Recovery method of 7-dehydrocholesterol

Abstract

The invention discloses a recovery method of 7-dehydrocholesterol, which comprises the following steps: pretreating a 7-dehydrocholesterol crystallization mother liquor serving as a raw material to obtain a crystallization mother liquor dry basis; dissolving the crystallization mother liquor dry basis by adopting an organic solvent, and filtering to obtain filtrate; adding a complexing agent into the filtrate, and filtering after complexing reaction to obtain a complex; the complexing agent is metal salt of divalent metal ions, and the metal salt can be dissolved in water; adding water into the complex for decomplexing, extracting and crystallizing; according to the recovery method, the 7-dehydrocholesterol (7-DHC) in the 7-dehydrocholesterol crystallization mother liquor can be effectively extracted, a 7-dehydrocholesterol product with the purity being 95% or above is obtained, and the yield is high. Meanwhile, the operation method is simple, easy to repeat and beneficial to industrialization.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of fine chemical technology, and particularly relates to a recovery method of 7-dehydrocholesterol. BACKGROUND

[0002] 7-dehydrocholesterol (7-DHC) is a kind of sterol compound, which naturally exists in the sebaceous glands of animal skin and its secretions, and is called vitamin D precursor. In the human body, 7-DHC can be converted from cholesterols metabolism, and is stored in subcutaneous tissue. When it is irradiated by sunlight or ultraviolet light, it can be converted into vitamin D3, so as to regulate calcium and phosphorus metabolism, promote bone health, promote the absorption of calcium and phosphorus by small intestinal mucosal cells, and thus prevent the occurrence of rickets.

[0003] At present, the main synthesis route of 7-DHC in industry is: taking cholesterols as raw material, and synthesizing through esterification, oxidation, hydrazone, dehydrazone, saponification and other chemical reactions. The process technology route is mature. However, the price of cholesterols on the market is relatively high, and the synthesis route of 7-DHC is long, so the cost of synthesizing 7-DHC is high. At present, the material (containing 10%-20% of 7-DHC) after recovering the solvent from the 7-DHC crystallization mother liquor in production is all treated as environmental protection, which not only causes high production cost of vitamin D3, but also pollutes the environment. If 7-DHC can be extracted from the scraps, the process has high economic benefits.

[0004] For example, Chinese patent CN101987861B discloses a purification method of 7-dehydrocholesterol scraps. The 7-dehydrocholesterol scraps containing by-product 3-hydroxycholesta-4,6-diene are dissolved in 2-10 times the volume of alcohol solvent based on the weight of the scraps, and stirred until the scraps are completely dissolved. Then, iron salt or aluminum salt is added to the system, and the stirring is continued until the impurity 3-hydroxycholesta-4,6-diene is completely reacted (catalytic reaction into ether under the action of iron salt or aluminum salt). The obtained solution is first extracted with hydrocarbon solvent, then separated and removed 3-hydroxycholesta-4,6-diene by silica gel chromatography column, and then recrystallized. However, the purification method depends on silica gel column chromatography, which is time-consuming and has high industrialization cost. Moreover, the purity of 7-dehydrocholesterol in the obtained product is low, which can only reach 68.5%-75.2%, and is not conducive to direct use.

[0005] For example, Chinese patent CN106397525B discloses a purification method of 7-dehydrocholesterol footprints. At a temperature of 30-50℃, 7-dehydrocholesterol footprints containing by-product 3-hydroxycholesta-4,6-diene are mixed with cyclohexane to be fully dissolved, and a raw material solution with a concentration of 1-50 g / mL is prepared. The raw material solution is fractionally extracted with an organic solvent (selected from one or more of sulfolane, N,N-dimethylformamide, N-methylpyrrolidone and dimethyl sulfoxide), and the extracted solution is collected and concentrated under reduced pressure. Then, ethyl acetate is used for crystallization to obtain purified 7-dehydrocholesterol. The purification method relies on specific nitrogen-containing and sulfur-containing organic solvents, and has high requirements for post-processing and operation accuracy. Meanwhile, the solvent consumption is large, which increases the production cost and environmental pressure. In addition, the yield cannot be guaranteed.

