A process for the preparation of calcitriol

Abstract

The present application provides a method for preparing calcitriol, which uses a vitamin D compound as a raw material to obtain a skeleton structure of calcitriol through a series of reactions, and then obtains calcitriol by carrying out a Grignard reaction on the skeleton structure and a halide. The method shortens the reaction route by splitting calcitriol into a skeleton structure and a side chain, selecting appropriate raw materials, and introducing a macromolecular protecting group into the raw material, thereby reducing the generation of isomers in the reaction process, effectively improving the yield, and being conducive to the industrialization of calcitriol.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, and more specifically, to a method for preparing calcitriol. Background Technology

[0002] Calcitriol, also known as 1α,25-dihydroxyvitamin D3, is a natural, fat-soluble hormone-like substance and the main active metabolite of vitamin D3. It is formed by the two-step hydroxylation of vitamin D3 in the liver and kidneys, and exerts its effects by binding to the 1α,25-dihydroxyvitamin D3 receptor (VDR). While a healthy body can convert ordinary vitamin D3 into active vitamin D3, individuals with impaired organ function require additional active D3 to ensure normal calcium and phosphorus metabolism. In addition to its classic calcium and phosphorus regulatory role, calcitriol also inhibits cell growth, induces cell differentiation, promotes tumor cell apoptosis, controls hormone levels, and regulates the immune system. Calcitriol and its analogues are commonly used to treat cancer, secondary hyperthyroidism, rickets, psoriasis, rheumatoid arthritis, osteoporosis, diabetes, and AIDS, and can improve the survival rate of dialysis patients.

[0003] Calcitriol is obtained through total synthesis and semi-synthesis. Total synthesis typically involves retrosynthetic analysis to break down the calcitriol molecule into two simpler fragments. The challenge of this method lies in synthesizing these two key fragments, which contain multiple chiral centers. The synthetic route is long and cumbersome, with difficult chiral control and very low yields. Although many studies have reported attempts, most suffer from complex processes, limited raw material sources, environmental unfriendliness, and safety risks, making industrialization virtually impossible. Currently, semi-synthetic methods mainly fall into two categories: one uses compounds with a vitamin D2 core or similar structures as starting materials, introducing an α-hydroxyl group into its A ring and modifying the side chain structure to obtain the target product. This method faces problems such as expensive raw materials and low overall yield. The other uses cholesterol-like structures as starting materials, introducing an α-hydroxyl group into the A ring and constructing a 5,7 double bond in the B ring, followed by a photochemical reaction to obtain the target product. However, photochemical reactions inevitably suffer from drawbacks such as high energy consumption, low conversion rate, poor selectivity, and difficult separation.

[0004] In the synthesis of calcitriol, semi-synthetic methods are obviously more valuable than total synthetic methods. The methods for introducing α-hydroxyl groups are similar, but the difficulty lies in finding suitable starting materials, shortening the synthetic route, and improving the yield. Summary of the Invention

[0005] Based on the above-mentioned technical problems existing in the prior art, the present invention provides a method for preparing calcitriol. The method involves splitting calcitriol into two intermediate fragments, which are obtained by using vitamin D intermediates as raw materials and then thermally isomerizing them through a broadening reaction. By optimizing and screening the photochemical substrate, high selectivity and conversion rate are obtained, and separation is also easier. After introducing an α-hydroxyl group at the 2-position through A-ring modification, calcitriol is obtained by introducing a side chain.

