Preparation method and application of canthaxanthin

Abstract

The application discloses a preparation method and application of canthaxanthin, and comprises the following steps: in the presence of beta-carotene, a catalyst, an additive and a solvent, the canthaxanthin is prepared by reaction at a temperature of-20 DEG C to 20 DEG C for 5-24 hours; the catalyst comprises a mixture of chlorate, metal iodide and inorganic acid; the additive comprises a mixture of raw materials represented by formula I, formula II and formula III, wherein the mass ratio of the raw materials represented by formula I, formula II and formula III is 1:(1.0-5.0):(1.0-5.0); and the total additive amount of the additive is 0.01-1 times the mass of the beta-carotene. The preparation method of the canthaxanthin has the characteristics of fast reaction speed, high product yield, less generation of three wastes, strong coloring capacity of the product and excellent thermal stability, and has great competitive advantage in the field of food and drug additives.

Description

TECHNICAL FIELD

[0001] The present application relates to a process and application, in particular to a preparation method and application of canthaxanthin. BACKGROUND

[0002] Canthaxanthin, also known as β-carotene-4,4'-dione, is a deep purple crystal or crystalline powder. Studies have shown that the activity of quenching active oxygen and the ability of removing free radicals of canthaxanthin is 2 times that of β-carotene and 50 times that of vitamin E, and it has a wide range of applications in aquaculture, feed additives, food colorants and pharmaceutical industries. In 1984, it was approved by FDA / WHO to be included in food additives, and it is one of the commonly used nutrients in poultry feed additives and human health care products.

[0003] The synthesis methods of canthaxanthin mainly include C40 route, C15+C10+C15 route and C10+C20+C10 route. Based on the consideration of lower equipment requirements, simplified process flow and stable product yield and quality, the mainstream production process in recent years is C40 route, which is concerned due to its short reaction route and relatively high yield.

[0004] The C40 route is to obtain canthaxanthin by directly oxidizing β-carotene, and the reaction expression is as follows:

[0005]

[0006] In 1980, BASF published patent US4212827, with a maximum crystallization yield of approximately 80% in the examples. In 2000, Toshiki Mori published patent CN1277191, evaluating the 1980 BASF protocol as difficult to control and prone to product deterioration. Therefore, he developed a method using elemental iodine as an initiator, achieving a maximum reaction yield of approximately 76% in the examples. However, elemental iodine is volatile and extremely toxic, hindering industrial production. To address the toxicity issue of elemental iodine, patent CN101633633A disclosed an interfacial catalytic oxidation reaction in a water-organic mixed phase, using hydrogen peroxide as a catalyst, with the addition of acidic chlorate and sodium iodide. The reaction yield was approximately 77%, and the reaction conditions were relatively mild. However, due to the emulsion-like nature of the reaction solution, separation was difficult, requiring extensive water washing to obtain a purified organic phase. This resulted in the generation of large amounts of inorganic salt wastewater. Based on Example 2, the average production of 1 gram of canthaxanthin generated approximately 300g of wastewater, resulting in a large volume of waste and significant waste treatment costs. Patent CN1417207A discloses a method using hypobromic acid, produced by combining sulfurous acid, bisulfite, or acidic sulfite with bromate, as an oxidant. This method achieves a canthaxanthin yield of 85% and shortens the reaction time. However, the generated hypobromic acid is unstable and remains in the product, slowly oxidizing the canthaxanthin crystals and significantly reducing its coloring performance. For example, at the same canthaxanthin concentration, it is insufficient in coloring egg yolks, making the eggs less competitive in the market.

[0007] Therefore, developing a green and environmentally friendly process for preparing canthaxanthin that produces less waste, has a high product yield, and strong coloring ability is still of great significance. Summary of the Invention

[0008] To address the above technical problems, this invention proposes a method for preparing canthaxanthin and its application.

[0009] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0010] A method for preparing canthaxanthin includes the following steps:

[0011] Canthaxanthin was prepared by reacting at -20°C to 20°C, preferably -10°C to 10°C, for 5-24 hours, preferably 10-20 hours, in the presence of β-carotene, catalyst, auxiliaries and solvent.

[0012] The catalyst comprises a mixture of chlorate, metal iodide and inorganic acid; the adjuvant comprises a mixture of raw materials represented by Formula I, Formula II and Formula III, wherein the mass ratio of the raw materials represented by Formula I, Formula II and Formula III is 1:(1.0-5.0):(1.0-5.0); the total amount of the adjuvant added is 0.01-1 times the mass of β-carotene.