[0006] The by-product 3-hydroxycholesta-4,6-diene mentioned in the above two patents is produced in the debromination process. The impurity is produced in the old process for producing 7-dehydrocholesterol: cholesterol bromination-dehydrobromination-saponification process. The process has poor reaction selectivity and has been basically eliminated. At present, the process for producing 7-dehydrocholesterol is cholesterol esterification-oxidation-hydrazone-derhydrazoning-saponification process. The by-product 3-hydroxycholesta-4,6-diene is extremely small or does not contain it. The material is basically removed in the subsequent oxidation crystallization and hydrazone crystallization. Therefore, the 7-dehydrocholesterol footprints (saponification crystallization mother liquor) almost do not contain 3-hydroxycholesta-4,6-diene. Meanwhile, the existing method involves a series of solvents for extraction or crystallization, and even uses column separation. The process is relatively complex, time-consuming, and high in cost. Even the purity is not ideal, which is not conducive to industrialization. SUMMARY

[0007] The purpose of the present application is to overcome one or more deficiencies of the prior art and provide an improved recovery method of 7-dehydrocholesterol.

[0008] Further, the recovery method of the present application can effectively extract 7-dehydrocholesterol (7-DHC) from 7-DHC crystallization mother liquor (also referred to as 7-DHC footprints). The purity of the obtained 7-DHC can reach more than 95%, and the yield is high. Meanwhile, the operation method is simple and easy to repeat, which is conducive to industrialization.

[0009] To achieve the above purpose, the technical scheme adopted by the present application is: A recovery method of 7-dehydrocholesterol, the recovery method comprising: using 7-dehydrocholesterol crystallization mother liquor as raw material, and pretreating the same to obtain crystallization mother liquor dry base; dissolving the crystallization mother liquor dry base with a first organic solvent, filtering, and obtaining a filtrate; The complexing agent is a metal salt of divalent metal ions, and the metal salt is soluble in water; The complex is added with water for decomplexing, extraction, and crystallization.

[0010] In the present application, the 7-dehydrocholesterol crystallization mother liquor is a crystallization mother liquor generated in the crystallization process when 7-DHC is generated by saponification reaction of the dehydra product (7-dehydrocholesterol ester) in the current production process of 7-dehydrocholesterol (cholesterol esterification-oxidation-hydrazone formation-dehydra-saponification process).

[0011] In some embodiments of the present application, the pretreatment process comprises a step of removing the solvent in the 7-dehydrocholesterol crystallization mother liquor; further, in the step of removing the solvent, the temperature is controlled at 45-55°C, and the vacuum degree is less than or equal to -0.1 MPa. Further, the recovery time of the solvent removal is 1-5 h, preferably 2-3 h.

[0012] In some embodiments of the present application, the first organic solvent comprises a lipid-soluble solvent. Further, the lipid-soluble solvent comprises a combination of one or more selected from n-hexane, ethyl acetate, and isopropyl acetate.

[0013] In some embodiments of the present application, the mass ratio of the first organic solvent to the dry basis of the crystallization mother liquor is 3-8:1, further 4-6:1.

[0014] In some embodiments of the present application, the first organic solvent is dissolved in the dry basis of the crystallization mother liquor at a dissolution temperature of 40-60°C. Further, the first organic solvent is dissolved in the dry basis of the crystallization mother liquor at a dissolution temperature of 45-55°C.

[0015] In some embodiments of the present application, the filtration for obtaining the filtrate is controlled to be carried out at the dissolution temperature of the dissolution. Hot filtration is beneficial for separating impurities and target substances, and filtration removes salt insoluble substances, so that the filtrate containing 7-DHC and other lipid-soluble impurities can be obtained.

[0016] In some embodiments of the present application, the divalent metal ions comprise a combination of one or more selected from calcium ions, manganese ions, ferrous ions, and zinc ions.

[0017] In some embodiments of the present application, the acid ion of the metal salt comprises chloride ions or nitrate ions.

[0018] According to some specific aspects of the present application, the metal salt comprises a combination of one or more selected from calcium chloride, manganese chloride, ferrous chloride, zinc chloride, calcium nitrate, ferrous nitrate, zinc nitrate, and manganese nitrate.

[0019] In some embodiments of the present application, the added mass of the complexing agent is 0.05-0.4 times, further 0.1-0.3 times, of the mass of the dry basis of the crystallization mother liquor.

[0020] According to some specific aspects of the present application, the added mass of the complexing agent is 0.05 times, 0.08 times, 0.1 times, 0.12 times, 0.15 times, 0.18 times, 0.2 times, 0.22 times, 0.25 times, 0.28 times, 0.3 times, 0.32 times, 0.35 times, 0.38 times, 0.4 times, etc. of the mass of the dry basis of the crystallization mother liquor.

[0021] In some embodiments of the present application, the complexing reaction is controlled to be carried out at 40-60℃, further at 45-55℃.

[0022] According to some specific aspects of the present application, the complexing reaction is controlled to be carried out at 40℃, 42℃, 45℃, 48℃, 50℃, 52℃, 55℃, 58℃ or 60℃.

