A process for the preparation of a 4AA diastereoisomer

Abstract

The application discloses a preparation method of 4AA diastereoisomer. Specifically disclosed is a preparation method of compound A5, which comprises the following steps: performing a reduction reaction on compound A3 in a solvent under the action of a reducing agent and a Lewis acid to obtain compound A5. The predetermined diastereoisomer is obtained through directional synthesis starting from commercial 4AA, and the reaction route is short and the yield is high.

Description

Technical Field

[0001] This invention relates to a method for preparing 4AA diastereomers. Background Technology

[0002] 4AA, chemically named (3R,4R)-4-acetyl-3-[(R)-(tert-butyldimethylsilyl)oxy]-2-azacyclobutanone, is a key starting material for the synthesis of penicillene and carbapenem antibiotic parent rings. It is mainly used in the synthesis of various penem antibiotics, such as imipenem, biapenem, meropenem, and faropenem.

[0003]

[0004] 4-AA has three chiral centers and one β-lactam ring, making its synthesis difficult. The synthesis process generates various diastereomers. To control the quality of 4AA preparation, it is necessary to prepare diastereomers of 4AA. The preparation and analysis of these diastereomers are crucial for improving the yield and purity of 4AA and for controlling the quality of the synthesized 4AA product. Summary of the Invention

[0005] To address the problems of poor isomer selectivity, difficult purification, the need for highly toxic substances, and difficulty in confirming the structure of impurities in the preparation of diastereomers of 4AA in the prior art, this invention provides a method for preparing diastereomers of 4AA (i.e., compound I). Starting from commercial 4AA, the method obtains the predetermined diastereomers through directed synthesis, with a short reaction route and high yield.

[0006] The present invention solves the above-mentioned technical problems through the following solution.

[0007] The present invention provides a method for preparing compound A5, which includes the following steps: in a solvent, under the action of a reducing agent and a Lewis acid, compound A3 undergoes a reduction reaction to obtain compound A5;

[0008]

[0009] In the reduction reaction, the solvent can be conventional in the art, preferably one or more of 1,4-dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, diethyl ether, chloroform, and dichloromethane; for example, tetrahydrofuran.

[0010] In the reduction reaction, the amount of solvent used can be conventional in the art. Preferably, the mass ratio of the solvent to the compound A3 is (5-20):1; for example, 10:1.

[0011] In the reduction reaction, the reducing agent can be conventional in the art. Preferably, the reducing agent is one or more of sodium borohydride, lithium aluminum hydride, and potassium borohydride, such as sodium borohydride and / or lithium aluminum hydride; more preferably, the reducing agent is sodium borohydride.

[0012] In the reduction reaction, the amount of reducing agent used can be conventional in the art. Preferably, the mass ratio of the reducing agent to the compound A3 is 1:(3-4); for example, 1:3.75.

[0013] In the reduction reaction, preferably, the Lewis acid is MgCl2 and / or ZnCl2; more preferably, the Lewis acid is MgCl2.

[0014] In the reduction reaction, the amount of Lewis acid used can be conventional in the art. Preferably, the mass ratio of the Lewis acid to the compound A3 is 1:(0.01 to 0.5); for example, 1:0.05.

[0015] In the reduction reaction, the temperature of the reduction reaction can be conventional in the art, preferably -20 to 40°C; for example, 0 to 20°C.

[0016] In the reduction reaction, conventional monitoring methods in the art, such as HPLC or TLC, are employed. The reaction is generally stopped when compound A3 disappears or ceases to react. Preferably, the reduction reaction takes 0.5 to 7 hours; for example, 1 or 5 hours.

[0017] In one embodiment, the reduction reaction is carried out by the following steps: the solvent, the Lewis acid and the compound A3 are mixed, the reducing agent is added at -20 to 10°C (e.g., -20 to 0 or 0 to 10°C), and the reaction is carried out at 0 to 20°C for 0.5 to 7 hours to obtain compound A5.

