A method for preparing fluorocalciferol

Abstract

This invention discloses a novel method for preparing fluorocalciferol, belonging to the field of pharmaceutical chemical synthesis. Compound 1 undergoes a 10-step reaction involving hydroxyl protection, double bond configuration inversion, C1-position oxidation, hydroxyl protection, double bond protection, ozonolysis, double bond deprotection, reduction, and iodination to yield compound 11. Compound 11 is then coupled with compound 12 via a coupling reaction to obtain a key intermediate 13, which is subsequently subjected to photo-induced configuration inversion and deprotection to obtain fluorocalciferol. This invention's method for preparing fluorocalciferol features high yield, a green and safe reaction process, avoids the use of toxic reagents, and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemical synthesis, and specifically relates to a method for preparing fluorocalciferol. Background Technology

[0002] Falecalcitriol, chemical name: 1α,3β,5Z,7E)-26,26,26,27,27,27-hexafluoro-9,10-open-cholest-5,7,10,(19)-trien-1,3,25-triol, also known as fluorocalcitriol, has the following structural formula:

[0003]

[0004] Flucalcidol is a novel third-generation active VDR agonist jointly developed by Sumitomo Pharmaceutical Co., Ltd. and Taisho Pharmaceutical Co., Ltd. Flucalcidol is an analogue of calcitriol, but it has a longer retention time in the body, requires a lower dosage, is less likely to cause hypercalcemia, and exhibits stronger biological activity than calcitriol. This drug can be used to treat secondary hyperparathyroidism and osteoporosis, among other calcium dysregulation disorders.

[0005] There are currently three main synthetic routes for fluorocalciferol:

[0006] One method uses cholesterol-like substances as starting materials, involves multiple reaction steps, and finally obtains the target compound through light inversion, as reported in US Patent 4248791A. The synthetic route is as follows:

[0007]

[0008] Such methods use expensive and difficult-to-obtain starting materials, and have low yields, with multi-step reactions yielding only around 20%. Multi-step reactions also use hazardous reagents such as n-butyllithium and potassium, and there are many impurities for which there are no effective purification methods, making them unsuitable for industrial production.

[0009] The second method involves synthesizing fluorocalciferol from vitamin D2 through multiple steps, such as the method disclosed in patent US6080879A, whose synthetic route is as follows:

[0010]

[0011] Starting with vitamin D2 derivatives, the reaction involves oxidation, reduction, ring-opening and inversion operations, and uses highly toxic reagents such as selenium dioxide and hexafluoroacetone. Fluorocalol is obtained through 12 steps, with a low yield and an overall yield of only 3.96%, making it unsuitable for industrial production.

[0012] Thirdly, using the CD ring derived from VD2 as the starting material, fluorocalciferol is obtained through multiple reaction steps, such as the preparation method of fluorocalciferol disclosed in patent CN112047820A, whose synthetic route is as follows:

[0013]

[0014] The tertiary hydroxyl group on the side chain of this fluorocalciferol CD-ring intermediate is protected with methoxymethyl ether (MOM), requiring the use of the highly toxic reagent chloromethyl methyl ether (MOMCl). The deprotection reaction also requires the use of the highly toxic methanesulfonic acid reagent. Therefore, this fluorocalciferol CD-ring intermediate is unsuitable as a raw material for the preparation of fluorocalciferol via a convergent synthetic route. Summary of the Invention

[0015] The purpose of this invention is to provide a method for preparing fluorocalciferol, in order to solve the problems of the existing technology, such as complicated synthetic routes, expensive starting materials, a large number of hazardous reagents, high risk, low yield of multi-step reaction, high production cost, and unsuitability for large-scale production.

[0016] The technical solution to achieve the above-mentioned objective is:

[0017] This invention provides a method for preparing fluorocalciferol, characterized by comprising the following steps:

[0018]

[0019] Step (1): Compound 1 is dissolved in organic solvent one and reacts with a silicon-based protecting group under the action of an alkali to obtain compound 2; the organic solvent one is one or more of tetrahydrofuran, dichloromethane, methanol, acetonitrile, 1,4-dioxane, and toluene, preferably dichloromethane;

[0020] Step (2): Dissolve compound 2 obtained in step one in organic solvent two, and react with sulfur dioxide to protect the double bond to obtain compound 3; the organic solvent two is one or more of tetrahydrofuran, dichloromethane, n-hexane, tert-butylmethylimidazolium, 1,4-dioxane, preferably dichloromethane; the molar ratio of compound 2 to sulfur dioxide is 1:10-20;

