Preparation method of vitamin D3 crystals

Abstract

The present invention relates to a method for preparing vitamin D3 crystals. The preparation method includes: carrying out an esterification reaction on crude vitamin D3 oil and n-butyryl chloride in acetone and an acid-binding agent at -20°C to 20°C, purifying the first reaction product obtained from the reaction to obtain vitamin D3 butyrate crystals, wherein the acid-binding agent is selected from sodium carbonate and / or potassium carbonate; in a mixed solvent of methanol and n-hexane, carrying out a hydrolysis reaction on vitamin D3 butyrate crystals and a strong base, and purifying the second reaction product obtained from the reaction to obtain vitamin D3 crystals. The preparation method of the present invention can effectively utilize previtamin D3 in crude vitamin D3 oil, significantly improve the yield of vitamin D3 crystals, and at the same time improve the quality of vitamin D3 crystals.

Description

Technical Field

[0001] The present invention relates to the technical field of fine chemical engineering, and particularly relates to a method for preparing vitamin D3 crystals. Background Art

[0002] Vitamin D3, also known as cholecalciferol, is an important vitamin variety. The main synthesis method is to use cholesterol as a raw material to obtain 7-dehydrocholesterol through esterification, oxidation, hydrazone formation, de-hydrazone, and hydrolysis; 7-dehydrocholesterol undergoes a ring-opening reaction under ultraviolet irradiation to obtain vitamin pre-D3 (P3); vitamin pre-D3 is converted into vitamin D3 through thermal isomerization. At this time, the synthesized vitamin D3 is a crude vitamin D3 oil with a potency of 28 million iu / g to 32 million iu / g, which cannot be used in the pharmaceutical industry. Moreover, the product also contains 7-dehydrocholesterol, tachysterol, lumisterol, vitamin pre-D3, and some other structurally similar by-products. These by-products have similar structures and properties, and further combination of column chromatography, supercritical CO2 column separation method, or chemical method is required to obtain vitamin D3 crystals with a potency of about 40 million iu / g.

[0003] The chemical method usually involves esterifying crude vitamin D3 oil with aryl acyl chloride to obtain vitamin D3 ester; recrystallizing vitamin D3 ester to obtain pure vitamin D3 ester crystals; and hydrolyzing and recrystallizing vitamin D3 ester crystals to obtain vitamin D3 crystals with a potency of about 40 million iu / g. However, the existing chemical method for preparing vitamin D3 crystals has problems such as the ineffective utilization of vitamin pre-D3 (P3) in crude vitamin D3 oil, resulting in low yield of vitamin D3 crystals. Summary of the Invention

[0004] Based on this, it is necessary to provide a method for preparing vitamin D3 crystals in view of the above problems; the preparation method can effectively utilize vitamin pre-D3 in crude vitamin D3 oil, significantly improve the yield of vitamin D3 crystals, and at the same time improve the quality of vitamin D3 crystals.

[0005] A method for preparing vitamin D3 crystals includes the following steps:

[0006] Esterify crude vitamin D3 oil and n-butyryl chloride in acetone and a deacidifying agent at -20°C to 20°C, and purify the obtained first reactant to obtain vitamin D3 n-butyrate crystals, where the deacidifying agent is selected from sodium carbonate and / or potassium carbonate;

[0007] In a mixed solvent of methanol and n-hexane, hydrolyze vitamin D3 n-butyrate crystals and a strong base, and purify the obtained second reactant to obtain vitamin D3 crystals.

[0008] In one embodiment, the molar ratio of the crude vitamin D3 oil to the n-butyryl chloride is from 1:1.1 to 1:1.5;

[0009] and / or, the mass ratio of the crude vitamin D3 oil to the acid-binding agent is from 1:0.2 to 1:0.5;

[0010] and / or, the concentration of the crude vitamin D3 oil in acetone is from 0.125 g / mL to 0.33 g / mL.

[0011] In one embodiment, the steps of purifying the first reaction product obtained from the reaction include:

[0012] Filtering the first reaction product to obtain a first filtrate and a first filter cake;

[0013] Mixing the first filter cake with acetone and heating to dissolve to obtain a first mixture;

[0014] Filtering the first mixture to obtain a second filtrate, and crystallizing the second filtrate to obtain vitamin D3 butyrate crystals.

[0015] In one embodiment, in the step of mixing the first filter cake with acetone and heating to dissolve, the acetone is obtained by recycling the first filtrate.

