Vitamin A isomerization method

Abstract

The invention discloses a method for isomerizing vitamin A. The method specifically comprises the following steps: in an inert atmosphere, carrying out isomerization reaction on VA crude oil in a solvent in the presence of a palladium catalyst, an alcamines auxiliary agent and a diphenylphosphine auxiliary agent to generate all-trans vitamin A. According to the method, 13-cis-vitamin A can be efficiently isomerized into all-trans-vitamin A, and meanwhile conversion of all-trans-vitamin A into 9-cis-vitamin A is inhibited. After the reaction is finished, 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 invention relates to an isomerization method, in particular to a vitamin A isomerization method. Background Art

[0002] Vitamin A is a fat-soluble vitamin that has important applications in the pharmaceutical, food, feed additive and cosmetic industries. Currently, all commercial vitamin A is a chemically synthesized product, with the representative processes being Roche's C6+C14 route and BASF's C5+C15 route. The isomer composition of vitamin A synthesized by different routes varies 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 increase the reaction yield and effectively reduce product costs, which is of great significance to industrial production.

[0003] Conventional isomerization methods are mainly divided into photoisomerization and chemical isomerization.

[0004] Patent US3838029A reports the photoisomerization process, which uses a certain wavelength of irradiation under the condition of a photosensitizer to achieve the conversion of the cis isomer to the all-trans isomer. However, most of the photosensitizers used are dyeing and highly toxic, and even have carcinogenic risks. At the same time, due to the particularity of the photocatalytic reaction, industrial scale-up is relatively difficult.

[0005] Patent US3384633A reports the use of iodine-catalyzed process for isomerization of vitamin A. In the post-processing process of the above reaction, sodium thiosulfate aqueous solution is required to reduce elemental iodine to sodium iodide, thereby generating a large amount of iodine-containing wastewater, increasing the amount of wastewater to be treated, and raising product costs, which is not conducive to industrial production. This process has been eliminated by the industry.

[0006] Patent US4051174A reports the use of palladium compounds as catalysts for vitamin A isomerization reactions. Compared with traditional iodine-catalyzed processes, this type of catalyst has the advantages of high reaction activity, simple post-treatment process, and less wastewater.

[0007] However, the inventors have found through research that there are obvious defects in using the above palladium-containing compound to carry out vitamin A isomerization reaction. First, in this catalyst system, the conversion efficiency of 9-cis vitamin A to all-trans vitamin A is low, and this process is more difficult to carry out in the presence of other cis isomers. Secondly, in the process of catalyzing the isomerization of 13-cis vitamin A using the above system, when the 13-cis vitamin A conversion rate reaches about 85%, the all-trans vitamin A content reaches a peak value, and the reaction continues. The 13-cis vitamin A conversion rate remains basically unchanged, and all-trans vitamin A begins to rapidly convert to 9-cis vitamin A. In this catalytic system, this process is irreversible, which will cause a decrease in product yield, so it is not desirable, and the isomerization reaction time needs to be strictly controlled to prevent the occurrence of side reactions. However, it is difficult to strictly control the reaction time in the actual production process. The main reason is that in addition to containing 13-cis isomers and all-trans isomers, VA crude oil also contains a certain amount of heavy components. Since this type of heavy component is complex and difficult to analyze, the main component is an analog of vitamin A, so it is collectively referred to as VA-like impurities. The content of such impurities will affect the activity of the catalyst, resulting in large fluctuations in the isomerization reaction rate. Even if the content of VA-like impurities is the same, the change in its composition will also lead to differences in the reaction time. This makes it very easy for over-reaction problems to occur during the isomerization process, resulting in a decrease in the reaction yield, which is particularly evident during industrial scale-up. Online equipment can be used in industrial production processes to monitor the content of each isomer. However, such online monitoring equipment is expensive, and after actual research, the response signals of vitamin A cis and trans isomers on such equipment are very similar. Although they can be barely distinguished, the error is large and the hysteresis is obvious, which still leads to frequent over-reaction problems.

