Preparation method of methylprednisolone or derivative thereof

Abstract

The invention relates to a preparation method of methylprednisolone or a derivative thereof, which comprises the following steps: mixing a compound 1, methanol, acetone cyanohydrin and a potassium carbonate solution, and reacting to obtain a compound 2; mixing the compound 2, dichloromethane, piperidine, imidazole and chloromethyl dimethyl chlorosilane, and reacting to obtain a compound 3; adding a lithium diisopropylamide solution into a mixed solution of a compound 3 and tetrahydrofuran, and reacting; adding into the mixed solution, keeping the temperature, heating, reacting and treating to obtain a compound 4; mixing the compound 4, N, N-dimethylformamide, potassium acetate, water and acetic acid, and reacting to obtain a compound 5; adding a liquid alkali solution into a mixed solution of the compound 5, dichloromethane and methanol, and carrying out heat preservation and reaction to obtain a compound I; according to the method disclosed by the invention, the cost of the raw materials is reduced, the pollution is reduced, and the yield and the purity of the product are improved.

Description

Technical Field

[0001] The present invention belongs to the technical field of steroid hormone preparation, and particularly relates to a preparation method of methylprednisolone or its derivatives. Background Art

[0002] Methylprednisolone, as a synthetic medium-acting glucocorticoid, has core pharmacological effects such as anti-inflammatory, immunosuppressive, and anti-allergic. Its anti-inflammatory intensity is 5 times that of hydrocortisone and 1.4 times that of prednisone, and it has the strongest affinity for glucocorticoid receptors. Its chemical structure is 11β,17α,21-trihydroxy-6α-methylpregn-1,4-diene-3,20-dione (C 22 H 30 O 5 ), and the unique 6α-methyl substitution group significantly reduces the mineralocorticoid-like effect.

[0003] The current main preparation route is as follows: Using pregnenolone as the raw material, through ketal protection, 11-keto reduction, 5(6)-double bond epoxidation, 6-methylation, 1(2)-dehydrogenation, 21-iodination, 21-position substitution, and 21-ester hydrolysis reactions to obtain methylprednisolone (see specifically Patent Authorization Announcement No. CN108912192B).

[0004]

[0005] The above preparation route involves simple arthrobacter fermentation dehydrogenation. Currently, the fermentation feedstock concentration is low (2-3%), and the production cycle is long (3-4 days); moreover, in the iodine substitution step, iodine is difficult to recover, resulting in high auxiliary material costs.

[0006] 16α-Methyl-9,11-dehydroprednisolone, commonly known as Vamorolone, CAS: 13209-41-1, this drug is an orally active dissociative steroid anti-inflammatory drug and membrane stabilizer. The cost of its original research route is relatively high and is not suitable for industrial large-scale production. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide a preparation method of methylprednisolone or its derivatives, which reduces the cost of raw materials, reduces pollution, and improves the yield and purity of the product.

[0008] The embodiment of the present invention provides a preparation method of methylprednisolone or its derivatives, including any one of the following reaction routes. Reaction route one includes the following steps:

[0009] Mix compound 1, methanol, acetone cyanohydrin and potassium carbonate solution, and react to obtain compound 2; the mass concentration of the potassium carbonate solution is 3.5 - 5%, the mass - volume ratio of compound 1 to methanol is 1:1.8 - 2.2, the mass - volume ratio of compound 1 to acetone cyanohydrin is 1:0.9 - 1.1, and the mass - volume ratio of compound 1 to potassium carbonate solution is 1:1.8 - 2.2;

[0010] Mix compound 2, dichloromethane, piperidine, imidazole and chloromethyldimethylchlorosilane, and react (preferably control the temperature below 10°C) to obtain compound 3; the mass - volume ratio of compound 2 to dichloromethane is 1:2.8 - 4.0, the mass ratio of compound 2 to piperidine is 1:0.22 - 0.28, the mass ratio of compound 2 to imidazole is 1:0.16 - 0.25, and the mass ratio of compound 2 to chloromethyldimethylchlorosilane is 1:0.5 - 0.6;

[0011] Add lithium diisopropylamide solution to the mixed solution of compound 3 and tetrahydrofuran, control the temperature below - 70°C, and react; cool down to below - 90°C, add the reaction solution to the mixed solution prepared from hydrochloric acid, hydrofluoric acid and potassium bisulfate, then heat up to 30 - 40°C, react for 2 - 3 h, cool down to below 30°C and adjust the pH to neutral, and process to obtain compound 4; the mass concentration of hydrochloric acid is 8 - 12%, the mass concentration of hydrofluoric acid is 35 - 45%, the volume ratio of hydrochloric acid to hydrofluoric acid is 1:0.8 - 1.2, and the volume - mass ratio of hydrochloric acid to potassium bisulfate is 1:0.05 - 0.07;

[0012] Mix compound 4, N,N - dimethylformamide, potassium acetate, water and acetic acid, and react to obtain compound 5;

[0013] Add liquid alkali solution to the mixed solution of compound 5, dichloromethane and methanol, keep warm and react to obtain compound Ⅰ;

[0014] Ferment compound Ⅰ (which is equivalent to enzymatic dehydrogenation, the same below), and react to obtain methylprednisolone or its derivatives;

[0015] Or ferment compound 5, and react to obtain compound 6;

[0016] Add liquid alkali solution to the mixed solution of compound 6, dichloromethane and methanol, keep warm, react to obtain methylprednisolone or its derivatives; the reaction route is as follows:

[0017]

[0018] Reaction route two includes the following steps:

[0019] Ferment compound 1, and react to obtain compound 7;

[0020] Compound 7, methanol, acetone cyanohydrin and potassium carbonate solution are mixed and reacted to obtain Compound 8; the mass concentration of the potassium carbonate solution is 3.5 - 5%, the mass - to - volume ratio of Compound 7 to methanol is 1:1.8 - 2.2, the mass - to - volume ratio of Compound 7 to acetone cyanohydrin is 1:0.9 - 1.1, and the mass - to - volume ratio of Compound 7 to potassium carbonate solution is 1:1.8 - 2.2;

[0021] Compound 8, dichloromethane, piperidine, imidazole and chloromethyldimethylchlorosilane are mixed and reacted to obtain Compound 9; the mass - to - volume ratio of Compound 8 to dichloromethane is 1:2.8 - 4.0, the mass ratio of Compound 8 to piperidine is 1:0.22 - 0.28, the mass ratio of Compound 8 to imidazole is 1:0.16 - 0.25, and the mass ratio of Compound 8 to chloromethyldimethylchlorosilane is 1:0.5 - 0.6;

[0022] Lithium diisopropylamide solution is added to the mixed solution of Compound 9 and tetrahydrofuran, the temperature is controlled below - 70 °C and reacted; the temperature is lowered to below - 90 °C, the reaction solution is added to the mixed solution prepared from hydrochloric acid, hydrofluoric acid and potassium bisulfate, then the temperature is raised to 30 - 40 °C and reacted for 2 - 3 h, and the temperature is lowered to below 30 °C to adjust the pH to neutral and processed to obtain Compound 10; the mass concentration of hydrochloric acid is 8 - 12%, the mass concentration of hydrofluoric acid is 35 - 45%, the volume ratio of hydrochloric acid to hydrofluoric acid is 1:0.8 - 1.2, and the volume - to - mass ratio of hydrochloric acid to potassium bisulfate is 1:0.05 - 0.07;

[0023] Compound 10, N,N - dimethylformamide, potassium acetate, water and acetic acid are mixed and reacted to obtain Compound 6;

[0024] Liquid caustic solution is added to the mixed solution of Compound 6, dichloromethane and methanol, heat - maintained and reacted to obtain methylprednisolone or its derivative;

[0025] The reaction route is as follows:

[0026]

[0027] Said R 1 is CH 3 or H, R 2 is OH or H, R 3 is CH 3 or H, is a single bond or a double bond. The above two reaction routes are applicable to methylprednisolone (R 1 is CH 3 ,R 2 is OH, R 3 is H, is a single bond), 16α - methyl - 9,11 - dehydroprednisolone (R1 is H, R 2 is H, R 3 is CH 3 , (wherein the double bond is involved) in the synthesis. When R 1 is H, R 2 is H, R 3 is CH 3 , is a double bond, the first route above is Reaction Route 1 and Reaction Route 2 in Patent Application 202510184058.4, and the second route above is Reaction Route 3 in Patent Application 202510184058.4.

[0028] Preferably, the mass-to-volume ratio of Compound 1 to methanol is 1:2, the mass-to-volume ratio of Compound 1 to acetone cyanohydrin is 1:1, and the mass-to-volume ratio of Compound 1 to potassium carbonate solution is 1:2; or, the mass-to-volume ratio of Compound 7 to methanol is 1:2, the mass-to-volume ratio of Compound 7 to acetone cyanohydrin is 1:1, and the mass-to-volume ratio of Compound 7 to potassium carbonate solution is 1:2.

[0029] Preferably, the mass-to-volume ratio of Compound 2 to dichloromethane is 1:3.5, the mass ratio of Compound 2 to piperidine is 1:0.25, the mass ratio of Compound 2 to imidazole is 1:0.2, and the mass ratio of Compound 2 to chloromethyldimethylchlorosilane is 1:0.55; or, the mass-to-volume ratio of Compound 8 to dichloromethane is 1:3.5, the mass ratio of Compound 8 to piperidine is 1:0.25, the mass ratio of Compound 8 to imidazole is 1:0.2, and the mass ratio of Compound 8 to chloromethyldimethylchlorosilane is 1:0.55.

[0030] Preferably, in the preparation step of Compound 3 or Compound 9, the reaction temperature is -5 - 0°C.

[0031] Preferably, in the preparation step of Compound 4 or Compound 10, the weight-to-volume ratio of Compound 3 or Compound 9 to tetrahydrofuran is 1:3.

