Preparation method of canthaxanthin

Abstract

The invention belongs to the technical field of fine chemical engineering, and particularly relates to a preparation method of canthaxanthin. The preparation method comprises the following steps: adding a catalyst and beta-carotene into a reaction solvent, adjusting the pH value of the solution to be acidic, pre-cooling the reaction solution, circularly injecting the reaction solution into a chromatographic column filled with oxidant particles through a peristaltic pump, returning to a reaction system, controlling the temperature of the circulating solution, washing with water after the reaction is finished, and drying to obtain beta-carotene. And after standing and layering, carrying out reduced pressure distillation on the obtained organic phase to separate the solvent, carrying out isomerization reaction, filtering, and recrystallizing to obtain canthaxanthin. According to the preparation method disclosed by the invention, the cis-isomer content is low in the reaction process, the isomerization reaction time is short, the efficiency is high, and the obtained cantharidin product is high in quality, less in residual inorganic salt and less in washing wastewater, and is more environment-friendly.

Description

Technical Field

[0001] The invention belongs to the technical field of fine chemicals, and particularly relates to a method for preparing cantharidin. Background Art

[0002] Canthaxanthin, also known as canthaxanthin and β-carotene-4,4'-dione, is one of the five main carotenoids such as β-carotene, astaxanthin, lycopene, lutein, and canthaxanthin. Due to the presence of multiple conjugated olefin bonds in the molecular structure of canthaxanthin, it has good coloring properties and antioxidant capacity. Its ability to quench free radicals is slightly worse than that of astaxanthin, nearly twice that of β-carotene, and nearly 50 times that of vitamin E (VE). In 1984, canthaxanthin was included in the list of food additives and corresponding quality standards were formulated. Now, canthaxanthin has been widely used in food, nutritional products, cosmetics, feed additives and other fields.

[0003] At present, the chemical synthesis routes of Cantharidin are mainly: (1) C15+C10+C15; (2) C9+C22+C9; (3) C40 oxidation method. Among them, the C15+C10+C15 and C9+C22+C9 routes have more process steps and are more complicated. Compared with the route of extending the carbon chain, the C40 oxidation method has simpler operation and equipment. The reaction formula of the C40 oxidation method is as follows: .

[0004] C40 oxidation method uses β-carotene as raw material for oxidation synthesis. International patent US4212827 uses halogen acid salt oxidation and iodine elemental catalysis to prepare Cantharidin. After the reaction is completed, there are many inorganic salts remaining in Cantharidin, and 225 times the amount of water of the raw material β-carotene is required for washing, and a lot of wastewater is generated, which is not environmentally friendly. Chinese patent CN 112552221 uses an oxidant, a catalyst and a strong acid salt of divalent manganese ions in a solvent to carry out an oxidation reaction to prepare Cantharidin. The raw materials of this method are added at one time, and many isomers are produced, and the isomerization reaction time requires 7-8h, which is long and inefficient. CN1417207 uses an in-situ system, and uses sulfurous acid, hydrogen sulfite or acid sulfite combined with bromate to produce hypobromous acid as an oxidant for preparation. The above-mentioned existing preparation methods will introduce inorganic salt impurities into the finished Cantharidin product, which reduces the product quality and produces some cis isomers. If the inorganic salts in the product are to be fully removed, multiple washings are required, which will produce a large amount of salt-containing wastewater. At the same time, the above oxidation reaction is a two-phase reaction, the oxidant is usually greatly excessive, and the raw material β-carotene and the product canthaxanthin are easily deteriorated in the acidic oxidation system for a long time, resulting in a decrease in yield. Summary of the invention

[0005] Based on the problems in the background technology that a lot of salt-containing wastewater is generated when preparing cantharidin, and cantharidin is easy to deteriorate in an oxidation system, the present invention proposes a novel cantharidin preparation method. In the reaction process of the preparation method, the content of cis-isomer is small, the isomerization reaction time is short, the efficiency is high, the obtained cantharidin product is high in quality, less in residual inorganic salts, less in washing wastewater, and more green and environmentally friendly.