[0023] In some embodiments of the present application, the complexing reaction is controlled to be carried out under stirring condition, and the stirring time is 0.5-2.0h, further 0.8-1.2h.

[0024] According to some specific aspects of the present application, the complexing time of the complexing reaction is controlled to be 0.5h, 0.8h, 1.0h, 1.2h, 1.5h, 1.8h, 2.0h, etc.

[0025] In some embodiments of the present application, the amount of water used for the decomplexing is controlled to be 1-3 times, further 2.3-2.8 times, of the mass of the dry basis of the crystallization mother liquor.

[0026] According to some specific aspects of the present application, the amount of water used for the decomplexing is controlled to be 1.0 times, 1.2 times, 1.5 times, 1.8 times, 2.0 times, 2.3 times, 2.5 times, 2.8 times, 3.0 times, etc. of the mass of the dry basis of the crystallization mother liquor.

[0027] In some embodiments of the present application, the decomplexing is controlled to be carried out at a temperature of 20-30℃, for example, at 20℃, 23℃, 25℃, 28℃ or 30℃.

[0028] In some embodiments of the present application, the decomplexing is controlled to be carried out under stirring condition, and the stirring time is 0.2-1.2h, further 0.4-0.6h.

[0029] According to some specific aspects of the present application, the stirring time of the decomplexing is controlled to be 0.2h, 0.4h, 0.6h, 0.8h, 1.0h, 1.2h, etc.

[0030] In some embodiments of the present application, the extraction is performed using a second organic solvent.

[0031] Further, the second organic solvent comprises a liposoluble solvent. Still further, the liposoluble solvent comprises n-hexane and / or ethyl acetate.

[0032] Further, the ratio of the mass of the second organic solvent to the mass of the water added for decomplexation is 0.5-1.5:1, further 0.6-1.2:1.

[0033] According to some specific aspects of the present application, the ratio of the mass of the second organic solvent to the mass of the water added for decomplexation is 0.5:1, 0.55:1, 0.6:1, 0.65:1, 0.7:1, 0.75:1, 0.8:1, 0.85:1, 0.9:1, 0.95:1, 1:1, 1.05:1, 1.1:1, 1.15:1, 1.2:1, 1.25:1, 1.3:1, 1.35:1, 1.4:1, 1.45:1, 1.5:1, etc.

[0034] In some embodiments of the present application, the extraction time of the extraction is controlled to be 10-40 min, further 15-30 min.

[0035] In some embodiments of the present application, after the extraction, an extracted organic phase is obtained, and the extracted organic phase is subjected to recovery of part of the solvent before the crystallization.

[0036] In some embodiments of the present application, the process of recovery of part of the solvent from the extracted organic phase is performed at a temperature of 45-55℃ and a vacuum degree of -0.1~ -0.01 MPa.

[0037] Further, the mass of the extracted organic phase after recovery of part of the solvent is controlled to be 0.15-0.6 times, further 0.25-0.5 times, of the mass before recovery, for example, it can be 0.15 times, 0.18 times, 0.20 times, 0.22 times, 0.25 times, 0.28 times, 0.30 times, 0.32 times, 0.33 times, 0.35 times, 0.36 times, 0.40 times, 0.42 times, 0.45 times, 0.48 times, 0.50 times, 0.52 times, 0.55 times, etc.

[0038] In some embodiments of the present application, before the crystallization, the material to be crystallized is first stirred and mixed (the stirring time may, for example, be 0.5-2 h), and then cooled to -15℃ to -5℃ for incubation and crystallization. Further, the temperature is controlled to be cooled to -10℃ to -8℃ for incubation and crystallization.

[0039] Further, the stirring is controlled to be carried out at 25-35℃.

[0040] Further, the cooling rate of the cooling is controlled to be 1-5℃ / 10min, for example, 1℃ / 10min, 1.5℃ / 10min, 2℃ / 10min, 2.5℃ / 10min, 3℃ / 10min, 3.5℃ / 10min, 4℃ / 10min, 4.5℃ / 10min, 5℃ / 10min, etc.

[0041] Further, the crystallization time of the crystallization is controlled to be 1-5 hours.

[0042] In some embodiments of the present application, after the crystallization, the filter cake is filtered and dried. Further, the drying is carried out at a temperature of 40-50℃ under a vacuum degree of less than or equal to -0.1MPa for not less than 3h.

