Preparation method of beta-carotene

Abstract

The invention discloses a preparation method of beta-carotene, which comprises the following steps: dissolving 3-methyl-5-(2, 6, 6-trimethyl-1-cyclohexene-1-yl)-2, 4-pentadienyl triphenylphosphine salt (C15 phosphine salt) cis-trans isomer and 2, 7-dimethyl-2, 4, 6-octtriene-1, 8-dialdehyde (C10) in water and a solvent system incompatible with the water, and carrying out wittig reaction under the action of alkali. The reaction system can prevent the byproduct inorganic salt from being wrapped in the product and reduce the content of inorganic salt impurities in the product. In addition, the proportion of cis-trans isomers of the C15 phosphonium salt is controlled, the hydrolysis side reaction of the C15 phosphonium salt is inhibited, and the reaction yield is increased.

Description

Technical Field

[0001] The invention relates to the field of beta-carotene synthesis, and in particular to a method for preparing all-trans beta-carotene through isomerization reaction. Background Art

[0002] β-Carotene (molecular formula C 40 H 56 β-carotene (β-carotene, with the structure shown below) is a precursor of vitamin A, commonly known as provitamin A, and is the first carotenoid to attract people's attention. β-carotene is an antioxidant with a detoxifying effect and is an indispensable nutrient for maintaining human health. In addition, β-carotene has significant functions in anti-cancer, prevention of cardiovascular disease, and cataracts, and can also prevent a variety of degenerative diseases caused by aging and senility. Therefore, it is widely used in the pharmaceutical, food, cosmetics, feed additives, dyes and other industries, and has a good market prospect.

[0003]

[0004] There are three main routes for the preparation of β-carotene. According to the carbon number of the raw materials, they can be divided into 2C15+C10 route, 2C19+C2 route, and C20+C20 route. Among them, the 2C15+C10 route can be divided into C15 phosphonate route and C15 phosphate route according to the raw materials. The C15 phosphonate route is characterized by the Wittig reaction, with relatively simple steps and low cost, which is very suitable for industrial application.

[0005] Currently, there are many technical reports on this method, such as US2006106257A1, US5689022A, CN108752251A, etc. The principle is that C15 phosphonate reacts with base to generate a ylide intermediate containing "C=P", and the intermediate reacts with aldehyde to generate a new double bond.

[0006]

[0007] In this route, the reaction of C15 phosphonium salt with alkali will produce inorganic salts as by-products. In the traditional process, the reaction is carried out in an organic solvent system, and the by-product salts may be coated in the product, resulting in a high amount of residual ions in the product. In view of this, there are also many technical attempts to solve this problem. For example, CN 113333025A has developed a catalyst that enables the reaction to be carried out under weak base conditions such as amines, but the catalyst preparation is complicated and is not conducive to industrial production. Summary of the invention

[0008] In view of the above problems existing in the prior art, the first object of the present invention is to provide a method for preparing β-carotene, which can avoid the by-product inorganic salts being encapsulated in the product and reduce the inorganic salt impurity content in the product.

[0009] The second purpose of the present invention is to improve the reaction yield by controlling the ratio of cis and trans isomers of C15 phosphonium salt, inhibiting the occurrence of C15 phosphonium salt hydrolysis side reaction, and improving the reaction yield.

[0010] To achieve the above object, the technical solution adopted by the present invention is as follows:

[0011] A method for preparing beta-carotene comprises the following steps:

[0012] The cis-trans isomers of C15 phosphonate and 2,7-dimethyl-2,4,6-octatriene-1,8-dialdehyde (C10) are dissolved in a solvent system and reacted under the action of a base to generate cis-trans isomers of beta-carotene. In the C15 phosphonate, the cis isomer accounts for 0.01%-25% of the total amount, preferably 1%-10%.

[0013] Furthermore, the cis- and trans-isomers of β-carotene are isomerized to obtain an all-trans β-carotene product.

[0014] In this process route, the ylide intermediate produced by the reaction is unstable. In addition to reacting with aldehydes, it can also undergo hydrolysis to generate hydrocarbons and triphenylphosphine oxide. This side reaction is one of the reasons for the low selectivity of the reaction, and the residual by-products will also cause the product purity to decrease. In an aqueous reaction system, this side reaction will inevitably be promoted. After research, when the proportion of cis isomers in the raw material C15 phosphine salt accounts for 0.01%-25% of the total amount, the selectivity and yield of the main reaction can be guaranteed to be unaffected. Reducing the proportion of cis isomers can be achieved by crystallization, thermal isomerization, etc. A lower proportion of cis isomers is beneficial to maintaining selectivity, but the higher standard separation requirements will lead to increased costs, which is economically unreasonable.

[0015] The structures of the C15 phosphonium salt, all-trans C15 phosphonium salt, cis-C15 phosphonium salt and C10 of the present invention are as follows:

[0016]

[0017] In the present invention, the molar ratio of the C10 to C15 phosphine salts is 1:2.05-3, preferably 1:2.3-2.5.