[0006] Specifically, the technical solution of the present invention is as follows:

[0007] A method for preparing calcitriol includes the following steps:

[0008] S1. Compound 1 is subjected to photochemical reaction and thermal isomerization reaction sequentially to obtain compound 2; the structural formula of compound 1 is: The structural formula of compound 2 is: Where R1 = Ts, R2 is H, One of TBS, TMS, and TES; the photochemical reaction conditions are: ultraviolet light wavelength 295-325nm; power 500-1000W;

[0009] S2. Compound 2 is mixed with dichloromethane and pyridine, and then 4-dimethylpyridine and toluenesulfonyl chloride are added at 0-5°C to react and obtain compound 3. The structural formula of compound 3 is:

[0010] S3. Dissolve compound 3 in dichloromethane, add an alcohol solvent and sodium bicarbonate to react and obtain compound 4. The structural formula of compound 4 is: Wherein, R represents methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl;

[0011] S4. Mix compound 4, selenium dioxide, dichloromethane, and pyridine, cool to 0-5°C, and add tert-butanol peroxide dropwise to react and obtain compound 5. The structural formula of compound 5 is:

[0012] S5. Dissolve compound 5 in ethyl acetate, add acetic acid, and react at room temperature to obtain compound 6. The structural formula of compound 6 is:

[0013] S6. Magnesium shavings and THF are mixed and heated. Then, compound 7 is added. The reaction system is then cooled to below -10°C. A mixture of copper chloride and lithium chloride is added, and the reaction proceeds. Compound 6 is then added, and the reaction is carried out at 0–5°C. After the reaction is complete, saturated ammonium chloride is added dropwise to quench the reaction, yielding calcitriol. The structural formula of compound 7 is [insert structural formula here]. Among them, X = one of Cl, Br, and I, and R3 is one of TBS, TMS, and TES.

[0014] In some implementations, step S1 specifically includes:

[0015] Photochemical reaction: Compound 1 is dissolved in an organic solvent to obtain a solution of Compound 1; the solution of Compound 1 is added to a photochemical reactor, and a photochemical reaction is carried out under ultraviolet light irradiation conditions of 295-325 nm wavelength and 500-1000 W power. The photochemical reaction solution is collected, concentrated, cooled and crystallized, and the solid and liquid are separated to collect the first filtrate; the first filtrate is then concentrated and cooled and crystallized to collect the second filtrate.

[0016] Thermal isomerization reaction: The second filtrate is concentrated to dryness and kept at a vacuum of -0.08 to -0.095 MPa and 60 to 80°C to carry out a thermal isomerization reaction to obtain a photochemical oil containing compound 2. The oil is then separated to obtain compound 2.

[0017] In some embodiments, in step S1, the photochemical reaction solution is concentrated under reduced pressure at a temperature below 30°C to 1 / 3 to 1 / 2 of its volume, kept at a temperature below -15°C, and then subjected to solid-liquid separation to obtain a first filtrate; the first filtrate is further concentrated to 1 / 20 to 1 / 15 of its volume, kept at a temperature below -15°C, and then subjected to solid-liquid separation again to obtain a second filtrate.

[0018] In some embodiments, after the thermal isomerization reaction, step S1 further includes a step of separation by crystallization, specifically: adding acetone to the photochemical oil, dissolving it at 50-60°C, adding water, stirring, cooling to room temperature at a rate of 0.3-0.5°C / min, and a solid precipitates out; then further cooling to -10°C and holding at that temperature to obtain the crystals of compound 2.

[0019] In some embodiments, the organic solvent is a mixture of ethyl acetate and methanol in a volume ratio of 1:1.

[0020] In some embodiments, in step S2, compound 2 and dichloromethane are mixed, pyridine is added under stirring, the temperature is controlled at 0-5°C, 4-dimethylaminopyridine is added, followed by toluenesulfonyl chloride to react. After the reaction is completed, the mixture is washed successively with water, sulfuric acid, and saturated sodium bicarbonate, concentrated under reduced pressure, replaced with ethyl acetate, cooled to crystallize, filtered, and dried to obtain compound 3.

[0021] In some embodiments, the first solvent is acetone.

[0022] In some embodiments, in step S3, compound 3 is dissolved in dichloromethane, and then an alcohol solvent and sodium bicarbonate are added to react. After the reaction is complete, the mixture is filtered, the filter cake is washed with dichloromethane, the organic phases are combined, washed with water, replaced with n-heptane, cooled to crystallize, filtered, and dried to obtain compound 4.