[0018] Preferably, the reduction reaction further includes the following post-processing steps: concentration, extraction, and concentration.

[0019] The preparation method of compound A5 may further include the following steps:

[0020] In a solvent, under the action of an oxidizing agent, compound A2 undergoes an oxidation reaction to yield compound A3;

[0021]

[0022] In the oxidation reaction, the solvent can be conventional in the art, preferably one or more of 1,4-dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, diethyl ether, chloroform, and dichloromethane; for example, dichloromethane and / or tetrahydrofuran.

[0023] In the oxidation reaction, the amount of solvent used can be conventional in the art. Preferably, the mass ratio of the solvent to the compound A2 is 1:(0.01 to 0.1); for example, 1:0.03.

[0024] In the oxidation reaction, the oxidant can be conventional in the art. Preferably, the oxidant is one or more of the following: Dysmart reagent, hydrogen peroxide, sodium hypochlorite, potassium permanganate, and manganese dioxide; for example, Dysmart reagent and / or sodium hypochlorite.

[0025] In the oxidation reaction, preferably, when the oxidant is sodium hypochlorite, 2,2,6,6-tetramethylpiperidine oxide (TEMPO) and potassium bromide are further added; preferably, the mass ratio of 2,2,6,6-tetramethylpiperidine oxide to compound A2 is 1:(20-40); for example, 1:30; preferably, the mass ratio of potassium bromide to compound A2 is 1:(0.5-0.8); for example, 1:0.6.

[0026] In the oxidation reaction, the amount of oxidant used can be conventional in the art. Preferably, the mass ratio of the oxidant to the compound A2 is 1:(0.1 to 0.4); for example, 1:0.12 or 1:0.25.

[0027] In the oxidation reaction, the temperature of the oxidation reaction can be conventional in the art. Preferably, the temperature of the oxidation reaction is -10 to 40°C, for example, 30°C or 35°C.

[0028] In the oxidation reaction, conventional monitoring methods in the art, such as HPLC or TLC, are employed. The reaction is generally stopped when compound A2 disappears or ceases to react. Preferably, the oxidation reaction takes 2–8 hours.

[0029] In one embodiment, the oxidation reaction is carried out by the following steps: after mixing the solvent and the compound A2, the oxidant is added at 0-10°C, and the temperature is raised to 25-35°C within 1-3 hours and held for 0.5-2 hours to obtain compound A3.

[0030] Preferably, the oxidation reaction further includes the following post-processing steps: adding ice water, separating the liquid phase, and concentrating the organic phase.

[0031] The preparation method of compound A5 may further include the following step: in a solvent, under the action of a deprotecting agent, compound 4AA undergoes a deprotection reaction to obtain compound A2;

[0032] The deprotecting agent is tetrabutylammonium fluoride (TBAF) or hydrochloric acid;

[0033]

[0034] In the deprotection reaction, the solvent can be conventional in the art. Preferably, the solvent is one or more of methanol, 1,4-dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, diethyl ether, chloroform, and dichloromethane; for example, tetrahydrofuran and / or methanol.

[0035] In the deprotection reaction, the amount of solvent used can be conventional in the art. Preferably, the mass molar ratio of the solvent to the compound 4AA is (1000-3000) g / mol; for example, 1500 g / mol or 2000 g / mol.

[0036] In the deprotection reaction, the amount of the deprotection reagent can be conventional in the art. Preferably, the molar ratio of the deprotection reagent to the compound 4AA is (1-1.5):1; for example, 1.15:1.

[0037] In the deprotection reaction, the temperature of the deprotection reaction can be conventional in the art. Preferably, the temperature of the deprotection reaction is 20-60°C, for example, 30°C or 40°C.

[0038] In the deprotection reaction, the deprotection reaction can be monitored using conventional methods in the art, such as HPLC or TLC. The reaction endpoint is generally reached when the compound 4AA disappears or ceases to react, at which point the reaction is stopped. Preferably, the deprotection reaction takes 10–25 hours, for example, 12 or 20 hours.

