A method for isomerization extraction of cis-β-apo-12'-carotenal, its product and application

Abstract

The invention discloses an isomerization extraction method of cis-β-apo-12'-carotenal and its products and applications, and the isomerization extraction method comprises the following steps: 1) uniformly mixing materials containing cis-β-apo-12'-carotenal with acid and solvent, cooling to carry out isomerization reaction until solid is precipitated; 2) heating to continue isomerization reaction to obtain a mixed solution containing more than 80% of all-trans isomers, crystallizing and precipitating the all-trans isomers from the mixed solution, and extracting. The isomerization extraction method of cis-β-apo-12'-carotenal provided by the present invention has simple isomerization extraction operation, high extraction yield, easy-to-obtain raw materials, low cost, and is suitable for large-scale industrial operation.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, and in particular to a method for isomer extraction of cis-β-apo-12'-carotene, and a product and application thereof. Background Art

[0002] β-Apo-12'-carotenal is a key intermediate in the synthesis of apocarotene, and is mainly used in the synthesis of β-apo-8'-carotenal, β-apo-8'-carotenic acid ethyl ester, aurantium, cryptoxanthin and β-carotene. Apocarotene is an important component of carotenoids. In food, it is mainly used for coloring edible oils, margarine, jam, jelly and beverage products; in the feed industry, it is widely used for coloring meat poultry, especially the skin, shanks and fat of broilers, as well as the coloring of poultry egg yolks.

[0003] At present, the world's largest carotenoid product manufacturers (such as Roche) all produce apocarotene compounds as their main products, which shows that it has a very broad market prospect. The reported synthesis methods of β-apo-12'-carotenal mainly include Wittig method and HWE method, and the synthetic products contain the cis isomer of β-apo-12'-carotenal.

[0004] For example, the Wittig method for synthesizing β-apo-12'-carotenal, which has been industrialized, is C15+C10, where C15 is vinyl-β-ionol and C10 is 2,7-dimethyl-2,4,6-octatriene-1,8-dialdehyde. The β-apo-12'-carotenal prepared by this route has multiple cis-isomers such as 9-Z, 13-Z, 13'-Z and 9,13'-di-Z isomers. The structural formulas of the cis-isomers are as follows: Figure 1 The cis isomer accounts for about 20% of the product. On the one hand, it cannot be precipitated in the form of a solid during the post-processing of the preparation of β-apo-12'-carotene. On the other hand, it is a viscous paste after extraction from the crystallization mother liquor, which is difficult to filter and purify, and is not conducive to direct use in subsequent reactions, affecting the quality and yield of the final product.

[0005] In view of this, it is indeed necessary to provide a technical solution to the above-mentioned technical problems. Summary of the invention

[0006] In order to overcome the deficiencies of the prior art, the object of the present invention is to provide a method for isomerization extraction of cis-β-apo-12'-carotenal with simple isomerization operation and high extraction yield.

[0007] To achieve the above object, the present invention provides the following technical solutions:

[0008] A method for isomeric extraction of cis-β-apo-12'-carotenal comprises the following steps:

[0009] 1) mixing the material containing cis-β-apo-12'-carotenal, acid and solvent uniformly, cooling and performing isomerization reaction until solid is precipitated;

[0010] 2) The temperature is raised to continue the isomerization reaction to obtain a mixed solution containing the isomerized all-trans isomer, and the all-trans isomer is crystallized from the mixed solution.

[0011] Preferably, the molar ratio of the acid to cis-β-apo-12'-carotenal is (0.1-0.2):1.

[0012] Preferably, the acid is an inorganic acid; the solvent is a polar solvent; the inorganic acid is first dispersed in the polar solvent to obtain an acid solution, and then the acid solution is added to the material containing cis-β-apo-12'-carotene.

[0013] Preferably, the structure of cis-β-apo-12'-carotenal includes one or a combination of two or more of 9-Z, 13-Z, 15-Z, 13'-Z, 9,13-di-Z, 9,13'-di-Z or 13,13'-di-Z isomers.

