Preparation method of 25-hydroxyvitamin D3 intermediate
By carrying out DA reaction under an inert gas atmosphere and combining with the crystallization purification step, the problems of low DA reaction yield and the use of highly toxic oxidants in the prior art are solved, and the preparation of an efficient and safe 25-hydroxyvitamin D3 intermediate is achieved, which is suitable for industrial production.
Patent Information
- Application Number
- CN202411882131.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-19
- Publication Date
- 2025-03-25
AI Technical Summary
In the existing preparation method of 25-hydroxyvitamin D3 intermediate, the DA reaction yield is not high, and the highly toxic oxidant lead tetraacetate is required. The raw material cost is high, making it difficult to achieve industrial mass production.
The 3β-tert-butyldimethylsiloxyergoster-5,7,22-triene and phthalidylhydrazide were mixed with an organic solvent under an inert gas atmosphere, followed by dropwise addition of a mixture of lead dioxide and acetic acid, and DA reaction was carried out, and the product was obtained by crystallization.
It improves the reaction yield, avoids the use of dangerous reagents, reduces the cost of raw materials, simplifies process operations, and is suitable for large-scale industrial production.
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Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of organic synthesis and relates to a method for preparing a 25-hydroxyvitamin D3 intermediate. Background Art
[0002] 25-Hydroxyvitamin D3, also known as 25-hydroxycholecalciferol, calcidiol, medically known as cholecalciferol, abbreviated as 25-OH-D3. The potency of 25-hydroxyvitamin D3 is 3-5 times that of vitamin D3, and the final biological activity expressed is 20-40 times that of vitamin D3. 25-Hydroxyvitamin D3 is easier to absorb than vitamin D3 and has higher biological activity. Direct supplementation of 25-hydroxyvitamin D3 not only shortens the metabolic process of vitamin D3 in the body and reduces the burden on the liver, but also avoids the effects of intestinal damage, liver and kidney dysfunction on absorption and utilization. 25-Hydroxyvitamin D3 is an important nutrient for maintaining bone health. It is more valuable than vitamin D3 in stimulating intestinal calcium absorption, regulating bone calcium and promoting phosphorus absorption.
[0003] 3β-tert-Butyldimethylsilyloxy-5a,8a-(1,4-dioxo-1,2,3,4-tetrahydro-phthalazine-2,3-diyl)ergosta-6,22-diene is a yellow solid and a key intermediate in the synthesis of 25-hydroxyvitamin D3 using ergosterol as raw material.
[0004] The currently reported synthesis methods of 3β-tert-butyldimethylsilyloxy-5a,8a-(1,4-dioxo-1,2,3,4-tetrahydro-phthalazine-2,3-diyl)ergosta-6,22-diene are as follows: In 1999, Ina Scherlitz-Hofmann et al., Institute of Organic Chemistry and Macromolecular Chemistry of Friedrich Schiller University Jena, reported the synthesis of ergosterol (compound 1) as raw material (Ina Scherlitz-Hofmann et al., Synthesis 1999, No.8, 1331–1334), firstly, tert-butyldimethylsilyl etherification was carried out at 25°C for 6h under the action of acid-binding agent imidazole to obtain 3β-tert-butyldimethylsilyloxyergosta-5,7,22-triene (compound 2) with a yield of 97%, and then, with phthalic acid hydrazide in dichloromethane, lead tetraacetate / acetic acid solution was added dropwise at -5 to 0°C, and DA reaction was carried out for 1.0h to obtain 3β-tert-butyldimethylsilyloxy-5a,8a-(1,4-dioxo-1,2,3,4-tetrahydro-phthalazine-2,3-diyl)ergosta-6,22-diene (compound 3) with a yield of 73%. The reaction route is as follows:
[0005]
[0006] This route uses phthaloyl hydrazide to protect the six-membered ring conjugated diene, which is first oxidized to phthalazine-1,4-dione under the action of the oxidant lead tetraacetate, and then reacts with 3β-tert-butyldimethylsilyloxyergosta-5,7,22-triene to react with DA to protect the conjugated double bonds. However, the yield of the DA reaction is not high, only 73%, and finally column separation is required. The oxidant lead tetraacetate used is highly toxic, extremely unstable in the air, and easily absorbs moisture and hydrolyzes. In addition, lead tetraacetate is extremely difficult to purchase and cannot be purchased in large quantities. It is also expensive, resulting in extremely high raw material costs for this route and bottlenecks in achieving industrial mass production. Summary of the invention
[0007] In order to overcome the deficiencies of the prior art, the purpose of the present invention is to provide a method for preparing a 25-hydroxyvitamin D3 intermediate, the raw materials of the preparation method are simple and easily available, the reaction route is convenient, the use of hazardous reagents is avoided, and the reaction yield is higher.