[0032] Preferably, in the preparation step of Compound 4 or Compound 10, the substance for adjusting the pH to neutral is sodium hydroxide solution.

[0033] Preferably, in the preparation step of Compound 5 in Reaction Route 1 or Compound 6 in Reaction Route 2, the weight-to-volume ratio of Compound 4 or Compound 10 to N,N-dimethylformamide is 1:5; the weight ratio of Compound 4 or Compound 10 to potassium acetate is 1:1.2; the weight-to-volume ratio of Compound 4 or Compound 10 to water is 1:0.2; the weight-to-volume ratio of Compound 4 or Compound 10 to acetic acid is 1:0.2.

[0034] Preferably, in the preparation step of Compound 5 in Reaction Route 1 or Compound 6 in Reaction Route 2, the reaction temperature is 60°C.

[0035] Preferably, in the preparation step of preparing methylprednisolone or its derivatives from Compound 6, the weight ratio of Compound 6 to the liquid alkali solution is 1:1; the weight-to-volume ratio of Compound 6 to dichloromethane is 1:10; the weight-to-volume ratio of Compound 6 to methanol is 1:6.

[0036] Preferably, in the preparation step of preparing methylprednisolone or its derivatives from Compound 6, the reaction temperature is 0 - 5°C.

[0037] In the preparation step of preparing methylprednisolone or its derivatives from Compound I in Reaction Route 1, or in the preparation step of preparing Compound 7 from Compound 1 in Reaction Route 2, the fermentation is carried out according to the method in Example 3 of CN115725522 A. The steps are as follows:

[0038] Weigh 1.5 g of the raw material (i.e., Compound I or Compound 1) into a conversion flask, add 3 mL of isopropanol, stir to disperse it evenly, then add 24 mL of potassium hydrogen phosphate - potassium dihydrogen phosphate buffer solution (pH 8.0, 0.05 M), and continue to stir evenly while maintaining the temperature at 30°C. Add the recombinant mutant strain M3 (M3 in Example 1 of CN115725522 A) with a final concentration of 100 g / L, and finally add 0.13 g of methylene blue sulfate, and the molar mass ratio of it to the substrate is 0.1:1. The reaction starts, and during the process, the pH of the system is controlled at 7.8 - 8.2 with 10% sodium hydroxide solution. Monitor the residual amount of the substrate by TLC during the reaction process. Take 0.2 ml of the reaction sample, add 0.3 ml of the extractant dichloromethane, shake well, centrifuge for 20 s, and absorb the lower clear liquid; the developing agent is chloroform:methanol:water = 6 ml:1 ml:0.03 ml, and it is visualized under ultraviolet light. At the 9th hour of the conversion, the conversion rate is 85%; at the 12th hour of the conversion, the conversion rate is 99%.

[0039] The beneficial effects of the present invention are that the production conditions of the present invention are simple, the yield is high, and it is suitable for large-scale industrial production.

[0040] In the preparation steps of Compound 2 and Compound 8 of the present invention, methanol, acetone cyanohydrin, and potassium carbonate solution are selected as reaction raw materials, and the concentration of the potassium carbonate solution is controlled, and the amounts of methanol, acetone cyanohydrin, and potassium carbonate solution are controlled, which significantly reduces the content of impurities and improves the yield and purity of the target product.

[0041] In the preparation steps of Compound 3 and Compound 9 of the present invention, dichloromethane, imidazole, and chloromethyldimethylchlorosilane are added, and the amounts of each raw material are controlled, which improves the yield and purity of the product and reduces the content of the reaction substrate.

[0042] In the preparation steps of Compound 4 and Compound 10 of the present invention, no silane reagent is added during the whole reaction, and concentrated hydrochloric acid is used for hydrolysis instead of dilute hydrochloric acid or other acids. By controlling the reaction time between 10 - 16 h, the product yield and purity can be significantly improved.

[0043] In the preparation steps of Compound 5 in Reaction Route 1 and Compound 6 in Reaction Route 2 of the present invention, water, acetic acid, and potassium acetate are added to the whole reaction system. Compared with the method of not adding water or not adding acetic acid, the product yield, purity can be significantly improved, and the content of the substrate can be reduced.

[0044] In the preparation step of preparing methylprednisolone or its derivatives from Compound 6 in this application, liquid alkali is used instead of other basic reagents, which can significantly improve the product yield, purity, and reduce the content of the substrate. Description of the Drawings

[0045] Figure 1 It is the HPLC chromatogram of the product 16α - methyl - 9,11 - dehydroprednisolone in the present invention.

[0046] Figure 2 It is the reaction route diagram of 16α - methyl - 9,11 - dehydroprednisolone in this application.

[0047] Figure 3 It is the 1H - NMR spectrum of the product 16α - methyl - 9,11 - dehydroprednisolone in the present invention.

[0048] Figure 4 It is the 13C - NMR spectrum of the product 16α - methyl - 9,11 - dehydroprednisolone in the present invention.

[0049] Figure 5 It is the HPLC chromatogram of the product methylprednisolone in the present invention.

[0050] Figure 6 It is the reaction route diagram of methylprednisolone in this application.

[0051] Figure 7 It is the 1H - NMR spectrum of the product methylprednisolone in the present invention.

[0052] Figure 8 It is the 13C - NMR spectrum of the product methylprednisolone in the present invention. Detailed Description of the Invention

[0053] In the examples, the volume V and weight w are determined according to the weight ratio of the main raw materials of their respective reactions. If the weight of the main raw material is 100 g, then 1V volume represents 100 mL, and 1w weight represents 100 g. For example, 2V methanol in Example 1 represents 200 mL of methanol, and 0.5V acetone cyanohydrin represents 50 mL of acetone cyanohydrin, and the others are similar.

[0054] Example 1

[0055] For Compound 1, the starting material 16α-methyl-4,9-androstadiene-3,17-dione was an externally purchased raw material, and its hydrogen spectrum and carbon spectrum data are as follows:

[0056] 1 H NMR(400MHz,CDCl 3 )δ5.73(d,J=4.9Hz,1H),5.52(dt,J=5.5,3.0Hz,1H),3.74-3.63(m,1H),2.64-2.29(m,6H),2.08(dp,J=12.3,5.6Hz,5H),1.90(tdd,J=12.8,9.3,4.0Hz,1H),1.59-1.46(m,1H),1.33(d,J=4.2Hz,3H),1.20(q,J=5.9,5.3Hz,1H),1.07(td,J=5.6,5.2,2.9Hz,3H),0.88(d,J=4.4Hz,3H).

[0057] 13 C NMR(101MHz,CDCl 3 )δ223.12,199.25,169.24,145.21,124.23,118.22,46.46,45.35,41.23,39.83,36.84,34.30,33.88,33.73,32.70,31.18,30.99,26.32,16.88,14.47.

[0058] Preparation of Compound 2: 16α-methyl-17α-hydroxy-17β-cyano-4,9-androstadien-3-one

[0059]

[0060] 100 g of Compound 1, 2V (i.e., 200 mL) of methanol, and 0.5V (i.e., 50 mL) of acetone cyanohydrin were added to a reaction flask and stirred for about 30 min. Then, a potassium carbonate solution prepared with 0.09w (i.e., 9 g) of potassium carbonate and 2V (i.e., 200 mL) of water was added, and the mixture was stirred at 32 °C for 24 hours. TLC was used to monitor until the reaction was basically complete. 15v (i.e., 1.5 L) of water was added to the reaction system and stirred for about 1 h, and an appropriate amount of hydrochloric acid was slowly added to adjust the pH of the system to 5. The mixture was filtered by suction and washed with water until neutral. The obtained wet product was slurried with 1.0V (100 mL) of methanol at 40 °C for 1 h, cooled to 5 °C, filtered by suction, rinsed with 0.2V (i.e., 20 mL) of methanol, and dried at 50 °C to obtain 100 g of white solid Compound 2. The yield was 100%, and the purity was 99.1%.

[0061] Compound 2: 11H NMR (400 MHz, CDCl 3 ) δ 5.73 (d, J = 1.7 Hz, 1H), 5.53 (dt, J = 6.1, 2.0 Hz, 1H), 3.74 - 3.63 (m, 1H), 2.87 (d, J = 1.3 Hz, 1H), 2.69 - 2.51 (m, 1H), 2.55 - 2.33 (m, 2H), 2.33 (ddd, J = 11.3, 3.9, 1.9 Hz, 1H), 2.23 - 2.03 (m, 2H), 1.93 (dtd, J = 12.3, 4.7, 2.7 Hz, 1H), 1.86 - 1.60 (m, 2H), 1.44 (tdd, J = 12.3, 6.5, 1.7 Hz, 1H), 1.33 (s, 2H), 1.26 - 1.04 (m, 1H), 1.08 (s, 1H), 1.06 (s, 1H), 0.97 (d, J = 0.8 Hz, 2H), 0.39 (s, 4H).

[0062] 13C NMR (101 MHz, CDCl3) δ 199.20, 169.26, 144.69, 124.22, 120.15, 118.26, 81.33, 49.68, 45.20, 43.00, 41.09, 38.04, 34.29, 33.80, 33.29, 32.82, 32.49, 32.11, 29.75, 26.27, 15.08.

[0063] Example 2

[0064] Preparation of Compound 3: 16α-Methyl-17β-cyano-17α-(chloromethyl)dimethylsilyloxy-4,9-androstadien-3-one

[0065]

[0066] 100 g of Compound 2, 3.5 V of dichloromethane, 0.25 w of piperidine, and 0.2 w of imidazole were stirred and cooled to 0 °C. 0.55 w of chloromethyl dimethylchlorosilane was slowly added dropwise. After completion, the reaction was kept warm for about 1 h, and TLC was used to monitor until there was basically no raw material. 1 V of 1% aqueous sodium carbonate solution was added to the system, and the mixture was allowed to stand and separated. The aqueous phase was extracted twice with 1 v of dichloromethane. The dichloromethane layers were combined, and the temperature was controlled at ≤ 40 °C and concentrated under reduced pressure to a paste. It was replaced twice with 1 V of 95% ethanol. Finally, 0.5 V of 95% ethanol by volume concentration was added, and the mixture was stirred and cooled to 0 °C, filtered by suction, and dried at 50 °C to obtain 122 g of white solid Compound 3. The yield was 122%, and the purity was 99.2%.

