CN112552221B

CN112552221B - Preparation method of cantharis yellow

Info

Publication number: CN112552221B
Application number: CN202011541359.1A
Authority: CN
Inventors: 马瑞达; 汤镇伟; 谢德刚; 赵家宇
Original assignee: Xiamen Kingdomway Vitamin Co ltd; Xiamen Kingdomway Group Co
Current assignee: Xiamen Kingdomway Vitamin Co ltd; Xiamen Kingdomway Group Co
Priority date: 2020-12-23
Filing date: 2020-12-23
Publication date: 2022-08-16
Anticipated expiration: 2040-12-23
Also published as: CN112552221A

Abstract

The invention belongs to the field of compound synthesis, and relates to a preparation method of canthaxanthin. The canthaxanthin prepared by the method provided by the invention has good oxidation effect, lower oxidant dosage and higher canthaxanthin yield which can reach over 86 percent, and the obtained canthaxanthin is purplish red needle-shaped crystal with the content of more than 90 percent. And moreover, the method provided by the invention is adopted to treat the water layer for recycling, so that the consumption of the oxidant can be reduced, the cost is reduced, and the discharge of the waste water without the halide is realized.

Description

Preparation method of cantharis yellow

Technical Field

The invention belongs to the field of compound synthesis, and particularly relates to a preparation method of cantharis yellow.

Background

Canthaxanthin is a carotenoid, exists in mushroom, algae, shell of animal, fish, shrimp, egg, etc., and has a small content, and its structure is shown in formula (1). In the food industry, canthaxanthin is widely used in products such as beverages, ice cream, biscuits, sauce, meat products and the like. Meanwhile, canthaxanthin is also widely used in the feed additive industry, and is mainly used for improving the color quality of eggs and the growth of specific fishes and shrimps. In recent years, in the pharmaceutical and health product industry, the action of canthaxanthin is also emphasized by people, and a great deal of research shows that canthaxanthin has the effects of preventing and treating various diseases, and the effects are associated with various biological activities such as oxidation resistance, immunity promotion and the like.

In 1977, BASF proposed a one-step oxidation process, in which sodium chlorate was used as an oxidant and iodide or iodine was used as a catalyst to oxidize β -carotene into canthaxanthin, the reaction process being shown in formula (2). However, the process has more side reactions, the yield is between 56% and 78.5%, the using amount of the oxidant is large, 10-60 times equivalent of the using amount of the beta-carotene is needed, a large amount of sodium chlorate-containing wastewater is generated, the environmental pollution is large, and the cost is high.

In 1980, Toshiki Mori et al used chlorate or bromate as an oxidant and iodine halide and iodide together as a co-catalyst to oxidize beta-carotene into canthaxanthin in a yield of 76%, but this method requires the use of large amounts of volatile iodine and iodine halide having special toxicity.

In 2005, wushilin et al oxidized beta-carotene to canthaxanthin using a photocatalytic method with at least one of manganese dioxide, selenium dioxide, hydrogen peroxide, halide salts, etc. as an oxidant, with mild reaction conditions, but with a yield of only 60% to 70%.

In 2011, Jinlu et al use iodine as a catalyst, and adopt a solid phase grinding method to mix beta-carotene with sodium chlorate and then carry out solid phase grinding, the yield can reach 77%, the method reduces the use of a large amount of organic solvents, but the solid phase grinding of sodium chlorate has certain danger, so the method is not suitable for industrial production.

Disclosure of Invention

The invention aims to overcome the defects of low yield and great environmental pollution of the cantharis yellow prepared by the existing method, and provides a green and environment-friendly method for preparing the cantharis yellow, which can improve the yield.

The inventor of the present invention has found, after intensive and extensive research, that the oxidation of β -carotene into canthaxanthin has a low yield is caused by the fact that the activity of the oxidant and its by-products is too high, and the raw materials and products are easily damaged under the condition of oxidation reaction (low pH), and the addition of the strong acid salt of divalent manganese ions as the co-catalyst during the oxidation reaction not only can protect the raw materials and products, but also can fully utilize the by-products while inhibiting the side reaction, thereby achieving the purposes of increasing the yield and reducing the dosage of the oxidant. Based on this, the present invention has been completed.