[0021] Step (3): Dissolve compound 3 obtained in step 2 in organic solvent 3, and react with base to remove double bond protection to obtain compound 4; the organic solvent 3 is one or more of methanol, ethanol, acetone, water, tetrahydrofuran, and diphenyl ether, preferably ethanol;

[0022] Step (4): Dissolve compound 4 obtained in step 3 in organic solvent 4, and oxidize it with an oxidizing agent to obtain compound 5; the organic solvent 4 is one or more of dichloromethane, methanol, acetonitrile, diethyl ether, and tetrahydrofuran, preferably acetonitrile and dichloromethane;

[0023] Step (5): Dissolve compound 5 obtained in step four in organic solvent five, and react with silicon-based protecting groups under the action of alkali to obtain compound 6; the organic solvent five is one or more of dichloromethane, water, methanol, acetonitrile, and toluene, preferably dichloromethane;

[0024] Step (6): Dissolve compound 6 obtained in step 5 in organic solvent 6, and react with sulfur dioxide to protect the double bond to obtain compound 7; the organic solvent 6 is one or more of isopropyl ether, diethyl ether, toluene, dichloromethane, n-hexane, and acetonitrile, preferably dichloromethane; the molar ratio of compound 6 to sulfur dioxide is 1:20-30.

[0025] Step (7): Dissolve compound 7 obtained in step six in organic solvent seven, and oxidize it with ozone to obtain compound 8; the organic solvent seven is one or more of dichloromethane, methanol, ethanol, tert-butyl methyl ether, and isopropanol, preferably dichloromethane and methanol;

[0026] Step (8): Dissolve compound 8 obtained in step seven in organic solvent eight, and react with a base to remove the double bond protection to obtain compound 9; the organic solvent eight is one or more of methanol, ethanol, acetonitrile, acetone, and water, preferably ethanol;

[0027] Step (9): Dissolve compound 9 obtained in step eight in organic solvent nine, and reduce it with a reducing agent to obtain compound 10; the organic solvent nine is one or more of toluene, ethanol, acetone, acetonitrile, and n-hexane, preferably dichloromethane and methanol;

[0028] Step (10): Dissolve compound 10 obtained in step nine in organic solvent ten, and obtain compound 11 by iodination reaction; the organic solvent ten is one or more of dichloromethane, methanol, acetone, 1,4-dioxane, ethyl acetate, toluene, N,N-dimethylformamide, preferably dichloromethane;

[0029] Step (11): Dissolve compound 11 obtained in step ten in organic solvent eleven, and couple it with compound 12 under the action of a catalyst to obtain compound 13; the organic solvent eleven is one or more of pyridine, methanol, ethyl acetate, dichloromethane, n-hexane, and toluene, preferably pyridine;

[0030] Step (12): Dissolve compound 13 obtained in step eleven in organic solvent twelfth, and then irradiate it to obtain compound 14; the organic solvent twelfth is one or more of methanol, acetonitrile, acetone, tetrahydrofuran, and 1-4 dioxane, preferably tetrahydrofuran;

[0031] Step (13): Dissolve compound 14 obtained in step 12 in organic solvent 13, and remove the hydroxyl protecting group under the action of a deprotecting reagent to obtain fluorocalciferol; the organic solvent 13 is one or more of dichloromethane, tetrahydrofuran, methanol, and acetonitrile, preferably tetrahydrofuran; the deprotecting reagent is one or more of tetra-n-butylammonium fluoride, camphor sulfonic acid, p-toluene sulfonic acid, and p-toluene sulfonic acid pyridinium salt, preferably tetra-n-butylammonium fluoride; the molar ratio of compound 14 to the deprotecting reagent is 1:4-9.

[0032] According to an embodiment of the present invention, the base in step (1) is one or more of imidazole, triethylamine, diisopropylethylamine, pyridine, potassium carbonate, and sodium hydride, preferably imidazole; the molar ratio of compound 1 to the base is 1:2-5; the silicon-based protecting group reagent in step (1) is one or more of trimethylchlorosilane, triethylchlorosilane, tert-butyldimethylchlorosilane, and triisopropylchlorosilane, preferably tert-butyldimethylchlorosilane; the molar ratio of compound 1 to the silicon-based protecting group reagent is 1:1-3.

