Preparation method of high-purity halcinonide intermediate

Abstract

The invention discloses a preparation method of a high-purity halcinonide intermediate, which comprises the following steps: dissolving 21-hydroxypregna-4, 9 (11), 16-tetraene-3, 20-dione-21-acetate in 30 times of volume of acetone, adding an acidic reagent, cooling to-30 DEG C to 0 DEG C, dropwise adding a potassium permanganate solution, carrying out heat preservation reaction for 1-2 hours, after the reaction is finished, filtering, and drying to obtain the high-purity halcinonide intermediate. Carrying out post-treatment on the obtained crude product to obtain a reaction product D-3; dissolving the D-3 in an organic solvent, and reacting with a bromination reagent in the presence of an acid catalyst to obtain D-4; and dissolving the D-4 in an organic solvent, and reacting with a weak base reagent under the protection of nitrogen to obtain the halcinonide intermediate D-5. The triene acetate (21-hydroxypregna-4, 9 (11), 16-tetraene-3, 20-dione-21-acetate) (D-2) is used as a raw material, the reaction process steps are few, meanwhile, auxiliary materials with high toxicity are not used, the reaction controllability is good, an intermediate and a final product are easy to purify, the purity is high, the product yield is high, the cost is low, and the method is suitable for large-scale production.

Description

Technical Field

[0001] The invention relates to the field of chemical drug synthesis, and in particular to a method for preparing a high-purity halcinonide intermediate. Background Art

[0002] Halcinonide, chemical name: 16α,17-[(1-methylethylidene)bis(oxy)]-11β-hydroxy-21-chloro-9-fluoropregn-4-ene-3,20-dione, is a synthetic potent glucocorticoid. Halcinonide is a fluorine-containing and chlorine-containing synthetic potent glucocorticoid for topical application, with mild anti-inflammatory, anti-allergic, antipruritic, and immunosuppressive effects. Halcinonide topical application can reduce the permeability of capillary walls and cell membranes, reduce wet penetration, and inhibit the formation and release of histamine and other inflammatory mediators. Topical application is not likely to cause systemic side effects, and has outstanding effects in the treatment of psoriasis and eczematous dermatitis. After percutaneous absorption, its pharmacokinetic behavior is the same as that of systemic application, that is, it binds to plasma proteins to varying degrees, is mainly excreted from the kidneys after liver metabolism, and is also partially excreted from the bile.

[0003] The chemical structure of the halcinonide intermediate D-5 is shown in Formula I: ...Formula i.

[0004] The synthetic route reported in "Study on the Synthesis of Steroidal Drug Halcinonide" (see reaction formula ii below) uses anecortave acetate as the starting material and prepares the halcinonide intermediate D-5 through dehydration, oxidation, bromination, and epoxidation. This process uses a 54-fold acetone / water mixed solution as a solvent in the preparation process of D-3, which limits the batch size of the product and is not conducive to production scale-up. Secondly, in the preparation process of D-5, D-5 is obtained by neutralization, concentration, and alcohol precipitation using sodium hydroxide aqueous solution. The operation is cumbersome, and the neutralization and concentration steps will lead to the degradation of D-5, and the purity of the final product is low: ……Formula ii.

[0005] Therefore, in order to simplify the preparation method of halcinonide intermediates, it is urgently necessary to develop a preparation method of halcinonide intermediates that is low-cost, simple in process and can be used for large-scale production. Summary of the invention

[0006] The object of the present invention is to provide a method for preparing a halcinonide intermediate which has high purity, few reaction steps and is suitable for industrialization.