[0014] Furthermore, the method further comprises an extraction step: taking the cis-β-apo-12'-carotenal which is not completely isomerized in the mixed solution after crystallization as a material containing cis-β-apo-12'-carotenal and further subjecting it to isomerization extraction.

[0015] Furthermore, the conditions for the isomerization reaction by cooling are: the temperature drops to below 10°C, and the isomerization reaction is carried out for 0.5 to 3.0 hours; the conditions for the isomerization reaction by heating are: the temperature is not higher than 20°C, and the isomerization reaction is carried out for 21.0 to 23.0 hours; after the isomerization is completed, the content of all-trans β-apo-12'-carotenal in the mixed solution accounts for ≥80%.

[0016] Furthermore, in step 2), the crystallization process is as follows: adding 8% to 12% of the solvent volume of water to the mixed solution after the isomerization reaction, then cooling and crystallizing; filtering and washing to obtain all-trans β-apo-12'-carotene solid.

[0017] Furthermore, the washing liquid used for washing is an alkaline 90% ethanol solution; washing is performed until the filtrate is neutral.

[0018] Another object of the present invention is to provide a β-apo-12'-carotenal, wherein the β-apo-12'-carotenal is extracted by the isomer extraction method of cis-β-apo-12'-carotenal provided by the first object of the present invention.

[0019] Another object of the present invention is to provide a use of β-apo-12'-carotenal extracted by the isomer extraction method of cis-β-apo-12'-carotenal provided by the first object of the present invention as an organic synthesis intermediate.

[0020] Compared with the prior art, the beneficial effects of the present invention are:

[0021] The isomerization extraction method of cis-β-apo-12'-carotenal provided by the present invention comprises the following steps: uniformly mixing a material containing cis-β-apo-12'-carotenal with an acid and a solvent, regulating the temperature of the mixed solution, first cooling the mixed solution until solids are precipitated, and then heating the mixed solution, and finally crystallizing the all-trans isomer in the mixed solution, and repeating the isomerization extraction operation of cis-β-apo-12'-carotenal in the mother liquor until the extraction is completed. The isomerization extraction method is simple to operate, has a high extraction yield, and is suitable for large-scale industrialization. In addition, the reaction raw materials used in the present invention are easy to obtain and low in cost, and bulk industrial products such as anhydrous ethanol and concentrated sulfuric acid are used, which are of great industrial value; in addition, the present invention does not use highly dangerous raw materials in the isomerization extraction process of cis-β-apo-12'-carotenal, and no harmful byproducts remain in the product, the production process is highly safe, and the product meets the use standards. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 are structural formulas of some cis-isomers of β-apo-12'-carotenal; in the figure: (a) is a 9-Z structure, (b) is a 13-Z structure, (c) is a 15-Z structure, (d) is a 13'-Z structure, (e) is a 9,13-di-Z structure, (f) is a 9,13'-di-Z structure, and (g) is a 13,13'-di-Z structure;

[0023] Figure 2 One of the flow charts of the isomeric extraction method of cis-β-apo-12'-carotenal provided by the present invention;

[0024] Figure 3 The present invention provides a second flow chart of a method for isomeric extraction of cis-β-apo-12'-carotenal. DETAILED DESCRIPTION

[0025] See also Figures 2-3 , Figure 2 One of the flow charts of the isomeric extraction method of cis-β-apo-12'-carotenal provided by the present invention; Figure 3 The present invention provides a second flow chart of a method for isomeric extraction of cis-β-apo-12'-carotenal.

[0026] The present invention provides a method for isomeric extraction of cis-β-apo-12'-carotenal, comprising the following steps:

[0027] 1) mixing the material containing cis-β-apo-12'-carotenal, acid and solvent uniformly, cooling and performing isomerization reaction until solid is precipitated;

[0028] 2) raising the temperature to continue the isomerization reaction to obtain a mixed solution containing the all-trans isomer, and crystallizing the all-trans isomer from the mixed solution.

[0029] After isomerization to the point where all-trans β-apo-12'-carotenal solid begins to precipitate, the temperature is naturally raised to continue isomerization, and the cis β-apo-12'-carotenal embedded in the precipitated all-trans β-apo-12'-carotenal solid can be slowly dissolved and then isomerized until the proportion of all-trans β-apo-12'-carotenal is monitored to be more than 80%, and then crystallization extraction is performed.

