A preparation method of mometasone furoate impurity reference substance

Abstract

The present invention belongs to the field of chemical pharmacy, and is particularly related to a method for preparing a furoate mometasone impurity reference substance. The present invention uses furoate mometasone as raw material, and the specific steps include: (1) compound A and oxidant a react in solvent 1 to obtain compound B; (2) compound B, alkaline substance and acylating agent react in solvent 2 to obtain compound C; (3) compound C and hydrogenation catalyst react in solvent 3 to obtain compound D; (4) compound D and oxidant b react in solvent 4 to obtain compound E; the final reaction obtains furoate mometasone impurity KSS178-08, which provides a basis for the research of furoate mometasone related substances. The inventive method is simple, raw materials are easy to obtain, and products are easily purified, with a yield of >65%, a purity of ≥98%, and the product can be used as a reference substance in impurity detection.

Description

Technical Field

[0001] The invention belongs to the field of chemical pharmacy, and particularly relates to a method for preparing a mometasone furoate impurity reference substance. Background Art

[0002] The chemical name of mometasone furoate is: 9,21-dichloro-11b,17-dihydroxy-16a-methylpregnane-1,4-diene-3,20-dione 17-(2-furoate), and its chemical structure is as follows:

[0003]

[0004] Mometasone furoate is a synthetic glucocorticoid with anti-inflammatory, anti-allergic, vasoconstriction, vascular permeability reduction, cell division inhibition and antipruritic effects. Its characteristics are that the intensity of action increases disproportionately with the increase in side effects, and it is only used once a day. Mometasone furoate has a good therapeutic effect on skin diseases that are effectively treated with corticosteroids, such as neurodermatitis, eczema, atopic dermatitis, seborrheic dermatitis, ethyl psoriasis and other skin inflammation and skin itching caused.

[0005] Long-term topical use of corticosteroids may cause adverse reactions: irritation, skin atrophy, hirsutism, perioral dermatitis, skin infiltration, secondary infection, and skin streak-like hyperpigmentation or hypopigmentation.

[0006] Chinese invention patent application CN201510996544.2 discloses a method for synthesizing mometasone furoate, using 9β,11β-epoxy-17α,21-dihydroxy-16α-methyl-1,4-pregnadiene-3,2-dione (8DM) as a starting material, performing a sulfonylation reaction to obtain compound 1, then reacting compound 1 with furoyl chloride to perform a chlorination reaction while esterifying, preparing compound 3 from compound 1 in one step, and then performing a ring opening in a hydrochloric acid-glacial acetic acid system to obtain mometasone furoate. The specific synthesis route is as follows:

[0007]

[0008] US invention patent application US5886200A discloses the following synthesis route for preparing mometasone furoate by one-pot reaction:

[0009]

[0010] Some impurities are generated in the process of synthesizing mometasone furoate, among which 6-acetoxy-9,21-dichloro-11β-hydroxy-16α-methyl-3,20-dioxo-5-pregn-1-en-17-ylfuran-2-carboxylate is a reduced impurity in the production process of mometasone furoate. This impurity is impurity I in the European Pharmacopoeia. The prior art has disclosed this component, but lacks a process for synthesizing this compound.

[0011] Therefore, it is necessary to develop a route for synthesizing 6-acetoxy-9,21-dichloro-11β-hydroxy-16α-methyl-3,20-dioxo-5-pregn-1-en-17-ylfuran-2-carboxylate. The synthesis of this compound as an impurity reference for mometasone furoate is of great significance for studying and controlling the quality of drug production and studying the adverse reactions of drug receptors. Summary of the invention

[0012] Aiming at the deficiency of the prior art that there is no preparation method of 6-acetoxy-9,21-dichloro-11β-hydroxy-16α-methyl-3,20-dioxo-5-pregn-1-ene-17-ylfuran-2-carboxylate, the present invention provides a preparation method of furoate mometasone impurity reference substance. The synthesis method of the present invention has few reaction steps, simple process, easy to obtain starting materials, high yield of target product, high purity, can meet the preparation requirements of the impurity, and is of great significance to the study of furoate mometasone impurities.

