A method for preparing natural or synthetic α-tocopheryl succinate monoesters

Abstract

The present invention discloses a preparation method of natural or synthetic α-tocopherol succinate monoester, which comprises using natural or synthetic α-tocopherol and succinic anhydride as raw materials, using a solid base as a catalyst, and successively adding them into an autoclave without adding an additional solvent; introducing nitrogen to displace air, and then protecting tocopherol with hydrogen; reacting continuously at a temperature of 30-80 °C for 2-5 hours; finally, the free tocopherol is less than 1%, and finally, pure α-tocopherol succinate monoester is obtained by crystallization with n-hexane, the GC content reaches more than 98%, and the molar yield reaches more than 90%. The present invention has the characteristics of safety, environmental protection, simple process, low ammonia nitrogen residue, high yield, low production cost, easy industrialization, etc.

Description

Technical Field

[0001] The present invention relates to the field of preparation of α-tocopherol succinate, and particularly to a method for preparing natural or synthetic α-tocopherol succinate. Background Art

[0002] Vitamin E contains phenolic hydroxyl groups in its structure and is relatively easy to be oxidized, which makes it lose its biological activity and function, bringing many inconveniences to the preparation and storage of vitamin E products.

[0003] Vitamin E significantly has functions such as anti-inflammatory, anti-aging, anti-tumor, prevention of cardiovascular diseases, and improvement of body immunity, and is an essential vitamin in human life activities.

[0004] Vitamin E includes natural vitamin E and synthetic vitamin E; natural vitamin E includes four configurations: α, β, γ, δ, all of which have optical activity. Synthetic vitamin E is mainly dl-α-tocopherol and has no optical activity.

[0005] Among the various isomers of vitamin E, the tocopherol with the α-configuration has the highest activity. Therefore, it is important to improve the stability of α-tocopherol.

[0006] α-Tocopherol succinate has received more and more attention due to its good stability, biological activity, and diverse functions. α-Tocopherol succinate is obtained by introducing a succinyl group onto the phenolic hydroxyl group of α-tocopherol. It not only retains the biological activity of tocopherol but also greatly improves its stability. At the same time, it is found that the anti-cancer activity of α-tocopherol succinate is higher than that of α-tocopherol. Therefore, α-tocopherol succinate has a broad application prospect.

[0007] The esterification reaction equation of α-tocopherol succinate of the present invention (taking synthetic α-tocopherol as an example):

[0008]

[0009] Esterification reaction equation

[0010] Among them: The structural formula of natural d-α-tocopherol succinate:

[0011]

[0012] Among them: The structural formula of synthetic dl-α-tocopherol succinate:

[0013]

[0014] For a long time, most of the synthesis methods of α-tocopherol succinate have problems such as solvent residue, catalyst residue, high production cost, and large equipment investment. The research on its preparation method has become one of the important topics of vitamin E drugs.

[0015] The preparation method disclosed in Chinese Patent CN104592191A uses lipase as a catalyst, which has a certain degree of innovation. However, organic solvents such as DMSO and halogenated hydrocarbons are used multiple times in the process, which have certain food safety risks; and the reaction time is relatively long, generally requiring 24 - 48 hours, and the production cycle is too long.

[0016] Organic amine reagents such as triethylamine, dialkylalkanolamines, pyridine, etc. are used in patents such as Chinese Patent CN1368050A, US Patent US2358046, Chinese Patent CN108409704A, US Patent 2007 / 0286825A1, US Patent US866498, Japanese Patent JP170757, etc.; organic amine reagents are likely to remain in the product finally; and a large amount of ammonia - nitrogen wastewater is generated during the process due to multiple washing and pH adjustment. The European food additive industry stipulates that the residue of triethylamine should be less than 5000 ppm.

[0017] In US Patent US3538119, a synthesis method for preparing α - tocopheryl succinate monoester is disclosed in a solvent - free system using anhydrous alkali metal catalysts such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium acetate, sodium acetate, etc. at 120 - 140 °C. During this process, due to the too - high reaction temperature, succinic anhydride is likely to sublime and block the reactor; and tocopherol is also likely to decompose at high temperature, resulting in a low yield. Inorganic alkali metal catalysts are likely to be lost or remain in the product during use. On the one hand, there is a problem of catalyst recycling; on the other hand, the catalyst remaining in the product affects the product quality. Summary of the Invention

[0018] In order to overcome the above - mentioned defects of the prior art, the present invention adopts a process catalyzed by solid base to solve the problems existing in the synthesis of α - tocopheryl succinate monoester.

[0019] The present invention provides a method for preparing natural or synthetic α - tocopheryl succinate monoester. The preparation method includes the following steps: 1) sequentially adding α - tocopherol, succinic anhydride, and solid base into an autoclave; the solid base is a strongly basic resin; 2) maintaining the hydrogen pressure in the autoclave at 1 - 100 kPa; 3) gradually heating and reacting at a temperature of 30 - 80 °C; 4) crystallizing and filtering to obtain a filtrate; subjecting the filtrate to cold precipitation and recrystallization to precipitate the wet product of α - tocopheryl succinate monoester; and 5) vacuum - drying the wet product of α - tocopheryl succinate monoester to obtain the refined product of α - tocopheryl succinate monoester.