[0008] The purpose of the present invention can be achieved by adopting the following technical solutions:
[0009] A method for preparing a 25-hydroxyvitamin D3 intermediate comprises the following steps:
[0010] S1. In an inert gas atmosphere, 3β-tert-butyldimethylsilyloxyergosta-5,7,22-triene and phthalic acid hydrazide are mixed with an organic solvent to form a dispersed system;
[0011] S2, adding a mixture of lead dioxide and acetic acid dispersed in an organic solvent dropwise into the dispersed system formed in step S1, and reacting to obtain a crude product of 3β-tert-butyldimethylsilyloxy-5a,8a-(1,4-dioxo-1,2,3,4-tetrahydro-phthalazine-2,3-diyl)ergosta-6,22-diene;
[0012] S3. The crude product of 3β-tert-butyldimethylsilyloxy-5a,8a-(1,4-dioxo-1,2,3,4-tetrahydro-phthalazine-2,3-diyl)ergosta-6,22-diene is crystallized and purified to obtain the product.
[0013] Furthermore, the organic solvent in step S1 and step S2 is one or two of dichloromethane, chloroform, and 1,2-dichloroethane; preferably, the organic solvent is dichloromethane.
[0014] Furthermore, in step S1, the molar volume ratio of 3β-tert-butyldimethylsilyloxyergosta-5,7,22-triene to the organic solvent is 1 mmol:(7.0-9.0) mL, and the molar ratio of 3β-tert-butyldimethylsilyloxyergosta-5,7,22-triene to phthalhydrazide is 1:(2.0-4.0), preferably 1:(2.8-3.2).
[0015] Furthermore, in step S2, the molar ratio of lead dioxide to acetic acid is 1:(2.0-4.0), and the molar volume ratio of lead dioxide to the organic solvent is 1 mmol:(1.0-3.0) mL.
[0016] Furthermore, in step S2, the molar ratio of 3β-tert-butyldimethylsilyloxyergosta-5,7,22-triene to lead dioxide is 1:(1.0-1.5).
[0017] Furthermore, in step S2, the lead dioxide and acetic acid are first dispersed in the organic solvent, and then the mixture is added dropwise into the reaction system under stirring to prevent the lead dioxide from settling to the bottom.
[0018] Furthermore, in step S2, the temperature for dripping the mixture of lead dioxide, acetic acid and organic solvent is between 20 and 35° C., the dripping time is 20 to 30 min, and after the dripping is completed, the reaction temperature is between 20 and 35° C., and the reaction time is 20 to 30 min.
[0019] Furthermore, in step S2, after the reaction is completed, neutral alumina is added to terminate the reaction, the molar ratio of neutral alumina to 3β-tert-butyldimethylsilyloxyergosta-5,7,22-triene is (5-10):1, the termination reaction is carried out between 25 and 35°C, and the termination reaction takes 6 to 12 minutes.
[0020] In the present invention, the reaction conversion rate and selectivity are high, and the product can be directly separated by recrystallization without passing through a column, which is more suitable for industrial production. Further, in step S3, the crystallization purification process is as follows:
[0021] Adding a crystallization solvent to a crude product of 3β-tert-butyldimethylsilyloxy-5a,8a-(1,4-dioxo-1,2,3,4-tetrahydro-phthalazine-2,3-diyl)ergosta-6,22-diene, heating to dissolve, then cooling, adding a mixed solvent of the crystallization solvent and water after solid precipitation, and continuing crystallization to obtain a product;
[0022] The crystallization solvent is one or more of methanol, ethanol, propanol, and butanol, and the crystallization solvent is preferably ethanol, and the amount used is 2.0 to 4.0 times that of the crude product (V / m), preferably 2.5 to 3.0 times; after the solid is precipitated from the system, water is added dropwise to adjust to 80 to 90% ethanol-water system (V / V), preferably 85 to 90% ethanol-water system.
[0023] Furthermore, in step S3, the crystallization temperature is between 15 and 25°C, preferably 20±2°C, and the crystallization time is 20 to 30 minutes.