[0013]

[0014] The present inventors surprisingly found that the raw material shown in formula I has the effect of improving the acid value of the organic phase in the system, improving the combination ability of the reaction substrate and the catalyst ion, and improving the reaction efficiency; the raw material shown in formula II is speculated to improve the interfacial tension between the organic phase and the aqueous phase, easily combine with the active center during the reaction, and make the catalytically active center more easily enter the organic phase, thereby playing the role of a phase transfer auxiliary agent; at the same time, after the reaction is completed, due to the electrophilic structure of formula II, it is more easily combined with the reaction intermediates, thereby removing the excess chlorite on the intermediates, so that the intermediates quickly form the product canthaxanthin in the oil phase, and the inorganic salt ions are quickly transferred to the aqueous phase, so that the water-oil two phases quickly form a clear phase interface, avoiding the subsequent water washing operation. The possible reaction principle is shown in the following reaction expression:

[0015]

[0016] In the figure, (I2, I-) represents the catalytic center of the inorganic salt oxidation reaction. In order to facilitate representation, R represents the molecular structure of the longer fatty chain in beta carotene.

[0017] Therefore, the introduction of the raw material shown in formula II can save a large amount of water washing water and eliminate complex operations, and the process flow is more efficient and environmentally friendly; at the same time, the synergistic blending of the raw materials shown in formula I and formula II promotes shorter reaction time and phase separation time, thereby improving the reaction efficiency. The introduction of the raw material shown in formula III is beneficial to improve the coloring performance of the product, for example, after feeding poultry as a feed additive, the color of the eggs can be more beautiful.

[0018] For the raw material shown in formula I, the preparation method of vitamin A triphenylphosphine salt in the industry can be referred to, for example, any one or several of the schemes shown in patents US3294844A, CN114057790A, CN101081829A, CN108822015A, and CN110452147A, specifically, vitamin A or its derivatives are used as raw materials, and reacted with triphenylphosphine under the action of an acid catalyst to prepare.

[0019] For the above-mentioned raw material of formula II, the process route in the patent CN101081854B can be referred to, 4-(2, 6, 6-trimethyl-3-hydroxy-1-cyclohexen-1-yl)-3-buten-2-one is used as a raw material, Darzens reaction is carried out with methyl chloroacetate in the presence of a base to obtain a tetradecanal; Wittig-Horner reaction is carried out with methylene bisphosphonate in the presence of a base to obtain 3-methyl-5-(2, 6, 6-trimethyl-3-hydroxycyclohexen-1-yl)-1, 3-pentadiene phosphonate dialkyl ester, rearrangement to obtain 3-methyl-5-(2, 6, 6-trimethyl-3-hydroxycyclohexen-1-yl)-2, 4-pentadiene phosphonate dialkyl ester, and then Wittig-Horner reaction is carried out with 2, 7-dimethyl-2, 4, 6-octatriene-1, 8-dial in the presence of a base to obtain the raw material of formula II, that is, 4, 4'-dihydroxy-β-carotene, and the reaction process is expressed as follows:

[0020]

[0021] For the above-mentioned raw material of formula III, the process route provided in the literature "Research on the structural changes of vitamin A acetate under heat treatment, Zhejiang University Journal, April 2013, Vol. 47 No. 4" can be referred to for preparation, which records that vitamin A acetate is stored at > 90℃ for > 9d to obtain a dimer, and the addition of glycerol tributyrate can shorten the reaction time. The process of cyclization and dimerization under heat treatment conditions is shown as follows:

[0022]

[0023] As some preferred examples of the present application, the addition amount of the chlorate salt is 1-20 times, preferably 5-15 times of the molar amount of β-carotene, the addition amount of the metal iodide is 0.01-1 times, preferably 0.1-0.5 times of the molar amount of β-carotene, and the addition amount of the inorganic acid is 0.01-5 times, preferably 0.05-2 times of the molar amount of β-carotene.

[0024] As some preferred examples of the present application, the chlorate salt is one or more of sodium chlorate, potassium chlorate, sodium hypochlorite, sodium hypochlorite, sodium chlorite, calcium hypochlorite, potassium perchlorate, sodium perchlorate, potassium chlorite;

[0025] Preferably, the metal iodide is one or more of sodium iodide, potassium iodide, ammonium iodide;

[0026] Preferably, the inorganic acid is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, hypochlorous acid, nitric acid.