[0016] In one embodiment, in the step of mixing the first filter cake with acetone and heating to dissolve, the temperature is from 30°C to 40°C;

[0017] and / or, in the step of crystallizing the second filtrate, the temperature is from -20°C to 10°C.

[0018] In one embodiment, the mass ratio of the methanol to the n-hexane is from 1:0.5 to 1:5.

[0019] In one embodiment, the mass ratio of the crude vitamin D3 oil to the mixed solvent is from 1:2 to 1:8.

[0020] In one embodiment, in the step of subjecting the vitamin D3 butyrate crystals and a strong base to a hydrolysis reaction, the temperature is from 20°C to 40°C and the time is from 1 h to 2 h.

[0021] In one embodiment, in the step of purifying the second reaction product obtained from the reaction, the second reaction product is directly mixed with water for washing, and then vitamin D3 crystals are obtained through layering, concentration, and crystallization.

[0022] In one embodiment, both the esterification reaction and the hydrolysis reaction are carried out in an atmosphere of a protective gas.

[0023] In the preparation method of the present invention, acetone is used as a solvent, and sodium carbonate and / or potassium carbonate are used as acid-binding agents. The esterification reaction temperature of crude vitamin D3 oil and n-butyryl chloride is strictly controlled at -20°C to 20°C. On the one hand, since the solubility of vitamin D3 butyrate crystals in acetone is low, as the esterification reaction proceeds, vitamin D3 butyrate crystals will continuously precipitate out in the reaction solution. With the precipitation of the esterification product, the concentration of the esterification product in the reaction solution is reduced, which is conducive to promoting the esterification reaction of vitamin D3 and n-butyryl chloride to move in the direction of forming the esterification product, thereby increasing the yield of vitamin D3 crystals. On the other hand, when acetone is used as the esterification reaction solvent, under the temperature condition of -20°C to 20°C, the ratio of vitamin D3 to pre-vitamin D3 is generally 10:1 to 30:1, which is conducive to the esterification reaction of vitamin D3 and n-butyryl chloride. However, as the reaction proceeds, the concentration of vitamin D3 will decrease. In order to keep the ratio of vitamin D3 to pre-vitamin D3 basically unchanged, pre-vitamin D3 will be thermally isomerized into vitamin D3. Moreover, when using medium-polarity acetone as the solvent, this temperature condition can promote the conversion of pre-vitamin D3 to vitamin D3, so that the pre-vitamin D3 in the crude vitamin D3 oil can be fully utilized, and the yield of vitamin D3 crystals can be increased.

[0024] In addition, when using sodium carbonate and / or potassium carbonate as acid-binding agents, on the one hand, since sodium carbonate and / or potassium carbonate can be dissolved in acetone in extremely small amounts and can react with the hydrogen chloride released in the esterification reaction to achieve the purpose of acid binding, thus avoiding the side reaction of deterioration of vitamin D3 and / or vitamin D3 butyrate, which is conducive to improving the quality of vitamin D3 crystals. On the other hand, the hydrogen chloride released in the esterification reaction reacts with sodium carbonate or potassium carbonate to form water, which will increase the water content of acetone, which is conducive to increasing the solubility of sodium carbonate and / or potassium carbonate in acetone, so that the acid-binding effect is better. At the same time, the unique water absorption of sodium carbonate or potassium carbonate can reduce the water content in acetone. Therefore, under the synergistic effect of these two effects, the esterification reaction is more stable and not easily affected by external factors.

[0025] Therefore, through the preparation method of the present invention, the pre-vitamin D3 in the crude vitamin D3 oil can be effectively utilized, the yield of vitamin D3 crystals can be significantly increased, and at the same time, the quality of vitamin D3 crystals can also be improved. Detailed Embodiments

[0026] For the convenience of understanding the present invention, the present invention will be described in more detail below. However, it should be understood that the present invention can be implemented in many different forms and is not limited to the embodiments or examples described herein. On the contrary, the purpose of providing these embodiments or examples is to make the understanding of the disclosure content of the present invention more thorough and comprehensive.

[0027] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the technical field to which this invention belongs. The terms used in the description of the present invention herein are for the purpose of describing specific embodiments or examples only and are not intended to limit the present invention.

