Preparation method of beta-apo-8 '-carotene acid ethyl ester

Abstract

The invention discloses a preparation method of beta-apo-8 '-carotene acid ethyl ester, which comprises the following steps: reacting C10 dialdehyde, C5 phosphonium ester and / or C5 phosphonium salt in the presence of an unsaturated dinitrogen heterocyclic compound under an alkaline condition to generate a C15 aldehyde ester intermediate; the method comprises the following steps: reacting a C15 aldehydeester intermediate with a C15 phosphonium salt in the presence of an unsaturated dinitrogen heterocyclic compound under an alkaline condition, and carrying out an isomerization reaction after the reaction is finished to generate beta-apo-8 '-carotene acid ethyl ester; the method is simple and efficient to operate and mild in reaction condition, the prepared apoate crystal is high in all-trans content, low in impurity residue, small in average size and free of agglomeration, and production of downstream preparations is facilitated; particularly, the unsaturated dinitrogen heterocyclic compound serving as the catalyst is wide in source, easy to obtain, low in cost and beneficial to industrial application.

Description

Technical Field

[0001] This invention relates to the field of fine chemical technology, specifically to a method for preparing ethyl β-apo-8′-carotene. Background Technology

[0002] Apoester (β-apo-8′-carotene ethyl ester) is an important carotenoid derivative. Its molecular structure contains a β-apocarotene backbone with an ethoxy group linked to the terminal ester bond. This unique structure gives apoester both the conjugated double bond system of carotenoids and the stability of ester compounds. Apoester products are widely used by scientists in various fields. In the cosmetics industry, they are used in lipsticks, nail polishes, eyeshadows, and other makeup products, providing natural and long-lasting color effects. In the pharmaceutical field, apoester is used as an antioxidant or nutritional supplement and participates in the metabolism of vitamin A precursors, exhibiting potential biological activity. Furthermore, apoester is also widely used as a functional nutritional colorant in food and feed production.

[0003] The structural formula of apoester (β-apo-8′-carotene ethyl ester) is as follows:

[0004]

[0005] Currently, the mainstream synthetic route for apoester reported in the literature is a stepwise process of C15+C10+C5 (C15+C10 and C25+C5), which can be roughly described as follows:

[0006]

[0007] It is worth noting that the process still has the following disadvantages: (1) It requires the use of different bases for two-step reaction, which is complicated; (2) Both steps require post-processing, and the C25 aldehyde intermediate needs to be crystallized, resulting in significant product loss and low overall synthesis efficiency; (3) The by-products include impurities such as β-carotene and TPPO, which are difficult to remove, resulting in low apoester content and severe crystal aggregation. Summary of the Invention

[0008] The purpose of this invention is to overcome one or more shortcomings of the prior art and provide an improved method for preparing ethyl β-apo-8′-carotene.

[0009] During extensive experimental research, the inventors of this invention unexpectedly discovered that when using unsaturated dinitrogen heterocyclic compounds as catalysts and controlling the reaction order of C15, C10, and C5 compounds—specifically, allowing C5 and C10 to react first, then directly adding C15 after the reaction is complete (without separating intermediate products) to continue the reaction, followed by isomerization—this process is not only simple and efficient, but also features mild reaction conditions, high all-trans content in the prepared apoester crystals, low impurity residue, small average crystal size, and no agglomeration, which is beneficial for downstream formulation production. In particular, the unsaturated dinitrogen heterocyclic compounds used as catalysts are widely available, readily accessible, and low in cost, facilitating industrial applications.

[0010] Further mechanistic analysis suggests that the unsaturated dinitrogen heterocyclic compound used in this invention interacts with the aldehyde carbonyl group in the C15 aldehyde ester intermediate formed by C10 dialdehydes and C5 phosphine esters and / or C5 phosphine salts through the lone pair electrons on the nitrogen atom in its special heterocyclic structure. This prevents the aldehyde carbonyl group from further reacting with C5 phosphine esters and / or C5 phosphine salts to generate C20 ester byproducts. Simultaneously, the presence of a base weakens the interaction between the unsaturated dinitrogen heterocyclic catalyst and the aldehyde carbonyl group in the C15 aldehyde ester with the addition of the C15 phosphine salt, and also synergistically promotes the formation of apoester products with the base.

[0011] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0012] A method for preparing ethyl β-apo-8′-carotene, the method comprising:

[0013] Under alkaline conditions, the compound shown in formula (I) (which can be abbreviated as C10 dialdehyde), the compound shown in formula (II) and / or the compound shown in formula (III) (the compound shown in formula (II) can be abbreviated as C5 phosphine ester, and the compound shown in formula (III) can be abbreviated as C5 phosphine salt) are reacted in the presence of an unsaturated diazonium heterocyclic compound to generate the compound shown in formula (IV).

[0014]

[0015] Under alkaline conditions, the compound shown in formula (Ⅳ) and the compound shown in formula (Ⅴ) (which can be referred to as C15 phosphine salt) are reacted in the presence of an unsaturated diazonium heterocyclic compound. After the reaction is completed, an isomerization reaction is carried out to generate β-apo-8′-carotene ethyl ester.