[0030] The invention provides a method for isomer extraction of cis-β-apo-12'-carotenal, which realizes isomer extraction of cis-β-apo-12'-carotenal which is difficult to directly utilize in industrial production process into corresponding all-trans isomers and precipitates them in solid form. The isomer extraction operation is simple and the extracted product can be directly utilized.

[0031] In one embodiment, the molar ratio of the acid to cis-β-apo-12'-carotenal is (0.1-0.2):1, specifically 0.1:1, 0.12:1, 0.14:1, 0.16:1, 0.18:1, 0.2:1 or any ratio between 0.1:1 and 0.2:1.

[0032] In one embodiment, the acid is an inorganic acid; the solvent is a polar solvent; the inorganic acid is first dispersed in the polar solvent to obtain an acid solution, and then the acid solution is added to the material containing cis-β-apo-12'-carotene.

[0033] In one embodiment, the cis structure of cis-β-apo-12'-carotenal includes one or a combination of two or more of 9-Z, 13-Z, 15-Z, 13'-Z, 9,13-di-Z, 9,13'-di-Z or 13,13'-di-Z isomers.

[0034] In one embodiment, the method further comprises the step of isomerizing the cis-β-apo-12'-carotenal incompletely isomerized in the mixed solution after crystallization as a material containing cis-β-apo-12'-carotenal and further performing isomerization extraction.

[0035] In one embodiment, the condition for cooling the isomerization reaction is: the temperature is reduced to below 10°C, and the isomerization reaction is carried out for 0.5 to 3.0 hours, specifically 0.5h, 1h, 1.5h, 2h, 2.5h, 3h or any value between 0.5 and 3.0h; the condition for heating the isomerization reaction is: the temperature is not higher than 20°C, and the isomerization reaction is carried out for 21.0 to 23.0 hours, specifically 21h, 21.5h, 22h, 22.5h, 23h or any value between 21.0 and 23.0h; after the isomerization is completed, the content of all-trans-β-apo-12'-carotenal in the mixed solution accounts for ≥80%, specifically 80%, 85%, 90%, 95%, 100% or any value between 80% and 100%.

[0036] In one embodiment, for step 2), the crystallization process is: adding 8% to 12% of the solvent volume of water to the mixed solution after the isomerization reaction, specifically 8%, 9%, 10%, 11%, 12% or any value between 8% and 12%, preferably 10%, and then cooling and crystallizing; filtering and washing to obtain all-trans β-apo-12'-carotene solid.

[0037] When the added water is less than 10%, the solvent accounts for more than 90% in the system, the precipitated all-trans β-apo-12'-carotenal solid is reduced, and the extraction yield is low; when the added water is more than 10%, other impurities will also precipitate together, resulting in unqualified precipitated β-apo-12'-carotenal solid content. In one embodiment, the washing liquid used for washing is an alkaline 90% ethanol solution; washing is performed until the filtrate is neutral.

[0038] The water content of the washing solvent is controlled at about 10%. If the water content is less than 10%, a large amount of all-trans β-apo-12'-carotenal solid will be washed away, resulting in a low extraction yield. If the water content is more than 10%, the solvent content is less than 90%, and the impurities in the precipitated all-trans β-apo-12'-carotenal solid cannot be removed, resulting in unqualified all-trans β-apo-12'-carotenal solid content.

[0039] The present invention also provides a β-apo-12'-carotenal, which is extracted by the isomerization extraction method of cis-β-apo-12'-carotenal in the above embodiment.

[0040] The present invention also provides a use of β-apo-12'-carotenal extracted by the isomer extraction method of cis-β-apo-12'-carotenal in the above embodiment as an organic synthesis intermediate.

[0041] Various embodiments of the present invention are discussed in detail below. Obviously, this is only for illustrative purposes, and the described embodiments are only some embodiments, rather than all embodiments.

