A compound of formula (I) or a salt thereof, wherein R1 is selected from the group consisting of:

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 the prior art, the present invention aims to provide a daunorubicin intermediate compound. Daunorubicin can be chemically synthesized using this intermediate compound.

[0009] The technical solution of the present invention is as follows:

[0010] A daunolide intermediate compound has the following structural formula:

[0011]

[0012] The preparation method is as follows: using 2,5-dihydroxybenzyl alcohol as a raw material, intermediate 1 is generated by protecting the phenolic hydroxyl group with MOM. Intermediate 1 undergoes a substitution reaction to generate intermediate 2. Intermediate 2 undergoes an electrophilic substitution reaction with compound 11 to generate intermediate 3. After intermediate 3 forms an acyl chloride, it is linked to a benzene ring through 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. Intermediate 5 undergoes ring-opening under the action of sodium salt of dimethyl sulfoxide, a strong nucleophile, to generate intermediate 6. Intermediate 6 is reduced under the action of a catalyst to obtain intermediate 7.

[0013] Its synthetic route is as follows:

[0014]

[0015] Specifically, the synthesis method mainly includes the following steps:

[0016] (a) 2,5-Dihydroxybenzyl alcohol reacts with chloromethyl methyl ether under the action of an acid-binding agent to generate intermediate 1; the reaction formula is as follows:

[0017]

[0018] The reaction solvent used in this reaction is selected from dichloromethane, chloroform, and DMF, with dichloromethane being the preferred solvent; the acid-binding agent is selected from diisopropylethylamine, triethylamine, and pyridine; the reaction temperature is 35–70°C; and the molar ratio of 2,5-dihydroxybenzyl alcohol, the acid-binding agent, and chloromethyl methyl ether is 1:3–6:2–4, preferably 1:3.8:2.8.

[0019] (b) Intermediate 1 undergoes a substitution reaction with a brominizing or iodinizing agent to generate intermediate 2; the reaction formula is as follows:

[0020]

[0021] The solvent used in this reaction is selected from tetrahydrofuran, n-hexane, toluene, and acetonitrile, preferably tetrahydrofuran or n-hexane; the brominating reagent is selected from hydrogen bromide, phosphorus tribromide, carbon tetrabromide, dibromotriphenylphosphine, or N,N-dicyclohexyl-N-methylcarbodiimide bromide; the iodizing reagent is selected from N,N-dicyclohexyl-N-methylcarbodiimide iodide; the molar ratio of intermediate 1 to the brominating reagent or iodizing reagent is 1:1 to 3, preferably 1:2.

[0022] (c) Intermediate 2 and compound 11 undergo an electrophilic substitution reaction in the presence of an organolithium reagent to generate intermediate 3; the reaction formula is as follows:

[0023]

[0024] The solvent used in this reaction is selected from one of tetrahydrofuran, n-hexane, cyclohexane, n-heptane, or diethyl ether, preferably tetrahydrofuran or n-hexane; the organolithium reagent is selected from n-butyllithium, tert-butyllithium, sec-butyllithium, phenyllithium, diisopropylaminolithium, or bis(trimethylsilylaminolithium), preferably bis(trimethylsilylaminolithium); the reaction temperature is -30 to -20°C; the molar ratio of compound 11, intermediate 2, and organolithium reagent is 1:1 to 3:2 to 4, preferably 1:2 to 2.5:2.5 to 3.5.

[0025] (d) Intermediate 3 reacts with thionyl chloride to form an acyl chloride, which then undergoes a Friedel-Crafts acylation reaction under the action of a Lewis acid to form intermediate 4; the reaction formula is as follows:

[0026]

[0027] The solvent for this reaction is selected from dichloromethane, chloroform, toluene, or 1,2-dichloroethane; preferably dichloromethane; the Lewis acid is selected from aluminum trichloride, tin tetrachloride, ferric trichloride, or boron trifluoride, preferably tin tetrachloride; the molar ratio of intermediate 3, thionyl chloride, and Lewis acid is 1:3 to 6:3 to 6, preferably 1:4.5:4.