[0039] Preferably, the deprotection reaction further includes the following post-processing steps: extraction and separation.

[0040] In the deprotection reaction, the separation in the post-processing step can be a conventional operation in the art; preferably, the separation is column chromatography.

[0041] The present invention also provides a method for preparing compound I, which includes the following steps:

[0042] (1) In a solvent, under the action of a deprotecting agent, compound 4AA undergoes a deprotection reaction to give compound A2;

[0043] The deprotecting agent is tetrabutylammonium fluoride (TBAF) or hydrochloric acid;

[0044]

[0045] (2) In the solvent, under the action of the oxidant, compound A2 undergoes an oxidation reaction to obtain compound A3;

[0046]

[0047] (3) In the solvent, under the action of a reducing agent and a Lewis acid, compound A3 undergoes a reduction reaction to obtain compound A5;

[0048]

[0049] (4) In a solvent, under the action of an alkali, compound A5 undergoes a hydroxyl protection reaction with tert-butyldimethylchlorosilane (TBSCl) to obtain compound I;

[0050]

[0051] In the preparation method of compound I, the conditions and operations of the deprotection reaction, the oxidation reaction and the reduction reaction are as described in any of the above schemes.

[0052] In the hydroxyl protection reaction, the solvent can be conventional in the art, preferably one or more of 1,4-dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, diethyl ether, chloroform, and dichloromethane; for example, dichloromethane and / or tetrahydrofuran.

[0053] In the hydroxyl protection reaction, the amount of solvent used can be conventional in the art. Preferably, the mass ratio of the solvent to the compound A5 is (5-20):1; for example, 10:1.

[0054] In the hydroxyl protection reaction, the base can be conventional in the art; preferably, the base is imidazole and / or triethylamine; more preferably, the base is imidazole.

[0055] In the hydroxyl protection reaction, the amount of base used can be conventional in the art. Preferably, the mass ratio of the base to the compound A5 is (1-1.2):1; for example, 1.07:1.

[0056] In the hydroxyl protection reaction, the amount of tert-butyldimethylchlorosilane used can be conventional in the art. Preferably, the mass ratio of tert-butyldimethylchlorosilane to compound A5 is (1-1.2):1; for example, 1.07:1.

[0057] In the hydroxyl protection reaction, the temperature of the hydroxyl protection reaction can be conventional in the art, preferably -10 to 50°C; for example, 0 to 10°C.

[0058] In the hydroxyl protection reaction, the hydroxyl protection reaction can be monitored using conventional methods in the art, such as HPLC or TLC. The reaction endpoint is generally reached when compound A5 disappears or ceases to react, at which point the reaction is stopped. Preferably, the hydroxyl protection reaction takes 10–15 hours; for example, 12 hours.

[0059] In one embodiment, the hydroxyl protection reaction is carried out by the following steps: the solvent, the base and the compound A5 are mixed, tert-butyldimethylchlorosilane is added at 0-10°C, and the mixture is reacted at 0-10°C for 10-15 hours to obtain compound I.

[0060] Preferably, the hydroxyl protection reaction further includes the following post-processing steps: concentration and separation.

[0061] In the hydroxyl protection reaction, the separation in the post-processing step can be a conventional operation in the art, preferably, the separation is column chromatography.

[0062] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0063] The reagents and raw materials used in this invention are all commercially available.

[0064] The positive and progressive effects of this invention are: it obtains the predetermined diastereomers through directional synthesis, with a short reaction route, high yield, and good selectivity. Attached Figure Description

[0065] Figure 1 This is the HPLC chromatogram of compound I in Example 4. Detailed Implementation

[0066] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0067] Example 1

[0068] 200 g of tetrahydrofuran, 28.7 g of 4AA, and 30 g of tetrabutylammonium fluoride were added to a 500 mL three-necked flask at 20 °C. The system was stirred at 40 °C for 12 h, and TLC showed that the starting material 4AA was completely consumed. The system was cooled to 20 °C and concentrated to remove tetrahydrofuran. 200 g of ethyl acetate and 100 g of ice water were added to the concentrate, and the mixture was separated. The upper organic phase was concentrated to dryness to obtain crude intermediate A2. Column chromatography was used to purify the crude intermediate A2 once to obtain 10.1 g of pure A2, with a yield of 58.4% and a purity of 98.7%.

