A method for synthesizing an epirubicin intermediate, daunorubicin

Abstract

The application belongs to the field of medicine synthesis, and particularly relates to a chemical synthesis method of an epirubicin intermediate, daunorubicin. The daunorubicin is synthesized by taking 2,5-dihydroxybenzyl alcohol as raw material, the route has low raw material cost, mild reaction condition, convenient post-treatment, high total yield, and has a good industrial application prospect.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine synthesis, and particularly relates to a synthesis method of an epirubicin intermediate, daunorubicin. BACKGROUND

[0002] Epirubicin is also known as epirubicin, which is an anthraquinone antibiotic, and its structural formula is as follows:

[0003]

[0004] Epirubicin is an anthracycline anti-tumor antibiotic developed by Pfizer for treating breast cancer, lung cancer and liver cancer, and was marketed in Europe in 1984 and in the United States in 1999. It has a wide range of applications in the treatment of leukemia, lymphoma and various solid tumors (including breast cancer, non-small cell tumors, cervical cancer and head and neck cancer). Its mechanism of action is to directly insert between DNA nucleobases, interfere with the transcription process, prevent the formation of mRNA, and thus inhibit the synthesis of DNA and RNA. In addition, epirubicin also has an inhibitory effect on topoisomerase II. It is a cell cycle non-specific drug and is effective for various transplanted tumors. Compared with doxorubicin, it has equal or slightly higher efficacy but less cardiotoxicity.

[0005] Currently, the preparation of epirubicin mainly uses daunorubicin obtained by fermentation as a raw material to prepare the finished product by chemical semi-synthesis. However, the raw material obtained by fermentation has the disadvantages of low efficiency, many impurities and poor reproducibility, which will directly lead to many impurities and poor reproducibility of the finished product of epirubicin, and generally requires resin column separation, which greatly increases the production cycle and poses a potential threat to drug safety. Pure chemical synthesis of epirubicin has become a new breakthrough point.

[0006] Daunorubicin is an important intermediate of epirubicin, which is usually prepared by recovering and processing daunorubicin fermentation broth, and there are few reports on its chemical synthesis method. Its structural formula is as follows:

[0007] SUMMARY

[0008] In order to overcome the shortcomings of the prior art, the purpose of the present application is to provide a chemical synthesis method of an epirubicin intermediate, daunorubicin, and the specific technical scheme is as follows:

[0009] A synthesis method of an epirubicin intermediate, daunorubicin, and its synthesis route is as follows:

[0010]

[0011] The step of preparing the intermediate 1 from 2,5-dihydroxybenzyl alcohol is as follows: 2,5-dihydroxybenzyl alcohol is dissolved in an organic solvent, diisopropyl ethylamine and chloromethyl methyl ether are added under nitrogen protection, stirring is carried out at 35-70°C until the reaction is completed, the reaction solution is poured into 5% sodium bicarbonate solution, stirring is carried out, standing is carried out, liquid separation is carried out, the water phase is extracted with dichloromethane or chloroform, the organic phase is collected, washing is carried out with water and saturated brine in sequence, the organic phase is dried with anhydrous sodium sulfate, the organic phase is collected by filtration, vacuum concentration is carried out, petroleum ether is added to make pulp, suction filtration is carried out, and vacuum drying is carried out to obtain the intermediate 1.

[0012] The step of preparing the intermediate 2 from the intermediate 1 is as follows: the intermediate 1 is placed in a reaction bottle, an organic solvent in which N,N'-dicyclohexyl-N-methyl carbodiimide iodide is dissolved is added, reaction is carried out under light protection at 25-55°C, the solvent is removed by vacuum evaporation, the residue is dissolved in n-hexane, water washing is carried out, the water phase is extracted with n-hexane, the organic phase is collected and dried with anhydrous sodium sulfate, suction filtration is carried out, the filtrate is vacuum concentrated, and the residue is recrystallized with a mixed solvent of dichloromethane and n-hexane to obtain the intermediate 2.

[0013] The step of preparing the intermediate 3 from the intermediate 2 is as follows: acid 11 is dissolved in an organic solvent, a solution of lithium bis-trimethylsilyl amide in tetrahydrofuran is slowly added dropwise under nitrogen protection at -78°C, an organic solvent in which the intermediate 2 is dissolved is added, stirring is carried out at -78 to -50°C for 1-3h, the temperature is raised to -30 to -20°C, stirring is carried out for 15-22h, after the reaction is completed, the reaction solution is poured into hydrochloric acid, isopropyl ether extraction is carried out, the organic phase is collected, drying is carried out with magnesium sulfate, the solvent is removed by vacuum evaporation, then the residue is dissolved in dichloromethane, washing is carried out with saturated sodium bicarbonate solution, the water phase is extracted with isopropyl ether, the organic phase is collected, drying is carried out with magnesium sulfate, and vacuum concentration is carried out to obtain the intermediate 3.

[0014] The step of preparing the intermediate 4 from the intermediate 3 is as follows: the intermediate 3 is placed in a reaction bottle, an organic solvent is added at room temperature, thionyl chloride is added under nitrogen protection, heating reflux reaction is carried out for 12h, the temperature is cooled to room temperature, tin tetrachloride is added, stirring is carried out at 20°C for 1h, the temperature is cooled to 0°C, crushed ice is added, liquid separation is carried out to collect the water phase, the water phase is extracted with dichloromethane, the organic phase is collected, washing is carried out with saturated sodium bicarbonate solution and saturated sodium chloride solution in sequence, drying is carried out with anhydrous magnesium sulfate, vacuum concentration is carried out to obtain the crude intermediate 4, and recrystallization is carried out with a mixed solution of tetrahydrofuran and n-hexane to obtain the intermediate 4.

[0015] The step of preparing intermediate 5 from intermediate 4 is as follows: under nitrogen protection, a reaction vessel is sequentially added with tetrahydrofuran solution, N, N-diethyl aniline borane, (R)-2-methyl CBS-oxazole borane tetrahydrofuran solution, temperature is controlled at 15-25°C, tetrahydrofuran solution of intermediate 4 is slowly added, reaction is carried out under temperature control below 25°C, methanol is slowly added dropwise, stirring is carried out, under reduced pressure, the solution is concentrated, dichloromethane is added, sulfuric acid is added dropwise under temperature control at 15-25°C, stirring is carried out, water is added for liquid separation, the organic phase is sequentially washed with water and saturated sodium chloride solution, anhydrous sodium sulfate is used for drying, filtration is carried out under suction, the filtrate is concentrated to dryness under reduced pressure, a mixed solution of tetrahydrofuran and diethyl ether is used for recrystallization, and intermediate 5 is obtained.

[0016] The step of preparing intermediate 6 from intermediate 5 is as follows: intermediate 5 is dissolved in tetrahydrofuran, temperature is controlled at 0°C under nitrogen protection, sodium dimethylsulfoxide is dissolved in a mixed solution of dimethylsulfoxide and tetrahydrofuran, and then is added dropwise, stirring is carried out at room temperature, after reaction is completed, extraction solvent and saturated ammonium chloride solution are added for stirring, liquid separation is carried out under static condition, the water phase is washed with extraction solvent, the organic phase is collected, the organic phase is washed with water, anhydrous sodium sulfate is used for drying, and intermediate 6 is obtained after concentration under reduced pressure.

[0017] The step of preparing intermediate 7 from intermediate 6 is as follows: intermediate 6 is dissolved in a mixed solution of tetrahydrofuran and water, amalgamated aluminum is added at room temperature, stirring is carried out under nitrogen protection, the solid is filtered out, the filter cake is washed with a small amount of tetrahydrofuran, the filtrate is concentrated under reduced pressure, aqueous diethyl ether is added, stirring is carried out, standing is carried out, liquid separation is carried out, the organic phase is dried with anhydrous sodium sulfate, the solvent is removed by evaporation under reduced pressure, and intermediate 7 is obtained after recrystallization.

[0018] The step of preparing intermediate 8 from intermediate 7 is as follows: intermediate 7 is added to a three-necked flask, is dissolved in dichloromethane, triethylamine and trimethylchlorosilane are added dropwise under nitrogen protection at 0°C, stirring is carried out until reaction is completed, the reaction solution is diluted with dichloromethane, the reaction solution is poured into ice water, extraction is carried out, the organic phase is sequentially washed with water and saturated brine, anhydrous sodium sulfate is used for drying, and intermediate 8 is obtained after filtration under suction.

[0019] The step of preparing intermediate 9 from intermediate 8 is as follows: a dichloromethane solution of intermediate 8 is prepared, aluminum chloride is added in batches, temperature is controlled at 0°C, a dichloromethane solution of compound 12 is slowly added dropwise, stirring is carried out at 0°C for 30 min, temperature is naturally increased to room temperature, stirring is carried out for 6-8 h, the reaction solution is poured into dilute hydrochloric acid at 0°C, stirring is carried out at 0°C for 10 min, stirring is carried out at room temperature for 0.5-1 h, liquid separation is carried out, the water phase is extracted with dichloromethane, the organic phase is collected, the organic phase is washed with saturated sodium bicarbonate solution, anhydrous sodium sulfate is used for drying, and intermediate 9 is obtained after concentration under reduced pressure, and recrystallization is carried out to obtain intermediate 9.