[0028] (e) Intermediate 4 undergoes a chiral reduction reaction under the action of a chiral catalyst and a reducing agent to generate intermediate 5, as shown in the following reaction formula:

[0029]

[0030] The chiral catalyst used in this reaction is (R)-2-methyl-CBS oxazolium borane, and the reducing agent is borane, which is selected from 2-methylpyridine borane and N,N-diethylaniline borane. The solvent used in this reaction is selected from tetrahydrofuran, dichloromethane, and chloroform. The molar ratio of intermediate 4 to reducing agent is 1:1, and the mass of (R)-2-methyl-CBS oxazolium borane added is 1 to 5% of the mass of intermediate 4.

[0031] (f) Intermediate 5 undergoes ring-opening reaction with sodium dimethyl sulfoxide (DMSO) as a strong affinity reagent to generate intermediate 6; the reaction formula is as follows:

[0032]

[0033] The reaction solvent used in this reaction is tetrahydrofuran, and the molar ratio of intermediate 5 to sodium salt of dimethyl sulfoxide is 1:3 to 5, preferably 1:4.17. After the reaction is completed, a saturated ammonium chloride solution is added to the reaction system for neutralization, and the system is extracted with an organic solvent, namely dichloromethane, ethyl acetate or chloroform, preferably dichloromethane.

[0034] (g) Intermediate 6 undergoes a reduction reaction under the action of a catalyst to generate intermediate 7, as shown in the following reaction formula:

[0035]

[0036] The catalyst used in this reaction is one of aluminum amalgam, zinc amalgam, or zinc powder, and the reaction solvent is a mixture of tetrahydrofuran and water. The molar ratio of intermediate 6 to catalyst is 1:15-25, preferably 1:18-22. After the reaction is completed, the crude intermediate 7 needs to be recrystallized and purified. The recrystallization solvent is selected from one of the following: a mixture of dichloromethane and isopropyl ether, a mixture of dichloromethane and diethyl ether, or a mixture of chloroform and diethyl ether, preferably a mixture of dichloromethane and isopropyl ether.

[0037] The following details the steps described above:

[0038] Step (a) Preparation of intermediate 1:

[0039]

[0040] Dissolve 2,5-dihydroxybenzyl alcohol in an organic solvent, add chloromethyl methyl ether and an acid-binding agent under nitrogen protection, stir at 35-70°C until the reaction is complete, cool down, pour the reaction solution into a 5% sodium bicarbonate solution, stir, let stand and separate, extract the aqueous phase with dichloromethane or chloroform, collect the organic phase and wash with water and saturated brine in sequence, dry the organic phase with anhydrous sodium carbonate, filter and collect the organic phase and concentrate under reduced pressure, add petroleum ether to make a slurry, filter, and dry under reduced pressure to obtain intermediate 1.

[0041] Preferably, the reaction solvent is selected from dichloromethane, chloroform, and DMF.

[0042] More preferably, the reaction solvent is dichloromethane.

[0043] Preferably, the acid-binding agent is selected from one of diisopropylethylamine, triethylamine, and pyridine.

[0044] Preferably, the reaction temperature is 35–70°C.

[0045] Preferably, the molar ratio of 2,5-dihydroxybenzyl alcohol, acid binder, and chloromethyl methyl ether is 1:3 to 6:2 to 4.

[0046] More preferably, the molar ratio of 2,5-dihydroxybenzyl alcohol, the acid-binding agent, and chloromethyl methyl ether is 1:3.8:2.8.

[0047] Preparation of intermediate 2 in step (b):

[0048] Preparation of iodide intermediate 2:

[0049]

[0050] Intermediate 1 was placed in a reaction flask, and an organic solvent containing N,N'-dicyclohexyl-N-methylcarbodiimide iodide was added. The reaction was carried out at 25–55 °C in the dark. The solvent was removed by vacuum distillation, and the residue was dissolved in n-hexane. The residue was washed with water, and the aqueous phase was extracted with 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 residue was recrystallized from a mixed solvent of dichloromethane and n-hexane to obtain iodide intermediate 2.