[0028] The present invention provides a method for preparing vitamin D3 crystals, comprising the following steps:

[0029] S1, carrying out an esterification reaction on crude vitamin D3 oil and n-butyryl chloride in acetone and an acid-binding agent at -20°C to 20°C, and purifying the obtained first reactant to obtain vitamin D3 butyrate crystals, wherein the acid-binding agent is selected from sodium carbonate and / or potassium carbonate;

[0030] S2, carrying out a hydrolysis reaction on vitamin D3 butyrate crystals and a strong base in a mixed solvent of methanol and n-hexane, and purifying the obtained second reactant to obtain vitamin D3 crystals.

[0031] In step S1, acetone is used as the solvent, and sodium carbonate and / or potassium carbonate is used as the acid-binding agent, and the esterification reaction temperature of crude vitamin D3 oil and n-butyryl chloride is strictly controlled at -20°C to 20°C. On the one hand, since the solubility of vitamin D3 butyrate crystals in acetone is low, as the esterification reaction proceeds, vitamin D3 butyrate crystals will continuously precipitate out in the reaction solution. With the precipitation of the esterification product, the concentration of the esterification product in the reaction solution is reduced, which is beneficial to promoting the esterification reaction of vitamin D3 and n-butyryl chloride to move in the direction of forming the esterification product, thereby increasing the yield of vitamin D3 crystals. On the other hand, when acetone is used as the esterification reaction solvent, under the temperature condition of -20°C to 20°C, the ratio of vitamin D3 to previtamin D3 is generally between 10:1 and 30:1, which is beneficial to the esterification reaction of vitamin D3 and n-butyryl chloride. However, as the reaction proceeds, the concentration of vitamin D3 will decrease. In order to keep the ratio of vitamin D3 to previtamin D3 basically unchanged, previtamin D3 will be thermally isomerized into vitamin D3. Moreover, when using moderately polar acetone as the solvent, this temperature condition can promote the conversion of previtamin D3 into vitamin D3, thereby making full use of previtamin D3 in crude vitamin D3 oil and increasing the yield of vitamin D3 crystals.

[0032] In addition, sodium carbonate and / or potassium carbonate are used as acid-binding agents. On the one hand, since sodium carbonate and / or potassium carbonate can be dissolved in acetone in extremely small amounts and can react with the hydrogen chloride released in the esterification reaction to achieve the purpose of acid binding, it is possible to avoid side reactions of deterioration of vitamin D3 and / or the butyrate of vitamin D3, which is beneficial to improving the quality of vitamin D3 crystals. On the other hand, the hydrogen chloride released in the esterification reaction reacts with sodium carbonate or potassium carbonate to form water, which will increase the water content of acetone and is beneficial to increasing the solubility of sodium carbonate and / or potassium carbonate in acetone, thereby making the acid-binding effect better. At the same time, the unique water absorption of sodium carbonate or potassium carbonate can reduce the water content in acetone, so that the esterification reaction is more stable under the synergistic effect of the two effects and is not easily affected by external factors.

[0033] Preferably, the molar ratio of the crude vitamin D3 oil to the butyryl chloride is 1:1.1 to 1:1.5, and more preferably 1:1.4 to 1:1.5, which can ensure that the butyryl chloride is in sufficient excess and can react the crude vitamin D3 oil completely, which is beneficial to improving the yield of vitamin D3 crystals.

[0034] More preferably, the butyryl chloride is added in batches, and even more preferably by dropping.

[0035] Preferably, the concentration of the crude vitamin D3 oil in acetone is 0.125 g / mL to 0.33 g / mL, and more preferably 0.2 g / mL to 0.25 g / mL, which is more beneficial to improving the yield of vitamin D3 crystals.

[0036] Preferably, the mass ratio of the crude vitamin D3 oil to the acid-binding agent is 1:0.2 to 1:0.5, and more preferably 1:0.3 to 1:0.4, which can make the esterification reaction better and is beneficial to further improving the quality of vitamin D3 crystals.

[0037] In one embodiment, the temperature of the esterification reaction is more preferably -10°C to 0°C.

[0038] In one embodiment, the steps of purifying the first reactant obtained by the reaction include:

[0039] S11, filtering the first reactant to obtain a first filtrate and a first filter cake;

[0040] S12, mixing the first filter cake with acetone and heating to dissolve it to obtain a first mixture;

[0041] S13, filtering the first mixture to obtain a second filtrate, and crystallizing the second filtrate to obtain vitamin D3 butyrate crystals.