[0018] In a specific embodiment, the reaction process is as follows: C15 phosphine salt, C10 and solvent are laid as the base, an alkali solution is added dropwise, and the reaction is kept warm after the addition of the alkali solution.

[0019] In the present invention, in order to achieve the above first purpose, the solvent system used comprises water and a water-incompatible solvent, wherein the water-incompatible solvent comprises one or more of dichloromethane, 1,2-dichloroethane, C1-C8 hydrocarbons (e.g., n-hexane, n-heptane, toluene), and ethyl acetate, wherein dichloromethane is preferred. Preferably, the amount of water is 1-5 times, preferably 2-4 times, the total mass of the cis- and trans-isomers of the C15 phosphonium salt, and the amount of the water-incompatible solvent is 1-8 times, preferably 2-6 times, the total mass of the cis- and trans-isomers of the C15 phosphonium salt.

[0020] In the present invention, the alkali is an aqueous solution of an inorganic alkali or alkaline salt, including one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, lithium bicarbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, among which sodium hydroxide is preferred. The concentration of the aqueous solution is 10%-70%, preferably 20%-50%;

[0021] Preferably, the molar ratio of C10 to alkali is 1:2-4, preferably 1:2.5-3.5.

[0022] In the present invention, the reaction temperature is 0-60°C, preferably 20-40°C; the reaction time includes the alkali solution dropwise addition time and the insulation time, the dropwise addition time is 0.5-3h, preferably 1-2h, and the insulation time is preferably 1-8h, preferably 2-6h.

[0023] The cis-trans isomers of β-carotene obtained by the reaction are subjected to solvent replacement and isomerization to obtain an all-trans carotene product, and this process is well known to those skilled in the art.

[0024] The positive effects of the present invention are:

[0025] (1) The present invention uses water and a water-incompatible solvent system to prepare β-carotene via a 2C15+C10 route, thereby improving the problem of inorganic salt coating in the product and reducing the ion content in the isomerized product to below 60 ppm.

[0026] (2) The present invention can control the occurrence of the C15 ylide hydrolysis side reaction by controlling the cis-isomer ratio in the raw material C15 phosphine salt, thereby improving the selectivity of the main reaction, and the side reaction selectivity is less than 0.5%. DETAILED DESCRIPTION

[0027] The present invention is further described in detail below in conjunction with the embodiments. The scope of the present invention includes but is not limited to the enumerated embodiments.

[0028] Unless otherwise specified, the reagents described in the present invention were purchased from Inokai Technology Co., Ltd.

[0029] Liquid chromatography characterization: Agilent 1260 liquid chromatograph, chromatographic column Sphersorb C18 column The UV-visible spectrophotometer was Hitachi L7420, the chromatography workstation data processing system was Chomatopac C-RIA, the flow rate was 1 mL / min, and the wavelength was 455 nm.

[0030] Inorganic salt ion content test method: Inductively coupled plasma optical emission spectroscopy (ICP-OES).

[0031] Example 1

[0032] 17.28g C10 (0.1mol, 95%), 126.54g C15 phosphonium salt (0.25mol, 99%, cis content 0.05%, X=Cl), 189.8g water, 1012methylene chloride were added to a three-necked flask. The temperature was raised to 40°C under mechanical stirring, and a 30% aqueous solution of 13.33g sodium hydroxide (0.32mol, 96%) was added dropwise for 2h. The reaction was continued for 5h after the addition was completed. After the reaction was completed, the mixture was cooled to room temperature, separated, and the yield of the organic phase was tested. After the yield was tested, the reaction solution was concentrated, 5 times the mass of ethanol of the theoretical yield of β-carotene was added, and the isomerization reaction was carried out at 110°C. After the reaction was completed, the product of all-trans β-carotene was obtained by filtration, washing, and drying.

[0033] The yield of the wittig reaction was 90%, the selectivity of the C15 ylide hydrolysis reaction was 0.2%, the yield of the all-trans product was 85% (note: the main loss was the filtrate loss during filtration), and the residual inorganic salt ions in the all-trans product after isomerization were 58 ppm.

[0034] Example 2

[0035] 17.28g C10 (0.1mol, 95%), 103.76g C15 phosphonium salt (0.205mol, 99%, cis content 5%, X=Cl), 259.4g water, 155.64g ethyl acetate were added to a three-necked flask. The temperature was raised to 60°C under mechanical stirring, and a 15% aqueous solution of 13.71g potassium hydroxide (0.22mol, 90%) was added dropwise for 1h. After the addition was completed, the reaction was continued for 8h. After the reaction was completed, the mixture was cooled to room temperature, separated, and the yield of the organic phase was tested. After the yield was tested, the reaction solution was subjected to isomerization reaction in the same manner as in Example 1 to obtain an all-trans β-carotene product.