[0007] Different from the prior art, the above technical solution provides a method for preparing a halcinonide intermediate, which comprises the following steps: Step 1: Dissolve 21-hydroxypregnane-4,9(11),16-tetraene-3,20-dione-21-acetate in acetone, add an acidic reagent, cool to -30°C~0°C, drop potassium permanganate solution and keep warm for 1~2h. After the reaction is completed, filter, beat the obtained crude product with 5~10 times the volume of acetone, control the temperature at 40~55°C for 1~3h, then cool to 10~25°C for crystallization, and then filter, Drying to obtain a reaction product D-3; the added 21-hydroxypregnane-4,9(11),16-tetraene-3,20-dione-21-acetate, acidic solution and potassium permanganate have a molar ratio of 1:3.0-4.0:1.25-1.35; the volume of acetone in the reaction solution is 30 times the mass of 21-hydroxypregnane-4,9(11),16-tetraene-3,20-dione-21-acetate; Step 2: dissolving D-3 obtained in step 1 in organic solvent B, cooling to -15°C~15°C, dropping an acid catalyst, and then adding N-bromosuccinimide NBS and keeping the temperature for reaction for 1~3h; after the reaction is completed, controlling the temperature at 10°C±5°C for crystallization for 1~3h, and filtering to obtain a reaction product D-4; wherein the molar ratio of the added D-3, acid catalyst, and N-bromosuccinimide NBS is 1:0.10-0.50:1.00-1.50; Step 3: Dissolve the D-4 obtained in step 2 in an organic solvent C, add a weak base reagent at 15-35° C. and a nitrogen atmosphere for 1-3 hours; after the reaction, add water for crystallization, and control the temperature at 0-25° C. for crystallization for 1-3 hours; finally, filter and dry to obtain the halcinonide intermediate D-5; the ratio of the amount of D-4 and the weak base reagent added is 1:19-2.1.

[0008] The present invention adopts the above-mentioned preparation method. In step 1, due to the use of 21-hydroxypregnane-4,9(11),16-tetraene-3,20-dione-21-acetate D-2 as a raw material, the amount of organic solvent used can be greatly reduced, and there is no need to perform steps such as concentration and neutralization, so that the overall reaction steps are few, the reaction cost is reduced, and the reaction is easy to industrialize. Step 1 adopts the above-mentioned post-treatment process, and acetone hot pulping is used to purify the crude product. This process can remove a large amount of impurities, so that the purity of the final product D-3 is ≥99%. The operation process is simple, and the prepared D-3 has high purity, thereby improving the purity of the final product. In step 3, a weak base reagent is used to replace the strong base reagent in the existing reaction, so that the impurity content of the final product is greatly reduced; at the same time, in the post-treatment process of step 3, there is no need to perform neutralization and concentration treatment. Since a large amount of by-products will be generated in the neutralization and concentration process, the present invention directly adds water for crystallization and filtration to obtain a product with a purity of ≥99%, and the yield of the product is ≥90%. It is not only simple to operate, but also suitable for industrial scale-up production. In addition, no highly toxic auxiliary materials are used in each step of the present invention, which is friendly to the environment and operators and has obvious competitive advantages.

[0009] Furthermore, in step 1, the potassium permanganate solution is a solution of potassium permanganate dissolved in a mixture of acetone and water, wherein the acetone and water are mixed in a volume ratio of 5:1; and the concentration of potassium permanganate in the solution is 0.19 mol / L-0.2 mol / L. In step 1, the potassium permanganate solution is used as an oxidant.

[0010] In the step 1, the acetone in the reaction solution includes the acetone used to dissolve 21-hydroxypregnane-4,9(11),16-tetraene-3,20-dione-21-acetate, and also includes the acetone in the potassium permanganate solution.

[0011] Further, in the step, after the reaction is completed, a sodium sulfite aqueous solution with a concentration of 0.86mol / L-1.63mol / L is added to quench the reaction, and in step 2, after the reaction is completed, a sodium sulfite aqueous solution with a concentration of 0.12mol / L-0.13mol / L is first added to quench the reaction. By quenching the reaction, the generation of impurities in the post-treatment process is reduced.

[0012] Furthermore, in step 2, the organic solvent B is acetone; and the volume of the added organic solvent B is 9.5-10.5 times the volume of D-3.

[0013] Furthermore, the acid catalyst in step 2 is: an aqueous solution of perchloric acid with a concentration of 0.19 mol / L-0.20 mol / L.

[0014] Furthermore, the weak base reagent in step 3 is a potassium carbonate aqueous solution with a concentration of 40%-50% by mass. In step 3 of the present invention, since a weak base reagent is used to replace the strong base reagent in the existing reaction, degradation of the product D-5 is avoided, so that the impurity content of the final product is greatly reduced.

