Isomerization method of vitamin A

Abstract

According to the isomerization method of the vitamin A, the cis-isomer of the vitamin A can be efficiently converted into all-trans-vitamin A through the reaction in the specific solvent, in addition, a certain amount of the second component solvent is introduced into the reaction system, and the conversion rate and selectivity of the isomerization reaction are greatly improved.

Description

Technical Field

[0001] The invention relates to the field of chemical synthesis, and in particular to a vitamin A isomerization process. Background Art

[0002] Vitamin A acetate is an important substance used in the fields of medicine, cosmetics, food, animal nutrition feed additives, etc. It is one of the essential nutrients for the human body and an indispensable trace element in the growth and development of children. Therefore, many chemists are committed to the synthesis research of vitamin A and its derivatives.

[0003] In order to isomerize the 11-cis isomer and 9-cis isomer of vitamin A acetate to the all-trans structure, there are three existing technologies: iodine catalysis, photocatalysis and metal catalysis. However, all three methods have certain defects and shortcomings. Among them, the catalyst commonly used in iodine catalysis is iodide salt, or iodine is used for catalytic reaction. A large amount of iodine-containing wastewater will be produced in this process, which will cause serious environmental pollution; photocatalytic isomerization reaction requires the addition of photosensitizer to the system in advance. The presence of photosensitizer will cause the instability of the structure of vitamin A acetate and bring great difficulties to the subsequent separation process; the catalytic system commonly used in metal catalysis is metal iodide or precious metal catalyst. The comprehensive utilization of catalysts in this process is low, the cost is high, the post-processing steps are complicated, and it is easy to cause environmental pollution. Summary of the invention

[0004] The present invention provides a new method for isomerization of vitamin A, which realizes the efficient conversion of cis-isomer of vitamin A into all-trans-vitamin A without adding an additional catalyst, and solves the problems of large pollution, poor catalytic efficiency, and high cost of using precious metal catalysts in the existing process.

[0005] To achieve the above object, the present invention adopts the following technical solutions:

[0006] A novel method for isomerization of vitamin A, comprising the following steps:

[0007] 1) Add a certain proportion of solvent and miscellaneous oil containing VA isomers into the reactor under stirring;

[0008] 2) raising the reactor to a certain temperature and reacting for a certain period of time;

[0009] 3) Add the second component solvent into the reaction kettle and continue to keep the temperature for a certain period of time;

[0010] 4) After the reaction is completed, high-purity all-trans VA oil is obtained through post-treatment.

[0011] In the present invention, preferably, the solvent in step 1) is one or more of toluene, xylene, ethylbenzene, and cumene, preferably toluene;

[0012] Preferably, the weight ratio of the solvent to the miscellaneous oil containing VA isomers (referred to as VA miscellaneous oil) in step 1) is 2 to 6:1, preferably 3 to 4:1;

[0013] Preferably, the VA miscellaneous oil in step 1) is first prepared by using β-vinylionol and triphenylphosphine as raw materials to prepare β-ionylethyl triphenylphosphonium salt, and then subjected to Wittig reaction with 4-acetoxy-2-methyl-but-2-enal, and concentrated after isomerization and crystallization, and the operation is a conventional prior art, wherein the all-trans content is ≤40%, and the total VA content is ≥70%, preferably ≥80%;

[0014] In the present invention, preferably, the certain temperature in step 2) is 40-120°C, preferably 60-80°C;

[0015] Preferably, the certain time in step 2) is 2-12 hours, preferably 4-6 hours;

[0016] In the present invention, preferably, the second component solvent in step 3) is one or more of dichloromethane, dichloroethane, and trichloroethane, preferably dichloromethane;

[0017] Preferably, in step 3), the amount of the second component solvent added is 1-20% by mass of the VA miscellaneous oil, preferably 5-10%;

[0018] Preferably, the reaction temperature in step 3) is 40-120°C, preferably 60-80°C;

[0019] Preferably, the reaction time of step 3) is 1-8h, preferably 3-5h;

[0020] In the present invention, preferably, the post-treatment method in step 4) is reduced pressure distillation, and the distillation temperature is controlled at 30° C.-60° C. and the pressure is 0.1-20 kPa.

[0021] In the present invention, the content of 11-cis isomer in the all-trans VA oil obtained by the above method is ≤0.5wt%, and the content of 9-cis isomer is ≤0.2wt%.

