Preparation method of maxacalcitol intermediate B
Through a new four-step synthesis route, the problems of harsh reaction conditions and complex substrates of the synthesis of masalcalciferol intermediate B in the prior art are solved, and the effects of simple operation, mild reaction conditions and high selective synthesis are achieved.
Patent Information
- Application Number
- CN202411835248.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-12-13
- Publication Date
- 2025-03-21
AI Technical Summary
The existing methods for synthesizing masalcalciferol intermediate B have harsh reaction conditions, requiring strong alkali and lower temperature conditions, and the substrate is complex, which limits the greenness and high efficiency of the synthesis.
A new synthesis route is adopted, including four steps: S1 step obtains compound b through different reaction conditions, S2 step reacts with methyl triphenylphosphine bromide and base to form compound c, S3 step uses diisobutyl aluminum hydride to obtain compound d, and S4 step converts compound d into masalcalciferol intermediate B under light using a catalyst.
Masacalcitol intermediate B is obtained with simple operation, mild reaction conditions and high selectivity, and has wide application prospects.
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Figure CN119661577A_ABST
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of organic chemical synthesis, and particularly relates to a maxacalcitol intermediate B compound and a preparation method thereof. Background Art
[0002] Active vitamin D3, as the most active form of vitamin D in the human body, not only has the function of regulating calcium and phosphorus metabolism, but is also a cell cycle regulator that affects cell proliferation, differentiation and apoptosis. It plays a variety of physiological functions in the body by binding to vitamin D receptors and is widely used in the treatment of osteoporosis, inflammation, skin diseases and other diseases.
[0003] Maxacalcitol (OCT) is an oxygen atom substituted at the C-22 position of active vitamin D3, developed by Chugai Pharmaceutical Co., Ltd. of Japan. Its ointment product was launched in 2001 and is mainly used to treat psoriasis and other psoriasis-like skin diseases. In addition to ointment, the clinical applications of maxacalcitol also include maxacalcitol injection, maxacalcitol lotion, etc. Maxacalcitol intermediate B is an important part of the synthesis of maxacalcitol. Therefore, developing a green and efficient preparation method for maxacalcitol intermediate B compound is a key content of modern organic chemistry research.
[0004] At present, there are two main methods for synthesizing maxacalcitol intermediate B:
[0005] 1) Using the ester corresponding to the maxacalcitol intermediate B (or other compounds containing oxygen atoms for bonding) to be reduced by diisobutylaluminum hydride (or other reducing conditions) under certain conditions, thereby producing the corresponding maxacalcitol intermediate B.
[0006]
[0007] 2) Under the catalysis of strong base and palladium, the corresponding reactants undergo Heck reaction, thereby undergoing a coupling reaction of substituted olefins to produce the corresponding maxacalcitol intermediate B.
[0008]
[0009] Although the above method can realize the synthesis of maxacalcitol intermediate B to a certain extent, there are still some limiting factors, such as the harsh reaction conditions, the need to use strong bases and low temperature conditions, and the relatively complex substrates. Therefore, it is of great significance to develop a greener and more efficient synthesis method. Summary of the invention
[0010] In view of the above-mentioned defects of the prior art, the present invention provides a method for preparing a maxacalcitol intermediate B. The method is simple to operate, has relatively mild reaction conditions, can obtain a maxacalcitol intermediate B with high selectivity, and has broad application prospects.