[0015] Furthermore, the organic solvent C in step 3 is a mixture of dichloromethane and methanol in a volume ratio of 1:1; the volume of the added organic solvent C is 9.5-10.5 times the volume of D-4. The above mixed solution can improve the solubility of D-4 in the solvent and better dissolve and remove impurities.

[0016] The present invention has the following beneficial effects: In step 1 of the present invention, since 21-hydroxypregnane-4,9(11),16-tetraene-3,20-dione-21-acetate is used as a raw material, the amount of organic solvent used can be greatly reduced, so that the overall reaction steps are reduced, the reaction cost is reduced, and the reaction is easy to industrialize.

[0017] In the post-treatment process of step 1 of the present invention, acetone hot beating is used to purify the crude product, and this process can remove a large amount of impurities, so that the purity of the final product D-3 is ≥99%. The operation process is simple, and the prepared D-3 has high purity, thereby improving the purity of the final product.

[0018] In step 3 of the present invention, a weak base reagent is used to replace the strong base reagent in the existing reaction, so that the impurity content of the final product is greatly reduced; at the same time, in the post-treatment process of step 3, there is no need to perform neutralization and concentration treatment, because the neutralization and concentration process will produce a large amount of by-products. In the present invention, water is directly added for crystallization and filtration to obtain a product with a purity of ≥99%, and the yield of the product is ≥90%. Not only is the operation simple, but also it is suitable for industrial scale-up production.

[0019] In each step of the present invention, no highly toxic auxiliary materials are used, which is friendly to the environment and operators and has obvious competitive advantages.

[0020] In summary, the present invention uses acetate triene (21-hydroxypregnane-4,9(11),16-tetraene-3,20-dione-21-acetate) (D-2) as a raw material, has a small number of reaction steps, does not use highly toxic auxiliary materials, and has good reaction controllability. The intermediates and final products are easy to purify and have high purity. The product yield is high and the cost is low, and it is suitable for large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 The D-3 prepared in Example 1 1 H-NMR spectrum; Figure 2 The D-3 prepared in Example 113 C-NMR spectrum; Figure 3 The D-5 obtained by the preparation of Example 1 1 H-NMR spectrum; Figure 4 The D-5 obtained by the preparation of Example 1 13 C-NMR spectrum. DETAILED DESCRIPTION

[0022] The following will further describe the specific implementation of the present invention in combination with the embodiments of the present invention, so that the technical solution of the present invention is easier to understand and grasp. It should be understood that the embodiments described herein are only used to explain part of the embodiments of the invention, rather than all of the embodiments. Other embodiments obtained by ordinary technicians in this field without creative work are all within the scope of protection of the present invention.

[0023] Example 1 A method for preparing a high-purity halcinonide intermediate comprises the following steps: Step 1 (reaction formula is shown in the following formula II): 11) Preparation of potassium permanganate solution: Dissolve 173.8 g (1.1 mol) of potassium permanganate in a mixed solution of 4.8 L acetone / 960 ml water, and stir at room temperature to obtain a potassium permanganate solution with a concentration of 0.19 mol / L.

[0024] 12) Preparation of sodium sulfite aqueous solution: Dissolve 65.68 g (0.52 mol) of sodium sulfite in 320 ml of water and stir to dissolve to obtain a sodium sulfite aqueous solution with a concentration of 1.63 mol / L.