[0013] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0014] A method for preparing a mometasone furoate impurity reference substance comprises the following steps:

[0015] (1) Compound A and oxidant a react in solvent 1 to obtain compound B;

[0016]

[0017] (2) Compound B, a basic substance and an acylating agent react in solvent 2 to obtain compound C;

[0018]

[0019] (3) Compound C reacts with a hydrogenation catalyst in solvent 3 to obtain compound D;

[0020]

[0021] (4) Compound D and oxidant b react in solvent 4 to obtain compound E;

[0022]

[0023] Where R is C 1-8 Acyl.

[0024] Preferably, the R is selected from any one of furoyl, acetyl and propionyl; and the oxidant a in step (1) is selected from one or more of selenium dioxide, m-chloroperbenzoic acid, hydrogen peroxide and tert-butyl peroxide.

[0025] Preferably, the solvent 1 in step (1) is at least one selected from tetrahydrofuran, 2-methyltetrahydrofuran, toluene, dichloromethane, chloroform, dioxane, acetone, dimethylformamide and dimethylacetamide.

[0026] Preferably, in step (1), the molar ratio of compound A to oxidant a is 1:2-8; the mass volume ratio of compound A to solvent 1 is 1 g:5-20 mL, preferably 1 g:8-12 mL.

[0027] Preferably, the reaction temperature in step (1) is 90-110° C., and the reaction time is 7-9 h.

[0028] Preferably, after the reaction in step (1), the steps of extraction, liquid separation, washing, drying, filtering, concentration and pulping are further included.

[0029] Preferably, the alkaline substance in step (2) is selected from at least one of pyridine, triethylamine, potassium carbonate and sodium hydroxide.

[0030] Preferably, the solvent 2 in step (2) is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, dichloromethane, chloroform, dioxane, acetone, dimethylformamide or dimethylacetamide.

[0031] Preferably, in step (2), the molar ratio of compound B to the alkaline substance is 1:0.5-6, preferably 1:4-5; the mass volume ratio of compound B to solvent 2 is 1 g:5-20 mL, preferably 1 g:8-12 mL.

[0032] Preferably, the acylating agent in step (2) comprises acetyl chloride; the molar ratio of compound B to acetyl chloride is 1:4.5-5.5; the reaction conditions are argon atmosphere, the reaction temperature is 0-10° C., and the reaction time is 18-20 h.

[0033] Preferably, after the reaction in step (2), the steps of extraction, liquid separation, washing, pH adjustment, drying, filtering and pulping are further included.

[0034] Preferably, the hydrogenation catalyst in step (3) is selected from any one of palladium carbon, platinum dioxide and Raney nickel.

[0035] Preferably, the solvent 3 in step (3) is at least one selected from tetrahydrofuran, acetic acid, 2-methyltetrahydrofuran, toluene, dichloromethane, chloroform, dioxane, acetone, methanol, ethanol and isopropanol.

[0036] Preferably, in step (3), the mass ratio of the compound C to the hydrogenation catalyst is 1:0.05-0.3, preferably 1:0.1-0.2; the mass volume ratio of the compound C to the solvent 3 is 1 g:5-20 mL, preferably 1 g:8-12 mL.

[0037] Preferably, the reaction conditions in step (3) are a hydrogen atmosphere, the reaction temperature is 20-30° C., and the reaction time is 3-5 h.

[0038] Preferably, after the reaction in step (3), the steps of extraction, washing, filtering, concentration and column chromatography separation are further included, and the eluent of the column chromatography is DCM:MeOH=200:1-100:1.

[0039] Preferably, the oxidant b in step (4) is selected from any one of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, 2-iodobenzoic acid and hydrogen peroxide.

[0040] Preferably, the solvent 4 in step (4) is at least one selected from tetrahydrofuran, 2-methyltetrahydrofuran, toluene, dichloromethane, chloroform, dioxane, acetone, methanol, ethanol and isopropanol.

