A method for the isomerization of vitamin a

Abstract

The application discloses a method for vitamin A isomerization, and particularly relates to a method for generating all-trans vitamin A by performing isomerization reaction on VA crude oil in a solvent in the presence of a palladium catalyst, an alcohol amine type auxiliary agent and a diphenyl phosphine type auxiliary agent under an inert atmosphere. The method can efficiently isomerize 13-cis vitamin A into all-trans vitamin A while inhibiting the conversion of all-trans vitamin A into 9-cis vitamin A. After the reaction is completed, the conversion rate of 13-cis vitamin A is greater than or equal to 95%, the selectivity of all-trans vitamin A is greater than or equal to 99%, and no 9-cis vitamin A is generated.

Description

TECHNICAL FIELD

[0001] The present application relates to an isomerization method, in particular to a method for isomerization of vitamin A. BACKGROUND

[0002] Vitamin A is a fat-soluble vitamin, which has important applications in the pharmaceutical, food, feed additive and cosmetic industries. Currently, commercial vitamin A is a chemical synthesis product, and the representative processes are the C6+C14 route of Roche and the C5+C15 route of BASF. The isomer compositions of vitamin A synthesized by different routes differ greatly. The main isomers in the crude vitamin A (i.e. VA crude oil) synthesized by the Roche route are 13-cis vitamin A and all-trans vitamin A. All-trans vitamin A has the highest biological activity. Converting 13-cis vitamin A to all-trans vitamin A can greatly improve the reaction yield and effectively reduce the product cost, which is of great significance for industrial production.

[0003] The conventional isomerization methods mainly include photoisomerization and chemical isomerization.

[0004] Patent US3838029A reports a photoisomerization process, in which the cis isomer is converted to the all-trans isomer under the condition of a photosensitizer and irradiation with a certain wavelength. However, most of the photosensitizers used have dyeing properties and are highly toxic, even with a risk of carcinogenesis. In addition, the photo-catalytic reaction is relatively difficult to scale up due to its special nature.

[0005] Patent US3384633A reports a vitamin A isomerization process using iodine as a catalyst. In the above reaction, sodium thiosulfate aqueous solution is used to reduce iodine to sodium iodide in the post-processing process, thereby generating a large amount of iodine-containing wastewater, increasing the wastewater treatment volume and product cost, which is not conducive to industrial production. This process has been eliminated by the industry.

[0006] Patent US4051174A reports a vitamin A isomerization reaction using a palladium-containing compound as a catalyst. Compared with the traditional iodine catalytic process, this type of catalyst has the advantages of high reaction activity, simple post-processing process, and less wastewater.

[0007] However, the inventors have found that the use of the above-mentioned palladium-containing compound in the isomerization of vitamin A has obvious defects. Firstly, in the catalyst system, the conversion of 9-cis vitamin A to all-trans vitamin A is low, and the process is more difficult to proceed in the presence of other cis isomers. Secondly, in the isomerization of 13-cis vitamin A using the above-mentioned system, when the conversion rate of 13-cis vitamin A reaches about 85%, the content of all-trans vitamin A reaches a peak, and the conversion rate of 13-cis vitamin A remains essentially unchanged, while all-trans vitamin A begins to rapidly convert to 9-cis vitamin A. In the catalyst system, this process is irreversible, which reduces the yield of the product, and thus is undesirable. The reaction time needs to be strictly controlled to prevent side reactions. However, it is difficult to strictly control the reaction time in actual production, mainly because the crude VA oil contains a certain amount of heavy components in addition to 13-cis isomers and all-trans isomers. The composition of these heavy components is complex and difficult to analyze, and the main component is a vitamin A analogue, so they are collectively referred to as VA-like impurities. The content of these impurities affects the activity of the catalyst, resulting in large fluctuations in the isomerization rate. Even if the content of VA-like impurities is the same, the composition of the impurities will still cause differences in the reaction time. This leads to the problem of over-reaction in the isomerization process, resulting in a decrease in the reaction yield. This phenomenon is particularly pronounced in industrial scale-up. In industrial production, online equipment can be used to monitor the content of each isomer. However, such online monitoring equipment is expensive, and through actual research, the response signals of the cis and trans isomers of vitamin A on such equipment are very similar, although they can be distinguished with difficulty, but the error is large, and the lag phenomenon is obvious, which still leads to frequent over-reaction problems.