[0069] Example 2

[0070] 200 g of dichloromethane, 10 g of potassium bromide, and 0.2 g of 2,2,6,6-tetramethylpiperidine oxide, along with 6 g of intermediate A2 prepared in Example 1, were added to a 500 mL three-necked flask at 20 °C. The system was cooled to 0–10 °C, and 50 g of a sodium hypochlorite solution with an effective content (based on Cl) of 11% was added dropwise. After the addition was complete, the system was heated to 30 °C over 2 hours and held at that temperature for 1 hour. TLC showed that the starting material A2 was completely consumed. 100 g of ice water was added to the system, and the mixture was separated. The upper aqueous phase was extracted once again with 100 g of dichloromethane. The combined organic phases were washed once with 5% sodium sulfite (50 g), dried, and concentrated under reduced pressure to obtain intermediate A3, weighing 4.7 g, with a yield of 78.5% and a purity of 93.2%. This intermediate was used directly for the next reduction step.

[0071] Example 3

[0072] 30 g of tetrahydrofuran, 3 g of intermediate A3 prepared in Example 2, and 150 mg of MgCl2 were added to a 250 mL three-necked flask at 20 °C. The system was cooled to 0–10 °C, and 0.8 g of sodium borohydride was added in portions. The system was stirred at 0–20 °C for 3 h. TLC showed that A3 was completely consumed. The tetrahydrofuran was removed by concentration below 40 °C. The resulting concentrate was dispersed in a mixture of 100 g ethyl acetate and 50 g ice water. The mixture was separated, and the organic phase was washed once with 20 g saturated sodium bicarbonate. The organic phase was then dried with 5 g anhydrous sodium sulfate for 2 h. The filtrate was filtered and concentrated under reduced pressure below 40 °C to obtain 2.8 g of product. 22%, target isomer It accounts for 78%.

[0073] Example 4

[0074] At 0–10 °C, 28 g of dichloromethane, 3 g of imidazole, and 2.8 g of the product obtained in Example 3 were added to a 250 mL three-necked flask. 1.6 g of TBSCl was added in portions, and the system was stirred at 0–10 °C for 12 h. TLC showed complete consumption of compound A5. The product was concentrated below 40 °C to remove dichloromethane, and the concentrate was purified by column chromatography to the diastereomer. Column chromatography yielded 1.3 g of a white solid. Yield: 43.0%, purity: 96.6%.

[0075] HPLC test:

[0076] Chromatographic conditions:

[0077] Column: Waters Xterra MS C18 (50*4.6mm, 2.5μm);

[0078] Mobile phase A: 7.8 mM phosphate solution of 1.5% acetonitrile.

[0079] Mobile phase B: 7.8 mM phosphate solution in 20% acetonitrile

[0080] Detection wavelength: 200 nm

[0081] Flow rate: 1.0 mL / min

[0082] Injection volume: 10 μL

[0083] Concentration: 1 mg / mL

[0084] The HPLC test results are shown in Table 1 and Figure 1 As shown:

[0085] Table 1

[0086]

[0087] H NMR(CDCl3,400M): 6.24(br,1H),5.71(br,1H),4.23~4.19(s,1H),2.13(s,3H),1.25(s,3H),0.88(s,9H),0.07~0.06(s,6H);

[0088] LC-MS calculated value: 287.16, measured value: 288.2.