[0067] Compound 3: 11H NMR (400 MHz, Chloroform-d) δ 5.59 (d, J = 5.5 Hz, 1H), 5.44 - 5.37 (m, 1H), 3.93 (s, 1H), 3.49 (t, J = 6.9 Hz, 1H), 2.54 - 2.41 (m, 4H), 2.46 - 2.37 (m, 2H), 2.41 - 2.28 (m, 4H), 2.32 - 2.15 (m, 2H), 2.12 - 1.93 (m, 2H), 1.88 - 1.76 (m, 1H), 1.73 - 1.63 (m, 1H), 1.67 - 1.48 (m, 1H), 1.38 - 1.21 (m, 1H), 1.20 (d, J = 1.9 Hz, 2H), 1.09 - 0.88 (m, 6H), 0.88 - 0.80 (m, 4H).

[0068] 13 13C NMR (101 MHz, CDCl 3 ) δ 200.53, 171.38, 144.12, 123.41, 120.71, 118.52, 78.51, 48.85, 48.64, 48.43, 48.33, 44.92, 41.51, 40.95, 37.62, 33.86, 33.44, 32.91, 32.71, 31.94, 31.35, 25.94, 16.15, 13.73.

[0069] Example 3

[0070] Preparation of Compound 4: 16α-Methyl-17α-hydroxy-21-chloro-4,9-androstadiene-3,20-dione

[0071]

[0072] 100 g of Compound 3 and 3.5 V of tetrahydrofuran were cooled to -75 °C under nitrogen protection, and an LDA solution was slowly added dropwise (LDA solution: 0.83 w of diisopropylamine and 0.07 w of lithium metal were added to the reaction flask under nitrogen protection, the system was heated to 40 °C, and a mixed solution prepared from 1.6 w of tetrahydrofuran and 0.48 w of styrene was slowly added dropwise. After completion, the reaction was carried out at 40 - 45 °C until no lithium remained, and it was cooled to 0 - 5 °C for standby). The temperature was controlled at < -70 °C, and the reaction was kept warm for about 1 h. TLC monitoring showed that there was basically no raw material. Then it was cooled to -90 °C and quickly pressed into a mixed solution prepared from 2.5 V of 10 wt% dilute hydrochloric acid, 2.5 V of 40 wt% dilute hydrofluoric acid, and 0.15 w of potassium bisulfate at 0 °C. The temperature was raised to 30 °C and the reaction was carried out for about 2.5 h. TLC monitoring showed that the intermediate reaction was complete. The system was cooled to 10 °C, and the temperature was controlled at < 30 °C. 20% NaOH solution was slowly added dropwise to adjust the pH of the system to 7. After standing and separating the liquid, the organic phase was concentrated under reduced pressure to a paste, and then 0.5 v of toluene was added and cooled to 0 °C. The system was filtered, washed with 0.3 w of methanol, and dried at 60 °C to obtain 78.5 g of a white solid Compound 4. The yield was 78.5%, and the purity was 99.3%.

[0073] Compound 4: 1 H NMR(400MHz,CDCl 3 )δ5.73(s,1H),5.51(d,J=5.6Hz,1H),4.63(d,J=16.7Hz,1H),4.30(d,J=16.7Hz,1H),3.72(q,J=7.0Hz,1H),3.14(dp,J=13.0,6.9Hz,1H),2.69(s,1H),2.51(dtd,J=36.9,13.1,11.9,4.7Hz,3H),2.34(dt,J=14.7,3.3Hz,1H),2.10(dd,J=9.4,6.2Hz,2H),2.03 - 1.82(m,3H),1.80 - 1.62(m,2H),1.42(ddd,J=13.6,8.8,5.3Hz,1H),1.33(s,3H),1.10(qd,J=13.1,3.8Hz,1H),0.95(d,J=7.2Hz,3H),0.71(s,3H).

[0074] 13 C NMR(101MHz,CDCl 3)δ203.20,199.55,169.94,144.48,123.96,118.48,91.62,58.43,48.37,47.70,47.22,40.99,37.45,36.85,34.22,33.74,32.83,32.63,32.05,26.21,15.11,14.52。

[0075] Example 4

[0076] Preparation of Compound 5: 16α-Methyl-17α-hydroxy-21-acetate-4,9-androstadiene-3,20-dione

[0077]

[0078] 100 g of Compound 4, 5V of N,N-dimethylformamide, 1.2W of potassium acetate, 0.2V of water and 0.2V of acetic acid were added to a reaction flask, and the temperature was raised to 60 °C for reaction for about 8 h. TLC was used to monitor until there was basically no raw material. The system was cooled to 0 °C and stirred for 2 h, then filtered. The wet product of Compound 5 was washed 3 times with 3v of hot water at 75 - 80 °C, and then dissolved clearly with 10V of dichloromethane and 5V of methanol. It was concentrated under reduced pressure to a paste, 3v of ethyl acetate was added, and it was heated to gentle reflux for pulping for 2 h. Then it was cooled to 5 °C, filtered, washed with 0.2V of methanol, and dried at 60 °C to obtain 80 g of white solid Compound 5. The yield was 80%, and the purity was 99.2%.

[0079] Compound 5: 1 H NMR(400MHz,CDCl 3 )δ5.74(d,J=1.7Hz,1H),5.57-5.50(m,1H),5.03(d,J=17.4Hz,1H),4.82(d,J=17.4Hz,1H),3.72(q,J=7.0Hz,1H),3.17-3.02(m,1H),2.71(dt,J=16.7,2.7Hz,1H),2.63-2.47(m,2H),2.51-2.41(m,1H),,2.35(dt,J=14.5,3.2Hz,1H),2.26-2.02(m,6H),2.02-1.81(m,2H),1.80-1.66(m,1H),1.41(ddd,J=12.6,8.9,5.4Hz,1H),1.33(s,3H),1.25(td,J=7.0,1.2Hz,1H),1.20-1.04(m,1H),0.94(d,J=7.1Hz,3H),0.73(s,3H)。

[0080] 13 C NMR(101MHz,CDCl3 ) δ 205.19, 199.53, 170.69, 169.91, 144.26, 123.96, 118.82, 91.12, 68.12, 47.72, 47.39, 40.99, 37.52, 36.70, 34.24, 33.76, 32.88, 32.86, 32.27, 32.10, 26.21, 20.54, 14.53, 14.45。

[0081] Example 5

[0082] Preparation of Compound I: 16α-Methyl-17α,21-dihydroxy-4,9-androstadiene-3,20-dione

[0083]

[0084] 100 g of Compound 5 was dissolved in 10V of dichloromethane and 6V of methanol. The temperature was lowered to 5°C, and 1w of 30% liquid alkali solution (i.e., sodium hydroxide solution) was slowly added dropwise. After the addition was complete, the mixture was kept warm and reacted for 0.5 h. TLC was used to monitor until the reaction was complete. 0.45w of glacial acetic acid was slowly added to quench the reaction. The system was concentrated under reduced pressure to a paste at ≤45°C. After being replaced with 1.5V of methanol twice, the temperature was lowered to 5°C and stirred for 1 h. Filtration was carried out. The wet product was added with 3w of water and slurried at 50°C for 2 h. The temperature was lowered to 25°C and filtered. Then, it was dissolved in 6V of dichloromethane and 4V of methanol, 0.05w of activated carbon was added for decolorization, and filtered. The filtrate was concentrated under reduced pressure. After being replaced with 1.0V of methanol twice, the temperature was lowered to 5°C and filtered. It was dried at 55°C to obtain 80 g of white solid Compound I. The yield was 80%, and the purity was 99.3%.

[0085] Compound I: 1 H NMR (400 MHz, CDCl 3)δ5.73(d, J = 1.7 Hz, 1H), 5.49(dd, J = 4.9, 2.7 Hz, 1H), 4.64(dd, J = 19.9, 3.3 Hz, 1H), 4.27(dd, J = 20.0, 3.6 Hz, 1H), 3.70(q, J = 7.0 Hz, 1H), 3.21(t, J = 4.8 Hz, 1H), 3.14 - 3.00(m, 1H), 2.71(s, 1H), 2.63(tt, J = 17.4, 2.4 Hz, 1H), 2.59 - 2.45(m, 1H), 2.49 - 2.38(m, 1H), 2.34(dt, J = 14.6, 3.2 Hz, 1H), 2.25 - 2.04(m, 3H), 2.02 - 1.83(m, 2H), 1.74(dt, J = 12.9, 11.0 Hz, 1H), 1.61(ddd, J = 16.8, 5.9, 1.8 Hz, 1H), 1.43(ddd, J = 12.8, 9.0, 5.4 Hz, 1H), 1.32(s, 3H), 1.10(qd, J = 12.8, 3.9 Hz, 1H), 0.94(d, J = 7.2 Hz, 3H), 0.70(s, 3H).

[0086] 13 C NMR(101 MHz, CDCl 3 )δ212.30, 199.56, 169.97, 144.36, 123.94, 118.62, 90.36, 67.71, 48.11, 47.36, 40.99, 37.47, 37.15, 34.20, 33.72, 33.00, 32.83, 32.40, 32.08, 26.20, 15.02, 14.57.