The method comprises the steps of carrying out oxidation reaction on beta-carotene in a solvent in the presence of an oxidant, a catalyst and a strong acid salt of a divalent manganese ion, standing for layering after the oxidation reaction is finished, washing and purifying an oil layer, concentrating to remove the solvent, adding an isomerization solvent for isomerization reaction, and filtering and drying after the isomerization reaction is finished to obtain the all-trans canthaxanthin.

Further, the oxidation reaction mode is that an oxidant, a catalyst and a strong acid salt of divalent manganese ions are dissolved in water, the pH value of the obtained water solution is adjusted to 3-5, and then the obtained water solution is mixed with an organic solution of beta-carotene and then is subjected to heat preservation to realize the oxidation reaction.

Further, the oxidant is an alkali metal halide, preferably potassium chlorate and/or sodium chlorate.

Furthermore, the molar ratio of the oxidant to the beta-carotene is (3-5): 1.

Further, the catalyst is an active metal iodide, preferably potassium iodide and/or sodium iodide.

Furthermore, the molar ratio of the catalyst to the beta-carotene is (0.03-0.15): 1.

Further, the strong acid salt of the divalent manganese ions is manganese sulfate and/or manganese chloride.

Furthermore, the molar ratio of the strong acid salt of the divalent manganese ions to the beta-carotene is (0.06-0.2): 1.

Further, the organic solvent in the oxidation reaction system is halogenated alkane, preferably at least one selected from dichloromethane, trichloromethane and dichloroethane.

Furthermore, the dosage ratio of the organic solvent to the beta-carotene is 500mL (10-30) g.

Further, the oxidation reaction conditions comprise that the reaction temperature is 0-10 ℃, preferably 0-5 ℃, and the reaction time is 2-5 hours, preferably 3-4 hours.

Further, the isomeric solvent is C2-C5 monohydric alcohol.

Furthermore, the dosage ratio of the isomeric solvent to the beta-carotene is 100mL (5-15 g).

Further, the isomerization reaction conditions include that the temperature is 70-100 ℃, and preferably 70-80 ℃; the time is 5 to 10 hours, preferably 7 to 8 hours.

Further, the preparation method of cantharidin further comprises the steps of adjusting the pH value of a water layer obtained by standing and layering to 3-5 with acid, then preserving the heat for 0.5-2 hours at 30-50 ℃ under the micro vacuum condition, cooling, supplementing an oxidant and a catalyst, and continuing to perform the oxidation reaction.

Furthermore, the vacuum degree of the micro vacuum is-0.005 to-0.02 MPa.

The canthaxanthin prepared by the method provided by the invention has good oxidation effect and high canthaxanthin yield which can reach over 86 percent, and the obtained canthaxanthin is purple red needle-shaped crystal with the content of more than 90 percent. Moreover, due to the use of the promoter of the strong acid salt of the divalent manganese ions, the dosage of the oxidant can be reduced to 3-5 times from about 20 times of that of the beta-carotene in the prior art. In addition, because the water layer obtained by standing and layering the oxidation reaction product is rich in the halide of the alkali metal, the environmental protection treatment pressure is very high, the method provided by the invention is adopted to treat the water layer for recycling, the problem is better solved, the consumption of the oxidant is reduced, and the discharge of the waste water without the halide is realized while the cost is reduced.

Detailed Description

In the present invention, β -carotene is subjected to an oxidation reaction in a solvent in the presence of an oxidizing agent, a catalyst and a strong acid salt of a divalent manganese ion, specifically, β -carotene, an oxidizing agent, a catalyst and a strong acid salt of a divalent manganese ion are dissolved in a solvent in an arbitrary order and then subjected to an oxidation reaction, for example, β -carotene may be dissolved in an organic solvent and an oxidizing agent, a catalyst and a strong acid salt of a divalent manganese ion may be dissolved in water independently of each other, and then the resulting organic solution and each aqueous solution may be mixed uniformly and then subjected to an oxidation reaction; or dissolving beta-carotene in an organic solvent, dissolving any two or three of an oxidant, a catalyst and a strong acid salt of divalent manganese ions in water, and uniformly mixing the obtained organic solution and each aqueous solution to perform an oxidation reaction. In a preferred embodiment, the oxidation reaction is carried out by dissolving an oxidant, a catalyst and a strong acid salt of divalent manganese ions in water, adjusting the pH value of the obtained aqueous solution to 3-5, mixing with an organic solution of beta-carotene, and then keeping the temperature to realize the oxidation reaction. When the aqueous solution and the organic solution of the beta-carotene are mixed, the aqueous solution can be added into the organic solution of the beta-carotene, the organic solution of the beta-carotene can also be added into the aqueous solution, and the aqueous solution and the organic solution of the beta-carotene can also be mixed in a concurrent flow mode.