[0089] Example 5

[0090] 150 g of methanol, 28.7 g of 4AA, and 5 g of concentrated hydrochloric acid were added to a 500 mL three-necked flask at 30 °C. The system was stirred at 30 °C for 20 h, and TLC showed that the starting material 4AA was completely consumed. 500 g of ice water and 150 g of dichloromethane were added to the system and stirred for 10 min. The mixture was separated, and the upper aqueous phase was extracted once with 150 g of dichloromethane. The combined organic phases were washed once with 150 g of saturated sodium bicarbonate, dried over sodium sulfate, and concentrated to remove the organic solvent. The resulting organic phase was concentrated to dryness to obtain crude intermediate A2. One column chromatography purification yielded 10.6 g of pure A2, with a yield of 61.3% and a purity of 93.6%.

[0091] Example 6

[0092] 200 g of tetrahydrofuran and 6 g of intermediate A2 prepared in Example 1 were added to a 500 mL three-necked flask at 20 °C. The system was cooled to 0–10 °C, and 24 g of Dess-Martin reagent (a commercially available oxidant) was added to the system in 5 batches, with each batch 30 min apart. After the addition was complete, the system was heated to 35 °C within 1 h and held at that temperature for 2 h. TLC showed that the starting material A2 was completely consumed. 100 g of ice water was added to the system, and the mixture was separated. The upper aqueous phase was extracted once with 100 g of dichloromethane. The combined organic phases were washed once with 5% sodium sulfite (50 g). After drying the organic phase, it was concentrated under reduced pressure to obtain intermediate A3, with a weight of 4.6 g, a yield of 76.1%, and a purity of 92.7%, which was directly used for the next reduction step.

[0093] Example 7

[0094] 30 g of tetrahydrofuran, 3 g of intermediate A3 prepared in Example 2, and 150 mg of MgCl2 were added to a 250 mL three-necked flask at 20 °C. The system was cooled to -20 to 0 °C, and 0.8 g of lithium aluminum hydride was added in portions. The system was stirred at 0 to 20 °C for 1 h. TLC showed that A3 was completely consumed. The tetrahydrofuran was removed by concentration below 30 °C. The resulting concentrate was dispersed in a mixture of 100 g of ethyl acetate and 50 g of ice water. The mixture was separated, and the organic phase was washed once with 20 g of saturated sodium bicarbonate. The organic phase was then dried with 5 g of anhydrous sodium sulfate for 2 h. The filtrate was filtered and concentrated under reduced pressure below 40 °C to obtain 2.7 g of product. 33%, target isomer It accounts for 67%.

[0095] Example 8

[0096] 30 g of tetrahydrofuran, 3 g of intermediate A3 prepared in Example 2, and 150 mg of ZnCl2 were added to a 250 mL three-necked flask at 20 °C. The system was cooled to -20 to 0 °C, and 0.8 g of sodium borohydride was added in portions. The system was stirred at 0 to 20 °C for 1 h. TLC showed that A3 was completely consumed. The tetrahydrofuran was removed by concentration below 30 °C. The resulting concentrate was dispersed in a mixture of 100 g ethyl acetate and 50 g ice water. The mixture was separated, and the organic phase was washed once with 20 g saturated sodium bicarbonate. The organic phase was then dried with 5 g anhydrous sodium sulfate for 2 h. The filtrate was filtered and concentrated under reduced pressure below 40 °C to obtain 2.7 g of product. 40%, target isomer It accounts for 60%.

[0097] Example 9

[0098] 30 g of tetrahydrofuran and 3 g of intermediate A3 prepared in Example 2 were added to a 250 mL three-necked flask at 20 °C. The system was cooled to 0–10 °C, and 0.8 g of sodium borohydride and 150 mg of ZnCl2 were added in portions. The system was stirred at 0–20 °C for 5 h. TLC showed that A3 was completely consumed. The tetrahydrofuran was removed by concentration below 40 °C. The resulting concentrate was dispersed in a mixture of 100 g of ethyl acetate and 50 g of ice water. The mixture was separated, and the organic phase was washed once with 20 g of saturated sodium bicarbonate. The organic phase was then dried with 5 g of anhydrous sodium sulfate for 2 h. The filtrate was filtered and concentrated under reduced pressure below 40 °C to obtain 2.5 g of the product. 27%, target isomer It is 73%.