[0087] Example 6

[0088] Preparation of Compound 7: 16α - Methyl - 1,4,9 - androstatriene - 3,17 - dione

[0089]

[0090] For the synthesis of Compound 7, 100 g of Compound 1 was used as the reaction substrate. Referring to the method in Example 3 of CN115725522 A, a fermentation system was obtained. The obtained fermentation system was filtered, and the filter cake was refluxed and extracted with 25V acetone for 2 h, followed by hot filtration. The filtrate was concentrated to a paste, cooled to 5°C, filtered, and the filter cake was refluxed and slurried with 3V acetone for 2 h. Then it was cooled to 10°C, filtered, and dried at 50°C to obtain 90 g of white solid Compound 7. The yield was 90%, and the purity was 99.6%.

[0091] Compound 7: 11H NMR (400 MHz, CDCl 3 ) δ 7.16 (dd, J = 10.1, 2.2 Hz, 1H), 6.24 (ddt, J = 10.2, 3.9, 1.7 Hz, 1H), 6.03 (p, J = 1.7 Hz, 1H), 5.58 - 5.50 (m, 1H), 4.16 - 3.30 (m, 1H), 2.73 - 2.53 (m, 1H), 2.57 - 2.42 (m, 1H), 2.46 - 2.37 (m, 1H), 2.29 - 2.17 (m, 1H), 2.05 - 1.98 (m, 2H), 1.98 - 1.84 (m, 1H), 1.71 (ddq, J = 12.5, 6.3, 1.8 Hz, 1H), 1.53 - 1.33 (m, 3H), 1.20 (tddd, J = 13.7, 8.4, 4.3, 2.0 Hz, 1H), 1.10 - 1.02 (m, 3H), 0.93 - 0.82 (m, 3H), 0.77 (s, 1H).

[0092] 13 13C NMR (101 MHz, CDCl 3 ) δ 222.54, 186.18, 166.21, 154.34, 143.42, 127.32, 123.92, 119.95, 58.26, 46.58, 45.96, 45.64, 39.64, 35.97, 33.75, 31.92, 31.03, 26.66, 16.76, 14.31.

[0093] Example 7

[0094] Compound 8: Preparation of 16α - methyl - 17α - hydroxy - 17β - cyano - 1,4,9 - androstatriene - 3 - one

[0095]

[0096] For the synthesis of Compound 8, 100 g of Compound 7 was used as the reaction substrate, and referring to the preparation method of Compound 2 in Example 1, 98 g of white solid Compound 8 was obtained. The yield was 98% and the purity was 99.3%.

[0097] Compound 8: 1 1H NMR (400 MHz, CDCl 3)δ7.17(d,J=10.1Hz,1H),6.19 - 6.12(m,1H),5.94(s,1H),5.49 - 5.42(m,1H),3.88(s,1H),3.52(q,J=7.0Hz,1H),2.53(pd,J=11.9,10.2,5.7Hz,2H),2.44 - 2.26(m,2H),2.16(td,J=10.7,9.6,5.0Hz,1H),2.06 - 1.95(m,1H),1.75 - 1.51(m,3H),1.42 - 1.30(m,1H),1.31(s,2H),1.15 - 0.97(m,4H),0.88(s,3H).

[0098] 13 C NMR(101MHz,CDCl 3 )δ187.19,168.54,156.01,142.48,126.62,123.18,120.68,120.55,78.48,48.77,46.18,45.28,41.52,36.92,34.75,33.12,32.07,31.57,26.43,16.15,13.76。

[0099] Example 8

[0100] Preparation of Compound 9: 16α - Methyl - 17β - cyano - 17α - chloromethyl dimethylsilyloxy - 1,4,9 - androstatriene - 3 - one

[0101]

[0102] For the synthesis of Compound 9, 100 g of Compound 8 was used as the reaction substrate, and referring to the preparation method of Compound 3 in Example 2, 122 g of white solid Compound 9 was obtained. The yield was 122% and the purity was 99.7%.

[0103] Compound 9: 1 H NMR(400MHz,CDCl 3)δ7.11(dd, J = 10.1, 3.5 Hz, 1H), 6.12 - 6.04(m, 1H), 5.91 - 5.84(m, 1H), 5.39(dd, J = 5.8, 3.2 Hz, 1H), 4.10(s, 2H), 4.00(d, J = 3.5 Hz, 1H), 3.16(d, J = 3.5 Hz, 3H), 2.67(d, J = 3.4 Hz, 2H), 2.13(d, J = 16.5 Hz, 2H), 1.56 - 1.42(m, 3H), 1.34 - 1.22(m, 4H), 0.93 - 0.80(m, 6H), 0.25 - 0.15(m, 6H).

[0104] 13 C NMR(101 MHz, CDCl 3 )δ186.96, 168.20, 155.73, 142.56, 126.53, 123.14, 119.98, 119.73, 80.97, 54.00, 49.62, 48.46, 45.99, 45.19, 42.65, 36.84, 34.51, 32.99, 32.30, 31.86, 29.23, 26.23, 15.81, 14.58.

[0105] Example 9

[0106] Preparation of Compound 10: 16α - Methyl - 17α - hydroxy - 21 - chloro - 1,4,9 - androstatriene - 3,20 - dione

[0107]

[0108] For the synthesis of Compound 10, 100 g of Compound 9 was used as the reaction substrate, and referring to the preparation method of Compound 4 in Example 3, 78 g of off - white solid Compound 10 was obtained. The yield was 78% and the purity was 99.6%.

[0109] Compound 10: 1 H NMR(400 MHz, CDCl 3)δ 7.19 (d, J = 10.1 Hz, 1H), 6.25 (dd, J = 10.2, 1.8 Hz, 1H), 6.02 (t, J = 1.5 Hz, 1H), 5.50 (dt, J = 6.0, 1.9 Hz, 1H), 4.63 (d, J = 16.9 Hz, 1H), 4.29 (d, J = 16.9 Hz, 1H), 3.11 (dd, J = 13.5, 4.6 Hz, 2H), 2.64 (dddd, J = 18.9, 13.7, 5.5, 2.1 Hz, 2H), 2.39 (ddd, J = 13.6, 4.4, 2.3 Hz, 1H), 2.32 - 2.20 (m, 1H), 2.17 - 2.04 (m, 1H), 1.88 - 1.78 (m, 1H), 1.78 - 1.58 (m, 2H), 1.47 - 1.37 (m, 1H), 1.39 (s, 3H), 1.26 - 1.07 (m, 1H), 0.92 (d, J = 7.2 Hz, 3H), 0.71 (s, 3H).

[0110] 13 C NMR (101 MHz, CDCl 3 )δ 203.30, 186.55, 167.47, 155.10, 142.67, 127.09, 123.58, 120.45, 91.58, 48.58, 47.94, 47.45, 46.02, 36.92, 36.67, 34.80, 32.98, 32.75, 32.16, 26.66, 15.05, 14.53.

[0111] Example 10

[0112] Preparation of Compound 6: 16α-Methyl-17α-hydroxy-21-acetate-1,4,9-androstatriene-3,20-dione

[0113]

[0114] For the synthesis of Compound 6, 100 g of Compound 10 was used as the reaction substrate, and referring to the preparation method of Compound 5 in Example 4, 83 g of white solid Compound 6 was obtained. The yield was 83% and the purity was 99.3%.

[0115] Example 11

[0116] Preparation of Compound 6: 16α-Methyl-17α-hydroxy-21-acetate-1,4,9-androstatriene-3,20-dione

[0117]

[0118] Synthesis of Compound 6: Using 100 g of Compound 5 as the reaction substrate, referring to the preparation method of Compound 7 in Example 6, 92 g of white solid Compound 6 was obtained. The yield was 92%, and the purity was 99.3%.

[0119] Compound 6: 1 H NMR(400MHz,CDCl 3 )δ7.17(d,J=10.2Hz,1H),6.23(dd,J=10.1,1.9Hz,1H),6.01(t,J=1.6Hz,1H),5.50(dt,J=6.0,1.9Hz,1H),4.96(d,J=17..6Hz,1H),4.82(d,J=17.5Hz,1H),3.11(s,1H),3.15 - 2.97(m,1H),2.62(dddd,J=15.6,13.7,,4.3,1.7Hz,2H),2.36(ddd,J=13.6,4.4,2.4Hz,1H),2.23(d,J=11.9Hz,1H),2.13(s,3H),2.17 - 2.04(m,1H),1.89 - 1.76(m,2H),1.68(dt,J=12.8,11.0Hz,1H),1.44 - 1.33(m,1H),1.36(s,,3H),1.25 - 1.05(m,1H),0.90(d,J=7.2Hz,3H),0.70(s,3H).

[0120] 13 C NMR(101MHz,CDCl 3 )δ205.31,186.51,170.64,167.46,155.11,142.45,127.04,123.55,120.82,91.10,68.29,47.99,47.58,46.01,36.80,36.73,34.82,33.00,32.38,32.19,26.67,20.54,14.46,14.41.

[0121] Example 12

[0122] Preparation of 16α - Methyl - 9,11 - Dehydroprednisolone

[0123]

[0124] Synthesis of 16α - Methyl - 9,11 - Dehydroprednisolone: Using 100 g of Compound 6 as the reaction substrate, referring to the preparation method of Compound I in Example 5, 89 g of white solid 16α - Methyl - 9,11 - Dehydroprednisolone was obtained. The yield was 89%, and the purity was 99.6%.

[0125] Example 13

[0126]

[0127] Synthesis of 16α-methyl-9,11-dehydroprednisolone: Using 100 g of Compound I as the reaction substrate, referring to the preparation method of Compound 7 in Example 6, 90 g of white solid 16α-methyl-9,11-dehydroprednisolone was obtained. The yield was 90%, and the purity was 99.5%.

