daunorubicin intermediate compounds

Abstract

The application belongs to the field of medicine synthesis, and specifically provides a daunorubicin intermediate compound. The daunorubicin can be synthesized by pure chemical synthesis by using the intermediate compound. The daunorubicin is synthesized by taking 2,5-dihydroxybenzyl alcohol as a raw material. The route has low raw material cost, mild reaction condition, convenient post-treatment, high total yield, and good industrial application prospect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis, specifically relating to a daunorubicin intermediate compound. Background Technology

[0002] Epirubicin, also known as epirubicin, is an anthraquinone antibiotic with the following structural formula:

[0003]

[0004] Epirubicin is an anthracycline antitumor antibiotic developed by Pfizer for the treatment of breast cancer, lung cancer, and liver cancer. It was launched in Europe in 1984 and in the United States in 1999. It has wide applications in the treatment of leukemia, lymphoma, and various solid tumors (including breast cancer, non-small cell lung cancer, cervical cancer, and head and neck cancer). Its mechanism of action is to directly intercalate between DNA nucleobase pairs, interfering with transcription and preventing mRNA formation, thereby inhibiting DNA and RNA synthesis. In addition, epirubicin also inhibits topoisomerase II. It is a cell cycle nonspecific drug and is effective against various transplanted tumors. Compared with doxorubicin, its efficacy is equal to or slightly higher, but its cardiotoxicity is lower.

[0005] Currently, epirubicin is mainly prepared by using daunorubicin obtained through fermentation as a raw material, and then chemically synthesizing the finished product. However, the raw material obtained through fermentation has disadvantages such as low efficiency, many impurities, and poor reproducibility. This directly leads to a high level of impurities and poor reproducibility in the finished epirubicin product, which generally requires resin column separation. This greatly increases the production cycle and poses a potential threat to drug safety. Therefore, the pure chemical synthesis of epirubicin has become a new breakthrough.

[0006] Daunorubicin is an important intermediate of epirubicin, mostly obtained by recovering daunorubicin fermentation broth; reports of chemical synthesis methods are scarce. Its structural formula is shown below:

[0007] Summary of the Invention

[0008] To overcome the shortcomings of existing technologies, the present invention aims to provide a daunorubicin intermediate compound. This intermediate compound allows for the pure chemical synthesis of daunorubicin. The technical solution of the present invention is as follows:

[0009] A daunolide intermediate compound has the following structural formula:

[0010]

[0011] The preparation method is as follows: using 2,5-dihydroxybenzyl alcohol as raw material, the phenolic hydroxyl group is protected by MOM to generate intermediate 1. Intermediate 1 is subjected to iodination reaction to generate intermediate 2 iodoalkane. Intermediate 2 undergoes electrophilic substitution reaction with compound 11 of acid to generate intermediate 3. After intermediate 3 is converted into acyl chloride, it is connected to benzene ring through Friedel-Crafts acylation reaction to form intermediate 4. The ketone hydroxyl group on the six-membered ring of intermediate 4 is chirally reduced to generate intermediate 5.

[0012] Its synthetic route is as follows:

[0013]

[0014] Preferably, 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°C until the reaction is complete. After cooling, the reaction solution is poured into a 5% sodium bicarbonate solution, 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, concentrated under reduced pressure, mixed with petroleum ether, filtered, and dried under reduced pressure to obtain intermediate 1.

[0015] 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°C in the dark. The solvent is removed by vacuum distillation, and the residue is dissolved in n-hexane. The residue is washed with water, and the aqueous phase is extracted with n-hexane. The organic phase is collected and dried with anhydrous sodium sulfate. The residue is filtered, concentrated under vacuum, and the residue is recrystallized from a mixed solvent of dichloromethane and n-hexane to obtain intermediate 2.

[0016] The steps for preparing intermediate 3 from intermediate 2 are as follows: Acid 11 is dissolved in an organic solvent, and under nitrogen protection at -78°C, a tetrahydrofuran solution of bis(trimethylsilylaminolithium) is slowly added dropwise. Then, an organic solvent containing intermediate 2 is added, and the mixture is stirred at -78 to -50°C for 1 to 3 hours. The temperature is then raised to -30 to -20°C and stirred for 15 to 22 hours. After the reaction is complete, the reaction solution is poured into hydrochloric acid, extracted with isopropyl ether, and the organic phase is collected. The organic phase is dried with magnesium sulfate, the solvent is removed under reduced pressure, and the solution is dissolved in dichloromethane. The solution is washed with saturated sodium bicarbonate solution, the aqueous phase is extracted with isopropyl ether, the organic phase is collected, dried with magnesium sulfate, and concentrated under reduced pressure to obtain intermediate 3.

[0017] 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 over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain crude intermediate 4. Intermediate 4 is then recrystallized from a mixed solution of tetrahydrofuran and n-hexane.

[0018] 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°C. Tetrahydrofuran solution of intermediate 4 is slowly added. The reaction is maintained at a constant temperature, controlled below 25°C. Methanol is slowly added dropwise, stirred, concentrated under reduced pressure, dichloromethane is added, sulfuric acid is added dropwise at 15-25°C, stirred, and water is added to ligate the mixture. 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 to dryness under reduced pressure. The mixture of tetrahydrofuran and diethyl ether is recrystallized to obtain intermediate 5.

[0019] More preferably, in the step of preparing intermediate 1 from 2,5-dihydroxybenzyl alcohol, the organic solvent is one of dichloromethane, chloroform, acetonitrile or DMF, more preferably, the organic solvent is dichloromethane; the molar ratio of 2,5-dihydroxybenzyl alcohol, diisopropylethylamine and chloromethyl methyl ether is 1:3 to 6:2 to 4, more preferably 1:3.8:2.8.

[0020] In the step of preparing intermediate 2 from intermediate 1, the organic solvent is one of tetrahydrofuran, n-hexane, toluene, or acetonitrile, more preferably, the organic solvent is tetrahydrofuran or n-hexane; the molar ratio of intermediate 1 to N,N'-dicyclohexyl-N-methylcarbodiimide iodide is 1:1 to 3, more preferably 1:2; the reaction temperature is 30 to 40°C.

[0021] 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, more preferably, the organic solvent is tetrahydrofuran or n-hexane; the molar ratio of acid 11, intermediate 2, and bis(trimethylsilylamine)lithium is 1:1 to 3:2 to 4, more preferably 1:2 to 2.5:2.5 to 3.5.

[0022] In the step of preparing intermediate 4 from intermediate 3, the organic solvent is dichloromethane, chloroform, toluene or 1,2-dichloroethane, more preferably dichloromethane; the molar ratio of intermediate 3, thionyl chloride and tin tetrachloride is 1:3 to 6:3 to 6, more preferably 1:4.5:4.

