillation is at a temperature of 20-60 ℃.
18. The method of claim 14, wherein the crystallization is at a temperature of-50 ℃ to 0 ℃ for a time of 2-8 hours.
19. The method of claim 18, wherein the crystallization is at a temperature of-30 ℃ to-5 ℃ for a period of 3-5 hours.
20. A method for preparing all-trans vitamin a acetate, comprising: firstly, contacting quaternary phosphonium salt and five-carbon aldehyde to generate a Wittig reaction, crystallizing the obtained Wittig reaction product to obtain all-trans vitamin A acetate crystals and a liquid phase containing 11-cis isomer of the vitamin A acetate, and treating the liquid phase according to the method of any one of claims 1-19 to obtain another part of all-trans vitamin A acetate.
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| FR92565E (en) * | 1964-04-24 | 1968-11-29 | Pfizer & Co C | Process for the esterification and isomerization of alpha vitamin compounds |
| CH504428A (en) * | 1964-04-24 | 1971-03-15 | Pfizer & Co C | Isomerisation of vitamin a |
| CN104130264A (en) * | 2014-08-14 | 2014-11-05 | 广东东阳光药业有限公司 | Method for transforming isomer |
| CN110204471A (en) * | 2019-06-12 | 2019-09-06 | 万华化学集团股份有限公司 | A kind of method of in-situ preparation catalysis of iodine vitamin A isomerization |
| CN113214126A (en) * | 2021-05-19 | 2021-08-06 | 万华化学集团股份有限公司 | Preparation method of vitamin A acetate |
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2022
- 2022-06-17 CN CN202210691430.7A patent/CN114957069B/en active Active
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|---|---|---|---|---|
| GB931896A (en) * | 1962-01-22 | 1963-07-24 | Sumitomo Chemical Co | Method for producing 2-trans-vitamin a acid compounds |
| US3384633A (en) * | 1964-04-24 | 1968-05-21 | Pfizer & Co C | Process for the isomerization of vitamin a and esters thereof |
| FR92565E (en) * | 1964-04-24 | 1968-11-29 | Pfizer & Co C | Process for the esterification and isomerization of alpha vitamin compounds |
| CH504428A (en) * | 1964-04-24 | 1971-03-15 | Pfizer & Co C | Isomerisation of vitamin a |
| CN104130264A (en) * | 2014-08-14 | 2014-11-05 | 广东东阳光药业有限公司 | Method for transforming isomer |
| CN110204471A (en) * | 2019-06-12 | 2019-09-06 | 万华化学集团股份有限公司 | A kind of method of in-situ preparation catalysis of iodine vitamin A isomerization |
| CN113214126A (en) * | 2021-05-19 | 2021-08-06 | 万华化学集团股份有限公司 | Preparation method of vitamin A acetate |
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