[0020] The preparation of epirubicin intermediate daunorubicin intermediate from intermediate 9 is as follows: intermediate 9 is dissolved in dichloromethane, and under nitrogen protection, the solution is cooled to 2-8°C, and dimethyl boron bromide dichloromethane solution is added dropwise, and the reaction is stirred at 2-8°C, after the reaction is completed, the reaction solution is poured into a mixture of saturated sodium bicarbonate and tetrahydrofuran, and stirred and settled to separate the liquid, the water phase is extracted with dichloromethane, the organic phase is collected, washed with saturated sodium chloride solution, and the organic phase is collected, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain daunorubicin intermediate.

[0021] Preferably, in the step of preparing intermediate 1 from 2,5-dihydroxybenzyl alcohol, the organic solvent is one of dichloromethane, chloroform, acetonitrile or DMF, and more preferably, the organic solvent is dichloromethane; the molar ratio of 2,5-dihydroxybenzyl alcohol, diisopropyl ethylamine and chloromethyl methyl ether is 1:3-6:2-4, and more preferably, 1:3.8:2.8.

[0022] Preferably, in the step of preparing intermediate 2 from intermediate 1, the organic solvent is one of tetrahydrofuran, n-hexane, toluene or acetonitrile, and more preferably, the organic solvent is tetrahydrofuran or n-hexane; the molar ratio of intermediate 1 and N,N'-dicyclohexyl-N-methyl carbodiimide iodide is 1:1-3, and more preferably, 1:2; and the reaction temperature is 30-40°C.

[0023] Preferably, in the step of preparing intermediate 3 from intermediate 2, the organic solvent for dissolving acid 11 or intermediate 2 is tetrahydrofuran, n-hexane, cyclohexane, n-heptane or diethyl ether, and more preferably, the organic solvent is tetrahydrofuran or n-hexane; the molar ratio of acid 11, intermediate 2 and lithium bis-trimethylsilyl amide is 1:1-3:2-4, and more preferably, 1:2-2.5:2.5-3.5.

[0024] Preferably, in the step of preparing intermediate 4 from intermediate 3, the organic solvent is dichloromethane, chloroform, toluene or 1,2-dichloroethane, and more preferably, the organic solvent is dichloromethane; the molar ratio of intermediate 3, thionyl chloride and tin tetrachloride is 1:3-6:3-6, and more preferably, 1:4.5:4.

[0025] Preferably, in the step of preparing intermediate 5 from intermediate 4, the molar ratio of intermediate 4 and N,N-diethyl aniline borane is 1:1; and the mass ratio of intermediate 4 and (R)-2-methyl-CBS-oxazaborolidine is 1:1%-5%.

[0026] Preferably, in the step of preparing intermediate 6 from intermediate 5, the molar ratio of intermediate 5 and sodium dimethyl sulfoxide salt is 1:3-5, and preferably, 1:4.17; and the extraction solvent after the reaction is completed is dichloromethane, chloroform or ethyl acetate, and preferably, dichloromethane.

[0027] Preferably, in the step of preparing intermediate 7 from intermediate 6, the molar ratio of intermediate 6 to mercury-aluminum amalgam is 1:15-25, more preferably 1:18-22; the recrystallization solvent is a mixture of dichloromethane and isopropyl ether, a mixture of dichloromethane and diethyl ether, or a mixture of chloroform and diethyl ether; more preferably, the recrystallization solvent is a mixture of dichloromethane and isopropyl ether.

[0028] Preferably, in the step of preparing intermediate 8 from intermediate 7, the molar ratio of intermediate 7 to trimethylsilyl chloride is 1:2-3, more preferably 1:2.2.

[0029] Preferably, in the step of preparing intermediate 9 from intermediate 8, the recrystallization process is first recrystallization with dichloromethane and isopropyl ether, and then recrystallization with ethanol and diethyl ether; the molar ratio of intermediate 8 to compound 12 is 1:1, and the molar ratio of intermediate 8 to aluminum trichloride is 1:3-6, more preferably 1:3-4.

[0030] Preferably, in the step of preparing daunomycin from intermediate 9, the molar ratio of intermediate 9 to dimethylboron bromide is 1:2-2.5, more preferably 1:2.

[0031] The present application uses 2,5-dihydroxybenzyl alcohol as a starting material to prepare daunomycin, an important intermediate of synthetic epirubicin. The route has low raw material cost, mild reaction conditions, convenient post-treatment, and high total yield, and has good prospects for industrial application. DETAILED DESCRIPTION

[0032] In order to better understand the content of the present application, the technical solutions of the present application are further illustrated by specific examples below, but these examples do not limit the present application.

[0033] In the following examples, the raw material 2,5-dihydroxybenzyl alcohol, acid 11 compound and compound 12 can be prepared by the following method or other methods, and the present application does not limit the source of raw materials.

[0034] 2,5-dihydroxybenzyl alcohol can be prepared by the following method:

[0035]

[0036] 2,5-dihydroxybenzyl alcohol 10 g and 50 ml of 35% concentrated hydrochloric acid were mixed, mechanically stirred at room temperature for 48 h, then placed in an ice water bath, and Na2CO3 was added in batches while stirring, and the pH value was adjusted to 2-3 after neutralization, then filtered, the filtrate was extracted with ethyl acetate (100 ml x 3), the organic phase was dried with anhydrous sodium sulfate, filtered, and then the ethyl acetate was evaporated under reduced pressure to obtain 6.38 g of light yellow solid, which was 2,5-dihydroxybenzyl alcohol.

[0037] The acid 11 compound can be prepared according to the method described in the literature Liebigs Ann. Chem. 1987, 515-520.

[0038] The compound 12 can be prepared by the following method:

[0039]

[0040] In a container, 4-methoxyphthalic acid 24.2 g, dichloromethane 240 ml, chlorosulfoxide 17.9 ml were added dropwise, after the end of the dropwise addition, the reaction was refluxed under nitrogen protection for 5 h; concentrated under reduced pressure to obtain compound 12.

[0041] Preparation of intermediate 1 in Example 1

[0042] 2,5-dihydroxybenzyl alcohol (14.0 g, 0.1 mol) was dissolved in 1.4 L of dichloromethane, and diisopropyl ethylamine (62.8 mL, 0.38 mol) and chloromethyl methyl ether (21.3 mL, 0.28 mol) were added under nitrogen protection, and the reaction was refluxed for 22 h while stirring; after the reaction was completed, the reaction solution was poured into 1.4 L of 5% sodium bicarbonate solution, stirred for about 10 min, and separated; the aqueous phase was extracted with dichloromethane (3 x 500 ml), and the combined organic phase was washed with 1.4 L of water, 1.4 L of saturated brine, and then dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a brown oil; 70 ml of petroleum ether was added and stirred for about 30 min, filtered, and dried under reduced pressure to obtain white solid, which was intermediate 1, with a molar yield of 97.8% and an HPLC purity of 98.2%.

[0043] Preparation of intermediate 1 in Example 2

[0044] 2,5-dihydroxybenzyl alcohol (14.0 g, 0.1 mol) was dissolved in 1 L of chloroform, and diisopropyl ethylamine (90.9 mL, 0.55 mol) and chloromethyl methyl ether (26.6 mL, 0.35 mol) were added under nitrogen protection, and the reaction was stirred at 48°C for 16 h; after the reaction was completed, the reaction solution was poured into 1.4 L of 5% sodium bicarbonate solution, stirred for about 10 min, and separated; the aqueous phase was extracted with chloroform (3 x 500 ml), and the combined organic phase was washed with 1 L of water, 1 L of saturated brine, and then dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a brown oil; 40 ml of petroleum ether was added and stirred for about 30 min, filtered, and dried under reduced pressure to obtain white solid, which was intermediate 1, with a molar yield of 95.5% and an HPLC purity of 97.3%.

[0045] Preparation of intermediate 1 in Example 3

[0046] The 2,5-dihydroxybenzyl alcohol (14.0 g, 0.1 mol) was dissolved in 1 L of acetonitrile, protected by nitrogen, and diisopropyl ethylamine (49.6 mL, 0.3 mol) and chloromethyl methyl ether (30.4 mL, 0.4 mol) were added, and stirring was maintained at 60 °C for 15 h; after the reaction was completed, the reaction solution was poured into 1.4 L of 5% sodium bicarbonate solution, and stirring was maintained for about 10 min, and the solution was separated, and the aqueous phase was extracted with chloroform (3 x 500 mL), and the combined organic phase was washed with 1 L of water, and the organic phase was washed with 1 L of saturated brine, and the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a brown oil, and 40 mL of petroleum ether was added to the oil, and the mixture was stirred for about 30 min, and the mixture was filtered under suction, and the white solid was dried under reduced pressure to obtain the intermediate 1, and the molar yield was 86.4%, and the HPLC purity was 94.6%.

[0047] Preparation of the intermediate 1 in Example 4

[0048] The 2,5-dihydroxybenzyl alcohol (14.0 g, 0.1 mol) was dissolved in 1 L of DMF, protected by nitrogen, and diisopropyl ethylamine (99.2 mL, 0.6 mol) and chloromethyl methyl ether (15.2 mL, 0.2 mol) were added, and stirring was maintained at 80 °C for 20 h; after the reaction was completed, the reaction solution was poured into 1.4 L of 5% sodium bicarbonate solution, and stirring was maintained for about 10 min, and the solution was separated, and the aqueous phase was extracted with dichloromethane (3 x 500 mL), and the combined organic phase was washed with 1.5 L of water, and the organic phase was washed with 1.5 L of saturated brine, and the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a brown oil, and 80 mL of petroleum ether was added to the oil, and the mixture was stirred for about 30 min, and the mixture was filtered under suction, and the white solid was dried under reduced pressure to obtain the intermediate 1, and the molar yield was 82.5%, and the HPLC purity was 95.3%.