[0033] According to an embodiment of the present invention, the base in step (3) is one or more of triethylamine, pyridine, sodium bicarbonate, and imidazole, preferably sodium bicarbonate; the molar ratio of compound 3 to the base is 1:3-12.

[0034] According to an embodiment of the present invention, the base in step (4) is one or more of imidazole, triethylamine, N-methyl-N-morpholine, and diisopropylethylamine, preferably N-methyl-N-morpholine and imidazole; the molar ratio of compound 4 to the base is 1:2-8; the oxidant in step (4) is one or more of hydrogen peroxide, peracetic acid, selenium dioxide, sodium chlorate, and sodium percarbonate, preferably selenium dioxide; the molar ratio of compound 4 to the oxidant is 1:0.5-1.5.

[0035] According to an embodiment of the present invention, the base in step (5) is one or more of pyridine, potassium carbonate, sodium hydroxide, triethylamine, and imidazole, preferably imidazole; the molar ratio of compound 5 to the base is 1:1-4; the silicon-based protecting group reagent in step (5) is one or more of trimethylchlorosilane, triethylchlorosilane, tert-butyldimethylchlorosilane, and triisopropylchlorosilane, preferably tert-butyldimethylchlorosilane; the molar ratio of compound 5 to the silicon-based protecting group reagent is 1:0.5-1.5.

[0036] According to an embodiment of the present invention, the base in step (8) is one or more of triethylamine, pyridine, imidazole, sodium hydroxide, and sodium bicarbonate, preferably sodium bicarbonate; the molar ratio of compound 8 to the base is 1:4-10.

[0037] According to an embodiment of the present invention, the reducing agent in step (9) is one or more of potassium borohydride, sodium borohydride, and stannous chloride, preferably sodium borohydride; the molar ratio of compound 9 to the reducing agent is 1:2-5.

[0038] According to an embodiment of the present invention, the iodination reagent in step (10) is triphenylphosphine and iodine; the molar ratio of compound 10 to the iodination reagent is 1:3-6; the base in step (10) is one or more of sodium hydroxide, triethylamine, imidazole, and pyridine, preferably imidazole; the molar ratio of compound 10 to the base is 1:5-8.

[0039] According to an embodiment of the present invention, the catalyst in step (11) is one or more of palladium acetate, triphenylphosphine palladium, nickel chloride hexahydrate, Raney nickel, and zinc, preferably nickel chloride hexahydrate and zinc; the molar ratio of compound 11 to catalyst is 1:4-6; the molar ratio of compound 11 to compound 12 is 1:4-6.

[0040] According to an embodiment of the present invention, the base in step (12) is one or more of triethylamine, imidazole, and pyridine, preferably triethylamine; the molar ratio of compound 13 to the base is 1:0.01-0.05. The photosensitizer is one or more of anthracene and 9-acetylanthracene, preferably 9-acetylanthracene; the molar ratio of compound 13 to the photosensitizer is 1:0.01-0.05.

[0041] Compared with the prior art, the beneficial effects of this invention are as follows:

[0042] (1) The present invention provides a method for preparing fluorocalciferol. The raw materials are relatively easy to obtain, the reaction conditions are mild and controllable, and the production cost can be reduced. Compared with the prior art, the multi-step reaction yield of the synthesis route of the present invention is above 80%, and the total yield can reach above 10%, which greatly improves the total reaction yield. Moreover, it avoids the use of dangerous reagents such as tert-butyllithium, sodium amalgam, tri-n-butyltin hydrogen, and carbon disulfide, which reduces the preparation risk and is suitable for industrial production.

[0043] (2) The flucalciferol product prepared by this invention has high purity, which solves the problem of many impurities in the existing synthetic route. The reaction does not have high requirements for equipment and improves the reaction yield. It is of great significance for subsequent research and control of drug production quality. Attached Figure Description

[0044] Figure 1 This is the 1H NMR spectrum of compound 6 from Example 1.

[0045] Figure 2 This is the 1H NMR spectrum of compound 10 from Example 1.

[0046] Figure 3 This is the mass spectrum of compound 11 from Example 1.

[0047] Figure 4 This is the 1H NMR spectrum of compound 13 from Example 1.

[0048] Figure 5 This is the 1H NMR spectrum of fluorocalciferol from Example 1.

[0049] Figure 6 This is the carbon NMR spectrum of fluorocalciferol from Example 1.