[0023] In some embodiments, in step S3, the alcohol solvent is one of methanol, ethanol, propanol, isopropanol, butanol, and tert-butanol, wherein the R group corresponds to the alkyl group of the alcohol solvent. Specifically, when R is methyl, the alcohol solvent is methanol; when R is ethyl, the alcohol solvent is ethanol; when R is propyl, the alcohol solvent is propanol; when R is isopropyl, the alcohol solvent is isopropanol, and so on.

[0024] In some embodiments, in step S4, compound 4, selenium dioxide, dichloromethane and pyridine are mixed, cooled to 0-5°C, and peroxytert-butanol is added to carry out the reaction; then water is added to the reaction solution and the mixture is separated, the organic phase is washed sequentially with saturated sodium bicarbonate and saturated sodium chloride, dried and concentrated, and the PE:EA ratio is 3-10:1 and separated by column chromatography to obtain compound 5.

[0025] In some embodiments, in step S5, after the reaction is complete, saturated sodium bicarbonate is added to adjust the pH of the system to 7, the organic phases are extracted with ethyl acetate and combined, the organic phases are washed with saturated sodium chloride, separated, dried with anhydrous sodium sulfate, and the ethyl acetate is distilled off to obtain compound 6.

[0026] In some embodiments, in step S6, magnesium shavings and THF are mixed and heated to 55-60°C. Then, compound 7 is added dropwise. After the magnesium shavings have reacted completely, the reaction system is cooled to below -10°C, the mixture is added dropwise, and then compound 6 is added. The reaction is carried out at 0-5°C. After the reaction is complete, the temperature is lowered to below -10°C, and saturated ammonium chloride is added dropwise to quench the reaction. The mixture is separated, tetrabutylammonium chloride is added to the organic phase, and the mixture is heated to 60°C to carry out the reaction. After the reaction is complete, the mixture is cooled, concentrated to dryness, and purified by silica gel column chromatography to obtain calcitriol.

[0027] In some embodiments, during step S6, the silica gel is 200-300 mesh, and the eluent is PE:EA = 1-2:1; DCM:MeOH = 20:1.

[0028] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0029] This invention prepares calcitriol by separating it into a skeletal structure and side chains. The skeletal structure of calcitriol is obtained by reacting an intermediate with a vitamin D-like structure through a specific preparation route. Finally, the side chains are connected to the skeletal structure by reacting with a halogenated product.

[0030] The method of this invention shortens the synthetic route of calcitriol, enabling its industrialization. Furthermore, the inventors discovered during experiments that the protective group with a large molecular structure—p-benzenesulfonyl—can reduce the formation of isomers during the reaction. Therefore, when selecting raw materials, compound 1 with the p-benzenesulfonyl protecting group is used as the raw material for photochemical reaction, followed by thermal isomerization and subsequent reactions, effectively improving the product yield. Detailed Implementation

[0031] Numerous specific details are set forth in the following description to provide a full understanding of the invention. However, the invention can be practiced in many other ways different from those described herein, and similar modifications can be made by those skilled in the art without departing from the spirit of the invention. Therefore, the invention is not limited to the specific embodiments disclosed below.

[0032] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the description of the invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0033] Example 1

[0034] The method for preparing calcitriol provided by this invention has the following reaction route:

[0035]

[0036] The specific process flow is as follows:

[0037] (1) Preparation of compound 2

[0038] Photochemical reaction: 300g of compound 1 was dissolved at a concentration of 3wt% in a solvent obtained by mixing 6L of ethyl acetate and 6L of methanol to obtain a solution of compound 1. The condenser, nitrogen, and high-pressure mercury lamp of the photochemical reactor were turned on. The high-pressure mercury lamp had a power of 500W and an ultraviolet wavelength of 295-325nm. The solution of compound 1 was added at a rate of 40mL / min at room temperature to carry out the photochemical reaction. The photochemical reaction solution was collected. The conversion rate was detected by HPLC to be about 80%. The solution was concentrated under reduced pressure below 30℃ to 1 / 3 of the total volume of the photochemical reaction solution. It was kept at -15℃ for 4h, filtered, and dried under reduced pressure to obtain the raw material compound 1 and the first filtrate. The mass of compound 1 was 45g. The first filtrate was further concentrated to 1 / 20 of the total volume of the first filtrate. It was kept at -15℃ for 6h, filtered, and dried under reduced pressure to obtain compound 1 and the second filtrate. The mass of compound 1 was 10g.