[0022] Compared with the prior art, the present invention has the following outstanding effects:

[0023] 1) The invention can efficiently complete the isomer conversion of vitamin A without adding additional catalysts;

[0024] 2) The post-processing is simple, and the product can be obtained by simple distillation;

[0025] 3) Compared with the existing process, this process produces almost no three wastes, greatly reduces production costs, and facilitates industrial production. DETAILED DESCRIPTION

[0026] It should be noted that the following detailed descriptions are all exemplary and are intended to provide further explanation of the present invention. Unless otherwise specified, all technical and scientific terms used herein have the same meanings as those generally understood by those of ordinary skill in the art to which the present invention belongs. The technical scheme of the present invention is further illustrated below by specific embodiments. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0027] Source of VA mixed oil: Wanhua Chemical.

[0028] Example 1

[0029] This embodiment provides a method for isomerization of vitamin A, comprising the following steps:

[0030] 1) Add 100 g of VA miscellaneous oil (total VA purity 87.5%, of which the total cis-VA content 47.5%) and 400 g of toluene into a reaction kettle under stirring, and stir to mix evenly;

[0031] 2) Raise the temperature of the reactor to 80°C and keep it warm for 6 hours;

[0032] 3) Add 10 g of dichloromethane to the reaction system and continue the reaction at the same temperature for 3 h;

[0033] 4) After the reaction is completed, the VA oil product is obtained by concentrating under reduced pressure (temperature 50°C, pressure 20 kPa).

[0034] The product obtained in Example 1 was subjected to the following tests:

[0035] 1) Yield test: isomerization conversion rate 99.7%, selectivity 99.8%.

[0036] 2) Purity test (HPLC): The total purity of the obtained VA oil is 87.3%, the content of all-trans VA is 87.05%, the content of 11-cis VA is 0.1%, and the content of 9-cis VA is 0.15%.

[0037] Example 2

[0038] 1) Add 100 g of VA miscellaneous oil (VA total purity 75%, of which the total content of cis-VA is 45%) and 200 g of xylene into the reactor under stirring, and stir to mix evenly;

[0039] 2) Raise the temperature of the reactor to 50°C and keep it warm for 12 hours;

[0040] 3) Add 2 g of ethylene dichloride to the reaction system and continue the reaction at the same temperature for 8 h;

[0041] 4) After the reaction is completed, the VA oil product is obtained by concentrating under reduced pressure (temperature 30°C, pressure 0.1 kPa).

[0042] The product obtained in Example 2 was subjected to the following tests:

[0043] 1) Yield test: isomerization conversion rate 99.6%, selectivity 99.7%.

[0044] 2) Purity test (HPLC): The total purity of the obtained VA oil was 75%, the content of all-trans VA was 74.68%, the content of 11-cis VA was 0.18%, and the content of 9-cis VA was 0.14%.

[0045] Example 3

[0046] 1) Add 100 g of VA miscellaneous oil (total VA purity 80.21%, cis-VA content 52.1%) and 600 g of cumene into a reaction kettle under stirring, and stir to mix evenly;

[0047] 2) Raise the temperature of the reactor to 120°C and keep it warm for 3 hours;

[0048] 3) Add 20 g of trichloroethane to the reaction system and continue the reaction at the same temperature for 1 h;

[0049] 4) After the reaction is completed, the VA oil product is obtained by concentrating under reduced pressure (temperature 60°C, pressure 20 kPa).

[0050] The product obtained in Example 3 was subjected to the following tests:

[0051] 1) Yield test: isomerization conversion rate 99.8%, selectivity 99.4%.

[0052] 2) Purity test (HPLC): The total purity of the obtained VA oil is 80.19%, the content of all-trans VA is 80.05%, the content of 11-cis VA is 0.11%, and the content of 9-cis VA is 0.03%.

[0053] Comparative Example

[0054] Patent CN100484919C mentions a way of isomerization of double bonds in carotenoids, that is, isomerization occurs in a high-boiling point polar solvent, the solvent includes glycerol, propylene glycol, monoacetin, diacetin or diethylene glycol monoethyl ester; in order to verify the feasibility of isomerization of vitamin A in this solvent system, the following comparative example is made.