[0016]

[0017] In equation (II), R1 and R2 are independently selected from C. 1-6 Alkyl group; formula (Ⅲ), where Y is an acid radical ion; formula (Ⅴ), where X is an acid radical ion.

[0018] According to some preferred and specific aspects of the invention, the unsaturated diazacyclic compound is one or more combinations selected from pyrazole or its derivatives, indazole or its derivatives, imidazole or its derivatives.

[0019] In some embodiments of the present invention, the unsaturated dinitrogen heterocyclic compound is a 5-20 membered ring.

[0020] In some preferred embodiments of the present invention, the unsaturated dinitrogen heterocyclic compound is selected from one or more combinations of compounds shown in formula (VI);

[0021] In equation (VI), one of A and B is N, and the other is CH; R3 and R4 are independently selected from H and C. 1-6 Alkyl, Halogenated C 1-6 Alkyl, halogen, nitro, C 6-12 Aromatic group, m is 1, 2, 3 or 4; E is absent, or E is C. 6-12 Aromatic group.

[0022] According to certain aspects of the present invention, R3 and R4 are independently selected from H, methyl, ethyl, n-propyl, isopropyl, halomethyl, haloethyl, halon-propyl, haloisopropyl, fluorine, chlorine, bromine, nitro, phenyl, methylphenyl, and naphthyl, and m is 1 or 2.

[0023] According to certain aspects of the invention, E is phenyl or naphthyl.

[0024] In some embodiments of the present invention, the unsaturated diazapyridine heterocyclic compound is selected from one or more combinations of pyrazole, 4-bromopyrazole, 4-chloropyrazole, 4-fluoropyrazole, 3-methylpyrazole, 3-ethylpyrazole, 3-propylpyrazole, 5-nitroinazole, 4-nitroinazole, 3-(trifluoromethyl)pyrazole, 3-(trifluoroethyl)pyrazole, imidazole, benzimidazole, 2-methylimidazolium, 2-ethylimidazolium, 2-propylimidazolium, 2-phenylimidazolium, indazole, 5-bromoinazole, 5-chloroinazole, 5-fluoroinazole, 5-methylinazole, 5-ethylinazole, 5-propylinazole, 6-nitroinazole, 6-methylinazole, 6-ethylinazole, and 6-propylinazole.

[0025] According to some preferred and specific aspects of the present invention, the compound shown in formula (I), the compound shown in formula (II), and / or the compound shown in formula (III) are controlled to react at -35 to -10°C, and further at -30 to -15°C, for example, at temperatures such as -35°C, -33°C, -30°C, -28°C, -25°C, -22°C, -20°C, -18°C, -16°C, -15°C, -13°C, or -10°C.

[0026] According to some preferred and specific aspects of the present invention, the compounds represented by formula (Ⅳ) and (Ⅴ) are controlled to react at -35 to -10°C, and further at -30 to -15°C, for example, at temperatures such as -35°C, -33°C, -30°C, -28°C, -25°C, -22°C, -20°C, -18°C, -16°C, -15°C, -13°C, or -10°C.

[0027] According to some preferred and specific aspects of the invention, the isomerization reaction is controlled to be carried out at 50-85°C, and further at 70-85°C, for example at temperatures such as 60°C, 62°C, 65°C, 68°C, 70°C, 72°C, 75°C, 77°C, 78°C, 79°C, 80°C, and 82°C.

[0028] According to some preferred and specific aspects of the present invention, the reactions of the compound represented by formula (I) with the compound represented by formula (II) and / or the compound represented by formula (III), and the reactions of the compound represented by formula (IV) with the compound represented by formula (V) are all carried out under the protection of a protective gas; further, the protective gas includes nitrogen and / or an inert gas, the inert gas including argon, helium, etc.

[0029] According to some specific aspects of the present invention, in the process of preparing the β-apo-8ˊ-carotene ethyl ester, after obtaining the compound shown in formula (Ⅳ) by reaction, the compound shown in formula (Ⅴ) is added directly without separation to carry out the reaction.

[0030] According to some preferred and specific aspects of the present invention, a method for preparing the ethyl β-apo-8ˊ-carotene acid comprises:

[0031] A first solution is prepared by mixing a base, an unsaturated diazacyclohexacyclic compound, and a first solvent; a second solution is prepared by mixing the compound of formula (I) with a second solvent; a third solution is prepared by mixing the compound of formula (II) and / or the compound of formula (III) with a third solvent; and a fourth solution is prepared by mixing the compound of formula (V) with a fourth solvent.

[0032] The third solution and a portion of the first solution are added to the second solution, and the reaction ends to obtain a reaction mixture. Then, the fourth solution and the remaining first solution are added to the reaction mixture, and the reaction is carried out. After the reaction ends, an isomerization reaction is performed to generate ethyl β-apo-8ˊ-carotene.

[0033] Furthermore, the first solvent, the second solvent, the third solvent, and the fourth solvent are all polar organic solvents.

[0034] Furthermore, the polar organic solvent is selected from one or more combinations of alcohol solvents, haloalkane solvents, nitrile solvents, and ester solvents.