[0039] Thermal isomerization reaction: The second filtrate was concentrated to dryness and kept at a vacuum of -0.08 to -0.095 MPa and 60 to 80 °C for 2 hours to carry out thermal isomerization reaction, and a photochemical oil containing compound 2 was obtained. The mass of the photochemical oil was 245 g.

[0040] Crystallization: Add 6 times the volume of acetone (1440 mL) to the photochemical oil, heat to 50 °C and stir to dissolve, add 1 volume of pure water (240 mL) dropwise, stir evenly, and slowly cool to room temperature at a rate of 0.3 °C / min. A solid precipitates out, which is the crystal of compound 2. Further cool to -10 °C at a rate of 0.3 °C / min, keep warm for 4 h, filter, and obtain 210 g of compound 2 crystals.

[0041] (2) Preparation of compound 3

[0042] 30g of compound 2 and 200mL of dichloromethane were added to a reaction flask. While stirring, 6g of pyridine was added, and the temperature of the reaction system was controlled at 0-5℃. 1.5g of 4-dimethylaminopyridine was added and stirred until completely dissolved. Then, 13g of toluenesulfonyl chloride was added. The reaction was monitored by TLC (PE:EA = 10:1) until the reaction was complete. The mixture was washed successively with water, 0.5mol / L sulfuric acid, and saturated sodium bicarbonate, dried, concentrated under reduced pressure, and replaced with ethyl acetate to obtain a thick concentrate. The concentrate was then cooled to 0-5℃ to crystallize, filtered, and dried to obtain 37g of compound 3 solid.

[0043] (3) Preparation of compound 4

[0044] 20g of compound 4 was dissolved in 200mL of dichloromethane, then 100mL of methanol and 26g of sodium bicarbonate were added, and the mixture was heated to 50℃ to react. The reaction was monitored by TLC (PE:EA = 10:1). After the reaction was completed, the mixture was filtered, and the filter cake was washed with a small amount of dichloromethane. The organic phases were combined, washed with water, dried, concentrated under reduced pressure, and replaced with n-heptane to form a viscous substance. The mixture was cooled to crystallize, filtered, and dried to obtain 14g of solid compound 4.

[0045] (4) Preparation of compound 5

[0046] 0.9 g selenium dioxide, 80 mL dichloromethane, 1.6 g pyridine, and 10 g compound 5 were added to a reaction flask. The mixture was cooled to 0–5 °C, and 3.6 g peroxytert-butanol was added dropwise. The mixture was stirred and monitored by TLC until the reactants were 1 hour old. Water was then added to the reaction system, and the mixture was stirred and separated. The organic phase was washed successively with saturated sodium bicarbonate and saturated sodium chloride, dried, concentrated under reduced pressure, and purified by silica gel column chromatography (PC:EA = 10:1) to obtain 4 g of compound 5, with a yield of 40%.

[0047] (5) Preparation of compound 6

[0048] 4 g of compound 5 was dissolved in 20 mL of ethyl acetate, and then 8 mL of acetic acid was added. After reacting at room temperature for 24 h, stirring was stopped, and saturated sodium bicarbonate was added to adjust the pH of the system to 7. The organic phases were extracted twice with ethyl acetate and then combined. The organic phases were washed with saturated sodium chloride, separated, dried with anhydrous sodium sulfate, and then ethyl acetate was distilled under reduced pressure until no liquid distilled off, yielding 4 g of compound 6 solid.

