Preparation method of fluorocalciferol

Abstract

The invention discloses a novel preparation method of fluorocalciferol, and belongs to the field of pharmaceutical chemical synthesis. The preparation method comprises the following steps: carrying out hydroxyl protection, double-bond configuration inversion, C1 site oxidation, hydroxyl protection, double-bond protection, ozonization, double-bond deprotection, reduction and iodination on a compound 1 to obtain a compound 11, docking the compound 11 with a compound 12 through a coupling reaction to obtain a key intermediate 13, and carrying out illumination configuration inversion and deprotection to obtain fluorocalciferol. The preparation method of the fluorocalciferol is high in yield, green and safe in reaction, free of toxic reagents and suitable for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemical synthesis, and particularly relates to a method for preparing fluorocalciferol. Background Art

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

[0003]

[0004] Fluorcalciferol is a third-generation new active VDR agonist jointly developed by Sumitomo Pharma Co., Ltd. and Taisho Pharmaceutical Co., Ltd. Fluorcalciferol is an analog of calcitriol, but it has a long retention time in the body, a low dosage, is less likely to cause hypercalcemia, and exhibits stronger biological activity than calcitriol. The drug can be used to treat calcium regulation disorders such as secondary hyperparathyroidism and osteoporosis.

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

[0006] One is to use cholesterol-like substances as the starting material, undergo multiple steps of reaction, and finally obtain the target substance by light irradiation, such as the synthesis method reported in U.S. Patent No. 4248791A, and the synthesis route is as follows:

[0007]

[0008] Such methods have expensive and difficult-to-obtain starting materials, low yields, and multi-step reaction yields of only about 20%. Multi-step reactions use dangerous reagents such as n-butyl lithium and potassium, and there are many impurities without effective purification methods, making them unsuitable for industrial production.

[0009] The second is a method for synthesizing fluorocalciferol using vitamin D2 as a starting material through a multi-step reaction, such as a method for preparing fluorocalciferol disclosed in patent US6080879A, the synthetic route of which is as follows:

[0010]

[0011] Vitamin D2 derivatives are used as starting materials, and operations such as oxidation, reduction, and ring-opening flipping are involved. Highly toxic reagents such as selenium dioxide and hexafluoroacetone are used in the reaction process. Fluorocalciferol is obtained through 12 steps of reaction with a low yield of only 3.96% in total, which is not suitable for industrial production.

[0012] The third method is to use the CD ring derived from VD2 as the starting material, and obtain fluorocalciferol through multi-step reaction splicing, such as the preparation method of fluorocalciferol disclosed in patent CN112047820A, and its synthesis route is as follows:

[0013]

[0014] The tertiary hydroxyl group of the CD ring intermediate of fluorocalciferol is protected by methoxymethyl ether (MOM), which requires the use of highly toxic reagent chloromethyl methyl ether (MOMCl), and the deprotection reaction also requires the use of highly toxic methanesulfonic acid reagent. Therefore, the CD ring intermediate of fluorocalciferol is not suitable as a material for preparing fluorocalciferol by a convergent synthesis route. Summary of the invention

[0015] The purpose of the present invention is to provide a method for preparing fluorocalciferol, so as to solve the problems in the prior art that the synthesis route of fluorocalciferol is complicated, the starting materials are expensive, more hazardous reagents are used, the risk is high, the yield of multi-step reactions is low, the production cost is high, and it is not suitable for large-scale production.