[0027] As some preferred examples of the present application, the solvent is a mixture of organic solvent and water, and the mass ratio of the two is (0.5-10):1, preferably (1-5):1.

[0028] Preferably, the organic solvent is one or more of dichloromethane, chloroform, carbon tetrachloride, dichloroethane, epichlorohydrin, and tetrachloroethane.

[0029] As some preferred examples of the present application, the reaction pressure is 0.01-1.0 MPa, preferably 0.1-0.5 MPa.

[0030] After the crude canthaxanthin prepared according to the above method is removed from the solvent, isomerization is carried out, and after the reaction is completed, filtration is carried out to obtain canthaxanthin crystals, i.e. canthaxanthin of the all-trans isomer.

[0031] Further, after the crude canthaxanthin prepared according to the above method is first allowed to stand and separate into organic and aqueous layers, the organic layer is separated, and the organic solvent is removed; an isomerization solvent is added, and the temperature is raised to 80-200°C, preferably 100-150°C, the reaction pressure is controlled to be 0.01-1.0 MPa, preferably 0.1-0.5 MPa, and the reaction is stirred for 7-20 h, preferably 10-15 h, after which the reaction is completed, filtration is carried out, and drying is carried out to obtain canthaxanthin crystals.

[0032] In preferred examples, the method for removing the organic solvent is a method commonly used in the field of traditional organic synthesis, such as reduced pressure distillation, atmospheric distillation, molecular distillation, and thin film evaporation, and reduced pressure distillation is preferred, which requires a shorter time for removing the solvent. The removal of the solvent is carried out at a pressure of 20-100 kPA, preferably 50-80 kPA, and a heating temperature of 30-120°C, preferably 50-100°C.

[0033] In preferred examples, the isomerization solvent is one or more of acetone, ethyl acetate, n-hexane, butyl formate, methyl acetate, ethanol, methanol, and tetrahydrofuran; further preferably, the amount of the isomerization solvent added is 0.5-100 times, preferably 1-50 times, the mass of the crude product after the removal of the organic solvent.

[0034] The canthaxanthin prepared according to the method described above is used in food and drug additives, especially in feed additives, food colorants, aquaculture, medicine, and health products.

[0035] The preparation method of canthaxanthin provided by the present application has the characteristics of fast reaction speed, high product yield, low generation of three wastes, strong coloring ability of the product, and excellent thermal stability, and has a great competitive advantage in the field of food and drug additives. BRIEF DESCRIPTION OF DRAWINGS

[0036] Figure 1is the nuclear magnetic hydrogen spectrum characterization chart of the raw material of formula I prepared in the preparation of the example.

[0037] Figure 2 is the nuclear magnetic hydrogen spectrum characterization chart of the raw material of formula II prepared in the preparation of the example.

[0038] Figure 3 is the nuclear magnetic hydrogen spectrum characterization chart of the raw material of formula III prepared in the preparation of the example. DETAILED DESCRIPTION

[0039] The application will be further described below through specific examples, and the examples described in the application are only used to illustrate the application and do not limit the scope of the application.

[0040] Unless otherwise specified, the raw materials and reagents used in the following examples of the application can be obtained by commercial channels. Among them, methylene bisphosphonic acid diethyl ester (CAS 69499-46-3) is prepared according to the following method in the literature "Dialkyl Bisphosphonate Platinum(II) Complex as a Potential Drug for Metastatic Bone Tumor, Chem. Pharm. Bull. 59(6) 710-713 (2011)":

[0041] Under the atmosphere of nitrogen, 14.4g of methylene bisphosphonic acid tetraethyl ester (CAS 1660-94-2, purchased from Aldrich Reagent Co., Ltd.) was placed in 109g of morpholine at 25℃, and after stirring uniformly, the temperature of the system was increased to 128℃ and the reflux reaction was continued for 6h. After the reaction was completed, the system was cooled to room temperature. After the pressure of the system was reduced from normal pressure to 1.34kpaA, the reaction liquid was concentrated under reduced pressure, and acetonitrile was recrystallized to obtain white powder of bisphosphonic acid morpholine salt. 200g of cation exchange resin IR-120 was added to 300mL of methanol containing 17.5g of bisphosphonic acid morpholine salt, and stirred at room temperature for 16 hours. After the reaction was completed, the filtrate was obtained by filtration and concentrated under vacuum, and the concentrate was purified by flash column chromatography (methanol: chloroform = 1:4) to obtain colorless product, i.e. methylene bisphosphonic acid diethyl ester.