In the present invention, the oxidizing agent may be an alkali metal halide, specifically, an alkali metal chlorate and/or bromate. The alkali metal chlorate may be at least one of lithium chlorate, potassium chlorate, and sodium chlorate, for example. The alkali metal bromate may be at least one of lithium bromate, potassium bromate, and sodium bromate, for example. From the viewpoint of availability of raw materials, potassium chlorate and/or sodium chlorate is particularly preferable as the oxidizing agent. In addition, the molar ratio of the oxidant to the beta-carotene is preferably (3-5): 1.

In the present invention, the catalyst may be an iodide of an active metal, specifically, at least one of lithium iodide, potassium iodide and sodium iodide, and preferably potassium iodide and/or sodium iodide. In addition, the molar ratio of the catalyst to the beta-carotene is preferably (0.03-0.15): 1.

The key point of the present invention is to add a strong acid salt of a divalent manganese ion, specific examples of which include, but are not limited to: at least one of manganese sulfate, manganese chloride, manganese nitrate, etc., preferably manganese sulfate and/or manganese chloride. The molar ratio of the strong acid salt of the divalent manganese ion to β -carotene is preferably (0.06 to 0.2):1, and may be, for example, 0.06:1, 0.07:1, 0.08:1, 0.09:1, 0.1:1, 0.11:1, 0.12:1, 0.13:1, 0.14:1, 0.15:1, 0.16:1, 0.17:1, 0.18:1, 0.19:1, 0.2:1, or the like.

In the present invention, the solvent in the oxidation reaction system generally contains both water and an organic solvent, and the organic solvent may be, for example, an aliphatic hydrocarbon, an alicyclic hydrocarbon, an aromatic hydrocarbon, a halogenated alkane, an alcohol, an ether, an ester, a ketone, or the like. Specific examples of the aliphatic hydrocarbon include, but are not limited to: pentane, hexane, octane, and the like. Specific examples of the alicyclic hydrocarbon include, but are not limited to: cyclohexane, cyclohexanone, tolucyclohexanone, and the like. Specific examples of the aromatic hydrocarbon include, but are not limited to: benzene, toluene, xylene, and the like. Specific examples of the halogenated alkanes include, but are not limited to: dichloromethane, trichloromethane, dichloroethane, and the like. Specific examples of the alcohol include, but are not limited to: methanol, ethanol, n-propanol, isopropanol, and the like. Specific examples of such ethers include, but are not limited to: diethyl ether, propylene oxide, and the like. Specific examples of such esters include, but are not limited to: methyl formate, ethyl formate, propyl formate, methyl acetate, ethyl acetate, propyl acetate, and the like. Specific examples of the ketone include, but are not limited to: acetone, methyl butanone, methyl isobutyl ketone, and the like. In addition, the ratio of the water usage amount to the oxidant usage amount in the oxidation reaction system is preferably 250mL (0.1-1) g. The ratio of the dosage of the organic solvent to the dosage of the beta-carotene in the oxidation reaction system is preferably 500mL (10-30) g.

The oxidation reaction conditions in the present invention are not particularly limited as long as the β -carotene can be converted into canthaxanthin. For example, the oxidation reaction conditions include a reaction temperature of 0 to 10 ℃, preferably 0 to 5 ℃; the reaction time can be 2-5 h, preferably 3-4 h.

In the present invention, the detergent and the washing method used for washing and purifying the oil layer are not particularly limited as long as unreacted raw materials and by-products remaining in the oil layer can be removed. In one embodiment, the oil layer is washed once with sodium thiosulfate solution and once with water.