[0016] The technical solution to achieve the above invention object is:

[0017] The present invention provides a method for preparing fluorocalciferol, characterized in that it comprises the following steps:

[0018]

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

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

[0021] Step (3): dissolving the compound 3 obtained in step 2 in an organic solvent 3, and reacting 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, preferably ethanol;

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

[0023] Step (5): dissolving the compound 5 obtained in step 4 in an organic solvent 5, and reacting with a silicon-based protecting group under the action of a base to obtain a compound 6; the organic solvent 5 is one or more of dichloromethane, water, methanol, acetonitrile, and toluene, preferably dichloromethane;

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

[0025] Step (7): dissolving the compound 7 obtained in step 6 in an organic solvent 7, and subjecting the mixture to ozone oxidation to obtain a compound 8; the organic solvent 7 is one or more of dichloromethane, methanol, ethanol, tert-butyl methyl ether, and isopropanol, preferably dichloromethane and methanol;

[0026] Step (8): dissolving the compound 8 obtained in step 7 in an organic solvent 8, and reacting with a base to remove the double bond protection to obtain compound 9; the organic solvent 8 is one or more of methanol, ethanol, acetonitrile, acetone, and water, preferably ethanol;

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

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

[0029] Step (11): dissolving the compound 11 obtained in step 10 in an organic solvent 11, and coupling with compound 12 in the presence of a catalyst to obtain compound 13; the organic solvent 11 is one or more of pyridine, methanol, ethyl acetate, dichloromethane, n-hexane, and toluene, preferably pyridine;

[0030] Step (12): dissolving the compound 13 obtained in step 11 in an organic solvent 12, and inverting the mixture under light to obtain compound 14; the organic solvent 12 is one or more of methanol, acetonitrile, acetone, tetrahydrofuran, 1-4-dioxane, preferably tetrahydrofuran;

[0031] Step (13): dissolving the compound 14 obtained in step 12 in an organic solvent 13, and removing the hydroxyl protecting group under the action of a deprotecting agent to obtain fluorocalciferol; the organic solvent 13 is one or more of dichloromethane, tetrahydrofuran, methanol, and acetonitrile, preferably tetrahydrofuran; the deprotecting agent is one or more of tetra-n-butylammonium fluoride, camphorsulfonic acid, p-toluenesulfonic acid, and p-toluenesulfonic acid pyridinium salt, preferably tetra-n-butylammonium fluoride; the molar ratio of the compound 14 to the deprotecting agent 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 trimethylsilyl chloride, triethylsilyl chloride, tert-butyldimethylsilyl chloride, and triisopropylsilyl chloride, preferably tert-butyldimethylsilyl chloride; 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 oxide, diisopropylethylamine, preferably N-methyl-N-morpholine oxide 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, 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 trimethylsilyl chloride, triethylsilyl chloride, tert-butyldimethylsilyl chloride, and triisopropylsilyl chloride, preferably tert-butyldimethylsilyl chloride; 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 iodine reaction reagent in step (10) is triphenylphosphine and iodine; the molar ratio of the compound 10 to the iodine reaction 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 the 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 the compound 11 to the catalyst is 1:4-6; the molar ratio of the compound 11 to the 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 the compound 13 to the base is 1:0.01-0.05. The photosensitizer is one or more of anthracene and 9-acetyl anthracene, preferably 9-acetyl anthracene; the molar ratio of the compound 13 to the photosensitizer is 1:0.01-0.05.

[0041] Compared with the prior art, the present invention has the following beneficial effects:

[0042] (1) The present invention provides a method for preparing fluorocalciferol, wherein the raw materials are easy to obtain, the reaction conditions are mild and controllable, and the production cost can be reduced. Compared with the prior art, the yield of multiple steps of the synthesis route of the present invention is above 80%, and the total yield can reach above 10%, which greatly improves the total yield of the reaction; and the use of dangerous test products such as tert-butyl lithium, sodium amalgam, tri-n-butyltin hydrogen, and carbon disulfide is avoided, thereby reducing the preparation risk and being suitable for industrial production.

[0043] (2) The fluorocalciferol product prepared by the present invention has high purity, which solves the problem of high impurities in the existing synthetic route of fluorocalciferol. The reaction does not require high equipment, and the reaction yield is improved, which is of great significance for subsequent research and control of drug production quality. BRIEF DESCRIPTION OF THE DRAWINGS

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

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

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

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

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

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

[0050] Figure 7 This is the mass spectrum of fluorocalciferol from Example 1. DETAILED DESCRIPTION

[0051] In order to make the purpose, technical scheme and advantages of the present invention clearer, the present invention is further described in detail. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention, that is, the embodiments described are only part of the embodiments of the present invention, rather than all the embodiments. Unless otherwise specified, the raw materials used can be obtained commercially or homemade.