[0041] Preferably, in step (4), the mass ratio of compound D to oxidant b is 1:0.5-3, preferably 1:0.8-1.5; the mass volume ratio of compound D to solvent 4 is 1 g:5-25 mL, preferably 1 g:15-20 mL.

[0042] Preferably, the reaction conditions in step (4) are argon atmosphere, the reaction temperature is 70-90° C., and the reaction time is 10-14 h.

[0043] Preferably, after the reaction in step (4), the steps of extraction, washing, drying, filtering, column chromatography separation and slurrying are further included, and the column chromatography is a dry column chromatography, and the eluent is DCM:MeOH=150:1-100:1.

[0044] Preferably, the preparation of the mometasone furoate impurity (compound shown in formula KSS178-08) comprises the following steps:

[0045] S1, compound KSS178-08-001 is oxidized at the allylic position under the action of selenium dioxide to obtain compound KSS178-08-01;

[0046] S2, compound KSS179-08-01 reacts with acetyl chloride under the action of pyridine to undergo acylation reaction to obtain compound KSS178-08-02;

[0047] S3, compound KSS178-08-02 reacts with hydrogen under the catalysis of platinum dioxide to obtain compound KSS178-08-03;

[0048] S4. Compound KSS178-08-03 was oxidized by DDQ to obtain compound KSS178-08.

[0049] The reaction route is as follows:

[0050]

[0051] Compared with the prior art, the present invention has the following beneficial effects:

[0052] (1) The present invention provides a method for synthesizing the mometasone furoate impurity (6-acetoxy-9,21-dichloro-11β-hydroxy-16α-methyl-3,20-dioxo-5-pregn-1-en-17-ylfuran-2-carboxylate), and the synthesis of the impurity has not been reported yet;

[0053] (2) The synthesis method of the present invention has a small number of reaction steps, a simple process, readily available starting materials, and a high yield of the target product, with the yield being >65%;

[0054] (3) The materials required by the present invention are easy to store and harmless, and the product is easy to purify with a purity of ≥98%, which can meet the preparation requirements of the impurity and has important significance for the study of mometasone furoate impurities. BRIEF DESCRIPTION OF THE DRAWINGS

[0055] Figure 1 1HNMR spectrum of pure KSS178-08-01 in Example 1, the solvent is deuterated DMSO;

[0056] Figure 2 1HNMR spectrum of pure KSS178-08-02 in Example 1, the solvent is deuterated DMSO;

[0057] Figure 3 1HNMR spectrum of pure KSS178-08 in Example 1, the solvent is deuterated DMSO;

[0058] Figure 4 This is the mass spectrum of pure KSS178-08 in Example 1;

[0059] Figure 5 This is the HPLC liquid phase spectrum of pure KSS178-08 in Example 1. DETAILED DESCRIPTION

[0060] The technical scheme of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary descriptions and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.

[0061] KSS178-08-001 (product number), from Beijing Compaison Pharmaceutical Technology Co., Ltd.

[0062] The raw materials and reagents used in the following examples are all commercially available or can be prepared by known methods.

[0063] Example 1

[0064] Step 1:

[0065]

[0066] 50g KSS178-08-001 (96mmol), 1,4-dioxane (500ml), 63.8g selenium dioxide (0.575mol) were added to a 1L three-necked flask, heated to 100℃, refluxed for 8h, and the raw material disappeared under TLC monitoring (developing solvent DCM:MeOH=20:1). Cooled to room temperature, water and EA (the volume ratio of water to EA was 2:1) were added to the reaction solution, stirred and filtered, the filtrate was separated, the organic phase was washed once with saturated NaCl, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and dichloromethane was added to slurry to obtain 27.2g of white solid (KSS178-08-01), with a yield of 54.4% and a purity of 98%.

[0067] KSS178-08-01 1 HNMR spectrum Figure 1 shown.