[0050] Figure 7 This is the mass spectrometry of fluorocalciferol from Example 1. Detailed Implementation

[0051] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail. It should be understood that the specific embodiments described herein are only illustrative of the invention and are not intended to limit the invention; that is, the described embodiments are merely some embodiments of the invention, not all embodiments. Unless otherwise specified, all raw materials used can be obtained commercially or in-house.

[0052] Example 1

[0053] Step (1): Add 200 ml of dichloromethane, compound 1 (20 g, 50 mmol), and imidazole (10.6 g, 150 mmol) sequentially to a 500 ml reaction flask. Purge the mixture three times with nitrogen, cool it to 0–10 °C, and add a dichloromethane solution of tert-butyldimethylchlorosilane (tert-butyldimethylchlorosilane: 11.6 g, dichloromethane: 100 ml) dropwise to the flask within a controlled temperature range of 0–25 °C for 30–60 min. After the addition is complete, stir the mixture at 25 °C ± 5 °C for 0.5–1 h, quench the reaction with water, separate the organic phase, dry and concentrate it, and purify it by column chromatography to obtain 24.7 g of compound 2, with a yield of 96%.

[0054] Step (2): Add compound 2 (24.7 g, 48.4 mmol) and 200 ml of dichloromethane to a 500 ml reaction flask. After stirring until dissolved, purge with nitrogen three times for protection. Cool to -20℃±5℃, introduce 55 g of sulfur dioxide gas, maintain the temperature and react for 2-4 h. Concentrate under reduced pressure, alkalize with neutral alumina and then column chromatography to obtain 27.3 g of compound 3, yield 98%.

[0055] Step (3): Add compound 3 (27.3g, 47.48mmol) and 350ml of 95% ethanol and sodium bicarbonate (36.2g, 0.43mol) to a 500ml reaction flask, stir and heat to 80℃ and reflux for 1-3h. After direct concentration to dryness, add 200ml of ethyl acetate and 200ml of water, stir to dissolve, let stand and separate the layers, separate the organic layer and concentrate to obtain 23.2g of compound 4, with a yield of 95.7%.

[0056] Step (4): Compound 4 (23.2 g, 45.4 mmol) was dissolved in 250 ml of acetonitrile and 650 ml of dichloromethane and added to a 1000 ml reaction flask. N-methyl-N-oxymorpholine (21 g, 0.18 mol), imidazole (8.8 g, 0.13 mol), and selenium dioxide (5.1 g, 46 mmol) were added. The mixture was heated to 55 °C and reacted for 2-3 h. The reaction was quenched with water, the organic layer was separated, washed with saturated sodium chloride, and the concentrated organic layer was purified by column chromatography to obtain 14.6 g of compound 5, with a yield of 61%.

[0057] Step (5): Add compound 5 (14.6 g, 27.7 mmol) and 400 ml of dichloromethane and imidazole (3.77 g, 55.4 mmol) to a 500 ml reaction flask, stir to dissolve at room temperature, add tert-butyldimethylchlorosilane (4.17 g, 27.7 mmol) dropwise while controlling the temperature below 25 °C, stir at room temperature for 1-4 h after addition, quench the reaction with water, separate the organic layer, concentrate and purify by column chromatography to obtain 15.4 g of compound 6, yield 86.7%.

[0058] Step (6): Add 130 ml of dichloromethane to a 250 ml reaction flask, add compound 6 (15.4 g, 24 mmol), stir at room temperature until dissolved, purge with nitrogen three times for protection, cool to -20℃±10℃ and introduce 39 g of sulfur dioxide, keep warm and stir for 1-3 h, directly concentrate and purify by column chromatography to obtain 16.1 g of compound 7, yield 95%.

[0059] Step (7): Add compound 7 (16.1 g, 22.8 mmol) and 150 ml of dichloromethane and 50 ml of methanol to a 250 ml reaction flask. Purge the mixture three times with nitrogen, stir and cool to -60 to -70 °C, introduce ozone at a flow rate of 4-6 L / min, and after 1-4 h of reaction, add 5% sodium bicarbonate solution to quench the reaction. Separate the organic layer, concentrate and purify by column chromatography to obtain 10.17 g of compound 8, with a yield of 70%.