[0042] In step S11, the first reactant is filtered, and the obtained first filter cake includes vitamin D3 butyrate, an acid-binding agent, and sodium butyrate / potassium butyrate, while the first filtrate includes an acetone solution of other impurities in the crude vitamin D3 oil except for vitamin D3.

[0043] Preferably, acetone can be recovered from the first filtrate. The recovered acetone can be used in the esterification reaction or to dissolve the first filter cake, enabling the comprehensive utilization of acetone. After recovering acetone, the remaining residual liquid is subjected to waste liquid treatment.

[0044] Furthermore, in step S12, the acetone is preferably the acetone recovered from the first filtrate, which helps reduce the variety of solvents and waste liquid.

[0045] More preferably, the mass of the acetone is 1 to 3 times the mass of the crude vitamin D3 oil, and the heating and dissolving temperature is 30°C to 40°C. Thus, the esterification product vitamin D3 butyrate will dissolve into the acetone, while impurities such as sodium butyrate / potassium butyrate and the acid-binding agent will be suspended in the acetone, which is beneficial to improving the yield of vitamin D3 butyrate crystallization.

[0046] In one embodiment, before mixing the first filter cake with acetone, it is preferred to wash the first filter cake.

[0047] In step S13, the temperature for crystallizing the second filtrate is preferably -20°C to 10°C, and more preferably -10°C to 0°C.

[0048] In one embodiment, it is preferred to mix the second filtrate with the washing liquid of the first filter cake for crystallization.

[0049] In step S2, in a mixed solvent of methanol and n-hexane, the hydrolysis reaction of vitamin D3 butyrate crystals and a strong base is carried out, which can not only increase the reaction rate but also prevent the second reactant from easily forming an emulsion layer during the purification process, thereby further improving the yield and quality of vitamin D3 crystals.

[0050] Preferably, the mass ratio of the methanol to the n-hexane is 1:0.5 to 1:5, and more preferably 1:1.0 to 1:1.2, which is more beneficial to improving the hydrolysis reaction rate and the washing quality of the post-treatment.

[0051] Preferably, the mass ratio of the crude vitamin D3 oil to the mixed solvent is 1:2 to 1:8, and more preferably 1:4 to 1:6.

[0052] Preferably, the strong base includes but is not limited to potassium hydroxide, and potassium hydroxide is preferred.

[0053] Preferably, in the step of subjecting vitamin D3 butyrate crystals to a hydrolysis reaction with a strong base, the temperature is 20°C to 40°C and the time is 1 h to 2 h, which is more conducive to preventing vitamin D3 from deteriorating while increasing the reaction rate, thereby improving the yield and quality.

[0054] Preferably, in the step of purifying the second reaction product obtained from the reaction, the second reaction product is directly mixed with water for washing, and then vitamin D3 crystals are obtained through layering, concentration, and crystallization. Compared with the method of first recovering the mixed solvent in the second reaction product and then washing, directly mixing the second reaction product with water for washing increases the amount of waste liquid, but can effectively reduce the heating time of vitamin D3, further effectively improving the yield and quality of vitamin D3 crystals.

[0055] In one embodiment, the second reaction product is directly mixed with water for washing. During layering, the mixed liquid of methanol and water in the lower layer is separated, and the n-hexane in the upper layer is recovered by reduced pressure concentration. Methyl formate 2 to 6 times the weight of the concentrated liquid is added for crystallization. After crystallization is completed, filtration is performed to obtain vitamin D3 crystals.

[0056] Preferably, both the esterification reaction and the hydrolysis reaction are carried out in an inert gas atmosphere to isolate air. Among them, the inert gas is preferably nitrogen.

[0057] Therefore, through the preparation method of the present invention, pre-vitamin D3 in vitamin D3 crude oil can be effectively utilized, significantly improving the yield of vitamin D3 crystals, and at the same time, the quality of vitamin D3 crystals can also be improved.

[0058] Hereinafter, the preparation method of the vitamin D3 crystals will be further described through the following specific examples.

[0059] It should be noted that the yield = [(m1 / M)×(U1 / 4000)] / [(m2 / M)×(U2 / 4000)], where m1 is the mass of the prepared vitamin D3 crystals, m2 is the mass of the vitamin D3 crude oil, M is the molar molecular weight of vitamin D3 (384.6), U1 is the potency of the prepared vitamin D3 crystals, and U2 is the potency of the vitamin D3 crude oil.