[0128] 16α-methyl-9,11-dehydroprednisolone:

[0129] 1 H NMR(400MHz,CDCl 3 )δ7.18(d,J = 10.2Hz,1H),6.25(dd,J = 10.2,1.9Hz,1H),6.03(t,J = 1.6Hz,1H),5.50(dt,J = 6.0,1.9Hz,1H),4.63(dd,J = 20.0,4.7Hz,1H),4.25(dd,J = 20.0,5.0Hz,1H),3.22(t,J = 4.9Hz,1H),3.14 - 2.99(m,1H),2.92(s,1H),2.62(dddd,J = 21.1,12.6,5.2,2.1Hz,2H),2.39(ddd,J = 13.6,4.4,2.4Hz,1H),2.34 - 2.20(m,1H),2.12(dtd,J = 12.4,4.9,2.3Hz,1H),1.92 - 1.67(m,2H),1.59(ddd,J = 16.9,5.9,1.8Hz,1H),1.43(ddd,J = 12.6,8.8,5.4Hz,1H),1.39(s,3H),1.16(dtd,J = 13.9,12.5,4.4Hz,1H),0.93(d,J = 7.2Hz,3H),0.72(s,3H).

[0130] 13 C NMR(101MHz,CDCl 3 )δ212.28,186.48,167.23,154.94,142.61,127.13,123.63,120.53,90.30,67.72,48.37,47.63,45.98,37.19,36.70,34.80,33.16,32.53,32.15,26.67,14.95,14.55.

[0131] The following table shows the HPLC results of the target product 16α-methyl-9,11-dehydroprednisolone:

[0132]

[0133] Example 14

[0134] The raw materials, weights, etc. of the reaction for preparing Compound 2 from Compound 1 in Example 1 were adjusted to optimize the reaction, and the yield and purity of the product were measured. See Table 1. The concentrations in Table 1 are only the purities after the reaction is completed and do not include the concentrations in the post-reaction treatment and refining processes.

[0135] Table 1

[0136]

[0137] The isomer is 16α-methyl-17β-hydroxy-17α-cyano-4,9-androstadien-3-one.

[0138] Example 15

[0139] The raw materials, weights, etc. of the reaction for preparing Compound 3 from Compound 2 in Example 2 were adjusted to optimize the reaction, and the yield and purity of the product were measured. See Table 2. The concentrations in Table 2 are only the purities after the reaction is completed and do not include the concentrations in the post-reaction treatment and refining processes.

[0140] Table 2

[0141]

[0142] It can be seen from Table 2 that if the dosage of chloromethyldimethylchlorosilane is too high, the purity and yield will be significantly reduced.

[0143] Example 16

[0144] The raw materials, weights, etc. of the reaction for preparing Compound 4 from Compound 3 in Example 3 were adjusted to optimize the reaction, and the yield and purity of the product were measured. See Table 3.

[0145] Table 3

[0146]

[0147] Example 17

[0148] The raw materials, weights, etc. of the reaction for preparing Compound 5 from Compound 4 in Example 4 were adjusted to optimize the reaction, and the yield and purity of the product were measured. See Table 4.

[0149] Table 4

[0150]

[0151] Example 18

[0152] Adjust the raw materials, weights, etc. of the reaction for preparing Compound I from Compound 5 in Example 5, optimize the reaction, and measure the yield and purity of the product. See Table 5.

[0153] Table 5

[0154]

[0155] Example 19

[0156] Compound 1 (CAS: 74915-67-6), the starting material 11β-hydroxy-6α-methyl-androst-4-ene-3,17-dione was prepared by the method of reference patent US2842572A. The hydrogen spectrum and carbon spectrum data are as follows:

[0157] 1 H NMR (400 MHz, CDCl 3 ) δ 5.69 (s, 1H, H-4), 4.42 (s, 1H, OH-11), 2.60 - 2.36 (m, 3H), 2.35 - 2.01 (m, 5H), 2.02 - 1.76 (m, 5H), 1.63 (tt, J = 12.8, 8.1 Hz, 1H), 1.45 (d, J = 3.1 Hz, 1H), 1.42 (s, 3H), 1.19 (td, J = 11.6, 5.1 Hz, 1H), 1.13 (s, 3H), 1.05 (d, J = 6.4 Hz, 3H, CH 3 -6), 0.98 (dd, J = 11.2, 3.1 Hz, 1H), 0.82 (q, J = 12.4 Hz, 1H).

[0158] 13 C NMR (101 MHz, CDCl 3 ) δ 216.3 (C-17), 199.9 (C-3), 175.3 (C-5), 119.9 (C-4), 68.0, 56.5, 52.3, 46.9, 40.9, 40.6, 39.7, 35.4, 35.1, 33.6, 33.0, 30.8, 22.3, 21.7, 18.3, 15.9.

[0159] Intermediate 2: Preparation of 17β-cyano-11β,17α-dihydroxy-6α-methyl-androst-4-en-3-one

[0160]

[0161] 100 g of Intermediate 1, 2 V (i.e., 200 mL) of methanol, and 0.5 V (i.e., 50 mL) of acetone cyanohydrin were added to a reaction flask and stirred for about 30 min. Then, a potassium carbonate solution prepared with 0.09 w (i.e., 9 g) of potassium carbonate and 2 V (i.e., 200 mL) of water was added, and the mixture was stirred at 32 °C for 24 hours. TLC monitoring was carried out until the reaction was basically complete. 15 v (i.e., 1.5 L) of water was added to the reaction system and stirred for about 1 h. An appropriate amount of hydrochloric acid was slowly added to adjust the pH of the system to 5. The mixture was filtered by suction and washed with water until neutral. The obtained wet product was slurried with 1.0 V (100 mL) of methanol at 40 °C for 1 h, cooled to 5 °C, filtered by suction, rinsed with 0.2 V (i.e., 20 mL) of methanol, and dried at 50 °C to obtain 100 g of a white solid, Intermediate 2. The weight yield was 102%, and the purity was 97.8%.

[0162] Intermediate 2: 1 H NMR (400 MHz, DMSO-d 6 ) δ 6.20 (s, 1H, OH-17), 5.49 (s, 1H, H-4), 4.43 (d, J = 3.3 Hz, 1H, OH-11), 4.28 (t, J = 3.2 Hz, 1H, H-11), 2.53 (d, J = 8.5 Hz, 1H), 2.40 - 2.15 (m, 3H), 2.10 - 1.77 (m, 6H), 1.74 - 1.54 (m, 3H), 1.47 - 1.38 (m, 1H), 1.35 (d, J = 1.8 Hz, 4H), 1.08 (d, J = 1.8 Hz, 3H), 0.97 (d, J = 6.3 Hz, 3H, CH 3 -6), 0.88 (dd, J = 11.1, 3.0 Hz, 1H), 0.71 (q, J = 12.3 Hz, 1H).

[0163] 13 C NMR (101 MHz, DMSO-d 6 ) δ 198.2 (C-3), 175.2 (C-5), 122.0 (-CN), 118.8 (C-4), 76.5, 66.3, 55.1, 48.7, 48.1, 41.9, 39.2, 38.2, 37.2, 34.1, 33.2, 32.5, 31.3, 23.5, 21.8, 18.4, 18.0.

[0164] Example 20

[0165] Preparation of Intermediate 3: 17β-Cyano-11β,17α-dihydroxy-6α-methyl-androst-4-ene-3-one-17-chloromethyl dimethyl silyl ether

[0166]

[0167] 100 g of intermediate 2, 3 V of dichloromethane, 0.25 w of piperidine, 0.2 w of imidazole were stirred and cooled to 0 °C, and 0.55 w of chloromethyldimethylchlorosilane was slowly added dropwise. After completion, the reaction was kept warm for about 1 h, and TLC was used to monitor until there was basically no raw material left. 1 V of 1% aqueous sodium carbonate solution was added to the system, and the mixture was allowed to stand for liquid separation. The aqueous phase was extracted twice with 1 v of dichloromethane. The dichloromethane layers were combined, and the temperature was controlled at ≤40 °C and concentrated under reduced pressure to a paste. The paste was replaced twice with 1 V of 95% ethanol. Finally, 0.5 V of ethanol with a volume concentration of 95% was added, and the mixture was stirred and cooled to 0 °C, then filtered by suction and dried at 50 °C to obtain 123 g of white solid intermediate 3. The weight yield was 123%, and the purity was 98%.

[0168] Intermediate 3: 1 H NMR(400MHz,DMSO-d 6 )δ5.50(s,1H,H-4),4.49(d,J=3.3Hz,1H,OH-11),4.29(t,J=3.4Hz,1H,H-11),2.97(s,2H,ClCH2Si),2.59-2.51(m,1H),2.46-2.36(m,1H),2.32(dd,J=12.1,4.5Hz,1H),2.20(dt,J=16.3,5.0Hz,1H),2.10-1.91(m,4H),1.84(td,J=12.9,4.6Hz,1H),1.74(p,J=4.0Hz,1H),1.70(d,J=3.3Hz,1H),1.58(dd,J=13.4,2.6Hz,1H),1.49-1.38(m,2H),1.36(s,3H),1.11(s,3H),1.09-1.01(m,1H),0.98(d,J=6.4Hz,3H,CH 3 -6),0.90(dd,J=11.0,3.2Hz,1H),0.72(q,J=12.0Hz,1H),0.30(s,3H,CH 3 Si-),0.28(s,3H,CH 3 Si-)。

[0169] 13 C NMR(101MHz,DMSO-d 6 )δ198.2(C-3),175.0(C-5),120.7(-CN),118.8(C-4),78.7,66.3,54.9,49.4,48.6,41.8,39.2,38.1,37.9,34.1,33.3,32.4,31.3,29.8,23.5,21.7,18.0,18.0,-2.2(CH 3 Si-),-2.3(CH3 Si-).