[0011] The chemical structural formula of the maxacalcitol intermediate B is shown in Formula I:
[0012]
[0013] The structural formulas of the relevant raw materials and products in the preparation of maxacalcitol intermediate B are as follows:
[0014]
[0015]
[0016] The synthetic route of the present invention is as follows:
[0017]
[0018] A method for preparing a maxacalcitol intermediate B, comprising four steps: step S1, step S2, step S3, and step S4;
[0019] The step S1 is selected from one of the following three methods: 1) Compound a, pyridinium dichromate, diatomaceous earth, and tert-butyl peroxide aqueous solution are mixed to react to obtain compound b; 2) Compound a, cuprous iodide, tert-butyl peroxide decane solution, and acetonitrile are mixed to react to obtain compound b; 3) Compound a, selenium dioxide, dichloromethane, sodium bicarbonate, and Dess-Martin reagent are mixed to react to obtain compound b;
[0020] The step S2 is to react compound b, methyltriphenylphosphine bromide, tetrahydrofuran and a base to generate compound c; the base is selected from one or more of sodium hydrogen sulfide and potassium tert-butoxide;
[0021] The step S3 comprises mixing compound c, diisobutylaluminum hydride n-hexane solution and n-hexane to react to obtain compound d;
[0022] The step S4 is to mix compound d, methyl tert-butyl ether and a catalyst to react to obtain a compound represented by formula I; the catalyst is selected from one or more of 9-fluorenone-4-carboxylic acid, anthracene and 9-acetylanthracene;
[0023] In some specific embodiments, the S1 step is selected from one of the following three methods: 1) pyridinium dichromate and diatomaceous earth are added to the solution of compound a, the temperature is reduced to 0-5°C, an aqueous solution of tert-butyl peroxide is added dropwise, the temperature is raised to room temperature, and after the reaction is completed, the compound b is purified; 2) the solution of compound a is protected by an inert gas, cuprous iodide is added, the temperature is reduced to 5-10°C, a decane solution of tert-butyl peroxide is added dropwise, the temperature is raised to room temperature for reaction, and then the temperature is raised to 50-60°C, and after the reaction is completed, the compound b is purified; 3) selenium dioxide is added to dichloromethane, and then a dichloromethane solution of tert-butyl peroxide is added, the temperature is reacted at room temperature, the temperature is reduced to 0-5°C, a dichloromethane solution of compound a is added dropwise, the temperature is raised to room temperature for further reaction, sodium bicarbonate and Dess-Martin reagent are added, and after the reaction is completed, the compound b is purified;
[0024] The step S2 is as follows: in an inert environment, methyl triphenylphosphine bromide is added to tetrahydrofuran, the temperature is lowered to 0-5°C, a base is added in batches under temperature control, a solution of compound b dissolved in tetrahydrofuran is dripped into the reaction solution under temperature control, and after the reaction is completed, the compound c is purified; the base is selected from one or more of sodium hydrogen sulfide and tert-butyl potassium;
[0025] The step S3 is as follows: Compound c is dissolved in n-hexane, cooled to -70 to -60°C under an inert environment, diisobutylaluminum hydride n-hexane solution is added dropwise, the temperature is raised to room temperature, and after the reaction is completed, the compound d is purified;
[0026] The step S3 is as follows: compound d is dissolved in methyl tert-butyl ether, added into a light irradiation reaction vessel, a catalyst is added, the temperature is lowered to -5 to 5°C, and after the light irradiation reaction is completed, the intermediate B of maxacalcitol is obtained by purification; the catalyst is selected from one or more of 9-fluorenone-4-carboxylic acid, anthracene, and 9-acetylanthracene.
[0027] More specific steps are:
[0028] S1 (Scheme 1), compound a is dissolved in benzene, diatomaceous earth and pyridinium dichromate are added, the temperature is lowered to 0-5°C, 70% tert-butyl peroxide aqueous solution is added dropwise, and then the temperature is raised to room temperature to react for 24 hours. After the reaction of the raw material, the raw material is filtered, and the filtrate is concentrated under reduced pressure and purified by column chromatography to obtain compound b;