[0020] In a preferred technical solution of the preparation method of the present invention, preferably, in step 1), the raw material α - tocopherol is natural d - α - tocopherol or synthetic dl - α - tocopherol.

[0021] In a preferred technical solution of the preparation method of the present invention, preferably, in step 1), the molar ratio of α-tocopherol to succinic anhydride is 1:1.1 to 2.5, preferably 1:1.1 to 1.6, and more preferably 1:1.1 to 1.2.

[0022] In a preferred technical solution of the preparation method of the present invention, preferably, in step 1), the weight ratio of the solid base to the tocopherol is 0.1 to 30%, preferably 1 to 20%, and more preferably 5 to 10%.

[0023] In a preferred technical solution of the preparation method of the present invention, preferably, in step 1), the strong basic resin is a strong basic quaternary amine resin, and the strong basic quaternary amine resin is a pyridine-type resin as shown in the solid base III configuration, an imidazole-type resin as shown in the solid base IV configuration, and a quaternary ammonium salt-type resin as shown in the solid base V configuration.

[0024] Examples of the solid base as a catalyst are as follows:

[0025] R1 is a resin material

[0026] Formula III: Solid base III configuration (i.e., pyridine-type resin) (self-made)

[0027] The preparation method of this solid base III configuration (i.e., pyridine-type resin) is as follows: Mix 111.6 g (1.063 mol) of 4-vinylpyridine, 83 g (0.638 mol) of divinylbenzene, 0.732 g (4.458 mmol) of azobisisobutyronitrile with 460 g of DMF as a solvent, stir and react at 70 °C for 20 h, then perform suction filtration under reduced pressure, wash the filter cake with ethyl acetate 3 times, and dry it in vacuum at 90 °C for 2 h to obtain 152 g of a powder catalyst.

[0028] R1 is a resin material

[0029] Formula IV: Solid base IV configuration (i.e., imidazole-type resin) (self-made)

[0030] The preparation method of this solid base IV configuration (i.e., imidazole-type resin) is as follows: Mix 100 g (1.063 mol) of 1-vinylimidazole, 83 g (0.638 mol) of divinylbenzene, 0.732 g (4.458 mmol) of azobisisobutyronitrile with 460 g of DMF as a solvent, stir and react at 70 °C for 20 h, then perform suction filtration under reduced pressure, wash the filter cake with ethyl acetate 3 times, and dry it in vacuum at 90 °C for 2 h to obtain 146 g of a powder catalyst.

[0031] R1 is a resin material

[0032] Formula V: Solid base V configuration (i.e., quaternary ammonium salt type resin) (self-made)

[0033] The preparation method of the solid base V configuration (i.e., quaternary ammonium salt type resin) is as follows: Mix 162.2 g (1.063 mol) of 4-chloromethylstyrene, 83 g (0.638 mol) of divinylbenzene, 0.732 g (4.458 mmol) of azobisisobutyronitrile with 460 g of DMF as the solvent, stir and react at 70 °C for 20 h, then filter under reduced pressure, wash the filter cake with ethyl acetate three times, and dry it in vacuum at 90 °C for 2 h to obtain 170 g of powder A. Take 150 g of powder A, add 200 ml of DMF, stir at 25 °C for 10 minutes, then slowly dropwise add trimethylamine solution (2 mol). After the addition is complete, keep the temperature for 2 hours and filter to obtain a white solid. Then put the white solid into hydrobromic acid for treatment for 1 hour to obtain the catalyst.

[0034] In a preferred technical solution of the preparation method of the present invention, preferably, in step 2), the hydrogen pressure is 50 - 80 KPa.

[0035] In a preferred technical solution of the preparation method of the present invention, preferably, in step 3), the reaction temperature is 55 - 70 °C, more preferably 60 - 65 °C, and most preferably the reaction time is 2 - 5 hours.

[0036] In a preferred technical solution of the preparation method of the present invention, preferably, in step 4), the crystallization condition is to add 1 - 10 times of n-hexane and cool and crystallize at 5 - 20 °C for 8 - 10 hours, and then filter to obtain a filtrate.

[0037] In a preferred technical solution of the preparation method of the present invention, preferably, in step 4), after the filtrate is washed with 1 - 10 times of hot water, it is cooled and recrystallized at -20 - -5 °C to precipitate a solid.

[0038] In a preferred technical solution of the preparation method of the present invention, preferably, in step 4), the α-tocopherol succinate monoester after recrystallization is dried in vacuum at 40 - 70 °C for 3 - 6 hours.

[0039] In short, the key innovative technology of the present invention is a technology that through solid base catalysis, α-tocopherol and succinic anhydride are subjected to an esterification reaction and then separated. In the present invention, all the raw and auxiliary materials used can be purchased from the market. The method of the present invention includes: taking α-tocopherol and succinic anhydride in a certain proportion as raw materials, using a solid base as a catalyst, and carrying out an esterification reaction under certain conditions. Then, through crystallization and filtration separation, α-tocopherol succinate monoester is obtained.

[0040] The esterification reaction of tocopherol using a solid base catalyst is a feature of the present invention. In this example, several simple solid base catalysts are given to illustrate the feasibility of the present invention. However, the solid base catalysts referred to in the present invention far exceed the scope of the examples given.