[0023] In the step of preparing intermediate 5 from intermediate 4, the molar ratio of intermediate 4 to N,N-diethylaniline borane is 1:1; the mass ratio of intermediate 4 to (R)-2-methyl-CBS-oxazolium borane is 1:1% to 5%.

[0024] A synthetic method for preparing daunorubicin using intermediate compound 5 is described below:

[0025]

[0026] Preferably, 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 over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate 6.

[0027] 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 by evaporation under reduced pressure, and the product is recrystallized to obtain intermediate 7.

[0028] 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 successively with water and saturated brine, dried over anhydrous sodium sulfate, and filtered to obtain intermediate 8.

[0029] The steps for preparing intermediate 9 from intermediate 8 are as follows: Aluminum trichloride is added in batches 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 stirred at room temperature for 0.5–1 h. The liquid-liquid phase is separated, the aqueous phase is extracted with dichloromethane, the organic phase is collected, 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.

[0030] 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°C. A dichloromethane solution of dimethylboron bromide is added dropwise, and the mixture is stirred at 2-8°C. After the reaction is complete, 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 then concentrated under reduced pressure to obtain epirubicin intermediate daunolide.

[0031] More preferably, in the step of preparing intermediate 6 from intermediate 5, the molar ratio of intermediate 5 to sodium dimethyl sulfoxide is 1:3 to 5, preferably 1:4.17; after the reaction is complete, the extraction solvent is dichloromethane, chloroform or ethyl acetate, preferably dichloromethane.

[0032] In the step of preparing intermediate 7 from intermediate 6, the molar ratio of intermediate 6 to aluminum amalgam is 1:15 to 25, more preferably 1:18 to 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.

[0033] In the step of preparing intermediate 8 from intermediate 7, the molar ratio of intermediate 7 to trimethylchlorosilane is 1:2 to 3, more preferably 1:2.2.

[0034] In the step of preparing intermediate 9 from intermediate 8, the recrystallization process involves first recrystallizing the product with dichloromethane and isopropyl ether, and then recrystallizing it 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 to 6, more preferably 1:3 to 4.

[0035] In the step of preparing daunorubicin from intermediate 9, the molar ratio of intermediate 9 to dimethylboron bromide is 1:2 to 2.5, more preferably 1:2.

[0036] This invention uses 2,5-dihydroxybenzyl alcohol as a raw material to prepare daunorubicin, an important intermediate for the synthesis of epirubicin. This route has low raw material costs, mild reaction conditions, convenient post-processing, and high overall yield, and has good prospects for industrial application. Detailed Implementation

[0037] To better understand the content of this invention, the technical solution of this invention will be further illustrated below through specific embodiments, but these embodiments do not limit this invention.

[0038] In the following examples, the raw materials 2,5-dihydroxybenzyl alcohol, compound 11, and compound 12 can be prepared by the following methods or by other methods. The present invention does not impose any restrictions on the source of the raw materials.

[0039] 2,5-Dihydroxybenzyl alcohol can be prepared by the following method:

[0040]

[0041] Mix 10g of 2,5-dimethoxybenzyl alcohol with 50ml of 35% concentrated hydrochloric acid. After stirring mechanically at room temperature for 48h, place the mixture in an ice-water bath and add Na2CO3 in batches while stirring to neutralize the pH value to 2-3. Filter the mixture and extract the filtrate with ethyl acetate (100ml×3). Combine the organic phases and dry them with anhydrous sodium sulfate. After filtration, distill off the ethyl acetate under reduced pressure to obtain 6.38g of light yellow solid, which is 2,5-dihydroxybenzyl alcohol.

[0042] Compound 11 of acid can be prepared according to the method in the literature Liebigs Ann. Chem. 1987, 515-520.

[0043] Compound 12 can be prepared by the following methods:

[0044]

[0045] 24.2 g of 4-methoxyphthalic acid and 240 ml of dichloromethane were added to a container, and 17.9 ml of thionyl chloride was slowly added dropwise. After the addition was completed, the mixture was refluxed under nitrogen protection for 5 h. The mixture was then concentrated under reduced pressure to obtain compound 12.

[0046] Preparation of Intermediate 1 in Example 1

[0047] 2,5-Dihydroxybenzyl alcohol (14.0 g, 0.1 mol) was dissolved in 1.4 L of dichloromethane under nitrogen protection. Diisopropylethylamine (62.8 mL, 0.38 mol) and chloromethyl methyl ether (21.3 mL, 0.28 mol) were added, and the mixture was stirred and refluxed for 22 h. After the reaction was completed, the mixture was cooled and poured into 1.4 L of 5% sodium bicarbonate solution. The mixture was stirred for about 10 min, and the aqueous phase was separated. The aqueous phase was extracted with dichloromethane (3 × 500 mL). The organic phases were collected and combined, and washed successively with 1.4 L of water and 1.4 L of saturated brine. The organic phases were then dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a brown oily substance. 70 mL of petroleum ether was added and the mixture was stirred for about 30 min. The mixture was filtered and dried under reduced pressure to obtain a white solid, which was intermediate 1. The molar yield was 97.8%, and the HPLC purity was 98.2%.

[0048] Preparation of Intermediate 1 in Example 2

[0049] 2,5-Dihydroxybenzyl alcohol (14.0 g, 0.1 mol) was dissolved in 1 L of chloroform under nitrogen protection. Diisopropylethylamine (90.9 mL, 0.55 mol) and chloromethyl methyl ether (26.6 mL, 0.35 mol) were added, and the mixture was stirred at 48 °C for 16 h. After the reaction was completed, the mixture was cooled and poured into 1.4 L of 5% sodium bicarbonate solution. The mixture was stirred for about 10 min, and the aqueous phase was extracted with chloroform (3 × 500 mL). The organic phases were collected and combined, and washed successively with 1 L of water and 1 L of saturated brine. The organic phases were then dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a brown oily substance. 40 mL of petroleum ether was added and the mixture was stirred for about 30 min. The mixture was filtered and dried under reduced pressure to obtain a white solid, which was intermediate 1. The molar yield was 95.5%, and the HPLC purity was 97.3%.