[0042] Example 1

[0043] A method for isomeric extraction of cis-β-apo-12'-carotenal comprises the following steps:

[0044] 1) Under nitrogen protection, 4.29 g of concentrated sulfuric acid (18% of the molar amount of pure β-apo-12'-carotenal) dissolved in 220 ml of anhydrous ethanol was added to a three-necked flask containing 230.0 g of cis-β-apo-12'-carotenal solution (purity 37.06%, pure product 85.2 g, all-trans isomer accounted for 58.68%) to obtain an isomeric solution;

[0045] 2) Stir the isomerized solution evenly and cool it to below 10°C. After 2.7 hours of isomerization, solid begins to precipitate.

[0046] 3) Naturally raise the temperature, during which the temperature of the isomerization solution is controlled not to be higher than 20° C. After 23.0 h of isomerization, the isomerization process is monitored by HPLC until the proportion of all-trans β-apo-12'-carotenal reaches 86.55%, and then the isomerization is stopped;

[0047] 4) After the isomerization is completed, 24.4 g of water is added to the isomerized solution, the temperature is lowered to 15° C., and stirred for 0.5 h to allow all-trans β-apo-12'-carotene to crystallize and precipitate, and the filter cake is obtained by filtration;

[0048] 5) washing the filter cake with 150 mL of 90% ethanol water (pH=8.50) adjusted to alkalinity until it is neutral, filtering the neutral filter cake and then washing it with 160 mL of 90% ethanol water, and draining the washed filter cake to obtain a wet product of β-apo-12'-carotene;

[0049] 6) The wet product was dried at 60° C. in a vacuum oven to obtain 88.44 g of a dry product. HPLC analysis showed that the content of all-trans β-apo-12′-carotenal in the dry product was 84.44% and the extraction yield was 87.65%.

[0050] 7) The crystallization mother liquor and the washing mother liquor were combined and concentrated under reduced pressure to recover ethanol. The pressure was reduced to about 100 mbar to recover the aqueous ethanol. The concentrate was transferred to a separatory funnel and extracted twice with 200 mL of petroleum ether respectively. The organic phases were combined and washed twice with 200 mL of 80% ethanol water respectively, and concentrated and dried to obtain 68.3 g of mother liquor.

[0051] Example 2

[0052] A method for isomeric extraction of cis-β-apo-12'-carotenal comprises the following steps:

[0053] 1) Under nitrogen protection, 4.68 g of concentrated sulfuric acid (20% of the molar amount of pure β-apo-12'-carotenal) dissolved in 240 ml of anhydrous ethanol was added to a three-necked flask containing 230.0 g of cis-β-apo-12'-carotenal solution (purity 34.83%, pure product 80.0 g, all-trans isomer accounted for 58.53%) to obtain an isomeric solution;

[0054] 2) Stir the isomerized solution evenly and cool it to below 10°C. After 2.0 hours of isomerization, solid begins to precipitate.

[0055] 3) Naturally raise the temperature, during which the internal temperature of the isomerization solution is controlled not to be higher than 20° C. After 21.1 h of isomerization, the isomerization process is monitored by HPLC until the proportion of all-trans β-apo-12'-carotenal reaches 83.62%, and then the isomerization is stopped;

[0056] 4) After the isomerization is completed, 26.7 g of water is added to the isomerized solution, the temperature is lowered to 15° C., and stirred for 0.5 h to allow all-trans β-apo-12'-carotene to crystallize and precipitate, and the filter cake is obtained by filtration;

[0057] 5) washing the filter cake with 160 mL of 90% ethanol water (pH=8.00) adjusted to alkalinity until it is neutral, filtering the neutral filter cake and then washing it with 150 mL of 90% ethanol water, and draining the washed filter cake to obtain a wet product of β-apo-12'-carotene;

[0058] 6) The wet product was dried at 60° C. in a vacuum oven to obtain 80.63 g of dry product. HPLC analysis showed that the content of all-trans β-apo-12′-carotenal in the dry product was 88.29% and the extraction yield was 88.99%.