[0049] Preparation of the intermediate 2 in Example 5

[0050] The intermediate 1 (18.0 g, 78.9 mmol, HPLC purity 98.2%) was placed in a 500 mL reaction bottle, and 270 mL of a tetrahydrofuran solution of N,N'-dicyclohexyl-N-methyl carbodiimide iodide (54.7 g, 158 mol) was added, and stirring was maintained at 30 °C for 3 h under nitrogen protection and in the dark, and the solvent was removed by evaporation under reduced pressure, and the residue was dissolved in 200 mL of n-hexane, and washed with water (100 mL x 3), and the aqueous phase was extracted with 150 mL of n-hexane, and the organic phase was collected and dried with anhydrous sodium sulfate, and filtered under suction, and the filtrate was concentrated under reduced pressure, and recrystallized with a dichloromethane and n-hexane mixed solvent to obtain the intermediate 2, and the molar yield was 96.0%, and the HPLC purity was 98.4%.

[0051] Preparation of the intermediate 2 in Example 6

[0052] Intermediate 1 (15.0 g, 65.7 mmol, HPLC purity 98.2%) was placed in a 500 mL reaction flask, added with 300 mL of toluene solution dissolved with N,N'-dicyclohexyl-N-methyl carbodiimide iodide (68.2 g, 197.1 mmol), stirred for 3 h at 25 °C under nitrogen protection and in dark, removed the solvent under reduced pressure, the residue was dissolved in 240 mL of n-hexane, washed with water (120 mL x 3) for three times, the aqueous phase was extracted with 200 mL of n-hexane, the organic phase was collected and dried with anhydrous sodium sulfate, filtered under suction, the filtrate was concentrated under reduced pressure, and recrystallized with a mixed solvent of dichloromethane and n-hexane to obtain intermediate 2, the molar yield was 93.1%, and the HPLC purity was 96.4%.

[0053] Preparation of intermediate 2 in Example 7

[0054] Intermediate 1 (15.0 g, 65.7 mmol, HPLC purity 98.2%) was placed in a 500 mL reaction flask, added with 300 mL of toluene solution dissolved with N,N'-dicyclohexyl-N-methyl carbodiimide iodide (68.2 g, 197.1 mmol), stirred for 3 h at 25 °C under nitrogen protection and in dark, removed the solvent under reduced pressure, the residue was dissolved in 240 mL of n-hexane, washed with water (120 mL x 3) for three times, the aqueous phase was extracted with 200 mL of n-hexane, the organic phase was collected and dried with anhydrous sodium sulfate, filtered under suction, the filtrate was concentrated under reduced pressure, and recrystallized with a mixed solvent of dichloromethane and n-hexane to obtain intermediate 2, the molar yield was 93.1%, and the HPLC purity was 96.4%.

[0055] Preparation of intermediate 2 in Example 8

[0056] Intermediate 1 (15.0 g, 65.7 mmol, HPLC purity 98.2%) was placed in a 500 mL reaction flask, added with 300 mL of toluene solution dissolved with N,N'-dicyclohexyl-N-methyl carbodiimide iodide (68.2 g, 197.1 mmol), stirred for 3 h at 25 °C under nitrogen protection and in dark, removed the solvent under reduced pressure, the residue was dissolved in 240 mL of n-hexane, washed with water (120 mL x 3) for three times, the aqueous phase was extracted with 200 mL of n-hexane, the organic phase was collected and dried with anhydrous sodium sulfate, filtered under suction, the filtrate was concentrated under reduced pressure, and recrystallized with a mixed solvent of dichloromethane and n-hexane to obtain intermediate 2, the molar yield was 93.1%, and the HPLC purity was 96.4%.

[0057] Preparation of intermediate 3 in Example 9

[0058] The acid 11 (5.0 g, 24.7 mmol) was dissolved in 200 mL of n-hexane, and 130 mL of a solution of lithium bis-trimethylsilylamide (8.27 g, 49.4 mmol) in tetrahydrofuran was slowly added dropwise at -78°C under nitrogen protection. After 20 min, 50 mL of a solution of intermediate 2 (12.5 g, 37.0 mmol, HPLC purity 98.4%) in n-hexane was added. The mixture was stirred at -78 to -50°C for 1 h, and then warmed to -30°C and stirred for 20 h. After the reaction was completed, the reaction solution was poured into 300 mL of 1 mol / L hydrochloric acid, and extracted with 150 mL of ether three times. The organic phase was collected and dried over MgSO4, and the solvent was removed by reduced pressure. The residue was dissolved in 250 mL of dichloromethane, and washed with 125 mL of saturated sodium bicarbonate solution three times. The aqueous phase was extracted with 150 mL of ether three times, and the organic phase was collected, dried over MgSO4, and concentrated by reduced pressure to obtain a white solid, which was intermediate 3, with a molar yield of 89.2% and an HPLC purity of 96.4%.

[0059] Preparation of intermediate 3 in Example 10

[0060] The acid 11 (5.0 g, 24.7 mmol) was dissolved in 200 mL of n-hexane, and 130 mL of a solution of lithium bis-trimethylsilylamide (8.27 g, 49.4 mmol) in tetrahydrofuran was slowly added dropwise at -78°C under nitrogen protection. After 20 min, 50 mL of a solution of intermediate 2 (12.5 g, 37.0 mmol, HPLC purity 98.4%) in n-hexane was added. The mixture was stirred at -78 to -50°C for 1 h, and then warmed to -30°C and stirred for 20 h. After the reaction was completed, the reaction solution was poured into 300 mL of 1 mol / L hydrochloric acid, and extracted with 150 mL of ether three times. The organic phase was collected and dried over MgSO4, and the solvent was removed by reduced pressure. The residue was dissolved in 250 mL of dichloromethane, and washed with 125 mL of saturated sodium bicarbonate solution three times. The aqueous phase was extracted with 150 mL of ether three times, and the organic phase was collected, dried over MgSO4, and concentrated by reduced pressure to obtain a white solid, which was intermediate 3, with a molar yield of 89.2% and an HPLC purity of 96.4%.

[0061] Preparation of intermediate 3 in Example 11

[0062] The acid 11 (5.0 g, 24.7 mmol) was dissolved in 200 mL of cyclohexane, and 200 mL of a solution of lithium bis-trimethylsilylamide (16.54 g, 98.8 mmol) in tetrahydrofuran was slowly added dropwise at -78°C under nitrogen protection. After 20 min, 50 mL of a solution of intermediate 2 (8.4 g, 24.7 mmol, HPLC purity 98.4%) in cyclohexane was added. The mixture was stirred at -78 to -50°C for 2 h, and then warmed to -25°C and stirred for 22 h. After the reaction was completed, the reaction solution was poured into 400 mL of 1 mol / L hydrochloric acid, and extracted with 200 mL of ether three times. The organic phase was collected, dried over MgSO4, and the solvent was removed under reduced pressure. The residue was dissolved in 400 mL of dichloromethane, and washed with 180 mL of saturated sodium bicarbonate solution three times. The aqueous phase was extracted with 200 mL of ether three times, and the organic phase was collected, dried over MgSO4, and concentrated under reduced pressure to obtain a white solid, which was intermediate 3, with a molar yield of 80.2% and an HPLC purity of 93.5%.

[0063] Preparation of intermediate 3 in Example 12

[0064] The acid 11 (5.0 g, 24.7 mmol) was dissolved in 200 mL of cyclohexane, and 200 mL of a solution of lithium bis-trimethylsilylamide (16.54 g, 98.8 mmol) in tetrahydrofuran was slowly added dropwise at -78°C under nitrogen protection. After 20 min, 50 mL of a solution of intermediate 2 (8.4 g, 24.7 mmol, HPLC purity 98.4%) in cyclohexane was added. The mixture was stirred at -78 to -50°C for 2 h, and then warmed to -25°C and stirred for 22 h. After the reaction was completed, the reaction solution was poured into 400 mL of 1 mol / L hydrochloric acid, and extracted with 200 mL of ether three times. The organic phase was collected, dried over MgSO4, and the solvent was removed under reduced pressure. The residue was dissolved in 400 mL of dichloromethane, and washed with 180 mL of saturated sodium bicarbonate solution three times. The aqueous phase was extracted with 200 mL of ether three times, and the organic phase was collected, dried over MgSO4, and concentrated under reduced pressure to obtain a white solid, which was intermediate 3, with a molar yield of 80.2% and an HPLC purity of 93.5%.

[0065] Preparation of intermediate 3 in Example 13

[0066] The acid 11 (10.0 g, 49.4 mmol) was dissolved in 400 mL of diethyl ether, and 200 mL of a solution of lithium bis-trimethylsilylamide (29.9 g, 148 mmol) in tetrahydrofuran was added dropwise slowly at -78 °C under nitrogen protection. After 20 min, 83 mL of a solution of intermediate 2 (41.6 g, 123 mmol, HPLC purity 98.4%) in diethyl ether was added. After stirring at -78 to -50 °C for 3 h, the temperature was raised to -20 °C and stirring was continued for 15 h. After the reaction was completed, the reaction solution was poured into 600 mL of 1 mol / L hydrochloric acid, and 300 mL of diethyl ether was added three times to extract the product. The organic phase was collected and dried over MgSO4, and the solvent was removed under reduced pressure. The residue was dissolved in 500 mL of dichloromethane, and 250 mL of saturated sodium bicarbonate solution was added three times to wash. The aqueous phase was extracted three times with 300 mL of diethyl ether, and the organic phase was collected, dried over MgSO4, and concentrated under reduced pressure to obtain a white solid, which was intermediate 3, with a molar yield of 88.5% and an HPLC purity of 95.2%.