[0029] S1 (Scheme 2), compound a is dissolved in acetonitrile, inert gas protection, cuprous iodide is added, the temperature is lowered to 5-10°C, a 5M tert-butyl peroxide decane solution is added dropwise, and then the temperature is raised to room temperature for reaction for 2 hours, and then the temperature is raised to 50-60°C for reaction for 24 hours. After the reaction of the raw materials is completed, the temperature is lowered to room temperature, saturated sodium bicarbonate aqueous solution is added, ethyl acetate is extracted, and then washed once with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution in sequence, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by dry column chromatography to obtain compound b;
[0030] S1 (Scheme 3), add selenium dioxide to dichloromethane, then add 5.0M tert-butyl peroxide dichloromethane solution, react at room temperature for 1h, then cool to 0-5°C, add compound a in dichloromethane dropwise, heat to room temperature for 10h, react the raw materials, add sodium bicarbonate and Dess-Martin reagent, react at room temperature for 3h, cool to 0-5°C after the intermediate reaction, add saturated sodium bicarbonate aqueous solution and 10% sodium thiosulfate aqueous solution to quench, separate the phases, extract with dichloromethane, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain compound b;
[0031] S2. Under an inert environment, methyltriphenylphosphonium bromide is added to dry tetrahydrofuran, the temperature is lowered to 0-5°C, a base (sodium hydrogen ions or tert-butyl potassium) is added in batches under temperature control to react for 1 hour, and then a mixture of compound b1 and compound b2 is dissolved in tetrahydrofuran and dripped into the reaction solution under temperature control. After dripping, the mixture is kept warm for 30 minutes, and the temperature is raised to room temperature for reaction for 3 hours. After the reaction of the raw materials is completed, a saturated aqueous ammonium chloride solution is added to quench the reaction, the mixture is extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by dry column chromatography to obtain compound c;
[0032] S3, compound c was dissolved in n-hexane, cooled to -70 to -60°C under an inert environment, 1M diisobutylaluminum hydride n-hexane solution was added dropwise, and then the temperature was raised to room temperature for reaction for 2h. After the reaction of the raw materials was completed, the temperature was lowered to 0 to 5°C, water was slowly added dropwise to quench, and 1M dilute hydrochloric acid was added dropwise to completely dissolve the solid, extracted with ethyl acetate, washed with saturated sodium bicarbonate aqueous solution and saturated brine once, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by dry column chromatography to obtain compound d;
[0033] S4. Compound d is dissolved in methyl tert-butyl ether, added to a light irradiation reaction vessel, and a catalyst (9-fluorenone-4-carboxylic acid or anthracene or 9-acetylanthracene) is added. The temperature is lowered to -5-5°C, and a 500W high-pressure mercury lamp is turned on for 6 hours of irradiation and maintained at -5-5°C. After the reaction of the raw materials is completed, the reaction solution is concentrated and purified by dry column chromatography to obtain the compound represented by the structure of formula I, i.e., maxacalcitol intermediate B.
[0034] In some specific embodiments, in the S1 step (Scheme 1), the molar ratio of compound a to pyridinium dichromate is 0.5:1 to 1:0.5, more preferably 1:1.0; the mass (g) to volume (ml) ratio of compound a to 70% aqueous tert-butyl peroxide solution is 1:1 to 1:2, more preferably 1:1.6 (i.e., 1 g of compound a corresponds to 1.6 ml of 70% aqueous tert-butyl peroxide solution); the mass (g) ratio of compound a to diatomaceous earth is 2:1 to 1:1, more preferably 1:0.7 (i.e., 1 g of compound a corresponds to 0.7 g of diatomaceous earth).
[0035] In some specific embodiments, in the step S1 (Scheme 2), the molar ratio of compound a to cuprous iodide is 1:0.1 to 1:0.5, more preferably 1:0.2; the mass (g) to volume (ml) ratio of compound a to tert-butyl peroxide decane solution (5M) and acetonitrile is 1:1.5 to 2:8 to 15, more preferably 1:1.9:10.0.
[0036] In some specific embodiments, in the step S1 (Scheme 3), the molar ratio of compound a to selenium dioxide is 1:0.5 to 1:1, more preferably 1:0.8; the molar ratio of compound a to sodium bicarbonate is 1:1.5 to 1:3, more preferably 1:2.5; the molar ratio of compound a to Dess-Martin reagent is 1:1 to 1:1.5, more preferably 1:1.1; the mass (g) to volume (ml) ratio of compound a to dichloromethane is 1:1.5 to 1:3.0, more preferably 1:2.0.
[0037] In some specific embodiments, in the step S2, when the base is sodium hydrogen, the molar ratio of compound b to methyltriphenylphosphonium bromide is 1:1.5-1:2.5, more preferably 1:2.1; the molar ratio of compound b to sodium hydrogen is 1:2.0-1:5.0, more preferably 1:2.6; the mass (g) to volume (ml) ratio of compound b to tetrahydrofuran is 1:15.0-1:25.0, more preferably 1:21.5.