[0041] The advantages of the present invention are as follows: (1) Product safety and reliability: Solvent-free and solid base catalysis are adopted, which have the advantages of being green, environmentally friendly, non-toxic, and pollution-free. Moreover, there is no solvent residue in the final product, especially the ammonia nitrogen residue is very small. (2) Economy: Since tocopherol is relatively stable in a hydrogen atmosphere and the main components are basically not degraded, and the catalyst can be recycled more than 5 times, the catalyst cost is relatively low. (3) Process safety: The entire process flow is simple, the equipment investment is small, the operation is solvent-free, and the safety risk at the production site is significantly reduced. Brief Description of the Drawings

[0042] Figure 1 Represents the refined α-tocopherol monosuccinate 1 H NMR;

[0043] Figure 2 Represents the refined α-tocopherol monosuccinate 13 C NMR;

[0044] Figure 3 Represents the refined α-tocopherol monosuccinate 13 C DEPT-135. Detailed Description of the Invention

[0045] The present invention will be further illustrated by the following examples. The examples of the present invention are only given for the purpose of illustrating the present invention, rather than limiting the present invention. In the present invention, all the raw and auxiliary materials used can be obtained from the market.

[0046] Example 1:

[0047] Take 100.0 g of natural d-α-tocopherol (α-tocopherol content 99.2%) and 30.0 g of succinic anhydride (molar ratio 1:1.2) as raw materials, use solid base type III as the catalyst, and the catalyst feeding ratio is 5% (by weight ratio of tocopherol, the same below). Add them to the autoclave in sequence; use N 2 to displace the air in the autoclave 3 times, and then use H 2Replace three times, then maintain a hydrogen pressure of 50 kPa, heat up to 60 °C, keep warm for 3.5 hours, end the reaction, cool down to below 50 °C, discharge the material, and measure the free tocopherol content to be 0.50%. Then add 3 times (volume ratio, the same below) of n-hexane, cool down to 4 °C, and crystallize succinic anhydride; separate α-tocopherol succinate monoester, solid base Ⅲ configuration catalyst and succinic anhydride by filtration for reuse in the next reaction operation. Add 2 times (volume ratio, the same below) of hot water to the alkane solution and wash it twice. Finally, perform cold precipitation at -10 °C for 8 hours, filter to obtain high-purity α-tocopherol succinate monoester fine product, and then vacuum dry the α-tocopherol succinate monoester fine product at a vacuum drying temperature of 40 °C to obtain 111.1 g of the final product; the molar yield of tocopherol reaches 91.1% (the lost tocopherol is basically in the crystallization mother liquor); the GC analysis content is 98.6%, and the measured total nitrogen residue is 0.01 mg / L (1 ppm = 1 mg / L, and the European food industry stipulates that the triethylamine residue is less than 5000 ppm, which is converted to total nitrogen of about less than 770 ppm).

[0048] The NMR data of the final product are as follows (see Figure 1 、 Figure 2 、 Figure 3 ):

[0049] 1 H NMR(400MHz,CDCl 3 )δ11.25(s,1H),2.95(t,J=5.9Hz,2H),2.84(t,J=6.0Hz,2H),2.62(t,J=6.5Hz,2H),2.13(s,3H),2.06(s,3H),2.02(s,3H),1.89–1.75(m,2H),1.61–1.53(m,3H),1.50–1.40(m,2H),1.38–1.24(m,12H),1.25–1.07(m,6H),0.93–0.90(m,12H);

[0050] 13 C NMR(126MHz,CDCl 3)δ178.03, 170.92, 149.30, 140.36, 126.59, 124.85, 122.88, 117.24, 74.91, 39.29, 37.46 (d, J = 3.0 Hz), 37.37, 37.31, 37.20, 32.69 (d, J = 2.0 Hz), 32.60 (d, J = 2.5 Hz), 29.12, 28.62, 27.89, 24.74 (d, J = 1.9 Hz), 24.37, 22.66, 22.57, 20.95, 20.50, 19.68, 19.62, 19.58, 19.55, 19.52, 12.79, 11.93, 11.73;

[0051] 13 C DEPT-135 (126 MHz, CDCl 3 )δ39.45, 37.62 (d, J = 3.0 Hz), 37.53, 37.47, 37.36, 32.86 (d, J = 2.5 Hz), 32.60 (d, J = 2.5 Hz), 29.28, 28.78, 28.05, 24.91 (d, J = 1.9 Hz), 24.52, 22.82, 22.72, 21.10, 20.65, 19.84, 19.78, 19.74, 19.71, 19.68, 12.95, 12.09, 11.89.

[0052] See Table 1: Results of the following recycling of the catalyst in Example 1.