[0067] Preparation of intermediate 4 in Example 14

[0068] Intermediate 3 (15.0 g, 36.4 mmol, HPLC purity 97.2%) was placed in a reaction flask, and 225 mL of dichloromethane was added at room temperature. Under nitrogen protection, 11.2 mL (0.164 mol) of thionyl chloride was added, and the reaction was heated to reflux for 12 h. After cooling to room temperature, 27.0 mL (0.146 mol) of tin tetrachloride was added, and the reaction was stirred at 20 °C for another 1 h. After the reaction was completed, the temperature was lowered to 0 °C, and 225 g of crushed ice was added. The aqueous phase was collected by liquid separation, and the aqueous phase was extracted three times with 120 mL of dichloromethane at 0 °C. The organic phase was collected and washed with 400 mL of saturated NaHCO3 solution and 400 mL of saturated NaCl solution, respectively. The organic phase was dried over anhydrous MgSO4, and concentrated under reduced pressure to obtain a crude product, intermediate 4, with a molar yield of 96.4% and an HPLC purity of 87.1%. The crude product was recrystallized from a mixture of tetrahydrofuran and n-hexane (1:3, by volume) to obtain intermediate 4, with a molar yield of 88.3% and an HPLC purity of 99.3%. mp: 158 °C, [α]20D = +48.4 (c = 0.48, CHCl3)].

[0069] Preparation of intermediate 4 in Example 15

[0070] The intermediate 3 (15.0 g, 36.4 mmol, HPLC purity 97.2%) was placed in a reaction flask, 225 mL of chloroform was added at room temperature, and thionyl chloride (12.6 mL, 0.173 mol) was added under nitrogen protection, and the reaction was heated to reflux for 12 h. After cooling to room temperature, tin tetrachloride (25.5 mL, 0.218 mol) was added, and the reaction was stirred at 20 °C for another 1 h. After the reaction was completed, 225 g of crushed ice was added, and the aqueous phase was collected by liquid separation. The aqueous phase was extracted with 120 mL of dichloromethane three times at 0 °C, and the combined organic phase was washed with 400 mL of saturated NaHCO3 solution and 400 mL of saturated sodium chloride solution, respectively. The organic phase was dried over anhydrous MgSO4, and concentrated under reduced pressure to obtain the crude intermediate 4 with a molar yield of 95.0% and an HPLC purity of 86.4%. The crude intermediate 4 was recrystallized with a mixture of tetrahydrofuran and n-hexane (1:3, by volume) to obtain the intermediate 4 with a molar yield of 84.0% and an HPLC purity of 98.9%. mp: 157 °C, [α]20D = +48.5 (c = 0.48, CHCl3)].

[0071] Preparation of intermediate 4 in example 16

[0072] The intermediate 3 (15.0 g, 36.4 mmol, HPLC purity 97.2%) was placed in a reaction flask, 225 mL of chloroform was added at room temperature, and thionyl chloride (12.6 mL, 0.173 mol) was added under nitrogen protection, and the reaction was heated to reflux for 12 h. After cooling to room temperature, tin tetrachloride (25.5 mL, 0.218 mol) was added, and the reaction was stirred at 20 °C for another 1 h. After the reaction was completed, 225 g of crushed ice was added, and the aqueous phase was collected by liquid separation. The aqueous phase was extracted with 120 mL of dichloromethane three times at 0 °C, and the combined organic phase was washed with 400 mL of saturated NaHCO3 solution and 400 mL of saturated sodium chloride solution, respectively. The organic phase was dried over anhydrous MgSO4, and concentrated under reduced pressure to obtain the crude intermediate 4 with a molar yield of 95.0% and an HPLC purity of 86.4%. The crude intermediate 4 was recrystallized with a mixture of tetrahydrofuran and n-hexane (1:3, by volume) to obtain the intermediate 4 with a molar yield of 84.0% and an HPLC purity of 98.9%. mp: 157 °C, [α]20D = +48.5 (c = 0.48, CHCl3)].

[0073] Preparation of intermediate 4 in example 17

[0074] Intermediate 3 (15.0 g, 36.4 mmol, HPLC purity 97.2%) was placed in a reaction flask, and 225 mL of 1,2-dichloroethane was added at room temperature. Under nitrogen protection, 15.9 mL of thionyl chloride (0.218 mol) was added, and the mixture was heated to reflux for 12 h. After cooling to room temperature, 12.8 mL of tin tetrachloride (0.109 mol) was added, and the mixture was stirred at 20 °C for another 1 h. After the reaction was complete, the temperature was lowered to 0 °C, and 225 g of crushed ice was added. The aqueous phase was collected by separation. Extracted three times with 120 mL × 3 dichloromethane at 0 °C, the organic phases were collected and combined, washed with 400 mL saturated NaHCO3 solution and 400 mL saturated sodium chloride solution respectively, dried over anhydrous MgSO4, and concentrated under reduced pressure to obtain crude intermediate 4 with a molar yield of 92.1% and HPLC purity of 83.6%. Crude intermediate 4 was then recrystallized from a mixed solution of tetrahydrofuran and n-hexane in a volume ratio of 1:3 to obtain intermediate 4 with a molar yield of 81.3% and HPLC purity of 96.3%. mp: 158 °C, [α]20D=+48.5 (c=0.48, CHCl3)).

[0075] Preparation of Intermediate 5 in Example 18

[0076] Under nitrogen protection, 80 mL of tetrahydrofuran was added to the reaction flask, and stirring was started. N,N-Diethylaniline borane (5.0 mL, 27.9 mmol) was added. Catalyst (R)-2-methyl-CBS-oxazolium borane ((R)-MeCBS) (0.22 g, 2%) was dissolved in 80 mL of tetrahydrofuran and added to the reaction flask. The reaction solution was kept at 15–25 °C. 220 mL of a tetrahydrofuran solution containing intermediate 4 (11.0 g, 27.9 mmol, HPLC purity 99.3%) was added dropwise using a constant pressure dropping funnel, ensuring the addition was completed over 2–3 hours. The reaction was maintained at this temperature for 10–20 minutes. After the reaction was complete, the temperature was controlled below 25 °C, and 32 mL of methanol was slowly added dropwise while stirring for 15 minutes. The mixture was concentrated under reduced pressure, and 300 mL of dichloromethane was added. 160 mL of methanol was added dropwise while maintaining the temperature at 15–25 °C. 2 mol / L sulfuric acid was used, and foaming occurred. After stirring for 15 min, 160 mL of water was added, and the mixture was separated. The organic phase was washed successively with 250 mL of water and 250 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The filtrate was then recrystallized from a 2:3 mixture of tetrahydrofuran and diethyl ether to give intermediate 5, with a molar yield of 94.2% and an HPLC purity of 98.8%.

[0077] Preparation of Intermediate 5 in Example 19

[0078] Into a reaction flask, 80 mL of tetrahydrofuran was added under nitrogen protection, and stirring was started. N,N-diethylaniline borane (5.0 mL, 27.9 mmol) was added, and the catalyst (R)-2-methyl-CBS-oxazaborolidine ((R)-MeCBS) (0.55 g, 5%) was dissolved in 80 mL of tetrahydrofuran and was added into the reaction flask in a flow. The reaction solution was controlled at 15-25 °C, and 220 mL of tetrahydrofuran solution containing intermediate 4 (11.0 g, 27.9 mmol, HPLC purity 99.3%) was added dropwise using a constant pressure dropping funnel, ensuring that the dropping was completed in 2-3 h. After 10-20 min of incubation, 32 mL of methanol was added slowly while the temperature was controlled below 25 °C. After stirring for 15 min, the solution was concentrated under reduced pressure. Then, 300 mL of dichloromethane was added, and 160 mL of 2 mol / L sulfuric acid was added dropwise while the temperature was controlled at 15-25 °C. Foam appeared, and the solution was stirred for 15 min. Then, 160 mL of water was added, and the solution was separated. The organic phase was washed with 250 mL of water and 250 mL of saturated sodium chloride solution, respectively, and was dried over anhydrous sodium sulfate. The solution was filtered, and the filtrate was concentrated under reduced pressure to dryness. Then, the solution was recrystallized using a mixture of tetrahydrofuran and diethyl ether (volume ratio 2:3) to obtain intermediate 5, with a molar yield of 92.7% and an HPLC purity of 97.2%.

[0079] Preparation of intermediate 6 in Example 20

[0080] Intermediate 5 (9.51 g, 24 mmol, HPLC purity 98.8%) was dissolved in 500 mL of tetrahydrofuran, and the solution was cooled to 0 °C under nitrogen protection. Then, 0.1 mol of sodium dimethylsulfoxide was dissolved in 50 mL of a mixture of dimethylsulfoxide and tetrahydrofuran and was added dropwise into the reaction flask. After 30 min of stirring at room temperature, 1.25 L of dichloromethane and 2.0 L of saturated ammonium chloride solution were added, and the solution was stirred for 5 min. After standing, the solution was separated, and the aqueous phase was washed with 1.25 L of dichloromethane twice. The combined organic phase was washed with 1.0 L of water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate 6, with a molar yield of 98.0% and an HPLC purity of 96.7%.