[0068] Step 2:

[0069]

[0070] 27.2g KSS178-08-02 (50.6mmol), DCM (272ml), 20.0g pyridine (253.1mmol) were added to a 500mL three-necked flask at room temperature, argon protection, cooled to 2°C, 19.9g acetyl chloride (253.1mmol) was added dropwise to the system, and the reaction was restored to room temperature for 20 hours, and the TLC thin layer chromatography plate was monitored (sample DCM dilution plate, add dilute hydrochloric acid to acidify, take the organic phase, developer: DCM: MeOH = 20: 1), and the raw material reaction was completed. Water was added to the system and stirred, and then the liquid was separated. Most of the pyridine was washed with hydrochloric acid aqueous solution, and then the pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution. The organic phase was washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and slurried with acetonitrile to obtain 22g of yellow solid (KSS178-08-02), with a yield of 75.8% and a purity of 99%.

[0071] KSS178-08-02 1 HNMR spectrum Figure 2 shown.

[0072] Step 3:

[0073]

[0074] 6g KSS178-08-02 (10.3mmol) was dissolved in THF (60ml), and platinum dioxide (0.6g) was added. The mixture was replaced with hydrogen and reacted at room temperature for 4h. TLC thin layer chromatography plate monitoring (sampling DCM dilution spot plate, developing solvent: DCM: MeOH = 20:1), the raw material reacted completely, filtered, ethyl acetate and water were added to the filtrate, stirred and separated, the organic phase was washed twice with brine, dried over anhydrous sodium sulfate, filtered, dried and concentrated, and the product was washed out by wet column chromatography (eluent: DCM: MeOH = 200:1-100:1), and 3.5g of white foamy solid (KSS178-08-03) was obtained by enrichment and concentration, with a yield of 58.3% and a purity of 80%.

[0075] Step 4:

[0076]

[0077] 3.5g KSS178-08-03 (6.00mmol), dioxane (70ml, 20V), 1.63g DDQ (7.2mmol) were added to a 250mL three-necked flask at room temperature, and the temperature was raised to 80°C for 12h under argon protection. LCMS showed that the basic reaction was completed, and the mixture was cooled to room temperature, stirred with water and ethyl acetate, and separated. The organic phase was washed twice with saturated sodium chloride, dried with anhydrous sodium sulfate, filtered, and directly mixed with the sample and dry column (eluent: DCM: MeOH = 150: 1-100: 1) for enrichment and concentration, and acetonitrile was added to slurry to obtain 2.4g of the product (KSS178-08-08), with a yield of 68% and a purity of 98.98%.

[0078] The 1HNMR spectrum of pure KSS178-08 is as follows Figure 3 As shown in the mass spectrometry Figure 4 As shown, the HPLC liquid phase spectrum is as follows Figure 5 As shown, the peak table of HPLC liquid phase spectrum is shown in Table 1.

[0079] Table 1 HPLC liquid phase spectrum peak table of compound KSS178-08

[0080] Peak Retention time area high area% 1 13.293 55639 2886 0.368 2 14.176 14973836 1284377 98.983 3 14.666 80808 6305 0.534 4 16.950 17363 1505 0.115 total 15127647 1295073 100.000

[0081] Example 2

[0082] Step 1:

[0083] 50g KSS178-08-001 (96mmol), dichloromethane (400ml), 82.8g m-chloroperbenzoic acid (0.48mol) were added to a 1L three-necked flask, heated to 40°C and refluxed, reacted for 8h, and TLC monitoring (developing solvent DCM: MeOH = 20:1) showed that the raw material disappeared. Cooled to room temperature, water was added to the reaction solution, stirred and filtered, the filtrate was separated, the organic phase was washed once with saturated NaCl, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and dichloromethane was added to slurry to obtain 25.8g of white solid (KSS178-08-01), with a yield of 51.6% and a purity of 97%.