[0042] Vitamin A acetate was purchased from BASF Chemical Co., Ltd., triphenylphosphine was purchased from Aldrich Reagent Co., Ltd., 4-(2,6,6-trimethyl-3-hydroxy-1-cyclohexen-1-yl)-3-buten-2-one (CAS 14398-34-6) was purchased from Hefei Ruikesheng Biological Technology Co., Ltd., and 2,7-dimethyl-2,4,6-octatriene-1,8-dial (CAS 5056-17-7) was purchased from Shanghai Qiao Chemical Technology Co., Ltd. Other common inorganic salts such as sodium iodide, chlorate, common organic solvents such as methanol, ethyl acetate, dichloromethane were purchased from Beijing Inokai Reagent Co., Ltd.

[0043] In the following examples of the present application, the content and purity of each component are tested and calculated by external standard method of high performance liquid chromatograph; the liquid chromatography conditions are as follows: chromatographic column: Waters XSelect HSS T3, 4.6 μm x 250 mm; sample size: 2-10 μL, fine tuning according to sample condition; column temperature: 40 DEG C; flow rate: 1 mL / min; detector: ultraviolet detector (UV), detection wavelength is 254-400 nm; mobile phase: acetonitrile / 0.1% phosphoric acid aqueous solution; when measuring, the mass fraction (content) of each detected substance is calculated according to the linear relationship between concentration and liquid peak area.

[0044] In the examples of the present application, an adiabatic kettle reactor is used, and the equipment is made of 304 material.

[0045] In the examples of the present application, the thermal stability of the product is measured by an advanced full-automatic laboratory reaction calorimetry equipment developed by Ciba-Geigy Company of Switzerland, which is called adiabatic reaction calorimeter, model IGG-RC1e, which can monitor the instantaneous heat release power of the reaction process and can also measure the thermal stability of the product.

[0046] The animal experiment grouping and feeding method involved in the present application is as follows:

[0047] Test materials and methods: the test chickens are 18-week-old local Sanhuang chickens. 84 Sanhuang chickens are randomly divided into 7 treatment groups, 12 chickens in each group, free feeding and drinking water, and immunization according to the conventional requirements.

[0048] Test grouping and management: the Sanhuang chickens in the 7 treatment groups are fed with feed added with the oculinum prepared in examples 1-5 of the present application and the oculinum provided in comparative examples 1-2, the dosage of the additive (i.e. oculinum crystal preparation) in the feed is 60 mg / kg, the feed is fed three times a day, 260 grams per column of chickens each time, and the residual feed of the last time must be removed each time.

[0049] Investigation index: randomly select the eggs laid by the Sanhuang chickens in each group after the seventh week of laying, test the color degree and color degree deviation of the egg yolk, and the calculation formula is as follows:

[0050] The color test was performed by color comparison with the aid of the Lovibond color fan.

[0051] Color deviation = (color of the egg yolk obtained by the present application - n) * 100% / n, n is the average color of the egg yolk obtained by feeding with BASF preparation (commercial name: Luconadin Red) and DSM preparation (commercial name: Galisor Red), respectively.

[0052]

Preparation of Examples

[0053] (1) Preparation of the raw material of formula I

[0054] 330.2 g (purity 99.5%) of vitamin A acetate was taken in 500 g of methanol, and 353.6 g (purity 99.9%) of triphenylphosphine was added thereto under a nitrogen atmosphere, and the stirring speed was set to 500 rpm to make the solid completely dispersed in the solution. The temperature of the system was adjusted to 48°C, and 152.1 g (purity 36.0%) of hydrochloric acid solution was added dropwise thereto, the dropwise addition time was controlled to 2 h, and after the dropwise addition was completed, the reaction was maintained for 5.5 h to obtain a reaction solution; the reaction solution was dried at 40°C to remove the solvent, and 200 g of ethyl acetate was added for crystallization, filtration, centrifugation and drying at 80°C for 12 h to obtain the raw material of formula I, which was characterized by nuclear magnetic resonance hydrogen spectrum as shown in Figure 1 .

[0055] (2) Preparation of the raw material of formula II

[0056] The 4,4'-dihydroxy β-carotene, i.e. the raw material of formula II, was prepared according to the scheme in CN101081854B Example, which was characterized by nuclear magnetic resonance hydrogen spectrum as shown in Figure 2 .