[0060] Example 1

[0061] Into a 1000 mL four-necked flask equipped with a stirring paddle, a nitrogen charging tube, a reflux condenser, and a constant-pressure dropping funnel, 150.0 g (0.3124 mol) of crude vitamin D3 oil (the potency of pre-vitamin D3 contained is 32040000 iu / g, and the content of pre-vitamin D3 detected by liquid-phase normalization method at a wavelength of 254 nm is 5.7%), 500 mL of acetone, and 54.0 g of potassium carbonate were added. 45.0 g (98.6%, 0.4162 mol) of n-butyryl chloride was added to the constant-pressure dropping funnel. Nitrogen was introduced into the four-necked flask, and the nitrogen flow rate was controlled at 0.5 L / min. After the nitrogen discharged from the reflux condenser, it was absorbed by an alkaline solution. The outer wall of the four-necked flask was cooled with an ethylene glycol aqueous solution in a low-temperature cooling bath, and the temperature of the low-temperature cooling bath was set at -8 °C. Stirring was started for cooling. When the internal temperature of the four-necked flask reached -5 °C, n-butyryl chloride was slowly and uniformly added dropwise over a period of 1.0 h. During the dropping process, light yellow vitamin D3 butyrate crystals gradually precipitated in the four-necked flask. After the addition of n-butyryl chloride was completed, stirring was continued for heat preservation reaction for 6 h. During this period, samples were continuously taken for detection (using liquid-phase normalization method to detect at a wavelength of 254 nm) of the residual vitamin D3 in the reaction solution. When the residual vitamin D3 was less than 1.0%, the esterification reaction was completed.

[0062] The first reaction product obtained from the reaction was filtered. The first filter cake obtained by filtration was slurried and washed with 150 mL of ice-cold acetone at 5 °C. The first filtrate was recovered under normal pressure and comprehensively utilized. The washed first filter cake was transferred to a 1000 mL four-necked flask equipped with a nitrogen charging tube and a reflux condenser, 350 mL of acetone was added, and the nitrogen flow rate was controlled at 0.5 L / min. The outer wall of the four-necked flask was heated with 40 °C hot water for dissolution, and the dissolution time was about 0.5 h. After dissolution, filtration was carried out while it was hot. The second filter cake obtained by filtration was slurried and washed with 50 mL of acetone. The second filter cake was the unreacted acid-binding agent and was treated as waste residue. After washing, the washing liquid and the second filtrate obtained by filtration were transferred to a 1000 mL three-necked flask. The outer wall of the three-necked flask was cooled with an ethylene glycol aqueous solution in a low-temperature cooling bath, and the temperature of the low-temperature cooling bath was set at -10 °C. Stirring was started for cooling crystallization. The crystallization time was 6 h. After crystallization was completed, filtration and air-drying were carried out to obtain vitamin D3 butyrate crystals, and the filtrate was recovered and comprehensively utilized.

[0063] Into a 1000 mL four-necked flask equipped with a stirring paddle, a nitrogen charging tube, and a reflux condenser, the air-dried vitamin D3 butyrate crystals were added, methanol: 130 g, n-hexane: 220 g, potassium hydroxide: 25.8 g (91.5%, 0.4216 mol). Nitrogen was introduced into the four-necked flask, and the nitrogen flow rate was controlled at 0.5 L / min. The four-necked flask was placed in a water bath, and the water temperature of the water bath was set at 40 °C. Stirring was started, and the hydrolysis reaction was started. The hydrolysis reaction time was about 1.0 h.

[0064] After the hydrolysis reaction was completed, 200 g of distilled water was added to the reaction flask. After stirring for 5 min, it was transferred to a separatory funnel. After standing for 10 min, the lower-layer mixture of methanol and water was separated, and then 200 g of distilled water was added to wash the upper-layer separation. The washed upper-layer separation was transferred to a 500 mL three-necked flask, and n-hexane was recovered under reduced pressure. The recovery vacuum degree was controlled at -0.085 MPa, and the recovery temperature was controlled at 40 °C. After the reduced-pressure recovery was completed, 300 g of methyl formate was added to the four-necked flask. The outer wall of the four-necked flask was cooled with an ethylene glycol aqueous solution in a low-temperature cooling bath. The temperature of the low-temperature cooling bath was set at -10 °C, and stirring was started for cooling crystallization. The crystallization time was about 8 h. After crystallization was completed, filtration and vacuum drying were carried out to obtain 102.3 g of vitamin D3 crystals, and the potency of the vitamin D3 crystals was 39.95 million iu / g, and the yield was 85.0%.

