A method for secondary extraction of calcifediol from a crystallization mother liquor of a crude calcifediol

Abstract

The application discloses a method for extracting calcifediol from a crystallization mother liquor of a calcifediol crude product. The method uses a crystallization technique to extract the crystallization mother liquor of the calcifediol crude product obtained through a photochemical reaction for a second time to obtain a calcifediol crystal with a higher content, and then through a recrystallization process, a crystalline pure product meeting product quality standards is obtained. The specific method is as follows: after the solvent of the mother liquor after purification of the calcifediol crude product is evaporated, an oily concentrate is obtained, the oily concentrate is dissolved with an organic solvent, then activated carbon is added to decolorize at a certain temperature, filtration is performed, cooling crystallization is performed, filtration is performed, the solid is dissolved with an organic solvent for a second time, cooling crystallization is performed, filtration is performed, and drying is performed to obtain a finished product. The application has the advantages of simple process, short flow, high efficiency and high product purity.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of calcifediol purification, and relates to a method for secondary extraction of calcifediol from a crystallization mother liquor of a calcifediol crude product. BACKGROUND

[0002] Calcifediol (25-hydroxyvitamin D3) is a derivative of vitamin D3, and its biological activity is 3-5 times that of vitamin D3. Calcifediol is more easily absorbed than vitamin D3, can be directly absorbed into the blood circulation from the intestinal tract, and the like. Calcifediol is an important nutrient for maintaining bone health, is an important indicator for checking whether there is osteoporosis, and is also an important indicator for detecting type II diabetes combined with kidney disease. In addition, calcifediol has a wide range of applications in the fields of health foods, medicines, and feed additives.

[0003] In recent years, the demand for calcifediol in the market has been increasing year by year, so it is important to develop a process route with simple process and low cost, and to recycle the tail oil and tailings separated.

[0004] At present, there is no literature reported that the mother liquor after separation and purification of calcifediol crude product obtained by photochemical reaction is used for secondary extraction of calcifediol. Patent CN103044301A discloses preparation of 25-hydroxyvitamin D3 from 25-hydroxy-7-dehydrocholesterol by photochemical reaction, and does not disclose the treatment method of the mother liquor after crystallization of calcifediol. Patent CN117342992A discloses a process for preparing calcifediol from phytosterol, and also does not disclose the crystallization process and subsequent treatment process. There is also a mention that the separation and extraction are all microbial fermentation enzyme production processes for converting vitamin D3 into calcifediol. Patents CN117964533A, CN103898004A, and CN110396058A all use column separation to preliminarily purify the converted mixture, and then use recrystallization to purify the mixture. These methods can obtain high-purity products, but the overall route has large solvent consumption, long cycle, and only patent CN117964533A mentions recycling the mother liquor, but the mother liquor also needs to be treated by silica gel column chromatography. SUMMARY

[0005] In order to solve the problems in the prior art, the purpose of the present application is to provide a method for secondary extraction of calcifediol from a crystallization mother liquor of a calcifediol crude product. The present application uses the crystallization mother liquor of the calcifediol crude product as a raw material, separates as much calcifediol as possible therefrom, and obtains a calcifediol pure product, so as to improve the overall extraction yield of calcifediol.

[0006] In order to achieve the above-mentioned purpose, the present application provides a method for secondary extraction of calcifediol from a crystallization mother liquor of a calcifediol crude product, which comprises the following steps:

[0007] (1) After the solvent of the crystallization mother liquor of calcifediol crude product is evaporated, the obtained oily concentrate is dissolved in an organic solvent at a certain temperature, a certain amount of activated carbon is added for decolorization at a certain temperature, and filtration is performed to obtain a mother liquor decolorization liquid;

[0008] (2) After the mother liquor decolorization liquid is added with a certain amount of water in proportion, gradient cooling crystallization is performed, and filtration is performed to obtain a mother liquor initial crystallization;

[0009] (3) The mother liquor initial crystallization is subjected to secondary dissolution in a solvent at a certain temperature, a certain amount of water is added, gradient cooling crystallization is performed, filtration is performed, and drying is performed to obtain a calcifediol finished product.

[0010] Further, in the step (1), the calcifediol crude product is obtained after the photochemical reaction of 25-hydroxy-7-dehydrocholesterol and the distillation of the raw material and the solvent.

[0011] Further, in the step (1), the oil-like concentrate has a calcifediol content of 10-40%, preferably 18-30%.

[0012] Further, in the step (1), the organic solvent is one or more than one 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, diethyl ether, preferably any one of a mixed solvent of acetonitrile and ethyl acetate, a mixed solvent of ethanol and n-heptane, and a mixed solvent of isopropanol and n-hexane.

