Method for secondarily extracting calcifediol from crystallization mother liquor of calcifediol crude product

Abstract

The invention discloses a method for secondarily extracting calcifediol from crystallization mother liquor of a calcifediol crude product. According to the method, crystallization mother liquor of a crude calcifediol product obtained through photochemical reaction is subjected to secondary extraction by utilizing a crystallization technology, high-content calcifediol crystals are obtained, and pure crystals meeting product quality standards are obtained through a recrystallization process. The method specifically comprises the following steps: evaporating mother liquor obtained after purification of a calcifediol crude product to remove a solvent so as to obtain an oily concentrate, dissolving the oily concentrate with an organic solvent, then adding activated carbon, carrying out decoloration, filtration, cooling crystallization and filtration at a certain temperature, carrying out secondary dissolution on a solid with the organic solvent, cooling crystallization, filtration and drying so as to obtain a finished product. The method has the advantages of simple process, short flow, high efficiency and high product purity.

Description

Technical Field

[0001] This invention belongs to the field of calcidiol purification and relates to a method for secondary extraction of calcidiol from the mother liquor of crude calcidiol crystallization. Background Technology

[0002] Calcidiol (25-hydroxyvitamin D3) is a derivative of vitamin D3, with 3-5 times the biological activity of vitamin D3. It is more easily absorbed than vitamin D3, directly entering the bloodstream from the intestines. Calcidiol is an important nutrient for maintaining bone health, a key indicator for detecting osteoporosis, and also an important indicator for detecting type 2 diabetes mellitus complicated by nephropathy. Furthermore, it has wide applications in health foods, pharmaceuticals, and feed additives.

[0003] In recent years, the demand for calcidiol has been growing every year. Therefore, while developing simple and low-cost process routes, it is also extremely important to reuse the separated tail oil and tailings.

[0004] Currently, there are no literature reports on a process for secondary extraction of calcidiol from the mother liquor after separation and purification of crude calcidiol obtained through photochemical reactions. Patent CN103044301A discloses the preparation of 25-hydroxyvitamin D3 from 25-hydroxy-7-dehydrocholesterol via photochemical reaction, but does not disclose a method for treating the mother liquor after calcidiol crystallization. Patent CN117342992A discloses a process for preparing calcidiol from phytosterols, but also does not disclose the crystallization process or subsequent processing techniques. Other methods mentioned involve the separation and extraction of vitamin D3 by microbial fermentation to produce enzymes that convert vitamin D3 into calcidiol. Patents CN117964533 A, CN103898004A, and CN110396058A all employ column separation for preliminary purification of the converted mixture, followed by recrystallization for further purification. Even if these methods yield high-purity products, the solvent consumption is high and the process is lengthy. Furthermore, only patent CN117964533A mentions the recovery and reuse of the mother liquor, but this still requires processing through silica gel column chromatography. Summary of the Invention

[0005] To address the problems in the prior art, the present invention aims to provide a method for secondary extraction of calcidiol from the mother liquor of crude calcidiol crystallization. This invention uses the mother liquor of crude calcidiol crystallization as raw material to separate calcidiol as much as possible and obtain pure calcidiol, thereby improving the overall extraction yield of calcidiol.

[0006] To achieve the above objectives, the present invention provides a method for secondary extraction of calcidiol from the mother liquor of crude calcidiol crystallization, the method comprising the following steps: (1) After removing the solvent from the crystallization mother liquor of crude calcidiol, the resulting oily concentrate is dissolved in an organic solvent at a certain temperature, and a certain amount of activated carbon is added for decolorization and filtration at a certain temperature to obtain a decolorized mother liquor. (2) After adding a certain amount of water to the mother liquor decolorizing solution in proportion, the solution is subjected to gradient cooling and crystallization, and then filtered to obtain the initial crystallization of the mother liquor; (3) The mother liquor is initially dissolved in a solvent at a certain temperature, a certain amount of water is added, and then the temperature is gradually reduced to crystallize. After filtration and drying, calcidiol product is obtained.

[0007] Furthermore, in step (1), the crude calcidiol is obtained by distilling off the raw materials and solvents after photochemical reaction of 25-hydroxy-7-dehydrocholesterol.

[0008] Furthermore, in step (1), the content of calcidiol in the oily concentrate is 10-40%, preferably 18-30%.

[0009] Further, in step (1), the organic solvent is one or more of toluene, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentane, cyclopentane, n-hexane, cyclohexane, n-heptane, n-octane, acetone, acetonitrile, tetrahydrofuran, methyl formate, ethyl formate, ethyl acetate, hexyl hexanoate, butyl acetate, and diethyl ether, preferably any one of a mixed solvent of acetonitrile and ethyl acetate, a mixed solvent of ethanol and n-heptane, or a mixed solvent of isopropanol and n-hexane.

[0010] Furthermore, in step (1), the ratio of each component in the mixed solvent is 1:0.1 to 1:10, preferably 1:1.

[0011] Furthermore, in step (1), the conditions for removing the solvent from the mother liquor are a temperature of 30℃~80℃ and a vacuum of ≤-0.05MPa, preferably a temperature of 50℃~70℃ and a vacuum of ≤-0.085MPa.