[0024] Compared with the prior art, the present invention has the following beneficial effects:
[0025] (1) The preparation method of the present invention uses 3β-tert-butyldimethylsilyloxyergosta-5,7,22-triene as a raw material, and first oxidizes phthalic acid hydrazide with lead dioxide to obtain a nitrene compound phthalazine-1,4-dione, which instantly provides a nitrene compound for the DA reaction. Since phthalazine-1,4-dione is unstable, it immediately reacts with 3β-tert-butyldimethylsilyloxyergosta-5,7,22-triene to obtain 3β-tert-butyldimethylsilyloxy-5a,8a-(1,4-dioxo-1,2,3,4-tetrahydro-phthalazine-2,3-diyl)ergosta-6,22-diene after it is generated, and a high-content crystalline product is obtained by simple crystallization. The reaction is carried out in one pot, while adding lead dioxide, and it is an instantaneous reaction. The reaction can be completed in a short time, the reaction route is short, and the reaction operation and post-treatment are simple. Therefore, the entire preparation process method requires less manpower, material and financial resources, and is suitable for large-scale industrial production.
[0026] (2) The reaction raw materials of the present invention, such as phthalic acid hydrazide, lead dioxide, acetic acid, dichloromethane, neutral alumina, etc., are all bulk industrial products, which are easily available, low in cost, and of great industrial value. In addition, no highly dangerous raw materials are used, and no other toxic or harmful by-products remain in the product. The production process is highly safe, and the product meets the use standards. DETAILED DESCRIPTION
[0027] The technical solution of the present invention will be clearly and completely described below in conjunction with specific embodiments. Obviously, the described embodiments are only partial embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative work are within the scope of protection of the present invention.
[0028] Example 1
[0029] A method for preparing a 25-hydroxyvitamin D3 intermediate comprises the following steps:
[0030] Under nitrogen protection, add 0.05mol 3β-tert-butyldimethylsilyloxyergosta-5,7,22-triene, 0.145mol phthalic acid hydrazide and 400mL dichloromethane to a three-necked flask equipped with a mechanical stirrer, stir at 300r / min and cool to about 30°C, add 0.065mol lead dioxide and 0.26mol acetic acid dispersed in 100mL dichloromethane dropwise, and the addition takes 24min. After the addition is completed, continue to react at 30°C for 30min, and monitor the reaction progress by TLC (developing solvent is petroleum ether: ethyl acetate = 4:1). After the reaction is completed, add 0.37mol neutral alumina to terminate the reaction, and stir the reaction for 0.2h. After the reaction was completed, the mixture was filtered and the filter cake was washed three times with 50 mL of dichloromethane, dried, and the filtrate was washed once with 100 mL of tap water and once with 100 mL of 3% aqueous sodium carbonate solution. The organic phase was directly concentrated under reduced pressure to recover the solvent to obtain 36.87 g of a crude concentrate with a liquid content of 84.22% and a yield of 92.55%.
[0031] Add 110 mL of anhydrous ethanol to the above concentrate, stir and heat to 50 ° C to dissolve completely, slowly cool to precipitate solid, add 12.2 mL of water dropwise to make 90% ethanol-water system (V / V), stir and cool to between 18 and 20 ° C to crystallize for 25 minutes, filter, and dry the filter cake in vacuum at 50 ° C to obtain 32.39 g of yellow crystals with a liquid content of 95.87% and a crystallization yield of 97.88%.
[0032] Example 2
[0033] A method for preparing a 25-hydroxyvitamin D3 intermediate comprises the following steps:
[0034] Under nitrogen protection, add 0.05mol 3β-tert-butyldimethylsilyloxyergosta-5,7,22-triene, 0.15mol phthalic acid hydrazide and 350mL dichloromethane to a three-necked flask equipped with a mechanical stirrer, stir at 320r / min and cool to about 25°C, then add 0.07mol lead dioxide and 0.275mol acetic acid dispersed in 80mL dichloromethane dropwise, which takes about 20min. After the addition, continue to react at 25°C for 25min, and monitor the reaction progress by TLC (developing solvent is petroleum ether: ethyl acetate = 4:1). After the reaction is completed, add 0.40mol neutral alumina to terminate the reaction, and stir for 6min. After the reaction was completed, the mixture was filtered and the filter cake was washed three times with 45 mL of dichloromethane and dried. The filtrate was washed once with 110 mL of tap water and once with 90 mL of a 3% aqueous sodium carbonate solution. The organic phase was directly concentrated under reduced pressure to recover the solvent to obtain 36.17 g of a crude concentrate with a liquid content of 85.24% and a yield of 91.89%.