[0060] Step (8): Add compound 8 (10.17 g, 15.96 mmol) and sodium bicarbonate (8 g, 95 mmol) to a 250 ml reaction flask, along with 120 ml of 95% ethanol. Heat to 80 °C and reflux for 1-2 h. After the reaction is complete, concentrate the reaction solution directly, add 220 ml of ethyl acetate and 220 ml of water for extraction, separate the organic layer, concentrate the organic layer, and purify by column chromatography to obtain 8.23 ​​g of compound 9, with a yield of 90%.

[0061] Step (9): Compound 9 (8.23 g, 14.36 mmol), 100 ml dichloromethane, and 100 ml methanol were added to a 250 ml reaction flask. Sodium borohydride (1.63 g, 43 mmol) was added while stirring at room temperature. The mixture was stirred at room temperature for 2 h. The reaction solution was directly concentrated, quenched with hydrochloric acid aqueous solution, and extracted with 200 ml ethyl acetate. The concentrated ethyl acetate was purified by column chromatography to obtain 7.1 g of compound 10, with a yield of 86%.

[0062] Step (10): Compound 10 (7.1 g, 12.35 mmol) was dissolved in 100 ml of dichloromethane for later use. Imidazole (5 g, 74.1 mmol), triphenylphosphine (5.2 g, 19.8 mmol), iodine (6.9 g, 27.2 mmol) and 100 ml of dichloromethane were added to a 250 ml reaction flask and stirred at room temperature for 20 min. After cooling to 10 °C, the dichloromethane solution of compound 10 was added, and stirring was continued at room temperature for 1.5 h. The reaction was quenched with 2% sodium thiosulfate. The organic layer was separated and concentrated by column chromatography to obtain 6.97 g of compound 11, with a yield of 82.4%.

[0063] Step (11): Dissolve compound 11 (6.97 g, 10.17 mmol) in 100 ml of pyridine for later use. Add nickel chloride hexahydrate (2.41 g, 10.17 mmol) and zinc (3.32 g, 50.85 mmol), compound 12 (9.87 g, 50.85 mmol) and 100 ml of pyridine to a 250 ml reaction flask. Heat to 50-60 °C and stir for 30 min, then cool to 25 °C. Add the pyridine solution of compound 11 to the reaction flask. Stir at room temperature for 2-4 h to quench the reaction. Extract and concentrate by column chromatography to obtain 5.88 g of compound 13, yield 76.7%.

[0064] Step (12): Add 90 ml of tetrahydrofuran to a 100 ml photoreactor, add compound 13 (5.88 g, 7.8 mmol), triethylamine (15.8 mg, 0.156 mmol), and 9-acetylanthracene (34.3 mg, 0.156 mmol) to the reactor, irradiate at 40 °C for more than 1 h, and directly concentrate the reaction solution to finally obtain 4.76 g of compound 14, with a yield of 81%.

[0065] Step (13): Add 14 (4.76 g, 7.58 mmol) and 50 ml tetrahydrofuran to a 100 ml reaction flask, add 38 ml TBAF (THF solution, 1 M), stir at room temperature for 1-3 h under nitrogen protection, quench the reaction with water, extract with dichloromethane, concentrate the organic layer, and precipitate by neutral alumina column chromatography to obtain 2.75 g fluorocalciferol, yield 83%.

[0066] Example 2

[0067] Step (1): Add 500 mL of dichloromethane, compound 1 (100 g, 0.25 mol), and imidazole (68 g, 1 mol) sequentially to a 2000 mL reaction flask. Cool to 0–10 °C and add a solution of tert-butyldimethylchlorosilane in dichloromethane (tert-butyldimethylchlorosilane: 75.4 g, dichloromethane: 500 mL) dropwise to the flask within a controlled temperature range of 0–25 °C for 1–2 h. After the addition is complete, stir the reaction at 25 °C ± 5 °C for 1–2 h. Quench the reaction with water, separate the organic phase, dry and concentrate, and purify by column chromatography to obtain 125 g of compound 2, with a yield of 97%.

[0068] Step (2): Add compound 2 (125g, 0.245mol) and 1200mL dichloromethane to a 2000mL reaction flask. After stirring until dissolved, purge with nitrogen three times for protection. Cool to -20℃±5℃ and introduce (283g, 4.4mol) sulfur dioxide gas. Maintain the temperature and react for 4-6h. Concentrate under reduced pressure, alkalize neutral alumina, and then perform column chromatography to obtain 135.2g of compound 3, with a yield of 96%.