[0059] 7) The crystallization mother liquor and the washing mother liquor were combined and concentrated under reduced pressure to recover ethanol. The pressure was reduced to about 100 mbar to recover the aqueous ethanol. The concentrate was transferred to a separatory funnel and extracted twice with 200 mL of petroleum ether respectively. The organic phases were combined and washed twice with 200 mL of 80% ethanol water respectively, and concentrated and dried to obtain 66.4 g of mother liquor.

[0060] Example 3

[0061] A method for isomeric extraction of cis-β-apo-12'-carotenal comprises the following steps:

[0062] 1) Under nitrogen protection, 3.44 g of concentrated sulfuric acid (15% of the molar amount of pure β-apo-12'-carotenal) dissolved in 200 ml of anhydrous ethanol was added to a three-necked flask containing 230.0 g of cis-β-apo-12'-carotenal solution (purity 35.66%, pure product 82.0 g, all-trans isomer accounted for 53.90%) to obtain an isomeric solution;

[0063] 2) Stir the isomerized solution evenly and cool it to below 10°C. After 3.0 hours of isomerization, solid begins to precipitate;

[0064] 3) Naturally raise the temperature, during which the internal temperature of the isomerization solution is controlled not to be higher than 20° C. After 23.0 h of isomerization, the isomerization process is monitored by HPLC until the proportion of all-trans β-apo-12'-carotenal reaches 87.96%, and then the isomerization is stopped;

[0065] 4) After the isomerization is completed, 22.2 g of water is added to the isomerized solution, the temperature is lowered to 15° C., and stirred for 0.5 h to allow all-trans β-apo-12'-carotene to crystallize and precipitate, and the filter cake is obtained by filtration;

[0066] 5) washing the filter cake with 170 mL of 90% ethanol water (pH=8.20) adjusted to alkalinity until it is neutral, filtering the neutral filter cake and then washing it with 160 mL of 90% ethanol water, and draining the washed filter cake to obtain a wet product of β-apo-12'-carotene;

[0067] 6) The wet product was dried at 60° C. in a vacuum oven to obtain 87.21 g of a dry product. HPLC analysis showed that the content of all-trans β-apo-12′-carotenal in the dry product was 86.36%, and the extraction yield was 91.85%.

[0068] 7) The crystallization mother liquor and the washing mother liquor were combined and concentrated under reduced pressure to recover ethanol. The pressure was reduced to about 100 mbar to recover the aqueous ethanol. The concentrate was transferred to a separatory funnel and extracted twice with 200 mL of petroleum ether respectively. The organic phases were combined and washed twice with 200 mL of 80% ethanol water respectively, and concentrated and dried to obtain 60.5 g of mother liquor.

[0069] Example 4

[0070] A method for isomeric extraction of cis-β-apo-12'-carotenal comprises the following steps:

[0071] 1) Under nitrogen protection, 1.45 g of concentrated sulfuric acid (20% of the molar amount of pure β-apo-12'-carotenal) dissolved in 200 ml of anhydrous ethanol was added to a three-necked flask containing the β-apo-12'-carotenal mother liquor (purity 13.32%, pure product 26.0 g, all-trans isomer accounted for 59.65%) recovered in Examples 1 to 3 to obtain an isomeric solution;

[0072] 2) Stir the isomerized solution evenly and cool it to below 10°C. After 3.0 hours of isomerization, solid begins to precipitate;

[0073] 3) Naturally raise the temperature, during which the temperature of the isomerization solution is controlled not to be higher than 20° C. After 22.8 h of isomerization, the isomerization process is monitored by HPLC until the proportion of all-trans β-apo-12'-carotenal reaches 84.72%, and then the isomerization is stopped;

[0074] 4) After the isomerization is completed, 22.2 g of water is added to the isomerized solution, the temperature is lowered to 15° C., and stirred for 0.5 h to allow all-trans β-apo-12'-carotene to crystallize and precipitate, and the filter cake is obtained by filtration;

[0075] 5) washing the filter cake with 160 mL of 90% ethanol water (pH=8.05) adjusted to alkalinity until it is neutral, filtering the neutral filter cake and then washing it with 160 mL of 90% ethanol water, and draining the washed filter cake to obtain a wet product of β-apo-12'-carotene;

[0076] 6) The wet product was dried at 60° C. in a vacuum oven to obtain 23.72 g of a dry product. HPLC analysis showed that the content of all-trans β-apo-12′-carotenal in the dry product was 81.73% and the extraction yield was 74.56%.