[0052] Example 1

[0053] Step (1): add 200 ml of dichloromethane, compound 1 (20 g, 50 mmol) and imidazole (10.6 g, 150 mmol) to a 500 ml reaction bottle in sequence, replace with nitrogen three times for protection, cool to 0-10°C, control the temperature at 0-25°C within 30-60 min, add a dichloromethane solution of tert-butyldimethylsilyl chloride (tert-butyldimethylsilyl chloride: 11.6 g, dichloromethane: 100 ml) dropwise to the bottle, stir at 25°C±5 for 0.5-1 h, add water to quench the reaction, separate the organic phase, dry and concentrate, and purify 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 bottle, stir to dissolve and then replace with nitrogen three times for protection, cool to -20°C ± 5, introduce 55 g of sulfur dioxide gas, maintain the temperature for 2-4 hours, concentrate under reduced pressure, alkalize neutral alumina and then column chromatography to obtain 27.3 g of compound 3, with a yield of 98%.

[0055] Step (3): Add compound 3 (27.3 g, 47.48 mmol) and 350 ml 95% ethanol and sodium bicarbonate (36.2 g, 0.43 mol) into a 500 ml reaction bottle, stir and heat to 80 °C and reflux for reaction for 1-3 h. Directly concentrate to dryness, add 200 ml ethyl acetate and 200 ml water, stir and dissolve, stand and separate, separate the organic layer and concentrate to obtain 23.2 g 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 into a 1000 ml reaction bottle. N-methyl-N-morpholine oxide (21 g, 0.18 mol), imidazole (8.8 g, 0.13 mol) and selenium dioxide (5.1 g, 46 mmol) were added. The temperature was raised to 55 °C and the reaction was carried out for 2-3 h. The mixture was quenched with water, the organic layer was separated, and the mixture was washed with saturated sodium chloride. The concentrated organic layer was purified by column chromatography to obtain 14.6 g of compound 5 in a yield of 61%.

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

[0058] Step (6): Add 130 ml of dichloromethane to a 250 ml reaction bottle, add compound 6 (15.4 g, 24 mmol), stir at room temperature until dissolved, replace with nitrogen three times for protection, cool to -20°C ± 10, introduce 39 g of sulfur dioxide, keep warm and stir for 1-3 hours, 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), 150 ml of dichloromethane and 50 ml of methanol to a 250 ml reaction bottle, replace the atmosphere with nitrogen three times, cool to -60 to -70 °C with stirring, 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 and purify by concentrator 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) and 120 ml of 95% ethanol to a 250 ml reaction bottle, heat to 80°C and reflux with stirring for 1-2 h. After the reaction is completed, directly concentrate the reaction solution, add 220 ml of ethyl acetate and 220 ml of water for extraction, separate the organic layer, concentrate the organic layer and purify it by column chromatography to obtain 8.23 ​​g of compound 9, with a yield of 90%.

[0061] Step (9): Add compound 9 (8.23 g, 14.36 mmol), 100 ml of dichloromethane and 100 ml of methanol to a 250 ml reaction bottle, add sodium borohydride (1.63 g, 43 mmol) while stirring at room temperature, stir at room temperature for 2 h, directly concentrate the reaction solution, quench with aqueous hydrochloric acid, and extract with 200 ml of ethyl acetate. Purify by concentrated ethyl acetate 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, 19.8 mmol), iodine (6.9 g, 27.2 mmol) and 100 ml of dichloromethane were added to a 250 ml reaction bottle and stirred at room temperature for 20 min. The mixture was cooled to 10°C and a dichloromethane solution of compound 10 was added. The mixture was stirred 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): Compound 11 (6.97 g, 10.17 mmol) was dissolved in 100 ml of pyridine for later use. 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 were added to a 250 ml reaction bottle. The temperature was raised to 50-60 ° C and stirred for 30 min, then cooled to 25 ° C. The pyridine solution of compound 11 was added to the reaction bottle, stirred at room temperature for 2-4 h, the reaction was quenched, and the extraction and concentration column chromatography were used to obtain 5.88 g of compound 13 with a yield of 76.7%.