[0035] In some embodiments of the present invention, the polar organic solvent is one or more combinations selected from methanol, ethanol, isopropanol, dichloromethane, chloroform, dichloroethane, acetonitrile, and ethyl acetate.

[0036] In some embodiments of the present invention, the amount of polar organic solvent used to prepare the first solution is 2-10 times the mass of the alkali, and more specifically, 3-6 times.

[0037] In some embodiments of the present invention, the second solution, the third solution, and the fourth solution are configured to be 2-15 times the mass of the compound represented by formula (I), the compound represented by formula (II), and / or the compound represented by formula (III) and the compound represented by formula (V), and more particularly, 2-8 times the mass.

[0038] In some embodiments of the present invention, the third solution and a portion of the first solution are added to the second solution in batches, and the fourth solution and the remaining first solution are added to the reaction mixture in batches. Further, the batch addition method includes dropwise addition.

[0039] In some embodiments of the present invention, during the preparation of the β-apo-8ˊ-carotene ethyl ester, the second solution is added to the reaction vessel, and the third solution and a portion of the first solution are simultaneously added dropwise to the reaction vessel (preferably, the dropwise addition time is controlled to be 0.5-6 hours, for example, 2-4 hours). After the dropwise addition is completed, the mixture is kept warm (preferably, the warming time is controlled to be 0.1-1 hours, for example, 0.1-0.3 hours). Then, the fourth solution and the remaining first solution are simultaneously added dropwise (preferably, the dropwise addition time is controlled to be 0.5-6 hours, for example, 2-4 hours). After the dropwise addition is completed, the mixture is kept warm (preferably, the warming time is controlled to be 0.5-8 hours, for example, 2-5 hours). Furthermore, before adding the solutions, the temperatures of the first, second, third, and fourth solutions are controlled at -35 to -10°C, for example, -30 to -15°C or -30 to -20°C, for example, the temperatures can be controlled at -35°C, -33°C, -30°C, -28°C, -25°C, -22°C, -20°C, -18°C, -16°C, -15°C, -13°C, or -10°C, etc.

[0040] In some embodiments of the present invention, the reactions of the compound represented by formula (I) with the compound represented by formula (II) and / or the compound represented by formula (III), and the reactions of the compound represented by formula (IV) with the compound represented by formula (V) are all carried out under stirring conditions; further, the stirring speed is controlled at 100-600 rpm, for example, 200-300 rpm. In some embodiments of the present invention, a portion of the first solution accounts for 40 wt.%-60 wt.% of the total first solution. Further, a portion of the first solution accounts for 45 wt.%-55 wt.% of the total first solution, for example, 45 wt.%, 46 wt.%, 47 wt.%, 48 wt.%, 49 wt.%, 50 wt.%, 51 wt.%, 52 wt.%, 53 wt.%, 54 wt.%, 55 wt.%, etc.

[0041] According to one specific aspect of the invention, a portion of the first solution comprises 50 wt.% of the total first solution.

[0042] In some embodiments of the present invention, the molar ratio of the compound represented by formula (I) to the compound represented by formula (II) and / or the compound represented by formula (III) is 1:1.0-1.5, and more specifically 1:1.0-1.1.

[0043] In some embodiments of the present invention, the molar ratio of the compound represented by formula (I) to the compound represented by formula (V) is 1:1.0-1.5, and more specifically 1:1.0-1.1.

[0044] In some embodiments of the present invention, the alkaline conditions are formed by adding alkali during the preparation process, and the molar ratio of all the alkali used to the compound shown in formula (I) is 2-4:1, or more specifically 2-2.5:1.

[0045] In some embodiments of the present invention, the alkaline conditions are formed by adding an alkali during the preparation process. The alkali is one or more of sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, n-butyllithium, sodium hydroxide, and potassium carbonate.

[0046] In some embodiments of the present invention, during the preparation process, the total amount of all unsaturated diaza-heterocyclic compounds added is 1 wt.% to 20 wt.% of the compound shown in formula (I), and more specifically 1 wt.% to 8 wt.%.

[0047] In some embodiments of the present invention, R1 and R2 are independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl. According to some specific aspects of the present invention, R1 and R2 are the same.

[0048] In some embodiments of the present invention, in formula (Ⅲ), Y is chloride ion, bromide ion or hydrogen sulfate ion.

[0049] In some embodiments of the present invention, in formula (V), X represents chloride ions, bromide ions, or hydrogen sulfate ions. In some embodiments of the present invention, water is added before the isomerization reaction, and the temperature is raised to the isomerization temperature of 50-85°C. After isomerization, the isomerized solution is cooled to a certain temperature for crystallization over a certain period of time, filtered, and dried to obtain crude apoester. The crude apoester is purified with a refining solvent under certain conditions, filtered, and dried in a vacuum oven to obtain the finished apoester product.

[0050] Furthermore, in some embodiments of the present invention, the amount of water added is 1 to 10 times the mass of the compound shown in formula (I), preferably 2 to 6 times.

[0051] Furthermore, in some embodiments of the present invention, the isomerization time of the isomerization reaction is controlled at 5 to 25 hours, preferably 15 to 20 hours.