[0057]

[0058] 40 g of 4-(2,6,6-trimethyl-3-hydroxy-1-cyclohexen-1-yl)-3-buten-2-one (compound 1) was mixed with 40 g of methyl chloroacetate and cooled to below -10°C, and 250 g of 30% sodium methoxide in methanol was added dropwise. After the dropwise addition was completed, the reaction was maintained at below 0°C for another 3 h, 100 mL of water was added, neutralized with acetic acid, and then 200 mL of ethyl acetate was added, the layers were separated, and the organic layer was washed with 100 mL of saturated sodium chloride aqueous solution, dried with anhydrous magnesium sulfate, filtered, and the solvent was removed under reduced pressure to obtain 2-methyl-4-(2,6,6-trimethyl-3-hydroxycyclohexen-1-yl)-2-butenal (compound 2).

[0059] Take 60% of sodium hydride 6.5 g, washed with n-hexane, then add anhydrous toluene 150 mL, drop 50 g of methylene bisphosphonic acid diethyl ester dissolved in 20 mL of anhydrous toluene under nitrogen protection, control the temperature below 25℃, after drop completion, react for half an hour, then drop 35 g of 2-methyl-4-(2,6,6-trimethyl-3-hydroxycyclohexen-1-yl)-2-butene aldehyde (compound 2) dissolved in 50 mL of anhydrous toluene, after drop completion, react for one hour, add 200 mL of water to wash and separate layers, dry the organic layer with anhydrous magnesium sulfate, filter, and remove the solvent under reduced pressure to obtain 3-methyl-5-(2,6,6-trimethyl-3-hydroxycyclohexen-1-yl)-1,3-pentadiene phosphonic acid diethyl ester (compound 3).

[0060] Take 4.0 g of potassium tert-butoxide, dissolve in 150 mL of anhydrous DMSO solution, drop 49 g of 3-methyl-5-(2,6,6-trimethyl-3-hydroxycyclohexen-1-yl)-1,3-pentadiene phosphonic acid diethyl ester (compound 3) under nitrogen protection, control the temperature at 25℃, after drop completion, react for 2 hours, after the reaction is completed, adjust the pH to neutral with 10% acetic acid aqueous solution, add 200 mL of water and 200 mL of ethyl acetate, separate the layers, wash the organic layer with 200 mL of water once, separate the layers, dry with anhydrous magnesium sulfate, filter, and remove the solvent under reduced pressure to obtain 3-methyl-5-(2,6,6-trimethyl-3-hydroxycyclohexen-1-yl)-2,4-pentadiene phosphonic acid diethyl ester (compound 4).

[0061] Dissolve 36 g of 3-methyl-5-(2,6,6-trimethyl-3-hydroxycyclohexen-1-yl)-2,4-pentadiene phosphonic acid diethyl ester (compound 4) in 250 mL of anhydrous tetrahydrofuran, control the temperature below -10℃, add 15 g of potassium tert-butoxide, continue to drop 8 g of 2,7-dimethyl-2,4,6-octatriene-1,8-dial (compound 5) dissolved in 100 mL of anhydrous tetrahydrofuran, after drop completion, react for more than three hours, after the reaction is completed, add 500 mL of water, stir at 80℃ for five hours under nitrogen protection, cool to room temperature, and filter to obtain purple red 4,4'-dihydroxy β-carotene (compound 6).

[0062] (3) Preparation of raw materials represented by formula III

[0063] Preparation according to the scheme provided in the reference “Study on the structural changes of vitamin A acetate under heat treatment, Zhejiang University Journal, April 2013, Vol. 47 No. 4”:

[0064] Under nitrogen atmosphere, 330.2 g (purity 99.5%) of vitamin A acetate was added into 500 g of n-heptane, the stirring speed was set to 200 rpm and the solid-liquid mixture was uniformly dispersed. The system temperature was set to 95 °C, 100 g of glyceryl tributyrate was added, and the reaction was stirred for 72 h. After the reaction was completed, the solvent was removed, when 20% of n-heptane remained, the system temperature was reduced to room temperature, and the solid was collected by centrifugal filtration. Then the solid was refluxed in 200 g of ethanol for 10 h, the system was cooled to -20 °C to crystallize the solid, and then dried at 70 °C for 12 h to obtain the raw material shown in formula III, with a purity of 91.5%. The hydrogen spectrum characterization is shown in formula III. Figure 3

[0065] [Example 1]

