Preparation method of methylprednisolone and intermediate compound thereof

Abstract

The invention belongs to the technical field of chemical synthesis, and particularly relates to a preparation method of methylprednisolone and an intermediate compound thereof. The preparation method comprises the following steps: by taking cortisone as a raw material, carrying out 17 and 21 site upper protecting groups and 3 site upper protecting groups, and carrying out reduction, so as to obtain a methylprednisolone intermediate compound shown as a formula V; and carrying out 5 and 6-site epoxidation, Grignard reaction, 3-site protecting group removal, 4 and 5-site dehydration elimination, 1 and 2-site dehydrogenation and 17 and 21-site protecting group removal on the compound in the formula V to obtain methylprednisolone. The structural formula of the compound of formula V is shown in the specification. The preparation process has the advantages of high yield, high purity, low cost, simplicity in operation and suitability for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis technology, specifically relating to a method for preparing methylprednisolone and its intermediate compounds. Background Technology

[0002] Methylprednisolone, also known as methylprednisolone, is a synthetic glucocorticoid, belonging to the class of intermediate-acting glucocorticoids. Methylprednisolone possesses anti-inflammatory, immunosuppressive, and anti-allergic effects and is widely used to treat various inflammatory diseases, autoimmune diseases, allergic diseases, eye diseases, and kidney diseases.

[0003] The chemical formula of methylprednisolone is C 22 H 30 O5, with a molecular weight of 374.47 and CAS number 83-43-2, has the following structural formula:

[0004]

[0005] I.

[0006] Many existing techniques have reported methods for synthesizing methylprednisolone (compound of formula I).

[0007] For example, US2968655A patent reports the use of 11α-hydroxyprogesterone as a starting material, followed by ketal protection, epoxidation, Grignard ring opening, deprotection, 11-position oxidation, 5-position hydroxyl elimination, and 6-position methyl transposition to obtain 6α-methyl-11-ketoprogesterone. This is then followed by protecting groups at positions 3 and 20, reduction at position 11, deprotection at positions 3 and 20, debromination at positions 3 and 20, iodination at position 21 (adding an acetyl group), dehydrogenation of selenium dioxide at positions 1 and 2, and hydrolysis to produce methylprednisolone. This route involves many steps, has a low yield (less than 1% overall), high cost, and uses selenium dioxide, which is toxic and harmful. The reaction route is as follows:

[0008]

[0009] For example, patent CN107840865A reports the use of 6α-methyl-17α-hydroxypregn-4-ene-21-chloro-3,20-dione as a starting material, followed by fermentation, oxidation, esterification, reduction, and hydrolysis to obtain methylprednisolone, with a total yield of approximately 60%. The raw materials for this route are not readily available and are not commercially available. The reaction route is as follows:

[0010]

[0011] Currently, the main challenge in the synthesis of methylprednisolone lies in the construction of the double bond at positions 1,2. Most methods employ fermentation, but this requires significant initial investment in strain selection, involves long reaction times, and is energy-intensive. Selenium dioxide oxidation, on the other hand, suffers from low selectivity and high toxicity. Therefore, it is necessary to investigate the synthetic process of methylprednisolone. Summary of the Invention

[0012] In view of this, one of the objectives of the present invention is to provide a method for preparing a compound of formula V.

[0013] To achieve the above objectives, the present invention adopts the following technical solution:

[0014] The method for preparing compound V involves using compound IV as a raw material and subjecting it to a reduction reaction under the action of a reducing agent and a Lewis acid to obtain compound V.

[0015] The reaction formula is as follows:

[0016] .

[0017] Furthermore, the reducing agent includes one or more of sodium borohydride and potassium borohydride, preferably sodium borohydride.

[0018] Furthermore, the molar ratio of the compound of formula IV to the reducing agent is 1.0:2.0 to 1.0:4.0, preferably 1.0:2.0; the molar ratio of the compound of formula IV to the Lewis acid is 1.0:2.0 to 1.0:8.0, preferably 1.0:2.0.

[0019] Furthermore, the Lewis acid includes any one or more of calcium chloride, zinc chloride, and ferrous chloride, preferably calcium chloride.

[0020] Furthermore, the reaction solvent in the reduction reaction is any one or more of methanol, ethanol, tetrahydrofuran, dioxane, and water, preferably a mixed solvent of ethanol and tetrahydrofuran.

[0021] Furthermore, the mass ratio of the compound of formula IV to the volume of the reaction solvent is 1:2~10.

[0022] Furthermore, the reaction temperature is 20℃~80℃, preferably 35℃~45℃.

[0023] Furthermore, the reaction time is 1 to 5 hours, preferably 1 to 3 hours, and more preferably 3 hours.

[0024] As a preferred option, the temperature is raised to 50~60℃ and the reaction is maintained for 3 hours; or the temperature is raised to 70~80℃ and the reaction is maintained for 1 hour; or the temperature is raised to 35℃~45℃ and the reaction is maintained for 3 hours.