[0025] 13) Add 320 g (0.87 mol) of 21-hydroxypregnane-4,9(11),16-tetraene-3,20-dione-21-acetate (abbreviated as D-2), 4.8 L of acetone and 159 g (3.46 mol) of formic acid to a 20 L reactor, cool in a refrigerator, set the temperature to -30 °C and stir to cool; control the temperature at -20 °C ± 10 °C, and slowly drop the potassium permanganate solution prepared in step 11) for 1 to 2 minutes. h; after the addition is completed, keep the temperature for reaction for 1 hour; after the reaction of the raw materials is complete as detected by TLC, the temperature is raised to 45°C±5°C, and the sodium sulfite aqueous solution prepared in step 12) is added dropwise; after the addition is completed, filter with diatomaceous earth while hot, and rinse the filter cake with 640ml of dichloromethane; the filtrate is concentrated under reduced pressure in a water bath at 35±5°C to obtain a yellow paste; 3.2L of water is added to the yellow paste and the mixture is slurried at room temperature for 2 hours; filter with suction, and rinse the filter cake with 640ml of water to obtain a wet product of D-3; The wet product D-3 was transferred to a 5L reaction bottle, 3.2L acetone was added, the temperature was raised to 55℃±5℃, and hot pulping was performed for 1h; the heating was turned off, and the product was transferred to a 10℃ refrigerator for cooling, the temperature was controlled at 10℃±5℃, and crystallization was performed for 1h; the product was filtered, and the filter cake was rinsed with 320ml of pre-cooled acetone to obtain 324.90g of the wet product; the filter cake was dried at 50℃±5℃ to constant weight to obtain 277.10g of D-3, with a molar yield of 79.31% and a purity of 99.41%.

[0026] The D-3 1 H-NMR spectrum is shown in Figure 1 , 13 C-NMR spectrum is shown in Figure 2 ; like Figure 1 and Figure 2 As shown, the D-3 NMR data are as follows: 1 H-NMR (400MHz, D6-DMSO): 0.546 (s, 3H); 0.967-1.008 (m, 1H); 1.243-1.296 (s, 3H); 1.534- 1.575 (m, 1H); 1.763-1.816 (m, 2H); 1.895-1.993 (m, 3H); 2.009-2.075 (m, 4H); 2.159 (m, 1H ); 2.248-2.341 (m, 2H); 2.433-2.456 (m, 1H); 2.512-2.681 (m, 2H); 4.741-4.787 (m, 1H); 4. 832-4.876 (m, 1H); 4.953-5.000 (m, 2H); 5.321-5.335 (s, 1H); 5.493 (s, 1H); 5.507 (s, 1H); 13 C-NMR (400MHz, D6-DMSO): 14.43 (primary carbon); 20.87 (primary carbon); 26.24 (primary carbon); 32.31 (secondary carbon); 32.39 (secondary carbon); 33.73 (secondary carbon); 34.38 (tertiary carbon); 34.76 (secondary carbon); 37.00 (tertiary carbon); 41.08 (quaternary carbon); 46.29 (secondary carbon); 46.94 (quaternary carbon); 68.89 (secondary carbon); 72.73 (tertiary carbon); 88.54 (quaternary carbon); 118.52 (tertiary carbon); 123.76 (quaternary carbon); 144.62 (tertiary carbon); 169.97 (quaternary carbon); 170.33 (quaternary carbon); 198.28 (quaternary carbon); 206.22 (quaternary carbon).

[0027] D-3 mass spectrum data: molecular formula is C 23 H 30O6, molecular weight is 402.49 (M), positive ion peak m / z=403.21 [M+H] + This is consistent with the molecular weight of the compound.

[0028] Formula II.

[0029] Step 2 (reaction formula see formula III): 21) Preparation of perchloric acid aqueous solution: Dissolve 6.48 g (64.5 mmol) of perchloric acid in 325 ml of water to obtain a 0.198 mol / L perchloric acid aqueous solution.

[0030] 22) Prepare sodium sulfite aqueous solution: Dissolve 40.704 g (323 mmol) of sodium sulfite in 2.6 L of water to obtain a sodium sulfite aqueous solution with a concentration of 0.124 mol / L.

[0031] 23) Add 130 g of D-3 (323 mmol) and 1.3 L of acetone to the reaction bottle and cool it in a refrigerator, and control the temperature at 10°C ± 5°C. Then, add the aqueous perchloric acid solution prepared in step 21) under stirring. Adjust the temperature to 0°C ± 5°C, add 74.73 g of N-bromosuccinimide (420 mmol) at one time, and then keep warm for 1 hour. After TLC detection, the raw material reaction is complete, and the aqueous sodium sulfite solution prepared in step 22) is added to quench the reaction. After the addition is completed, control the temperature at 10°C ± 5°C for crystallization for 1 hour. Filter by suction, rinse the filter cake with 520 ml of water until the filtrate is colorless, and the filter cake is the product D-4. D-4 has a wet weight of 245 g and a purity of 98.77%, and is directly used in the next step.