[0084] Step 2:

[0085] 25.8g KSS178-08-02 (48mmol), toluene (207ml), 19.4g triethylamine (192mmol) were added to a 500mL three-necked flask at room temperature, argon protection, cooled to 0°C, 19.9g acetyl chloride (253.1mmol) was added dropwise to the system, and the reaction was restored to room temperature for 20 hours, and the reaction was monitored by TLC thin layer chromatography plate (sample DCM dilution plate, add dilute hydrochloric acid to acidify, take the organic phase, developer: DCM: MeOH = 20: 1), and the raw material reaction was completed. Water was added to the system and stirred, and then the liquid was separated. Most of the pyridine was washed with hydrochloric acid aqueous solution, and then the pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution. The organic phase was washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and slurried with acetonitrile to obtain 20.5g of yellow solid (KSS178-08-02), with a yield of 74.4% and a purity of 98%.

[0086] Step 3:

[0087] 6g KSS178-08-02 (10.3mmol) was dissolved in acetone (48ml), and Raney nickel (0.9g) was added. The mixture was replaced with hydrogen and reacted at room temperature for 4h. TLC thin layer chromatography plate monitoring (sampling DCM dilution spot plate, developing solvent: DCM: MeOH = 20:1), the raw material reacted completely, filtered, ethyl acetate and water were added to the filtrate, stirred and separated, the organic phase was washed twice with brine, dried over anhydrous sodium sulfate, filtered, dried and concentrated, and the product was washed out by wet column chromatography (eluent: DCM: MeOH = 200:1-100:1), and 3.52g of white foamy solid (KSS178-08-03) was obtained by enrichment and concentration, with a yield of 58.6% and a purity of 78%.

[0088] Step 4:

[0089] 3.5g KSS178-08-03 (6.00mmol), tetrahydrofuran (53ml), 1.34g IBX (4.8mmol) were added to a 250mL three-necked flask at room temperature, and the temperature was raised to 80°C for 12h under argon protection. LCMS showed that the basic reaction was completed, and the mixture was cooled to room temperature, and water and ethyl acetate were added and stirred, and the liquid was separated. The organic phase was washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and directly mixed with the sample and dry column (eluent: DCM: MeOH = 150: 1-100: 1) was enriched and concentrated, and acetonitrile was added to slurry to obtain 2.37g of the product (KSS178-08-08), with a yield of 67.1% and a purity of 98.2%.

[0090] Example 3

[0091] Step 1:

[0092] 50g KSS178-08-001 (96mmol), 2-methyltetrahydrofuran (600ml), 34.6g tert-butyl peroxide (0.384mol) were added to a 1L three-necked flask, heated to 80°C, reacted for 8h, and the raw material disappeared under TLC monitoring (developing solvent DCM: MeOH = 20:1). Cooled to room temperature, water and EA (the volume ratio of water to EA was 1:1) were added to the reaction solution, stirred and filtered, the filtrate was separated, the organic phase was washed once with saturated NaCl, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and dichloromethane was added to slurry to obtain 26.9g of white solid (KSS178-08-01), with a yield of 53.8% and a purity of 97.5%.

[0093] Step 2:

[0094] 26.9g KSS178-08-02 (50mmol), dimethylformamide (322ml), 31.0g potassium carbonate (225mmol) were added to a 500mL three-necked flask at room temperature, argon protection, cooled to 5°C, 17.7g acetyl chloride (225mmol) was added dropwise to the system, and the reaction was restored to room temperature for 20 hours, and the TLC thin layer chromatography plate was monitored (sampled DCM dilution point plate, added dilute hydrochloric acid to acidify, and the organic phase was taken, and the developing solvent was DCM: MeOH = 20: 1). The raw material reaction was completed. Water was added to the system and stirred, and then the liquid was separated. Most of the pyridine was washed with hydrochloric acid aqueous solution, and then the pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution. The organic phase was washed twice with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and slurried with acetonitrile to obtain 21.3g of yellow solid (KSS178-08-02), with a yield of 74.2% and a purity of 99%.