[0064] Step (12): Add 90 ml of tetrahydrofuran to a 100 ml light irradiation reactor, 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) into the reactor, irradiate with light for more than 1 h at below 40°C, and directly concentrate the reaction solution to finally obtain 4.76 g of compound 14, with a yield of 81%.

[0065] Step (13): 14 (4.76 g, 7.58 mmol) and 50 ml of tetrahydrofuran were added to a 100 ml reaction bottle, and 38 ml of TBAF (THF solution, 1 M) was added. Under nitrogen protection, the mixture was stirred at room temperature for 1-3 h. Water was added to quench the reaction, and the mixture was extracted with dichloromethane. The organic layer was concentrated and purified by neutral alumina column chromatography to obtain 2.75 g of 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) to a 2000 ml reaction bottle in sequence, cool to 0-10°C, control the temperature at 0-25°C within 1-2 h, add a dichloromethane solution of tert-butyldimethylsilyl chloride (tert-butyldimethylsilyl chloride: 75.4 g, dichloromethane: 500 ml) dropwise to the bottle, stir at 25°C±5 for 1-2 h, add water to quench the reaction, 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 (125 g, 0.245 mol) and 1200 mL of dichloromethane to a 2000 mL reaction bottle, stir to dissolve and then replace with nitrogen three times for protection, cool to -20°C ± 5, introduce sulfur dioxide gas (283 g, 4.4 mol), maintain the temperature for 4-6 hours, concentrate under reduced pressure, alkalize neutral alumina and then perform column chromatography to obtain 135.2 g of compound 3, with a yield of 96%.

[0069] Step (3): Add compound 3 (135.2 g, 235 mmol) and 1500 ml 95% ethanol and sodium bicarbonate (148 g, 1.76 mol) into a 3000 ml reaction bottle, stir and heat to 80 °C and reflux for reaction for 3-5 h, directly concentrate to dryness, add 1600 ml ethyl acetate and 1600 ml water, stir and dissolve, stand and separate, 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 into a 3000 ml reaction bottle. N-methyl-N-morpholine oxide (104 g, 0.888 mol), imidazole (30.2 g, 0.444 mol) and selenium dioxide (29.56 g, 266.4 mol) were added. The temperature was raised to 55 °C and the reaction was carried out for 3-5 h. The mixture was quenched with water, the organic layer was separated, and the mixture was washed with saturated sodium chloride. The concentrated organic layer was purified by column chromatography to obtain 75.2 g of compound 5 in a yield of 64.3%.

[0071] Step (5): Add compound 5 (75.2 g, 142.7 mmol) and 500 ml of dichloromethane, as well as imidazole (29.1 g, 428.1 mmol) to a 1000 ml reaction bottle, stir at room temperature to dissolve, add tert-butyldimethylsilyl chloride (25.8 g, 171.2 mmol) while controlling the temperature below 25 degrees Celsius, stir at room temperature for 3-6 hours, add water to quench the reaction, separate the organic layer, and purify by concentrator 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 bottle, stir at room temperature to dissolve, cool to -20°C ± 10, introduce sulfur dioxide (101.2 g, 1.58 mol), keep warm and stir for 3-5 hours, 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 into a 1000 ml reaction bottle, stir and cool to -60 to -70 ° C, introduce ozone at a flow rate of 4-6 L / min, and after 3-6 h of reaction, add 5% sodium bicarbonate solution to quench the reaction. Separate the organic layer and purify it by concentrating 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 95% ethanol to a 1000 ml reaction bottle, add sodium bicarbonate (51.4 g, 0.345 mol) under stirring, raise the temperature to 80°C and reflux with stirring for 2-4 h. After the reaction is completed, directly concentrate the reaction solution, add 700 ml ethyl acetate and 700 ml water for extraction, separate the organic layer, concentrate the organic layer and purify it by column chromatography to obtain 43 g of compound 9, with a yield of 92%.