[0170] Example 21

[0171] Intermediate 4: Preparation of 21-chloro-11β,17α-dihydroxy-6α-methyl-pregn-4-ene-3,20-dione

[0172]

[0173] 100 g of Intermediate 3 and 3.5 V of tetrahydrofuran were cooled to -75°C under nitrogen protection, and an LDA solution was slowly added dropwise (LDA solution: 0.83 w of diisopropylamine and 0.07 w of lithium metal were added to the reaction flask under nitrogen protection, the temperature of the system was raised to 40°C, and a mixed solution prepared from 1.6 w of tetrahydrofuran and 0.48 w of styrene was slowly added dropwise. After completion, the reaction was carried out at 40 - 45°C until no lithium remained, and it was cooled to 0 - 5°C for standby). The temperature was controlled at < -70°C, and the reaction was kept warm for about 1 h. TLC was monitored until there was basically no raw material. Then it was cooled to -90°C and quickly pressed into a mixed solution prepared from 2.5 V of 10 wt% dilute hydrochloric acid, 2.5 V of 40 wt% dilute hydrofluoric acid, and 0.15 w of potassium bisulfate at 0°C. The temperature was raised to 30°C and the reaction was carried out for about 2.5 h. TLC was monitored until the intermediate reaction was complete. The temperature of the system was cooled to 10°C, and 20% NaOH solution was slowly added dropwise while controlling the temperature at < 30°C to adjust the pH of the system to 7. After standing and separating the liquid, the organic phase was concentrated under reduced pressure to a paste, and then 0.5 v of toluene was added and cooled to 0°C. The system was filtered, washed with 0.3 w of methanol, and dried at 60°C to obtain 77 g of a white solid Intermediate 4. The yield was 77%, and the purity was 96.5%.

[0174] Intermediate 4:

[0175] 1 H NMR(400 MHz, DMSO-d 6)δ5.50(s,1H,H-4),5.48(s,1H,OH-17),4.75(d,J=17.0Hz,1H,H-21),4.37(d,J=17.0Hz,1H,H-21),4.29(d,J=3.4Hz,1H,OH-11),4.26(t,J=3.2Hz,1H,H-11),3.49-3.39(m,5H),2.63-2.51(m,2H),2.33(ddd,J=16.7,12.2,4.7Hz,1H),2.20(dt,J=16.3,5.1Hz,1H),2.08-1.88(m,4H),1.88-1.74(m,1H),1.64(dt,J=10.6,7.2Hz,2H),1.55(dd,J=13.5,2.5Hz,1H),1.46(dt,J=14.6,7.5Hz,1H),1.34(s,3H),1.28(dd,J=11.4,6.0Hz,1H),1.05(td,J=7.0,0.9Hz,7H),0.98(d,J=6.3Hz,3H,CH 3 -6),0.89(dd,J=11.1,3.1Hz,1H),0.76(s,3H),0.74-0.66(m,1H).

[0176] 13 C NMR(101MHz,DMSO-d 6 )δ203.3(C-20),198.2(C-3),175.4(C-5),118.8(C-4),89.3,66.6,56.1,55.3,51.3,48.8,46.6,42.0,39.2,39.0,34.2,33.3,33.1,32.5,31.0,23.3,21.8,18.6,18.1,17.1.

[0177] Example 22

[0178] Intermediate 5: 21 - Acetoxy - 11β,17α,21 - trihydroxy - 6α - methyl - pregn - 4 - ene - 3,20 - dione

[0179]

[0180] 100 g of intermediate 4, 5 V of N,N-dimethylformamide, 1.2 W of potassium acetate, 0.2 V of water and 0.2 V of acetic acid were added to a reaction flask, and the temperature was raised to 60 °C for reaction for about 8 h. When TLC monitoring showed that there was basically no raw material left, the temperature of the system was lowered to 0 °C and stirred for 2 h. Then, filtration was carried out. The wet intermediate 5 was washed 3 times with 3 v of hot water at 75 - 80 °C, and then dissolved clearly with 10 V of dichloromethane and 5 V of methanol. It was concentrated under reduced pressure to a paste state, 3 v of ethyl acetate was added, and the temperature was raised to slightly reflux for pulping for 2 h. Then, the temperature was lowered to 5 °C, filtration was carried out, and it was washed with 0.2 V of methanol and dried at 60 °C to obtain 83 g of white solid intermediate 5. The yield was 83%, and the purity was 99.4%.

[0181] Intermediate 5:

[0182] 1 H NMR(400MHz,DMSO-d 6 )δ5.50(s,1H,H-4),5.39(s,1H,OH-17),5.08(d,J=17.6Hz,1H,H-21),4.74(d,J=17.6Hz,1H,H-21),4.35(d,J=3.9Hz,1H,OH-11),4.26(t,J=3.6Hz,1H,H-11),2.59-2.44(m,3H),2.34(ddd,J=16.7,12.2,4.8Hz,1H),2.20(dt,J=16.3,5.1Hz,1H),2.09(d,J=1.3Hz,3H),2.04(td,J=9.5,8.8,4.7Hz,2H),1.94(ddd,J=14.7,9.4,3.6Hz,3H),1.83(td,J=12.8,4.1Hz,1H),1.65(h,J=7.0Hz,3H),1.51-1.39(m,1H),1.35(s,3H),1.32-1.21(m,1H),0.98(d,J=6.3Hz,3H,CH 3 -6),0.89(dd,J=11.1,3.1Hz,1H),0.76(s,3H),0.75-0.65(m,1H).

[0183] 13 C NMR(101MHz,DMSO-d 6 )δ205.3(C-20),198.2(C-3),175.4(C-5),169.7(OCCH3),118.7(C-4),88.6,67.5,66.5,55.4,51.5,46.9,42.0,39.2,34.2,33.2,33.2,32.5,30.9,23.3,21.8,20.4,18.1,16.6.

[0184] Example 23

[0185] The preparation method of Intermediate 6 is the same as that of Compound 7 in Example 6, and Intermediate 6 is prepared by using Intermediate 5.

[0186]

[0187] Preparation of Methylprednisolone: 11β,17α,21 - Trihydroxy - 6α - methyl - pregn - 1,4 - diene - 3,20 - dione

[0188]

[0189] 100 g of Intermediate 6 was dissolved in 10V of dichloromethane and 6V of methanol. The temperature was lowered to 5°C, and 1w of 30% liquid alkali solution (i.e., sodium hydroxide solution) was slowly added dropwise. After the addition was completed, the mixture was kept warm and reacted for 0.5 h. The reaction was monitored by TLC until it was complete. 0.45w of glacial acetic acid was slowly added to quench the reaction. The system was concentrated under reduced pressure to a paste at ≤45°C. After being replaced with 1.5V of methanol twice, the temperature was lowered to 5°C and stirred for 1 h. The mixture was filtered by suction. The wet product was added with 3w of water and slurried at 50°C for 2 h. The temperature was lowered to 25°C and filtered. Then it was dissolved in 6V of dichloromethane and 4V of methanol, 0.05w of activated carbon was added for decolorization, and filtered. The filtrate was concentrated under reduced pressure. After being replaced with 1.0V of methanol twice, the temperature was lowered to 5°C and filtered by suction, and dried at 55°C to obtain 89 g of white solid methylprednisolone. The weight yield was 89%, and the purity was 99.79%.

[0190] Intermediate 6: 1 H NMR(400MHz,DMSO - d 6) δ 7.32 (d, J = 10.1 Hz, 1H, H-1), 6.17 (dd, J = 10.1, 1.8 Hz, 1H, H-2), 5.82 (t, J = 1.7 Hz, 1H, H-4), 5.76 (s, 1H, OH-21), 5.49 (s, 1H, OH-17), 4.74 (d, J = 17.0 Hz, 1H, H-21), 4.65 (d, J = 3.2 Hz, 1H, OH-11), 4.38 (d, J = 17.0 Hz, 1H, H-21), 4.33 - 4.22 (m, 1H, H-11), 2.65 (dq, J = 11.4, 5.2 Hz, 1H), 2.56 (ddd, J = 14.6, 11.1, 2.2 Hz, 1H), 2.12 (td, J = 11.0, 4.1 Hz, 1H), 2.04 (dq, J = 12.5, 4.6, 4.2 Hz, 1H), 1.88 (dd, J = 13.6, 3.6 Hz, 1H), 1.70 - 1.52 (m, 3H), 1.51 - 1.40 (m, 1H), 1.38 (s, 3H), 1.31 (dd, J = 11.2, 6.1 Hz, 1H), 1.04 (d, J = 6.3 Hz, 3H, CH 3 -6), 0.85 (dd, J = 11.2, 3.4 Hz, 1H), 0.78 (s, 3H), 0.71 (q, J = 12.1 Hz, 1H).

[0191] 13 C NMR (101 MHz, DMSO-d 6 ) δ 203.2 (C-20), 185.1 (C-3), 173.4 (C-5), 157.2 (C-1), 126.7 (C-2), 118.8 (C-4), 89.2, 68.3, 55.8, 54.9, 50.8, 48.8, 46.7, 44.0, 42.8, 33..0, 32.4, 30.8, 23.4, 21.3, 17.6, 17.0.

[0192] Example 24

[0193] Intermediate 7: Preparation of 11β-Hydroxy-6α-methyl-androst-1,4-diene-3,17-dione

[0194]

[0195] Synthesis of Intermediate 7: Using 100 g of Intermediate 1 as the reaction substrate, referring to the method in Example 3 of CN115725522 A, a fermentation system was obtained. The obtained fermentation system was filtered, and the filter cake was refluxed and extracted with 25V of acetone for 2 h, followed by hot filtration. The filtrate was concentrated to a paste, cooled to 5 °C, filtered, and the filter cake was refluxed and slurried with 3V of acetone for 2 h, cooled to 10 °C, filtered, and dried at 50 °C to obtain 87 g of white solid Intermediate 7. The weight yield was 87%, and the purity was 98.5%.