[0095] Step 3:

[0096] 6g KSS178-08-02 (10.3mmol) was dissolved in THF (60ml), palladium carbon (1.2g) was added, hydrogen was replaced, and the reaction was carried out at room temperature for 4h. TLC thin layer chromatography plate monitoring (sampling DCM dilution spot plate, developing solvent: DCM: MeOH = 20:1), the raw material reaction was complete, suction filtration, ethyl acetate and water were added to the filtrate, stirred and separated, the organic phase was washed twice with brine, dried over anhydrous sodium sulfate, filtered, dried and concentrated, wet column chromatography (eluent: DCM: MeOH = 200:1-100:1) flushed out the product, enriched and concentrated to obtain 3.48g of white foamy solid (KSS178-08-03), with a yield of 58% and a purity of 75%.

[0097] Step 4:

[0098] 3.4g KSS178-08-03 (5.82mmol), methanol (61ml), 1.98g DDQ (8.73mmol) were added to a 250mL three-necked flask at room temperature, and the temperature was raised to 80°C for 12h under argon protection. LCMS showed that the basic reaction was completed, and the mixture was cooled to room temperature, stirred with water and ethyl acetate, and separated. The organic phase was washed twice with saturated sodium chloride, dried with anhydrous sodium sulfate, filtered, and directly mixed with the sample and dried by column (eluent: DCM:MeOH=150:1-100:1) for enrichment and concentration, and acetonitrile was added to slurry to obtain 2.24g of the product (KSS178-08-08), with a yield of 65.8% and a purity of 98%.

[0099] Comparative Example 1

[0100] The preparation process is consistent with that of Example 1, except that in step 1: 50 g KSS178-08-001 (96 mmol), 1,4-dioxane (500 ml), and 49.9 g manganese dioxide (0.575 mol) are added to a 1L three-necked flask, heated to 80°C and refluxed, reacted for 8 hours, and the raw materials disappeared under TLC monitoring (developing agent DCM: MeOH = 20: 1). The rest is consistent with that of Example 1, and 13 g of white solid (KSS178-08-01) is obtained in step 1, with a yield of 25% and a purity of 95%.

[0101] Comparative Example 2

[0102] The preparation process is consistent with that in Example 1, except that in step 2: 27.2g KSS178-08-02 (50.6mmol), DCM (272ml), 32.7g DIEA (253.1mmol) are added to a 500mL three-necked flask at room temperature, argon is protected, the temperature is cooled to 2°C, 19.9g acetyl chloride (253.1mmol) is added dropwise to the system, and the reaction is resumed to room temperature for 20 hours, and the reaction of the raw materials is completed by monitoring the TLC thin layer chromatography plate. The rest is consistent with that in Example 1, and 14.5g of yellow solid (KSS178-08-02) is obtained in step 2, with a yield of 50.1% and a purity of 86%.

[0103] Comparative Example 3

[0104] The preparation process is the same as that of Example 1, except that in step 3: 1 g of KSS178-08-02 (10.3 mmol) was dissolved in THF (10 ml), Rh / C (0.1 g) was added, hydrogen was replaced, and the reaction was carried out at room temperature for 4 h. TLC thin layer chromatography plate monitoring (sampling DCM dilution spot plate, developing solvent: DCM: MeOH = 20:1), the raw material basically did not react.

[0105] Comparative Example 4

[0106] The preparation process is the same as that of Example 1, except that in step 2: 3.5 g KSS178-08-03 (6.00 mmol), dioxane (70 ml, 20 V), and 0.8 g selenium dioxide (7.2 mmol) are added to a 250 mL three-necked flask at room temperature, and the mixture is protected by argon and heated to 80° C. for 12 h. LCMS shows that the basic reaction is complete, and the rest is the same as that of Example 1. Step 4 obtains 1 g of the product (KSS178-08), with a yield of 28.3% and a purity of 96%.

[0107] The above detailed description is a specific description of one feasible embodiment of the present invention. The embodiment is not intended to limit the patent scope of the present invention. Any equivalent implementation or modification that does not deviate from the present invention should be included in the scope of the technical solution of the present invention.