[0050] Preparation of Intermediate 1 in Example 3

[0051] 2,5-Dihydroxybenzyl alcohol (14.0 g, 0.1 mol) was dissolved in 1 L of acetonitrile under nitrogen protection. Diisopropylethylamine (49.6 mL, 0.3 mol) and chloromethyl methyl ether (30.4 mL, 0.4 mol) were added, and the mixture was stirred at 60 °C for 15 h. After the reaction was completed, the mixture was cooled and poured into 1.4 L of 5% sodium bicarbonate solution. The mixture was stirred for about 10 min, and the aqueous phase was extracted with chloroform (3 × 500 mL). The organic phases were collected and combined, and washed successively with 1 L of water and 1 L of saturated brine. The organic phases were then dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a brown oily substance. 40 mL of petroleum ether was added and the mixture was stirred for about 30 min. The mixture was filtered and dried under reduced pressure to obtain a white solid, which was intermediate 1. The molar yield was 86.4%, and the HPLC purity was 94.6%.

[0052] Preparation of Intermediate 1 in Example 4

[0053] 2,5-Dihydroxybenzyl alcohol (14.0 g, 0.1 mol) was dissolved in 1 LDMF under nitrogen protection. Diisopropylethylamine (99.2 mL, 0.6 mol) and chloromethyl methyl ether (15.2 mL, 0.2 mol) were added, and the mixture was stirred at 80 °C for 20 h. After the reaction was completed, the mixture was cooled and poured into 1.4 L of 5% sodium bicarbonate solution. The mixture was stirred for about 10 min, and the aqueous phase was separated. The aqueous phase was extracted with dichloromethane (3 × 500 mL). The organic phases were collected and combined, and washed successively with 1.5 L of water and 1.5 L of saturated brine. The organic phases were then dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a brown oily substance. 80 mL of petroleum ether was added and the mixture was stirred for about 30 min. The mixture was filtered and dried under reduced pressure to obtain a white solid, which was intermediate 1. The molar yield was 82.5%, and the HPLC purity was 95.3%.

[0054] Preparation of Intermediate 2 in Example 5

[0055] Intermediate 1 (18.0 g, 78.9 mmol, HPLC purity 98.2%) was placed in a 500 mL reaction flask, and 270 mL of tetrahydrofuran solution containing N,N'-dicyclohexyl-N-methylcarbodiimide iodide (54.7 g, 158 mol) was added. The mixture was stirred for 3 h at 30 °C under nitrogen protection in the dark. The solvent was removed by vacuum distillation, and the residue was dissolved in 200 mL of n-hexane. The residue was washed three times with water (100 mL × 3). The aqueous phase was extracted with 150 mL of n-hexane, and the organic phase was collected and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under vacuum. Intermediate 2 was recrystallized from a mixed solvent of dichloromethane and n-hexane with a molar yield of 96.0% and an HPLC purity of 98.4%.

[0056] Preparation of Intermediate 2 in Example 6

[0057] Intermediate 1 (15.0 g, 65.7 mmol, HPLC purity 98.2%) was placed in a 500 mL reaction flask, and 200 mL of n-hexane solution containing N,N'-dicyclohexyl-N-methylcarbodiimide iodide (34.1 g, 98.55 mmol) was added. The mixture was stirred for 3 h at 40 °C under nitrogen protection in the dark. The solvent was removed by vacuum distillation, and the residue was dissolved in 150 mL of n-hexane and washed three times with water (80 mL × 3). The aqueous phase was extracted with 100 mL of n-hexane, and the organic phase was collected and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under vacuum. Intermediate 2 was recrystallized from a mixed solvent of dichloromethane and n-hexane with a molar yield of 94.3% and an HPLC purity of 97.8%.

[0058] Preparation of Intermediate 2 in Example 7

[0059] Intermediate 1 (15.0 g, 65.7 mmol, HPLC purity 98.2%) was placed in a 500 mL reaction flask, and 300 mL of toluene solution containing N,N'-dicyclohexyl-N-methylcarbodiimide iodide (68.2 g, 197.1 mmol) was added. The mixture was stirred for 3 h at 25 °C under nitrogen protection in the dark. The solvent was removed by vacuum distillation, and the residue was dissolved in 240 mL of n-hexane. The residue was washed three times with water (120 mL × 3). The aqueous phase was extracted with 200 mL of n-hexane, and the organic phase was collected and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under vacuum. The filtrate was recrystallized from a mixed solvent of dichloromethane and n-hexane to give intermediate 2 with a molar yield of 93.1% and an HPLC purity of 96.4%.

[0060] Preparation of Intermediate 2 in Example 8

[0061] Intermediate 1 (15.0 g, 65.7 mmol, HPLC purity 98.2%) was placed in a 500 mL reaction flask, and 200 mL of acetonitrile solution containing N,N'-dicyclohexyl-N-methylcarbodiimide iodide (22.7 g, 65.7 mmol) was added. The mixture was stirred at 55 °C under nitrogen protection for 3 h in the dark. The solvent was removed by vacuum distillation, and the residue was dissolved in 150 mL of n-hexane. The residue was washed three times with water (80 mL × 3), and the aqueous phase was extracted with 100 mL of n-hexane. The organic phase was collected and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under vacuum. The filtrate was recrystallized from a mixed solvent of dichloromethane and n-hexane to give intermediate 2, with a molar yield of 83.6% and an HPLC purity of 94.7%.

[0062] Preparation of Intermediate 3 in Example 9

[0063] Acid 11 (5.0 g, 24.7 mmol) was dissolved in 200 mL of n-hexane. Under nitrogen protection at -78 °C, 130 mL of tetrahydrofuran solution containing bis(trimethylsilylaminolithium) (8.27 g, 49.4 mmol) was slowly added dropwise. After 20 min, 50 mL of n-hexane solution containing intermediate 2 (12.5 g, 37.0 mmol, HPLC purity 98.4%) was added. The mixture was stirred at -78 to -50℃ for 1 hour, then heated to -30℃ and stirred for 20 hours. After the reaction was complete, the reaction solution was poured into 300 mL of 1 mol / L hydrochloric acid and extracted three times with 150 mL × 3 diethyl ether. The organic phase was collected, dried over MgSO4, and the solvent was removed under reduced pressure. The residue was dissolved in 250 mL of dichloromethane and washed three times with 125 mL × 3 saturated sodium bicarbonate solution. The aqueous phase was extracted three times with 150 mL × 3 diethyl ether. The organic phases were collected and combined, dried over MgSO4, and concentrated under reduced pressure to obtain an off-white solid, which was intermediate 3. The molar yield was 89.2%, and the HPLC purity was 96.4%.