[0035] Add 100 mL of anhydrous ethanol to the above concentrate, stir and heat to 50 ° C to dissolve completely, slowly cool to precipitate solid, add 13.6 mL of water dropwise to adjust to 88% ethanol-water system (V / V), stir and cool to 20-22 ° C for crystallization for 30 min, filter, and dry the filter cake in vacuum at 50 ° C to obtain 31.66 g of yellow crystals with a liquid content of 95.48% and a crystallization yield of 98.05%.
[0036] Example 3
[0037] A method for preparing a 25-hydroxyvitamin D3 intermediate comprises the following steps:
[0038] Under nitrogen protection, add 0.05mol 3β-tert-butyldimethylsilyloxyergosta-5,7,22-triene, 0.155mol phthalic acid hydrazide and 425mL dichloromethane to a three-necked flask equipped with a mechanical stirrer, stir at 300r / min and cool to about 28°C, add 0.06mol lead dioxide and 0.25mol acetic acid dispersed in 75mL dichloromethane dropwise, which takes about 20min. After the addition, continue to react at 28°C for 25min, and monitor the reaction progress by TLC (developing solvent is petroleum ether: ethyl acetate = 4:1). After the reaction is completed, add 0.375mol neutral alumina to terminate the reaction, and stir the reaction for 10min. After the reaction was completed, the mixture was filtered and the filter cake was washed three times with 50 mL of dichloromethane and dried. The filtrate was washed once with 80 mL of tap water and once with 85 mL of a 3% aqueous sodium carbonate solution. The organic phase was directly concentrated under reduced pressure to recover the solvent to obtain 36.59 g of a crude concentrate with a liquid content of 85.08% and a yield of 92.79%.
[0039] Add 110 mL of anhydrous ethanol to the above concentrate, stir and heat to 50 ° C to dissolve completely, slowly cool to precipitate solid, add 17.9 mL of water dropwise to adjust to 86% ethanol-water system (V / V), stir and cool to 19-21 ° C for crystallization for 20 min, filter, and vacuum dry the filter cake at 50 ° C to obtain 32.27 g of yellow crystals with a liquid content of 94.97% and a crystallization yield of 98.45%.
[0040] Example 4
[0041] A method for preparing a 25-hydroxyvitamin D3 intermediate comprises the following steps:
[0042] Under nitrogen protection, add 0.05mol 3β-tert-butyldimethylsilyloxyergosta-5,7,22-triene, 0.14mol phthalic acid hydrazide and 375mL dichloromethane to a three-necked flask equipped with a mechanical stirrer, stir at 320r / min and cool to about 30°C, then add 0.075mol lead dioxide and 0.265mol acetic acid dispersed in 90mL dichloromethane, which takes about 26min. After the addition, continue to react at 30°C for 30min, and monitor the reaction progress by TLC (developing solvent is petroleum ether: ethyl acetate = 4:1). After the reaction is completed, add 0.425mol neutral alumina to terminate the reaction, and stir the reaction for 8min. After the reaction was completed, the mixture was filtered and the filter cake was washed three times with 50 mL of dichloromethane, dried, and the filtrate was washed once with 100 mL of tap water and once with 100 mL of 3% aqueous sodium carbonate solution. The organic phase was directly concentrated under reduced pressure to recover the solvent to obtain 36.44 g of a crude concentrate with a liquid content of 85.37% and a yield of 92.73%.
[0043] Add 91 mL of anhydrous ethanol to the above concentrate, stir and heat to 50 ° C to dissolve completely, slowly cool to precipitate solid, add 16.0 mL of water dropwise to adjust to 85% ethanol-water system (V / V), stir and cool to 18-22 ° C for crystallization for 30 min, filter, and dry the filter cake at 50 ° C in vacuum to obtain 32.12 g of yellow crystals with a liquid content of 95.43% and a crystallization yield of 98.52%.