[0043] Thanks to the above technical solution, the present application has the following advantages compared with the prior art: Based on the defects of the prior art in recovering 7-dehydrocholesterol, the present application first utilizes the characteristics that salt impurities are difficult to dissolve in organic solvents (for example, lipid-soluble solvents), dissolves and filters to remove the salt substances in the saponification mother liquor, then utilizes the complexing effect of divalent metal ions such as calcium chloride with 7-DHC, the complexation is based on the coordination of divalent metal ions such as calcium ions with the hydroxyl groups or double bonds in the cholesterols, selectively extracts 7-DHC, and finally precipitates 7-DHC through decomplexation, extraction and crystallization; Practice shows that (1) the reagents used in the present application are low-cost reagents, which can save production cost; (2) through the combination of low-cost complexing technology and solvent recovery process, the efficient recovery of 7-DHC is realized, the process is simple and efficient, and is suitable for industrialization; (3) the extraction rate of 7-dehydrocholesterol in the crystallization mother liquor of 7-dehydrocholesterol in the present application can reach more than 80%, and the purity of the purified 7-DHC can reach more than 95%, which can be directly used as a raw material for preparing vitamin D3 by light reaction. BRIEF DESCRIPTION OF DRAWINGS

[0044] Figure 1 The liquid chromatogram of the crystallization mother liquor dry basis (the content of 7-dehydrocholesterol is about 12%) in the production process of 7-dehydrocholesterol in the embodiments of the present application; Figure 2 The liquid chromatogram of 7-dehydrocholesterol (the content of 7-dehydrocholesterol is about 95%) recovered by the recovery method of embodiment 10 of the present application. DETAILED DESCRIPTION

[0045] The above scheme is further described in conjunction with specific examples; it should be understood that these examples are used to illustrate the basic principles, main features and advantages of the present application, and the present application is not limited in scope by the following examples; the implementation conditions used in the examples can be further adjusted according to specific requirements, and the implementation conditions not specified are usually the conditions in conventional experiments.

[0046] In the following examples, all raw materials are obtained from commercial sources or prepared by conventional methods in the art, unless otherwise specified.

[0047] Examples 1 to 6 investigate the effect of each step of obtaining the complex on the recovery of 7-dehydrocholesterol in the recovery process of 7-dehydrocholesterol.

[0048] In the following, the saponification crystallization mother liquor dry basis is obtained by the following method: the 7-dehydrocholesterol crystallization mother liquor is recovered at a temperature of 50℃, a vacuum degree of ≤-0.10MPa and for 2.5h to obtain the saponification crystallization mother liquor dry basis (the mass content of 7-dehydrocholesterol is about 12%).

[0049] Example 1: This example provides a recovery method of 7-dehydrocholesterol, which comprises a preparation process of a complex, the preparation process comprising: (1) 20g of saponification crystallization mother liquor dry basis (the mass content of 7-dehydrocholesterol is 12%), 100g of ethyl acetate is added, and it is dissolved by stirring at 50℃, and then it is filtered while hot to remove 17.6g of insoluble salts, and the 7-dehydrocholesterol in the filtrate is 2.4g; (2) 3g of calcium chloride is added to the filtrate obtained in step (1), and it is stirred at 50℃ for 1h, and then it is filtered to obtain a complex; wherein the mass of 7-dehydrocholesterol in the filtrate is 0.2g.

[0050] Example 2: This example provides a recovery method of 7-dehydrocholesterol, which comprises a preparation process of a complex, the preparation process comprising: (1) 20g of saponification crystallization mother liquor dry basis (the mass content of 7-dehydrocholesterol is 12%), 100g of ethyl acetate is added, and it is dissolved by stirring at 50℃, and then it is filtered while hot to remove 17.6g of insoluble salts, and the 7-dehydrocholesterol in the filtrate is 2.4g; (2) 3g of manganese chloride is added to the filtrate obtained in step (1), and it is stirred at 50℃ for 1h, and then it is filtered to obtain a complex; wherein the mass of 7-dehydrocholesterol in the filtrate is 0.5g.

[0051] Example 3: This example provides a recovery method of 7-dehydrocholesterol, which comprises a preparation process of a complex, the preparation process comprising: (1) 20 g of saponification crystallization mother liquor dry base (mass content of 7-dehydrocholesterol 12%), add 100 g of ethyl acetate, 50°C stirring to dissolve, hot filtration, remove insoluble salt 17.6 g, 7-dehydrocholesterol 2.4 g in the filtrate; (2) To the filtrate obtained in step (1), add 3 g of ferrous chloride, 50°C stirring for 1 h, filtration, to obtain a complex; wherein, the mass of 7-dehydrocholesterol in the filtrate is 0.7 g.