[0064] Preparation of Intermediate 3 in Example 10

[0065] Acid 11 (10.0 g, 49.4 mmol) was dissolved in 400 mL of tetrahydrofuran. Under nitrogen protection at -78 °C, 200 mL of tetrahydrofuran solution containing bis(trimethylsilylaminolithium) (29.9 g, 148 mmol) was slowly added dropwise. After 20 min, 83 mL of tetrahydrofuran solution containing intermediate 2 (41.6 g, 123 mmol, HPLC purity 98.4%) was added. The mixture was stirred at -78 to -50°C for 3 hours, then heated to -20°C and stirred for 15 hours. After the reaction was complete, the reaction solution was poured into 600 mL of 1 mol / L hydrochloric acid and extracted three times with 300 mL × 3 diethyl ether. The organic phase was collected and dried over MgSO4. The solvent was removed under reduced pressure. The residue was dissolved in 500 mL of dichloromethane and washed three times with 250 mL × 3 saturated sodium bicarbonate solution. The aqueous phase was extracted three times with 300 mL × 3 diethyl ether. The combined organic phases were collected, dried over MgSO4, and concentrated under reduced pressure to obtain an off-white solid, which was intermediate 3. The molar yield was 91.3%, and the HPLC purity was 97.2%.

[0066] Preparation of intermediate 3 in Example 11

[0067] Dissolve acid 11 (5.0 g, 24.7 mmol) in 200 mL of cyclohexane. Under nitrogen protection at -78 °C, slowly add 200 mL of tetrahydrofuran solution containing bis(trimethylsilylamine)lithium (16.54 g, 98.8 mmol). After 20 min, add 50 mL of cyclohexane solution containing intermediate 2 (8.4 g, 24.7 mmol, HPLC purity 98.4%). The mixture was stirred at -78 to -50°C for 2 hours, then heated to -25°C and stirred for 22 hours. After the reaction was complete, the reaction solution was poured into 400 mL of 1 mol / L hydrochloric acid and extracted three times with 200 mL × 3 diethyl ether. 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 three times with 180 mL × 3 saturated sodium bicarbonate solution. The aqueous phase was extracted three times with 200 mL × 3 diethyl ether. The combined organic phases were collected, dried over MgSO4, and concentrated under reduced pressure to obtain an off-white solid, which was intermediate 3. The molar yield was 80.2%, and the HPLC purity was 93.5%.

[0068] Preparation of intermediate 3 in Example 12

[0069] Dissolve acid 11 (5.0 g, 24.7 mmol) in 200 mL of n-heptane. Under nitrogen protection at -78 °C, slowly add 200 mL of tetrahydrofuran solution containing bis(trimethylsilylaminolithium) (8.27 g, 49.4 mmol). After 20 min, add 100 mL of n-heptane solution containing intermediate 2 (25.0 g, 74.1 mmol, HPLC purity 98.4%). The mixture was stirred at -78 to -50°C for 2 hours, then heated to -25°C and stirred for 22 hours. After the reaction was complete, the reaction solution was poured into 400 mL of 1 mol / L hydrochloric acid and extracted three times with 200 mL × 3 diethyl ether. 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 three times with 180 mL × 3 saturated sodium bicarbonate solution. The aqueous phase was extracted three times with 200 mL × 3 diethyl ether. The combined organic phases were collected, dried over MgSO4, and concentrated under reduced pressure to obtain an off-white solid, which was intermediate 3. The molar yield was 87.6%, and the HPLC purity was 94.8%.

[0070] Preparation of intermediate 3 in Example 13

[0071] Dissolve acid 11 (10.0 g, 49.4 mmol) in 400 mL of diethyl ether. Under nitrogen protection at -78 °C, slowly add 200 mL of tetrahydrofuran solution containing bis(trimethylsilylaminolithium) (29.9 g, 148 mmol). After 20 min, add 83 mL of diethyl ether solution containing intermediate 2 (41.6 g, 123 mmol, HPLC purity 98.4%). The mixture was stirred at -78 to -50°C for 3 hours, then heated to -20°C and stirred for 15 hours. After the reaction was complete, the reaction solution was poured into 600 mL of 1 mol / L hydrochloric acid and extracted three times with 300 mL × 3 diethyl ether. The organic phase was collected and dried over MgSO4. The solvent was removed under reduced pressure. The residue was dissolved in 500 mL of dichloromethane and washed three times with 250 mL × 3 saturated sodium bicarbonate solution. The aqueous phase was extracted three times with 300 mL × 3 diethyl ether. The combined organic phases were collected, dried over MgSO4, and concentrated under reduced pressure to obtain an off-white solid, which was intermediate 3. The molar yield was 88.5%, and the HPLC purity was 95.2%.

[0072] Preparation of intermediate 4 in Example 14

[0073] 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 of thionyl chloride (0.164 mol) was added, and the mixture was heated to reflux for 12 h. After cooling to room temperature, 27.0 mL of tin tetrachloride (0.146 mol) was added, and the mixture was stirred at 20 °C for another 1 h. Once the reaction was complete, the temperature was lowered to 0 °C, and 225 g of crushed ice was added. The aqueous phase was collected separately and stored at 0 °C. The sample was extracted three times with 120 mL of dichloromethane each time. The organic phases were collected and combined, and washed with 400 mL of saturated NaHCO3 solution and 400 mL of saturated sodium chloride solution, respectively. The organic phases were dried over anhydrous MgSO4 and concentrated under reduced pressure to obtain crude intermediate 4 with a molar yield of 96.4% and an HPLC purity of 87.1%. 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 88.3% and an HPLC purity of 99.3%. mp: 158℃, [α]20D=+48.4 (c=0.48, CHCl3)).

[0074] Preparation of Intermediate 4 in Example 15

[0075] Intermediate 3 (15.0 g, 36.4 mmol, HPLC purity 97.2%) was placed in a reaction flask, and 225 mL of chloroform was added at room temperature. Under nitrogen protection, 12.6 mL of thionyl chloride (0.173 mol) was added, and the mixture was heated to reflux for 12 h. After cooling to room temperature, 25.5 mL of tin tetrachloride (0.218 mol) was added, and the mixture was stirred at 20 °C for another 1 h. Once 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 and stored at 0 °C. Extracted three times with 120 mL × 3 dichloromethane, the organic phases were collected and combined, and washed with 400 mL saturated NaHCO3 solution and 400 mL saturated sodium chloride solution, respectively. The organic phases were dried over anhydrous MgSO4 and concentrated under reduced pressure to obtain crude intermediate 4 with a molar yield of 95.0% and an HPLC purity of 86.4%. 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 84.0% and an HPLC purity of 98.9%. mp: 157℃, [α]20D=+48.5 (c=0.48, CHCl3)).