[0044] Example 5
[0045] A method for preparing a 25-hydroxyvitamin D3 intermediate comprises the following steps:
[0046] Under nitrogen protection, add 0.05mol 3β-tert-butyldimethylsilyloxyergosta-5,7,22-triene, 0.16mol phthalic acid hydrazide and 410mL chloroform to a three-necked flask equipped with a mechanical stirrer, stir at 300r / min and cool to about 30°C, add 0.0675mol lead dioxide and 0.255mol acetic acid dispersed in 85mL chloroform dropwise, and add dropwise for 24min. After the dropwise addition, continue to react at 30°C for 30min, and monitor the reaction progress by TLC (developing solvent is petroleum ether: ethyl acetate = 4:1). After the reaction is completed, add 0.41mol neutral alumina to terminate the reaction, and stir the reaction for 0.2h. After the reaction was completed, the mixture was filtered and the filter cake was washed three times with 50 mL of chloroform and dried. The filtrate was washed once with 100 mL of tap water and once with 100 mL of a 3% aqueous sodium carbonate solution. The organic phase was directly concentrated under reduced pressure to recover the solvent to obtain 37.21 g of a crude concentrate with a liquid content of 83.52% and a yield of 92.63%.
[0047] Add 105 mL of anhydrous ethanol to the above concentrate, stir and heat to 50 ° C to dissolve completely, slowly cool to precipitate solid, add 11.7 mL of water dropwise to adjust to 90% ethanol-water system (V / V), stir and cool to 20-22 ° C for crystallization for 25 min, filter, and vacuum dry the filter cake at 50 ° C to obtain 31.92 g of yellow crystals with a liquid content of 94.75% and a crystallization yield of 97.64%.
[0048] Comparative Example 1
[0049] A method for preparing a 25-hydroxyvitamin D3 intermediate comprises the following steps:
[0050] Under nitrogen protection, add 0.0703 mol of phthalic acid hydrazide to a three-necked reaction bottle containing 0.0148 mol of 3β-tert-butyldimethylsilyloxyergosta-5,7,22-triene dissolved in 450 mL of dichloromethane and pre-cooled to 0-5°C, and then drop 0.0257 mol of lead dioxide dissolved in 80 ml of acetic acid solution into the system for 20 minutes. After the addition, continue to react at 0-5°C for 1.0 h, and monitor the reaction progress by TLC (developing solvent is cyclohexane: ethyl acetate = 20:1). After the reaction is completed, add 30.0 g of neutral alumina to terminate the reaction, and stir the reaction at 0°C for 30 minutes. After the reaction was completed, the product was filtered and the filter cake was washed three times with 50 mL of dichloromethane and dried. The filtrate was washed with saturated sodium bicarbonate water and water, and then dried with sodium sulfate. The product was concentrated and dried to obtain a crude concentrate, which was passed through a 230.0 g silica gel column and eluted with cyclohexane: ethyl acetate = 20:1 to obtain 7.25 g of a yellow solid. Liquid phase analysis showed a content of 95.27% and a yield of 69.55%.
[0051] The above results show that the lead dioxide of the present invention is not only easier to obtain, but also has a higher yield.
[0052] Comparative Example 2
[0053] A method for preparing a 25-hydroxyvitamin D3 intermediate comprises the following steps:
[0054] Under nitrogen protection, add 0.05mol 3β-tert-butyldimethylsilyloxyergosta-5,7,22-triene, 0.15mol phthalic acid hydrazide and 350mL dichloromethane to a three-necked flask equipped with a mechanical stirrer, stir at 320r / min and cool to about 25°C, add 0.07mol lead sulfate (IV) and 0.275mol acetic acid dispersed in 80mL dichloromethane dropwise, and add dropwise for 20min. After the dropwise addition, continue to react at 15°C for 30min, and monitor the reaction progress by TLC (developing solvent is petroleum ether: ethyl acetate = 4:1). After the reaction is completed, add 0.40mol neutral alumina to terminate the reaction, and stir the reaction for 0.2h. After the reaction was completed, the mixture was filtered and the filter cake was washed three times with 45 mL of dichloromethane and dried. The filtrate was washed once with 110 mL of tap water and once with 90 mL of a 3% aqueous sodium carbonate solution. The organic phase was directly concentrated under reduced pressure to recover the solvent to obtain 36.46 g of a crude concentrate with a liquid content of 75.42% and a yield of 81.95%.
[0055] Add 100 mL of anhydrous ethanol to the above concentrate, stir and heat to 50 ° C to dissolve completely, slowly cool to precipitate solid, add 13.6 mL of water dropwise to adjust to 88% ethanol-water system (V / V), stir and cool to 20-22 ° C for crystallization for 30 min, filter, and vacuum dry the filter cake at 50 ° C to obtain 30.27 g of yellow crystals with a liquid content of 84.67% and a crystallization yield of 93.22%.