[0032] Formula III.

[0034] Step 3 (reaction formula see formula IV): 31) Prepare potassium carbonate aqueous solution: dissolve 89 g potassium carbonate in 100 ml water.

[0035] 32) Add 245 g (323 mmol) of the wet product D-4 from the previous step, 650 ml of dichloromethane, and 650 ml of methanol to a 1L three-necked flask and cool it in a refrigerator, setting the temperature to 15°C. Replace with nitrogen three times, control the temperature at 25°C±5°C, and drop the potassium carbonate aqueous solution prepared in step 31). After the addition is complete, keep warm for 1 hour, and the reaction is complete as detected by TLC, and then drop 1200 ml of water. After the addition is complete, control the temperature at 20°C±5°C for crystallization for 3 hours. Filter by suction, and wash the filter cake with a mixed solvent of 150 ml methanol / 210 ml water, and the wet product is 161 g; the filter cake is air-dried at 50°C±5°C to constant weight, and 99.41 g of D-5 white solid is obtained, and the total molar yield of D-3 to D-5 is 81.76%, and the purity is 98.267%.

[0036] Formula IV.

[0037] The D-5 1 H-NMR spectrum is shown in Figure 3 , 13 C-NMR spectrum is shown in Figure 4 ; Depend on Figure 3 and Figure 4 It can be seen that the D-5 NMR data are as follows; 1 H-NMR (400MHz, D6-DMSO): 0.724 (s, 3H); 1.332 (s, 3H); 1.402-1.520 (m, 3H); 1.609-1.737 (m, 3H); 2.086-2.514 (m, 8H); 3.43 4 (s, 1H); 4.062-4.075 (d, 1H); 4.110-4.123 (d, 1H); 4.611-4.640 (m, 1H); 4.722-4.774 (m, 3H); 5.317 (m, 1H); 5.691 (s, 1H); 13 C-NMR (400MHz, D6-DMSO): 17.62 (primary carbon); 23.80 (primary carbon); 25.58 (secondary carbon); 28.84 (secondary carbon); 30.76 (secondary carbon); 31.08 (tertiary carbon); 34.03 (tertiary carbon); 34.62 (secondary carbon); 35.10 (secondary carbon); 39.42 (quaternary carbon); 44.64 (secondary carbon); 45.84 (quaternary carbon); 60.19 (secondary carbon); 65.52 (tertiary carbon); 67.09 (tertiary carbon); 71.46 (tertiary carbon); 87.98 (quaternary carbon); 123.99 (tertiary carbon); 170.44 (quaternary carbon); 197.96 (quaternary carbon); 211.85 (quaternary carbon).

[0038] D-5 mass spectrum data: molecular formula C 21 H 28 The molecular weight of O6 is 376.45 (M), and the negative ion peak m / z is 375.8 [MH] - This is consistent with the molecular weight of the compound.

[0039] Example 2 Step 1: 11) Preparation of potassium permanganate solution: Dissolve 181.7 g of potassium permanganate in a mixed solution of 4.8 L of acetone and 960 ml of water, and stir at room temperature to obtain a 0.2 mol / L potassium permanganate solution.

[0040] 12) Preparation of sodium sulfite aqueous solution: Dissolve 65.68 g (0.52 ml) of sodium sulfite in 320 ml of water and stir to dissolve to obtain a sodium sulfite aqueous solution.