[0053] Table 1

[0054] Number of applications Free tocopherol (%) Molar yield (%) GC content (%) 1 0.50 91.1 98.6 2 0.43 90.7 99.2 3 0.61 92.4 98.8 4 0.47 90.0 99.1 5 0.52 93.0 98.9

[0055] Example 2:

[0056] Take 100.0 g of natural d-α-tocopherol (α-tocopherol content 99.2%) and 27.5 g of succinic anhydride (molar ratio 1:1.1) as raw materials, use solid base type IV configuration as the catalyst, and the catalyst feeding ratio is 6.5%. Add them into the autoclave in sequence; use N 2 Replace the air in the autoclave 3 times, and then use H 2Replace three times, then maintain the hydrogen pressure at 50 kPa, raise the temperature to 60 °C, keep warm for 4 hours, end the reaction, cool down to below 50 °C, discharge the material, and measure that the free tocopherol content is 0.72%. Add 3 times of n-hexane again, cool down to 4 °C, and crystallize out succinic anhydride; separate α-tocopherol monosuccinate, solid base type IV configuration catalyst and succinic anhydride by filtration for reuse in the next reaction operation. Add 2 times of hot water to the alkane solution and wash twice. Finally, perform cold precipitation at -10 °C for 8 hours, filter to obtain high-purity α-tocopherol monosuccinate fine product, and then vacuum-dry the α-tocopherol monosuccinate fine product at a vacuum drying temperature of 60 °C to obtain the final product of 115.5 g; the molar yield of tocopherol reaches 94.7%; the GC analysis content is 99.1%, and the measured total nitrogen residue is 0.013 mg / L.

[0057] The NMR data of the final product are as follows (see Figure 1 、 Figure 2 、 Figure 3 ):

[0058] 1 H NMR(400MHz,CDCl 3 )δ11.25(s,1H),2.95(t,J=5.9Hz,2H),2.84(t,J=6.0Hz,2H),2.62(t,J=6.5Hz,2H),2.13(s,3H),2.06(s,3H),2.02(s,3H),1.89–1.75(m,2H),1.61–1.53(m,3H),1.50–1.40(m,2H),1.38–1.24(m,12H),1.25–1.07(m,6H),0.93–0.90(m,12H);

[0059] 13 C NMR(126MHz,CDCl 3 )δ178.03,170.92,149.30,140.36,126.59,124.85,122.88,117.24,74.91,39.29,37.46(d,J=3.0Hz),37.37,37.31,37.20,32.69(d,J=2.0Hz),32.60(d,J=2.5Hz),29.12,28.62,27.89,24.74(d,J=1.9Hz),24.37,22.66,22.57,20.95,20.50,19.68,19.62,19.58,19.55,19.52,12.79,11.93,11.73;

[0060] 13C DEPT-135(126MHz,CDCl 3 ) δ 39.45, 37.62 (d, J = 3.0 Hz), 37.53, 37.47, 37.36, 32.86 (d, J = 2.5 Hz), 32.60 (d, J = 2.5 Hz), 29.28, 28.78, 28.05, 24.91 (d, J = 1.9 Hz), 24.52, 22.82, 22.72, 21.10, 20.65, 19.84, 19.78, 19.74, 19.71, 19.68, 12.95, 12.09, 11.89。

[0061] Example 3:

[0062] Take 100.0 g of synthetic dl-α-tocopherol (α-tocopherol content 98.2%) and 25.1 g of succinic anhydride (molar ratio 1:1.1) as raw materials, use solid base type Ⅳ configuration as the catalyst, and the catalyst feeding ratio is 7%. Add them into the autoclave in sequence; use N 2 Replace the air in the autoclave 3 times, and then use H 2 Replace 3 times. Then maintain a hydrogen pressure of 60 kPa, heat up to 65 °C, keep warm for 4 hours. After the reaction ends, cool down to below 50 °C and discharge. The content of free tocopherol is measured to be 0.50%. Then add 3 times of n-hexane, cool down to 4 °C, and succinic anhydride crystallizes out; separate α-tocopherol succinate monoester, solid base type Ⅳ configuration catalyst and succinic anhydride by filtration for reuse in the next reaction operation. Add 2 times of hot water to the alkane solution and wash 2 times. Finally, cool and crystallize at -10 °C for 8 hours, filter to obtain α-tocopherol succinate monoester of relatively high purity. Then vacuum dry the α-tocopherol succinate monoester at a vacuum drying temperature of 50 °C to obtain 110.5 g of the final product; the molar yield of tocopherol reaches 91.2%; the GC analysis content is 99.3%, and the total nitrogen residue is measured to be 0.009 mg / L.

[0063] The NMR data of the final product are as follows (see Figure 1 , Figure 2 , Figure 3 ):

[0064] 1 H NMR (400 MHz, CDCl 3)δ11.25(s,1H),2.95(t,J=5.9Hz,2H),2.84(t,J=6.0Hz,2H),2.62(t,J=6.5Hz,2H),2.13(s,3H),2.06(s,3H),2.02(s,3H),1.89–1.75(m,2H),1.61–1.53(m,3H),1.50–1.40(m,2H),1.38–1.24(m,12H),1.25–1.07(m,6H),0.93–0.90(m,12H);

[0065] 13 C NMR(126MHz,CDCl 3 )δ178.03,170.92,149.30,140.36,126.59,124.85,122.88,117.24,74.91,39.29,37.46(d,J=3.0Hz),37.37,37.31,37.20,32.69(d,J=2.0Hz),32.60(d,J=2.5Hz),29.12,28.62,27.89,24.74(d,J=1.9Hz),24.37,22.66,22.57,20.95,20.50,19.68,19.62,19.58,19.55,19.52,12.79,11.93,11.73;

[0066] 13 C DEPT-135(126MHz,CDCl 3 )δ39.45,37.62(d,J=3.0Hz),37.53,37.47,37.36,32.86(d,J=2.5Hz),32.60(d,J=2.5Hz),29.28,28.78,28.05,24.91(d,J=1.9Hz),24.52,22.82,22.72,21.10,20.65,19.84,19.78,19.74,19.71,19.68,12.95,12.09,11.89。