[0075] Step (9): Add compound 9 (43 g, 75 mmol), 350 ml of dichloromethane and 350 ml of methanol to a 1000 ml reaction bottle, add sodium borohydride (9.9 g, 0.262 mol) while stirring at room temperature, stir at room temperature for 2 h, directly concentrate the reaction solution, quench with aqueous hydrochloric acid, and extract with 500 ml of ethyl acetate. Purify by concentrated ethyl acetate column chromatography to obtain 38 g 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 bottle and stirred at room temperature for 20 min. The mixture was cooled to 10°C and a dichloromethane solution of compound 10 was added. The mixture was stirred 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 in 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 into a 1000 ml reaction bottle, heat to 50-60 ° C and stir to activate for 30 min, then cool to 25 ° C, add the pyridine solution of compound 11 into the reaction bottle, stir at room temperature for 3-5 h, quench the reaction, and 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, compound 13 (33.44 g, 44.4 mmol), triethylamine (100 mg, 1 mmol) and 9-acetylanthracene (220 mg, 1 mmol) to a 500 ml photoirradiation reactor, and irradiate with light for more than 2 h at below 40°C. Directly concentrate the reaction solution and purify it by column chromatography to obtain 3.24 g of compound 14 with a yield of 81.5%.

[0079] Step (13): Add compound 14 (27.25 g, 36.2 mmol) and 40 ml of tetrahydrofuran into a 100 ml reaction bottle, add 40 ml of TBAF (THF solution, 1 M), stir at room temperature for 3-6 h under nitrogen protection, add water to quench the reaction, extract with dichloromethane, concentrate the organic layer, and chromatograph on a neutral alumina column to obtain 15.57 g of fluorocalciferol, with a yield of 82%.