[0081] Preparation of intermediate 6 in Example 21

[0082] Intermediate 5 (9.51 g, 24 mmol, HPLC purity 98.8%) was dissolved in 500 mL of tetrahydrofuran, and the solution was cooled to 0 °C under nitrogen protection. Then, 0.12 mol of sodium dimethylsulfoxide was dissolved in 50 mL of a mixture of dimethylsulfoxide and tetrahydrofuran and was added dropwise into the reaction flask. After 30 min of stirring at room temperature, 1.25 L of dichloromethane and 2.0 L of saturated ammonium chloride solution were added, and the solution was stirred for 5 min. After standing, the solution was separated, and the aqueous phase was washed with 1.25 L of dichloromethane twice. The combined organic phase was washed with 1.0 L of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate 6, with a molar yield of 96.1% and an HPLC purity of 95.4%.

[0083] Preparation of Example 22 intermediate 6

[0084] Intermediate 5 (9.51 g, 24 mmol, HPLC purity 98.8%) was dissolved in 500 mL of tetrahydrofuran, under nitrogen protection, cooled to 0 °C, 0.072 mol of sodium dimethylsulfoxide was dissolved in 50 mL of dimethylsulfoxide and tetrahydrofuran mixed solution and dropped into the reaction bottle, stirred at room temperature for 30 min, the reaction was completed, 1250 mL of ethyl acetate and 2.0 L of saturated ammonium chloride solution were added and stirred for 5 min, and then separated into water and organic phases. The aqueous phase was washed with 1.25 L x 2 ethyl acetate twice, and the combined organic phase was washed with 1.0 L of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate 6 with a molar yield of 91.9% and an HPLC purity of 95.6%.

[0085] Preparation of Example 23 intermediate 7

[0086] Intermediate 6 (9.13 g, 23.5 mmol, HPLC purity 96.7%) was dissolved in a mixed solution of 250 mL of tetrahydrofuran and 25 mL of water, under nitrogen protection, and aluminum amalgam (11.9 g, 0.43 mol) was added at room temperature. After stirring for 90 min, the solid was filtered off, the filter cake was washed with a small amount of tetrahydrofuran, and the filtrate was concentrated under reduced pressure. A mixed solution of 200 mL of ether and 50 mL of water was added to the concentrated solution, stirred, and allowed to stand. The aqueous phase was separated, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The concentrated solution was recrystallized from a mixed solution of dichloromethane and isopropyl ether (1:1.8, by volume) to obtain intermediate 7 with a molar yield of 91.6% and an HPLC purity of 99.6%. [a]20D = +8.0 (c = 1.78, chloroform)

[0087] Preparation of Example 24 intermediate 7

[0088] Intermediate 6 (9.13 g, 23.5 mmol, HPLC purity 96.7%) was dissolved in a mixed solution of 250 mL of tetrahydrofuran and 25 mL of water, under nitrogen protection, and aluminum amalgam (10.0 g, 0.36 mol) was added at room temperature. After stirring for 90 min, the solid was filtered off, the filter cake was washed with a small amount of tetrahydrofuran, and the filtrate was concentrated under reduced pressure. A mixed solution of 200 mL of ether and 50 mL of water was added to the concentrated solution, stirred, and allowed to stand. The aqueous phase was separated, the organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The concentrated solution was recrystallized from a mixed solution of dichloromethane and ether (1:1.8, by volume) to obtain intermediate 7 with a molar yield of 86.4% and an HPLC purity of 99.0%. [a]20D = +8.0 (c = 1.78, chloroform)

[0089] Preparation of Example 25 intermediate 7

[0090] Intermediate 6 (9.13 g, 23.5 mmol, HPLC purity 96.7%) was dissolved in a mixture of 250 mL of tetrahydrofuran and 25 mL of water, protected by nitrogen, stirred for 90 min at room temperature, the solid was filtered off, the filter cake was washed with a small amount of tetrahydrofuran, the filtrate was concentrated under reduced pressure, a mixture of 200 mL of diethyl ether and 50 mL of water was added to the concentrated solution, stirred, and allowed to stand, the aqueous phase was separated, the organic phase was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The concentrated solution was recrystallized from a mixture of chloroform and diethyl ether (volume ratio 1:2.3) to obtain intermediate 7 with a molar yield of 89.5% and an HPLC purity of 99.2%. [a]20D= +8.1 (c = 1.78, chloroform)

[0091] Preparation of intermediate 8 in Example 26

[0092] A three-necked flask was charged with intermediate 7 (7.0 g, 21.5 mmol, HPLC purity 99.6%), dissolved in 42 mL of dichloromethane, and triethylamine (6.0 mL, 43 mmol) was added dropwise at 0°C under nitrogen protection, followed by the dropwise addition of trimethylchlorosilane (6.00 mL, 47.3 mmol). The reaction was stirred at 0°C for 1-2 h, the reaction was completed, 100 mL of dichloromethane was added to dilute the reaction system, the reaction solution was poured into 100 mL of ice water, the organic phase was extracted and collected, washed with 100 mL of water twice, washed with 100 mL of saturated brine twice, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate 8 with a molar yield of 98.7% and an HPLC purity of 98.4%.

[0093] Preparation of intermediate 8 in Example 27

[0094] A three-necked flask was charged with intermediate 7 (7.0 g, 21.5 mmol, HPLC purity 99.6%), dissolved in 42 mL of dichloromethane, and triethylamine (6.0 mL, 43 mmol) was added dropwise at 0°C under nitrogen protection, followed by the dropwise addition of trimethylchlorosilane (6.00 mL, 47.3 mmol). The reaction was stirred at 0°C for 1-2 h, the reaction was completed, 100 mL of dichloromethane was added to dilute the reaction system, the reaction solution was poured into 100 mL of ice water, the organic phase was extracted and collected, washed with 100 mL of water twice, washed with 100 mL of saturated brine twice, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate 8 with a molar yield of 98.7% and an HPLC purity of 98.4%.

[0095] Preparation of intermediate 9 in Example 28

[0096] To the reaction flask was added a solution of intermediate 8 (10.1 g, 21.5 mmol, HPLC purity 98.4%) in dichloromethane, aluminium trichloride (8.6 g, 64.5 mmol) was added portionwise, the temperature was lowered to 0 °C, a solution of compound 12 (5.0 g, 21.5 mmol) in 30 mL of dichloromethane was added dropwise slowly, the temperature was allowed to rise to room temperature after 30 min stirring at 0 °C, the reaction was stirred for 6-8 h, the reaction was poured into 70 mL of 3% HCl solution, the temperature was kept at 0 °C for 10 min with stirring, the temperature was allowed to rise to room temperature for 0.5-1 h with stirring, the reaction was allowed to stand to separate the layers, the organic phase was separated, the aqueous phase was extracted with 40 mL of dichloromethane, the organic phase was collected, the organic phase was washed with 100 mL of saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the concentrate was recrystallized from a mixture of dichloromethane and isopropyl ether (1:4, v / v), then recrystallized from a mixture of ethanol and diethyl ether (1:5, v / v) to give intermediate 9. Molar yield 93.9%, HPLC purity 99.7%.

[0097] Preparation of intermediate 9 in example 29

[0098] To the reaction flask was added a solution of intermediate 8 (10.1 g, 21.5 mmol, HPLC purity 98.4%) in dichloromethane, aluminium trichloride (8.6 g, 64.5 mmol) was added portionwise, the temperature was lowered to 0 °C, a solution of compound 12 (5.0 g, 21.5 mmol) in 30 mL of dichloromethane was added dropwise slowly, the temperature was allowed to rise to room temperature after 30 min stirring at 0 °C, the reaction was stirred for 6-8 h, the reaction was poured into 70 mL of 3% HCl solution, the temperature was kept at 0 °C for 10 min with stirring, the temperature was allowed to rise to room temperature for 0.5-1 h with stirring, the reaction was allowed to stand to separate the layers, the organic phase was separated, the aqueous phase was extracted with 40 mL of dichloromethane, the organic phase was collected, the organic phase was washed with 100 mL of saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, the concentrate was recrystallized from a mixture of dichloromethane and isopropyl ether (1:4, v / v), then recrystallized from a mixture of ethanol and diethyl ether (1:5, v / v) to give intermediate 9. Molar yield 93.9%, HPLC purity 99.7%.

[0099] Preparation of daunorubicin in example 30

[0100] The intermediate 9 (9.3 g, 19.1 mmol, HPLC purity 99.7%) was dissolved in 120 mL of dichloromethane, protected by nitrogen, cooled to 2-8 °C, and 20 mL of a dichloromethane solution containing dimethyl boron bromide (4.6 g, 38.2 mmol) was added dropwise. The reaction was stirred at 2-8 °C for 2 h. The reaction solution was poured into a mixture of 80 mL of saturated sodium bicarbonate solution and 120 mL of tetrahydrofuran, stirred for 15 min, and separated. The aqueous phase was extracted with 80 mL of dichloromethane three times, and the organic phase was collected and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to obtain a soft red ketone, with a molar yield of 98.2% and an HPLC purity of 99.5%.