[0025] Furthermore, the reaction is carried out under nitrogen protection.

[0026] As a preferred option, dioxane was taken, and anhydrous zinc chloride and sodium borohydride were added under stirring. The mixture was stirred at 20-30°C for 30 minutes, compound IV was added, and the temperature was raised to 50-60°C. The reaction was maintained at this temperature for 3 hours to obtain compound V.

[0027] As a preferred method, compound IV is mixed with dioxane, stirred until dissolved, calcium chloride ethanol solution is added, the temperature is raised to 70℃~80℃, sodium borohydride is added in portions, and the reaction is maintained at this temperature for 1 hour to obtain compound V.

[0028] As a preferred method, compound IV is mixed with tetrahydrofuran, stirred until dissolved, calcium chloride ethanol solution is added, followed by sodium borohydride, and the temperature is raised to 35℃~45℃. The reaction is maintained at this temperature for 3 hours to obtain compound V.

[0029] Preferably, the calcium chloride ethanol solution is prepared by mixing calcium chloride and ethanol at a mass ratio of 1:8 to 20; more preferably, the mass ratio of calcium chloride to ethanol is 1:10 to 16.

[0030] Furthermore, HPLC was used to monitor the reaction of the raw materials until it was complete.

[0031] Furthermore, the post-processing steps of the reduction reaction include: cooling the reaction solution obtained from the reduction reaction, adding glacial acetic acid solution to carry out the reaction, filtration or centrifugation, rinsing, and drying under reduced pressure to obtain compound V.

[0032] As a preferred option, the temperature is lowered to 0℃~10℃.

[0033] Preferably, after adding glacial acetic acid solution, stir at 0℃~10℃ for 30~60 minutes.

[0034] As a preferred method, rinsing with water is recommended.

[0035] Furthermore, the compound of formula IV is prepared by the following method:

[0036] 1) Compound II is protected at positions 17 and 21 under paraformaldehyde and acidic conditions to obtain compound III;

[0037] 2) The compound of formula III obtained in step 1) has a protecting group at the 3-position under the action of ethylene glycol, catalyst and dehydrating agent to obtain compound of formula IV;

[0038] The reaction formula is as follows:

[0039]

[0040] .

[0041] Furthermore, in step 1), the acid used includes one or more of sulfuric acid and perchloric acid, preferably sulfuric acid.

[0042] Further, in step 1), the molar ratio of the compound of formula II to the paraformaldehyde is 1.0:2.0 to 1.0:5.0, preferably 1.0:3.0.

[0043] Further, in step 1), the molar ratio of the compound of formula II to the acid is 1.0:2.0 to 1.0:4.0, preferably 1.0:2.4.

[0044] Further, in step 1), the reaction solvent is a mixture of dichloromethane and water; preferably, the mass ratio of dichloromethane to water is 1:10~20, more preferably 1:15~16.

[0045] Furthermore, in step 1), the reaction temperature of the upper protective reaction is 0℃~30℃, preferably 20℃~30℃.

[0046] Furthermore, in step 1), the reaction time of the upper protective reaction is 3 to 5 hours, preferably 4 hours.

[0047] Furthermore, in step 1), the reaction is carried out under nitrogen protection.

[0048] As a preferred embodiment, step 1) specifically includes: taking cortisone, adding dichloromethane and water, stirring to react; after cooling the reaction solution, adding acid, heating to react, and obtaining compound III.

[0049] As a preferred option, the temperature is lowered to 0℃~10℃.

[0050] Preferably, in step 1), the post-processing steps include: after the reaction is complete, adding ice water, stirring and separating the liquid, extracting the aqueous phase twice with dichloromethane, and combining the organic phases; the obtained organic phase is washed, evaporated under reduced pressure, cooled to crystallize, centrifuged, and dried under reduced pressure to obtain compound III.

[0051] Further, in step 2), the catalyst includes any one or more of p-toluenesulfonic acid and p-toluenesulfonic acid pyridine, preferably p-toluenesulfonic acid; the dehydrating agent includes any one or more of triethyl orthoformate, trimethyl orthoformate, and triethyl orthopropionate, preferably triethyl orthoformate.

[0052] Further, in step 2), the mass ratio of the compound of formula III to the catalyst is 1.0:0.01 to 1.0:0.05, preferably 1:0.02.

[0053] Further, in step 2), the molar ratio of the compound of formula III to the dehydrating agent is 1.0:1.0 to 1.0:4.0, preferably 1.0:1.4.

[0054] Furthermore, in step 2), both the reaction solvent and the reaction reagent are ethylene glycol.

[0055] Furthermore, in step 2), the mass ratio of compound III to ethylene glycol is 1.0 g / ml to 5.0 g / ml, preferably 2.0 ml / g.

[0056] Furthermore, in step 2), the reaction temperature is 20℃~55℃, preferably 50℃~55℃.