[0006] In order to achieve the above object, the present invention provides the following technical solutions: The invention aims to provide a preparation method of cantharidin, which comprises the following steps: putting a catalyst and beta-carotene into a reaction bottle pre-added with a reaction solvent and deionized water, adjusting the pH value of the solution to be acidic, pre-cooling the reaction solution, then circulating the reaction solution into a chromatography column filled with oxidant particles through a peristaltic pump and returning the reaction solution to the reaction system, controlling the temperature of the circulating liquid, washing with water after the reaction is completed, standing and stratifying, performing isomerization reaction after removing the solvent from the obtained organic phase by reduced pressure distillation, filtering and recrystallizing to obtain cantharidin.

[0007] The present invention adopts a packing column filled with oxidant particles as a reactor. During the oxidation reaction, the reaction liquid circulates and contacts with the oxidant for reaction, and the content of the cis-isomer produced is small, which can effectively reduce the time of the isomerization reaction and greatly improve the reaction efficiency. At the same time, the inorganic salts remaining in the reaction liquid after the oxidation is completed are also greatly reduced, which is beneficial to subsequent washing and reduces the generation of waste water.

[0008] Furthermore, in the above technical solution, the oxidant particles are any one of alkali metal halides, alkaline earth metal halides, and ammonium halides, preferably sodium chlorate or potassium chlorate.

[0009] Furthermore, in the above technical solution, the weight of the oxidant particles is 4 to 6 times the weight of β-carotene, preferably 4 to 5 times.

[0010] Furthermore, in the above technical solution, the reaction solvent is a halogenated alkane, preferably dichloromethane, and the volume mass ratio (mL / g) of the used amount to the β-carotene is 75 to 85:1; the volume mass ratio (mL / g) of the added amount of the deionized water to the β-carotene is 0.8 to 1.5:1.

[0011] Furthermore, in the above technical solution, the catalyst is a composite catalyst, which is a mixture of iodine and metal iodide in a mass ratio of 1:3-5, and the usage amount is 8-12% of the mass of the β-carotene, preferably 10%.

[0012] Furthermore, in the above technical solution, the catalyst is a mixture of I2 and KI in a mass ratio of 1:4 to 4.5.

[0013] Furthermore, in the above technical solution, the temperature of the circulating liquid is -15 to 5°C, preferably -5 to 0°C; the flow rate of the circulating solution is 300 to 550 mL / min, preferably 400 to 500 mL / min.

[0014] Furthermore, in the above technical solution, the reaction solvent is a halogenated alkane, preferably dichloromethane; the pH is adjusted to 5.0 to 6.0; and the reaction solution is pre-cooled to -10 to -5°C.

[0015] Furthermore, in the above technical solution, the solvent for the isomerization reaction is any one of alkanes, halogenated alkanes, esters, and alcohols, preferably ethanol and n-propyl acetate; the temperature is 75 to 110° C., and the time is 1.5 to 2 hours.

[0016] Furthermore, in the above technical solution, the recrystallization solvent is one or more of water, halogenated alkanes, alcohols, and ketones, preferably a mixed solvent of dichloromethane and ethanol in a volume ratio of 1:1.5 to 1.8; the heating reflux temperature of the recrystallization is 30 to 70°C, and the time is 2 to 3 hours.

[0017] Compared with the prior art, the present invention has the following beneficial effects: The present invention uses a packing column filled with oxidant particles as a partial reactor. During the oxidation reaction, the reaction liquid circulates and contacts with the oxidant for reaction, the content of the generated cis-isomer is small, and less impurities such as inorganic salts remain, so that the subsequent isomerization reaction speed is fast, and the problem of cantharidin staying in the acidic oxidation system for a long time and deteriorating in the prior art is avoided. The finished product has good quality, high ultraviolet content and high yield; at the same time, the impurities are small, the subsequent washing wastewater is greatly reduced, the wastewater treatment cost is low, the process is simple, and it is more green and environmentally friendly. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments recorded in the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0019] Figure 1 It is a schematic diagram of the structure of the oxidation reaction device of the present invention. DETAILED DESCRIPTION

[0020] The experimental methods in the following examples are conventional methods unless otherwise specified. The raw materials involved in the following examples are common commercial products and can be purchased from the market unless otherwise specified.

[0021] The above-mentioned technical features of the present invention and the technical features specifically described below (such as implementation cases) can be combined with each other to form a new or preferred technical solution.