[0066] In a 5 L three-necked flask, 94 g (0.175 mol) of β-carotene, 1 g of the raw material shown in formula I, 2 g of the raw material shown in formula II, 3 g of the raw material shown in formula III, and 5015 g of solvent (2507.5 g of dichloromethane and 2507.5 g of deionized water) were mixed and stirred, and the system reaction temperature was adjusted to -10 °C. After the system temperature was stable and the solid material was uniformly dispersed in the solvent, a mixed solution of sodium chlorate, sodium iodide and sulfuric acid was added, and the molar ratio of β-carotene, sodium chlorate, sodium iodide, sulfuric acid was 1:12:0.225:0.01. After 17 h of reaction at -10 °C and a pressure of 0.1 MPa, the stirring was stopped, and the canthaxanthin reaction solution was obtained.

[0067] During the above oxidation reaction process, it was found that the reaction conditions were relatively mild, the maximum reaction temperature was 0 °C, and the maximum heat release rate was 105 W. Therefore, the heat release rate of the reaction under this process was very slow, and local high temperature was not formed, thereby affecting the chemical stability and quality of the product.

[0068] The reaction liquid was allowed to stand and separate, and it was found that the reaction liquid had a clear phase interface within 5 min, with the upper layer being the aqueous phase and the lower layer being the organic phase. The organic phase was analyzed to have a canthaxanthin crude product yield of 90.5% (calculated based on β-carotene). Then, under the conditions of a temperature of 50 °C and a pressure of 35 kPa A, the solvent was removed, 100.0 g of ethyl acetate was added for isomerization reaction, the reaction temperature was controlled to be 100 °C under stirring, the reaction pressure was 0.01 MPa, and the reaction was stopped after 10 h. After the reaction liquid was cooled and filtered, the dried crystals were collected, and the canthaxanthin purity was analyzed to be 99.9%, with the total trans-canthaxanthin content being 96.7%. The total solid mass was 100.1 g, and the final product yield was calculated to be 89.5%.

[0069] During the above isomerization reaction process, it was found that the reaction temperature increased from 100 °C to 101 °C, the reaction conditions were relatively mild, and almost no heat was released, so local high temperature was not generated.​

[0070] Example 2

[0071] 94 g (0.175 mol) of β-carotene, 1 g of the raw material shown in formula I, 5 g of the raw material shown in formula II, 5 g of the raw material shown in formula III, and 4700 g of solvent (4272 g of dichloromethane and 28 g of deionized water) were mixed and stirred in a 5 L three-necked flask, and the reaction temperature of the system was adjusted to -20 °C. After the temperature of the system was stabilized and the solid material was uniformly dispersed in the solvent, a mixed solution of sodium chlorate, sodium iodide, and sulfuric acid was added, and the molar ratio of β-carotene, sodium chlorate, sodium iodide, and sulfuric acid was 1:5:0.1:0.05. After the reaction was stopped after 24 h at -20 °C and a pressure of 0.2 MPa, an all-trans-canthaxanthin reaction solution was obtained.

[0072] The reaction solution was allowed to stand and separate, and an obvious phase interface was observed in the reaction solution within 7 min, in which the upper layer was an aqueous phase and the lower layer was an organic phase. The organic phase was analyzed, and the yield of the crude canthaxanthin was 89.4% (calculated based on β-carotene). Then, the solvent was removed under the conditions of a temperature of 30 °C and a pressure of 20 kPaA, and 4000.0 g of ethyl acetate was added for isomerization. The reaction temperature was controlled to be 200 °C under stirring, and the reaction was stopped after 7 h at a reaction pressure of 1.0 MPa. After the reaction solution was cooled, the dried crystals were collected by filtration, and the purity of the canthaxanthin was analyzed to be 99.9%, in which the proportion of all-trans-canthaxanthin was 97.4%. The total solid mass was 87.7 g, and the yield of the final product was calculated to be 88.7%.

[0073] Example 3

[0074] 94 g (0.175 mol) of β-carotene, 10 g of the raw material shown in formula I, 10 g of the raw material shown in formula II, 10 g of the raw material shown in formula III, and 3760 g of solvent (3342 g of dichloromethane and 417 g of deionized water) were mixed and stirred in a 5 L three-necked flask, and the reaction temperature of the system was adjusted to -15 °C. After the temperature of the system was stabilized and the solid material was uniformly dispersed in the solvent, a mixed solution of sodium chlorate, sodium iodide, and sulfuric acid was added, and the molar ratio of β-carotene, sodium chlorate, sodium iodide, and sulfuric acid was 1:10:0.03:0.04. After the reaction was stopped after 20 h at -15 °C and a pressure of 0.3 MPa, an all-trans-canthaxanthin reaction solution was obtained.