Claims

1. A method for preparing fluorocalciferol, characterized in that: The following steps are involved: Step (1): Compound 1 is dissolved in an organic solvent 1, and reacted with a silicon-based protecting group under the action of a base to obtain Compound 2; the organic solvent 1 is one or more of tetrahydrofuran, dichloromethane, methanol, acetonitrile, 1,4-dioxane, and toluene, preferably dichloromethane; Step (2): dissolving the compound 2 obtained in step 1 in an organic solvent 2, and reacting with sulfur dioxide to protect the double bond to obtain compound 3; the organic solvent 2 is one or more of tetrahydrofuran, dichloromethane, n-hexane, tert-butylmethylimidazole, 1,4-dioxane, preferably dichloromethane; the molar ratio of the compound 2 to sulfur dioxide is 1:10-20; Step (3): dissolving the compound 3 obtained in step 2 in an organic solvent 3, and reacting 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, preferably ethanol; Step (4): dissolving the compound 4 obtained in step 3 in an organic solvent 4, and oxidizing with an oxidant to obtain compound 5; the organic solvent 4 is one or more of dichloromethane, methanol, acetonitrile, ether, and tetrahydrofuran, preferably acetonitrile and dichloromethane; Step (5): dissolving the compound 5 obtained in step 4 in an organic solvent 5, and reacting with a silicon-based protecting group under the action of a base to obtain a compound 6; the organic solvent 5 is one or more of dichloromethane, water, methanol, acetonitrile, and toluene, preferably dichloromethane; Step (6): dissolving the compound 6 obtained in step 5 in an organic solvent 6, and reacting with sulfur dioxide to protect the double bond to obtain compound 7; the organic solvent 6 is one or more of isopropyl ether, ethyl ether, toluene, dichloromethane, n-hexane, and acetonitrile, preferably dichloromethane; the molar ratio of the compound 6 to sulfur dioxide is 1:20-30; Step (7): dissolving the compound 7 obtained in step 6 in an organic solvent 7, and subjecting the mixture to ozone oxidation to obtain a compound 8; the organic solvent 7 is one or more of dichloromethane, methanol, ethanol, tert-butyl methyl ether, and isopropanol, preferably dichloromethane and methanol; Step (8): dissolving the compound 8 obtained in step 7 in an organic solvent 8, and reacting with a base to remove the double bond protection to obtain compound 9; the organic solvent 8 is one or more of methanol, ethanol, acetonitrile, acetone, and water, preferably ethanol; Step (9): dissolving the compound 9 obtained in step eight in an organic solvent nine, and reducing the compound 10 with a reducing agent; the organic solvent nine is one or more of toluene, ethanol, acetone, acetonitrile, and n-hexane, preferably dichloromethane and methanol; Step (10): dissolving the compound 10 obtained in step nine in an organic solvent ten, and subjecting the mixture to iodination reaction to obtain a compound 11; the organic solvent ten is one or more of dichloromethane, methanol, acetone, 1,4-dioxane, ethyl acetate, toluene, and N,N-dimethylformamide, preferably dichloromethane; Step (11): dissolving the compound 11 obtained in step 10 in an organic solvent 11, and coupling with compound 12 in the presence of a catalyst to obtain compound 13; the organic solvent 11 is one or more of pyridine, methanol, ethyl acetate, dichloromethane, n-hexane, and toluene, preferably pyridine; Step (12): dissolving the compound 13 obtained in step 11 in an organic solvent 12, and inverting the mixture under light to obtain compound 14; the organic solvent 12 is one or more of methanol, acetonitrile, acetone, tetrahydrofuran, 1-4-dioxane, preferably tetrahydrofuran; Step (13): dissolving the compound 14 obtained in step 12 in an organic solvent 13, and removing the hydroxyl protecting group under the action of a deprotecting agent to obtain fluorocalciferol; the organic solvent 13 is one or more of dichloromethane, tetrahydrofuran, methanol, and acetonitrile, preferably tetrahydrofuran; the deprotecting agent is one or more of tetra-n-butylammonium fluoride, camphorsulfonic acid, p-toluenesulfonic acid, and p-toluenesulfonic acid pyridinium salt, preferably tetra-n-butylammonium fluoride; the molar ratio of the compound 14 to the deprotecting agent 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, preferably imidazole; the molar ratio of compound 1 to the base is 1:2-5; In the step (1), the silicon-based protecting group reagent is one or more of trimethylsilyl chloride, triethylsilyl chloride, tert-butyldimethylsilyl chloride, and triisopropylsilyl chloride, preferably tert-butyldimethylsilyl chloride; the molar ratio of the compound 1 to the silicon-based protecting group reagent 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, preferably sodium bicarbonate; 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 oxide, and diisopropylethylamine, preferably N-methyl-N-morpholine oxide 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 the 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, 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 trimethylsilyl chloride, triethylsilyl chloride, tert-butyldimethylsilyl chloride, and triisopropylsilyl chloride, preferably tert-butyldimethylsilyl chloride; 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, preferably 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, preferably sodium borohydride; 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 iodine reagent in step (10) is triphenylphosphine and iodine; the molar ratio of compound 10 to the iodine 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 the compound 10 to the base is 1:5-8.

9. The method for preparing fluorocalciferol according to claim 1, characterized in that: In the step (11), the catalyst 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 the compound 11 to the catalyst is 1:4-6; the molar ratio of the compound 11 to the 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, 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-acetyl anthracene, preferably 9-acetyl anthracene; the molar ratio of the compound 13 to the photosensitizer is 1:0.01-0.05.

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