[0067] Example 4:

[0068] Take 100.0 g of synthetic d-α-tocopherol (α-tocopherol content 99.2%) and 25.3 g of succinic anhydride (molar ratio 1:1.1) as raw materials, use a solid base V configuration as the catalyst, and the catalyst feeding ratio is 7%. Add them to the autoclave in sequence; use N 2 Replace the air in the autoclave 3 times, and then use H 2Replace three times, then maintain a hydrogen pressure of 1.0 kPa, heat up to 50 °C, keep warm for 4 hours, end the reaction, discharge the material, and measure the free tocopherol content to be 0.51%. Add 3 times of n-hexane again, cool down to 5 °C, and crystallize out succinic anhydride; separate α-tocopherol monosuccinate, solid base Ⅳ configuration catalyst and succinic anhydride by filtration for reuse in the next reaction operation. Add 2 times of hot water to the alkane solution and wash it twice. Finally, cool and precipitate at -20 °C for 8 hours, filter to obtain high-purity α-tocopherol monosuccinate fine product, and then vacuum dry the α-tocopherol monosuccinate fine product at a vacuum drying temperature of 40 °C to obtain the final product of 111.2 g; the molar yield of tocopherol reaches 91.5%; the GC analysis content is 99.5%, and the measured total nitrogen residue is 0.0075 mg / L.

[0069] The NMR data of the final product are as follows (see Figure 1 、 Figure 2 、 Figure 3 ):

[0070] 1 H NMR(400MHz,CDCl 3 )δ11.25(s,1H),2.95(t,J=5.9Hz,2H),2.84(t,J=6.0Hz,2H),2.62(t,J=6.5Hz,2H),2.13(s,3H),2.06(s,3H),2.02(s,3H),1.89–1.75(m,2H),1.61–1.53(m,3H),1.50–1.40(m,2H),1.38–1.24(m,12H),1.25–1.07(m,6H),0.93–0.90(m,12H);

[0071] 13 C NMR(126MHz,CDCl 3 )δ178.03,170.92,149.30,140.36,126.59,124.85,122.88,117.24,74.91,39.29,37.46(d,J=3.0Hz),37.37,37.31,37.20,32.69(d,J=2.0Hz),32.60(d,J=2.5Hz),29.12,28.62,27.89,24.74(d,J=1.9Hz),24.37,22.66,22.57,20.95,20.50,19.68,19.62,19.58,19.55,19.52,12.79,11.93,11.73;

[0072] 13C DEPT-135(126MHz,CDCl 3 ) δ 39.45, 37.62 (d, J = 3.0 Hz), 37.53, 37.47, 37.36, 32.86 (d, J = 2.5 Hz), 32.60 (d, J = 2.5 Hz), 29.28, 28.78, 28.05, 24.91 (d, J = 1.9 Hz), 24.52, 22.82, 22.72, 21.10, 20.65, 19.84, 19.78, 19.74, 19.71, 19.68, 12.95, 12.09, 11.89。

[0073] Example 5:

[0074] Take 100.0 g of synthetic dl-α-tocopherol (α-tocopherol content 98.2%) and 27.4 g of succinic anhydride (molar ratio 1:1.2) as raw materials, use solid base type III configuration as the catalyst, and the catalyst feeding ratio is 8.5%. Add them into the autoclave in sequence; use N 2 to displace the air in the autoclave 3 times, and then use H 2 to displace 3 times. Then maintain a hydrogen pressure of 80 kPa, heat up to 75 °C, keep warm for 3 hours. After the reaction is over, cool down to below 50 °C and discharge. The content of free tocopherol is measured to be 0.50%. Then add 3 times of n-hexane, cool down to 4 °C, and succinic anhydride crystallizes out; separate α-tocopherol succinate monoester, solid base type III catalyst and succinic anhydride by filtration for reuse in the next reaction operation. Add 2 times of hot water to the alkane solution and wash 2 times. Finally, cool and precipitate at -10 °C for 8 hours, filter to obtain α-tocopherol succinate monoester with relatively high purity. Then vacuum dry the α-tocopherol succinate monoester at a vacuum drying temperature of 70 °C to obtain the final product 109.1 g; the molar yield of tocopherol reaches 90.3%; the GC analysis content is 98.8%, and the total nitrogen residue is measured to be 0.015 mg / L.

[0075] The NMR data of the final product are as follows (see Figure 1 , Figure 2 , Figure 3 ):

[0076] 1 H NMR (400 MHz, CDCl 3)δ11.25(s,1H),2.95(t,J=5.9Hz,2H),2.84(t,J=6.0Hz,2H),2.62(t,J=6.5Hz,2H),2.13(s,3H),2.06(s,3H),2.02(s,3H),1.89–1.75(m,2H),1.61–1.53(m,3H),1.50–1.40(m,2H),1.38–1.24(m,12H),1.25–1.07(m,6H),0.93–0.90(m,12H);