[0057] Preferably, in step 2), the dehydrating agent is slowly added dropwise to the reaction solution, and after the addition is complete, the reaction is kept at a constant temperature for 0.3 to 1 hour; preferably 0.5 hours.

[0058] Preferably, step 2) of the post-processing steps includes: after the reaction is complete, cooling to 20℃~25℃, adding 5% sodium bicarbonate solution, stirring at 20℃~25℃ for 1 hour, centrifuging, rinsing, and drying under reduced pressure to obtain compound IV.

[0059] A second objective of this invention is to provide a method for preparing a compound of formula VI.

[0060] To achieve the above objectives, the present invention adopts the following technical solution:

[0061] The preparation method of compound VI includes the following steps:

[0062] i) Prepare compound V using the aforementioned method;

[0063] ii) The compound V obtained in step i) undergoes an epoxidation reaction at positions 5 and 6 under the action of a peroxide to obtain compound VI;

[0064] Step ii) The reaction formula is as follows:

[0065] .

[0066] Further, in step ii), the oxidant includes any one or more of monoperoxyphthalic acid, peroxyformic acid, peracetic acid, and phthalic anhydride / 30% hydrogen peroxide, preferably phthalic anhydride / 30% hydrogen peroxide.

[0067] Furthermore, in step ii), the reaction solvent is dichloromethane.

[0068] Furthermore, in step ii), the reaction temperature is 0℃~30℃, preferably 0℃~10℃.

[0069] Furthermore, in step ii), the reaction time is 1 to 5 hours, preferably 1 to 2 hours.

[0070] Furthermore, the preparation method of the peracid solution in step ii) includes: adding ethyl acetate to phthalic anhydride, adding 30% hydrogen peroxide while stirring, and stirring at room temperature for 2-3 hours to obtain the solution.

[0071] Preferably, the mass ratio of phthalic anhydride, ethyl acetate and 30% hydrogen peroxide is 1:4~5:2~3.

[0072] As a preferred embodiment, step ii) specifically includes: dissolving compound V, stirring and cooling to 0℃~10℃, adding superacid solution dropwise, keeping the temperature below 10℃, and after the addition is complete, stirring the reaction to obtain compound VI.

[0073] Preferably, in step ii), the post-processing steps include: after the reaction is complete, slowly add sodium carbonate / sodium sulfite / aqueous solution, keep the temperature below 30°C, stir until dissolved, and then sequentially perform separation, extraction, vacuum evaporation and recrystallization treatments to obtain compound VI by vacuum drying.

[0074] Preferably, the recrystallization solvent is ethyl acetate; the preferred recrystallization conditions are heating to 70℃~78℃ and stirring for 1 hour, followed by cooling to 0℃~10℃ and crystallization for 1 hour.

[0075] The third objective of this invention is to provide a method for preparing methylprednisolone.

[0076] To achieve the above objectives, the present invention adopts the following technical solution:

[0077] The preparation method of methylprednisolone includes the following steps:

[0078] (1) Compound VI was prepared using the aforementioned method;

[0079] (2) The compound of formula VI obtained in step (1) reacts with a methyl Grignard reagent to obtain compound of formula VII;

[0080] (3) The compound of formula VII obtained in step (2) is deprotected at the 3-position under acidic conditions to obtain compound of formula VIII;

[0081] (4) The compound of formula VIII obtained in step (3) undergoes dehydration elimination at positions 4 and 5 under alkaline conditions to obtain compound of formula IX;

[0082] (5) The compound of formula IX obtained in step (4) is dehydrogenated at the 1 and 2 positions by 2,3-dichloro-5,6-dicyanophenyl quinone (DDQ) to obtain compound of formula X;

[0083] (6) The compound X obtained in step (5) is deprotected at positions 17 and 21 under acidic conditions to obtain compound I;

[0084] The reaction equations for steps (2)-(6) are as follows:

[0085]

[0086]

[0087]

[0088]

[0089] .

[0090] Further, in step (2), the methyl Grignard reagent includes any one or more of methyl magnesium bromide, methyl magnesium chloride, and methyl magnesium iodide, preferably methyl magnesium bromide; the molar ratio of the compound of formula VI to the Grignard reagent is 1.0:2.5~1.0:8.0, preferably 1.0:4.0.

[0091] Furthermore, in step (2), the reaction solvent is any one or more of toluene, 2-methyltetrahydrofuran, and dioxane, preferably toluene.

[0092] Furthermore, in step (2), the reaction temperature is 80℃~110℃, preferably 80℃~90℃.

[0093] Furthermore, in step (2), the reaction time is 1 to 3 hours, preferably 2 hours.

[0094] As a preferred option, the post-processing steps in step (2) include: after the reaction is complete, cooling to 0℃~10℃, adding acetic acid aqueous solution dropwise, adding ethyl acetate, stirring at 20℃~30℃ to dissolve, separating the liquid, extracting, evaporating under reduced pressure to dryness, and obtaining compound VII.