In the present invention, the isomerization solvent is preferably a monohydric alcohol of C2-C5, and specific examples thereof include, but are not limited to: at least one of ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol, isopentanol, and tert-pentanol. In addition, the dosage ratio of the isomerization solvent to the beta-carotene is preferably 100mL (5-15) g.

The isomerization reaction conditions in the present invention are not particularly limited as long as the isomers of canthaxanthin in the oxidation reaction product can be converted into all-trans canthaxanthin. For example, the isomerization conditions include a temperature of 70 to 100 ℃, preferably 70 to 80 ℃; the time can be 5-10 h, preferably 7-8 h.

In the present invention, in order to reduce the loss of the product, it is preferable to filter the isomerization reaction product after cooling to normal temperature. The filtration method may be, for example, filter pressing, suction filtration, or the like.

In a preferred embodiment, the preparation method of canthaxanthin provided by the invention further comprises the steps of adjusting the pH value of an aqueous layer obtained by standing and layering to 3-5 by using acid, then preserving the temperature for 0.5-2 h at 30-50 ℃ under the micro vacuum condition, cooling, supplementing an oxidant and a catalyst, and continuing to perform an oxidation reaction. The method realizes the recycling of the water layer, not only can reduce the consumption of the oxidant, but also can realize the discharge of the waste water containing the halide without the alkali metal. The degree of vacuum of the micro vacuum is preferably-0.005 to-0.02 MPa.

The present invention will be described in detail below by way of examples. The examples of embodiments are intended to be illustrative of the invention and are not to be construed as limiting the invention. The examples do not specify particular techniques or conditions, and are performed according to the techniques or conditions described in the literature in the art or according to the product specifications. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.

In the following examples and comparative examples, canthaxanthin content was measured as follows:

the instrument comprises the following steps: agilent 1200; a chromatographic column: etherlite Hypersil ODS 25 um × 4.6mm × 250mm, detector: UV; wavelength: 465 nm; the column temperature is 25 ℃, the flow rate is 1.0mL/min, and the mobile phase is acetonitrile, water and n-amyl alcohol, wherein the volume ratio is 92:7: 1; the amount of the sample was 10.0. mu.L.

Example 1

0.30g (0.0018mol) of potassium iodide, 0.46g (0.0036mol) of manganese chloride and 19.43g (0.1825mol) of sodium chlorate were dissolved in 250mL of water, and the pH of the resulting aqueous solution was adjusted to 4 with 5% dilute hydrochloric acid for use.

Adding 20g of beta-carotene (98.0%, 0.0365mol) and 500mL of dichloromethane into a 1000mL reaction kettle, starting stirring, adding the aqueous solution, vacuumizing and supplementing nitrogen for three times, cooling to 0-5 ℃, and preserving heat for 3 hours. Standing and layering after heat preservation, washing an oil layer once by using 150mL of 2.5% w/v sodium thiosulfate solution and once by using water, concentrating to be dry, adding 200mL of ethanol, preserving the heat at 70 ℃ for isomerization for 8h, cooling to the normal temperature, filtering under reduced pressure, and drying to obtain 19.91g of all-trans canthaxanthin with the content of 95.5% and the yield of 92.2%.

Example 2

0.18g (0.0011mol) of potassium iodide, 0.28g (0.0022mol) of manganese chloride and 11.66g (0.1095mol) of sodium chlorate were dissolved in 250mL of water, and the pH of the resulting aqueous solution was adjusted to 4 with 5% dilute hydrochloric acid for further use.

Adding 20g of beta-carotene (98.0%, 0.0365mol) and 500mL of dichloromethane into a 1000mL reaction kettle, starting stirring, adding the aqueous solution, vacuumizing and supplementing nitrogen for three times, cooling to 0-5 ℃, and preserving heat for 3 hours. Standing and layering after heat preservation, washing an oil layer once by using 150mL of 2.5% w/v sodium thiosulfate solution and once by using water, concentrating to be dry, adding 200mL of ethanol, preserving the heat at 70 ℃ for isomerization for 8h, cooling to the normal temperature, filtering under reduced pressure, and drying to obtain 19.71g of all-trans canthaxanthin with the content of 90.5% and the yield of 86.5%.