[0013] Further, in the step (1), the proportion of each component in the mixed solvent is 1:0.1-1:10, preferably 1:1.

[0014] Further, in the step (1), the conditions for evaporating the solvent of the mother liquor are a temperature of 30-80°C and a vacuum of ≤-0.05 MPa, preferably a temperature of 50-70°C and a vacuum of ≤-0.085 MPa.

[0015] Further, in the step (1), the volume of the mixed organic solvent is 2-15 times, preferably 5-10 times, the mass of the concentrate.

[0016] Further, in the step (1), the dissolution temperature is controlled at 35-80°C, preferably 50-70°C.

[0017] Further, in the step (1), the amount of activated carbon is 0.1%-2%, preferably 0.5-1%, of the mass of the concentrate.

[0018] Further, in the step (1), the temperature for decolorization is controlled at 50-80°C, preferably 50-60°C.

[0019] Further, in the step (2), the water is 0.1-5 times, preferably 1-2 times the mass of the mother liquor decolorization solution.

[0020] Further, in the step (2), the gradient temperature control range is 1-15°C / h, preferably 5-10°C / h.

[0021] Further, in the step (2), the final temperature control range is -15-15°C, preferably -5-5°C.

[0022] Further, in the step (2), the initial crystallization mother liquor calciferol content (including crystallization water) is ≥80%, preferably 85%.

[0023] Further, in the step (2), the calciferol extraction yield is ≥75%, preferably ≥80%.

[0024] Further, in the 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, hexyl hexanoate, preferably any one of isopropanol and n-hexane mixed solvent, acetonitrile and n-heptane mixed solvent, ethyl acetate and ethanol mixed solvent.

[0025] Further, in the step (3), the ratio of each component in the mixed solvent is 1:0.1-1:10, preferably 1:1.

[0026] Further, in the step (3), the temperature for dissolution is controlled at 40-80°C, preferably 50-60°C.

[0027] Further, in the step (3), the water is 0.1-5 times, preferably 1-2 times the mass of the initial crystallization mother liquor.

[0028] Further, in the step (3), the gradient temperature control range is 0.5-10°C / h, preferably 2-5°C / h.

[0029] Further, in the step (3), the final temperature control range is -25-5°C, preferably -15--5°C.

[0030] Further, in the step (3), the drying temperature is controlled at 20-60°C, preferably 30-40°C.

[0031] Further, in the step (3), the calcifediol content (including crystal water) in the calcifediol finished product is ≥ 94%, preferably > 97%, and more preferably ≥ 98%.

[0032] Further, in the step (3), the crystallization yield is ≥ 85%, preferably ≥ 90%, and more preferably ≥ 93%.

[0033] Further, the crystallization mother liquor in the step (3) can be repeatedly operated in the steps (1) to (3) after being collected by mixing multiple batches.

[0034] Compared with the prior art, the present application has the following beneficial effects:

[0035] The present application uses a specific mixed solvent system to realize secondary extraction of calcifediol from the calcifediol crude product crystallization mother liquor, obtain mother liquor primary crystals by crystallization, and realize efficient separation of the mother liquor primary crystals, and then obtain high-purity calcifediol products by recrystallization with high yield. This scheme avoids the use of time-consuming and solvent-consuming column separation method, and efficiently and highly yields high-purity calcifediol products, meeting the process requirements of green development. DETAILED DESCRIPTION

[0036] In order to make the technical solutions and advantages of the present application clearer, the present application will be further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present application and not to limit the present application.

[0037] Example 1

[0038] After the calcifediol crude product crystallization mother liquor was evaporated at 55℃ under vacuum-0.085MPa, 1.0kg of oil-like concentrate (calcifediol content 15.1%) was obtained. The concentrate was dissolved in 5L of organic solvent mixed at a volume ratio of 1:1 of acetonitrile and ethyl acetate at 55℃, 5g of activated carbon was added for decolorization at 55℃ for 0.5h, and then filtered. The decolorized liquid was added with 1.5kg of water, and gradient cooling was performed at a cooling rate of 5℃ / h to-5℃, and then kept for 5h, and then filtered to obtain mother liquor primary crystals 154.6g (calcifediol content 80.1%, yield 82.1%). The primary crystals were dissolved in 1L of organic solvent mixed at a volume ratio of 1:1 of acetonitrile and n-heptane at 55℃, 100g of water was added, gradient cooling was performed at a cooling rate of 5℃ / h to-10℃, and then kept for 5h, and then filtered, and then dried under vacuum at 50℃ to obtain calcifediol finished product 115.3g, calcifediol content 95.2%, yield 88.6%.