[0055] Since vitamin A will undergo an ester exchange reaction when heated in polar protic solvents such as propylene glycol and glycerol, it is not feasible for isomerization to occur in propylene glycol and glycerol solvents. The following comparative examples only verify the other three solvents.

[0056] Example 1:

[0057] 300g VA miscellaneous oil (total purity of VA is 87.5%, of which cis-VA content is 37.5%) and 700g monoacetin are added to a 1000mL three-necked flask, the reaction temperature is controlled at 140°C, nitrogen is protected from light and the reaction is carried out for 4 hours, then the temperature is lowered to 100°C, and the reaction is continued for 25 hours. After the reaction is completed, the VA oil is concentrated to obtain VA oil. After quantitative analysis by liquid chromatography, the purity of VA oil is 63%, of which cis-isomer is 39.3%. Vitamin A cannot complete the conversion of isomers to all-trans VA under this reaction system, and all-trans VA has deteriorated due to long-term high temperature conditions.

[0058] Example 2:

[0059] 300g VA miscellaneous oil (total purity of VA is 87.5%, of which cis-VA content is 37.5%) and 700g diacetin are added to a 1000mL three-necked flask, the reaction temperature is controlled at 140°C, nitrogen is protected from light and the reaction is carried out for 4 hours, then the temperature is lowered to 100°C, and the reaction is continued for 25 hours. After the reaction is completed, the VA oil is concentrated to obtain VA oil. After quantitative analysis by liquid chromatography, the purity of VA oil is 72%, of which cis-isomer is 36.3%. Vitamin A cannot complete the conversion of isomers to all-trans VA under this reaction system, and all-trans VA has deteriorated due to long-term high temperature conditions.

[0060] Example 3:

[0061] 300g VA miscellaneous oil (total purity of VA is 87.5%, of which cis-VA content is 37.5%) and 700g diethylene glycol monoethyl ester were added to a 1000mL three-necked flask, the reaction temperature was controlled at 140°C, nitrogen was protected from light and the reaction was carried out for 4 hours, then the temperature was lowered to 100°C, and the reaction was continued for 25 hours. After the reaction was completed, the VA oil was concentrated to obtain VA oil. After quantitative analysis by liquid chromatography, the purity of VA oil was 81.5%, of which cis-isomers were 36.8%. Vitamin A could not complete the conversion of isomers to all-trans VA under this reaction system, and all-trans VA was deteriorated due to long-term high temperature conditions.

Claims

1. A method for isomerization of vitamin A, characterized in that: The method comprises the following steps: 1) Add a certain proportion of solvent and miscellaneous oil containing VA isomers into the reactor under stirring; 2) raising the reactor to a certain temperature and reacting for a certain period of time; 3) Add the second component solvent into the reaction kettle and continue to keep the temperature for a certain period of time; 4) After the reaction is completed, high-purity all-trans VA oil is obtained through post-treatment.

2. The heterogeneous method according to claim 1, characterized in that: In the miscellaneous oil containing VA isomers in step 1), the all-trans content is ≤40%, and the total VA content is ≥70%, preferably ≥80%.

3. The isomerization method according to claim 1 or 2, characterized in that: The solvent in step 1) is one or more of toluene, xylene, ethylbenzene, and cumene, preferably toluene.

4. The isomerization method according to any one of claims 1 to 3, characterized in that: Step 1) The weight ratio of the solvent to the VA miscellaneous oil is 2 to 6:

1.

5. The heterogeneous method according to claim 1, characterized in that: In step 2), the certain temperature is 40-120° C., and the certain time is 2-12 hours.

6. The heterogeneous method according to claim 1, characterized in that: Step 3) the second component solvent is one or more of dichloromethane, dichloroethane, trichloroethane, preferably dichloromethane.

7. The isomerization method according to claim 1 or 6, characterized in that: Step 3) The amount of the second component solvent added is 1-20% of the mass of the VA miscella oil.

8. The isomerization method according to any one of claims 1 to 7, characterized in that: Step 3) The reaction temperature is 40-120°C and the reaction time is 1-8h.

9. The heterogeneous method according to claim 1, characterized in that: Step 4) The post-treatment method is vacuum distillation, the distillation temperature is 30°C-60°C, and the pressure is 0.1-20kPa.

10. The heterogeneous method according to claim 1, characterized in that: The content of 11-cis isomer in all-trans VA oil is ≤0.5%, and the content of 9-cis isomer is ≤0.2%.