[0008] In view of the above problems, it is very necessary to develop a method for the isomerization of vitamin A, which can prevent the conversion of all-trans vitamin A to 9-cis vitamin A while ensuring that 13-cis vitamin A can be normally converted to all-trans vitamin A, so as to improve the operability and convenience of the isomerization process in industrial production and improve the product yield. Summary of the invention

[0009] In order to solve the above technical problems, the present invention provides a method for isomerization of vitamin A. The 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 purpose, the technical solution adopted by the present invention is as follows:

[0011] A vitamin A isomerization method comprises the following steps: in an inert atmosphere, crude VA oil is subjected to an isomerization reaction in a solvent in the presence of a palladium catalyst, an alcohol amine auxiliary agent and a diphenylphosphine auxiliary agent to generate all-trans vitamin A.

[0012] The present invention unexpectedly found in the research that when a certain amount of alcohol amine auxiliary agent and diphenylphosphine auxiliary agent are additionally introduced into the palladium-catalyzed isomerization reaction 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. Even if the overreaction lasts for more than 5 hours, the presence of 9-cis vitamin A is not detected in the reaction system. In the method of the present invention, the conversion rate of 13-cis vitamin A can be greatly increased to 95% or more.

[0013] In some embodiments, the VA crude oil, with its total mass as 100%, comprises the following components in mass concentrations: 50-60wt% of 13-cis vitamin A, 25-30wt% of all-trans vitamin A, and the remainder of VA-like substances. The VA crude oil can be synthesized by referring to the C6+C14 route known in the industry.

[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 0.01-1.0 wt %, preferably 0.05-0.5 wt %, calculated as the mass of the metal element relative to the mass of 13-cis vitamin A in the crude VA oil.

[0016] In some embodiments, the alcoholamine auxiliary agent is one or more of methanolamine, ethanolamine, diethanolamine, and triethanolamine;

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

[0018] In some embodiments, the diphenylphosphine auxiliary agent is one or more of 1,2-bis(diphenylphosphine)ethane, 1,4-bis(diphenylphosphine)butane, and bis(2-diphenylphosphinophenyl)ether;

[0019] Preferably, the amount of the diphenylphosphine auxiliary agent is 1-4 times, preferably 2-3 times, the mass of the palladium catalyst.

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

[0021] In some embodiments, the solvent is at least one of C5-C18 alkanes, C6-C9 aromatic hydrocarbons, and C1-C6 alcohols, preferably at least one of n-heptane, toluene, and isopropanol;

[0022] Among them, C5-C18 alkanes include C5-C18 straight-chain alkanes, C5-C18 branched-chain alkanes and C5-C18 cycloalkanes, and more preferably n-hexane, n-heptane, petroleum ether, etc.;

[0023] C6-C9 aromatic hydrocarbons include benzene, toluene, xylene, trimethylbenzene, etc.;

[0024] C1-C6 alcohols are methanol, ethanol, propanol, isopropanol, butanol, pentanol, hexanol, etc.;

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

[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 invention has the following beneficial effects:

[0028] 1) Effectively inhibit the conversion of all-trans vitamin A to 9-cis vitamin A. After overreaction for 5 hours, no 9-cis vitamin A was detected in the reaction solution, which reduced the product loss rate and improved the operability and convenience of the isomerization process.

[0029] 2) The isomerization reaction efficiency and the conversion rate of 13-cis vitamin A to all-trans vitamin A are greatly improved, and the reaction conversion rate is increased from about 85% to 95% or above, the reaction yield is greatly improved, the reaction time is shortened, and the production cost can be effectively reduced. DETAILED DESCRIPTION

[0030] The present invention is further described below by means of specific examples. The examples described in the present invention are only used to illustrate the present invention and do not limit the scope of the present invention.

[0031] The sources of catalysts in each embodiment of the present invention are as follows:

[0032] Palladium acetate: ≥99%, Aladdin

[0033] Palladium nitrate: ≥99%, Aladdin

[0034] Palladium chloride: ≥99%, Aladdin

[0035] Potassium tetrachloropalladate: ≥99%, Aladdin

[0036] The sources and compositions of the VA crude oil used in the embodiments and comparative examples of the present invention are as follows:

[0037] VA crude oil A: It comes from Wanhua Chemical's small-scale trial process for vitamin A synthesis. The product composition is: 52.5% 13-cis vitamin A, 29.6% all-trans vitamin A, and 17.9% VA-like impurities.

[0038] VA crude oil B: comes from Wanhua Chemical's small-scale trial process for vitamin A synthesis. The product composition is: 54.3% 13-cis vitamin A, 26.6% all-trans vitamin A, and 19.1% VA-like impurities.