[0012] Furthermore, in step (1), the volume of the mixed organic solvent is 2 to 15 times that of the concentrated substance, preferably 5 to 10 times.

[0013] Furthermore, in step (1), the dissolution temperature is controlled at 35℃~80℃, preferably 50℃~70℃.

[0014] Furthermore, in step (1), the amount of activated carbon used is 0.1% to 2% of the concentrated mass, preferably 0.5% to 1%.

[0015] Furthermore, in step (1), the decolorization temperature is controlled at 50℃~80℃, preferably 50℃~60℃.

[0016] Furthermore, in step (2), the mass of water is 0.1 to 5 times the mass of the mother liquor decolorizing liquid, preferably 1 to 2 times.

[0017] Furthermore, in step (2), the gradient cooling temperature control range is 1℃ / h ~ 15℃ / h, preferably 5℃ / h ~ 10℃ / h.

[0018] Furthermore, in step (2), the final temperature control range is -15℃ to 15℃, preferably -5℃ to 5℃.

[0019] Furthermore, in step (2), the content of calcidiol (including water of crystallization) in the initial crystallization of the mother liquor is ≥80%, preferably 85%.

[0020] Furthermore, in step (2), the calcidiol extraction yield is ≥75%, preferably ≥80%.

[0021] Furthermore, in step (3), the solvent is one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-hexane, cyclohexane, n-heptane, n-octane, acetone, acetonitrile, tetrahydrofuran, ethyl formate, ethyl acetate, and hexyl hexanoate, preferably a mixed solvent of isopropanol and n-hexane, a mixed solvent of acetonitrile and n-heptane, or a mixed solvent of ethyl acetate and ethanol.

[0022] Furthermore, in step (3), the ratio of each component in the mixed solvent is 1:0.1 to 1:10, preferably 1:1.

[0023] Furthermore, in step (3), the dissolution temperature is controlled at 40℃~80℃, preferably 50~60℃.

[0024] Furthermore, in step (3), the mass of water is 0.1 to 5 times the mass of the initial crystallization of the mother liquor, preferably 1 to 2 times.

[0025] Furthermore, in step (3), the gradient cooling temperature control range is 0.5℃~10℃ / h, preferably 2~5℃ / h.

[0026] Furthermore, in step (3), the final temperature control range is -25℃ to 5℃, preferably -15℃ to -5℃.

[0027] Furthermore, in step (3), the drying temperature is controlled at 20℃~60℃, preferably 30℃~40℃.

[0028] Furthermore, in step (3), the calcidiol content (including water of crystallization) in the calcidiol product is ≥94%, preferably greater than ≥97%, and more preferably ≥98%.

[0029] Furthermore, in step (3), the crystallization yield is ≥85%, preferably ≥90%, and more preferably ≥93%.

[0030] Furthermore, the crystallization mother liquor in step (3) can be repeatedly processed after multiple batches of mixing and collection, from step (1) to step (3).

[0031] Compared with the prior art, the beneficial effects of the present invention are as follows: This invention employs a specific mixed solvent system to achieve secondary extraction of calcidiol from the mother liquor of crude calcidiol crystallization. The mother liquor is initially crystallized, and this initial crystallization is efficiently separated. Then, recrystallization yields a high-purity calcidiol product in a high yield. This method avoids the use of time-consuming and solvent-intensive column separation methods, achieving a high-efficiency and high-yield high-purity calcidiol product, thus meeting the process requirements of green development. Detailed Implementation

[0032] To make the technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are only for explaining the present invention and are not intended to limit the present invention.

[0033] Example 1 The mother liquor from the crude calcidiol crystallization was subjected to solvent removal at 55 °C under a vacuum of -0.085 MPa to yield 1.0 kg of oily concentrate (calcidiol content 15.1%) was dissolved in 5 L of an organic solvent containing acetonitrile and ethyl acetate in a 1:1 volume ratio at 55 °C. 5 g of activated carbon was added, and the solution was decolorized at 55 °C for 0.5 h. After filtration, 1.5 kg of water was added to the decolorized solution, and the solution was subjected to a gradient cooling at a rate of 5 °C / h, maintaining the temperature at -5 °C for 5 h. The solution was then filtered to obtain 154.6 g of initial crystallized mother liquor (calcidiol content 80.1%, yield 82.1%). This solution was dissolved in 1 L of an organic solvent containing acetonitrile and n-heptane in a 1:1 volume ratio at 55 °C. 100 g of water was added, and the solution was subjected to a gradient cooling at a rate of 5 °C / h, maintaining the temperature at -10 °C for 5 h. The solution was then filtered and vacuum dried at 50 °C to obtain 115.3 g of finished calcidiol product with a calcidiol content of 95.2% and a yield of 88.6%.