[0077] 13 C NMR(126MHz,CDCl 3 )δ178.03,170.92,149.30,140.36,126.59,124.85,122.88,117.24,74.91,39.29,37.46(d,J=3.0Hz),37.37,37.31,37.20,32.69(d,J=2.0Hz),32.60(d,J=2.5Hz),29.12,28.62,27.89,24.74(d,J=1.9Hz),24.37,22.66,22.57,20.95,20.50,19.68,19.62,19.58,19.55,19.52,12.79,11.93,11.73;

[0078] 13 C DEPT-135(126MHz,CDCl 3 )δ39.45,37.62(d,J=3.0Hz),37.53,37.47,37.36,32.86(d,J=2.5Hz),32.60(d,J=2.5Hz),29.28,28.78,28.05,24.91(d,J=1.9Hz),24.52,22.82,22.72,21.10,20.65,19.84,19.78,19.74,19.71,19.68,12.95,12.09,11.89。

[0079] Example 6:

[0080] Take 100.0 g of synthetic dl-α-tocopherol (α-tocopherol content 98.2%) and 27.4 g of succinic anhydride (molar ratio 1:1.2) as raw materials, use solid base type III configuration as the catalyst, and the catalyst feeding ratio is 8.5%. Add them into the autoclave in sequence; use N 2 Replace the air in the autoclave 3 times, and then use H 2Replace three times, then maintain a hydrogen pressure of 80 kPa, heat up to 75 °C, keep the temperature for 3 hours, end the reaction, cool down to below 50 °C, discharge the material, and measure the free tocopherol content to be 0.50%. Add 3 times of n-hexane, cool down to 4 °C, and crystallize succinic anhydride; separate α-tocopherol succinate monoester, solid base Ⅲ configuration catalyst and succinic anhydride by filtration for reuse in the next reaction operation. Add 2 times of hot water to the alkane solution and wash it twice. Finally, perform cold precipitation at -10 °C for 8 hours, filter to obtain high-purity α-tocopherol succinate monoester product. Then, vacuum dry the α-tocopherol succinate monoester product at a vacuum drying temperature of 70 °C to obtain 109.1 g of the final product; the molar yield of tocopherol reaches 90.3%; the GC analysis content is 98.8%, and the measured total nitrogen residue is 0.015 mg / L.

[0081] The NMR data of the final product are as follows (see Figure 1 、 Figure 2 、 Figure 3 ):

[0082] 1 H NMR(400MHz,CDCl 3 )δ11.25(s,1H),2.95(t,J=5.9Hz,2H),2.84(t,J=6.0Hz,2H),2.62(t,J=6.5Hz,2H),2.13(s,3H),2.06(s,3H),2.02(s,3H),1.89–1.75(m,2H),1.61–1.53(m,3H),1.50–1.40(m,2H),1.38–1.24(m,12H),1.25–1.07(m,6H),0.93–0.90(m,12H);

[0083] 13 C NMR(126MHz,CDCl 3 )δ178.03,170.92,149.30,140.36,126.59,124.85,122.88,117.24,74.91,39.29,37.46(d,J=3.0Hz),37.37,37.31,37.20,32.69(d,J=2.0Hz),32.60(d,J=2.5Hz),29.12,28.62,27.89,24.74(d,J=1.9Hz),24.37,22.66,22.57,20.95,20.50,19.68,19.62,19.58,19.55,19.52,12.79,11.93,11.73;

[0084] 13C DEPT-135(126MHz,CDCl 3 ) δ 39.45, 37.62 (d, J = 3.0 Hz), 37.53, 37.47, 37.36, 32.86 (d, J = 2.5 Hz), 32.60 (d, J = 2.5 Hz), 29.28, 28.78, 28.05, 24.91 (d, J = 1.9 Hz), 24.52, 22.82, 22.72, 21.10, 20.65, 19.84, 19.78, 19.74, 19.71, 19.68, 12.95, 12.09, 11.89。

[0085] Example 7:

[0086] Take 100.0 g of synthetic dl-α-tocopherol (α-tocopherol content 99.0%) and 27.5 g of succinic anhydride (molar ratio 1:1.2) as raw materials, use solid base type IV configuration as the catalyst, and the catalyst feeding ratio is 10%. Add them to the autoclave in sequence; use N 2 Replace the air in the autoclave 3 times, and then use H 2 Replace 3 times, then maintain a hydrogen pressure of 100 kPa, heat up to 80 °C, keep warm for 3 hours, end the reaction, cool down to below 50 °C, discharge the material, and measure the free tocopherol content to be 0.67%. Then add 3 times of n-hexane, cool down to 20 °C, and crystallize out succinic anhydride; separate α-tocopherol monosuccinate, solid base type V configuration catalyst and succinic anhydride by filtration for reuse in the next reaction operation. Add 2 times of hot water to the alkane solution and wash 2 times. Finally, perform cold precipitation at -5 °C for 8 hours, filter to obtain α-tocopherol monosuccinate fine product with relatively high purity, and then vacuum dry the α-tocopherol monosuccinate fine product at a vacuum drying temperature of 65 °C to obtain 109.1 g of the final product; the molar yield of tocopherol reaches 91.1%; the GC analysis content is 98.9%, and the total nitrogen residue is measured to be 0.008 mg / L.