[0052] Furthermore, in some embodiments of the present invention, the cooling and crystallization temperature is controlled between -5 and 30°C, preferably between 5 and 15°C. Even further, the crystallization time is controlled between 1 and 10 hours, preferably between 3 and 6 hours.

[0053] Furthermore, in some embodiments of the present invention, the drying temperature of the crude product is 30–70°C, preferably 50–60°C. Even further, the drying time is 5–20 hours, preferably 5–10 hours.

[0054] Furthermore, in some embodiments of the present invention, the refining solvent is one or more combinations selected from acetone, cyclohexanone, 3-pentanone, ethyl acetate, n-hexane, cyclohexane, and n-heptane.

[0055] Furthermore, in some embodiments of the present invention, the amount of the refining solvent is 2 to 20 times the mass of crude apoester, preferably 5 to 10 times.

[0056] Furthermore, in some embodiments of the present invention, the refining temperature is controlled at 30–80°C, preferably 50–80°C. Even further, the refining pressure is controlled at 0–0.2 MPa, preferably 0.1–0.2 MPa. The refining time is controlled at 1–8 h, preferably 2–5 h.

[0057] Furthermore, in some embodiments of the present invention, the drying temperature of the vacuum oven is 30–70°C, preferably 40–55°C. Even further, the drying time is controlled between 5–20 hours, preferably 8–12 hours.

[0058] Due to the application of the above-mentioned technical solution, the present invention has the following advantages compared with the prior art:

[0059] Addressing the problems existing in the preparation of apoester (β-apo-8′-carotene ethyl ester), this invention innovatively controls the reaction sequence of C15, C10, and C5 compounds and uses an unsaturated dinitrogen heterocyclic compound as a catalyst. This dual regulation cleverly avoids the formation of a series of byproducts, such as the C20 ester, during the reaction, efficiently achieving the direct preparation of high-quality apoester products via the C10+C5+C15 process. This overturns previous stepwise production processes involving the crystallization and purification of C25 aldehyde intermediates, which involved C15+C10+C5 (C15+C10 and C25+C5) steps. The reaction process requires only one base, and the post-processing is relatively simple. In particular, the catalyst is readily available and easy to obtain, significantly reducing the production cost of apoester products and improving production efficiency.

[0060] Meanwhile, the process of this invention is simple, the reaction conditions are mild, the reaction risk is low, and the production safety factor is high, which is conducive to the industrialization of this apoester synthesis process. Furthermore, in this invention, the C30 reaction yield can reach over 99%, the post-treatment yield can reach over 96%, and the overall yield can reach over 95%. The purity of the prepared apoester product can reach over 99%, the content of byproducts such as β-carotene is low, even as low as 0.1% to 0.2%, the all-trans content can reach over 99.5%, the residual triphenylphosphine oxide is low, as low as below 50 ppm, and the apoester crystals have a small average size and no agglomeration, which is beneficial to the production of downstream formulations. Attached Figure Description

[0061] Figure 1 The high-performance liquid chromatography (HPLC) chromatogram of apoester (β-apo-8′-carotene ethyl ester) prepared in Example 1 of this invention. Detailed Implementation

[0062] The above-mentioned solution will be further described below with reference to specific embodiments; it should be understood that these embodiments are used to illustrate the basic principles, main features and advantages of the present invention, and the present invention is not limited to the scope of the following embodiments; the implementation conditions used in the embodiments can be further adjusted according to specific requirements, and the implementation conditions not specified are usually the conditions in conventional experiments.

[0063] Unless otherwise specified in the following examples, all raw materials are commercially available or prepared by conventional methods in the art.

[0064] The apoester product prepared in this embodiment of the invention was subjected to high performance liquid reverse phase chromatography (HPLC) for apparent content determination. The chromatographic conditions were as follows: column: Suplex pkb-100-C18 250mm*4.6mm*5μm; mobile phase: isopropanol:ammonium acetate:acetonitrile:methanol = 20:0.2:455:450; flow rate: 0.6mL / min; detection wavelength: 453nm; column temperature: 30℃; acquisition time: 20min.

[0065] The structural formula of C10 dialdehyde is as follows: The structural formula of C5 ethyl phosphate is: The structural formula of C5 methyl phosphate is: The structural formula of C5 chlorophosphine salt is: The structural formula of C15 chlorophosphine salt is:

[0066] The structural formula of C15 bromophosphine salt is:

[0067] Example 1:

[0068] This example provides a method for preparing apoester (β-apo-8′-carotene ethyl ester), the method comprising:

[0069] Under nitrogen protection, 30g of 98.5% C10 dialdehyde and 180g of ethanol were added to a 5L three-necked flask and stirred until dissolved at room temperature. Under nitrogen protection, 1.5g of 99% 3-methylpyrazole, 28g of 99% sodium ethoxide, and 120g of ethanol were prepared as the alkali solution to be added. Under nitrogen protection, 49.5g of 98% C5 ethyl phosphate and 100g of ethanol were similarly prepared as the C5 ethyl phosphate solution to be added. The temperature inside the three-necked flask was controlled at -25℃, and the stirring speed was controlled at 260rpm. Both solutions were pre-cooled to -20℃ and then added simultaneously over a period of 3 hours (approximately half of the alkali solution was added). The temperature inside the reaction solution was controlled between -23℃ and -27℃ throughout the addition process. After the addition was complete, the reaction was maintained at this temperature for another 0.2 hours. Liquid chromatography analysis showed that the residual C10 dialdehyde was <1%. A C15 chlorophosphonate solution with a purity of 98.3% was prepared by mixing 94.3g of C15 chlorophosphonate with 190g of ethanol and pre-cooled to -20°C. The C15 chlorophosphonate solution and the remaining alkaline solution were then added dropwise over a period of 3 hours, with the internal temperature of the reaction solution controlled between -23°C and -27°C throughout the process. After the addition was complete, the reaction was continued at this temperature for another 3 hours. Liquid chromatography analysis showed that the residual C15 aldehyde ester (i.e., the compound shown in formula (Ⅳ)) was <1%, indicating the reaction was complete and a C30 reaction solution was obtained.

[0070] 100 mL of water was added to the C30 reaction solution, and the temperature of the reaction solution was raised to 79 °C for high-temperature isomerization for 16 h. After isomerization, the isomerized solution was cooled to 10 °C and crystallized for 5 h. The solution was then filtered and dried in a vacuum drying oven at 60 °C for 5 h to obtain 83 g of crude apoester. 500 g of acetone was added to the crude product, and the temperature was raised to 75 °C at a pressure of 0.16 MPa for purification for 5 h. After cooling to room temperature, the solution was filtered and dried in a vacuum drying oven at 60 °C for 8 h to obtain 80 g of the finished apoester product. Its high-performance liquid chromatography (HPLC) chromatogram is shown below. Figure 1 As shown. The yield of C10 dialdehyde was 96.3%, the purity of apocyanide was 99.8%, the trans-cis ratio was 99.7:0.3, the residual triphenylphosphine oxide was 28 ppm, and the D of apocyanide crystals was... 90 It is 50.6 μm.

[0071] Example 2:

[0072] This example provides a method for preparing apoester (β-apo-8′-carotene ethyl ester), the method comprising:

[0073] Under nitrogen protection, 30g of 98.5% C10 dialdehyde and 200g of ethanol were added to a 5L three-necked flask and stirred until dissolved at room temperature. Under nitrogen protection, 1.2g of 99% imidazole, 35g of 99% sodium ethoxide, and 150g of ethanol were prepared as the alkali solution to be added. Under nitrogen protection, 52.2g of 98% C5 ethyl phosphate and 95g of ethanol were similarly prepared as the C5 ethyl phosphate solution to be added. The temperature inside the three-necked flask was controlled at -20℃, and the stirring speed was controlled at 300rpm. Both solutions were pre-cooled to -15℃ and added simultaneously over 2 hours (approximately half of the alkali solution was added). The temperature inside the reaction solution was controlled between -18℃ and -22℃ throughout the addition process. After addition was complete, the reaction was maintained at this temperature for another 0.3 hours. Liquid chromatography analysis showed that the residual C10 dialdehyde was <1%. A C15 chlorophosphonate solution with a purity of 98.3% was prepared by mixing 94.3g of C15 chlorophosphonate with 200g of ethanol and pre-cooling to -15℃. The C15 chlorophosphonate solution and the remaining alkaline solution were then added dropwise simultaneously over 3 hours, with the internal temperature of the reaction solution controlled between -18℃ and -22℃ throughout the process. After the addition was complete, the reaction was maintained at this temperature for another 3 hours. Liquid chromatography analysis showed that the residual C15 aldehyde ester was <1%, indicating the reaction was complete and a C30 reaction solution was obtained.

[0074] 100 mL of water was added to the C30 reaction solution, and the temperature of the reaction solution was raised to 79 °C for high-temperature isomerization for 16 h. After isomerization, the isomer solution was cooled to 15 °C and crystallized for 5 h. The solution was filtered and dried in a vacuum drying oven at 60 °C for 5 h to obtain 72 g of crude apoester. 400 g of acetone was added to the crude product, and the temperature was raised to 72 °C at a pressure of 0.14 MPa for purification for 5 h. After cooling to room temperature, the solution was filtered and dried in a vacuum drying oven at 60 °C for 8 h to obtain 71.43 g of finished apoester. The yield of C10 dialdehyde was 85.1%, the purity of apoester was 98.8%, the trans-cis ratio was 98.9:1.1, the residual triphenylphosphine oxide was 47 ppm, and the D of apoester crystals was... 90 It is 62μm.