[0065] Example 2

[0066] The difference between Example 2 and Example 1 was that in the esterification reaction, the temperature of the low-temperature cooling bath was set at -20 °C, and stirring was started for cooling. When the internal temperature of the four-necked flask reached -15 °C, n-butyryl chloride was slowly and uniformly added dropwise, the dropping time was 1.0 h, and the holding time was 20 h. Finally, 105.8 g of vitamin D3 crystals were obtained, and the potency of the vitamin D3 crystals was 39.93 million iu / g, and the yield was 87.9%.

[0067] Example 3

[0068] The difference between Example 3 and Example 1 was that in the esterification reaction, the temperature of the low-temperature cooling bath was set at 20 °C, and stirring was started for cooling. When the internal temperature of the four-necked flask reached 15 °C, n-butyryl chloride was slowly and uniformly added dropwise, the dropping time was 1.0 h, and the holding time was 3 h. Finally, 96.4 g of vitamin D3 crystals were obtained, and the potency of the vitamin D3 crystals was 39.97 million iu / g, and the yield was 80.2%.

[0069] Example 4

[0070] The difference between Example 4 and Example 1 was that 37.5 g (98.6%, 0.3469 mol) of n-butyryl chloride was added to the constant-pressure dropping funnel, the dropping time was 1.0 h, and the holding time was 10 h. Finally, 101.6 g of vitamin D3 crystals were obtained, and the potency of the vitamin D3 crystals was 39.94 million iu / g, and the yield was 84.4%.

[0071] Example 5

[0072] Example 5 is different from Example 1 in that 51.0 g (98.6%, 0.4717 mol) of n-butyryl chloride is added to the constant-pressure dropping funnel, the dropping time is 1.0 h, and the heat preservation time is 4.5 h. Finally, 103.9 g of vitamin D3 crystals are obtained, and the potency of the vitamin D3 crystals is 39.95 million iu / g, and the yield is 86.4%.

[0073] Example 6

[0074] Example 6 is different from Example 1 in that 51.0 g (98.6%, 0.4717 mol) of n-butyryl chloride is added to the constant-pressure dropping funnel, and the temperature of the low-temperature cooling bath is set at -20 °C during the esterification reaction, and stirring is started for cooling. When the internal temperature of the four-necked flask reaches -15 °C, n-butyryl chloride is slowly and uniformly added dropwise, the dropping time is 1.0 h, and the heat preservation time is 12 h. Finally, 107.5 g of vitamin D3 crystals are obtained, and the potency of the vitamin D3 crystals is 39.93 million iu / g, and the yield is 89.3%.

[0075] Example 7

[0076] Example 7 is different from Example 1 in that after the hydrolysis reaction is completed, the mixed solvent is recovered under reduced pressure, the recovery vacuum degree is controlled at -0.085 MPa, and the recovery temperature is controlled at 40 °C. After the recovery is completed, 300 mL of n-hexane and 200 g of distilled water are added to the reaction flask, and after stirring for 5 min, it is transferred to a separatory funnel. After standing for 10 min, the lower layer of methanol is separated, and then 200 g of distilled water is added for washing and water separation. The washed upper layer is transferred to a 1000 mL three-necked flask and the n-hexane is recovered under reduced pressure, the recovery vacuum degree is controlled at -0.085 MPa, and the recovery temperature is controlled at 40 °C. After the reduced-pressure recovery is completed, 300 g of methyl formate is added to the three-necked flask, and the outer wall of the three-necked flask is cooled with an ethylene glycol aqueous solution in a low-temperature cooling bath, the temperature of the low-temperature cooling bath is set at -10 °C, and stirring is started for cooling crystallization, and the crystallization time is about 8 h. After crystallization is completed, filtration and vacuum drying are carried out.

[0077] Finally, 97.3 g of vitamin D3 crystals are obtained, and the potency of the vitamin D3 crystals is 39.95 million iu / g, and the yield is 80.9%.