[0087] The NMR data of the final product are as follows (see Figure 1 , Figure 2 , Figure 3 ):

[0088] 1 H NMR (400 MHz, CDCl 3)δ11.25(s,1H),2.95(t,J=5.9Hz,2H),2.84(t,J=6.0Hz,2H),2.62(t,J=6.5Hz,2H),2.13(s,3H),2.06(s,3H),2.02(s,3H),1.89–1.75(m,2H),1.61–1.53(m,3H),1.50–1.40(m,2H),1.38–1.24(m,12H),1.25–1.07(m,6H),0.93–0.90(m,12H);

[0089] 13 C NMR(126MHz,CDCl 3 )δ178.03,170.92,149.30,140.36,126.59,124.85,122.88,117.24,74.91,39.29,37.46(d,J=3.0Hz),37.37,37.31,37.20,32.69(d,J=2.0Hz),32.60(d,J=2.5Hz),29.12,28.62,27.89,24.74(d,J=1.9Hz),24.37,22.66,22.57,20.95,20.50,19.68,19.62,19.58,19.55,19.52,12.79,11.93,11.73;

[0090] 13 C DEPT-135(126MHz,CDCl 3 )δ39.45,37.62(d,J=3.0Hz),37.53,37.47,37.36,32.86(d,J=2.5Hz),32.60(d,J=2.5Hz),29.28,28.78,28.05,24.91(d,J=1.9Hz),24.52,22.82,22.72,21.10,20.65,19.84,19.78,19.74,19.71,19.68,12.95,12.09,11.89。

[0091] Example 8:

[0092] Take 100.0 g of synthetic dl-α-tocopherol (α-tocopherol content 99.2%) and 25.3 g of succinic anhydride (molar ratio 1:1.1) as raw materials, use solid base type III configuration as the catalyst, and the catalyst feeding ratio is 7%. Add them into the autoclave in sequence; use N 2 Replace the air in the autoclave 3 times, and then use H 2Replace three times, then maintain a hydrogen pressure of 80 kPa, heat up to 30 °C, keep warm for 5 hours, end the reaction, discharge the material, and measure that the free tocopherol content is 0.51%. Then add 3 times of n-hexane, cool down to 10 °C, and crystallize succinic anhydride; separate α-tocopherol succinate monoester, solid base Ⅳ configuration catalyst and succinic anhydride by filtration for reuse in the next reaction operation. Add 2 times of hot water to the alkane solution and wash it twice. Finally, perform cold precipitation at -50 °C for 8 hours, filter to obtain α-tocopherol succinate monoester with relatively high purity, and then vacuum dry this α-tocopherol succinate monoester at a vacuum drying temperature of 70 °C to obtain 112.1 g of the final product; the molar yield of tocopherol reaches 92.4%; the GC analysis content is 99.2%, and the measured total nitrogen residue is 0.009 mg / L.

[0093] The NMR data of the final product are as follows (see Figure 1 、 Figure 2 、 Figure 3 ):

[0094] 1 H NMR (400 MHz, CDCl 3 ) δ 11.25 (s, 1H), 2.95 (t, J = 5.9 Hz, 2H), 2.84 (t, J = 6.0 Hz, 2H), 2.62 (t, J = 6.5 Hz, 2H), 2.13 (s, 3H), 2.06 (s, 3H), 2.02 (s, 3H), 1.89–1.75 (m, 2H), 1.61–1.53 (m, 3H), 1.50–1.40 (m, 2H), 1.38–1.24 (m, 12H), 1.25–1.07 (m, 6H), 0.93–0.90 (m, 12H);

[0095] 13 C NMR (126 MHz, CDCl 3 ) δ 178.03, 170.92, 149.30, 140.36, 126.59, 124.85, 122.88, 117.24, 74.91, 39.29, 37.46 (d, J = 3.0 Hz), 37.37, 37.31, 37.20, 32.69 (d, J = 2.0 Hz), 32.60 (d, J = 2.5 Hz), 29.12, 28.62, 27.89, 24.74 (d, J = 1.9 Hz), 24.37, 22.66, 22.57, 20.95, 20.50, 19.68, 19.62, 19.58, 19.55, 19.52, 12.79, 11.93, 11.73;

[0096] 13C DEPT-135(126MHz,CDCl 3 ) δ 39.45, 37.62 (d, J = 3.0 Hz), 37.53, 37.47, 37.36, 32.86 (d, J = 2.5 Hz), 32.60 (d, J = 2.5 Hz), 29.28, 28.78, 28.05, 24.91 (d, J = 1.9 Hz), 24.52, 22.82, 22.72, 21.10, 20.65, 19.84, 19.78, 19.74, 19.71, 19.68, 12.95, 12.09, 11.89。

[0097] Example 9: Control Example (Triethylamine Catalysis)

[0098] Take 100.0 g of natural d-α-tocopherol (α-tocopherol content 99.2%) and 27.5 g of succinic anhydride (molar ratio 1:1.1) as raw materials, use triethylamine as the catalyst, and the catalyst feeding ratio is 2% (mass ratio of tocopherol), and add them into the autoclave in sequence; use N 2 Replace the air in the autoclave 3 times, heat up to 30 °C, keep warm for 4 hours, end the reaction, discharge the material, and measure that the free tocopherol content is 0.42%. Then add 3 times of n-hexane, cool down to 4 °C, and crystallize out succinic anhydride; separate α-tocopherol monosuccinate, triethylamine and succinic anhydride by filtration. Add 2 times of hot water to the alkane solution and wash 2 times. Finally, cool and precipitate at -10 °C for 8 hours, filter to obtain α-tocopherol monosuccinate with relatively high purity, and then vacuum dry this α-tocopherol monosuccinate at a vacuum drying temperature of 60 °C to obtain 115.5 g of the final product; the molar yield of tocopherol reaches 95.8%; the GC analysis content is 99.2%, and the total nitrogen residue is measured to be 5000 mg / L.