[0049] (6) Preparation of calcitriol

[0050] 2g of magnesium shavings and 60mL of THF were added to a reaction flask and heated to 55℃. 16.4g of compound 7 was added dropwise. After the magnesium shavings reacted completely, the reaction system was cooled to -10℃, and 15mL of a mixture of 0.4g / mL copper chloride solution and 0.4g / mL lithium chloride solution was added dropwise. After the addition was complete, the reaction was allowed to proceed for 10min. Then, 4g of compound 6 was added, and the system temperature was maintained at 0-5℃. The reaction was monitored by TLC. After the reaction was complete, the temperature was lowered to -10℃, and 5mL of saturated ammonium chloride was added dropwise to quench the reaction. The mixture was separated. 1g of tetrabutylammonium chloride was added to the organic phase, and the mixture was heated to 60℃. The reaction was monitored by TLC. After the reaction was complete, the mixture was cooled to room temperature, concentrated to dryness under reduced pressure, and purified by silica gel column chromatography (silica gel: 200-300 mesh, eluent: PE:EA = 2.1, DCM:MeOH = 20:1) to obtain 2.4g of calcitriol.

[0051] Comparative Example 1

[0052] The difference between this comparative example and Example 1 is that the structural formula of the starting material compound 1a is:

[0053]

[0054] The preparation of compound 2a is as follows:

[0055] Photochemical reaction: 300g of compound 1 was dissolved at a concentration of 3wt% in a solvent obtained by mixing 6L of ethyl acetate and 6L of methanol to obtain a solution of compound 1. The condenser, nitrogen, and high-pressure mercury lamp of the photochemical reactor were turned on. The high-pressure mercury lamp had a power of 500W and an ultraviolet wavelength of 295-325nm. The solution of compound 1 was added at a rate of 40mL / min at room temperature to carry out the photochemical reaction. The photochemical reaction solution was collected. The conversion rate was detected by HPLC to be about 60%. The solution was concentrated under reduced pressure below 30℃ to 1 / 3 of the total volume of the photochemical reaction solution. It was kept at -15℃ for 4h, filtered, and dried under reduced pressure to obtain the raw material compound 1 and the first filtrate. The mass of compound 1 was 30g. The first filtrate was further concentrated to 1 / 20 of the total volume of the first filtrate. It was kept at -15℃ for 6h, filtered, and dried under reduced pressure to obtain compound 1 and the second filtrate. The mass of compound 1 was 20g.

[0056] Thermal isomerization reaction: The second filtrate was concentrated to dryness and kept at a vacuum of -0.08 to -0.095 MPa and 60 to 80°C for 2 hours to carry out thermal isomerization reaction, and a photochemical oil containing compound 2 was obtained. The mass of the photochemical oil was 250 g.

[0057] Crystallization: Add 6 times the volume of acetone (1440 mL) to the photochemical oil, heat to 50 °C and stir to dissolve, add 1 volume of pure water (240 mL) dropwise, stir evenly, and slowly cool to room temperature at a rate of 0.3 °C / min. A solid precipitates out, which is the crystal of compound 2. Further cool to -10 °C at a rate of 0.3 °C / min, keep warm for 4 h, filter, and obtain 100 g of compound 2 crystals.

[0058] Comparative Example 2

[0059] The difference between this comparative example and Comparative Example 1 is that in the structural formula of the starting material compound 1b, R1 = Ac;

[0060] The preparation of compound 2b is as follows:

[0061] Photochemical reaction: 300g of compound 1 was dissolved at a concentration of 3wt% in a solvent obtained by mixing 6L of ethyl acetate and 6L of methanol to obtain a solution of compound 1. The condenser, nitrogen, and high-pressure mercury lamp of the photochemical reactor were turned on. The high-pressure mercury lamp had a power of 500W and an ultraviolet wavelength of 295-325nm. The solution of compound 1 was added at a rate of 40mL / min at room temperature to carry out the photochemical reaction. The photochemical reaction solution was collected. The conversion rate was detected by HPLC to be about 50%. The solution was concentrated under reduced pressure below 30℃ to 1 / 3 of the total volume of the photochemical reaction solution. It was kept at -15℃ for 4h, filtered, and dried under reduced pressure to obtain the raw material compound 1 and the first filtrate. The mass of compound 1 was 50g. The first filtrate was further concentrated to 1 / 20 of the total volume of the first filtrate. It was kept at -15℃ for 6h, filtered, and dried under reduced pressure to obtain compound 1 and the second filtrate. The mass of compound 1 was 20g.