[0069] Step (3): Add compound 3 (135.2 g, 235 mmol) and 1500 ml of 95% ethanol and sodium bicarbonate (148 g, 1.76 mol) to a 3000 ml reaction flask, stir and heat to 80 °C and reflux for 3-5 h. After direct concentration to dryness, add 1600 ml of ethyl acetate and 1600 ml of water, stir to dissolve, let stand and separate the layers, separate the organic layer and concentrate to obtain 113.46 g of compound 4, with a yield of 94.5%.

[0070] Step (4): Compound 4 (113.46 g, 0.222 mol) was dissolved in 800 ml of acetonitrile and 1800 ml of dichloromethane and added to a 3000 ml reaction flask. N-methyl-N-oxymorpholine (104 g, 0.888 mol), imidazole (30.2 g, 0.444 mol), and selenium dioxide (29.56 g, 266.4 mol) were added. The mixture was heated to 55 °C and reacted for 3-5 h. The reaction was quenched with water, the organic layer was separated, washed with saturated sodium chloride, and the concentrated organic layer was purified by column chromatography to obtain 75.2 g of compound 5, with a yield of 64.3%.

[0071] Step (5): Compound 5 (75.2 g, 142.7 mmol) and 500 ml of dichloromethane and imidazole (29.1 g, 428.1 mmol) were added to a 1000 ml reaction flask and stirred to dissolve at room temperature. Tert-butyldimethylchlorosilane (25.8 g, 171.2 mmol) was added at a temperature below 25 degrees Celsius. After the addition was complete, the mixture was stirred at room temperature for 3-6 h. The reaction was quenched with water, the organic layer was separated, and the product was concentrated and purified by column chromatography to obtain 81.9 g of compound 6, with a yield of 89.5%.

[0072] Step (6): Add 500 ml of dichloromethane and compound 6 (81.9 g, 127.8 mmol) to a 1000 ml reaction flask, stir at room temperature to dissolve, cool to -20℃±10 and introduce (101.2 g, 1.58 mol) sulfur dioxide, keep warm and stir for 3-5 h, and directly concentrate and purify by column chromatography to obtain 84.7 g of compound 7, with a yield of 94%.

[0073] Step (7): Add compound 7 (84.7 g, 120.1 mmol), 500 ml of dichloromethane, and 125 ml of methanol to a 1000 ml reaction flask, stir and cool to -60 to -70 °C, introduce ozone at a flow rate of 4-6 L / min, and after the reaction is completed in 3-6 h, add 5% sodium bicarbonate solution to quench the reaction, separate the organic layer, concentrate and purify by column chromatography to obtain 51.9 g of compound 8, with a yield of 67.8%.

[0074] Step (8): Add compound 8 (51.9 g, 81.5 mmol) and 500 ml of 95% ethanol to a 1000 ml reaction flask, and add sodium bicarbonate (51.4 g, 0.345 mol) while stirring. After the addition is complete, heat to 80 °C and reflux for 2-4 h. After the reaction is complete, concentrate the reaction solution directly, add 700 ml of ethyl acetate and 700 ml of water for extraction, separate the organic layer, concentrate the organic layer and purify by column chromatography to obtain 43 g of compound 9, with a yield of 92%.

[0075] Step (9): Add compound 9 (43g, 75mmol), 350ml dichloromethane, and 350ml methanol to a 1000ml reaction flask. Add sodium borohydride (9.9g, 0.262mol) while stirring at room temperature. Stir at room temperature for 2 hours. Directly concentrate the reaction solution, quench with hydrochloric acid aqueous solution, and extract with 500ml ethyl acetate. Purify by column chromatography with concentrated ethyl acetate to obtain 38g of compound 10, with a yield of 88%.

[0076] Step (10): Compound 10 (38 g, 66 mmol) was dissolved in 250 ml of dichloromethane for later use. Imidazole (27 g, 396 mmol), triphenylphosphine (34.6 g, 132 mmol), iodine (50.3 g, 198 mmol) and 600 ml of dichloromethane were added to a 1000 ml reaction flask and stirred at room temperature for 20 min. After cooling to 10 °C, the dichloromethane solution of compound 10 was added, and stirring was continued at room temperature for 3 h. The reaction was quenched with 2% sodium thiosulfate. The organic layer was separated and concentrated by column chromatography to obtain 38 g of compound 11, with a yield of 84.1%.