[0095] Furthermore, in step (3), the acid includes any one or more of sulfuric acid, hydrochloric acid, hydrobromic acid, and perchloric acid, preferably sulfuric acid; the molar ratio of the compound of formula VII to the acid is 1.0:1.8~1.0:3.0, preferably 1.0:2.0.

[0096] Furthermore, in step (3), the deprotection reaction temperature is 0℃~30℃, preferably 20℃~25℃.

[0097] Furthermore, in step (3), the reaction time is 0.5 to 1 hour, preferably 0.5 hours.

[0098] Furthermore, in step (3), the reaction solvent is methanol.

[0099] Preferably, the post-processing step (3) includes:

[0100] After the reaction was complete, sodium carbonate aqueous solution was slowly added at 20℃~25℃, stirred at 20℃~25℃ for 0.5~1 hours, centrifuged, and washed with water; toluene was added to the obtained solid, stirred and heated to 60℃~65℃, stirred for 1 hour, then cooled to 0℃~10℃ to crystallize for 1 hour, centrifuged, ethanol was added to the solid, the above operation was repeated, and the solid was dried under reduced pressure to obtain compound VIII.

[0101] Furthermore, in step (4), the alkali includes any one or more of sodium hydroxide and potassium hydroxide, preferably potassium hydroxide; the molar ratio of the compound of formula VIII to the alkali is 1.0:0.3~1.0:1.0, preferably 1.0:0.6.

[0102] Furthermore, in step (4) the dehydration elimination reaction, the reaction solvent is any one or more of methanol, ethanol, ethylene glycol, isopropanol, and n-butanol, preferably isopropanol.

[0103] Furthermore, in step (4), the reaction temperature is 65~90℃, preferably 75℃~83℃.

[0104] Furthermore, in step (4), the reaction time is 1 to 3 hours, preferably 2 hours.

[0105] As a preferred option, the post-processing steps of step (4) include: after the reaction is complete, cool down to below 20°C, add acetic acid aqueous solution, stir at 0°C~10°C for 1 hour, centrifuge, wash, add water to the filter cake and stir, centrifuge, wash with water, dry under reduced pressure to obtain compound IX.

[0106] Furthermore, in step (5) the dehydrogenation reaction, the molar ratio of the compound of formula IX to the DDQ is 1.0:1.1 to 1.0:2.0, preferably 1.0:1.3.

[0107] Furthermore, in step (5), the reaction solvent is any one or more of toluene and dioxane, preferably dioxane.

[0108] Furthermore, in step (5), the reaction temperature is 60℃~120℃, preferably 95℃~105℃.

[0109] Furthermore, in step (5), the reaction time is 3 to 5 hours, preferably 4 hours.

[0110] As a preferred option, the post-processing steps in step (5) include: after the reaction is complete, most of the solvent is evaporated under reduced pressure, the temperature is lowered to 20℃~30℃, 1% sodium hydroxide solution is slowly added, stirring is continued for 1 hour, centrifugation is performed, and after washing, the solid is transferred to the reaction vessel, methanol and dichloromethane are added, the temperature is raised to 50℃~60℃, and the temperature is maintained for 1 hour, then the temperature is lowered to 0℃~10℃ to crystallize for 1 hour, centrifugation is performed, and the solid is dried under reduced pressure to obtain compound X.

[0111] Furthermore, in step (6), the acid includes any one or more of sulfuric acid, perchloric acid, and hydrobromic acid, preferably perchloric acid; the mass ratio of the compound of formula X to the acid is 1.0:3.0~1.0:10.0, preferably 1.0:5.0.

[0112] Furthermore, in step (6) the deprotection reaction, the reaction solvent is any one or more of methanol, ethanol, and dichloromethane, preferably a mixed solvent of ethanol and dichloromethane.

[0113] Furthermore, in step (6), the reaction temperature is 0℃~20℃, preferably 0℃~5℃.

[0114] Furthermore, in step (6), the reaction time is 3 to 5 hours, preferably 4 hours.

[0115] As a preferred option, the post-processing steps of step (6) include: after the reaction is complete, adjust the pH to 6~7, evaporate the solvent under reduced pressure, cool to 0℃~5℃ and stir for 30 minutes, centrifuge, wash with water, rinse with cold methanol, add methanol to the obtained solid, stir at 0℃~5℃ for 30 minutes, filter, rinse, and dry under reduced pressure to obtain methylprednisolone.

[0116] As a preferred method, the pH is adjusted to 6-7 by adding 10% sodium hydroxide solution dropwise at 0℃~5℃.