[0022] The raw materials involved in the embodiments of the present invention are either existing commercially available products or can be prepared according to existing methods, and the testing methods are industry methods.

[0023] Example 1 A method for preparing Cantharidin, comprising the following steps: 0.20g I2, 0.80g KI, 10.00g β-carotene were put into a reaction bottle added with 800mL dichloromethane and 10mL deionized water, and dilute hydrochloric acid was added dropwise to adjust the pH of the solution to 5.0-6.0. At the same time, the reaction solution was pre-cooled to -10°C, and then the reaction solution was circulated into a chromatography column filled with 50.00g sodium chlorate particles through a peristaltic pump and returned to the reaction system. The circulating liquid flow rate was 450mL / min, and the circulating liquid temperature was controlled to be -5-0°C. After the reaction was completed (sampling HPLC detection judgment), it was washed twice with 100mL deionized water, and after standing and stratification, the obtained organic phase was vacuum distilled to separate the solvent, and 200mL ethanol was added to isomerize the reaction at 75-80°C for 2h, filtered, and the filter cake was added with 75mL dichloromethane and 130mL ethanol, heated to reflux at 30-40°C for 3h, cooled for crystallization, filtered, and dried to obtain dark purple crystals 8.94 g, the UV content was 99.56% and the yield was 85.00%.

[0024] Example 2 A method for preparing Cantharidin, comprising the following steps: 0.20g I2, 0.80g KI, 10.00g β-carotene were put into a reaction bottle added with 800mL dichloromethane and 10mL deionized water, acetic acid was added dropwise to adjust the pH of the solution to 5.0-6.0, and the reaction solution was pre-cooled to -10°C, and then the reaction solution was circulated into a chromatography column filled with 40.00g potassium chlorate particles through a peristaltic pump and returned to the reaction system. The circulating liquid flow rate was 400mL / min, and the circulating liquid temperature was controlled to be -5-0°C. After the reaction was completed (sampling HPLC detection judgment), it was washed twice with 100mL deionized water, and after standing and stratification, the obtained organic phase was vacuum distilled to separate the solvent, and 200mL ethanol was added to isomerize the reaction at 75-80°C for 2h, filtered, and the filter cake was added with 75mL dichloromethane and 130mL ethanol and heated to reflux at 30-40°C for 3h, cooled for crystallization, filtered, and dried to obtain dark purple crystals 8.42 g, the UV content was 99.26% and the yield was 80.01%.

[0025] Example 3 A method for preparing Cantharidin, comprising the following steps: 0.20g I2, 0.80g KI, 10.00g β-carotene were added to a reaction bottle with 800mL dichloromethane and 10mL deionized water, and dilute hydrochloric acid was added dropwise to adjust the pH of the solution to 5.0-6.0. At the same time, the reaction solution was pre-cooled to -10°C, and then the reaction solution was circulated into a chromatography column filled with 50.00g sodium chlorate particles through a peristaltic pump and returned to the reaction system. The circulating liquid flow rate was 450mL / min, and the circulating liquid temperature was controlled to be -5-0°C. After the reaction was completed (sampling HPLC detection judgment), the organic phase was allowed to stand and stratified, and the organic phase was separated and washed twice with 100mL water. After standing and stratification, the obtained organic phase was distilled under reduced pressure to separate the solvent, and 250mL of n-propyl acetate was added to isomerize at 100-110°C for 1.5h, filtered, and the filter cake was added with 75mL chloroform and 130mL ethanol, heated to reflux at 55-70°C for 2h, cooled and crystallized, filtered, and dried to obtain dark purple crystals 8.55 g, the UV content was 98.23% and the yield was 81.23%.