[0038] In some specific embodiments, in the step S2, when the base is tert-butyl potassium, the molar ratio of compound b, methyltriphenylphosphonium bromide and tert-butyl potassium is 1:2.1:2.5, the molar ratio of compound b and methyltriphenylphosphonium bromide is 1:1.5-1:2.5, and more preferably 1:2.1; the molar ratio of compound b and potassium tert-butoxide is 1:2.0-1:3.0, and more preferably 1:2.5; the mass (g) to volume (ml) ratio of compound b to tetrahydrofuran is 1:15.0-1:25.0, and more preferably 1:21.5.
[0039] In some specific embodiments, in the step S3, the mass (g) to volume (ml) ratio of compound c and diisobutylaluminum hydride n-hexane solution is 1:4.0 to 1:7.0, more preferably 1:5.0; the mass (g) to volume (ml) ratio of compound c and n-hexane is 1:8.0 to 1:15.0, more preferably 1:10.0.
[0040] In some specific embodiments, in the step S4, the molar ratio of compound d to the catalyst (9-fluorenone-4-carboxylic acid or anthracene or 9-acetylanthracene) is 1:0.5 to 1:0.2, more preferably 1:0.1, and the mass (g) to volume (ml) ratio of compound d to methyl tert-butyl ether is 1:50 to 1:100, more preferably 1:80.
[0041] The above compounds are used as reference substances or standard substances in the quality control of the intermediate B compound of maxacalcitol.
[0042] Compared with the prior art, the present invention has the following beneficial effects:
[0043] The present invention discloses for the first time a method for preparing the compound, which is a new synthetic route with relatively mild reaction conditions, simple operation, low requirements on equipment, and the ability to obtain the maxacalcitol intermediate B with high selectivity, thus having broad application prospects.
[0044] The conception of the present invention and the technical effects produced will be further described below to fully understand the purpose, characteristics and effects of the present invention. DETAILED DESCRIPTION
[0045] In order to make the technical means, creative features, objectives and effects of the invention easier to understand, the invention is further described below. However, the invention is not limited to the following implementation cases.
[0046] It should be noted that the embodiments of this specification are only used to match the contents disclosed in the specification so that people familiar with this technology can understand and read them. They are not used to limit the conditions under which the present invention can be implemented. Therefore, they have no substantive technical significance. Anything that does not involve creative work should still fall within the scope of the technical contents disclosed in the present invention without affecting the effects and purposes that can be achieved by the present invention.
[0047] Example 1
[0048] S1 (Scheme 1): 42.8 g of compound a was dissolved in 800 ml of benzene, 30 g of diatomaceous earth and 29.7 g of pyridinium dichromate were added, the temperature was lowered to 0-5°C, 69 ml of 70% tert-butyl peroxide aqueous solution was added dropwise, and then the temperature was raised to room temperature to react for 24 h; the filtrate was filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 37.3 g of compound b with a yield of 84.3%.
[0049] Example 2
[0050] S1 (Scheme 2): 42.8 g of compound a was dissolved in 430 ml of acetonitrile, and 3.8 g of cuprous iodide was added under inert gas protection. The temperature was lowered to 5-10°C, and 80 ml of 5 M tert-butyl peroxide decane solution was added dropwise. The temperature was then raised to room temperature for reaction for 2 h, and then raised to 50-60°C for reaction for 24 h. After the reaction of the raw materials, the temperature was lowered to room temperature, saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate. The mixture was then washed with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution in turn, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 40.0 g of compound b with a yield of 90.5%.
[0051] Example 3
[0052] S1 (Scheme 3): 8.8 g of selenium dioxide was added to 220 ml of dichloromethane, and then 50 ml of a 5.0 M dichloromethane solution of tert-butyl peroxide was added. The mixture was reacted at room temperature for 1 h, and then the temperature was lowered to 0-5°C. A dichloromethane solution of compound a (42.8 g of compound a / 85 ml of dichloromethane) was added dropwise. After the addition, the mixture was heated to room temperature and reacted for 10 h. After the reaction of the raw materials was completed, 21 g of sodium bicarbonate and 46.7 g of Dess-Martin reagent were added and the mixture was reacted at room temperature for 3 h. After the intermediate reaction was completed, the mixture was cooled to 0-5°C, 300 ml of a saturated aqueous sodium bicarbonate solution and 300 ml of a 10% aqueous sodium thiosulfate solution were added to quench the mixture, the phases were separated, the mixture was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 38.9 g of compound b with a yield of 88.2%.