[0196] Intermediate 7: 1 H NMR(400MHz,DMSO-d 6 )δ7.32(d,J=10.1Hz,1H,H-1),6.18(dd,J=10.1,1.8Hz,1H,H-2),5.83(t,J=1.7Hz,1H,H-4),4.84(dd,J=3.6,1.0Hz,1H,OH-11),4.24(t,J=3.3Hz,1H,H-11),2.68(dt,J=12.2,5.8Hz,1H),2.41(dd,J=18.5,8.8Hz,1H),2.24(qd,J=11.2,4.3Hz,1H),2.13(dt,J=12.6,4.6Hz,1H),2.01-1.75(m,3H),1.58(tt,J=12.1,8.6Hz,1H),1.41(s,3H),1.25(dd,J=13.9,3.4Hz,1H),1.17(ddd,J=12.5,10.7,5.6Hz,1H),1.07(d,J=6.7Hz,3H,CH 3 -6),1.06(s,3H),0.92(dd,J=11.2,3.3Hz,1H),0.74(q,J=12.3Hz,1H).

[0197] 13 C NMR(101MHz,DMSO-d 6 )δ218.5(C-17),185.1(C-3),173.3(C-5),157.1(C-1),126.7(C-2),118.9(C-4),68.1,56.0,50.6,46.5,44.0,41.3,40.2,34.8,32.3,30.3,21.5,21.4,17.6,15.4。

[0198] Example 25

[0199] Preparation of Intermediate 8: 17β-Cyano-11β,17α-dihydroxy-6α-methyl-androst-1,4-diene-3-one

[0200]

[0201] Synthesis of Intermediate 8: Using 100 g of Intermediate 7 as the reaction substrate, referring to the preparation method of Intermediate 2 in Example 18, 98 g of white solid Intermediate 8 was obtained. The yield was 98%, and the purity was 97.8%.

[0202] Intermediate 8: 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.32 (d, J = 10.1 Hz, 1H, H-1), 6.21 (s, 1H, OH-17), 6.17 (dd, J = 10.1, 1.8 Hz, 1H, H-2), 5.81 (t, J = 1.7 Hz, 1H, H-4), 4.80 (d, J = 3.2 Hz, 1H, OH-11), 4.34 - 4.26 (m, 1H, H-11), 2.65 (dt, J = 11.5, 5.6 Hz, 1H), 2.29 (ddd, J = 14.2, 9.0, 2.9 Hz, 1H), 2.18 - 1.98 (m, 2H), 1.87 (ddd, J = 17.4, 9.5, 5.1 Hz, 1H), 1.76 - 1.54 (m, 3H), 1.39 (s, 5H), 1.11 (s, 3H), 1.04 (d, J = 6.3 Hz, 3H, CH 3 -6), 0.84 (dd, J = 11.2, 3.4 Hz, 1H), 0.71 (q, J = 12.2 Hz, 1H).

[0203] 13 C NMR (101 MHz, DMSO-d 6 ) δ 185.1 (C-3), 173.2 (C-5), 157.2 (C-1), 126.7 (C-2), 121.9 (-CN), 118.8 (C-4), 76.5, 68.1, 55.6, 48.2, 48.1, 43.9, 42.7, 37.9, 37.1, 32.4, 31.1, 23.7, 21.3, 18.3, 17.6.

[0204] Example 26

[0205] Intermediate 9: Preparation of 17β-cyano-11β,17α-dihydroxy-6α-methyl-androst-1,4-diene-3-one-17-chloromethyldimethylsilyl ether

[0206]

[0207] Synthesis of Intermediate 9: Using 100 g of Intermediate 8 as the reaction substrate, referring to the preparation method of Intermediate 3 in Example 19, 122 g of white solid Intermediate 9 was obtained. The yield was 122%, and the purity was 98.8%.

[0208] Intermediate 9: 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.32 (d, J = 10.1 Hz, 1H, H-1), 6.17 (dd, J = 10.1, 1.8 Hz, 1H, H-2), 5.82 (s, 1H, H-4), 4.83 (d, J = 3.2 Hz, 1H, OH-11), 4.31 (t, J = 3.4 Hz, 1H, H-11), 2.94 (s, 2H, ClCH2Si), 2.75 - 2.56 (m, 1H), 2.40 (ddd, J = 14.6, 10.8, 3.2 Hz, 1H), 2.18 - 1.89 (m, 3H), 1.71 (ddd, J = 15.5, 8.3, 3.8 Hz, 1H), 1.67 - 1.53 (m, 2H), 1.49 - 1.31 (m, 5H), 1.13 (s, 3H), 1.04 (d, J = 6.4 Hz, 3H, CH 3 -6), 0.88 (dd, J = 11.3, 3.3 Hz, 1H), 0.71 (q, J = 12.1 Hz, 1H), 0.28 (s, 3H, CH3Si-), 0.26 (s, 3H, CH3Si-).

[0209] 13 C NMR (101 MHz, DMSO-d 6 ) δ 185.1 (C-3), 173.1 (C-5), 157.1 (C-1), 126.7 (C-2), 120.6 (-CN), 118.9 (C-4), 78.7, 68.0, 55.4, 49.5, 48.1, 43.9, 42.6, 37.8, 37.7, 32.3, 31.1, 29.8, 23.7, 21.2, 17.9, 17.5, -2.3 (CH 3 Si-), -2.3 (CH 3 Si-).

[0210] Example 27

[0211] Preparation of Intermediate 10: 21-Chloro-11β,17α-dihydroxy-6α-methyl-pregn-1,4-diene-3,20-dione

[0212]

[0213] Synthesis of Intermediate 10: Using 100 g of Intermediate 9 as the reaction substrate, referring to the preparation method of Intermediate 4 in Example 20, 80 g of off-white solid Intermediate 10 was obtained. The yield was 80%, and the purity was 96.5%.

[0214] Intermediate 10:

[0215] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.32 (dd, J = 10.1, 1.8 Hz, 1H, H-1), 6.17 (dd, J = 10.0, 2.2 Hz, 1H, H-2), 5.81 (s, 1H, H-4), 5.48 (d, J = 1.7 Hz, 1H, OH-17), 4.74 (dd, J = 16.9, 1.8 Hz, 1H, H-21), 4.64 (t, J = 2.4 Hz, 1H, OH-11), 4.38 (dd, J = 17.0, 1.8 Hz, 1H, H-21), 4.28 (d, J = 4.6 Hz, 1H, H-11), 2.64 (dt, J = 12.0, 5.9 Hz, 1H), 2.60 - 2.52 (m, 1H), 2.11 (td, J = 11.2, 4.1 Hz, 1H), 2.06 - 1.98 (m, 1H), 1.88 (dt, J = 13.5, 2.6 Hz, 1H), 1.70 - 1.52 (m, 3H), 1.45 (dt, J = 14.5, 7.3 Hz, 1H), 1.38 (d, J = 1.8 Hz, 3H), 1.31 (dd, J = 11.3, 6.3 Hz, 1H), 1.04 (d, J = 6.3 Hz, 3H, CH 3 -6), 0.85 (dt, J = 11.0, 2.3 Hz, 1H), 0.78 (d, J = 1.8 Hz, 3H), 0.70 (q, J = 12.6, 12.1 Hz, 1H).

[0216] 13 C NMR (101 MHz, DMSO-d 6 ) δ 203.7 (C-20), 185.6 (C-3), 173.8 (C-5), 157.7 (C-1), 127.2 (C-2), 119.2 (C-4), 89.6, 68.8, 56.3, 51.2, 49.2, 47.1, 44.4, 43.3, 39.2, 33.5, 32.9, 31.2, 23.9, 21.7, 18.1, 17.5.

[0217] Example 28

[0218] Preparation of Intermediate 6: 21 - Acetoxy - 11β,17α,21 - trihydroxy - 6α - methyl - pregn - 1,4 - diene - 3,20 - dione

[0219]

[0220] For the synthesis of Intermediate 6, using 100 g of Intermediate 10 as the reaction substrate, referring to the preparation method of Intermediate 5 in Example 21, 92 g of white solid Intermediate 6 was obtained. The yield was 92%, and the purity was 99.65%.

[0221] Intermediate 6: 1 H NMR(400MHz,DMSO - d6)δ7.33(d,J = 10.1Hz,1H,H - 1),6.18(dd,J = 10.1,1.8Hz,1H,H - 2),5.82(t,J = 1.7Hz,1H,H - 4),5.40(s,1H,OH - 17),5.06(d,J = 17.6Hz,1H,H - 21),4.74(d,J = 11.1Hz,1H,H - 21),4.71(d,J = 2.6Hz,1H,OH - 11),4.28(p,J = 3.3Hz,1H,H - 11),3.17(d,J = 5.2Hz,3H),2.71 - 2.58(m,1H),2.16 - 2.09(m,1H),2.09(s,3H),2.03(dt,J = 12.5,4.3Hz,1H),1.92 - 1.83(m,1H),1.62(ddd,J = 15.9,10.2,2.8Hz,3H),1.50 - 1.41(m,1H),1.38(s,3H),1.30(dd,J = 11.3,6.1Hz,1H),1.04(d,J = 6.3Hz,3H,CH 3 -6),0.85(dd,J = 11.2,3.3Hz,1H),0.78(s,3H),0.70(q,J = 12.1Hz,1H).

[0222] 13 C NMR(101MHz,DMSO - d 6 )δ205.3(C - 20),185.1(C - 3),173.5(C - 5),169.8(OCCH 3 ),157.3(C - 1),126.7(C - 2),118.8(C - 4),88.6,68.3,67.5,55.9,51.0,48.6,47.0,44.0,42.9,33.1,32.4,30.8,23.5,21.3,20.4,17.6,16.5.