[0039] Example 2

[0040] The mother liquor of the crude calcitriol crystals is concentrated to 1.2 kg of an oily concentrate (calcitriol content 27.3%) at 55°C under vacuum at -0.085 MPa, dissolved in 10 L of an organic solvent of ethanol and n-heptane mixed at a volume ratio of 1:1 at 55°C, decolorized by adding 12 g of activated carbon at 55°C for 0.5 h, filtered, and the decolorized solution is cooled at a gradient of 5°C / h to 0°C, maintained for 5 h, and then filtered to obtain 331.9 g of initial crystals of the mother liquor (calcitriol content 84.3%, yield 85.4%), dissolved in 1.5 L of an organic solvent of ethanol and ethyl acetate mixed at a volume ratio of 1:1 at 55°C, cooled at a gradient of 5°C / h to -10°C, maintained for 5 h, and then filtered and dried under vacuum at 40°C to obtain 259.3 g of finished calcitriol product (calcitriol content 97.2%, yield 90.1%).

[0041] Example 3

[0042] The mother liquor of the crude calcitriol crystals is concentrated to 1.2 kg of an oily concentrate (calcitriol content 27.3%) at 55°C under vacuum at -0.085 MPa, dissolved in 10 L of an organic solvent of ethanol and n-heptane mixed at a volume ratio of 1:1 at 55°C, decolorized by adding 12 g of activated carbon at 55°C for 0.5 h, filtered, and the decolorized solution is cooled at a gradient of 5°C / h to 0°C, maintained for 5 h, and then filtered to obtain 331.9 g of initial crystals of the mother liquor (calcitriol content 84.3%, yield 85.4%), dissolved in 1.5 L of an organic solvent of ethanol and ethyl acetate mixed at a volume ratio of 1:1 at 55°C, cooled at a gradient of 5°C / h to -10°C, maintained for 5 h, and then filtered and dried under vacuum at 40°C to obtain 259.3 g of finished calcitriol product (calcitriol content 97.2%, yield 90.1%).

[0043] The above-described examples are only a preferred embodiment of the present application, and do not limit the present application in any form. Other variants and modifications can be made without departing from the technical solutions recited in the claims.

Claims

1. A method for secondary extraction of calcifediol from a crystallization mother liquor of a crude calcifediol, characterized in that, The crude calcifediol is obtained by distilling off the raw material and solvent after photochemical reaction of 25-hydroxy-7-dehydrocholesterol; the method comprises the following steps: (1) dissolving the oil-like concentrate obtained by distilling off the solvent from the crude calcifediol at a certain temperature with an organic solvent, adding a certain amount of activated carbon to decolorize at a certain temperature, and filtering to obtain a mother liquor decolorizing solution; (2) adding a certain amount of water to the mother liquor decolorizing solution according to a proportion, gradient cooling crystallization, filtering, and obtaining a mother liquor primary crystal; (3) secondary dissolving the mother liquor primary crystal with a solvent at a certain temperature, adding a certain amount of water, gradient cooling crystallization, filtering, drying, and obtaining a calcifediol finished product.

2. The method of claim 1, wherein, In the step (1), the organic solvent is one or more than one 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 acetate, butyl acetate, and diethyl ether.

3. The method of claim 1, wherein, In the step (1), the conditions for distilling off the solvent from the mother liquor are a temperature of 30-80°C and a vacuum of ≤-0.05 MPa.

4. The method of claim 1, wherein, In the step (1), the volume of the organic solvent is 2-15 times the mass of the oil-like concentrate; and the dissolving temperature is controlled at 35-80°C.

5. The method of claim 1, wherein, In the step (1), the amount of activated carbon is 0.1-2% of the mass of the concentrate; and the decolorizing temperature is controlled at 50-80°C.

6. The method of claim 1, wherein, In the step (2), the mass of water is 0.1-5 times the mass of the mother liquor decolorizing solution; and the gradient cooling temperature control range is 1-15°C / h, and the final temperature control range is -15-15°C.

7. The method of claim 1, wherein, In the step (3), the solvent is one or more than one 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 acetate.

8. The method of claim 1, wherein, In the step (3), the dissolving temperature is controlled at 40-80°C, the mass of water is 0.1-5 times the mass of the mother liquor primary crystal, the gradient cooling temperature control range is 0.5-10°C / h, the final temperature control range is -25-5°C, and the drying temperature is controlled at 20-60°C.

9. The method of claim 1, wherein, The crystallization mother liquor in the step (3) can be repeatedly operated according to the steps (1)-(3) after being mixed and collected in batches.