[0008] In view of the above problems, it is necessary to develop an isomerization method for vitamin A that can convert 13-cis vitamin A to all-trans vitamin A while preventing the conversion of all-trans vitamin A to 9-cis vitamin A, thereby improving the operability and convenience of the isomerization process in industrial production and increasing the product yield. SUMMARY

[0009] To solve the above technical problems, the present application provides a method for isomerizing vitamin A. This method can efficiently isomerize 13-cis vitamin A to all-trans vitamin A while inhibiting the conversion of all-trans vitamin A to 9-cis vitamin A. After the reaction is completed, the conversion rate of 13-cis vitamin A is ≥95%, the selectivity of all-trans vitamin A is ≥99%, and no 9-cis vitamin A is produced.

[0010] To achieve the above-mentioned purposes, the technical solutions adopted by the present application are as follows:

[0011] A method for isomerization of vitamin A, wherein crude VA oil is subjected to isomerization reaction in the presence of a palladium catalyst, an alcohol amine assistant, a diphenyl phosphine assistant, in a solvent under inert atmosphere, to produce all-trans vitamin A.

[0012] The present application surprisingly found in the research that when a certain amount of alcohol amine assistant and diphenyl phosphine assistant are additionally introduced into the palladium catalyzed isomerization system, the reaction efficiency is higher, the reaction time is shorter, and the conversion process of all-trans vitamin A to 9-cis vitamin A is effectively inhibited, that is, even if the reaction time is more than 5h, the presence of 9-cis vitamin A is not detected in the reaction system. In the method of the present application, the conversion rate of 13-cis vitamin A can be greatly improved to 95% or more.

[0013] In some embodiments, the crude VA oil contains the following mass concentrations of each component, based on 100% of the total mass of the crude VA oil: 13-cis vitamin A 50-60wt%, all-trans vitamin A 25-30wt%, and the balance of VA-like substances. The crude VA oil can be obtained after synthesis according to the industry-known C6+C14 route.

[0014] In some embodiments, the palladium catalyst is one or more of palladium acetate, palladium nitrate, potassium tetrachloropalladate, and palladium chloride.

[0015] Preferably, the amount of the palladium catalyst is 0.01-1.0wt%, preferably 0.05-0.5wt%, of the mass of the metal element relative to the 13-cis vitamin A in the crude VA oil.

[0016] In some embodiments, the alcohol amine assistant is one or more of methanol amine, ethanol amine, diethanol amine, and triethanol amine.

[0017] Preferably, the amount of the alcohol amine assistant is 30-80wt%, preferably 40-70wt%, of the mass of the palladium catalyst.

[0018] In some embodiments, the diphenyl phosphine assistant is one or more of 1,2-bis(diphenylphosphino)ethane, 1,4-bis(diphenylphosphino)butane, and bis(2-diphenylphosphinophenyl)ether.

[0019] Preferably, the amount of the diphenyl phosphine assistant is 1-4 times, preferably 2-3 times, of the mass of the palladium catalyst.

[0020] In some embodiments, the reaction temperature of the isomerization reaction is 30-90℃, preferably 40-80℃, and / or the reaction time of the isomerization reaction is 1-10h, preferably 2-8h.

[0021] In some embodiments, the solvent is at least one of C5-C18 alkane, C6-C9 aromatic hydrocarbon, C1-C6 alcohol, preferably at least one of n-heptane, toluene, isopropanol;

[0022] The C5-C18 alkane includes C5-C18 straight-chain alkane, C5-C18 branched-chain alkane and C5-C18 cycloalkane, more preferably n-hexane, n-heptane, petroleum ether, etc.

[0023] The C6-C9 aromatic hydrocarbon includes benzene, toluene, xylene, trimethylbenzene, etc.

[0024] The C1-C6 alcohol is methanol, ethanol, propanol, isopropanol, butanol, amyl alcohol, hexanol, etc.

[0025] Preferably, the solvent is used in an amount of 5-50wt%, preferably 10-40wt%, based on the mass concentration of VA crude oil in the solvent.

[0026] In some embodiments, the inert atmosphere is provided by a reaction-inert gas; the reaction-inert gas is selected from nitrogen and / or argon.

[0027] Compared with the prior art, the present application has the following beneficial effects:

[0028] 1) effectively inhibits the conversion of all-trans vitamin A to 9-cis vitamin A, no 9-cis vitamin A is detected in the reaction solution after 5h of excessive reaction, reduces the product loss rate, and improves the operability and convenience of the isomerization process;

[0029] 2) greatly improves the isomerization reaction efficiency and the conversion rate of 13-cis vitamin A to all-trans vitamin A, increases the reaction conversion rate from about 85% to 95% or more, greatly improves the reaction yield, and shortens the reaction time, which can effectively reduce the production cost. DETAILED DESCRIPTION

[0030] The present application will be further described below by specific examples, which are only used to illustrate the present application and do not limit the scope of the present application.