[0117] The beneficial effects of this invention are as follows:

[0118] 1. The method for preparing methylprednisolone provided by this invention uses cortisone as raw material, and proceeds through acetal protection at positions 17 and 21, ethylene glycol protection at position 3, reduction, epoxidation at positions 5 and 6, Grignard reaction, removal of protection at position 3, dehydration at positions 4 and 5, dehydrogenation at positions 1 and 2, and removal of protection at positions 17 and 21 to obtain methylprednisolone. The process uses readily available raw materials, generates little waste acid and wastewater, produces no toxic or harmful reagents, does not involve microbial fermentation, consumes little energy, and is suitable for industrial production.

[0119] 2. This invention provides a new method for preparing methylprednisolone, wherein the compound of formula VII is a new intermediate for the synthesis of methylprednisolone, which has not been reported in the literature and has important innovative significance. It can be used for the mass production of methylprednisolone, saving costs and improving efficiency.

[0120] 3. The method for preparing methylprednisolone provided by this invention has the advantages of high yield, low cost, good quality, short reaction time, simple operation, no fermentation process involved, low initial investment, and suitability for industrial production. The total yield is over 38%, and the purity is over 99.9%. Attached Figure Description

[0121] Figure 1 The MS spectrum of compound III;

[0122] Figure 2 The MS spectrum of compound IV;

[0123] Figure 3 The MS spectrum of compound V;

[0124] Figure 4 MS spectrum of compound VI;

[0125] Figure 5 The MS spectrum of compound VII;

[0126] Figure 6 The MS spectrum of compound VIII;

[0127] Figure 7 The MS spectrum of compound IX;

[0128] Figure 8 The MS spectrum of compound X;

[0129] Figure 9 The IR spectrum of compound I;

[0130] Figure 10 MS chromatogram of compound I;

[0131] Figure 11 For compound I 1 H-NMR spectrum;

[0132] Figure 12 The HPLC chromatogram of compound I is shown below.

[0133] Figure 13 This is the overall synthesis route diagram for methylprednisolone. Detailed Implementation

[0134] The technical solution of the present invention will be described more clearly and completely below with reference to specific embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of them. Therefore, based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the protection scope of the present invention.

[0135] In this embodiment of the invention, the overall synthetic route of methylprednisolone is as follows: Figure 13 As shown: Methylprednisolone was obtained by using cortisone as raw material, followed by acetal protection at positions 17 and 21, ethylene glycol protection at position 3, reduction, epoxidation at positions 5 and 6, Grignard reaction, removal of protection at position 3, dehydration at positions 4 and 5, dehydrogenation at positions 1 and 2, and removal of protection at positions 17 and 21.

[0136] Example 1. Preparation of Compound III

[0137]

[0138] In a 50L reactor, add 3.8kg of cortisone (compound II), 25.2kg of dichloromethane, 950g of paraformaldehyde, and 1.65kg of water. Stir, introduce nitrogen gas, cool the reaction solution to 0℃~10℃, add 2.48kg of sulfuric acid dropwise, and after the addition is complete, raise the temperature to 20℃~30℃ and keep the reaction at this temperature for 4 hours. Take a sample for HPLC monitoring to ensure that the purity of the main peak is greater than 90%.

[0139] After the reaction was complete, 19.0 kg of ice water was added to the reactor, and the mixture was stirred and separated. The aqueous phase was extracted twice with 7.6 kg of dichloromethane. The combined organic phases were washed once each with 7.6 kg of 5% sodium bicarbonate aqueous solution and 7.6 kg of water. The organic phase was evaporated to dryness under reduced pressure, and 3.0 kg of methanol was added. The mixture was stirred and evaporated to dryness under reduced pressure. 9.0 kg of methanol was added to the residue, and the mixture was heated to 60-65°C and stirred for 1 hour. Then, the temperature was lowered to 0-10°C to crystallize for 1 hour. The crystals were centrifuged, washed with cold methanol, and the filter cake was dried under reduced pressure to obtain 3624 g of compound III, with a yield of 85.4% and an HPLC purity of 96.7%. The MS chromatogram of compound III is shown below. Figure 1 As shown.

[0140] Example 2. Preparation of Compound IV

[0141]

[0142] In a 50L reactor, 7.3kg of ethylene glycol and 3213g of compound III were added. Under nitrogen protection, 160.7g of p-toluenesulfonic acid was added with stirring. The temperature was raised to 50℃~55℃, and 1656g of triethyl orthoformate was added dropwise over approximately 3~5 hours. After the addition was complete, the reaction was maintained at this temperature for 0.5 hours, and the reaction was monitored by TLC to ensure the raw materials were fully reacted.

[0143] After the reaction was complete, the temperature was lowered to 20℃~25℃, and 16.1 kg of 5% sodium bicarbonate aqueous solution was added. The mixture was stirred at 20℃~25℃ for 1 hour, centrifuged, washed with water, washed with cold ethanol, and dried under reduced pressure to obtain 3394 g of compound IV, with a yield of 95.2% and an HPLC purity of 92.4%. The MS chromatogram of compound IV is shown below. Figure 2 As shown.