[0026] Comparative Example 1 A method for preparing Cantharidin, comprising the following steps: 0.20g I2, 0.80g KI, 10.00g β-carotene were put into a reaction bottle added with 800mL dichloromethane and 10mL deionized water, and dilute hydrochloric acid was added dropwise to adjust the pH of the solution to 5.0-6.0. At the same time, the reaction solution was pre-cooled to -10°C, and then the reaction solution was circulated into a chromatography column filled with 50.00g sodium bromate particles through a peristaltic pump and returned to the reaction system. The circulating liquid flow rate was 450mL / min, and the circulating liquid temperature was controlled to be -5-0°C. After the reaction was completed (sampling HPLC detection judgment), the organic phase was separated and washed twice with 100mL water. After standing and stratification, the obtained organic phase was distilled under reduced pressure to separate the solvent, and 200mL ethanol was added to isomerize the reaction at 75-80°C for 2h, filtered, 75mL dichloromethane and 130mL ethanol were added to the filter cake and heated to reflux at 30-40°C for 3h, cooled for crystallization, filtered, and dried to obtain dark purple crystals 6.54 g, the UV content was 97.13% and the yield was 62.18%.

[0027] Comparative Example 2 A method for preparing Cantharidin, comprising the following steps: 0.20g I2, 0.80g KI, 10.00g β-carotene were put into a reaction bottle added with 800mL dichloromethane and 100mL deionized water, and dilute hydrochloric acid was added dropwise to adjust the pH of the solution to 5.0-6.0. At the same time, the reaction solution was pre-cooled to -10°C, and then the reaction solution was circulated into a chromatography column filled with 50.00g sodium chlorate particles through a peristaltic pump and returned to the reaction system. The circulating liquid flow rate was 450mL / min, and the circulating liquid temperature was controlled to be -5-0°C. After the reaction was completed (sampling HPLC detection judgment), the organic phase was separated and washed twice with 100mL water. After standing and stratification, the obtained organic phase was distilled under reduced pressure to separate the solvent, and 200mL ethanol was added to isomerize the reaction at 75-80°C for 2h, filtered, 75mL dichloromethane and 130mL ethanol were added to the filter cake and heated to reflux at 30-40°C for 3h, cooled for crystallization, filtered, and dried to obtain dark purple crystals 8.26 g, the UV content was 95.23% and the yield was 78.52%.

[0028] Comparative Example 3 A method for preparing Cantharidin, comprising the following steps: 0.20g I2, 0.80g KI, 10.00g β-carotene were added to a reaction bottle with 800mL dichloromethane and 10mL deionized water, and dilute hydrochloric acid was added dropwise to adjust the pH of the solution to 5.0-6.0. At the same time, the reaction solution was pre-cooled by 10°C, and then the reaction solution was circulated into a chromatography column filled with 50.00g sodium chlorate particles through a peristaltic pump and returned to the reaction system. The circulating liquid flow rate was 450mL / min, and the circulating liquid temperature was controlled to be -5-0°C. After the reaction was completed (sampling HPLC detection judgment), the organic phase was allowed to stand and stratified, and the organic phase was separated and washed twice with 100mL water. After standing and stratification, the obtained organic phase was distilled under reduced pressure to separate the solvent, and 200mL ethanol was added to isomerize the reaction at 75-80°C for 2h, filtered, and the filter cake was added with 75mL dichloromethane and 130mL ethanol and heated to reflux at 30-40°C for 3h, cooled for crystallization, filtered, and dried to obtain dark purple crystals 6.90 g, the UV content was 94.88% and the yield was 65.55%.

[0029] Comparative Example 4 A method for preparing Cantharidin, comprising the following steps: Add 5 mL of water to 0.20 g of I2 and 0.80 g of KI and stir to dissolve. Add 250 mL of water to 50.00 g of sodium chlorate. mL of water was stirred and dissolved, 10.00g of β-carotene and 800mL of dichloromethane solvent were added into the reactor, dilute hydrochloric acid was added dropwise to adjust the pH of the solution to 5.0-6.0, and the reaction solution was pre-cooled to -10°C, and then the prepared I2 / KI solution and sodium chlorate solution were added into the reactor, and the circulating liquid temperature was controlled to -5-0°C. After the reaction was completed (sampling and HPLC detection judgment), it was washed with 1000mL of water for 3 times, and after standing and stratification, the obtained organic phase was distilled under reduced pressure to separate the solvent, and then 200mL of ethanol was added to isomerize the reaction at 75-80°C for 2h, filtered, and the filter cake was added with 75mL of dichloromethane and 130mL of ethanol, heated to reflux at 30-40°C for 3h, cooled for crystallization, filtered, and dried to obtain 7.50g of dark purple crystals, the ultraviolet content of which was 96.03% and the yield was 71.25%.