[0053] Structural characterization of compound b: 1 H NMR (300MHz, CDCl3) δ: 0.21 (s, 12H), 0.98 (s, 18H), 1.28 (t, J = 11.8Hz, 3H), 1.90-1.92 (m, 1H), 2.05-2.0 9(m,1H),2.40-2.48(m,2H),3.47-3.56(m,1H),4.13-4.18(m,3H),5.08-5.26(m,2H),5.65-5.73(m,1H).
[0054] Example 4
[0055] S2: Under an inert environment, 35.8 g of methyltriphenylphosphonium bromide was dissolved in 440 ml of dry tetrahydrofuran, cooled to 0-5°C, and 5 g of sodium hydrogen (60% content) was added in batches under temperature control to react for 1 h. Then, a solution of 21.4 g of compound b (from Example 1) dissolved in 20 ml of tetrahydrofuran was dripped into the reaction solution under temperature control. After the dripping, the mixture was kept warm for 30 min, and the mixture was heated to room temperature for 3 h. After the reaction of the raw materials was completed, a saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 18.2 g of compound c with a yield of 85.4%.
[0056] Example 5
[0057] S2: Under an inert environment, 35.8 g of methyltriphenylphosphonium bromide was dissolved in 440 ml of dry tetrahydrofuran, cooled to 0-5°C, and 13.6 g of potassium tert-butoxide was added in batches under temperature control to react for 1 h. Then, a solution of 21.4 g of compound b (from Example 2) dissolved in 20 ml of tetrahydrofuran was dripped into the reaction solution under temperature control. After dripping, the solution was kept warm for 30 min, and the temperature was raised to room temperature for reaction for 3 h. After the reaction of the raw materials was completed, a saturated aqueous ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 18.7 g of compound c with a yield of 87.6%.
[0058] Structural characterization of compound c: 1 H-NMR(300MHz, CDCl3)δ:0.06(s,6H),0.07(s,6H),0.87(s,9H),0.91(s,9H),1.21-1.27(m,3H),1.73-1.77(m,1H),1.91-1.98(m,1H),2. 23-2.66(m,1H),3.30-3.39(m,1H),4.04-4.16(m,2H),4.20-4.27(m, 1H),4.50-4.60(m,1H),5.07(s,1H),5.09(s,1H),5.61-5.91(m,1H).
[0059] Example 6
[0060] S3: 35g of compound c (from Examples 4 and 5) was dissolved in 350ml of n-hexane. Under an inert environment, the temperature was lowered to -70 to -60°C, 173.8ml of 1M diisobutylaluminum hydride n-hexane solution was added dropwise, and then the temperature was raised to room temperature for reaction for 2h. After the reaction of the raw materials was completed, the temperature was lowered to 0 to 5°C, 47ml of water was slowly added dropwise to quench, and 1M hydrochloric acid was added dropwise to completely dissolve the solid. The solid was extracted with ethyl acetate, washed with saturated sodium bicarbonate aqueous solution and saturated brine once, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 30.4g of compound d with a yield of 96.0%.
[0061] Structural characterization of compound d: 1 H NMR(300MHz, CDCl3)δ:0.06(s,6H),0.07(s,6H),0.89(s,18H),1.75-1.90(m,2H),2.17-2.27(m,1H),2.3 9-2.41(m,1H),4.16-4.30(m,3H),4.39-4.50(m,1H),4.95(m,1H),4.97-5.17(m,1H),5.53-5.78(m,1H).
[0062] Example 7
[0063] S4: 10g of compound d was dissolved in 800ml of methyl tert-butyl ether, added to a light irradiation reaction container, 0.56g of 9-fluorenone-4-carboxylic acid was added, the temperature was lowered to -5 to 5°C, and a 500W high-pressure mercury lamp was turned on to irradiate the reaction for 6h and maintained at -5 to 5°C. After the raw material reaction was completed, the reaction solution was concentrated to dryness and purified by column chromatography to obtain 9.8g of the product, maxacalcitol intermediate B, with a yield of 98.0%.