[0041] 13) Add 320 g of 21-hydroxypregnane-4,9(11),16-tetraene-3,20-dione-21-acetate (abbreviated as D-2), 4.8 L of acetone and 159 g of formic acid to a 20 L reactor, cool in a refrigerator, set the temperature to -30°C and stir to cool; control the temperature at -10°C±10°C, slowly drop the potassium permanganate solution prepared in step 11) for 1-2 h; after the drop is complete, keep the temperature for reaction for 1 h; after TLC detection, the reaction of the raw materials is complete, then raise the temperature to 45°C±5°C, and drop the sodium sulfite aqueous solution prepared in step 12); after the drop is complete, filter with diatomaceous earth while hot, and rinse the filter cake with 640 ml of dichloromethane; concentrate the filtrate under reduced pressure in a water bath at 35±5°C to obtain a yellow paste; add 3.2 L of water to the yellow paste and beat at room temperature for 2 h; filter with suction, and rinse the filter cake with 640 ml of water to obtain a wet product D-3; The wet product D-3 was transferred to a 5L reaction bottle, 3.2L of acetone was added, the temperature was raised to 40℃±5℃, and hot pulping was performed for 3h; the heating was turned off, the product was transferred to a 10℃ refrigerator for cooling, the temperature was controlled at 20℃±5℃, and crystallization was performed for 1h; the product was filtered, and the filter cake was rinsed with 320ml of pre-cooled acetone to obtain 324.90g of the wet product; the filter cake was dried at 50℃±5℃ to constant weight to obtain 273.22g of D-3, with a molar yield of 78.20% and a purity of 99.21%.

[0042] Step 2: 21) Preparation of perchloric acid aqueous solution: Dissolve 6.48 g (64.5 mmol) of perchloric acid in 325 ml of water to obtain a 0.198 mol / L perchloric acid aqueous solution.

[0043] 22) Prepare sodium sulfite aqueous solution: Dissolve 40.704 g (323 mmol) of sodium sulfite in 2.6 L of water to obtain a sodium sulfite aqueous solution with a concentration of 0.124 mol / L.

[0044] 23) Add 130 g of D-3 (323 mmol) and 1.3 L of acetone to the reaction bottle and cool it in a refrigerator, and control the temperature at 10°C ± 5°C. Then, add the aqueous perchloric acid solution prepared in step 21) under stirring. Adjust the temperature to 0°C ± 5°C, add 74.73 g of N-bromosuccinimide (420 mmol) at one time, and then keep warm for 3 hours. After TLC detection, the raw material reaction is complete, and the aqueous sodium sulfite solution prepared in step 22) is added to quench the reaction. After the addition is completed, control the temperature at 10°C ± 5°C for crystallization for 3 hours. Filter by suction, rinse the filter cake with 520 ml of water until the filtrate is colorless, and the filter cake is the product D-4. D-4 has a wet weight of 238 g and a purity of 98.97%, and is directly used in the next step.

[0045] Step 3: 31) Prepare potassium carbonate aqueous solution: dissolve 89 g potassium carbonate in 100 ml water.

[0046] 32) Add 238 g (323 mmol) of the wet product D-4 from the previous step, 650 ml of dichloromethane, and 650 ml of methanol to a 1L three-necked flask and cool it in a refrigerator, setting the temperature to 15°C. Replace with nitrogen three times, control the temperature at 30°C ± 5°C, and drop the potassium carbonate aqueous solution prepared in step 31). After the dropwise addition is completed, keep the reaction warm for 1 hour. After the reaction is complete as detected by TLC, add 1200 ml of water. After the dropwise addition is completed, control the temperature at 5°C ± 5°C for crystallization for 1 hour. Filter by suction, and wash the filter cake with a mixed solvent of 150 ml methanol / 210 ml water, yielding 161 g of wet product; the filter cake is air-dried at 50°C ± 5°C to constant weight, yielding 97.41 g of white solid D-5, with a total molar yield of 80.12% from D-3 to D-5 and a purity of 98.267%.