[0075] The reaction solution was allowed to stand and separate into phases. It was observed that the reaction solution formed a clear phase interface within 4 minutes, with the upper layer being the aqueous phase and the lower layer being the organic phase. The organic phase was analyzed to determine the yield of the crude canthaxanthin product, which was 87.9% (calculated based on β-carotene). The solvent was then removed under conditions of a temperature of 40°C and a pressure of 30 kPaA. Then, 2000.0 g of ethyl acetate was added to perform the isomerization reaction. The reaction temperature was controlled to be 150°C under stirring, and the reaction pressure was 2.0 MPa. After 10 hours of reaction, the reaction was stopped. The reaction solution was cooled and filtered, and the dried crystals were collected. The purity of the canthaxanthin was 99.9%, and the proportion of all-trans canthaxanthin was 97.1%. The total solid mass was 86.9 g, and the final product yield was calculated to be 87.1%.

[0076] [Example 4]

[0077] In a 5 L three-necked flask, 94 g (0.175 mol) of β-carotene, 13.4 g of a raw material of Formula I, 67.1 g of a raw material of Formula II, 13.4 g of a raw material of Formula III, and 4230 g of a solvent (3525 g of dichloromethane and 705 g of deionized water) were mixed and stirred. The reaction temperature of the system was adjusted to -10°C. After the temperature of the system was stabilized and the solid materials were uniformly dispersed in the solvent, a mixed solution of sodium chlorate, sodium iodide, and sulfuric acid was added. The molar ratio of β-carotene, sodium chlorate, sodium iodide, and sulfuric acid was 1:15:0.1:5. After 5 hours of reaction at -10°C and a pressure of 0.4 MPa, the stirring was stopped, and a canthaxanthin reaction solution was obtained.

[0078] The reaction solution was allowed to stand and separate into phases. It was observed that the reaction solution formed a clear phase interface within 9 minutes, with the upper layer being the aqueous phase and the lower layer being the organic phase. The organic phase was analyzed to determine the yield of the crude canthaxanthin product, which was 86.7% (calculated based on β-carotene). The solvent was then removed under conditions of a temperature of 100°C and a pressure of 80 kPaA. Then, 1000.0 g of ethyl acetate was added to perform the isomerization reaction. The reaction temperature was controlled to be 110°C under stirring, and the reaction pressure was 10.0 MPa. After 20 hours of reaction, the reaction was stopped. The reaction solution was cooled and filtered, and the dried crystals were collected. The purity of the canthaxanthin was 99.9%, and the proportion of all-trans canthaxanthin was 98.1%. The total solid mass was 86.5 g, and the final product yield was calculated to be 86.1%.

[0079] [Example 5]

[0080] Mix 94 g (0.175 mol) of β-carotene, 15.7 g of the raw material shown in formula I, 15.7 g of the raw material shown in formula II, 15.7 g of the raw material shown in formula III, and 5640 g of solvent (3760 g of dichloromethane and 1880 g of deionized water) in a 5 L three-necked flask, stir, and adjust the reaction temperature of the system to 20 °C. After the temperature of the system is stable and the solid material is uniformly dispersed in the solvent, add a mixed solution of sodium chlorate, sodium iodide, and sulfuric acid to it, and add according to the molar ratio of β-carotene, sodium chlorate, sodium iodide, and sulfuric acid 1:15:1.0:2. Stop stirring after 10 h of reaction at 20 °C and a pressure of 0.5 MPa to obtain a canthaxanthin reaction solution.

[0081] Let the reaction solution stand and separate, and an obvious phase interface can be seen in the reaction solution within 6 min, in which the upper layer is the aqueous phase and the lower layer is the organic phase. Take the organic phase to analyze the crude canthaxanthin yield, which is 89.4% (calculated based on β-carotene). Then remove the solvent under the condition of a temperature of 120 °C and a pressure of 100 kPaA, and then add 100.0 g of ethyl acetate for isomerization reaction. Stir and control the reaction temperature to be 80 °C, and the reaction pressure to be 0.2 MPa. End the reaction after 15 h. Cool the reaction solution, filter, collect the dried crystals, analyze the purity of canthaxanthin, which is 97.6%, and the proportion of all-trans canthaxanthin, which is 95.2%. The total solid mass is 88.4 g, and the final product yield is calculated to be 87.4%.

