A process for the preparation of beta-carotene

Abstract

The application discloses a preparation method of beta-carotene, which comprises the following steps: 3-methyl-5-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4-pentadienyl triphenyl phosphonium salt (C15 phosphonium salt) cis-trans isomer and 2,7-dimethyl-2,4,6-octatriene-1,8-dial (C10) are dissolved in a water and a water incompatible solvent system, and Wittig reaction is generated under the action of an alkali. The reaction system can avoid that by-product inorganic salt is wrapped in the product, and the content of inorganic salt impurities in the product is reduced. In addition, the proportion of C15 phosphonium salt cis-trans isomer is controlled, a C15 phosphonium salt hydrolysis side reaction is inhibited, and the reaction yield is improved.

Description

Technical Field

[0001] This invention relates to the field of β-carotene synthesis, and more specifically to a method for preparing all-trans β-carotene via an isomerization reaction. Background Technology

[0002] β-Carotene (molecular formula C 40 H 56 β-carotene (with the structure shown below) is a precursor to vitamin A, commonly known as provitamin A, and was one of the first carotenoids to attract attention. β-carotene is an antioxidant with detoxifying properties and is an essential nutrient for maintaining human health. Furthermore, β-carotene has significant functions in anti-cancer activity, prevention of cardiovascular disease, and cataracts, and can also prevent various degenerative diseases caused by aging. Therefore, it is widely used in the pharmaceutical, food, cosmetic, feed additive, and dye industries, and has a promising market prospect.

[0003]

[0004] There are three main routes for the preparation of β-carotene, which can be divided into the 2C15+C10 route, the 2C19+C2 route, and the C20+C20 route, depending on the number of carbon atoms in the raw materials. The 2C15+C10 route can be further divided into the C15 phosphine salt route and the C15 phosphate ester route, depending on the raw materials. The C15 phosphine salt route is characterized by the Wittig reaction, which is relatively simple, low-cost, and very suitable for industrial applications.

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

[0006]

[0007] In this route, the reaction of C15 phosphine salts with alkali produces inorganic salts as a byproduct. In traditional processes, the reaction is carried out in an organic solvent system, and these byproduct salts may coat the product, resulting in a high residual ion content. Many technologies have been attempted to address this issue. For example, CN 113333025A developed a catalyst that allows the reaction to proceed under weakly alkaline conditions such as amines; however, the catalyst preparation is complex and not conducive to industrial production. Summary of the Invention

[0008] To address the aforementioned problems in the prior art, the first objective of this invention is to provide a method for preparing β-carotene that avoids byproduct inorganic salts being encapsulated in the product, thereby reducing the content of inorganic salt impurities in the product.

[0009] The second objective of this invention is to improve the reaction yield by controlling the ratio of cis-trans isomers of C15 phosphine salt, thereby suppressing the hydrolysis side reaction of C15 phosphine salt and improving the reaction yield.

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

[0011] A method for preparing β-carotene includes the following steps:

[0012] The cis-trans isomer of C15 phosphine salt is dissolved in a solvent system with 2,7-dimethyl-2,4,6-octtrien-1,8-dialdehyde (C10), and reacts under the action of a base to generate the cis-trans isomer of β-carotene. The cis isomer accounts for 0.01%-25% of the total amount of the C15 phosphine salt, preferably 1%-10%.

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

[0014] In this process, the ylide intermediate produced by the reaction is unstable and, in addition to reacting with aldehydes, can undergo hydrolysis to generate hydrocarbons and triphenylphosphine oxide. This side reaction is one of the reasons for the low reaction selectivity, and the residual byproducts also reduce product purity. In an aqueous reaction system, this side reaction is inevitably promoted. Studies have shown that when the proportion of cis isomers in the raw material C15 phosphine salt is between 0.01% and 25% of the total, the selectivity and yield of the main reaction remain unaffected. Reducing the proportion of cis isomers can be achieved through crystallization, thermal isomerization, etc. A lower proportion of cis isomers is beneficial for maintaining selectivity, but higher separation standards would lead to increased costs, which is economically unreasonable.

[0015] The structures of the C15 phosphine salt, all-trans C15 phosphine salt, cis C15 phosphine salt, and C10 salt described in this invention are as follows:

[0016]

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

[0018] In one specific embodiment, the reaction process involves laying a base of C15 phosphine salt, C10 solvent, and adding an alkaline solution dropwise, followed by maintaining the temperature for the reaction after the alkaline solution has been added.

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

[0020] In this invention, the alkali is an aqueous solution of an inorganic alkali 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, with sodium hydroxide being 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, more preferably 1:2.5-3.5.

[0022] In this invention, the reaction temperature is 0-60℃, preferably 20-40℃; the reaction time includes the alkali addition time and the heat preservation time, the addition time is 0.5-3h, preferably 1-2h, and the heat preservation time is preferably 1-8h, preferably 2-6h.

[0023] The reaction yields β-carotene cis-trans isomers, which are then subjected to solvent displacement and isomerization to obtain all-trans carotene product. This process is well known to those skilled in the art.

[0024] The positive effects of this invention are as follows:

[0025] (1) The present invention uses water and a water-insoluble solvent system to prepare β-carotene via the 2C15+C10 route, which can improve the problem of coating inorganic salts in the product and reduce the ion content in the isomerized product to below 60ppm.

[0026] (2) By controlling the proportion of cis-isocyanates in the raw material C15 phosphine salt, the present invention can control the occurrence of C15 ylide hydrolysis side reactions, improve the selectivity of the main reaction, and the selectivity of the side reactions is less than 0.5%. Detailed Implementation

[0027] The present invention will be further described in detail below with reference to the embodiments. The scope of the present invention includes, but is not limited to, the listed embodiments.