[0031] The catalysts in the embodiments of the present application are as follows:

[0032] Palladium acetate: ≥99%, Aldrich

[0033] Palladium nitrate: ≥99%, Aldrich

[0034] Palladium chloride: ≥99%, Aldrich

[0035] Potassium tetrachloropalladate: ≥99%, Aldrich

[0036] VA crude oil sources and compositions used in the embodiments and comparative examples of the present application:

[0037] VA crude oil A: from a small-scale process for vitamin A synthesis in Wanhua Chemical, product composition: 52.5% 13-cis vitamin A, 29.6% all-trans vitamin A, 17.9% VA-like impurities.

[0038] VA crude oil B: from a small-scale process for vitamin A synthesis in Wanhua Chemical, product composition: 54.3% 13-cis vitamin A, 26.6% all-trans vitamin A, 19.1% VA-like impurities.

[0039] VA crude oil C: from a small-scale process for vitamin A synthesis in Wanhua Chemical, product composition: 59.6% 13-cis vitamin A, 25.2% all-trans vitamin A, 15.2% VA-like impurities.

[0040] The analysis methods involved in the following embodiments of the present application are as follows:

[0041] Liquid chromatography: Agilent LC-1200 high-performance liquid chromatograph, chromatographic analysis conditions: determined according to the conditions specified in GB 14750-2010. The contents of 13-cis vitamin A, 9-cis vitamin A and all-trans vitamin A were determined by external standard method.

[0042] [Example 1]

[0043] The isomerization reaction was carried out according to the following steps:

[0044] 50 g of VA crude oil A was weighed and added to 150 g of n-heptane to prepare a mixed solution. Then 0.1384 g of palladium acetate, 0.0692 g of triethanolamine and 0.3461 g of 1,2-bis(diphenylphosphino)ethane were added. After the reaction system was replaced with nitrogen for 10 min, it was stirred at 60°C for 5 h. After the reaction was completed, the composition of the reaction solution was analyzed by high-performance liquid chromatography, and the isomerization reaction results are shown in Table 1.

[0045] [Example 2]

[0046] The isomerization reaction was carried out according to the following steps:

[0047] 50 g of VA crude oil B was weighed and added to 450 g of toluene to prepare a mixed solution. Then 0.0226 g of palladium chloride, 0.0090 g of ethanolamine and 0.0452 g of 1,4-bis(diphenylphosphino)butane were added. After the reaction system was replaced with nitrogen for 10 min, it was stirred at 40°C for 8 h. After the reaction was completed, the composition of the reaction solution was analyzed by high-performance liquid chromatography, and the isomerization reaction results are shown in Table 1.

[0048] [Example 3]

[0049] The isomerization reaction was carried out according to the following steps:

[0050] 50 g of VA crude oil C was weighed and mixed with 75 g of isopropyl alcohol to prepare a mixed solution. Then, 0.3226 g of palladium nitrate, 0.2258 g of diethanolamine, and 0.9678 g of bis(2-diphenylphosphinophenyl) ether were added. After the reaction system was replaced with nitrogen for 10 min, the reaction was stirred at 80°C for 2 h. After the reaction was completed, the composition of the reaction solution was analyzed by high performance liquid chromatography, and the isomerization reaction results are shown in Table 1.

[0051]

Example 4

[0052] The isomerization reaction was carried out according to the following steps:

[0053] 50 g of VA crude oil A was weighed and mixed with 950 g of n-heptane to prepare a mixed solution. Then, 0.0081 g of potassium tetrachloropalladate, 0.0064 g of methanolamine, and 0.0322 g of 1,2-bis(diphenylphosphino)ethane were added. After the reaction system was replaced with nitrogen for 10 min, the reaction was stirred at 90°C for 1 h. After the reaction was completed, the composition of the reaction solution was analyzed by high performance liquid chromatography, and the isomerization reaction results are shown in Table 1.

[0054]

Example 5

[0055] The isomerization reaction was carried out according to the following steps:

[0056] 50 g of VA crude oil A was weighed and mixed with 50 g of n-heptane to prepare a mixed solution. Then, 0.5538 g of palladium acetate, 0.1661 g of triethanolamine, and 0.5538 g of 1,2-bis(diphenylphosphino)ethane were added. After the reaction system was replaced with nitrogen for 10 min, the reaction was stirred at 30°C for 10 h. After the reaction was completed, the composition of the reaction solution was analyzed by high performance liquid chromatography, and the isomerization reaction results are shown in Table 1.