[0078] Example 8

[0079] Example 8 is different from Example 1 in that 150.0 g (0.2741 mol) of crude vitamin D3 oil (the potency of pre-vitamin D3 contained is 28.11 million iu / g, and the content of pre-vitamin D3 detected by liquid phase normalization method at a wavelength of 254 nm is 5.3%), 500 mL of acetone, and 54 g of sodium carbonate are added; the temperature of the low-temperature cooling bath is set at -10 °C, and stirring is started for cooling. When the internal temperature of the four-necked flask reaches -5 °C, n-butyryl chloride is slowly and uniformly added dropwise, and the dropping time is 1.0 h.

[0080] For hydrolysis, 200 g of methanol, 150 g of n-hexane, and 20.2 g (91.5%, 0.3301 mol) of potassium hydroxide are added. The water temperature of the water bath is set at 20 °C, and the hydrolysis reaction time is about 2 h.

[0081] Finally, 87.4 g of vitamin D3 crystals are obtained, and the potency of the vitamin D3 crystals is 39.96 million iu / g, and the yield is 82.8%.

[0082] Example 9

[0083] Example 9 is different from Example 1 in that the esterification reaction is carried out in air, and 150.0 g (0.2741 mol) of crude vitamin D3 oil (the potency of pre-vitamin D3 contained is 28.11 million iu / g, and the content of pre-vitamin D3 detected by liquid phase normalization method at a wavelength of 254 nm is 5.3%), 500 mL of acetone, 27.0 g of potassium carbonate, and 27.0 g of sodium carbonate are added; the temperature of the low-temperature cooling bath is set at 10 °C, and stirring is started for cooling. When the internal temperature of the four-necked flask reaches 5 °C, n-butyryl chloride is slowly and uniformly added dropwise, and the dropping time is 1.0 h.

[0084] Both the first filter cake and the second filter cake are washed with methanol. The outer wall of the four-necked flask is heated and dissolved with 35 °C hot water, and the dissolution time is about 1 h; the temperature of the low-temperature cooling bath is set at 5 °C, and stirring is started for cooling crystallization. The crystallization time is 12 h. After crystallization is completed, filtration and air-drying are carried out to obtain vitamin D3 n-butyrate crystals.

[0085] The hydrolysis reaction is carried out in air, 200 g of methanol, 150 g of n-hexane, and 20.2 g (91.5%, 0.3301 mol) of potassium hydroxide are added. The water temperature of the water bath is set at 30 °C, and the hydrolysis reaction time is about 1.5 h.

[0086] Finally, 84.9 g of vitamin D3 crystals are obtained, and the potency of the vitamin D3 crystals is 39.98 million iu / g, and the yield is 80.5%.

[0087] Comparative Example 1

[0088] The difference between Comparative Example 1 and Example 1 is that in the esterification reaction, the temperature of the low-temperature cooling bath was set at -30°C, and stirring was started for cooling. When the internal temperature of the four-necked flask reached -25°C, n-butyryl chloride was slowly and uniformly added dropwise over a period of 1.0 h, and the holding time was 24 h. In the final reaction solution, 16.3% of vitamin D3 remained and did not decrease further, and the reaction failed.

[0089] Comparative Example 2

[0090] The difference between Comparative Example 2 and Example 1 is that in the esterification reaction, 500 mL of n-hexane was added as a solvent for the reaction. After the esterification reaction was completed, the esterification reaction solution was transferred to a separatory funnel, 100 mL of deionized water was added for washing, standing, layering, and discarding the water, and the washing was repeated twice for a total of three washes. After washing, the n-hexane solution was transferred to a 1000 mL four-necked flask equipped with a nitrogen filling tube and a recovery condenser, and the internal temperature was controlled not to exceed 40°C to recover n-hexane under reduced pressure. After the recovery of n-hexane was completed, 400 mL of acetone was added to the four-necked flask, the nitrogen flow rate was controlled at 0.5 L / min, and the outer wall of the four-necked flask was heated with hot water at 40°C for dissolution, and the dissolution time was about 0.5 h. After dissolution, the outer wall of the four-necked flask was cooled with an ethylene glycol aqueous solution in a low-temperature cooling bath, the temperature of the low-temperature cooling bath was set at -10°C, stirring was started for cooling crystallization, the crystallization time was 6 h, after crystallization was completed, filtration was carried out to obtain vitamin D3 butyrate crystals. The filtrate was recovered and comprehensively utilized for acetone, and the filter cake was dried and then subjected to a hydrolysis reaction.

[0091] Finally, 88.6 g of vitamin D3 crystals were obtained, and the potency of the vitamin D3 crystals was 39.97 million iu / g, and the yield was 73.7%.