[0076] Preparation of Intermediate 4 in Example 16

[0077] Intermediate 3 (15.0 g, 36.4 mmol, HPLC purity 97.2%) was placed in a reaction flask, and 225 mL of toluene was added at room temperature. Under nitrogen protection, 8.0 mL of thionyl chloride (0.109 mol) was added, and the mixture was heated to reflux for 12 h. After cooling to room temperature, 25.5 mL of tin tetrachloride (0.218 mol) was added, and the mixture was stirred at 20 °C for another 1 h. Once 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 and stored at 0 °C. Extracted three times with 120 mL × 3 dichloromethane, the organic phases were collected and combined, and washed with 400 mL saturated NaHCO3 solution and 400 mL saturated sodium chloride solution, respectively. The organic phase was dried over anhydrous MgSO4 and concentrated under reduced pressure to obtain crude intermediate 4 with a molar yield of 90.1% and an HPLC purity of 85.7%. 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 80.4% and an HPLC purity of 98.0%. mp: 156 °C, [α]20D = +48.4 (c = 0.48, CHCl3)).

[0078] Preparation of Intermediate 4 in Example 17

[0079] 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)).

[0080] Preparation of Intermediate 5 in Example 18

[0081] 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%.

[0082] Preparation of Intermediate 5 in Example 19

[0083] 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) (0.55 g, 5%) 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. The mixture was separated, and the organic phase was washed successively with 250 mL of water and 250 mL of saturated sodium chloride solution. The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The solution was then recrystallized from a 2:3 mixture of tetrahydrofuran and diethyl ether to give intermediate 5, with a molar yield of 92.7% and an HPLC purity of 97.2%.

[0084] Preparation of Intermediate 6 in Example 20

[0085] Intermediate 5 (9.51 g, 24 mmol, HPLC purity 98.8%) was dissolved in 500 mL of tetrahydrofuran. Under nitrogen protection, the solution was cooled to 0 °C. 0.1 mol of sodium dimethyl sulfoxide was dissolved in 50 mL of a mixed solution of dimethyl sulfoxide and tetrahydrofuran and added dropwise to the reaction flask. The reaction was stirred at room temperature for 30 min until complete. 1.25 L of dichloromethane and 2.0 L of saturated ammonium chloride solution were added and stirred for 5 min. The mixture was allowed to stand and separated. The aqueous phase was washed twice with 1.25 L × 2 dichloromethane. The combined organic phases were washed with 1.0 L of water and dried with anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 6 with a molar yield of 98.0% and an HPLC purity of 96.7%.

[0086] Preparation of intermediate 6 in Example 21

[0087] Intermediate 5 (9.51 g, 24 mmol, HPLC purity 98.8%) was dissolved in 500 mL of tetrahydrofuran. Under nitrogen protection, the solution was cooled to 0 °C. 0.12 mol of sodium dimethyl sulfoxide was dissolved in 50 mL of a mixed solution of dimethyl sulfoxide and tetrahydrofuran and added dropwise to the reaction flask. The reaction was stirred at room temperature for 30 min until complete. 1250 mL of chloroform and 2.0 L of saturated ammonium chloride solution were added and stirred for 5 min. The mixture was allowed to stand and separated. The aqueous phase was washed twice with 1.25 L × 2 chloroform. The combined organic phases were 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%.

[0088] Preparation of intermediate 6 in Example 22

[0089] Intermediate 5 (9.51 g, 24 mmol, HPLC purity 98.8%) was dissolved in 500 mL of tetrahydrofuran. Under nitrogen protection, the solution was cooled to 0 °C. 0.072 mol of sodium dimethyl sulfoxide was dissolved in 50 mL of a mixed solution of dimethyl sulfoxide and tetrahydrofuran and added dropwise to the reaction flask. The mixture was stirred at room temperature for 30 min until the reaction was complete. 1250 mL of ethyl acetate and 2.0 L of saturated ammonium chloride solution were added and stirred for 5 min. The mixture was allowed to stand and separated. The aqueous phase was washed twice with 1.25 L × 2 ethyl acetate. The combined organic phases were washed with 1.0 L of water and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to give intermediate 6, with a molar yield of 91.9% and an HPLC purity of 95.6%.

[0090] Preparation of intermediate 7 in Example 23

[0091] 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 (11.9 g, 0.43 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. A mixture of 200 mL diethyl ether and 50 mL water was added to the concentrate, and 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 concentrate 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 91.6% and an HPLC purity of 99.6%. [α]20D = +8.0 (c = 1.78, chloroform)

[0092] Preparation of intermediate 7 in Example 24

[0093] 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 (10.0 g, 0.36 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. A mixture of 200 mL diethyl ether and 50 mL water was added to the concentrate, and 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 concentrate was then recrystallized from a mixture of dichloromethane and diethyl ether in a volume ratio of 1:1.8 to obtain intermediate 7, with a molar yield of 86.4% and an HPLC purity of 99.0%. [α]20D = +8.0 (c = 1.78, chloroform)

[0094] Preparation of intermediate 7 in Example 25

[0095] 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 (16.0 g, 0.58 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. A mixture of 200 mL diethyl ether and 50 mL water was added to the concentrate, and 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 concentrate was then recrystallized from a mixture of chloroform and diethyl ether in a volume ratio of 1:2.3 to obtain intermediate 7, with a molar yield of 89.5% and an HPLC purity of 99.2%. [α]20D = +8.1 (c = 1.78, chloroform)

[0096] Preparation of intermediate 8 in Example 26

[0097] 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 (6.00 mL, 47.3 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 reaction 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 organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain intermediate 8. The molar yield was 98.7%, and the HPLC purity was 98.4%.

[0098] Preparation of Intermediate 8 in Example 27

[0099] 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 (8.1 mL, 64.5 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 reaction 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 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 96.5% and an HPLC purity of 98.2%.

[0100] Preparation of Intermediate 9 in Example 28

[0101] Add a dichloromethane solution of intermediate 8 (10.1 g, 21.5 mmol, HPLC purity 98.4%) to a reaction flask, add aluminum trichloride (8.6 g, 64.5 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, allow to stand and separate the liquid, separate the organic phase, extract the aqueous phase with 40 mL of dichloromethane, collect the organic phase, wash the organic phase with 100 mL of saturated sodium bicarbonate solution, dry with anhydrous sodium sulfate, concentrate under reduced pressure, recrystallize the concentrate with a 1:4 volume ratio of dichloromethane and isopropyl ether, and then recrystallize with a 1:5 volume ratio of ethanol and diethyl ether to obtain intermediate 9. The molar yield was 93.9%, and the HPLC purity was 99.7%.

[0102] Preparation of intermediate 9 in Example 29

[0103] Add a dichloromethane solution of intermediate 8 (10.1 g, 21.5 mmol, HPLC purity 98.4%) to the reaction flask, add aluminum trichloride (17.2 g, 129 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, allow to stand and separate the liquid, separate the organic phase, extract the aqueous phase with 40 mL of dichloromethane, collect the organic phase, wash the organic phase with 100 mL of saturated sodium bicarbonate solution, dry with anhydrous sodium sulfate, concentrate under reduced pressure, recrystallize the concentrate with a 1:4 volume ratio of dichloromethane and isopropyl ether, and then recrystallize with a 1:5 volume ratio of ethanol and diethyl ether to obtain intermediate 9. The molar yield was 93.4%, and the HPLC purity was 99.5%.