[0082] [Comparative Example 1]

[0083] Use commercially available Kangdinglu red (from BASF Chemical Co., Ltd.) as the canthaxanthin provided in Comparative Example 1.

[0084] [Comparative Example 2]

[0085] Use commercially available Galisun red (from Evonik Chemical Co., Ltd.) as the canthaxanthin provided in Comparative Example 2.

[0086] [Application Example]

[0087] Use the canthaxanthin crystal preparations provided in each example and comparative example as chicken feed additives, respectively, and feed Sanhuang chickens with the feed under the same external environment according to the method in the literature “Research on the synthesis route of canthaxanthin and the process of its microcapsule preparation, Peng Zhiqiang, Master's Thesis of South China University of Technology, 2009, pp. 39-50” to produce chicken eggs. Detect the color intensity and color intensity deviation of randomly selected chicken eggs, and the test results are shown in Table 1.

[0088] The preparation of the canthaxanthin crystal formulation is as follows: a 30 wt% gelatin solution is prepared at 80°C and stirred and homogenized using a high-speed homogenizer; a 4.0 wt% canthaxanthin dichloromethane solution is prepared, heated and dissolved at 40°C, and then added to the gelatin solution at a solution mass ratio of 1:1, sheared for 1 h, and then fed into a 60°C spray granulation tower at a rate of 10 g / s, and the canthaxanthin crystal formulation is obtained from the tower.

[0089] Table 1, Color intensity and color intensity deviation test of eggs

[0090]

[0091]

[0092] The above only describes the preferred embodiments of the present application, and it should be noted that, for those skilled in the art, several improvements and supplements can be made without departing from the method of the present application, and these improvements and supplements should also be considered within the protection scope of the present application.

Claims

1. A method for preparing canthaxanthin, characterized in that, Includes the following steps: Canthaxanthin was prepared by reacting at -20°C to 20°C for 5-24 hours in the presence of β-carotene, catalyst, auxiliaries and solvent. The catalyst comprises a mixture of chlorate, metal iodide and inorganic acid; the adjuvant comprises a mixture of raw materials represented by Formula I, Formula II and Formula III, wherein the mass ratio of the raw materials represented by Formula I, Formula II and Formula III is 1:(1.0-5.0):(1.0-5.0); the total amount of the adjuvant added is 0.01-1 times the mass of β-carotene. The chlorate is one or more of sodium chlorate, potassium chlorate, sodium hypochlorite, sodium hypochlorite, sodium chlorite, calcium hypochlorite, potassium perchlorate, sodium perchlorate, and potassium chlorite. The metal iodide is one or more of sodium iodide, potassium iodide, and ammonium iodide; The inorganic acid is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, hypochlorous acid, and nitric acid.

2. The method for preparing canthaxanthin according to claim 1, characterized in that, Canthaxanthin was prepared by reacting β-carotene, a catalyst, an auxiliary agent, and a solvent at a temperature of -10°C to 10°C for 10-20 hours.

3. The method for preparing canthaxanthin according to claim 1, characterized in that, In the catalyst, the amount of chlorate added is 1-20 times the molar amount of β-carotene, the amount of metal iodide added is 0.01-1 times the molar amount of β-carotene, and the amount of inorganic acid added is 0.01-5 times the molar amount of β-carotene.

4. The method for preparing canthaxanthin according to claim 1, characterized in that, In the catalyst, the amount of chlorate added is 5-15 times the molar amount of β-carotene, the amount of metal iodide added is 0.1-0.5 times the molar amount of β-carotene, and the amount of inorganic acid added is 0.05-2 times the molar amount of β-carotene.

5. The method for preparing canthaxanthin according to any one of claims 1-4, characterized in that, The solvent is a mixture of an organic solvent and water, with a mass ratio of (0.5-10):

1.

6. The method for preparing canthaxanthin according to claim 5, characterized in that, The solvent is a mixture of an organic solvent and water, with a mass ratio of (1-5):

1.

7. The method for preparing canthaxanthin according to claim 5, characterized in that, The organic solvent is one or more of dichloromethane, trichloromethane, carbon tetrachloride, dichloroethane, epichlorohydrin, and tetrachloroethane.

8. The method for preparing canthaxanthin according to any one of claims 1-4, characterized in that, The reaction pressure is 0.01-1.0 MPa.

9. The method for preparing canthaxanthin according to claim 8, characterized in that, The reaction pressure is 0.1-0.5 MPa.

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