[0077] Step (11): Dissolve compound 11 (38 g, 55.5 mmol) in 250 ml of pyridine for later use. Add nickel chloride hexahydrate (13.2 g, 55.5 mmol) and zinc (18.14 g, 277.5 mmol), compound 12 (64.6 g, 333 mmol) and 400 ml of pyridine to a 1000 ml reaction flask. Heat to 50-60 °C and stir for 30 min to activate. Then cool to 25 °C and add the pyridine solution of compound 11 to the reaction flask. Stir at room temperature for 3-5 h to quench the reaction. Extract and concentrate by column chromatography to obtain 33.44 g of compound 13, with a yield of 80%.

[0078] Step (12): Add 200 ml of tetrahydrofuran to a 500 ml photoreactor, add compound 13 (33.44 g, 44.4 mmol), triethylamine (100 mg, 1 mmol), and 9-acetylanthracene (220 mg, 1 mmol), irradiate at 40 °C for more than 2 h, directly concentrate the reaction solution, and purify by column chromatography to obtain 3.24 g of compound 14, with a yield of 81.5%.

[0079] Step (13): Compound 14 (27.25 g, 36.2 mmol) and 40 ml tetrahydrofuran were added to a 100 ml reaction flask. 40 ml TBAF (THF solution, 1 M) was added. The mixture was stirred at room temperature for 3-6 h under nitrogen protection. The reaction was quenched with water, extracted with dichloromethane, and the organic layer was concentrated. 15.57 g of fluorocalciferol was obtained by neutral alumina column chromatography, with a yield of 82%.

Claims

1. A method for preparing fluorocalciferol, characterized in that, Includes the following steps: Step (1): Compound 1 is dissolved in organic solvent 1 and reacts with a silicon-based protecting group under the action of an alkali to obtain compound 2; the organic solvent 1 is one or more of tetrahydrofuran, dichloromethane, methanol, acetonitrile, 1,4-dioxane, and toluene. Step (2): Dissolve compound 2 obtained in step one in organic solvent two, and react with sulfur dioxide to protect the double bond to obtain compound 3; the organic solvent two is one or more of tetrahydrofuran, dichloromethane, n-hexane, tert-butyl methyl ether, and 1,4-dioxane; the molar ratio of compound 2 to sulfur dioxide is 1:10-20. Step (3): Dissolve compound 3 obtained in step 2 in organic solvent 3, and react with a base to remove the double bond protection to obtain compound 4; the organic solvent 3 is one or more of methanol, ethanol, acetone, water, tetrahydrofuran, and diphenyl ether. Step (4): Dissolve compound 4 obtained in step 3 in organic solvent 4, and oxidize it with an oxidizing agent to obtain compound 5; the organic solvent 4 is one or more of dichloromethane, methanol, acetonitrile, diethyl ether, and tetrahydrofuran; Step (5): Dissolve compound 5 obtained in step four in organic solvent five, and react with silicon-based protecting groups under the action of alkali to obtain compound 6; the organic solvent five is one or more of dichloromethane, water, methanol, acetonitrile, and toluene; Step (6): Dissolve compound 6 obtained in step 5 in organic solvent 6, and react with sulfur dioxide to protect the double bond to obtain compound 7; the organic solvent 6 is one or more of isopropyl ether, diethyl ether, toluene, dichloromethane, n-hexane, and acetonitrile; the molar ratio of compound 6 to sulfur dioxide is 1:20-30. Step (7): Dissolve compound 7 obtained in step six in organic solvent seven, and oxidize it with ozone to obtain compound 8; the organic solvent seven is one or more of dichloromethane, methanol, ethanol, tert-butyl methyl ether, and isopropanol. Step (8): Dissolve compound 8 obtained in step seven in organic solvent eight, and react with a base to remove the double bond protection to obtain compound 9; the organic solvent eight is one or more of methanol, ethanol, acetonitrile, acetone, and water; Step (9): Dissolve compound 9 obtained in step eight in organic solvent nine, and reduce it with a reducing agent to obtain compound 10; the organic solvent nine is one or more of toluene, ethanol, acetone, acetonitrile, and n-hexane; Step (10): Dissolve compound 10 obtained in step nine in organic solvent ten, and obtain compound 11 by iodination reaction; wherein the organic solvent ten is one or more of dichloromethane, methanol, acetone, 1,4-dioxane, ethyl acetate, toluene, N,N-dimethylformamide; Step (11): Dissolve compound 11 obtained in step ten in organic solvent eleven, and couple it with compound 12 under the action of a catalyst to obtain compound 13; the organic solvent eleven is one or more of pyridine, methanol, ethyl acetate, dichloromethane, n-hexane, and toluene. Step (12): Dissolve compound 13 obtained in step eleven in organic solvent twelfth, and then irradiate it to obtain compound 14; the organic solvent twelfth is one or more of methanol, acetonitrile, acetone, tetrahydrofuran, and 1-4 dioxane. Step (13): Dissolve compound 14 obtained in step 12 in organic solvent 13, and remove the hydroxyl protecting group under the action of a deprotecting reagent to obtain fluorocalciferol; the organic solvent 13 is one or more of dichloromethane, tetrahydrofuran, methanol, and acetonitrile; the deprotecting reagent is one or more of tetra-n-butylammonium fluoride, camphor sulfonic acid, p-toluenesulfonic acid, and p-toluenesulfonic acid pyridinium salt; the molar ratio of compound 14 to the deprotecting reagent is 1:4-9.