[0064] Example 8
[0065] S4: 10g of compound d was dissolved in 800ml of methyl tert-butyl ether, added to a light irradiation reaction container, and 0.45g of anthracene was added. The temperature was lowered to -5-5°C, and a 500W high-pressure mercury lamp was turned on to irradiate for 6h and maintained at -5-5°C. After the raw material reaction was completed, the reaction solution was concentrated to dryness and purified by column chromatography to obtain 9.5g of the product, maxacalcitol intermediate B, with a yield of 95.0%.
[0066] Example 9
[0067] S4: 10g of compound d was dissolved in 800ml of methyl tert-butyl ether, added to a light irradiation reaction container, and 0.55g of 9-acetylanthracene was added. The temperature was lowered to -5 to 5°C, and a 500W high-pressure mercury lamp was turned on to irradiate the reaction for 6h and maintained at -5 to 5°C. After the reaction of the raw materials was completed, the reaction solution was concentrated to dryness and purified by column chromatography to obtain 9.6g of the product, maxacalcitol intermediate B, with a yield of 96.0%.
[0068] Formula I structural characterization: 1 H NMR (300MHz, CDCl3) δ: 0.06 (s, 6H), 0.07 (s, 6H), 0.88 (s, 9H), 0.89 (s, 9H), 1.81-1.84 (m, 2H), 2.17 (dd, J = 8.0, 12.0Hz, 1H), 2.39 (br dd,J=4.0,12.0Hz,1H),4.16-4.21(m,3H),4.39(m,1H),4.76(m,1H),5.17(m,1H),5.53(t,J=8.0Hz,1H).
[0069] The preferred specific embodiments of the present invention are described in detail above. It should be understood that ordinary technicians in the field can make many modifications and changes based on the concept of the present invention without creative work. Therefore, all technical solutions that can be obtained by technicians in the technical field based on the concept of the present invention through logical analysis, reasoning or limited experiments on the basis of the prior art should be within the scope of protection determined by the claims.
Claims
1. A method for preparing a maxacalcitol intermediate B, characterized in that: The method has a structure as shown in Formula I, and includes four steps: S1 step, S2 step, S3 step and S4 step; The step S1 is selected from one of the following three methods: 1) Compound a, pyridinium dichromate, diatomaceous earth, and tert-butyl peroxide aqueous solution are mixed to react to obtain compound b; 2) Compound a, cuprous iodide, tert-butyl peroxide decane solution, and acetonitrile are mixed to react to obtain compound b; 3) Compound a, selenium dioxide, dichloromethane, sodium bicarbonate, and Dess-Martin reagent are mixed to react to obtain compound b; The step S2 is to react compound b, methyltriphenylphosphine bromide, tetrahydrofuran and a base to generate compound c; the base is selected from one or more of sodium hydrogen sulfide and potassium tert-butoxide; The step S3 comprises mixing compound c, diisobutylaluminum hydride n-hexane solution and n-hexane to react to obtain compound d; The step S4 is to mix compound d, methyl tert-butyl ether and a catalyst to react to obtain a compound represented by formula I; the catalyst is selected from one or more of 9-fluorenone-4-carboxylic acid, anthracene and 9-acetylanthracene; The compound of formula I, compound a, compound b, compound c, and compound d are respectively as follows:
2. The preparation method according to claim 1, characterized in that: The step S1 is selected from one of the following three methods: 1) adding pyridinium dichromate and diatomaceous earth to the solution of compound a, cooling to 0-5°C, dripping tert-butyl peroxide aqueous solution, heating to room temperature, and purifying after the reaction to obtain compound b; 2) the solution of compound a is protected by inert gas, adding cuprous iodide, cooling to 5-10°C, dripping tert-butyl peroxide decane solution, heating to room temperature for reaction, and then heating to 50-60°C, and purifying after the reaction to obtain compound b; 3) adding selenium dioxide to dichloromethane, and then adding tert-butyl peroxide dichloromethane solution, reacting at room temperature, cooling to 0-5°C, dripping the dichloromethane solution of compound a, heating to room temperature for continuous reaction, adding sodium bicarbonate and Dess-Martin reagent, and purifying after the reaction to obtain compound b; The step S2 is as follows: in an inert environment, methyl triphenylphosphine bromide is added to tetrahydrofuran, the temperature is lowered to 0-5°C, a base is added in batches under temperature control, a solution of compound b dissolved in tetrahydrofuran is dripped into the reaction solution under temperature control, and after the reaction is completed, the compound c is purified; the base is selected from one or more of sodium hydrogen sulfide and tert-butyl potassium; The step S3 is as follows: Compound c is dissolved in n-hexane, cooled to -70 to -60°C under an inert environment, diisobutylaluminum hydride n-hexane solution is added dropwise, the temperature is raised to room temperature, and after the reaction is completed, the compound d is purified; The step S3 is as follows: compound d is dissolved in methyl tert-butyl ether, added into a light irradiation reaction vessel, a catalyst is added, the temperature is lowered to -5 to 5°C, and after the light irradiation reaction is completed, the intermediate B of maxacalcitol is obtained by purification; the catalyst is selected from one or more of 9-fluorenone-4-carboxylic acid, anthracene, and 9-acetylanthracene.