[0104] Example 30 Preparation of daunorubicin

[0105] Intermediate 9 (9.3 g, 19.1 mmol, HPLC purity 99.7%) was dissolved in 120 mL of dichloromethane. Under nitrogen protection, the solution was cooled to 2-8 °C, and 20 mL of a dichloromethane solution containing dimethylboron bromide (4.6 g, 38.2 mmol) was added dropwise. The mixture was kept at 2-8 °C and stirred for 2 h. The reaction solution was then poured into a mixture of 80 mL of saturated sodium bicarbonate solution and 120 mL of tetrahydrofuran solution and stirred for 15 min. The mixture was separated, and the aqueous phase was extracted three times with 80 mL × 3 dichloromethane. The organic phases were collected and combined, washed with 160 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain daunorubicin with a molar yield of 98.2% and an HPLC purity of 99.5%.

[0106] Preparation of intermediate 1 in Comparative Example 1

[0107] 2,5-Dihydroxybenzyl alcohol (14.0 g, 0.1 mol) was dissolved in 1.4 L of n-heptane under nitrogen protection. Diisopropylethylamine (62.8 mL, 0.38 mol) and chloromethyl methyl ether (21.3 mL, 0.28 mol) were added, and the mixture was stirred and refluxed for 22 h. After the reaction was completed, the mixture was cooled and poured into 1.4 L of 5% sodium bicarbonate solution. The mixture was stirred for about 10 min, and the aqueous phase was separated. The aqueous phase was extracted with dichloromethane (3 × 500 mL), and the organic phases were collected and combined. The organic phases were washed successively with 1.4 L of water and 1.4 L of saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a brown oily substance. 70 mL of petroleum ether was added and the mixture was stirred for about 30 min. The mixture was filtered and dried under reduced pressure to obtain a white solid, which was intermediate 1. The molar yield was 68.5%, and the HPLC purity was 92.3%.

[0108] Preparation of intermediate 1 in Comparative Example 2

[0109] 2,5-Dihydroxybenzyl alcohol (14.0 g, 0.1 mol) was dissolved in 1.4 L of dichloromethane under nitrogen protection. Diisopropylethylamine (33.0 mL, 0.2 mol) and chloromethyl methyl ether (38.0 mL, 0.5 mol) were added, and the mixture was stirred and refluxed for 22 h. After the reaction was completed, the mixture was cooled and poured into 1.4 L of 5% sodium bicarbonate solution. The mixture was stirred for about 10 min, and the aqueous phase was separated. The aqueous phase was extracted with dichloromethane (3 × 500 mL), and the organic phases were collected and combined. The organic phases were washed successively with 1.4 L of water and 1.4 L of saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a brown oily substance. 70 mL of petroleum ether was added and the mixture was stirred for about 30 min. The mixture was filtered and dried under reduced pressure to obtain a white solid, which was intermediate 1. The molar yield was 55.2%, and the HPLC purity was 93.8%.

[0110] Preparation of intermediate 2 in Comparative Example 3

[0111] Intermediate 1 (18.0 g, 78.9 mmol, HPLC purity 98.2%) was placed in a 1000 mL reaction flask, and 500 mL of tetrahydrofuran solution containing N,N'-dicyclohexyl-N-methylcarbodiimide iodide (137 g, 394.5 mol) was added. The mixture was stirred for 3 h at 30 °C under nitrogen protection, protected from light. The solvent was removed by vacuum distillation, and the residue was dissolved in 200 mL of n-hexane. The residue was washed three times with water (100 mL × 3). The aqueous phase was extracted with 150 mL of n-hexane, and the organic phase was collected and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure. Intermediate 2 was recrystallized from a 1:3 (v / v) mixture of dichloromethane and n-hexane to obtain the intermediate, with a molar yield of 90.6%.

[0112] HPLC purity: 78.5%.

[0113] Preparation of intermediate 3 in Comparative Example 4

[0114] Dissolve acid 11 (5.0 g, 24.7 mmol) in 200 mL of n-hexane. Under nitrogen protection at -78 °C, slowly add 200 mL of tetrahydrofuran solution containing bis(trimethylsilylaminolithium) (20.60 g, 123 mmol). After 20 min, add 50 mL of tetrahydrofuran solution containing intermediate 2 (33.3 g, 98.4 mmol, HPLC purity 98.4%). The mixture was stirred at -78 to -50°C for 1 hour, then heated to -30°C and stirred for 20 hours. After the reaction was complete, the reaction solution was poured into 300 mL of 1 mol / L hydrochloric acid and extracted three times with 150 mL × 3 diethyl ether. The organic phase was collected and dried over MgSO4. The solvent was removed under reduced pressure. The residue was dissolved in 250 mL of dichloromethane and washed three times with 125 mL × 3 saturated sodium bicarbonate solution. The aqueous phase was extracted three times with 150 mL × 3 diethyl ether. The combined organic phases were collected, dried over MgSO4, and concentrated under reduced pressure to obtain an off-white solid, which was intermediate 3. The molar yield was 75.1%, and the HPLC purity was 81.8%.

[0115] Preparation of intermediate 4 in Comparative Example 5

[0116] 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, 5.0 mL of thionyl chloride (72.8 mmol) was added, and the mixture was heated to reflux for 12 h. After cooling to room temperature, 13.5 mL of tin tetrachloride (72.8 mmol) was added, and the mixture was stirred at 20 °C for another 1 h. Once the reaction was complete, the temperature was lowered to 0 °C, and 225 g of crushed ice was added. The aqueous phase was collected separately and stored at 0 °C. The sample was extracted three times with 120 mL of dichloromethane each time. The organic phases were collected and combined. The organic phases were washed successively with 400 mL of saturated NaHCO3 solution and 400 mL of saturated sodium chloride solution, dried over anhydrous MgSO4, and concentrated under reduced pressure to obtain crude intermediate 4 with a molar yield of 78.3% and an HPLC purity of 76.8%. 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 60.9% and an HPLC purity of 90.7%. mp: 157℃, [α]20D=+48.1 (c=0.48, CHCl3)).