[0052] Example 4: The example provides a 7-dehydrocholesterol recovery method, which includes a complex preparation process, the preparation process comprising: (1) 20 g of saponification crystallization mother liquor dry base (mass content of 7-dehydrocholesterol 12%), add 100 g of ethyl acetate, 50°C stirring to dissolve, hot filtration, remove insoluble salt 17.6 g, 7-dehydrocholesterol 2.4 g in the filtrate; (2) To the filtrate obtained in step (1), add 3 g of zinc chloride, 50°C stirring for 1 h, filtration, to obtain a complex; wherein, the mass of 7-dehydrocholesterol in the filtrate is 0.8 g.

[0053] Example 5: The example provides a 7-dehydrocholesterol recovery method, which includes a complex preparation process, the preparation process comprising: (1) 20 g of saponification crystallization mother liquor dry base (mass content of 7-dehydrocholesterol 12%), add 100 g of ethyl acetate, 50°C stirring to dissolve, hot filtration, remove insoluble salt 17.6 g, 7-dehydrocholesterol 2.4 g in the filtrate; (2) To the filtrate obtained in step (1), add 4 g of calcium chloride, 50°C stirring for 1 h, filtration, to obtain a complex; wherein, the mass of 7-dehydrocholesterol in the filtrate is 0.1 g.

[0054] Example 6: The example provides a 7-dehydrocholesterol recovery method, which includes a complex preparation process, the preparation process comprising: (1) 20 g of saponification crystallization mother liquor dry base (mass content of 7-dehydrocholesterol 12%), add 100 g of ethyl acetate, 50°C stirring to dissolve, hot filtration, remove insoluble salt 17.6 g, 7-dehydrocholesterol 2.4 g in the filtrate; (2) To the filtrate obtained in step (1), add 6 g of calcium chloride, 50°C stirring for 1 h, filtration, to obtain a complex; wherein, the mass of 7-dehydrocholesterol in the filtrate is 0.1 g.

[0055] Comparative Example 1: The example provides a recovery method of 7-dehydrocholesterol, the recovery method comprising a preparation process of a complex, the preparation process comprising: (1) 20 g of saponification crystallization mother liquor dry base (mass content of 7-dehydrocholesterol 12%), 100 g of ethyl acetate is added, stirred and dissolved at 50°C, filtered while hot, 17.6 g of insoluble salts are removed, and 2.4 g of 7-dehydrocholesterol is in the filtrate; (2) 3 g of urea is added to the filtrate obtained in step (1), stirred at 50°C for 1 h, filtered, and the complex is obtained; wherein the mass of 7-dehydrocholesterol in the filtrate is 1.8 g.

[0056] Based on the relatively better comprehensive effect of example 5 in examples 1-6, further explore the recovery effect of 7-dehydrocholesterol in the recovery process of 7-dehydrocholesterol to the extraction step in examples 7 to 8.

[0057] Example 7: The example provides a recovery method of 7-dehydrocholesterol, the recovery method comprising a preparation process of a complex, the preparation process comprising:

[0058] The specific process includes: (1) 20 g of saponification crystallization mother liquor dry base (mass content of 7-dehydrocholesterol 12%), 100 g of ethyl acetate is added, stirred and dissolved at 50°C, filtered while hot, 17.6 g of insoluble salts are removed, and 2.4 g of 7-dehydrocholesterol is in the filtrate; (2) 4 g of calcium chloride is added to the filtrate obtained in step (1), stirred at 50°C for 1 h, filtered, and the complex is obtained; wherein the mass of 7-dehydrocholesterol in the filtrate is 0.1 g. The filtered complex is mixed with 50 g of water, stirred at 25°C for 0.5 h, and then decomplexed, 30 g of ethyl acetate is added, extracted at 25°C for 20 min, and then separated into an upper organic solvent layer (also referred to as an extraction organic phase) and a lower water layer (also referred to as a raffinate phase, the mass of 7-dehydrocholesterol in the water layer is 0.05 g).

[0059] Example 8: The example provides a recovery method of 7-dehydrocholesterol, the recovery method comprising a preparation process of a complex, the preparation process comprising:

[0060] The specific process includes: (1) 20 g of saponification crystallization mother liquor dry base (mass content of 7-dehydrocholesterol 12%), 100 g of ethyl acetate is added, stirred and dissolved at 50°C, filtered while hot, 17.6 g of insoluble salts are removed, and 2.4 g of 7-dehydrocholesterol is in the filtrate; (2) To the filtrate obtained in step (1), 4 g of calcium chloride was added, and stirred at 50 °C for 1 h, and filtered to obtain a complex; wherein the mass of 7-dehydrocholesterol in the filtrate was 0.1 g; The complex obtained by filtration was mixed with 50 g of water, and stirred at 25 °C for 0.5 h to perform decomplexation, and then 50 g of ethyl acetate was added, and extracted at 25 °C for 20 min, and then allowed to stand, and separated into an upper organic solvent layer (which can also be referred to as an extracted organic phase) and a lower water layer (which can also be referred to as a raffinate phase, and the mass of 7-dehydrocholesterol in the water layer was 0.02 g).