[0030] Compared with Example 1, in Comparative Example 1, sodium bromate particles are used as an oxidant. Since its oxidizing property is weaker than that of sodium chlorate and its relative molecular weight is larger, its oxidizing ability is worse at the same dosage, and the yield of the finally obtained Cantharidin is low and the quality is poor; in Comparative Example 2, 100 mL of deionized water is added to the reaction solution. Due to the excess of water, the Cantharidin crystals obtained by the reaction contain inorganic salts such as chlorate. Subsequently, the salt substances cannot be removed by washing with the same amount of water, and a large amount of all-trans isomers are converted into cis isomers, thereby reducing the quality of Cantharidin; in Comparative Example 3, the temperature of the reaction solution is 10°C. Since the raw material β-carotene and the product Cantharidin are both conjugated polyene structures, they are easily deteriorated at this higher temperature, which affects the yield and quality of Cantharidin; Comparative Example 4 adopts a one-pot method, and the oxidant is in contact with the raw materials β-carotene and Cantharidin for a long time, resulting in more isomers, impurities, etc., which affect the yield and quality of Cantharidin.

[0031] In summary, the preparation method of the present invention has a short contact time between the oxidant and beta-carotene and canthaxanthin, less cis-isomers and impurities are produced, the isomerization reaction time after the oxidation reaction is short and fast, less waste water is produced, the obtained canthaxanthin has a high ultraviolet content of 99.56%, the yield is also high and can reach 85%, and the quality is good.

[0032] Finally, it should be emphasized that the above is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various changes and modifications. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for preparing Cantharidin, characterized in that: The method comprises the following steps: putting a catalyst and beta-carotene into a reaction bottle pre-added with a reaction solvent and deionized water, adjusting the pH value of the solution to be acidic, pre-cooling the reaction solution, then circulating the reaction solution into a chromatography column filled with oxidant particles through a peristaltic pump and returning the reaction solution to the reaction system, controlling the temperature of the circulating liquid, washing with water after the reaction is completed, standing and stratifying, performing isomerization reaction after decompressing and distilling the obtained organic phase to separate the solvent, filtering and recrystallizing to obtain cantharidin.

2. The preparation method according to claim 1, characterized in that: The oxidant particles are any one of alkali metal halides, alkaline earth metal halides, and ammonium halides, preferably sodium chlorate or potassium chlorate.

3. The preparation method according to claim 1, characterized in that: The weight of the oxidant particles is 4 to 6 times, preferably 4 to 5 times, the weight of β-carotene.

4. The preparation method according to claim 1, characterized in that: The reaction solvent is a halogenated alkane, preferably dichloromethane, and the volume mass ratio of the used amount to the beta-carotene is 75-85:1; the volume mass ratio of the added amount of deionized water to the beta-carotene is 0.8-1.5:

1.

5. The preparation method according to claim 1, characterized in that: The catalyst is a composite catalyst, which is a mixture of iodine and metal iodide in a mass ratio of 1:3-5, and the usage amount is 8-12% of the mass of the β-carotene, preferably 10%.

6. The preparation method according to claim 5, characterized in that: The catalyst is a mixture of I2 and KI in a mass ratio of 1:4 to 4.

5.

7. The preparation method according to claim 1, characterized in that: The temperature of the circulating liquid is -15 to 5°C, preferably -5 to 0°C; the flow rate of the circulating solution is 300 to 550 mL / min, preferably 400 to 500 mL / min.

8. The preparation method according to claim 1, characterized in that: The pH is adjusted to 5.0-6.0; the reaction solution is pre-cooled to -10--5°C.

9. The preparation method according to claim 1, characterized in that: The solvent for the isomerization reaction is any one of alkanes, halogenated alkanes, esters, and alcohols, preferably ethanol or n-propyl acetate; the temperature is 75 to 110° C., and the reaction time is 1.5 to 2 hours.

10. The preparation method according to claim 1, characterized in that: The solvent for the recrystallization is one or more of water, halogenated alkane, alcohol, and ketone, preferably a mixed solvent of dichloromethane and ethanol in a volume ratio of 1:1.5-1.8; the heating reflux temperature for the recrystallization is 30-70° C., and the time is 2-3 hours.

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