[0117] Preparation of intermediate 4 in Comparative Example 6

[0118] 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, 25.0 mL of thionyl chloride (364 mmol) was added, and the mixture was heated to reflux for 12 h. After cooling to room temperature, 13.5 mL of tin tetrachloride (72.8 mmol) was added, and the mixture was stirred at 20 °C for another 1 h. Once the reaction was complete, the temperature was lowered to 0 °C, and 225 g of crushed ice was added. The aqueous phase was collected separately and stored at 0 °C. The sample was extracted three times with 120 mL of dichloromethane each time. The organic phases were collected and combined. The organic phases were washed successively with 400 mL of saturated NaHCO3 solution and 400 mL of saturated sodium chloride solution, dried over anhydrous MgSO4, and concentrated under reduced pressure to obtain crude intermediate 4 with a molar yield of 79.6% and an HPLC purity of 62.7%. 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 50.7% and an HPLC purity of 82.3%. mp: 156℃, [α]20D=+48.4 (c=0.48, CHCl3)).

[0119] Preparation of intermediate 5 in Comparative Example 7

[0120] Under nitrogen protection, 80 mL of tetrahydrofuran was added to the reaction flask, and stirring was started. N,N-Diethylaniline borane (2.5 mL, 13.9 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, keeping it below 25 °C. 32 mL of methanol was slowly added dropwise, and the mixture was stirred 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. The mixture was stirred for 15 min, then 160 mL of water was added. The mixture was allowed to stand and separated. The organic phase was washed with 250 mL of water and 250 mL of saturated sodium chloride solution. The solution was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness under reduced pressure. The solution was recrystallized from a 2:3 volume ratio of tetrahydrofuran and diethyl ether to give intermediate 5, with a molar yield of 90.1% and an HPLC purity of 56.3%.

[0121] Preparation of intermediate 6 in Comparative Example 8

[0122] Intermediate 5 (9.51 g, 24 mmol, HPLC purity 98.8%) was dissolved in 500 mL of tetrahydrofuran. Under nitrogen protection, the solution was cooled to 0 °C. 0.05 mol of sodium dimethyl sulfoxide was dissolved in 50 mL of a mixed solution of dimethyl sulfoxide and tetrahydrofuran and added dropwise to the reaction flask. The reaction was stirred at room temperature for 30 min until complete. 1250 mL of dichloromethane and 2.0 L of saturated ammonium chloride solution were added and stirred for 5 min. The mixture was allowed to stand and separated. The aqueous phase was washed twice with 1.25 L × 2 dichloromethane. The combined organic phases were washed with 1.0 L of water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give intermediate 6, with a molar yield of 76.6% and an HPLC purity of 89.7%.

[0123] Preparation of intermediate 7 in Comparative Example 9

[0124] 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)

[0125] Preparation of intermediate 8 in Comparative Example 10

[0126] 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%.

[0127] Preparation of intermediate 9 in Comparative Example 11

[0128] 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%.

[0129] Preparation of daunorubicin in Comparative Example 12

[0130] Intermediate 9 (9.3 g, 19.1 mmol, HPLC purity 99.7%) was dissolved in 120 mL of dichloromethane. Under nitrogen protection, the solution was cooled to 2-8 °C, and 20 mL of a dichloromethane solution containing dimethylboron bromide (11.5 g, 95.5 mmol) was added dropwise. The mixture was kept at 2-8 °C and stirred for 2 h. The reaction solution was then poured into a mixture of 80 mL of saturated sodium bicarbonate solution and 120 mL of tetrahydrofuran solution and stirred for 15 min. The mixture was separated, and the aqueous phase was extracted three times with 80 mL × 3 dichloromethane. The organic phases were collected and combined, washed with 160 mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain daunorubicin with a molar yield of 92.5% and an HPLC purity of 84.2%.

[0131] Comparative Example 13

[0132]

[0133] Compound I (8.1 g, 24 mmol) was dissolved in 500 mL of tetrahydrofuran. Under nitrogen protection, the solution was cooled to 0 °C. 0.1 mol of sodium dimethyl sulfoxide was dissolved in 50 mL of a mixed solution of dimethyl sulfoxide and tetrahydrofuran and added dropwise to the reaction flask. The mixture was stirred at room temperature for 30 min until the reaction was complete. 1250 mL of dichloromethane and 2.0 L of saturated ammonium chloride solution were added and stirred for 5 min. The mixture was allowed to stand and separated. The aqueous phase was washed twice with 1.25 L × 2 dichloromethane. The combined organic phases were washed with 1.0 L of water and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to obtain compound II with a molar yield of 64.2% and an HPLC purity of 79.4%.

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

[0135] 1 H NMR (400MHz, CDCl3): δ=6.71~6.74(m,3H,ArH); 6.06(s,2H,OCH2O); 6.05(s,2H,O CH2O); 3.27(s,3H,OCH3); 3.26(s,3H,OCH3); 4.84(s,2H,CH2OH); 2.87(s,1H,OH)

[0136] ESI-MS (M / Z) = 251[M+Na] +

[0137] Intermediate 2 was analyzed by 1H-NMR and MS mass spectrometry:

[0138] 1 H NMR (400MHz, CDCl3): δ=6.68~6.71(m,2H,ArH); 6.64(s,1H,ArH); 6.05(s,2H,OCH) 2O); 6.04(s,2H,OCH2O); 3.26(s,3H,OCH3); 3.25(s,3H,OCH3); 4.35(s,2H,CH2I);

[0139] ESI-MS(M / Z) = 361[M+Na] +

[0140] Intermediate 3 was analyzed by 1H-NMR and MS mass spectrometry:

[0141] 1 H 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).

[0142] ESI-MS (M / Z) = 435[M+Na] + .

[0143] Intermediate 4 was analyzed by 1H-NMR and MS mass spectrometry:

[0144] 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).

[0145] ESI-MS (M / Z) = 417[M+Na] + .

[0146] Intermediate 5 was analyzed by 1H-NMR and MS mass spectrometry:

[0147] 1 H NMR (400MHz, CDCl3): δ = 7.73 (s, 2H, ArH); 6.05 (s, 2H, OCH2O); 6.03 (s, 2H, OCH2O); 5.30 (s, 1H); 5.21~5.25 (m, 1H,); 3.28 (s, 3H, OCH3); 3.26 (s, 3H, OCH3); 3.25 (dd, J = 18.0Hz, 2.0Hz, 1H); 3.23 (d, J = 9.0Hz, 1H, OH); 2.81 (d, J = 18.0Hz, 1H); 2.43 (m, 1H); 2.32 (m, 1H); 0.98 (s, 9H, tBu).

[0148] ESI-MS (M / Z) = 419[M+Na] + .