[0075] Example 3:

[0076] This example provides a method for preparing apoester (β-apo-8′-carotene ethyl ester), the method comprising:

[0077] Under nitrogen protection, 30g of 98.5% C10 dialdehyde and 200g of ethanol were added to a 5L three-necked flask and stirred until dissolved at room temperature. Under nitrogen protection, 1.8g of 99% 5-bromoindazole, 25g of 99% sodium ethoxide, and 100g of ethanol were prepared as the alkali solution to be added. Under nitrogen protection, 47g of 98% C5 ethyl phosphate and 90g of ethanol were similarly prepared as the C5 ethyl phosphate solution to be added. The temperature inside the three-necked flask was controlled at -25℃, and the stirring speed was controlled at 260rpm. Both solutions were pre-cooled to -20℃ and added simultaneously over 3 hours (approximately half of the alkali solution was added). The temperature inside the reaction solution was controlled between -23℃ and -27℃ throughout the addition process. After addition was complete, the reaction was maintained at this temperature for another 0.2 hours. Liquid chromatography analysis showed that the residual C10 dialdehyde was <2%. A C15 chlorophosphonate solution with a purity of 98.3% was prepared by mixing 94.3g of C15 chlorophosphonate with 180g of ethanol and pre-cooled to -20℃. The C15 chlorophosphonate solution and the remaining alkaline solution were then added dropwise simultaneously over 3 hours, with the internal temperature of the reaction solution controlled between -23℃ and -27℃ throughout the process. After the addition was complete, the reaction was maintained at this temperature for another 3 hours. Liquid chromatography analysis showed that the residual C15 aldehyde ester was <3%, indicating the reaction was complete and a C30 reaction solution was obtained.

[0078] 100 mL of water was added to the C30 reaction solution, and the temperature of the reaction solution was raised to 79 °C for high-temperature isomerization for 16 h. After isomerization, the isomerized solution was cooled to 10 °C and crystallized for 5 h. The solution was filtered and dried in a vacuum drying oven at 60 °C for 5 h to obtain 60 g of crude apoester. 350 g of acetone was added to the crude product, and the temperature was raised to 75 °C at a pressure of 0.16 MPa for purification for 5 h. After cooling to room temperature, the solution was filtered and dried in a vacuum drying oven at 60 °C for 8 h to obtain 72.5 g of finished apoester. The yield of C10 dialdehyde was 86.7%, the purity of apoester was 99.1%, the trans-cis ratio was 98.2:1.8, the residual triphenylphosphine oxide was 50 ppm, and the D90 of apoester crystals was 65 μm.

[0079] Example 4:

[0080] This example provides a method for preparing aporyl ester (β-apor-8′-carotene ethyl ester), which is the same as the aporyl ester preparation method in Example 1, except that an equimolar amount of C15 bromophosphine salt is used instead of C15 chlorophosphine salt as the raw material. Other operations and parameters remain unchanged, yielding 76.1 g of aporyl ester product. The yield of C10 dialdehyde is 91.1%, the purity of aporyl ester is 99.2%, the trans-cis ratio is 99.3:0.7, the residual triphenylphosphine oxide is 45 ppm, and the D of aporyl ester crystals is... 90 It is 49μm.

[0081] Example 5:

[0082] This example provides a method for preparing aporyl ester (β-apor-8ˊ-carotene ethyl ester), which is the same as the aporyl ester preparation method in Example 1, except that an equimolar amount of C5 methyl phosphate is used instead of C5 ethyl phosphate as the raw material. Other operations and parameters remain unchanged, yielding 73g of aporyl ester product. The yield of C10 dialdehyde is 86.9%, the purity of aporyl ester is 98.7%, the trans-cis ratio is 99.1:0.9, the residual triphenylphosphine oxide is 70ppm, and the D of aporyl ester crystals is... 90 It is 62μm.

[0083] Example 6:

[0084] This example provides a method for preparing aporyl ester (β-apor-8ˊ-carotene ethyl ester), which is the same as the aporyl ester preparation method in Example 1, except that 3-methylpyrazole is replaced with an equimolar amount of 4-bromopyrazole as the catalyst. Other operations and parameters remain unchanged, yielding 68.9 g of aporyl ester product. The yield of C10 dialdehyde is 81.6%, the purity of aporyl ester is 98.2%, the trans-cis ratio is 98.5:1.5, the residual triphenylphosphine oxide is 70 ppm, and the D of aporyl ester crystals is... 90 It is 51μm.

[0085] Example 7:

[0086] This example provides a method for preparing aporyl ester (β-apor-8ˊ-carotene ethyl ester), which is the same as the aporyl ester preparation method in Example 1, except that an equimolar amount of benzimidazole is used instead of 3-methylpyrazole as the catalyst. Other operations and parameters remain unchanged, yielding 67.3 g of aporyl ester product. The yield of C10 dialdehyde is 79.5%, the purity of aporyl ester is 97.9%, the trans-cis ratio is 96.5:4.5, the residual triphenylphosphine oxide is 95 ppm, and the D of aporyl ester crystals is... 90 It is 89μm.

[0087] Example 8:

[0088] This example provides a method for preparing aporyl ester (β-apor-8ˊ-carotene ethyl ester), which is the same as the aporyl ester preparation method in Example 1, except that 3-methylpyrazole is replaced with an equimolar amount of 5-methylindazole as the catalyst. Other operations and parameters remain unchanged, yielding 71.5 g of aporyl ester product. The yield of C10 dialdehyde is 83.9%, the purity of aporyl ester is 97.3%, the trans-cis ratio is 98.1:1.9, the residual triphenylphosphine oxide is 81 ppm, and the D of aporyl ester crystals is... 90 It is 108μm.