3. The preparation method according to any one of claims 1 or 2, characterized in that In the step S1, the molar ratio of compound a to pyridinium dichromate is 0.5:1 to 1:0.5; the mass is measured in g and the volume is measured in ml; the mass volume ratio of compound a to 70% tert-butyl peroxide aqueous solution is 1:1 to 1:2; and the mass ratio of compound a to diatomaceous earth is 2:1 to 1:
1.
4. The preparation method according to any one of claims 1 or 2, characterized in that In the step S1, the molar ratio of compound a to cuprous iodide is 1:0.1 to 1:0.5; the mass volume ratio of compound a to tert-butyl peroxide decane solution and acetonitrile is 1:1.5 to 2:8 to 15.
5. The preparation method according to any one of claims 1 or 2, characterized in that: In the step S1, the molar ratio of compound a to selenium dioxide is 1:0.5 to 1:1; the molar ratio of compound a to sodium bicarbonate is 1:1.5 to 1:3; the molar ratio of compound a to Dess-Martin reagent is 1:1 to 1:1.5; the mass is measured in g and the volume is measured in ml, and the mass-to-volume ratio of compound a to dichloromethane is 1:1.5 to 1:3.
0.
6. The preparation method according to any one of claims 1 or 2, characterized in that: In the step S2, the base is sodium hydrogen, the molar ratio of compound b to methyltriphenylphosphonium bromide is 1:1.5 to 1:2.5; the molar ratio of compound b to sodium hydrogen is 1:2 to 1:5; the mass is measured in g and the volume is measured in ml, and the mass-volume ratio of compound b to tetrahydrofuran is 1:15 to 1:
25.
7. The preparation method according to any one of claims 1 or 2, characterized in that: In the step S2, the base is tert-butyl potassium, the molar ratio of compound b to methyltriphenylphosphonium bromide is 1:1.5 to 1:2.5; the molar ratio of compound b to potassium tert-butoxide is 1:2 to 1:3; the mass is measured in g and the volume is measured in ml, and the mass-to-volume ratio of compound b to tetrahydrofuran is 1:15 to 1:
25.
8. The preparation method according to any one of claims 1 or 2, characterized in that: In the step S3, the mass is measured in g and the volume is measured in ml. The mass-to-volume ratio of compound c to diisobutylaluminum hydride n-hexane solution is 1:4 to 1:7; the mass-to-volume ratio of compound c to n-hexane is 1:8 to 1:
15.
9. The preparation method according to any one of claims 1 or 2, characterized in that: In the step S4, the molar ratio of compound d to the catalyst is 1:0.5 to 1:0.2, the mass is measured in g, the volume is measured in ml, and the mass volume ratio of compound d to methyl tert-butyl ether is 1:50 to 1:100; the catalyst is one or more of 9-fluorenone-4-carboxylic acid, anthracene, and 9-acetylanthracene.
10. Use of the compound prepared by the preparation method according to claims 1 to 9 as a reference substance or standard substance in the quality control of the intermediate B compound of maxacalcitol.