[0149] Intermediate 6 was analyzed by 1H-NMR and MS mass spectrometry:

[0150] 1H NMR (300MHz, DMSO-d6) δ = 6.78 (d, J = 8.6Hz, 1H, Ar-H); 6.77 (d, J = 8.8Hz, 1H, Ar-H); 6.15 (s, 2H, OCH2O); 6.14 (s, 2H, OCH2O); 5.11~5.1 8(m,1H,1-H);3.87(S,1H,COCH2SO);3.85(S,1H,3-OH);3.78(d,J=3.6Hz,1H,1-OH);3.36(s,3H,OCH3);3.34(s,3H,OCH3);3.16(dd,J gem =17.7Hz, J 2b,4a =2.2Hz, 1H, 4a-H); 2.90 (d, J) gem =17.7Hz,1H,4b-H);2.76(s,3H,SOCH3);2.32~2.38(m,1H,2b-H);2.22(dd,J gem =14.4Hz, J 1a,2a =4.6Hz, 1H, 2a-H).

[0151] ESI-MS(M / Z) = 411[M+Na] + .

[0152] Intermediate 7 was analyzed by 1H-NMR and MS mass spectrometry:

[0153] 1 H NMR (300MHz, DMSO-d6) δ = 6.76 (d, J = 8.6Hz, 1H, Ar-H); 6.75 (d, J = 8.8Hz, 1H, Ar-H); 6.15 (s, 2H, OCH2O); 6.14 (s, 2H, OCH2O) ;5.10~5.17(m,1H,1-H);3.84(S,1H,3-OH);3.78(d,J=3.6Hz,1H,1-OH);3.36(s,3H,OCH3);3.34(s,3H,OCH3);3.14(dd,J gem =17.7Hz, J 2b,4a =2.2Hz, 1H, 4a-H); 2.88 (d, J) gem =17.7Hz,1H,4b-H);2.46(s,3H,COCH3);2.32~2.38(m,1H,2b-H);2.22(dd,J gem =14.4Hz, J 1a,2a =4.6Hz, 1H, 2a-H).

[0154] ESI-MS (M / Z) = 349[M+Na]+ .

[0155] Intermediate 8 was analyzed by 1H-NMR and MS mass spectrometry:

[0156] 1 H NMR (300MHz, DMSO-d6) δ = 6.75 (d, J = 8.6 Hz, 1H, Ar-H), δ = 6.74 (d, J = 8.8 Hz, 1H, Ar-H), 6.13 (s, 2H, OC H2O),6.12(s,2H,OCH2O),5.11~5.18(m,1H,1-H),3.36(s,3H,OCH3),3.34(s,3H,OCH3),3.13(dd,J gem =17.7Hz, J 2b,4a =2.2Hz, 1H, 4a-H), 2.86(d, J) gem =17.7Hz,1H,4b-H),2.44(s,3H,COCH3),2.30~2.36(m,1H,2b-H),2.20(dd,J gem =14.4Hz, J 1a,2a =4.6Hz,1H,2a-H),0.09(s,9H,CH3).

[0157] ESI-MS (M / Z) = 494 [M + Na] + .

[0158] Intermediate 9 was analyzed by 1H-NMR and MS mass spectrometry:

[0159] 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).

[0160] ESI-MS (M / Z) = 509[M+Na]+ .

[0161] daunorubicin was analyzed by 1H-NMR and MS mass spectrometry:

[0162] 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).

[0163] ESI-MS(M / Z) = 421[M+Na] + .

Claims

1. A daunolide intermediate compound, as shown in Formula 5, has the following structural formula: 。 2. A method for preparing the intermediate compound according to claim 1, characterized in that, Includes the following steps: Using 2,5-dihydroxybenzyl alcohol as a starting material, intermediate 1 is generated by protecting the phenolic hydroxyl group with MOM. Intermediate 1 undergoes an iodination reaction to generate intermediate 2, an iodoalkane. Intermediate 2 undergoes an electrophilic substitution reaction with compound 11 of acid 11 to generate intermediate 3. Intermediate 3 forms an acyl chloride, which is then linked to a benzene ring via a Friedel-Crafts acylation reaction to form intermediate 4. The ketone hydroxyl group on the six-membered ring of intermediate 4 is chirally reduced to generate intermediate 5. The synthetic route is as follows: 。 3. The preparation method according to claim 2, characterized in that, 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°C until the reaction is complete. After cooling, the reaction solution is poured into a 5% sodium bicarbonate solution, 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, concentrated under reduced pressure, mixed with petroleum ether, filtered, and dried under reduced pressure to obtain intermediate 1.

4. The preparation method according to claim 2, characterized in that, 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, and the residue is dissolved in n-hexane. The residue is washed with water, and the aqueous phase is extracted with n-hexane. The organic phase is collected and dried with anhydrous sodium sulfate. The residue is filtered, concentrated under vacuum, and the residue is recrystallized with a mixed solvent of dichloromethane and n-hexane to obtain intermediate 2.

5. The preparation method according to claim 2, characterized in that, 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 the 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.

6. The preparation method according to claim 2, characterized in that, 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 over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain crude intermediate 4. Intermediate 4 is then recrystallized from a mixed solution of tetrahydrofuran and n-hexane.

7. The preparation method according to claim 2, characterized in that, 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, 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, water is added to ligate the mixture, the organic phase is washed sequentially with water and saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and the filtrate is concentrated to dryness under reduced pressure. The mixture of tetrahydrofuran and diethyl ether is recrystallized to obtain intermediate 5.

8. Use of the intermediate compound according to claim 1 in the preparation of daunorubicin.

9. The preparation method according to claim 3, characterized in that, In the step of preparing intermediate 1 from 2,5-dihydroxybenzyl alcohol, the organic solvent is one of dichloromethane, chloroform, acetonitrile or DMF; the molar ratio of 2,5-dihydroxybenzyl alcohol, diisopropylethylamine and chloromethyl methyl ether is 1:3~6:2~4.

10. The preparation method according to claim 3, characterized in that, In the step of preparing intermediate 1 from 2,5-dihydroxybenzyl alcohol, the organic solvent is dichloromethane; the molar ratio of 2,5-dihydroxybenzyl alcohol, diisopropylethylamine and chloromethyl methyl ether is 1:3.8:2.

8.

11. The preparation method according to claim 4, characterized in that, In the step of preparing intermediate 2 from intermediate 1, the organic solvent is one of tetrahydrofuran, n-hexane, toluene or acetonitrile; the molar ratio of intermediate 1 to N,N'-dicyclohexyl-N-methylcarbodiimide iodide is 1:1~3; and the reaction temperature is 30~40℃.

12. The preparation method according to claim 4, characterized in that, In the step of preparing intermediate 2 from intermediate 1, the organic solvent is tetrahydrofuran or n-hexane; the molar ratio of intermediate 1 to N,N'-dicyclohexyl-N-methylcarbodiimide iodide is 1:2.

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