[0036] The yield of the wittig reaction was 89%, the selectivity of the C15 ylide hydrolysis reaction was 0.3%; the yield of the all-trans product was 84% ​​(note: the main loss was the filtrate loss during filtration), and the residual inorganic salt ions in the all-trans product after isomerization were 59 ppm.

[0037] Example 3

[0038] 17.28 g C10 (0.1 mol, 95%), 170.52 g C15 phosphonium salt (0.3 mol, 99%, cis content 25%, X = HSO4) were added into a three-necked flask. - ), 682g water, 506.14g n-heptane. Keep the temperature at 20°C under mechanical stirring, add 42.83g sodium carbonate (0.4mol, 99%) dissolved in 20% aqueous solution, the addition time is 3h, and the reaction is continued for 1h after the addition is completed. After the reaction is completed, cool to room temperature, separate the liquid, and test the yield of the organic phase. After testing the yield, the reaction solution is subjected to isomerization reaction in the same manner as in Example 1 to obtain the all-trans β-carotene product.

[0039] The yield of the wittig reaction was 88%, the selectivity of the C15 ylide hydrolysis reaction was 0.4%, the yield of the all-trans product was 83% (note: the main loss was the filtrate loss during filtration), and the residual inorganic salt ions in the all-trans product after isomerization were 55 ppm.

[0040] Comparative Example 1

[0041] The operation described in Reference Example 1 was followed, except that the cis-isomer content of the raw material C15 phosphonium salt was 50%.

[0042] The yield of the wittig reaction was 80%, the selectivity of the C15 ylide hydrolysis reaction was 2%, and the residual inorganic salt ions in the all-trans product after isomerization were 58 ppm.

[0043] Comparative Example 2

[0044] Refer to the operation described in Example 1 of patent CN108752251A. The selectivity of C15 ylide hydrolysis reaction is 1%, and the inorganic salt ion residue in the all-trans product after isomerization is 210ppm.

[0045] It is easy to understand that the above embodiments are only examples for clear explanation and do not mean that the present invention is limited thereto. For ordinary technicians in the relevant field, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived from this are still within the protection scope of the present invention.

Claims

1. A method for preparing beta-carotene, characterized in that: The cis-trans isomers of C15 phosphonate and 2,7-dimethyl-2,4,6-octatriene-1,8-dialdehyde are dissolved in a solvent system and react under the action of a base to generate cis-trans isomers of beta-carotene; wherein the cis-isomer in the C15 phosphonate accounts for 0.01%-25%, preferably 1%-10%.

2. The method according to claim 1, characterized in that: The C15 phosphonium salt structure is shown below:

3. The method according to claim 1 or 2, characterized in that: The molar ratio of 2,7-dimethyl-2,4,6-octatriene-1,8-dialdehyde to C15 phosphine salt is 1:2.05-3, preferably 1:2.3-2.

5.

4. The method according to any one of claims 1 to 3, characterized in that: The solvent system is water and a water-incompatible solvent system. Preferably, the water-incompatible solvent includes one or more of dichloromethane, 1,2-dichloroethane, C1-C8 hydrocarbons, and ethyl acetate, among which dichloromethane is preferred.

5. The method according to claim 4, characterized in that The amount of the water-incompatible solvent is 1-8 times, preferably 2-6 times, the total mass of the cis and trans isomers of the C15 phosphonium salt.

6. The method according to claim 4 or 5, characterized in that: In the water and water-incompatible solvent system, the amount of water used is 1-5 times, preferably 2-4 times, the total mass of the cis and trans isomers of the C15 phosphonium salt.

7. The method according to any one of claims 1 to 6, characterized in that: The base is an inorganic base or an alkaline salt, including one or more of lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, lithium bicarbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate, among which sodium hydroxide is preferred; the base is used in the form of an aqueous solution, and the concentration of the aqueous solution is 10%-70%, preferably 20%-50%.

8. The method according to any one of claims 1 to 7, characterized in that: The molar ratio of the 2,7-dimethyl-2,4,6-octatriene-1,8-dialdehyde to the base is 1:2-4, preferably 1:2.5-3.

5.

9. The method according to any one of claims 1 to 8, characterized in that: The reaction process comprises the following steps: C15 phosphonate, 2,7-dimethyl-2,4,6-octatriene-1,8-dialdehyde and solvent are used as the base, an alkali solution is added dropwise, and the reaction is carried out by heat preservation after the addition of the alkali solution. The reaction temperature is 0-60°C, preferably 20-40°C. The reaction time includes the alkali solution addition time and the heat preservation time. The addition time is 0.5-3h, preferably 1-2h, and the heat preservation time is 1-8h, preferably 2-6h.

10. The method according to any one of claims 1 to 9, characterized in that: The cis-trans isomers of β-carotene are isomerized to obtain the all-trans β-carotene product.

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