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

[0040] The analytical methods involved in the following embodiments of the present invention are:

[0041] Liquid chromatography: High performance liquid chromatograph, Agilent LC-1200, chromatographic analysis conditions: Determined in accordance with 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 the external standard method.

[0042] [Example 1]

[0043] The isomerization reaction was carried out as follows:

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

[0045] [Example 2]

[0046] The isomerization reaction was carried out as follows:

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

[0048] [Example 3]

[0049] The isomerization reaction was carried out as follows:

[0050] Weigh 50g of VA crude oil C, add 75g of isopropanol to prepare a mixed solution. Then add 0.3226g of palladium nitrate, 0.2258g of diethanolamine, and 0.9678g of bis(2-diphenylphosphinophenyl)ether. After nitrogen is introduced into the reaction system for 10min, stir and react at 80°C for 2h. After the reaction is completed, the composition of the reaction solution is analyzed by high performance liquid chromatography, and the results of the isomerization reaction are listed in Table 1.

[0051] [Example 4]

[0052] The isomerization reaction was carried out as follows:

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

[0054] [Example 5]

[0055] The isomerization reaction was carried out as follows:

[0056] Weigh 50g of VA crude oil A, add 50g of n-heptane to prepare a mixed solution. Then add 0.5538g of palladium acetate, 0.1661g of triethanolamine, and 0.5538g of 1,2-bis(diphenylphosphine)ethane. After nitrogen is introduced into the reaction system for 10 minutes, stir and react at 30°C for 10 hours. After the reaction is completed, the composition of the reaction solution is analyzed by high performance liquid chromatography, and the isomerization reaction results are listed in Table 1.

[0057] [Comparative Example 1]

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

[0059] [Comparative Example 2]

[0060] The isomerization reaction was carried out in a manner substantially the same as in Example 1, except that triethanolamine and 1,2-bis(diphenylphosphine)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(diphenylphosphine)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 no triethanolamine was added to the reaction system.

[0065] Table 1. Isomerization experimental results

[0066]

[0067]

[0068] The above is only a preferred embodiment of the present invention. It should be pointed out that ordinary technicians in this field can make several improvements and supplements without departing from the method of the present invention. These improvements and supplements should also be regarded as the scope of protection of the present invention.

Claims

1. A method for isomerization of vitamin A, characterized in that: Under an inert atmosphere, VA crude oil is subjected to an isomerization reaction in a solvent in the presence of a palladium catalyst, an alcoholamine auxiliary, and a diphenylphosphine auxiliary to generate all-trans vitamin A.

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

3. The method for 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; Preferably, the amount of the palladium catalyst is 0.01-1.0 wt %, preferably 0.05-0.5 wt %, calculated as the mass of the metal element relative to the mass of 13-cis vitamin A in the crude VA oil.

4. The method for isomerization of vitamin A according to any one of claims 1 to 3, characterized in that: The alcoholamine auxiliary agent is one or more of methanolamine, ethanolamine, diethanolamine and triethanolamine; Preferably, the amount of the alcohol amine auxiliary agent is 30-80wt% of the mass of the palladium catalyst, preferably 40-70wt%.

5. The method for isomerization of vitamin A according to claim 4, characterized in that: The diphenylphosphine auxiliary agent is one or more of 1,2-bis(diphenylphosphine)ethane, 1,4-bis(diphenylphosphine)butane, and bis(2-diphenylphosphinophenyl)ether; Preferably, the amount of the diphenylphosphine auxiliary agent is 1-4 times, preferably 2-3 times, the mass of the palladium catalyst.

6. The method for isomerization of vitamin A according to claim 5, characterized in that: The reaction temperature of the isomerization reaction is 30-90° C., preferably 40-80° C., and / or the reaction time of the isomerization reaction is 1-10 h, preferably 2-8 h.

7. The method for isomerization of vitamin A according to claim 6, characterized in that: The solvent is at least one of C5-C18 alkanes, C6-C9 aromatic hydrocarbons, and C1-C6 alcohols, preferably at least one of n-heptane, toluene, and isopropanol; Preferably, the amount of the solvent is based on a mass concentration of VA crude oil in the solvent of 5-50wt%, preferably 10-40wt%.

8. The method for isomerization of vitamin A according to claim 7, 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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