[0047] Example 3 A method for preparing a high-purity halcinonide intermediate comprises the following steps: Step 1: Add 55.6 kg of acetone, 1.39 kg (3.79 mol) of D-2, and 0.61 kg (13.26 mol) of formic acid to a 100L reactor, stir until the solid is completely dissolved, control the internal temperature at -10±5°C, and start to drop potassium permanganate solution (0.77 kg (4.87 mol) KMnO4 dissolved in a pre-mixed solution of 4.058 kg water and 16 kg (20.29 L) acetone). After the addition is complete, keep warm for 1.5 hours. After TLC detection, the reaction is complete, slowly raise the temperature, and start to drop sodium sulfite aqueous solution (0.83 kg (6.59 mol) of sodium sulfite dissolved in 7.65 kg water, with a concentration of 0.86 mol / L) at an internal temperature of 20°C. After the addition is complete, continue to raise the temperature to 45°C and stir for 10 minutes. Filter while hot, and rinse the filter cake with 2.22 kg of dichloromethane. The filtrate was concentrated under reduced pressure at 40°C to recover acetone. After completion, 146 kg of water was added to the filter cake, and the temperature was controlled at 10±5°C for 2 hours. Filter by suction, and rinse the filter cake with 2.22 kg of water. The filter cake was transferred to a 20L reactor, 6.95L of acetone was added, the temperature was controlled at 55°C±5°C, and hot slurry was performed for 1 hour. Cool down, crystallize at 10°C±5°C for 1 hour, filter by suction, rinse the filter cake with 1.39L of pre-cooled acetone, and dry the filter cake in a blast oven at 50°C±5°C. 1.36 kg of D-3 was obtained, with a molar yield of 90% and a purity of 99.6%.

[0048] Step 2: 21) Preparation of perchloric acid aqueous solution: Dissolve 64.76 g (0.645 mol) of perchloric acid in 3.25 L of water to obtain a 0.198 mol / L perchloric acid aqueous solution.

[0049] 22) Preparation of sodium sulfite aqueous solution: Dissolve 407.04 g (3.23 mol) of sodium sulfite in 26 L of water to obtain a sodium sulfite aqueous solution with a concentration of 0.124 mol / L.

[0050] 23) Add 1.3 kg of D-3 (3.23 mol) and 13 L of acetone to the reaction bottle and cool it in a refrigerator, and control the temperature at 10°C ± 5°C. Then, add the aqueous perchloric acid solution prepared in step 21) under stirring. Adjust the temperature to 0°C ± 5°C, add 745 g of N-bromosuccinimide NBS at one time, and keep the reaction for 1 hour. After TLC detection, the raw material reaction is complete, and the aqueous sodium sulfite solution prepared in step 22) is added to quench the reaction. After the addition is completed, control the temperature at 10°C ± 5°C for crystallization for 1 hour. Filter by suction, rinse the filter cake with 5.2 L of water until the filtrate is colorless, and obtain D-4. D-4 has a wet weight of 2.50 kg and a purity of 98.77%, and is directly used in the next step.

[0051] Step 3: 31) Prepare potassium carbonate aqueous solution: Dissolve 801 g of potassium carbonate in 900 ml of water to obtain potassium carbonate aqueous solution.

[0052] 32) Add 2.5 kg of D-4 (wet product) (D-4 is calculated based on the feed amount of D-3, 3.23 mol), 5.85 L of dichloromethane, and 5.85 L of methanol to a 5 L three-necked flask and cool to 25 °C in a refrigerator. Replace with nitrogen three times, control the temperature at 25 °C ± 5 °C, and drop the potassium carbonate aqueous solution prepared in step 31). After the addition is complete, keep warm for 1 hour, and the reaction is complete as detected by TLC. Continue to drop 10.8 L of water into the reaction solution, and after the addition is complete, control the temperature at 10 °C ± 5 °C for crystallization for 1 hour. Filter with suction, and rinse the filter cake with a mixed solvent of 1.35 L of methanol / 1.89 L of water to obtain 1.62 kg of wet product; The wet product was dried at 50°C ± 5°C to constant weight to obtain 1004 g of white solid D-5. The total molar yield of D-3 to D-5 was 91.76%, and the purity of D-5 was 99.27%.

[0053] It should be noted that, in this article, relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variants thereof are intended to cover non-exclusive inclusion, so that the process, method, article or terminal device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or terminal device. In the absence of further restrictions, the elements defined by the sentence "include..." or "comprise..." do not exclude the existence of other elements in the process, method, article or terminal device including the elements. In addition, in this article, "greater than", "less than", "exceed" and the like are understood to exclude the number itself; "above", "below", "within" and the like are understood to include the number itself.