[0101] Preparation of intermediate 1 in Comparative Example 1

[0102] The 2,5-dihydroxybenzyl alcohol (14.0 g, 0.1 mol) was dissolved in 1.4 L of n-heptane, protected by nitrogen, and diisopropyl ethylamine (62.8 mL, 0.38 mol) and chloromethyl methyl ether (21.3 mL, 0.28 mol) were added. The reaction was refluxed and stirred for 22 h. After the reaction was completed, the reaction solution was cooled and poured into 1.4 L of a 5% sodium bicarbonate solution. The mixture was stirred for about 10 min, separated, and the aqueous phase was extracted with dichloromethane (3 x 500 mL). The organic phase was collected and dried over anhydrous sodium sulfate. The organic phase was washed with 1.4 L of water, 1.4 L of saturated brine, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to obtain a brown oil. Petroleum ether (70 mL) was added and the mixture was stirred for about 30 min. The mixture was filtered and the filtrate was dried under reduced pressure to obtain a white solid, which was intermediate 1, with a molar yield of 68.5% and an HPLC purity of 92.3%.

[0103] Preparation of intermediate 1 in Comparative Example 2

[0104] The 2,5-dihydroxybenzyl alcohol (14.0 g, 0.1 mol) was dissolved in 1.4 L of n-heptane, protected by nitrogen, and diisopropyl ethylamine (62.8 mL, 0.38 mol) and chloromethyl methyl ether (21.3 mL, 0.28 mol) were added. The reaction was refluxed and stirred for 22 h. After the reaction was completed, the reaction solution was cooled and poured into 1.4 L of a 5% sodium bicarbonate solution. The mixture was stirred for about 10 min, separated, and the aqueous phase was extracted with dichloromethane (3 x 500 mL). The organic phase was collected and dried over anhydrous sodium sulfate. The organic phase was washed with 1.4 L of water, 1.4 L of saturated brine, and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to obtain a brown oil. Petroleum ether (70 mL) was added and the mixture was stirred for about 30 min. The mixture was filtered and the filtrate was dried under reduced pressure to obtain a white solid, which was intermediate 1, with a molar yield of 68.5% and an HPLC purity of 92.3%.

[0105] Preparation of intermediate 2 in Comparative Example 3

[0106] The intermediate 1 (18.0 g, 78.9 mmol, HPLC purity 98.2%) was placed in a 1000 mL reaction bottle, 500 mL of tetrahydrofuran solution of N, N'-dicyclohexyl-N-methyl carbodiimide iodide (137 g, 394.5 mmol) was added, stirred for 3 h at 30 °C under nitrogen protection and in the dark, the solvent was removed under reduced pressure, the residue was dissolved in 200 mL of n-hexane, washed with water (100 mL x 3) three times, the aqueous phase was extracted with 150 mL of n-hexane, the organic phase was collected and dried with anhydrous sodium sulfate, filtered under suction, and the filtrate was concentrated under reduced pressure, and recrystallized with a mixed solvent of dichloromethane and n-hexane in a volume ratio of 1:3 to obtain the intermediate 2, with a molar yield of 90.6% and an HPLC purity of 78.5%.

[0107] Preparation of intermediate 3 in Comparative Example 4

[0108] The acid 11 (5.0 g, 24.7 mmol) was dissolved in 200 mL of n-hexane, and 200 mL of tetrahydrofuran solution of lithium bis-trimethylsilyl amide (20.60 g, 123 mmol) was slowly added dropwise at -78 °C under nitrogen protection, after 20 min, 50 mL of tetrahydrofuran solution of the intermediate 2 (33.3 g, 98.4 mmol, HPLC purity 98.4%) was added. Stirred for 1 h at -78 to -50 °C, warmed to -30 °C and stirred for 20 h, the reaction was completed, the reaction liquid was poured into 300 mL of 1 mol / L hydrochloric acid, extracted with 150 mL x 3 of ether three times, the organic phase was collected and dried with MgSO4, the solvent was removed under reduced pressure, the residue was dissolved in 250 mL of dichloromethane, washed with 125 mL x 3 of saturated sodium bicarbonate solution three times, the aqueous phase was extracted with 150 mL x 3 of ether three times, the organic phase was collected and dried with MgSO4, and concentrated under reduced pressure to obtain a white solid, which was the intermediate 3, with a molar yield of 75.1% and an HPLC purity of 81.8%.

[0109] Preparation of intermediate 4 in Comparative Example 5

[0110] The intermediate 3 (15.0 g, 36.4 mmol, HPLC purity 97.2%) was placed in a reaction flask, 225 mL of dichloromethane was added at room temperature, and thionyl chloride (5.0 mL, 72.8 mmol) was added under nitrogen protection. The reaction was heated to reflux for 12 h, cooled to room temperature, and tin tetrachloride (13.5 mL, 72.8 mmol) was added. The reaction was stirred at 20 °C for another 1 h. After the reaction was completed, 225 g of crushed ice was added, and the aqueous phase was collected by liquid separation. The aqueous phase was extracted with 120 mL of dichloromethane three times at 0 °C. The combined organic phase was washed with 400 mL of saturated NaHCO3 solution and 400 mL of saturated sodium chloride solution, respectively, dried over anhydrous MgSO4, and concentrated under reduced pressure to obtain the crude intermediate 4 with a molar yield of 78.3% and an HPLC purity of 76.8%. The crude intermediate 4 was recrystallized from a mixture of tetrahydrofuran and n-hexane (1:3, by volume) to obtain the intermediate 4 with a molar yield of 60.9% and an HPLC purity of 90.7%. mp: 157 °C, [α]20D = +48.1 (c = 0.48, CHCl3)].

[0111] Preparation of intermediate 4 in Comparative Example 6

[0112] The intermediate 3 (15.0 g, 36.4 mmol, HPLC purity 97.2%) was placed in a reaction flask, 225 mL of dichloromethane was added at room temperature, and thionyl chloride (5.0 mL, 72.8 mmol) was added under nitrogen protection. The reaction was heated to reflux for 12 h, cooled to room temperature, and tin tetrachloride (13.5 mL, 72.8 mmol) was added. The reaction was stirred at 20 °C for another 1 h. After the reaction was completed, 225 g of crushed ice was added, and the aqueous phase was collected by liquid separation. The aqueous phase was extracted with 120 mL of dichloromethane three times at 0 °C. The combined organic phase was washed with 400 mL of saturated NaHCO3 solution and 400 mL of saturated sodium chloride solution, respectively, dried over anhydrous MgSO4, and concentrated under reduced pressure to obtain the crude intermediate 4 with a molar yield of 78.3% and an HPLC purity of 76.8%. The crude intermediate 4 was recrystallized from a mixture of tetrahydrofuran and n-hexane (1:3, by volume) to obtain the intermediate 4 with a molar yield of 60.9% and an HPLC purity of 90.7%. mp: 157 °C, [α]20D = +48.1 (c = 0.48, CHCl3)].

[0113] Preparation of intermediate 5 in Comparative Example 7

[0114] Into a reaction flask, 80 mL of tetrahydrofuran was added under nitrogen protection, and stirring was started. N,N-diethylaniline borane (2.5 mL, 13.9 mmol) was added, and the catalyst (R)-2-methyl-CBS-oxazaborolidine ((R)-MeCBS) (0.22 g, 2%) was dissolved in 80 mL of tetrahydrofuran and was added into the reaction flask in a flow. The reaction solution was controlled at 15-25 °C, and 220 mL of tetrahydrofuran solution containing intermediate 4 (11.0 g, 27.9 mmol, HPLC purity 99.3%) was added dropwise using a constant pressure dropping funnel, ensuring that the dropping was completed in 2-3 h. The reaction was incubated for 10-20 min, and the temperature was controlled below 25 °C. Then, 32 mL of methanol was slowly added dropwise, and stirring was performed for 15 min. The solution was concentrated under reduced pressure, 300 mL of dichloromethane was added, and 160 mL of 2 mol / L sulfuric acid was added dropwise while controlling the temperature at 15-25 °C. There was foam during the addition. After stirring for 15 min, 160 mL of water was added, and the solution was allowed to stand and separate. The organic phase was washed with 250 mL of water and 250 mL of saturated sodium chloride solution, and was dried over anhydrous sodium sulfate. The solution was filtered under suction, and the filtrate was concentrated under reduced pressure to dryness. The solution was recrystallized from a mixture of tetrahydrofuran and diethyl ether (volume ratio 2:3) to obtain intermediate 5, with a molar yield of 90.1% and an HPLC purity of 56.3%.

[0115] Preparation of intermediate 6 in Comparative Example 8

[0116] Intermediate 5 (9.51 g, 24 mmol, HPLC purity 98.8%) was dissolved in 500 mL of tetrahydrofuran, and the solution was cooled to 0 °C under nitrogen protection. 0.05 mol of sodium dimethylsulfoxide was dissolved in 50 mL of a mixture of dimethylsulfoxide and tetrahydrofuran, and the solution was added dropwise into the reaction flask. After stirring at room temperature for 30 min, the reaction was completed. Then, 1250 mL of dichloromethane and 2.0 L of saturated ammonium chloride solution were added, and stirring was performed for 5 min. The solution was allowed to stand and separate, and the aqueous phase was washed twice with 1.25 L of dichloromethane. The combined organic phase was washed with 1.0 L of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate 6, with a molar yield of 76.6% and an HPLC purity of 89.7%.