2. The method for preparing fluorocalciferol according to claim 1, characterized in that, The base in step (1) is one or more of imidazole, triethylamine, diisopropylethylamine, pyridine, potassium carbonate, and sodium hydride; the molar ratio of compound 1 to the base is 1:2-5; the silicon-based protecting agent in step (1) is one or more of trimethylchlorosilane, triethylchlorosilane, tert-butyldimethylchlorosilane, and triisopropylchlorosilane; the molar ratio of compound 1 to the silicon-based protecting agent is 1:1-3.

3. The method for preparing fluorocalciferol according to claim 1, characterized in that, The base in step (3) is one or more of triethylamine, pyridine, sodium bicarbonate, and imidazole; the molar ratio of compound 3 to the base is 1:3-12.

4. The method for preparing fluorocalciferol according to claim 1, characterized in that, The base in step (4) is one or more of imidazole, triethylamine, N-methyl-N-morpholine, and diisopropylethylamine; the molar ratio of compound 4 to the base is 1:2-8; the oxidant in step (4) is one or more of hydrogen peroxide, peracetic acid, selenium dioxide, sodium chlorate, and sodium percarbonate; the molar ratio of compound 4 to the oxidant is 1:0.5-1.

5.

5. The method for preparing fluorocalciferol according to claim 1, characterized in that, The base in step (5) is one or more of pyridine, potassium carbonate, sodium hydroxide, triethylamine, and imidazole; the molar ratio of compound 5 to the base is 1:1-4; the silicon-based protecting group reagent in step (5) is one or more of trimethylchlorosilane, triethylchlorosilane, tert-butyldimethylchlorosilane, and triisopropylchlorosilane; the molar ratio of compound 5 to the silicon-based protecting group reagent is 1:0.5-1.

5.

6. The method for preparing fluorocalciferol according to claim 1, characterized in that, The base in step (8) is one or more of triethylamine, pyridine, imidazole, sodium hydroxide, and sodium bicarbonate; the molar ratio of compound 8 to the base is 1:4-10.

7. The method for preparing fluorocalciferol according to claim 1, characterized in that, The reducing agent in step (9) is one or more of potassium borohydride, sodium borohydride, and stannous chloride; the molar ratio of compound 9 to the reducing agent is 1:2-5.

8. The method for preparing fluorocalciferol according to claim 1, characterized in that, The iodination reagent in step (10) is triphenylphosphine and iodine; the molar ratio of compound 10 to the iodination reagent is 1:3-6; The base in step (10) is one or more of sodium hydroxide, triethylamine, imidazole, and pyridine; the molar ratio of compound 10 to the base is 1:5-8.

9. The method for preparing fluorocalciferol according to claim 1, characterized in that, In step (11), the catalyst is nickel chloride hexahydrate and zinc; the molar ratio of compound 11 to the catalyst is 1:4-6; the molar ratio of compound 11 to compound 12 is 1:4-6.

10. The method for preparing fluorocalciferol according to claim 1, characterized in that, The base in step (12) is one or more of triethylamine, imidazole, and pyridine; the molar ratio of compound 13 to the base is 1:0.01-0.05; the photosensitizer is one or more of anthracene and 9-acetylanthracene; the molar ratio of compound 13 to the photosensitizer is 1:0.01-0.05.

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