Example 3

0.61g (0.0037mol) of potassium iodide, 0.92g (0.0073mol) of manganese chloride, and 19.43g (0.1825mol) of sodium chlorate were dissolved in 250mL of water, and the pH of the resulting aqueous solution was adjusted to 4 with 5% dilute hydrochloric acid for use.

Adding 20g of beta-carotene (98.0%, 0.0365mol) and 500mL of dichloromethane into a 1000mL reaction kettle, starting stirring, adding the aqueous solution, vacuumizing and supplementing nitrogen for three times, cooling to 0-5 ℃, and preserving heat for 3 hours. Standing and layering after heat preservation, washing an oil layer once by using 150mL of 2.5% w/v sodium thiosulfate solution and once by using water, concentrating to be dry, adding 200mL of ethanol, preserving the heat at 70 ℃ for isomerization for 8h, cooling to the normal temperature, filtering under reduced pressure, and drying to obtain 20.11g of all-trans canthaxanthin with the content of 93.2% and the yield of 90.9%.

Example 4

0.27g (0.0018mol) of sodium iodide, 0.55g (0.0037mol) of manganese sulfate and 13.42g (0.1095mol) of potassium chlorate were dissolved in 250mL of water, and the pH of the resulting aqueous solution was adjusted to 5 with 5% dilute hydrochloric acid for further use.

Adding 20g of beta-carotene (98.0%, 0.0365mol) and 500mL of dichloromethane into a 1000mL reaction kettle, starting stirring, adding the aqueous solution, vacuumizing and supplementing nitrogen for three times, cooling to 5-10 ℃, and preserving heat for 5 hours. Standing for layering after heat preservation is finished, washing an oil layer once by using 150mL of 2.5% w/v sodium thiosulfate solution and once by using water, concentrating to be dry, adding 200mL of ethanol, preserving the heat at 70 ℃ for isomerization for 8h, cooling to normal temperature, filtering under reduced pressure, and drying to obtain 19.87g of all-trans canthaxanthin, wherein the content of the all-trans canthaxanthin is 90.8%, and the yield of the all-trans canthaxanthin is 87.5%.

Example 5

0.30g (0.0018mol) of potassium iodide, 0.46g (0.0036mol) of manganese chloride and 19.43g (0.1825mol) of sodium chlorate were dissolved in 250mL of water, and the pH of the resulting aqueous solution was adjusted to 3 with 5% dilute hydrochloric acid for use.

Adding 20g of beta-carotene (98.0%, 0.0365mol) and 500mL of dichloromethane into a 1000mL reaction kettle, starting stirring, adding the aqueous solution, vacuumizing and supplementing nitrogen for three times, cooling to 0-5 ℃, and preserving heat for 3 hours. Standing and layering after heat preservation, washing an oil layer once by using 150mL of 2.5% w/v sodium thiosulfate solution and once by using water, concentrating to be dry, adding 200mL of ethanol, preserving the heat at 70 ℃ for isomerization for 8h, cooling to normal temperature, filtering under reduced pressure, and drying to obtain 20.35g of all-trans canthaxanthin with the content of 90.4% and the yield of 89.2%.

Example 6

The aqueous layer obtained in example 1 was allowed to stand and delaminate, the pH was adjusted to 4 with 5% diluted hydrochloric acid, the aqueous layer was heated to 40 ℃ under a vacuum of-0.01 MPa, and the temperature was maintained for 1 hour, after which the aqueous layer was cooled to room temperature, and the amounts of sodium chlorate, potassium iodide and manganese chloride contained in the aqueous layer were measured, and the aqueous layer was subjected to oxidation reaction after adding sufficient amounts of sodium chlorate, potassium iodide and β -carotene according to the formulation of example 1, and the other test conditions were the same as in example 1. The above procedure was repeated 5 times, and the results are shown in Table 1 below.