[0117] Preparation of intermediate 7 in Comparative Example 9

[0118] Intermediate 6 (9.13 g, 23.5 mmol, HPLC purity 96.7%) was dissolved in a mixture of 250 mL tetrahydrofuran and 25 mL water under nitrogen protection. Aluminum amalgam (6.6 g, 0.24 mol) was added at room temperature, and the mixture was stirred for 90 min. The solid was filtered off, and the filter cake was washed with a small amount of tetrahydrofuran. The filtrate was concentrated under reduced pressure, and a mixture of 200 mL diethyl ether and 50 mL water was added. The mixture was stirred, allowed to stand, and the aqueous phase was separated. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The solution was then recrystallized from a mixture of dichloromethane and isopropyl ether in a volume ratio of 1:1.8 to obtain intermediate 7, with a molar yield of 76.8% and an HPLC purity of 87.9%. [α]20D = +7.9 (c = 1.78, chloroform)

[0119] Preparation of intermediate 8 in Comparative Example 10

[0120] Intermediate 7 (7.0 g, 21.5 mmol, HPLC purity 99.6%) was added to a three-necked flask and dissolved in 42 mL of dichloromethane. Under nitrogen protection at 0 °C, triethylamine (6.0 mL, 43 mmol) was added dropwise, followed by trimethylchlorosilane (13.5 mL, 107.5 mmol). The mixture was stirred at 0 °C for 1–2 h. After the reaction was complete, 100 mL of dichloromethane was added to dilute the mixture. The reaction solution was poured into 100 mL of ice water, and the organic phase was extracted and collected. The organic phase was washed twice with 100 mL × 2 water and twice with 100 mL × 2 saturated brine. The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under reduced pressure to obtain intermediate 8. The molar yield was 92.7%, and the HPLC purity was 78.6%.

[0121] Preparation of intermediate 9 in Comparative Example 11

[0122] Add a dichloromethane solution of intermediate 8 (10.1 g, 21.5 mmol, HPLC purity 98.4%) to a reaction flask, add aluminum trichloride (4.3 g, 32.2 mmol) in portions, cool to 0 °C, slowly add 30 mL of dichloromethane solution containing compound 12 (5.0 g, 21.5 mmol), stir at 0 °C for 30 min, allow to rise naturally to room temperature, stir for 6-8 h, pour the reaction solution into 70 mL of 3% HCl solution, keep warm at 0 °C and stir for 10 min, stir at room temperature for 0.5-1 h, separate the organic phase, extract the aqueous phase with 40 mL of dichloromethane, collect the organic phase, wash with 100 mL of saturated sodium bicarbonate solution, dry with anhydrous sodium sulfate, concentrate under reduced pressure, recrystallize from a 1:4 volume ratio of dichloromethane and isopropyl ether, and then recrystallize from a 1:5 volume ratio of ethanol and diethyl ether to obtain intermediate 9. The molar yield was 90.5%, and the HPLC purity was 81.3%.

[0123] Preparation of daunorubicin in Comparative Example 12

[0124] Intermediate 9 (9.3 g, 19.1 mmol, HPLC purity 99.7%) was dissolved in 120 mL of dichloromethane, and the solution was cooled to 2-8 °C under nitrogen protection. Then 20 mL of a dichloromethane solution containing dimethyl boron bromide (11.5 g, 95.5 mmol) was added dropwise. The solution was stirred at 2-8 °C for 2 h. The reaction solution was poured into a mixture of 80 mL of saturated sodium bicarbonate solution and 120 mL of tetrahydrofuran, and stirred for 15 min. The aqueous phase was extracted with 80 mL of dichloromethane three times, and the combined organic phase was washed with 160 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain flavylium, with a molar yield of 92.5% and an HPLC purity of 84.2%.

[0125] Intermediate 1 was analyzed by 1H-NMR and MS:

[0126] 1 H NMR (400 MHz, CDCl3): δ = 6.71-6.74 (m, 3H, ArH); 6.06 (s, 2H, OCH2O); 6.05 (s, 2H, OCH2O); 3.27 (s, 3H, OCH3); 3.26 (s, 3H, OCH3); 4.84 (s, 2H, CH2OH); 2.87 (s, 1H, OH)

[0127] ESI-MS (M / Z) = 251 [M+Na] +

[0128] Intermediate 2 was analyzed by 1H-NMR and MS:

[0129] 1 H NMR (400 MHz, CDCl3): δ = 6.68-6.71 (m, 2H, ArH); 6.64 (s, 1H, ArH); 6.05 (s, 2H, OCH2O); 6.04 (s, 2H, OCH2O); 3.26 (s, 3H, OCH3); 3.25 (s, 3H, OCH3); 4.35 (s, 2H, CH2I);

[0130] ESI-MS (M / Z) = 361 [M+Na] +

[0131] Intermediate 3 was analyzed by 1H-NMR and MS:

[0132] 1H NMR (400MHz, CDCl3): δ = 11.35 (brs, 1H, COOH); 6.77~6.79 (m, 2H, ArH); 6.70 (s, 1H, ArH); 6.05 ( s,2H,OCH2O); 6.04(s,2H,OCH2O); 5.12(s,1H); 3.27(s,3H,OCH3); 3.26(s,3H,OCH3); 3.09(d,J gem =14.2Hz, 1H); 3.03 (d, J) gem =14.2Hz, 1H); 2.92 (d, J) gem =16.4Hz,1H,CH2COOH);2.70(d,J gem =16.4Hz,1H,CH2COOH);0.97(s,9H,tBu).

[0133] ESI-MS (M / Z) = 435[M+Na] + .

[0134] Intermediate 4 was analyzed by 1H-NMR and MS mass spectrometry:

[0135] 1 H NMR (400MHz, CDCl3): δ = 7.04 (d, J = 9.1Hz, 1H); 6.86 (d, J = 9.1Hz, 1H); 6.04 (s, 2H, OCH 2O); 6.03 (s, 2H, OCH2O); 5.13 (s, 1H); 3.27 (s, 3H, OCH3); 3.26 (s, 3H, OCH3); 3.34 (d, J gem =18.0Hz, 1H); 3.22(d, J) gem =18.2Hz,1H); 2.90((s,2H); 0.97(s,9H,tBu).

[0136] ESI-MS (M / Z) = 417[M+Na] + .

[0137] Intermediate 5 was analyzed by 1H-NMR and MS mass spectrometry:

[0138] 1H NMR (400 MHz, CDC13): δ = 7.73 (s, 2H, ArH); 6.05 (s, 2H, OCH20); 6.03 (s, 2H, OCH20); 5.30 (s, 1H); 5.21-5.25 (m, 1H); 3.28 (s, 3H, OCH3); 3.26 (s, 3H, OCH3); 3.25 (dd, J = 18.0 Hz, 2.0 Hz, 1H); 3.23 (d, J = 9.0 Hz, 1H, OH); 2.81 (d, J = 18.0 Hz, 1H); 2.43 (m, 1H); 2.32 (m, 1H); 0.98 (s, 9H, tBu).

[0139] ESI-MS (M / Z) = 419 [M + Na] + .

[0140] Intermediate 6 was analyzed by1H-NMR and MS spectrometry:

[0141] 1 H NMR (300 MHz, DMSO-d6) δ = 6.78 (d, J = 8.6 Hz, 1H, Ar-H); 6.77 (d, J = 8.8 Hz, 1H, Ar-H); 6.15 (s, 2H, OCH20); 6.14 (s, 2H, OCH20); 5.11-5.18 (m, 1H, 1-H); 3.87 (S, 1H, COCH2SO); 3.85 (S, 1H, 3-OH); 3.78 (d, J = 3.6 Hz, 1H, 1-OH); 3.36 (s, 3H, OCH3); 3.34 (s, 3H, OCH3); 3.16 (dd, J = 17.7 Hz, J = 2.2 Hz, 1H, 4a-H); 2.90 (d, J = 17.7 Hz, 1H, 4b-H); 2.76 (s, 3H, SOCH3); 2.32-2.38 (m, 1H, 2b-H); 2.22 (dd, J = 14.4 Hz, J = 4.6 Hz, 1H, 2a-H). gem 2b,4a gem gem 1a,2a

[0142] ESI-MS (M / Z) = 411 [M + Na] + .

[0143] Intermediate 7 was analyzed by1H-NMR and MS spectrometry:

[0144] 1 ​​​​​H NMR (300 MHz, DMSO-d6) δ = 6.76 (d, J = 8.6 Hz, 1 H, Ar-H); 6.75 (d, J = 8.8 Hz, 1 H, Ar-H); 6.15 (s, 2H, OCH20); 6.14 (s, 2H, OCH20); 5.10-5.17 (m, 1 H, 1-H); 3.84 (S, 1 H, 3-OH); 3.78 (d, J = 3.6 Hz, 1 H, 1-OH); 3.36 (s, 3H, OCH3); 3.34 (s, 3H, OCH3); 3.14 (dd, J gem = 17.7 Hz, J 2b,4a = 2.2 Hz, 1 H, 4a-H); 2.88 (d, J gem = 17.7 Hz, 1 H, 4b-H); 2.46 (s, 3H, COCH3); 2.32-2.38 (m, 1 H, 2b-H); 2.22 (dd, J gem = 14.4 Hz, J 1a,2a = 4.6 Hz, 1 H, 2a-H).

[0145] ESI-MS (M / Z) = 349 [M + Na] + .