[0054] It should be noted that, although the above embodiments have been described in this article, the patent protection scope of the present invention is not limited thereby. Therefore, based on the innovative concept of the present invention, changes and modifications made to the embodiments described herein, or equivalent structures or equivalent process changes made using the contents of the present invention specification, directly or indirectly applying the above technical solutions to other related technical fields are all included in the patent protection scope of the present invention.

Claims

1. A method for preparing a high-purity halcinonide intermediate, characterized in that: It includes the following steps: Step 1: Dissolve 21-hydroxypregnane-4,9(11),16-tetraene-3,20-dione-21-acetate in acetone, add an acidic reagent, cool to -30°C~0°C, drop potassium permanganate solution and keep warm for 1~2h. After the reaction is completed, filter, beat the obtained crude product with 5~10 times the volume of acetone, control the temperature at 40~55°C for 1~3h, then cool to 10~25°C for crystallization, and then filter, Drying to obtain a reaction product D-3; the added 21-hydroxypregnane-4,9(11),16-tetraene-3,20-dione-21-acetate, acidic solution and potassium permanganate have a molar ratio of 1:3.0-4.0:1.25-1.35; the volume of acetone in the reaction solution is 30 times the mass of 21-hydroxypregnane-4,9(11),16-tetraene-3,20-dione-21-acetate; Step 2: dissolving D-3 obtained in step 1 in organic solvent B, cooling to -15°C~15°C, dropping an acid catalyst, and then adding N-bromosuccinimide NBS and keeping the temperature for reaction for 1~3h; after the reaction is completed, controlling the temperature at 10°C±5°C for crystallization for 1~3h, and filtering to obtain a reaction product D-4; wherein the molar ratio of the added D-3, acid catalyst, and N-bromosuccinimide NBS is 1:0.10-0.50:1.00-1.50; Step 3: dissolving D-4 obtained in step 2 in an organic solvent C, adding a weak base reagent to react for 1 to 3 hours at 15 to 35° C. and in a nitrogen atmosphere; after the reaction, adding water to crystallize, controlling the temperature at 0 to 25° C. to crystallize for 1 to 3 hours; finally filtering and drying to obtain the halcinonide intermediate D-5; the ratio of the amount of D-4 and the weak base reagent added is 1:1.9-2.

1.

2. The method for preparing a high-purity halcinonide intermediate according to claim 1, characterized in that: The acidic reagent in step 1 is formic acid.

3. The method for preparing a high-purity halcinonide intermediate according to claim 1, characterized in that: In step 1, the potassium permanganate solution is a solution of potassium permanganate dissolved in a mixture of acetone and water, wherein the acetone and water are mixed in a volume ratio of 5:1; and the concentration of potassium permanganate in the solution is 0.19 mol / L-0.2 mol / L.

4. The method for preparing a high-purity halcinonide intermediate according to claim 1, characterized in that: In the step 1, after the reaction is completed, a sodium sulfite aqueous solution with a concentration of 0.86 mol / L-1.63 mol / L is added to quench the reaction. In the step 2, after the reaction is completed, a sodium sulfite aqueous solution with a concentration of 0.12 mol / L-0.13 mol / L is added to quench the reaction.

5. The method for preparing a high-purity halcinonide intermediate according to claim 1, characterized in that: In the step 2, the organic solvent B is acetone; the volume of the added acetone is 9.5-10.5 times the volume of D-3.

6. The method for preparing a high-purity halcinonide intermediate according to claim 1, characterized in that: The acid catalyst in step 2 is: a perchloric acid aqueous solution with a concentration of 0.19 mol / L-0.20 mol / L.

7. The method for preparing a high-purity halcinonide intermediate according to claim 1, characterized in that: The weak base reagent in step 3 is: a potassium carbonate aqueous solution with a mass percentage concentration of 40%-50%.

8. The method for preparing a high-purity halcinonide intermediate according to claim 1, characterized in that: The organic solvent C in step 3 is a mixture of dichloromethane and methanol in a volume ratio of 1:1; the volume of the added organic solvent C is 9.5-10.5 times the volume of D-4.

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