[0057]

Comparative Example 1

[0058] The isomerization reaction was carried out according to the same method as in Example 1, except that triethanolamine and 1,2-bis(diphenylphosphino)ethane were not added to the reaction system.

[0059]

Comparative Example 2

[0060] The isomerization reaction was carried out according to the same method as in Example 1, except that triethanolamine and 1,2-bis(diphenylphosphino)ethane were not added to the reaction system, and the reaction time was extended to 6 h.

[0061]

Comparative Example 3

[0062] The isomerization reaction was carried out in substantially the same manner as in Example 1, except that 1,2-bis(diphenylphosphino)ethane was not added to the reaction system.

[0063]

Comparative Example 4

[0064] The isomerization reaction was carried out in substantially the same manner as in Example 1, except that triethanolamine was not added to the reaction system.

[0065] Table 1, Isomerization Experiment Results

[0066]

[0067]

[0068] The above only is the preferred embodiment of the present application, should be noted that for the ordinary skilled in the art, without departing from the method of the present application, can also make a number of improvements and supplements, these improvements and supplements should also be considered within the scope of the present application.

Claims

1. A method for isomerization of vitamin A, characterized in that, VA crude oil is isomerized in the presence of a palladium catalyst, an alcohol amine assistant, a diphenyl phosphine assistant, in a solvent under an inert atmosphere to produce all-trans vitamin A; the alcohol amine assistant is one or more of methanol amine, ethanol amine, diethanol amine, and triethanol amine; the diphenyl phosphine assistant is one or more of 1,2-bis(diphenylphosphino)ethane, 1,4-bis(diphenylphosphino)butane, and bis(2-diphenylphosphinophenyl)ether.

2. The method of isomerization of vitamin A according to claim 1, characterized in that, the VA crude oil contains the following mass concentrations of components: 50-60wt% of 13-cis vitamin A, 25-30wt% of all-trans vitamin A, and the balance of VA-like substances, based on 100% of the total mass of the VA crude oil.

3. The method of isomerization of vitamin A according to claim 1, characterized in that, the palladium catalyst is one or more of palladium acetate, palladium nitrate, potassium tetrachloropalladate, and palladium chloride.

4. The method of isomerization of vitamin A according to claim 3, characterized in that, the amount of the palladium catalyst is 0.01-1.0wt% of the mass of the metal element relative to the mass of 13-cis vitamin A in the VA crude oil.

5. The method of isomerization of vitamin A according to claim 4, characterized in that, the amount of the palladium catalyst is 0.05-0.5wt% of the mass of the metal element relative to the mass of 13-cis vitamin A in the VA crude oil.

6. The method of isomerization of vitamin A according to any one of claims 1-5, characterized in that, the amount of the alcohol amine assistant is 30-80wt% of the mass of the palladium catalyst.

7. The method of isomerization of vitamin A according to claim 6, characterized in that, the amount of the alcohol amine assistant is 40-70wt% of the mass of the palladium catalyst.

8. The method of isomerization of vitamin A according to claim 6, characterized by that, the amount of the diphenyl phosphine assistant is 1-4 times the mass of the palladium catalyst.

9. The method of isomerization of vitamin A according to claim 8, characterized in that, the amount of the diphenyl phosphine assistant is 2-3 times the mass of the palladium catalyst.

10. The method of isomerization of vitamin A according to claim 8, characterized in that, the reaction temperature of the isomerization reaction is 30-90℃, and / or the reaction time of the isomerization reaction is 1-10h.

11. The method of isomerization of vitamin A according to claim 10, characterized in that, the reaction temperature of the isomerization reaction is 40-80℃, and / or the reaction time of the isomerization reaction is 2-8h.

12. The method of isomerization of vitamin A according to claim 10, characterized in that, the solvent is at least one of C5-C18 alkanes, C6-C9 aromatic hydrocarbons, and C1-C6 alcohols.

13. The method of isomerization of vitamin A according to claim 12, characterized in that, the solvent is at least one of n-heptane, toluene, and isopropyl alcohol.

14. The method of isomerization of vitamin A according to claim 12, characterized in that, the amount of the solvent is 5-50wt% of the mass concentration of the VA crude oil in the solvent.

15. The method of isomerization of vitamin A according to claim 14, characterized in that, the amount of the solvent is 10-40wt% of the mass concentration of the VA crude oil in the solvent.

16. The method of isomerization of vitamin A according to claim 12, characterized in that, the inert atmosphere is provided by a reaction inert gas; the reaction inert gas is selected from nitrogen and / or argon.

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