[0061] Based on the relatively better comprehensive effect of Example 8 in Examples 7-8, further exploration of the entire complete recovery process of 7-dehydrocholesterol on the recovery effect of 7-dehydrocholesterol was carried out in Examples 9-11.

[0062] Example 9: The present example provides a recovery method of 7-dehydrocholesterol, which comprises: (1) 20 g of dry basis of saponification crystallization mother liquor (mass content of 7-dehydrocholesterol was 12%), 100 g of ethyl acetate was added, and stirred to dissolve at 50 °C, and then filtered while hot to remove 17.6 g of insoluble salts, and the mass of 7-dehydrocholesterol in the filtrate was 2.4 g; (2) To the filtrate obtained in step (1), 4 g of calcium chloride was added, and stirred at 50 °C for 1 h, and filtered to obtain a complex; wherein the mass of 7-dehydrocholesterol in the filtrate was 0.1 g; The complex obtained by filtration was mixed with 50 g of water, and stirred at 25 °C for 0.5 h to perform decomplexation, and then 50 g of ethyl acetate was added, and extracted at 25 °C for 20 min, and then allowed to stand, and separated into an upper organic solvent layer (which can also be referred to as an extracted organic phase) and a lower water layer (which can also be referred to as a raffinate phase, and the mass of 7-dehydrocholesterol in the water layer was 0.02 g). The organic solvent layer was recovered at a recovery temperature of 50 °C and a vacuum degree of -0.08 MPa to recover part of the solvent until the total mass was 1 / 2 of that before recovery, to obtain a concentrated liquid; (3) The concentrated liquid was stirred at 30 °C for 1 h, and then cooled to -9 °C ± 1 °C at a cooling rate of 3 °C / 10 min, and then incubated for 3 h, and then filtered, and the obtained filter cake was dried at 45 °C and a vacuum degree of ≤-0.10 MPa for 3.5 h to obtain 1.90 g of 7-dehydrocholesterol with an external standard of 95.60%, and the total yield was 75.68%.

[0063] Example 10: The present example provides a recovery method of 7-dehydrocholesterol, which comprises: (1) 20 g of saponification crystallization mother liquor dry base (7-dehydrocholesterol mass content 12%), add 100 g of ethyl acetate, stir and dissolve at 50°C, filter while hot, remove 17.6 g of insoluble salts, 7-dehydrocholesterol 2.4 g in the filtrate; (2) Add 4 g of calcium chloride to the filtrate obtained in step (1), stir at 50°C for 1 h, filter to obtain a complex; wherein the mass of 7-dehydrocholesterol in the filtrate is 0.1 g; Mix the complex obtained by filtering with 50 g of water, stir at 25°C for 0.5 h to perform decomplexing, then add 50 g of ethyl acetate, extract at 25°C for 20 min, stand, separate the layers, and separate the upper organic solvent layer (which can also be referred to as the extracted organic phase) and the lower water layer (which can also be referred to as the raffinate phase, the mass of 7-dehydrocholesterol in the water layer is 0.02 g); Recover part of the solvent from the organic solvent layer at a recovery temperature of 50°C and a vacuum degree of -0.08 MPa until the total mass is 1 / 3 of that before recovery, to obtain a concentrated solution; (3) Stir the concentrated solution at 30°C for 1 h, then reduce the temperature to -9°C ± 1°C at a rate of 3°C / 10 min, and keep the temperature for 3 h, filter, and dry the filter cake at 45°C and a vacuum degree of ≤-0.10 MPa for 3.5 h to obtain 2.03 g of 7-dehydrocholesterol with an external standard of 95.10%, and the total yield is 80.44%.