[0144] Example 3. Preparation of compound V

[0145]

[0146] In a 5L reaction flask, 500ml of dioxane was added under nitrogen protection. 76.3g of anhydrous zinc chloride and 42.4g of sodium borohydride were added with stirring. The mixture was stirred at 20-30℃ for 30 minutes. 100g of compound IV was added, and the temperature was raised to 50-60℃. The reaction was maintained at this temperature for 3 hours, and HPLC was used to monitor the completeness of the reaction. The mixture was then cooled to 0-10℃, and a solution prepared with 1.0kg of ice water and 67.2g of acetic acid was slowly added to the reaction solution. After the addition was complete, the mixture was stirred at 0-10℃ for 30-60 minutes. The mixture was filtered, washed with water, and dried under reduced pressure to obtain 90.4g of compound V, with a yield of 90.0% and an HPLC purity of 92.0%.

[0147] Example 4. Preparation of compound V

[0148]

[0149] In a 30L reactor, 600g of compound IV and 3.0kg of dioxane were added under nitrogen protection and stirred until dissolved. A solution prepared with 298g of calcium chloride and 3.0kg of ethanol was added, and the mixture was heated to 70-80℃. 203g of sodium borohydride was added in portions, and the reaction was maintained at this temperature for 1 hour. HPLC was used to monitor the completeness of the reaction. After the reaction was complete, the reaction solution was cooled to 0-10℃, and a solution prepared with 6.0kg of ice water and 403g of acetic acid was slowly added. After the addition was complete, the mixture was stirred at 0-10℃ for 30-60 minutes, centrifuged, washed with water, and dried under reduced pressure to obtain 560.5g of compound V, with a yield of 93.0% and an HPLC purity of 92.9%.

[0150] Example 5. Preparation of compound V

[0151]

[0152] In a 50L reactor, 1565g of compound IV and 5.6kg of tetrahydrofuran were added. Under nitrogen protection, the mixture was stirred until dissolved. A solution prepared with 389g of calcium chloride and 6.2kg of ethanol was added, followed by 265.2g of sodium borohydride. The temperature was raised to 35℃~45℃ and the reaction was maintained for 3 hours. HPLC was used to monitor the complete reaction of the starting materials. After the reaction was complete, the reaction solution was cooled to 0℃~10℃. A solution prepared with 15.7kg of ice water and 1.05kg of acetic acid was slowly added to the reaction solution. After the addition was complete, the mixture was stirred at 0℃~10℃ for 30~60 minutes, centrifuged, washed with water, and dried under reduced pressure to obtain 1497g of compound V, with a yield of 95.2% and an HPLC purity of 93.0%. The MS chromatogram of compound V is shown below. Figure 3 As shown.

[0153] Example 6. Preparation of Compound VI

[0154]

[0155] Preparation of peracid: Add 884g of phthalic anhydride and 4.0kg of ethyl acetate to a reaction flask, add 1354g of 30% hydrogen peroxide while stirring, stir at room temperature for 2-3 hours, and set aside.

[0156] In a 50L reactor, add 1339g of compound V and 31.9kg of dichloromethane. Stir and cool to 0℃~10℃. Add the prepared superacid solution dropwise while keeping the temperature below 10℃. After the addition is complete, stir and react at 0℃~10℃ for 1h~2h. Monitor the reaction of the raw materials by TLC until the reaction is basically complete.

[0157] After the reaction is complete, slowly add sodium carbonate / sodium sulfite / aqueous solution (664.4g sodium carbonate / 1242g sodium sulfite / 10.7kg water), keep the temperature below 30℃, stir at 20℃~30℃ until dissolved, separate the liquid and extract the aqueous phase with 3.5kg dichloromethane, combine the organic phases, wash with 6.7kg water, and evaporate the organic phase to dryness under reduced pressure.

[0158] 12.0 kg of ethyl acetate was added to the reaction vessel, and the mixture was stirred at 70℃~78℃ for 1 hour. The temperature was then lowered to 0℃~10℃ for crystallization for 1 hour. The crystals were centrifuged, washed with cold ethyl acetate, and dried under reduced pressure to obtain 1176 g of compound VI, with a yield of 84.8% and an HPLC purity of 97.4%. The MS chromatogram of compound VI is shown below. Figure 4 As shown.

[0159] Example 7. Preparation of Compound VII

[0160]

[0161] 2161 g of compound VI and 9.42 kg of toluene were added to a 50 L reactor under nitrogen protection. The mixture was stirred, and 6.2 L of a 3MCH3MgBr solution of 2-methyltetrahydrofuran was slowly added. The temperature was raised to 80-90 °C and the mixture was stirred for 2 hours. The reaction was monitored by TLC until the reactants were fully reacted. After the reaction was complete, the temperature was lowered to 0-10 °C, and 1357 g / 1081 g of an aqueous acetic acid solution was added dropwise. 9.75 kg of ethyl acetate was added, and the mixture was stirred at 20-30 °C until dissolved. The mixture was separated, and the aqueous phase was extracted twice with 3.9 kg of ethyl acetate. The combined organic phases were washed once with 10.8 kg of saturated brine. The mixture was evaporated to dryness under reduced pressure to obtain compound VII, which was used directly in the next reaction. The MS spectrum of compound VII is shown below. Figure 5 As shown.