[0034] Example 2 The mother liquor from the crude calcidiol crystallization was subjected to solvent removal at 55 °C under a vacuum of -0.085 MPa to yield 1.2 kg of oily concentrate (calcidiol content 27.3%) was dissolved in 10 L of an organic solvent containing ethanol and n-heptane in a 1:1 volume ratio at 55 °C. 12 g of activated carbon was added, and the solution was decolorized at 55 °C for 0.5 h. After filtration, 1.2 kg of water was added to the decolorized solution, and the solution was subjected to a gradient cooling at a rate of 5 °C / h, maintaining the temperature at 0 °C for 5 h. The solution was then filtered, yielding 331.9 g of initial crystallized mother liquor (calcidiol content 84.3%, yield 85.4%). This solution was dissolved in 1.5 L of an organic solvent containing ethanol and ethyl acetate in a 1:1 volume ratio at 55 °C. 200 g of water was added, and the solution was subjected to a gradient cooling at a rate of 5 °C / h, maintaining the temperature at -10 °C for 5 h. The solution was then filtered and vacuum dried at 40 °C to obtain 259.3 g of finished calcidiol product with a calcidiol content of 97.2% and a yield of 90.1%.

[0035] Example 3 The mother liquor from the crude calcidiol crystallization was subjected to solvent removal at 55 °C under a vacuum of -0.085 MPa to yield 1.5 A 1 kg oily concentrate (calcidiol content 32.8%) was dissolved in 20 L of an organic solvent containing a 1:1 volume ratio of isopropanol and n-hexane at 55 °C. 15 g of activated carbon was added, and the solution was decolorized at 55 °C for 0.5 h. After filtration, 0.8 kg of water was added to the decolorized solution, and the solution was subjected to a gradient cooling at a rate of 5 °C / h, maintaining the temperature at 5 °C for 5 h. The solution was then filtered, yielding 487.9 g of initial crystallized mother liquor (calcidiol content 85.4%, yield 84.7%). This solution was dissolved in 3 L of an organic solvent containing a 1:1 volume ratio of ethanol and n-hexane at 60 °C. 250 g of water was added, and the solution was subjected to a gradient cooling at a rate of 5 °C / h, maintaining the temperature at -10 °C for 5 h. The solution was then filtered and vacuum dried at 40 °C to obtain 463.1 g of finished calcidiol product with a calcidiol content of 98.2% and a yield of 93.2%.

[0036] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the present invention in any way. Other variations and modifications are possible without departing from the technical solutions described in the claims.

Claims

1. A method for secondary extraction of calcidiol from the mother liquor of crude calcidiol crystallization, characterized in that, The method includes the following steps: (1) After removing the solvent from the crystallization mother liquor of crude calcidiol, the resulting oily concentrate is dissolved in an organic solvent at a certain temperature, and a certain amount of activated carbon is added for decolorization and filtration at a certain temperature to obtain a decolorized mother liquor. (2) After adding a certain amount of water to the mother liquor decolorizing solution in proportion, the solution is subjected to gradient cooling and crystallization, and then filtered to obtain the initial crystallization of the mother liquor; (3) The mother liquor is initially dissolved in a solvent at a certain temperature, a certain amount of water is added, and then the temperature is gradually lowered to crystallize. After filtration and drying, calcidiol product is obtained.

2. The method according to claim 1, characterized in that, In step (1), the crude calcidiol is obtained by distilling off the raw materials and solvents after photochemical reaction of 25-hydroxy-7-dehydrocholesterol.

3. The method according to claim 1, characterized in that, In step (1), the mixed organic solvent is one or more of toluene, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentane, cyclopentane, n-hexane, cyclohexane, n-heptane, n-octane, acetone, acetonitrile, tetrahydrofuran, methyl formate, ethyl formate, ethyl acetate, hexyl hexanoate, butyl acetate, and diethyl ether.

4. The method according to claim 1, characterized in that, In step (1), the conditions for removing the solvent from the mother liquor are a temperature of 30℃~80℃ and a vacuum of ≤-0.05MPa.

5. The method according to claim 1, characterized in that, In step (1), the volume of the mixed organic solvent is 2 to 15 times that of the oil concentrate; the dissolution temperature is controlled between 35°C and 80°C.

6. The method according to claim 1, characterized in that, In step (1), the amount of activated carbon used is 0.1% to 2% of the concentrated material mass; the decolorization temperature is controlled at 50℃ to 80℃.

7. The method according to claim 1, characterized in that, In step (2), the mass of water is 0.1 to 5 times the mass of the mother liquor decolorizing liquid; the gradient cooling temperature control range is 1℃ / h to 15℃ / h, and the final temperature control range is -15℃ to 15℃.

8. The method according to claim 1, characterized in that, In step (3), the solvent is one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-hexane, cyclohexane, n-heptane, n-octane, acetone, acetonitrile, tetrahydrofuran, ethyl formate, ethyl acetate, and hexyl hexanoate.

9. The method according to claim 1, characterized in that, In step (3), the dissolution temperature is controlled at 40℃ to 80℃, the mass of water is 0.1 to 5 times the mass of the mother liquor at initial crystallization, the gradient cooling temperature control range is 0.5℃ to 10℃ / h, the final temperature control range is -25℃ to 5℃, and the drying temperature is controlled at 20℃ to 60℃.

10. The method according to claim 1, characterized in that, The crystallization mother liquor in step (3) can be repeatedly processed after multiple batches of mixing and collection, from step (1) to step (3).