[0062] Thermal isomerization reaction: The second filtrate was concentrated to dryness and kept at a vacuum of -0.08 to -0.095 MPa and 60 to 80°C for 2 hours to carry out thermal isomerization reaction, and a photochemical oil containing compound 2 was obtained. The mass of the photochemical oil was 230 g.

[0063] Crystallization: Add 6 times the volume of acetone (1440 mL) to the photochemical oil, heat to 50 °C and stir to dissolve, add 1 volume of pure water (240 mL) dropwise, stir evenly, and slowly cool to room temperature at a rate of 0.3 °C / min. A solid precipitates out, which is the crystal of compound 2. Further cool to -10 °C at a rate of 0.3 °C / min, keep warm for 4 h, filter, and obtain 70 g of compound 2 crystals.

[0064] Comparative Example 3

[0065] The difference between this comparative example and Comparative Example 1 is that in the structural formula of the starting material compound 1b, OR1 = Br, and the preparation of compound 2 is as follows:

[0066] Photochemical reaction: 300g of compound 1 was dissolved at a concentration of 3wt% in a solvent obtained by mixing 6L of ethyl acetate and 6L of methanol to obtain a solution of compound 1. The condenser, nitrogen, and high-pressure mercury lamp of the photochemical reactor were turned on. The high-pressure mercury lamp had a power of 500W and an ultraviolet wavelength of 295-325nm. The solution of compound 1 was added at a rate of 40mL / min at room temperature to carry out the photochemical reaction. The photochemical reaction solution was collected. The conversion rate was detected by HPLC to be about 40%. The solution was concentrated under reduced pressure below 30℃ to 1 / 3 of the total volume of the photochemical reaction solution. It was kept at -15℃ for 4h, filtered, and dried under reduced pressure to obtain the raw material compound 1 and the first filtrate. The mass of compound 1 was 40g. The first filtrate was further concentrated to 1 / 20 of the total volume of the first filtrate. It was kept at -15℃ for 6h, filtered, and dried under reduced pressure to obtain compound 1 and the second filtrate. The mass of compound 1 was 7g.

[0067] Thermal isomerization reaction: The second filtrate was concentrated to dryness and kept at a vacuum of -0.08 to -0.095 MPa and 60 to 80 °C for 2 hours to carry out thermal isomerization reaction, and a photochemical oil containing compound 2 was obtained. The mass of the photochemical oil was 253 g.

[0068] Crystallization: Add 6 times the volume of acetone (1440 mL) to the photochemical oil, heat to 50 °C and stir to dissolve, add 1 volume of pure water (240 mL) dropwise, stir evenly, and slowly cool to room temperature at a rate of 0.3 °C / min. No solid precipitates. Further cool to -10 °C at a rate of 0.3 °C / min and keep warm for 4 hours. No solid precipitates, indicating that crystallization is difficult.

[0069] Comparative Example 4

[0070] The difference between this embodiment and Example 1 is that in the structural formula of starting material compound 1d, R1 = Ts and R2 = Ac; the preparation of compound 2d is as follows:

[0071] Photochemical reaction: 300g of compound 1 was dissolved at a concentration of 3wt% in a solvent obtained by mixing 6L of ethyl acetate and 6L of methanol to obtain a solution of compound 1. The condenser, nitrogen, and high-pressure mercury lamp of the photochemical reactor were turned on. The high-pressure mercury lamp had a power of 500W and an ultraviolet wavelength of 295-325nm. The solution of compound 1 was added at a rate of 40mL / min at room temperature to carry out the photochemical reaction. The photochemical reaction solution was collected. The conversion rate was detected by HPLC to be about 80%. The solution was concentrated under reduced pressure below 30℃ to 1 / 3 of the total volume of the photochemical reaction solution. It was kept at -15℃ for 4h, filtered, and dried under reduced pressure to obtain the raw material compound 1 and the first filtrate. The mass of compound 1 was 40g. The first filtrate was further concentrated to 1 / 20 of the total volume of the first filtrate. It was kept at -15℃ for 6h, filtered, and dried under reduced pressure to obtain compound 1 and the second filtrate. The mass of compound 1 was 5g.

[0072] Thermal isomerization reaction: The second filtrate was concentrated to dryness and kept at a vacuum of -0.08 to -0.095 MPa and 60 to 80 °C for 2 hours to carry out thermal isomerization reaction, and a photochemical oil containing compound 2d was obtained. The mass of the photochemical oil was 255 g.

[0073] Crystallization: Add 6 times the volume of acetone (1440 mL) to the photochemical oil, heat to 50 °C and stir to dissolve, add 1 volume of pure water (240 mL) dropwise, stir evenly, and slowly cool to room temperature at a rate of 0.3 °C / min. A solid precipitates out, which is the crystal of compound 2. Further cool to -10 °C at a rate of 0.3 °C / min, keep warm for 4 h, filter, and obtain 170 g of compound 2 crystals.

[0074] Examples 2-4

[0075] The difference between Examples 2-4 and Example 1 is that the alcohol solvent added during the preparation of compound 4 is different, while the preparation process and other conditions are the same. The types of solvents added in each example, the R structure in the obtained compound 4, the yield of different compounds 4 in the preparation of compound 5, and the final mass of calcitriol are shown in Table 1 below:

[0076] Table 1

[0077]

[0078]

[0079] In summary, the preparation method of the present invention shortens the synthetic route and effectively improves the product yield by selecting the R1 group in the raw material and the R group in the intermediate compound 4.

[0080] The technical features of the above embodiments can be combined in any way. For the sake of brevity, 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, they should be considered to be within the scope of this specification.

[0081] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

Claims

1. A process for the preparation of calcitriol, characterized in that, Includes the following steps: S1. Compound 1 is subjected to photochemical reaction and thermal isomerization reaction sequentially to obtain compound 2; the structural formula of compound 1 is: The structural formula of compound 2 is: Where R1=Ts, R2 is H, One of them; the photochemical reaction conditions are: ultraviolet light wavelength 295~325nm; power 500~1000W; S2. Compound 2 is mixed with dichloromethane and pyridine, and then 4-dimethylpyridine and toluenesulfonyl chloride are added at 0~5°C to react and obtain compound 3. The structural formula of compound 3 is: ; S3. Dissolve compound 3 in dichloromethane, add an alcohol solvent and sodium bicarbonate to react and obtain compound 4. The structural formula of compound 4 is: Wherein, R is methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl; S4. Compound 4, selenium dioxide, dichloromethane, and pyridine are mixed, cooled to 0-5°C, and peroxytert-butanol is added dropwise to react and obtain compound 5. The structural formula of compound 5 is: ; S5. Dissolve compound 5 in ethyl acetate, add acetic acid, and react at room temperature to obtain compound 6. The structural formula of compound 6 is: ; S6. Mix magnesium shavings and THF, heat, then add compound 7 to react. Next, cool the reaction system to below -10°C, then add a mixture of copper chloride and lithium chloride to react. Add compound 6 again and react at 0-5°C. After the reaction is complete, quench the reaction with saturated ammonium chloride dropwise to obtain calcitriol. The structural formula of compound 7 is [insert structural formula here]. Among them, X = one of Cl, Br, and I, and R3 is one of TBS, TMS, and TES.