[0162] Example 8. Preparation of compound VIII

[0163]

[0164] To compound VII, 8.7 kg of methanol was added, followed by the addition of 1825 g of 50% sulfuric acid. The reaction was carried out at 20°C–25°C for 0.5 hours, with TLC monitoring to ensure complete reaction of the starting material. After the reaction was complete, a solution prepared from 1035 g of sodium carbonate and 21.61 kg of water was slowly added at 20°C–25°C. After the addition was complete, the mixture was stirred at 20°C–25°C for 0.5–1 hour, centrifuged, and washed with water. The solid was transferred to a 30 L reactor under nitrogen protection, and 9.7 kg of toluene was added. The mixture was stirred and heated to 60°C–65°C for 1 hour, then cooled to 0°C–10°C for 1 hour to allow crystallization. The solid was then centrifuged. The solid was transferred to a 30 L reactor under nitrogen protection, and 8.6 kg of ethanol was added. The above steps were repeated, and the mixture was dried under reduced pressure to obtain 1787 g of compound VIII. The yield of compounds VII to VIII was 88.0%, and the HPLC purity was 98.5%. The MS chromatogram of compound VIII is shown below. Figure 6 As shown.

[0165] Example 9. Preparation of compound IX

[0166]

[0167] In a 30L reactor, 1827g of compound VIII was added under nitrogen protection. 5.7kg of isopropanol was added, and the mixture was stirred and heated to 75℃~83℃. A solution of 156.6g KOH / 1.4kg isopropanol was added, and the reaction was maintained at this temperature for 2 hours. HPLC monitoring was used to monitor the reaction progress. After the reaction was complete, the temperature was lowered to below 20℃, and a solution of 201.1g acetic acid / 1.8kg water was added. The mixture was stirred at 0℃~10℃ for 1 hour, centrifuged, washed with cold isopropanol, and the filter cake was transferred to a 30L reactor. 9.1kg of water was added, and the mixture was stirred at room temperature for 15 minutes. The mixture was centrifuged, washed with water, and dried under reduced pressure to obtain 1683g of compound IX, with a yield of 96.1% and an HPLC purity of 94.6%. The MS chromatogram of compound IX is shown below. Figure 7 As shown.

[0168] Example 10. Preparation of compound X

[0169]

[0170] In a 30L reactor, 1500g of compound IX and 7.7kg of dioxane were added under nitrogen protection. 1058g of 2,3-dichloro-5,6-dicyanophenyl quinone (DDQ) was added with stirring. The temperature was raised to 95℃~105℃ and maintained for 4 hours. HPLC monitoring was used to monitor the reaction progress. After the reaction was complete, most of the solvent was evaporated under reduced pressure. The temperature was lowered to 20℃~30℃, and 15.0kg of 1% sodium hydroxide solution was slowly added. Stirring was continued at 20℃~30℃ for 1 hour. The mixture was centrifuged, washed with water, and rinsed with cold methanol. The solid was transferred to a reactor, and 11.9kg of methanol and 200g of dichloromethane were added. The temperature was raised to 50℃~60℃ and maintained for 1 hour. The temperature was lowered to 0℃~10℃ for crystallization for 1 hour. The crystals were centrifuged, rinsed with cold methanol, and dried under reduced pressure to obtain 1224g of compound X, with a yield of 82.0% and an HPLC purity of 98.2%. The MS chromatogram of compound X is shown below. Figure 8 As shown.

[0171] Example 11. Preparation of methylprednisolone (compound I)

[0172]

[0173] In a 30L reactor, 1200g of compound X, 9.5kg of ethanol, and 15.9kg of dichloromethane were added. Under nitrogen protection, the mixture was stirred and cooled to 0℃~5℃. 6.0kg of perchloric acid was slowly added, and the reaction was maintained at this temperature for 4 hours. The reaction of the starting material was monitored by HPLC until complete. 10% sodium hydroxide solution was added dropwise at 0℃~5℃ to adjust the pH to 6~7. After the addition was complete, the solvent was evaporated under reduced pressure, and the mixture was cooled to 0℃~5℃ and stirred for 30 minutes. The mixture was centrifuged, washed with water, and rinsed with cold methanol. The solid was transferred to a reaction flask, and 4.74kg of methanol was added. The mixture was stirred at 0℃~5℃ for 30 minutes, filtered, rinsed with cold methanol, and dried under reduced pressure to obtain compound I, i.e., 919g of methylprednisolone, with a yield of 85.2%.