TABLE 1

Number of times of application	1	2	3	4	5
						Cantharis yellow content	94.9％	94.7％	95.7％	94.2％	95.0％
Yield of	91.8％	92.0％	92.4％	91.4％	91.9％

Comparative example 1

Canthaxanthin was prepared according to the method of example 1, except that manganese chloride was not added and the other conditions were the same as in example 1, to obtain 13.18g of all-trans canthaxanthin, content of which was 70.4%, yield of 45.0%.

Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made in the above embodiments by those of ordinary skill in the art without departing from the principle and spirit of the present invention.

Claims

1. A process for preparing cantharidin includes oxidizing beta-carotene in solvent in the presence of oxidant, catalyst and strong acid salt of bivalent Mn ion, where the oxidant is alkali metal halide and the catalyst is active metal iodide, laying aside for layering, washing oil layer, concentrating to remove solvent, adding isomerizing solvent, isomerizing reaction, filtering and drying.

2. The method for preparing canthaxanthin according to claim 1, wherein the oxidation reaction is carried out by dissolving an oxidant, a catalyst and a strong acid salt of a divalent manganese ion in water, adjusting the pH of the obtained aqueous solution to 3 to 5, mixing the aqueous solution with an organic solution of β -carotene, and then maintaining the temperature to effect the oxidation reaction.

3. The method for preparing canthaxanthin in accordance with claim 1, wherein said oxidizing agent is potassium chlorate and/or sodium chlorate.

4. The method for preparing canthaxanthin of claim 3, wherein the molar ratio of the oxidant to the β -carotene is (3-5): 1.

5. The method for preparing canthaxanthin of claim 1, wherein said catalyst is potassium iodide and/or sodium iodide.

6. The method for preparing canthaxanthin of claim 5, wherein the molar ratio of the catalyst to the β -carotene is (0.03-0.15): 1.

7. The method for preparing canthaxanthin according to claim 1, wherein the strong acid salt of a divalent manganese ion is manganese sulfate and/or manganese chloride.

8. The method for preparing canthaxanthin of claim 7, wherein the molar ratio of the strong acid salt of divalent manganese ion to β -carotene is (0.06-0.2): 1.

9. The process for preparing cantharis yellow according to claim 1, wherein the organic solvent in the oxidation reaction system is halogenated alkane.

10. The process for preparing canthaxanthin in accordance with claim 9, wherein the organic solvent in the oxidation reaction system is at least one selected from the group consisting of dichloromethane, chloroform and dichloroethane.

11. The method for preparing canthaxanthin of claim 9, wherein the dosage ratio of the organic solvent to the β -carotene is 500mL (10-30) g.

12. The method for preparing cantharis yellow according to claim 1, wherein the oxidation reaction conditions include a reaction temperature of 0 to 10 ℃ and a reaction time of 2 to 5 hours.

13. The method for preparing cantharis yellow according to claim 12, wherein the reaction temperature of the oxidation reaction is 0 to 5 ℃.

14. The method for preparing canthaxanthin of claim 12, wherein the reaction time of the oxidation reaction is 3 to 4 hours.

15. The method for preparing canthaxanthin of claim 1, wherein the isomeric solvent is a monohydric alcohol of C2-C5.

16. The method for preparing canthaxanthin of claim 15, wherein the dosage ratio of the isomeric solvent to the β -carotene is 100mL (5-15) g.

17. The method for preparing canthaxanthin according to claim 1, wherein the isomerization reaction is carried out at a temperature of 70 to 100 ℃ for 5 to 10 hours.

18. The method for preparing canthaxanthin of claim 17, wherein the temperature of the isomerization reaction is 70 to 80 ℃.

19. The method for preparing canthaxanthin of claim 17, wherein the time of the isomerization reaction is 7 to 8 hours.

20. The method for preparing canthaxanthin according to any one of claims 1 to 19, wherein the method further comprises adjusting the pH of an aqueous layer obtained by standing and layering to 3 to 5 with an acid, then keeping the temperature at 30 to 50 ℃ for 0.5 to 2 hours under a slight vacuum condition, cooling, adding an oxidizing agent and a catalyst, and continuing to apply the mixture to an oxidation reaction.

21. The method for preparing cantharis yellow according to claim 20, wherein the degree of vacuum of the micro vacuum is-0.005 to-0.02 MPa.