[0099] The NMR data of this final product are as follows (see Figure 1 , Figure 2 , Figure 3 ):

[0100] 1 H NMR (400 MHz, CDCl 3 ) δ 11.25 (s, 1H), 2.95 (t, J = 5.9 Hz, 2H), 2.84 (t, J = 6.0 Hz, 2H), 2.62 (t, J = 6.5 Hz, 2H), 2.13 (s, 3H), 2.06 (s, 3H), 2.02 (s, 3H), 1.89–1.75 (m, 2H), 1.61–1.53 (m, 3H), 1.50–1.40 (m, 2H), 1.38–1.24 (m, 12H), 1.25–1.07 (m, 6H), 0.93–0.90 (m, 12H);

[0101] 13 13C NMR (126 MHz, CDCl 3 ) δ 178.03, 170.92, 149.30, 140.36, 126.59, 124.85, 122.88, 117.24, 74.91, 39.29, 37.46 (d, J = 3.0 Hz), 37.37, 37.31, 37.20, 32.69 (d, J = 2.0 Hz), 32.60 (d, J = 2.5 Hz), 29.12, 28.62, 27.89, 24.74 (d, J = 1.9 Hz), 24.37, 22.66, 22.57, 20.95, 20.50, 19.68, 19.62, 19.58, 19.55, 19.52, 12.79, 11.93, 11.73;

[0102] 13 13C DEPT-135 (126 MHz, CDCl 3 ) δ 39.45, 37.62 (d, J = 3.0 Hz), 37.53, 37.47, 37.36, 32.86 (d, J = 2.5 Hz), 32.60 (d, J = 2.5 Hz), 29.28, 28.78, 28.05, 24.91 (d, J = 1.9 Hz), 24.52, 22.82, 22.72, 21.10, 20.65, 19.84, 19.78, 19.74, 19.71, 19.68, 12.95, 12.09, 11.89.

[0103] It should be noted that the above-mentioned invention content and specific implementation manners are intended to prove the practical application of the technical solution provided by the present invention, including the preparation method of the catalyst; it should not be construed as a limitation on the protection scope of the present invention. Those skilled in the art can make various modifications, equivalent substitutions, or improvements within the spirit and principle of the present invention.

Claims

1. A preparation method of natural or synthetic α-tocopherol succinate monoester, the preparation method comprising the following steps: 1) Sequentially put α-tocopherol, succinic anhydride, and solid base into an autoclave; the solid base is a strongly basic resin; the strongly basic resin is a pyridine-type resin as shown in the solid base III configuration, an imidazole-type resin as shown in the solid base IV configuration, or a quaternary ammonium salt-type resin as shown in the solid base V configuration; R1 is a resin material R1 is a resin material R1 is a resin material 2) Keep the hydrogen pressure in the autoclave at 1-100 kPa; 3) Gradually raise the temperature and react at a temperature of 30-80 °C; 4) Crystallize and filter to obtain a filtrate; subject the filtrate to cold precipitation and recrystallization to precipitate wet α-tocopherol succinate monoester; and 5) Vacuum-dry the wet α-tocopherol succinate monoester to obtain high-quality α-tocopherol succinate monoester.

2. The method according to claim 1, wherein, in step 1), the α-tocopherol is natural d-α-tocopherol or synthetic dl-α-tocopherol.

3. The method according to claim 1, wherein, in step 1), the molar ratio of α-tocopherol to succinic anhydride is 1:1.1-2.

5.

4. The method according to claim 3, wherein, in step 1), the molar ratio of α-tocopherol to succinic anhydride is 1:1.1-1.

6.

5. The method according to claim 4, wherein, in step 1), the molar ratio of α-tocopherol to succinic anhydride is 1:1.1-1.

2.

6. The method according to claim 1, wherein, in step 1), the weight ratio of the solid base to the α-tocopherol is 0.1-30%.

7. The method according to claim 6, wherein, in step 1), the weight ratio of the solid base to the α-tocopherol is 1-20%.

8. The method according to claim 7, wherein, in step 1), the weight ratio of the solid base to the α-tocopherol is 5-10%.

9. The method according to claim 1, wherein, in step 2), the hydrogen pressure in the autoclave is 50-80 kPa.

10. The method according to claim 1, wherein, in step 3), the reaction temperature is 50-75 °C and the reaction time is 2-5 hours.

11. The method according to claim 1, wherein, in step 4), the crystallization conditions are adding 1-10 times n-hexane and cold-precipitating at a temperature of 5-20 °C for 8-10 hours, and filtering to obtain a filtrate.

12. The method according to claim 11, wherein, in step 4), after the filtrate is washed with 1-10 times hot water, it is cold-precipitated and recrystallized at a temperature of -20 to -5 °C to precipitate a solid.

13. The method according to claim 12, wherein, in step 4), the recrystallized α-tocopherol succinate monoester is vacuum-dried at 40-70 °C for 3-6 hours.

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