[0174] Further determination of the IR, MS, and other properties of the prepared compound I 1 ¹H-NMR and HPLC. IR detection results are as follows: Figure 9 Table 1 shows the MS detection results. Figure 10 As shown in Table 2, 1 H-NMR detection results are as follows Figure 11 Table 3 shows the HPLC detection results. Figure 12 As shown in Table 4.

[0175] Table 1. IR Integral Results of Methylprednisolone

[0176]

[0177] Table 2. MS Results of Methylprednisolone

[0178]

[0179] Table 3. Methylprednisolone 1 H-NMR integration results table

[0180]

[0181] Table 4. HPLC integration results of methylprednisolone

[0182]

Claims

1. A method for preparing compound V, characterized in that, Compound of formula IV was prepared by reduction reaction under the action of reducing agent and Lewis acid using compound IV as raw material; The reaction formula is as follows: 。 2. The preparation method according to claim 1, characterized in that, The reducing agent includes any one or more of sodium borohydride and potassium borohydride.

3. The preparation method according to claim 1, characterized in that, The molar ratio of the compound of formula IV to the reducing agent is 1.0:2.0 to 1.0:4.0; the molar ratio of the compound of formula IV to the Lewis acid is 1.0:2.0 to 1.0:8.

0.

4. The preparation method according to claim 1, characterized in that, The Lewis acid includes any one or more of calcium chloride, zinc chloride, and ferrous chloride.

5. The preparation method according to claim 1, characterized in that, The reaction solvent in the reduction reaction is any one or more of methanol, ethanol, tetrahydrofuran, dioxane, and water.

6. The preparation method according to claim 1, characterized in that, The reaction temperature is 20℃~80℃.

7. The preparation method according to claim 1, characterized in that, The compound of formula IV was prepared by the following method: 1) Compound II is protected at positions 17 and 21 under paraformaldehyde and acidic conditions to obtain compound III; 2) The compound of formula III obtained in step 1) has a protecting group at the 3-position under the action of ethylene glycol, catalyst and dehydrating agent to obtain compound of formula IV; The reaction formula is as follows: 。 8. The preparation method according to claim 7, characterized in that, In step 1), the acid used includes any one or more of sulfuric acid and perchloric acid.

9. The preparation method according to claim 7, characterized in that, In step 2), the catalyst includes one or more of p-toluenesulfonic acid and p-toluenesulfonic acid pyridine; the dehydrating agent includes one or more of triethyl orthoformate, trimethyl orthoformate, and triethyl orthopropionate.

10. A method for preparing a compound of formula VI, characterized in that, Includes the following steps: i) Prepare compound V by the method according to any one of claims 1 to 9; ii) The compound V obtained in step i) undergoes an epoxidation reaction at positions 5 and 6 under the action of a peroxide to obtain compound VI; Step ii) The reaction formula is as follows: 。 11. The preparation method according to claim 10, characterized in that, In step ii), the oxidant includes any one or more of monoperoxyphthalic acid, peroxyformic acid, peracetic acid, and phthalic anhydride / 30% hydrogen peroxide.

12. A method for preparing methylprednisolone, characterized in that, Includes the following steps: (1) The method described in any one of claims 10-11 is used to prepare compound of formula VI; (2) The compound of formula VI obtained in step (1) reacts with a methyl Grignard reagent to obtain compound of formula VII; (3) The compound of formula VII obtained in step (2) is deprotected at the 3-position under acidic conditions to obtain compound of formula VIII; (4) The compound of formula VIII obtained in step (3) undergoes dehydration elimination at positions 4 and 5 under alkaline conditions to obtain compound of formula IX; (5) The compound of formula IX obtained in step (4) is dehydrogenated at positions 1 and 2 under the action of DDQ to obtain compound of formula X; (6) The compound X obtained in step (5) is deprotected at positions 17 and 21 under acidic conditions to obtain compound I; The reaction equations for steps (2)-(6) are as follows: 。 13. The preparation method according to claim 12, characterized in that, In step (2), the methyl Grignard reagent includes any one or more of methyl magnesium bromide, methyl magnesium chloride, and methyl magnesium iodide; the molar ratio of the compound of formula VI to the Grignard reagent is 1.0:2.5~1.0:8.

0.

14. The preparation method according to claim 12, characterized in that, In step (3), the acid includes any one or more of sulfuric acid, hydrochloric acid, hydrobromic acid, and perchloric acid; the molar ratio of the compound of formula VII to the acid is 1.0:1.8~1.0:3.

0.

15. The preparation method according to claim 12, characterized in that, In step (4), the base includes any one or more of sodium hydroxide and potassium hydroxide; the molar ratio of the compound of formula VIII to the base is 1.0:0.3~1.0:1.

0.

16. The preparation method according to claim 12, characterized in that, In step (6), the acid includes any one or more of sulfuric acid, perchloric acid, and hydrobromic acid; the mass ratio of the compound of formula X to the acid is 1.0:3.0~1.0:10.0.

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