[0089] Example 9:

[0090] This example provides a method for preparing aporyl ester (β-apor-8ˊ-carotene ethyl ester), which is the same as the aporyl ester preparation method in Example 1, except that an equimolar amount of C5 chlorophosphine salt is used instead of C5 ethyl phosphate as the catalyst. Other operations and parameters remain unchanged, yielding 77.2 g of aporyl ester product. The yield of C10 dialdehyde is 92.7%, the purity of aporyl ester is 99.5%, the trans-cis ratio is 99.3:0.7, the residual triphenylphosphine oxide is 52 ppm, and the D of aporyl ester crystals is... 90 It is 47μm.

[0091] Comparative Example 1:

[0092] Following the apoester preparation method of Example 1, the difference being that 3-methylpyrazole was not added to the alkaline solution preparation, while other operations and parameters remained unchanged, yielding 30g of apoester product. The yield of C10 dialdehyde was 34.4%, the apoester purity was 95%, the trans-cis ratio was 91:9, the triphenylphosphine oxide residue was 88ppm, and the Do of apoester crystals was... 90 It is 109μm.

[0093] Comparative Example 2:

[0094] The apoester preparation method of Example 1 was followed, except that C10 dialdehyde, C15 chlorophosphine salt, C5 ethyl phosphate, and 3-methylpyrazole were directly added to the reaction flask in a one-pot manner, while other operations and parameters remained unchanged, yielding 25.9 g of apoester product. The yield of C10 dialdehyde was 30.1%, the purity of apoester was 96.5%, the trans-cis ratio was 85:7, the residual triphenylphosphine oxide was 325 ppm, and the Do of apoester crystals was... 90 It is 92μm.

[0095] Comparative Example 3:

[0096] The preparation method of apoprase in Example 1 was followed, except that the C15 chlorophosphine salt solution and the alkaline solution were first added dropwise to the C10 dialdehyde solution. After the C15 chlorophosphine salt solution was added, the remaining alkaline solution and the C5 ethyl phosphate solution were added dropwise simultaneously. Other operations and parameters remained unchanged, yielding 19.7 g of apoprase product. The yield of C10 dialdehyde was 20.7%, the purity of apoprase was 87.2%, the trans-cis ratio was 75:24, the residual triphenylphosphine oxide was 510 ppm, and the Do of apoprase crystals was... 90 It is 152μm.

[0097] Comparative Example 4:

[0098] This example provides a method for preparing aporyl ester (β-apor-8ˊ-carotene ethyl ester), which is the same as the aporyl ester preparation method in Example 1, except that 3-methylpyrazole is replaced with an equimolar amount of aniline as the catalyst, while other operations and parameters remain unchanged, yielding 52.1 g of aporyl ester product. The yield of C10 dialdehyde is 61.8%, the purity of aporyl ester is 98.3%, the trans-cis ratio is 96.9:3.1, the residual triphenylphosphine oxide is 35 ppm, and the D of aporyl ester crystals is... 90 It is 60μm.

[0099] Comparative Example 5:

[0100] This example provides a method for preparing aporyl ester (β-apor-8ˊ-carotene ethyl ester), which is the same as the aporyl ester preparation method in Example 1, except that 3-methylpyrazole is replaced with an equimolar amount of pyridine as the catalyst. Other operations and parameters remain unchanged, yielding 37.1 g of aporyl ester product. The yield of C10 dialdehyde is 42.4%, the purity of aporyl ester is 94.7%, the trans-cis ratio is 92:8, the residual triphenylphosphine oxide is 175 ppm, and the D of aporyl ester crystals is... 90 It is 100μm.

[0101] The above embodiments are only for illustrating the technical concept and features of the present invention, and are intended to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be construed as limiting the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

[0102] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

Claims

1. A process for the preparation of β-apo-8'-carotenal ethyl ester, characterized in that, The preparation method comprises: reacting a compound represented by formula (I), a compound represented by formula (II) and / or a compound represented by formula (III) in the presence of an unsaturated diazacyclic compound under basic conditions to generate a compound represented by formula (IV); reacting the compound represented by formula (IV) and a compound represented by formula (V) in the presence of an unsaturated diazacyclic compound under basic conditions, and then performing isomerization to generate ethyl beta-apo-8'-carotenate. wherein, in formula (II), R1, R2are independently selected from C 1-6 alkyl; formula (III), Y is an acid ion; formula (V), X is an acid ion.

2. The process for the preparation of ethyl β-apo-8'-carotenate according to claim 1, characterized in that, The unsaturated diazacyclic compound is a combination of one or more selected from pyrazole or a derivative thereof, indazole or a derivative thereof, and imidazole or a derivative thereof; and / or, the unsaturated diazacyclic compound is a 5-20-membered ring.

3. The process for the preparation of ethyl β-apo-8'-carotenate according to claim 1, characterized in that, The unsaturated diazacyclic compound is a combination of one or more selected from compounds represented by formula (VI); In formula (VI), one of A, B is N and the other is CH; R3, R4are independently selected from H, C 1-6 alkyl, haloC 1-6 alkyl, halo, nitro, C 6-12 aromatic, m is 1, 2, 3 or 4; E is absent or E is C 6-12 aromatic.