[0056] The above-mentioned embodiments are only preferred embodiments of the present invention and cannot be used to limit the scope of protection of the present invention. Any non-substantial changes and substitutions made by technicians in this field on the basis of the present invention shall fall within the scope of protection required by the present invention.
Claims
1. A method for preparing a 25-hydroxyvitamin D3 intermediate, characterized in that: The following steps are involved: S1. In an inert gas atmosphere, 3β-tert-butyldimethylsilyloxyergosta-5,7,22-triene and phthalic acid hydrazide are mixed with an organic solvent to form a dispersed system; S2, adding a mixture of lead dioxide and acetic acid dispersed in an organic solvent dropwise into the dispersed system formed in step S1, and reacting to obtain a crude product of 3β-tert-butyldimethylsilyloxy-5a,8a-(1,4-dioxo-1,2,3,4-tetrahydro-phthalazine-2,3-diyl)ergosta-6,22-diene; S3. The crude product of 3β-tert-butyldimethylsilyloxy-5a,8a-(1,4-dioxo-1,2,3,4-tetrahydro-phthalazine-2,3-diyl)ergosta-6,22-diene is crystallized and purified to obtain the product.
2. The method for preparing a 25-hydroxyvitamin D3 intermediate according to claim 1, characterized in that: The organic solvent in step S1 and step S2 is a halogenated hydrocarbon solvent, preferably one or two of dichloromethane, chloroform, and 1,2-dichloroethane; more preferably dichloromethane.
3. The method for preparing a 25-hydroxyvitamin D3 intermediate according to claim 1, characterized in that: In step S1, the molar volume ratio of 3β-tert-butyldimethylsilyloxyergosta-5,7,22-triene to the organic solvent is 1 mmol:(7.0-9.0) mL, and the molar ratio of 3β-tert-butyldimethylsilyloxyergosta-5,7,22-triene to phthalhydrazide is 1:(2.0-4.0).
4. The method for preparing a 25-hydroxyvitamin D3 intermediate according to claim 1, characterized in that: In step S2, the molar ratio of lead dioxide to acetic acid is 1:(2.0-4.0), and the molar volume ratio of lead dioxide to the organic solvent is 1 mmol:(1.0-3.0) mL.
5. The method for preparing a 25-hydroxyvitamin D3 intermediate according to claim 1, characterized in that: In step S2, the molar ratio of 3β-tert-butyldimethylsilyloxyergosta-5,7,22-triene to lead dioxide is 1:(1.0-1.5).
6. The method for preparing a 25-hydroxyvitamin D3 intermediate according to claim 1, characterized in that: In step S2, after lead dioxide and acetic acid are dispersed in an organic solvent, the mixture of lead dioxide, acetic acid and the organic solvent is added dropwise into the reaction system while maintaining stirring.
7. The method for preparing a 25-hydroxyvitamin D3 intermediate according to claim 6, characterized in that: In step S2, the temperature for dripping the mixture of lead dioxide, acetic acid and organic solvent is between 20 and 35° C., and the dripping time is 20 to 30 min. After the dripping is completed, the reaction temperature is between 20 and 35° C., and the reaction time is 20 to 30 min.
8. The method for preparing a 25-hydroxyvitamin D3 intermediate according to claim 1, characterized in that: In step S2, after the reaction is completed, neutral alumina is added to terminate the reaction. The molar ratio of neutral alumina to 3β-tert-butyldimethylsilyloxyergosta-5,7,22-triene is (5-10):
1. The termination reaction is carried out between 25 and 35° C. and takes 6 to 12 minutes.
9. The method for preparing a 25-hydroxyvitamin D3 intermediate according to claim 1, characterized in that: In step S3, the crystallization purification process is as follows: Add a crystallization solvent to the crude product of 3β-tert-butyldimethylsilyloxy-5a,8a-(1,4-dioxo-1,2,3,4-tetrahydro-phthalazine-2,3-diyl)ergosta-6,22-diene, heat to dissolve, then cool, add water to prepare a mixed solvent after solid precipitation, and continue crystallization to obtain the product; The crystallization solvent is one or more of methanol, ethanol, propanol, and butanol, and the crystallization solvent is preferably ethanol, and the usage ratio of the crude product is 2.0-4.0 mL: 1 g; The volume concentration of the crystallization solvent in the mixed solvent is 80-90%.
10. The method for preparing a 25-hydroxyvitamin D3 intermediate according to claim 9, characterized in that: In step S3, the crystallization temperature is between 15 and 25° C., and the crystallization time is between 20 and 30 minutes.