[0092] Comparative Example 3

[0093] The difference between Comparative Example 3 and Example 1 is that in the esterification reaction, 59.5 g (0.4164 mol) of benzoyl chloride was added.

[0094] Finally, 97.3 g of vitamin D3 crystals were obtained, and the potency of the vitamin D3 crystals was 37.59 million iu / g, and the yield was 76.1%.

[0095] Comparative Example 4

[0096] The difference between Comparative Example 4 and Example 1 is that in the hydrolysis reaction, 350 g of n-hexane was added instead of 130 g of methanol and 220 g of n-hexane.

[0097] Since n-hexane could not dissolve potassium hydroxide, the hydrolysis reaction could not proceed, and the experiment failed.

[0098] Comparative Example 5

[0099] The difference between Comparative Example 5 and Example 1 is that 54.0 g of potassium bicarbonate was added instead of 54.0 g of potassium carbonate in the esterification reaction.

[0100] Finally, 93.2 g of vitamin D3 crystals were obtained, and the titer of the vitamin D3 crystals was 39.99 million iu / g, and the yield was 77.6%.

[0101] The technical features of the above-described embodiments can be combined arbitrarily. For the sake of brevity of description, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered as the scope described in this specification.

[0102] The above-described embodiments only represent several implementation manners of the present invention, and the description is relatively specific and detailed, but it should not be construed as a limitation on the scope of the invention patent. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can be made, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the present invention patent shall be subject to the appended claims.

Claims

1. A method for preparing vitamin D3 crystals, characterized in that, It includes the following steps: Esterify vitamin D3 crude oil and n-butyryl chloride in acetone and an acid-binding agent at -20°C to 20°C, and purify the first reaction product obtained from the reaction to obtain vitamin D3 butyrate crystals. The acid-binding agent is selected from sodium carbonate and / or potassium carbonate; In a mixed solvent of methanol and n-hexane, hydrolyze vitamin D3 butyrate crystals and a strong base, and purify the second reaction product obtained from the reaction to obtain vitamin D3 crystals.

2. The preparation method of vitamin D3 crystals according to claim 1, characterized in that, The molar ratio of the vitamin D3 crude oil to the n-butyryl chloride is 1:1.1 to 1:1.5; And / or, the mass ratio of the vitamin D3 crude oil to the acid-binding agent is 1:0.2 to 1:0.5; And / or, the concentration of the vitamin D3 crude oil in acetone is 0.125 g / mL to 0.33 g / mL.

3. The method for preparing vitamin D3 crystals according to claim 1 or 2, characterized in that, The step of purifying the first reaction product obtained from the reaction includes: Filter the first reaction product to obtain a first filtrate and a first filter cake; Mix the first filter cake with acetone and heat to dissolve to obtain a first mixture; Filter the first mixture to obtain a second filtrate, and crystallize the second filtrate to obtain vitamin D3 butyrate crystals.

4. The method for preparing vitamin D3 crystals according to claim 3, characterized in that, In the step of mixing the first filter cake with acetone and heating to dissolve, the acetone is obtained by recycling the first filtrate.

5. The preparation method of vitamin D3 crystal according to claim 3, wherein, In the step of mixing the first filter cake with acetone and heating to dissolve, the temperature is 30°C to 40°C; And / or, in the step of crystallizing the second filtrate, the temperature is -20°C to 10°C.

6. The preparation method of vitamin D3 crystals according to claim 1, characterized in that, The mass ratio of the methanol to the n-hexane is 1:0.5 to 1:

5.

7. The preparation method of vitamin D3 crystal according to claim 1, wherein, The mass ratio of the vitamin D3 crude oil to the mixed solvent is 1:2 to 1:

8.

8. The preparation method of vitamin D3 crystals according to claim 1, characterized in that, In the step of hydrolyzing vitamin D3 butyrate crystals and a strong base, the temperature is 20°C to 40°C, and the time is 1 h to 2 h.

9. The preparation method of vitamin D3 crystals according to claim 1, wherein, In the step of purifying the second reaction product obtained from the reaction, directly mix the second reaction product with water for washing, and then obtain vitamin D3 crystals through layering, concentration, and crystallization.

10. The preparation method of vitamin D3 crystals according to claim 1, wherein, Both the esterification reaction and the hydrolysis reaction are carried out in an inert gas atmosphere.