4. The process for the preparation of ethyl β-apo-8'-carotenate according to claim 3, characterized in that, R3 and R4 are independently selected from H, methyl, ethyl, n-propyl, isopropyl, halogenated methyl, halogenated ethyl, halogenated n-propyl, halogenated isopropyl, fluorine, chlorine, bromine, nitro, phenyl, methylphenyl, naphthyl, m is 1 or 2; and / or, E is phenyl or naphthyl.

5. The process for the preparation of ethyl β-apo-8ˊ-carotenate according to any one of claims 1-4, characterized in that, The unsaturated diazacyclic compound is a combination of one or more selected from pyrazole, 4-bromopyrazole, 4-chloropyrazole, 4-fluoropyrazole, 3-methylpyrazole, 3-ethylpyrazole, 3-propylpyrazole, 5-nitroindazole, 4-nitroindazole, 3-(trifluoromethyl)pyrazole, 3-(trifluoroethyl)pyrazole, imidazole, benzimidazole, 2-methylimidazole, 2-ethylimidazole, 2-propylimidazole, 2-phenylimidazole, indazole, 5-bromoindazole, 5-chloroindazole, 5-fluoroindazole, 5-methylindazole, 5-ethylindazole, 5-propylindazole, 6-nitroindazole, 6-methylindazole, 6-ethylindazole, 6-propylindazole.

6. The method for preparing ethyl β-apo-8ˊ-carotene according to claim 1, characterized in that, In the process of preparing the ethyl beta-apo-8'-carotenate, after the compound represented by formula (IV) is obtained by reaction, the compound represented by formula (V) is directly added for reaction without separation.

7. The method of preparing ethyl β-apo-8ˊ-carotenate according to claim 1 or 6, characterized in that, The method for preparing the ethyl beta-apo-8'-carotenate comprises: mixing a base, an unsaturated diazacyclic compound and a first solvent to prepare a first solution; mixing a compound represented by formula (I) and a second solvent to prepare a second solution; mixing a compound represented by formula (II) and / or a compound represented by formula (III) and a third solvent to prepare a third solution; and mixing a compound represented by formula (V) and a fourth solvent to prepare a fourth solution; adding the third solution and part of the first solution into the second solution to generate a reaction mixture after reaction; then adding the fourth solution and the remaining first solution into the reaction mixture to perform reaction, and then performing isomerization to generate ethyl beta-apo-8'-carotenate.

8. The method for preparing ethyl β-apo-8ˊ-carotene according to claim 7, characterized in that, The first solvent, the second solvent, the third solvent, and the fourth solvent are all polar organic solvents. Further, the polar organic solvent is selected from one or more combinations of alcohol solvents, haloalkane solvents, nitrile solvents, and ester solvents; and / or, the third solution and a portion of the first solution are added to the second solution in batches, and the fourth solution and the remaining first solution are added to the reaction mixture in batches. Further, the batch addition method includes dropwise addition; and / or, a portion of the first solution accounts for 40 wt.%-60 wt.% of the total first solution.

9. The method for preparing ethyl β-apo-8ˊ-carotene according to claim 1, characterized in that, The reaction of the compound shown in formula (I), the compound shown in formula (II), and / or the compound shown in formula (III) is controlled to proceed at -35 to -10°C, and further at -30 to -15°C; and / or, the reaction of the compound shown in formula (IV) and the compound shown in formula (V) is controlled to proceed at -35 to -10°C, and further at -30 to -15°C; and / or, the isomerization reaction is controlled to proceed at 50-85°C, and further at 70-85°C; and / or, the reaction of the compound shown in formula (I) with the compound shown in formula (II) and / or the compound shown in formula (III), and the reaction of the compound shown in formula (IV) with the compound shown in formula (V) are all carried out under a protective gas, further comprising nitrogen and / or an inert gas.

10. The process for the preparation of ethyl β-apo-8'-carotenate according to claim 1, characterized in that, The molar ratio of the compound represented by formula (I) to the compound represented by formula (II) and / or the compound represented by formula (III) is 1:1.0-1.5, more specifically 1:1.0-1.1; and / or, the molar ratio of the compound represented by formula (I) to the compound represented by formula (V) is 1:1.0-1.5, more specifically 1:1.0-1.1; and / or, in the preparation process, the alkaline conditions are formed by adding alkali, and the total amount of alkali used is in a molar ratio of 2-4:1 to the compound represented by formula (I), more specifically 2-2.5:1; and / or, in the preparation process, the alkaline conditions are formed by adding alkali. The base is selected from one or more combinations of sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, n-butyllithium, sodium hydroxide, and potassium carbonate; and / or, in the preparation process, the total amount of all unsaturated diazacyclic compounds added is 1 wt.% to 20 wt.%, more specifically 1 wt.% to 8 wt.%, of the compound shown in formula (I); and / or, R1 and R2 are independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl; and / or, in formula (III), Y is chloride, bromide, or hydrogen sulfate; and / or, in formula (V), X is chloride, bromide, or hydrogen sulfate.

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