[0099] Example 11

[0100] At 0–10 °C, 28 g of tetrahydrofuran, 3 g of triethylamine, and 2.8 g of the product obtained in Example 3 were added to a 250 mL three-necked flask. 1.6 g of TBSCl was added in portions, and the system was stirred at 0–10 °C for 12 h. TLC showed complete consumption of A5. The product was concentrated below 40 °C to remove dichloromethane, and the concentrate was purified by column chromatography to obtain diastereomers. Column chromatography yielded 1.0 g of a white solid. Yield: 33.1%, purity: 98.1%.

[0101] Comparative Example 1

[0102] 30 g of tetrahydrofuran and 3 g of intermediate A3 prepared in Example 2 were added to a 250 mL three-necked flask at 20 °C. The system was cooled to 0–10 °C, and 0.8 g of sodium borohydride was added in portions. The system was stirred at 0–20 °C for 5 h. TLC showed that A3 was completely consumed. The tetrahydrofuran was removed by concentration below 40 °C. The resulting concentrate was dispersed in a mixture of 100 g ethyl acetate and 50 g ice water. The mixture was separated, and the organic phase was washed once with 20 g saturated sodium bicarbonate. The organic phase was then dried with 5 g anhydrous sodium sulfate for 2 h. The filtrate was filtered and concentrated under reduced pressure below 40 °C to obtain 2.8 g of product. 84%, target isomer It is 16%.

Claims

1. A method for preparing compound A5, characterized in that, It includes the following steps: In a solvent, under the action of a reducing agent and a Lewis acid, compound A3 undergoes a reduction reaction to yield compound A5; the Lewis acid is MgCl2 and / or ZnCl2; the solvent is one or more selected from 1,4-dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, diethyl ether, chloroform, and dichloromethane; the reducing agent is one or more selected from sodium borohydride, lithium aluminum hydride, and potassium borohydride. 。 2. The method for preparing compound A5 as described in claim 1, characterized in that, In the reduction reaction, the mass ratio of the solvent to the compound A3 is (5~20):1; And / or, in the reduction reaction, the mass ratio of the reducing agent to the compound A3 is 1:(3~4). And / or, in the reduction reaction, the Lewis acid is MgCl2; And / or, in the reduction reaction, the mass ratio of the Lewis acid to the compound A3 is 1:(0.01~0.5). And / or, in the reduction reaction, the temperature of the reduction reaction is -20~40℃; And / or, in the reduction reaction, the duration of the reduction reaction is 0.5 to 7 hours; And / or, the reduction reaction may further include the following post-processing steps: concentration, extraction, and concentration.

3. The method for preparing compound A5 as described in claim 1, characterized in that, In the reduction reaction, the solvent is tetrahydrofuran; And / or, in the reduction reaction, the mass ratio of the solvent to the compound A3 is 10:1; And / or, in the reduction reaction, the reducing agent is sodium borohydride and / or lithium aluminum hydride; And / or, in the reduction reaction, the mass ratio of the reducing agent to the compound A3 is 1:3.75; And / or, in the reduction reaction, the mass ratio of the Lewis acid to the compound A3 is 1:0.05; And / or, in the reduction reaction, the temperature of the reduction reaction is 0~20℃; And / or, in the reduction reaction, the duration of the reduction reaction is 1 or 5 hours.

4. The method for preparing compound A5 as described in claim 1, characterized in that, In the reduction reaction, the reducing agent is sodium borohydride.

5. The method for preparing compound A5 as described in claim 1, characterized in that, The reduction reaction is carried out by the following steps: the solvent, the Lewis acid and the compound A3 are mixed, the reducing agent is added at -20~10℃, and the reaction is carried out at 0~20℃ for 0.5~7h to obtain compound A5.