[0064] Example 11: The example provides a recovery method of 7-dehydrocholesterol, which comprises: (1) 20 g of saponification crystallization mother liquor dry base (7-dehydrocholesterol mass content 12%), add 100 g of ethyl acetate, stir and dissolve at 50°C, filter while hot, remove 17.6 g of insoluble salts, 7-dehydrocholesterol 2.4 g in the filtrate; (2) Add 4 g of calcium chloride to the filtrate obtained in step (1), stir at 50°C for 1 h, filter to obtain a complex; wherein the mass of 7-dehydrocholesterol in the filtrate is 0.1 g; Mix the complex obtained by filtering with 50 g of water, stir at 25°C for 0.5 h to perform decomplexing, then add 50 g of ethyl acetate, extract at 25°C for 20 min, stand, separate the layers, and separate the upper organic solvent layer (which can also be referred to as the extracted organic phase) and the lower water layer (which can also be referred to as the raffinate phase, the mass of 7-dehydrocholesterol in the water layer is 0.02 g); Recover part of the solvent from the organic solvent layer at a recovery temperature of 50°C and a vacuum degree of -0.08 MPa until the total mass is 1 / 4 of that before recovery, to obtain a concentrated solution; (3) The concentrated solution is stirred at 30℃ for 1 hour, then cooled to -9℃±1℃ at a cooling rate of 3℃ / 10 min, and kept at -9℃±1℃ for 3 hours. The obtained filter cake is dried at 45℃ under a vacuum degree of ≤-0.10 MPa for 3.5 hours to obtain 2.06 g of 7-dehydrocholesterol with an external standard of 95.02%, and the total yield is 81.56%.

[0065] As can be seen from the above Examples 1 to 11 and Comparative Example 1, the complexing effects of different complexing agents on 7-dehydrocholesterol are different, and the complexing effect of calcium chloride is the best. After the organic layer after extraction is recovered to 1 / 3-1 / 4, low-temperature crystallization can obtain 7-dehydrocholesterol with a purity of more than 95%, and the total yield is more than 80% (Examples 10, 11).

[0066] Further, the recovery method of 7-dehydrocholesterol of the present application is to further extract high-purity 7-dehydrocholesterol from the crystallization mother liquor in the production process of 7-dehydrocholesterol. As shown in Figure 1 , it is the liquid chromatogram of the dry basis (content of about 12%) of the crystallization mother liquor in the production process of 7-dehydrocholesterol, as shown in Figure 2 , it is the liquid chromatogram of the high-purity 7-dehydrocholesterol (content of about 95%) finally obtained by Example 10 of the present application.

[0067] As can be seen from Figure 1 , the crystallization mother liquor dry basis in the production process of 7-dehydrocholesterol without being treated by the method of the present application has many impurity peaks (main peak 9.05 min, apparent 73.29%), as shown in Figure 2 , after being treated by the recovery method of the present application, high-purity 7-dehydrocholesterol can be recovered (main peak 9.07 min, apparent 99.63%).

[0068] Further, the inventors of the present application believe that the mechanism of calcium chloride complexing 7-dehydrocholesterol is a chemical process based on coordination bond. Ca 2+ as the central ion coordinates with the two hydroxyl oxygen atoms on the C3 position of the two 7-DHC molecules to form an insoluble solid complex. The high selectivity of this method may be due to the specific sterol structure of 7-DHC, which enables it to form a stable complex, while many other types of impurities cannot. Compared with manganese chloride (MnCl2), ferrous chloride (FeCl2) and zinc chloride (ZnCl2), calcium chloride (CaCl2) has significant advantages when forming a complex with 7-DHC for purification. These advantages mainly include cost, stability, selectivity, operation convenience and subsequent treatment, etc., which are as follows: (1) excellent stability: although anhydrous CaCl2 also absorbs moisture, the Ca 2+Very stable, not oxidized by air, ensuring the repeatability and controllability of the reaction process, has obvious advantages compared with manganese chloride (MnCl2) and ferrous chloride (FeCl2). 2+ (2) Good selectivity: Ca 2+ (3) Extremely low cost and toxicity: CaCl2 is a common chemical product, low in price. Calcium ions are non-toxic, which means that it has almost no safety risk to the final product, simple subsequent treatment, and small environmental pressure. 2+ (4) Easy to operate: the whole process has no color change, and the product is a white solid, easy to observe, filter and wash. The decomplexing can be easily completed by using water, and Ca 2+ is washed into the water phase and separated completely.

[0069] The above examples are only for illustrating the technical concept and characteristics of the present application, and the purpose is to enable those skilled in the art to understand the content of the present application and to implement it, and cannot limit the protection scope of the present application. Any equivalent changes or modifications made in accordance with the spirit and essence of the present application shall be covered within the protection scope of the present application.