[0028] Unless otherwise specified, all reagents described in this invention were purchased from Innovent Biologics Inc.

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

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

[0031] Example 1

[0032] In a three-necked flask, 17.28 g of C10 (0.1 mol, 95%), 126.54 g of C15 phosphine salt (0.25 mol, 99%, cis content 0.05%, X = Cl), 189.8 g of water, and 10¹² g of dichloromethane were added. The mixture was heated to 40 °C with mechanical stirring, and a 30% aqueous solution containing 13.33 g of sodium hydroxide (0.32 mol, 96%) was added dropwise over 2 hours. After the addition was complete, the reaction was continued for another 5 hours. After the reaction was complete, 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, and ethanol at five times the theoretical yield of β-carotene was added. An isomerization reaction was carried out at 110 °C. After the reaction was complete, the product was obtained by filtration, washing, and drying to obtain the all-trans β-carotene product.

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

[0034] Example 2

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

[0036] The yield of the Wittig reaction was 89%, and 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 inorganic salt ion residue in the all-trans product after isomerization was 59 ppm.

[0037] Example 3

[0038] 17.28 g of C10 (0.1 mol, 95%) and 170.52 g of C15 phosphine salt (0.3 mol, 99%, cis content 25%, X = HSO4) were added to a three-necked flask. - 682 g of water and 506.14 g of n-heptane were added. The mixture was kept at 20°C with mechanical stirring, and a 20% aqueous solution containing 42.83 g of sodium carbonate (0.4 mol, 99%) was added dropwise over 3 hours. After the addition was complete, the reaction was continued for another hour. After the reaction was complete, the mixture was cooled to room temperature, separated, and the yield of the organic phase was tested. Following the yield test, the reaction solution was subjected to isomerization using the same method as in Example 1 to obtain the all-trans β-carotene product.

[0039] The yield of the wittig reaction was 88%, and 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 loss of filtrate during filtration), and the inorganic salt ion residue in the all-trans product after isomerization was 55 ppm.

[0040] Comparative Example 1

[0041] The operation is the same as described in Example 1, except that the content of the cis isomer of the raw material C15 phosphine salt is 50%.

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

[0043] Comparative Example 2

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

[0045] It is readily understood that the above embodiments are merely illustrative examples for clear explanation and do not imply that the invention is limited thereto. Those skilled in the art will recognize that other variations or modifications can be made based on the above description. It is neither necessary nor possible to exhaustively list all possible implementations. However, obvious variations or modifications derived therefrom remain within the scope of protection of this invention.

Claims

1. A process for the preparation of β-carotene, characterized in that: The cis-isomer of C15 phosphonium salt accounts for 0.01%-25% in the C15 phosphonium salt.

2. The method of claim 1, wherein, The cis-isomer of C15 phosphonium salt accounts for 1%-10% in the C15 phosphonium salt.

3. The method of claim 1, wherein, The structure of the C15 phosphonium salt is shown as follows:

4. The method according to any one of claims 1 to 3, characterized in that, The molar ratio of 2,7-dimethyl-2,4,6-octatriene-1,8-dial to the C15 phosphonium salt is 1:2.05-3.

5. The method according to any one of claims 1 to 3, characterized in that, The molar ratio of 2,7-dimethyl-2,4,6-octatriene-1,8-dial to the C15 phosphonium salt is 1:2.3-2.

5.

6. 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.

7. The method of claim 6, wherein, The water-incompatible solvent includes one or more of dichloromethane, 1,2-dichloroethane, C1-C8 hydrocarbons, and ethyl acetate.

8. The method of claim 6, wherein, The amount of the water-incompatible solvent is 1-8 times the total mass of the C15 phosphonium salt cis-trans isomer.

9. The method of claim 8, wherein, The amount of the water-incompatible solvent is 2-6 times the total mass of the C15 phosphonium salt cis-trans isomer.

10. The method of claim 6, wherein, In the water and water-incompatible solvent system, the amount of water is 1-5 times the total mass of the C15 phosphonium salt cis-trans isomer.

11. The method of claim 10, wherein, In the water and water-incompatible solvent system, the amount of water is 2-4 times the total mass of the C15 phosphonium salt cis-trans isomer.

12. The method of claim 1, wherein, 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; the base is used in the form of an aqueous solution, and the concentration of the aqueous solution is 10%-70%.

13. The method of claim 12, wherein, The concentration of the aqueous solution is 20%-50%.

14. The method of claim 1 or 12, wherein, The molar ratio of 2,7-dimethyl-2,4,6-octatriene-1,8-dial to the base is 1:2-4.

15. The method of claim 14, wherein, The molar ratio of 2,7-dimethyl-2,4,6-octatriene-1,8-dial to the base is 1:2.5-3.

5.

16. The method of claim 1, wherein, The reaction process is that the C15 phosphonium salt, 2,7-dimethyl-2,4,6-octatriene-1,8-dial, and the solvent are laid on the bottom, the base solution is added dropwise, and the reaction is carried out after the base solution is added dropwise; the reaction temperature is 0-60°C, the reaction time includes the dropwise addition time of the base solution and the holding time, the dropwise addition time is 0.5-3h, and the holding time is 1-8h.

17. The method of claim 16, wherein, The reaction temperature is 20-40°C, the dropwise addition time is 1-2h, and the holding time is 2-6h.

18. The method of claim 1, wherein, The cis-trans isomer of β-carotene is isomerized to obtain all-trans β-carotene product.

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