6. The method for preparing compound A5 as described in claim 1, characterized in that, The reduction reaction is carried out by the following steps: the solvent, the Lewis acid and the compound A3 are mixed, and the reducing agent is added at -20~0 or 0~10°C. The mixture is reacted at 0~20°C for 0.5~7 hours to obtain compound A5.

7. The method for preparing compound A5 according to claim 1, characterized in that, The preparation method of compound A5 further includes the following steps: In a solvent, under the action of an oxidizing agent, compound A2 undergoes an oxidation reaction to yield compound A3; 。 8. The method for preparing compound A5 as described in claim 7, characterized in that, In the oxidation reaction, the solvent is one or more selected from 1,4-dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, diethyl ether, chloroform, and dichloromethane; And / or, in the oxidation reaction, the mass ratio of the solvent to the compound A2 is 1:(0.01~0.1). And / or, in the oxidation reaction, the oxidant is one or more of the following: Desmond reagent, hydrogen peroxide, sodium hypochlorite, potassium permanganate, and manganese dioxide; And / or, in the oxidation reaction, the mass ratio of the oxidant to the compound A2 is 1:(0.1~0.4). And / or, in the oxidation reaction, the temperature of the oxidation reaction is -10~40℃; And / or, in the oxidation reaction, the oxidation reaction time is 2 to 8 hours; And / or, the oxidation reaction may further include the following post-processing steps: adding ice water, separating the liquid phase, and concentrating the organic phase.

9. The method for preparing compound A5 as described in claim 7, characterized in that, In the oxidation reaction, the solvent is dichloromethane and / or tetrahydrofuran; And / or, in the oxidation reaction, the mass ratio of the solvent to the compound A2 is 1:0.03; And / or, in the oxidation reaction, the oxidant is a Des Martin reagent and / or sodium hypochlorite; when the oxidant is sodium hypochlorite, 2,2,6,6-tetramethylpiperidine oxide and potassium bromide are further added; And / or, in the oxidation reaction, the mass ratio of the oxidant to the compound A2 is 1:0.12 or 1:0.25; And / or, in the oxidation reaction, the temperature of the oxidation reaction is 30°C or 35°C.

10. The method for preparing compound A5 as described in claim 9, characterized in that, In the oxidation reaction, when the oxidant is sodium hypochlorite, the mass ratio of 2,2,6,6-tetramethylpiperidine oxide to compound A2 is 1:(20~40); and / or, the mass ratio of potassium bromide to compound A2 is 1:(0.5~0.8).

11. The method for preparing compound A5 as described in claim 9, characterized in that, In the oxidation reaction, when the oxidant is sodium hypochlorite, the mass ratio of 2,2,6,6-tetramethylpiperidine oxide to compound A2 is 1:30; and / or, the mass ratio of potassium bromide to compound A2 is 1:0.

6.

12. The method for preparing compound A5 as described in claim 7, characterized in that, The oxidation reaction is carried out through the following steps: after mixing the solvent and the compound A2, the oxidant is added at 0~10℃, and the temperature is raised to 25~35℃ within 1~3h and kept at that temperature for 0.5~2h to obtain compound A3.

13. The method for preparing compound A5 as described in claim 7, characterized in that, The preparation method of compound A5 further includes the following steps: in a solvent, under the action of a deprotecting agent, compound 4AA undergoes a deprotection reaction to obtain compound A2; The deprotecting agent is tetrabutylammonium fluoride or hydrochloric acid; 。 14. The method for preparing compound A5 as described in claim 13, characterized in that, In the deprotection reaction, the solvent is one or more of methanol, 1,4-dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, diethyl ether, chloroform, and dichloromethane; And / or, in the deprotection reaction, the mass molar ratio of the solvent to the compound 4AA is (1000~3000) g / mol; And / or, in the deprotection reaction, the molar ratio of the deprotection reagent to the compound 4AA is (1~1.5):1; And / or, in the deprotection reaction, the temperature of the deprotection reaction is 20~60℃; And / or, in the deprotection reaction, the deprotection reaction time is 10-25 hours; And / or, the deprotection reaction further includes the following post-processing steps: extraction and separation.