[0070] The endpoints of the ranges and any values claimed herein are not limited to the precise values. The ranges should be interpreted as being inclusive of values adjacent to the recited ranges. For values which are less than one, combinations of the minimum value, or increments thereof, are also included. The upper and lower limits of these smaller ranges can independently be included or excluded in the smaller ranges, and the junction of the smaller ranges can be included or excluded. The ranges and amounts are approximate, and the compositions can be combined with other compositions such as those described herein.

Claims

1. A method for recovering 7-dehydrocholesterol, characterized by, The recovery method comprises: The recovery method comprises: The recovery method comprises: The recovery method comprises: The recovery method comprises:

2. The recovery process of 7-dehydrocholesterol according to claim 1, characterized by, The first organic solvent comprises a fat-soluble solvent, and further, the fat-soluble solvent comprises a combination of one or more selected from n-hexane, ethyl acetate, and isopropyl acetate; and / or, the mass ratio of the first organic solvent to the crystallization mother liquor dry base is 3-8:1, and further, 4-6:1; and / or, the first organic solvent is used to dissolve the crystallization mother liquor dry base at a dissolution temperature of 40-60 DEG C; and / or, the filtration for obtaining the filtrate is controlled to be carried out at the dissolution temperature of the dissolution.

3. The recovery method of 7-dehydrocholesterol according to claim 1, characterized by, The divalent metal ion comprises a combination of one or more selected from calcium ion, manganese ion, ferrous ion, and zinc ion; and / or, the acid radical ion of the metal salt comprises chloride ion or nitrate radical.

4. The recovery method of 7-dehydrocholesterol according to claim 1 or 3, characterized by, The metal salt comprises a combination of one or more selected from calcium chloride, manganese chloride, ferrous chloride, zinc chloride, calcium nitrate, ferrous nitrate, zinc nitrate, and manganese nitrate.

5. The recovery method of 7-dehydrocholesterol according to claim 1, characterized by, The addition mass of the complexing agent is 0.05-0.4 times, and further, 0.1-0.3 times, of the mass of the crystallization mother liquor dry base; and / or, the complexing reaction is controlled to be carried out at 40-60 DEG C, and further, at 45-55 DEG C; and / or, the complexing reaction is controlled to be carried out under stirring, and the stirring time is 0.5-2h, and further, 0.8-1.2h.

6. The recovery process of 7-dehydrocholesterol according to claim 1, characterized by, The water used for the decomplexing is controlled to be used in an amount of 1-3 times, and further, 2.3-2.8 times, of the mass of the crystallization mother liquor dry base; and / or, the decomplexing is controlled to be carried out at a temperature of 20-30 DEG C; and / or, the decomplexing is controlled to be carried out under stirring, and further, the stirring time is 0.2-1.2h, and further, 0.4-0.6h.

7. The recovery method of 7-dehydrocholesterol according to claim 1, characterized by, The extraction is carried out using a second organic solvent; Further, the second organic solvent comprises a fat-soluble solvent, and further, the fat-soluble solvent comprises n-hexane and / or ethyl acetate; Further, the mass ratio of the second organic solvent to the water added in the decomplexing is 0.5-1.5:1, and further, 0.6-1.2:

1.

8. The recovery process of 7-dehydrocholesterol according to claim 1, characterized by, After the extraction, an extracted organic phase is obtained, and the extracted organic phase is subjected to recovery of part of the solvent and then to the crystallization; Further, the extraction time of the extraction is controlled to be 10-40min, and further, 15-30min; Further, the recovery of part of the solvent from the extracted organic phase is controlled to be carried out at a temperature of 45-55 DEG C and a vacuum degree of -0.1~-0.01 MPa; Further, the mass of the extracted organic phase after the recovery of part of the solvent is controlled to be 0.15-0.6 times, and further, 0.25-0.5 times, of the mass before the recovery.

9. The recovery process of 7-dehydrocholesterol according to claim 1, characterized by, Before the crystallization, the material to be crystallized is stirred and mixed, and then cooled to -15 to -5 DEG C, and crystallized by keeping the temperature; further, the temperature is controlled to -10 to -8 DEG C for keeping the crystallization; Further, the stirring and mixing is controlled to be carried out at 25-35 DEG C; Further, the cooling rate of the cooling is controlled to be 1-5 DEG C / 10 min; Further, the crystallization time of the crystallization is controlled to be 1-5 hours.

10. The recovery process of 7-dehydrocholesterol according to claim 1, characterized by, The pretreatment process comprises a step of removing the solvent from the 7-dehydrocholesterol crystallization mother liquor; further, in the step of removing the solvent, the temperature is controlled to be 40-50 DEG C, and the vacuum degree is less than or equal to -0.1 MPa.

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