Claims

1. A method for preparing a mometasone furoate impurity reference substance, characterized in that: The following steps are involved: (1) Compound A and oxidant a react in solvent 1 to obtain compound B; (2) Compound B, a basic substance and an acylating agent react in solvent 2 to obtain compound C; (3) Compound C reacts with a hydrogenation catalyst in solvent 3 to obtain compound D; (4) Compound D and oxidant b react in solvent 4 to obtain compound E; Among them, the above R are C 1-8 Acyl.

2. The preparation method according to claim 1, characterized in that: The R is selected from any one of furoyl, acetyl and propionyl; the oxidant a in step (1) is selected from one or more of selenium dioxide, m-chloroperbenzoic acid, hydrogen peroxide and tert-butyl peroxide; the solvent 1 is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, dichloromethane, chloroform, dioxane, acetone, dimethylformamide and dimethylacetamide.

3. The preparation method according to claim 1, characterized in that: The molar ratio of compound A to the oxidant in step (1) is 1:2-8; the mass volume ratio of compound A to solvent 1 is 1 g:5-20 mL.

4. The preparation method according to claim 1, characterized in that: The reaction temperature in step (1) is 90-110° C. and the reaction time is 7-9 hours. After the reaction, the steps of extraction, separation, washing, drying, filtering, concentration and pulping are also included.

5. The preparation method according to claim 1, characterized in that: In step (2), the alkaline substance is selected from at least one of pyridine, triethylamine, potassium carbonate and sodium hydroxide; and the solvent 2 is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, dichloromethane, chloroform, dioxane, acetone, dimethylformamide or dimethylacetamide.

6. The preparation method according to claim 1, characterized in that: The molar ratio of the compound B to the alkaline substance in step (2) is 1:0.5-6; the mass volume ratio of the compound B to the solvent 2 is 1g:5-20mL.

7. The preparation method according to claim 1, characterized in that: The acylating agent in step (2) includes acetyl chloride, and the molar ratio of compound B to acetyl chloride is 1:4.5-5.5; the reaction conditions are argon atmosphere, the reaction temperature is 0-10°C, and the reaction time is 18-20h; after the reaction, the steps of extraction, separation, washing, pH adjustment, drying, filtering and pulping are also included.

8. The preparation method according to claim 1, characterized in that: The hydrogenation catalyst in step (3) is selected from any one of palladium carbon, platinum dioxide and Raney nickel; the solvent 3 is selected from at least one of tetrahydrofuran, acetic acid, 2-methyltetrahydrofuran, toluene, dichloromethane, chloroform, dioxane, acetone, methanol, ethanol and isopropanol.

9. The preparation method according to claim 1, characterized in that: In step (3), the mass ratio of compound C to hydrogenation catalyst is 1:0.05-0.3; the mass volume ratio of compound C to solvent is 1g:5-20mL.

10. The preparation method according to claim 1, characterized in that: The reaction conditions in step (3) are a hydrogen atmosphere, a reaction temperature of 20-30° C., and a reaction time of 3-5 h; after the reaction, the steps of extraction, washing, filtering, concentration and column chromatography separation are also included, and the eluent for the column chromatography separation is DCM:MeOH=200:1-100:

1.

11. The preparation method according to claim 1, characterized in that: In step (4), the oxidant b is selected from any one of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, 2-iodobenzoic acid and hydrogen peroxide; the solvent 4 is selected from at least one of tetrahydrofuran, 2-methyltetrahydrofuran, toluene, dichloromethane, chloroform, dioxane, acetone, methanol, ethanol and isopropanol.

12. The preparation method according to claim 1, characterized in that: In step (4), the mass ratio of compound D to oxidant b is 1:0.5-3; the mass volume ratio of compound D to solvent 4 is 1 g:5-25 mL.

13. The preparation method according to claims 1-12, characterized in that: The reaction conditions in step (4) are argon atmosphere, the reaction temperature is 70-90° C., and the reaction time is 10-14 h; after the reaction, the steps of extraction, washing, drying, filtering, column chromatography separation and pulping are also included, and the column chromatography is a dry column, and the eluent is DCM:MeOH=150:1-100:1.

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