[0077] 7) The crystallization mother liquor and the washing mother liquor were combined and concentrated under reduced pressure to recover ethanol. The pressure was reduced to about 100 mbar to recover the aqueous ethanol. The concentrate was transferred to a separatory funnel and extracted twice with 200 mL of petroleum ether respectively. The organic phases were combined and washed three times with 100 mL of 80% ethanol water each, and concentrated and dried to obtain 52.8 g of mother liquor.

[0078] In the above embodiment, the isomerization conditions are mild, the operation is simple, the raw materials used in the reaction are anhydrous ethanol and concentrated sulfuric acid, the raw materials are easily available, the cost is low, and there are no other harmful byproducts remaining in the product, the production process is highly safe, and the extraction yield can reach more than 90%. The ethanol in the extraction process can be recycled, and the repeated isomerization in Example 4 by combining the crystallization mother liquor of other batches of extraction processes with the washing mother liquor greatly improves the isomerization extraction yield of cis-β-apo-12'-carotenal, which has extremely high industrial value and is suitable for large-scale industrial use.

[0079] The above-mentioned embodiments are only preferred embodiments of the present invention and cannot be used to limit the scope of protection of the present invention. Any non-substantial changes and substitutions made by technicians in this field on the basis of the present invention shall fall within the scope of protection required by the present invention.

Claims

1. A method for isomeric extraction of cis-β-apo-12'-carotenal, characterized in that: The following steps are involved: 1) mixing the material containing cis-β-apo-12'-carotenal, acid and solvent uniformly, cooling and performing isomerization reaction until solid is precipitated; 2) heating to continue the isomerization reaction to obtain a mixed solution containing the isomerized all-trans isomer, and crystallizing the all-trans isomer from the mixed solution; The acid is an inorganic acid; the solvent is a polar solvent; the inorganic acid is first dispersed in the polar solvent to obtain an acid solution, and then the acid solution is added to the material containing cis-β-apo-12'-carotene; The conditions for the isomerization reaction when the temperature is lowered to below 10°C are as follows: the isomerization reaction lasts for 0.5 to 3.0 hours; the conditions for the isomerization reaction when the temperature is raised are as follows: the temperature is not higher than 20°C, and the isomerization reaction lasts for 21.0 to 23.0 hours; In step 2), the crystallization process is as follows: adding 8% to 12% of the solvent volume of water to the mixed solution after the isomerization reaction, then cooling and crystallizing; filtering and washing to obtain all-trans β-apo-12'-carotene solid.

2. The isomeric extraction method of cis-β-apo-12'-carotenal according to claim 1, characterized in that: The molar ratio of the acid to cis-β-apo-12'-carotenal is (0.1-0.2):

1.

3. The isomeric extraction method of cis-β-apo-12'-carotenal according to claim 1, characterized in that: The structure of cis-β-apo-12'-carotenal includes one or a combination of two or more of 9-Z, 13-Z, 15-Z, 13'-Z, 9,13-di-Z, 9,13'-di-Z or 13,13'-di-Z isomers.

4. A method for isomeric extraction of cis-β-apo-12'-carotenal as claimed in any one of claims 1 to 3, characterized in that: The method further comprises the step of isomerization extraction of the cis-β-apo-12'-carotenal which is not completely isomerized in the mixed solution after crystallization as a material containing cis-β-apo-12'-carotenal.

5. The isomeric extraction method of cis-β-apo-12'-carotenal according to claim 4, characterized in that: After isomerization is completed, the content of all-trans β-apo-12'-carotenal in the mixed solution accounts for ≥80%.

6. The isomeric extraction method of cis-β-apo-12'-carotenal according to claim 1, characterized in that: The washing liquid used for washing is an alkaline 90% ethanol solution; washing is performed until the filtrate is neutral.

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