[0223] Example 29

[0224] Adjust the raw materials, weights, etc. of the reaction for preparing Intermediate 2 from the compound in Example 18, optimize the reaction, and measure the yield and purity of the product. See Table 6. The concentrations in Table 6 are only the purities after the reaction is completed and do not include the concentrations in the post-reaction treatment and refining processes.

[0225] Table 6

[0226]

[0227]

[0228] The isomer is 16α-methyl-17β-hydroxy-17α-cyano-4,9-androstadien-3-one.

[0229] Example 30

[0230] Adjust the raw materials, weights, etc. of the reaction for preparing Intermediate 3 from Intermediate 2 in Example 19, optimize the reaction, and measure the yield and purity of the product. See Table 7. The concentrations in Table 7 are only the purities after the reaction is completed and do not include the concentrations in the post-reaction treatment and refining processes.

[0231] Table 7

[0232]

[0233] It can be seen from Table 7 that if the dosage of chloromethyldimethylchlorosilane is too high, the purity and yield will be significantly reduced.

[0234] Example 31

[0235] Adjust the raw materials, weights, etc. of the reaction for preparing Intermediate 4 from Intermediate 3 in Example 20, optimize the reaction, and measure the yield and purity of the product. See Table 8.

[0236] Table 8

[0237]

[0238]

[0239] Example 32

[0240] Adjust the raw materials, weights, etc. of the reaction for preparing Intermediate 5 from Intermediate 4 in Example 21, optimize the reaction, and measure the yield and purity of the product. See Table 9. The concentrations in Table 9 are only the purities after the reaction is completed and do not include the concentrations in the post-reaction treatment and refining processes.

[0241] Table 9

[0242]

[0243] Example 33

[0244] The raw materials, weights, etc. of the reaction for preparing methylprednisolone from Intermediate 6 of Example 22 were adjusted to optimize the reaction, and the yield and purity of the product were measured. See Table 10. The concentrations in Table 10 are only the purities after the reaction is completed and do not include the concentrations in the post-treatment and refining processes after the reaction.

[0245] Table 10

[0246]

[0247] Those of ordinary skill in the art should understand that: the discussion of any of the above embodiments is only exemplary and is not intended to imply that the scope of protection of this application is limited to these examples; under the concept of this application, the technical features in the above embodiments or different embodiments can also be combined, and the steps can be implemented in any order, and there are many other variations in different aspects of one or more embodiments in this application as described above, and they are not provided in detail for the sake of brevity.

[0248] One or more embodiments in this application are intended to cover all such substitutions, modifications, and variations that fall within the broad scope of this application. Therefore, any omissions, modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of one or more embodiments in this application shall be included within the scope of protection of this application.

Claims

1. A method for preparing methylprednisolone or its derivatives, characterized in that: It includes any of the following reaction routes, wherein reaction route 1 includes the following steps: Compound 1, methanol, acetone cyanohydrin and potassium carbonate solution are mixed and reacted to obtain compound 2; the mass concentration of the potassium carbonate solution is 3.5-5%, the mass volume ratio of the compound 1 to methanol is 1:1.8-2.2, the mass volume ratio of the compound 1 to acetone cyanohydrin is 1:0.9-1.1, and the mass volume ratio of the compound 1 to the potassium carbonate solution is 1:1.8-2.2; Compound 2, dichloromethane, piperidine, imidazole and chloromethyldimethylsilyl chloride are mixed and reacted to obtain compound 3; the mass volume ratio of compound 2 to dichloromethane is 1:2.8-4.0, the mass ratio of compound 2 to piperidine is 1:0.22-0.28, the mass ratio of compound 2 to imidazole is 1:0.16-0.25, and the mass ratio of compound 2 to chloromethyldimethylsilyl chloride is 1:0.5-0.6; Adding lithium diisopropylamide solution to a mixed solution of compound 3 and tetrahydrofuran, controlling the temperature to be lower than -70°C, reacting; cooling to below -90°C, adding the reaction solution to a mixed solution of hydrochloric acid, hydrofluoric acid and potassium bisulfate, then heating to 30-40°C, reacting for 2-3h, cooling to below 30°C, adjusting the pH to neutral, treating to obtain compound 4; the mass concentration of hydrochloric acid is 8-12%, the mass concentration of hydrofluoric acid is 35-45%, the volume ratio of hydrochloric acid to hydrofluoric acid is 1:0.8-1.2, and the volume mass ratio of hydrochloric acid to potassium bisulfate is 1:0.05-0.07; Compound 4, N,N-dimethylformamide, potassium acetate, water and acetic acid are mixed and reacted to obtain compound 5; The liquid alkali solution is added to a mixed solution of compound 5, dichloromethane and methanol, and the mixture is kept warm for reaction to obtain compound I; fermenting compound I to obtain methylprednisolone or its derivatives; Alternatively, compound 5 is fermented to obtain compound 6; Adding the liquid alkali solution to a mixed solution of compound 6, dichloromethane and methanol, keeping the temperature, and reacting to obtain methylprednisolone or a derivative thereof; The reaction route is as follows: Reaction route 2 includes the following steps: Compound 1 is fermented to obtain compound 7; Compound 7, methanol, acetone cyanohydrin and potassium carbonate solution are mixed and reacted to obtain compound 8; the mass concentration of the potassium carbonate solution is 3.5-5%, the mass volume ratio of the compound 7 to methanol is 1:1.8-2.2, the mass volume ratio of the compound 7 to acetone cyanohydrin is 1:0.9-1.1, and the mass volume ratio of the compound 7 to the potassium carbonate solution is 1:1.8-2.2; Compound 8, dichloromethane, piperidine, imidazole and chloromethyldimethylsilyl chloride are mixed and reacted to obtain compound 9; the mass volume ratio of compound 8 to dichloromethane is 1:2.8-4.0, the mass ratio of compound 8 to piperidine is 1:0.22-0.28, the mass ratio of compound 8 to imidazole is 1:0.16-0.25, and the mass ratio of compound 8 to chloromethyldimethylsilyl chloride is 1:0.5-0.6; Adding lithium diisopropylamide solution to a mixed solution of compound 9 and tetrahydrofuran, controlling the temperature below -70°C, reacting; cooling to below -90°C, adding the reaction solution to a mixed solution of hydrochloric acid, hydrofluoric acid and potassium bisulfate, then heating to 30-40°C, reacting for 2-3h, cooling to below 30°C, adjusting the pH to neutral, treating to obtain compound 10; the mass concentration of hydrochloric acid is 8-12%, the mass concentration of hydrofluoric acid is 35-45%, the volume ratio of hydrochloric acid to hydrofluoric acid is 1:0.8-1.2, and the volume mass ratio of hydrochloric acid to potassium bisulfate is 1:0.05-0.07; Compound 10, N,N-dimethylformamide, potassium acetate, water and acetic acid are mixed and reacted to obtain compound 6; Adding the liquid alkali solution to a mixed solution of compound 6, dichloromethane and methanol, keeping the temperature, and reacting to obtain methylprednisolone or a derivative thereof; The reaction route is as follows: R1 is CH3 or H, R2 is OH or H, R3 is CH3 or H, It is a single bond or a double bond.

2. The preparation method according to claim 1, characterized in that: The mass volume ratio of the compound 1 to methanol is 1:2, the mass volume ratio of the compound 1 to acetone cyanohydrin is 1:1, and the mass volume ratio of the compound 1 to potassium carbonate solution is 1:2; alternatively, the mass volume ratio of the compound 7 to methanol is 1:2, the mass volume ratio of the compound 7 to acetone cyanohydrin is 1:1, and the mass volume ratio of the compound 7 to potassium carbonate solution is 1:

2.

3. The preparation method according to claim 1, characterized in that: The mass volume ratio of compound 2 to dichloromethane is 1:3.5, the mass ratio of compound 2 to piperidine is 1:0.25, the mass ratio of compound 2 to imidazole is 1:0.2, and the mass ratio of compound 2 to chloromethyldimethylsilyl chloride is 1:0.55; alternatively, the mass volume ratio of compound 8 to dichloromethane is 1:3.5, the mass ratio of compound 8 to piperidine is 1:0.25, the mass ratio of compound 8 to imidazole is 1:0.2, and the mass ratio of compound 8 to chloromethyldimethylsilyl chloride is 1:0.

55.

4. The preparation method according to claim 1 or 3, characterized in that: In the preparation step of compound 3 or compound 9, the reaction temperature is -5-0°C.

5. The preparation method according to claim 1, characterized in that: In the preparation step of compound 4 or compound 10, the weight volume ratio of compound 3 or compound 9 to tetrahydrofuran is 1:

3.

6. The preparation method according to claim 1 or 5, characterized in that: In the preparation step of compound 4 or compound 10, the substance for adjusting the pH to neutral is a sodium hydroxide solution.

7. The preparation method according to claim 1, characterized in that: In the preparation steps of compound 5 of reaction route 1 or compound 6 of reaction route 2, the weight volume ratio of compound 4 or compound 10 to N,N-dimethylformamide is 1:5; the weight volume ratio of compound 4 or compound 10 to potassium acetate is 1:1.2; the weight volume ratio of compound 4 or compound 10 to water is 1:0.2; and the weight volume ratio of compound 4 or compound 10 to acetic acid is 1:0.

2.

8. The preparation method according to claim 1 or 7, characterized in that: In the preparation step of compound 5 in reaction scheme 1 or compound 6 in reaction scheme 2, the reaction temperature is 60°C.

9. The preparation method according to claim 1, characterized in that: In the preparation step of preparing methylprednisolone or its derivatives from compound 6, the weight ratio of compound 6 to liquid alkali solution is 1:1; the weight volume ratio of compound 6 to dichloromethane is 1:10; and the weight volume ratio of compound 6 to methanol is 1:

6.

10. The preparation method according to claim 1 or 9, characterized in that: In the preparation step of compound 6 for preparing methylprednisolone or its derivatives, the reaction temperature is 0-5°C.

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