[0146] Intermediate 8 was analyzed by 1H-NMR and MS spectra:

[0147] 1 H NMR (300 MHz, DMSO-d6) δ = 6.75 (d, J = 8.6 Hz, 1 H, Ar-H), δ = 6.74 (d, J = 8.8 Hz, 1 H, Ar-H), 6.13 (s, 2H, OCH20), 6.12 (s, 2H, OCH20), 5.11-5.18 (m, 1 H, 1-H), 3.36 (s, 3H, OCH3), 3.34 (s, 3H, OCH3), 3.13 (dd, J gem = 17.7 Hz, J 2b,4a = 2.2 Hz, 1 H, 4a-H), 2.86 (d, J gem = 17.7 Hz, 1 H, 4b-H), 2.44 (s, 3H, COCH3), 2.30-2.36 (m, 1 H, 2b-H), 2.20 (dd, J gem = 14.4 Hz, J 1a,2a = 4.6 Hz, 1 H, 2a-H), 0.09 (s, 9H, CH3).

[0148] ESI-MS (M / Z) = 494 [M + Na] + .

[0149] Intermediate 9 was analyzed by 1H-NMR and MS mass spectrometry:

[0150] 1 H NMR (300MHz, CDCl3) δ = 8.03 (d, 1H, J = 7.6Hz, 4-H); 7.80 (t, 1H, J = 8.2Hz, 3-H); 7.42 (d, 1H, J = 8.4Hz, 2-H); 6.35 (s, 2H, OCH2O); 6.28 (s, 2H, OCH2O) ;5.32(brs,1H,10-H);4.60(s,1H,8-OH);4.06(s,3H,OCH3);3.77(brs,1H,10-OH);3.55(s,3H,OCH2OCH3);3.49(s,3H,OCH2OCH3);3.06(AB,2H,J AB =18.6Hz, 7-H); 2.41 (s, 3H, COCH3); 2.35 (d, 1H, J = 14.6Hz, 9-H); 2.17 (dd, 1H, J = 4.8Hz, 9-H).

[0151] ESI-MS (M / Z) = 509[M+Na] + .

[0152] daunorubicin was analyzed by 1H-NMR and MS mass spectrometry:

[0153] 1 H NMR(300MHz, CDCl3)δ=14.01(brs,1H,11-OH);13.24(s,1H,6-OH);8.04(d,1H,J=7.6Hz,4-H);7.81(t,1H,J=8.2Hz,3-H);7 .42(d,1H,J=8.4Hz,2-H);5.30(brs,1H,10-H);4.57(s,1H,8-OH);4.05(s,3H,OCH3);3.77(brs,1H,10-OH);3.06(AB,2H,J AB =18.6Hz, 7-H); 2.41 (s, 3H, COCH3); 2.35 (d, 1H, J = 14.6Hz, 9-H); 2.35 (dd, 1H, J = 4.8Hz, 9-H).

[0154] ESI-MS(M / Z) = 421[M+Na] + .

Claims

1. A method for synthesizing daunorubicin, an intermediate of epirubicin, characterized in that, The synthesis route is as follows: ， The steps for preparing intermediate 1 from 2,5-dihydroxybenzyl alcohol are as follows: 2,5-dihydroxybenzyl alcohol is dissolved in an organic solvent, and diisopropylethylamine and chloromethyl methyl ether are added under nitrogen protection. The mixture is stirred at 35~70℃ until the reaction is complete. The mixture is then cooled, and the reaction solution is poured into a 5% sodium bicarbonate solution. The mixture is stirred, allowed to stand, and separated. The aqueous phase is extracted with dichloromethane or chloroform, and the organic phase is collected. The organic phase is washed successively with water and saturated brine, dried with anhydrous sodium sulfate, filtered, collected, and concentrated under reduced pressure. Petroleum ether is added to form a slurry, filtered, and dried under reduced pressure to obtain intermediate 1. The steps for preparing intermediate 2 from intermediate 1 are as follows: intermediate 1 is placed in a reaction flask, and an organic solvent containing N,N'-dicyclohexyl-N-methylcarbodiimide iodide is added. The reaction is carried out at 25~55℃ in the dark. The solvent is removed by vacuum distillation. The residue is dissolved in n-hexane, washed with water, and the aqueous phase is extracted with n-hexane. The organic phase is collected and dried with anhydrous sodium sulfate. The mixture is filtered, and the filtrate is concentrated under vacuum. The residue is recrystallized with a mixed solvent of dichloromethane and n-hexane to obtain intermediate 2. The steps for preparing intermediate 3 from intermediate 2 are as follows: Dissolve acid 11 in an organic solvent, slowly add a tetrahydrofuran solution of bis(trimethylsilylaminolithium) under nitrogen protection at -78℃, add an organic solvent containing intermediate 2, stir and react at -78~-50℃ for 1~3h, raise the temperature to -30~-20℃ and stir and react for 15~22h. After the reaction is complete, pour the reaction solution into hydrochloric acid, extract with isopropyl ether, collect the organic phase, dry with magnesium sulfate, remove the solvent under reduced pressure, dissolve in dichloromethane, wash with saturated sodium bicarbonate solution, extract the aqueous phase with isopropyl ether, collect the organic phase, dry with magnesium sulfate, and concentrate under reduced pressure to obtain intermediate 3. The steps for preparing intermediate 4 from intermediate 3 are as follows: intermediate 3 is placed in a reaction flask, an organic solvent is added at room temperature, thionyl chloride is added under nitrogen protection, the mixture is heated to reflux for 12 h, tin tetrachloride is added after cooling to room temperature, the mixture is stirred at 20 °C for 1 h, the temperature is lowered to 0 °C, crushed ice is added, the aqueous phase is collected by separation, the aqueous phase is extracted with dichloromethane, the organic phase is collected, washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain crude intermediate 4. Intermediate 4 is obtained by recrystallization from a mixed solution of tetrahydrofuran and n-hexane. The steps for preparing intermediate 5 from intermediate 4 are as follows: Under nitrogen protection, tetrahydrofuran solution, N,N-diethylaniline borane, and (R)-2-methylCBS-oxazolium borane tetrahydrofuran solution are added sequentially to the reaction vessel. The temperature is controlled at 15~25℃. Tetrahydrofuran solution of intermediate 4 is slowly added. The reaction is maintained at a constant temperature, and the temperature is controlled below 25℃. Methanol is slowly added dropwise, stirred, concentrated under reduced pressure, dichloromethane is added, sulfuric acid is added dropwise at 15~25℃, stirred, and water is added to liquidate the organic phase. The organic phase is then washed sequentially with water and saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to dryness. The tetrahydrofuran and diethyl ether mixture is recrystallized to obtain intermediate 5. The steps for preparing intermediate 6 from intermediate 5 are as follows: intermediate 5 is dissolved in tetrahydrofuran solvent, and under nitrogen protection, the temperature is lowered to 0°C. Sodium dimethyl sulfoxide is dissolved in a mixed solution of dimethyl sulfoxide and tetrahydrofuran and added dropwise. The reaction is stirred at room temperature. After the reaction is complete, extraction solvent and saturated ammonium chloride solution are added and stirred. The mixture is allowed to stand and separated. The aqueous phase is washed with extraction solvent, and the organic phase is collected. The organic phase is washed with water, dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate 6. The steps for preparing intermediate 7 from intermediate 6 are as follows: intermediate 6 is dissolved in a mixed solution of tetrahydrofuran and water, aluminum amalgam is added at room temperature, the mixture is stirred under nitrogen protection, the solid is filtered off, the filter cake is washed with a small amount of tetrahydrofuran, the filtrate is concentrated under reduced pressure, an aqueous solution of diethyl ether is added, the mixture is stirred, allowed to stand, the liquid is separated, the organic phase is dried with anhydrous sodium sulfate, the solvent is removed under reduced pressure, and the product is recrystallized to obtain intermediate 7. The steps for preparing intermediate 8 from intermediate 7 are as follows: intermediate 7 is added to a three-necked flask and dissolved in dichloromethane. Under nitrogen protection at 0°C, triethylamine and trimethylchlorosilane are added dropwise and stirred until the reaction is complete. The reaction solution is diluted with dichloromethane and poured into ice water for extraction. The organic phase is washed with water and saturated brine in sequence, dried with anhydrous sodium sulfate, and filtered to obtain intermediate 8. The steps for preparing intermediate 9 from intermediate 8 are as follows: Aluminum trichloride is added in portions to a dichloromethane solution of intermediate 8, the temperature is lowered to 0°C, and a dichloromethane solution of compound 12 is slowly added dropwise. The mixture is stirred at 0°C for 30 min, then allowed to naturally rise to room temperature and stirred for 6–8 h. The reaction solution is poured into dilute hydrochloric acid at 0°C, stirred at 0°C for 10 min, and then stirred at room temperature for 0.5–1 h. The mixture is separated into liquid and aqueous phases, extracted with dichloromethane, and the organic phase is collected. The organic phase is washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude intermediate 9. Intermediate 9 is then recrystallized to obtain intermediate 9. The steps for preparing epirubicin intermediate daunolide from intermediate 9 are as follows: intermediate 9 is dissolved in dichloromethane, and under nitrogen protection, the temperature is lowered to 2-8℃. A dichloromethane solution of dimethylboron bromide is added dropwise, and the mixture is stirred at 2-8℃. After the reaction is completed, the reaction solution is poured into a mixed solution of saturated sodium bicarbonate and tetrahydrofuran, stirred, allowed to stand, and separated. The aqueous phase is extracted with dichloromethane, and the organic phase is collected. The organic phase is washed with saturated sodium chloride solution, separated, and the organic phase is dried with anhydrous sodium sulfate. The organic phase is concentrated under reduced pressure to obtain epirubicin intermediate daunolide.

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