15. The method for preparing compound A5 as described in claim 14, characterized in that, In the deprotection reaction, the solvent is tetrahydrofuran and / or methanol; And / or, in the deprotection reaction, the mass molar ratio of the solvent to the compound 4AA is 1500 g / mol or 2000 g / mol; And / or, in the deprotection reaction, the molar ratio of the deprotection reagent to the compound 4AA is 1.15:1; And / or, in the deprotection reaction, the temperature of the deprotection reaction is 30°C or 40°C; And / or, in the deprotection reaction, the duration of the deprotection reaction is 12 or 20 hours; And / or, in the deprotection reaction, in the post-treatment, the separation is column chromatography.

16. A method for preparing compound I, characterized in that, It includes the following steps: (1) In a solvent, under the action of a deprotecting agent, compound 4AA undergoes a deprotection reaction to give compound A2; The deprotecting agent is tetrabutylammonium fluoride or hydrochloric acid; ； (2) In the solvent, under the action of the oxidizing agent, compound A2 undergoes an oxidation reaction to obtain compound A3; ； (3) In the solvent, under the action of a reducing agent and a Lewis acid, compound A3 undergoes a reduction reaction to give compound A5; ； (4) In a solvent, under the action of an alkali, compound A5 undergoes a hydroxyl protection reaction with tert-butyldimethylchlorosilane to obtain compound I; ； The conditions and operations in the deprotection reaction are as described in any one of claims 13-15; The conditions and operations in the oxidation reaction are as described in any one of claims 7-12; The conditions and operations in the reduction reaction are as described in claims 1-6.

17. The method for preparing compound I according to claim 16, characterized in that, In the hydroxyl protection reaction, The solvent is one or more selected from 1,4-dioxane, tetrahydrofuran, ethylene glycol dimethyl ether, methyl tert-butyl ether, diethyl ether, chloroform, and dichloromethane; And / or, in the hydroxyl protection reaction, the mass ratio of the solvent to the compound A5 is (5~20):1; And / or, in the hydroxyl protection reaction, the base is imidazole and / or triethylamine; And / or, in the hydroxyl protection reaction, the mass ratio of the base to the compound A5 is (1~1.2):1; And / or, in the hydroxyl protection reaction, the mass ratio of tert-butyldimethylchlorosilane to compound A5 is (1~1.2):1; And / or, in the hydroxyl protection reaction, the temperature of the hydroxyl protection reaction is -10~50℃; And / or, in the hydroxyl protection reaction, the duration of the hydroxyl protection reaction is 10-15 hours; And / or, the hydroxyl protection reaction further includes the following post-processing steps: concentration and separation; And / or, the hydroxyl protection reaction is carried out by the following steps: the solvent, the base and the compound A5 are mixed, tert-butyldimethylchlorosilane is added at 0~10°C, and the mixture is reacted at 0~10°C for 10~15 h to obtain compound I.

18. The method for preparing compound I according to claim 17, characterized in that, In the hydroxyl protection reaction, the solvent is dichloromethane and / or tetrahydrofuran; And / or, in the hydroxyl protection reaction, the mass ratio of the solvent to compound A5 is 10:1; And / or, in the hydroxyl protection reaction, the base is an imidazole; And / or, in the hydroxyl protection reaction, the mass ratio of the base to the compound A5 is 1.07:1; And / or, in the hydroxyl protection reaction, the mass ratio of tert-butyldimethylchlorosilane to compound A5 is 1.07:1; And / or, in the hydroxyl protection reaction, the temperature of the hydroxyl protection reaction is 0~10℃; And / or, in the hydroxyl protection reaction, the duration of the hydroxyl protection reaction is 12 hours; And / or, in the hydroxyl protection reaction, the separation is column chromatography.

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