2. The method for preparing calcitriol according to claim 1, characterized in that, In step S1, specifically: Photochemical reaction: Dissolve compound 1 in an organic solvent to obtain a solution of compound 1; subject the solution of compound 1 to a photochemical reaction under ultraviolet light with a wavelength of 295~325nm and a power of 500~1000W, and collect the photochemical reaction solution; The photochemical reaction solution was concentrated and cooled to crystallize, followed by solid-liquid separation, and the first filtrate was collected. The first filtrate is then concentrated and cooled to crystallize, and the second filtrate is collected. Thermal isomerization reaction: The second filtrate is concentrated to dryness and kept at a vacuum of -0.08 to -0.095 MPa and 60 to 80°C to carry out a thermal isomerization reaction to obtain a photochemical oil containing compound 2. The oil is then separated to obtain compound 2.

3. The method for preparing calcitriol according to claim 2, characterized in that, In step S1, after the thermal isomerization reaction, a step of separation by crystallization is also included, specifically: a first solvent is added to the photochemical oil, dissolved at 50~60℃, then water is added, stirred, and cooled to room temperature at a rate of 0.3~0.5℃ / min, resulting in solid precipitation; then further cooled to below -10℃ and kept at that temperature to obtain the crystals of compound 2.

4. The method for preparing calcitriol according to claim 1, characterized in that, In step S2, compound 2 and dichloromethane are mixed, pyridine is added under stirring, the temperature is controlled at 0~5℃, 4-dimethylaminopyridine is added, followed by toluenesulfonyl chloride to react. After the reaction is completed, the mixture is washed successively with water, sulfuric acid, and saturated sodium bicarbonate, concentrated under reduced pressure, replaced with ethyl acetate, cooled to crystallize, filtered, and dried to obtain compound 3.

5. The method for preparing calcitriol according to claim 1, characterized in that, In step S3, compound 3 is dissolved in dichloromethane, and then an alcohol solvent and sodium bicarbonate are added to react. After the reaction is complete, the mixture is filtered, the filter cake is washed with dichloromethane, the organic phases are combined, washed with water, dried, concentrated, replaced with n-heptane, cooled to crystallize, filtered, and dried to obtain compound 4.

6. The method for preparing calcitriol according to claim 1, characterized in that, In step S4, compound 4, selenium dioxide, dichloromethane and pyridine are mixed, cooled to 0~5℃, and peroxytert-butanol is added to carry out the reaction; then water is added to the reaction solution and the mixture is separated. The organic phase is washed with saturated sodium bicarbonate and saturated sodium chloride in sequence, dried and concentrated. The PE:EA ratio is 3~10:1 and the compound 5 is obtained by column chromatography.

7. The method for preparing calcitriol according to claim 1, characterized in that, In step S5, after the reaction is complete, saturated sodium bicarbonate is added to adjust the pH of the system to 7. The organic phases are extracted with ethyl acetate and combined. The organic phases are washed with saturated sodium chloride, separated, dried with anhydrous sodium sulfate, and then distilled off with ethyl acetate to obtain compound 6.

8. The method for preparing calcitriol according to claim 1, characterized in that, In step S6, magnesium shavings and THF are mixed and heated to 55-60°C. Then, compound 7 is added dropwise. After the magnesium shavings have reacted completely, the reaction system is cooled to below -10°C, and the mixture is added dropwise to carry out the reaction. Then, compound 6 is added, and the reaction is carried out at 0-5°C. After the reaction is complete, the temperature is lowered to below -10°C, and saturated ammonium chloride is added dropwise to quench the reaction. The mixture is separated, and tetrabutylammonium chloride is added to the organic phase. The mixture is then heated to 60°C to carry out the reaction. After the reaction is complete, the mixture is cooled, concentrated to dryness, and purified by silica gel column chromatography to obtain calcitriol.

9. The method for preparing calcitriol according to claim 8, characterized in that, In step S6, during the silica gel column chromatography purification process, the silica gel is 200-300 mesh, and the eluent ratios are PE:EA = 1-2:1 and DCM:MeOH = 20:1.

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