[0051] Preferably, the solvent used in this reaction is selected from one of tetrahydrofuran, n-hexane, toluene, and acetonitrile.

[0052] More preferably, the solvent used in this reaction is tetrahydrofuran or n-hexane.

[0053] Preferably, the molar ratio of intermediate 1 to N,N'-dicyclohexyl-N-methylcarbodiimide iodide is 1:1 to 3.

[0054] More preferably, the molar ratio of intermediate 1 to N,N'-dicyclohexyl-N-methylcarbodiimide iodide is 1:2.

[0055] Preparation of bromide intermediate 2:

[0056]

[0057] Intermediate 1 was dissolved in dichloromethane and stirred in an ice-water bath for 10 minutes. Phosphorus tribromide, a bromide reagent, was slowly added dropwise. After the addition was complete, the reaction was continued in an ice-water bath. The reaction solution was diluted with dichloromethane, washed successively with water and saturated saline solution, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain bromide intermediate 2.

[0058] In a preferred embodiment, the brominating agent can be hydrogen bromide, carbon tetrabromide, dibromotriphenylphosphine, or N,N-dicyclohexyl-N-methylcarbodiimide bromide, all of which can yield intermediate 2-bromine.

[0059] Preferably, the molar ratio of intermediate 1 to the brominizing agent is 1:1 to 3, and more preferably 1:2.

[0060] Preparation of intermediate 3 in step (c):

[0061]

[0062] Compound 11 was dissolved in an organic solvent, cooled to -78°C, and slowly added dropwise in a tetrahydrofuran solution of the organolithium reagent bis(trimethylsilylaminolithium) under nitrogen protection. An organic solvent containing intermediate 2 was added, and the mixture was stirred at -78 to -50°C for 1 to 3 hours. The temperature was then raised to -30 to -20°C and stirred for 15 to 22 hours. After the reaction was complete, the reaction solution was poured into hydrochloric acid, extracted with isopropyl ether, and the organic phase was collected. The organic phase was dried with magnesium sulfate, the solvent was removed under reduced pressure, and the solution was dissolved in dichloromethane. The solution was washed with saturated sodium bicarbonate solution, and the aqueous phase was extracted with isopropyl ether. The organic phase was collected, dried with magnesium sulfate, and concentrated under reduced pressure to obtain intermediate 3.

[0063] In another preferred embodiment, the above-mentioned organolithium reagent can also be selected from n-butyllithium, tert-butyllithium, sec-butyllithium, phenyllithium or diisopropylaminolithium to obtain intermediate 3.

[0064] Preferably, the solvent used in this reaction is selected from one of tetrahydrofuran, n-hexane, cyclohexane, n-heptane, or diethyl ether, and more preferably tetrahydrofuran or n-hexane.

[0065] Preferably, the molar ratio of compound 11, intermediate 2 and organolithium reagent is 1:1 to 3:2 to 4.

[0066] More preferably, the molar ratio of compound 11, intermediate 2 and organolithium reagent is 1:2 to 2.5:2.5 to 3.5.

[0067] Preparation of intermediate 4 in step (d):

[0068]

[0069] Intermediate 3 was placed in a reaction flask, and an organic solvent was added at room temperature. Thionyl chloride was added under nitrogen protection, and the mixture was heated to reflux for 12 hours. After cooling to room temperature, tin tetrachloride Lewis acid was added, and the mixture was stirred at 20°C for 1 hour. The temperature was lowered to 0°C, crushed ice was added, and the aqueous phase was collected by separation. The aqueous phase was extracted with dichloromethane, and the organic phase was collected. The organic phase was 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 was then recrystallized from a mixed solution of tetrahydrofuran and n-hexane.

[0070] In a preferred embodiment, the Lewis acid can also be aluminum trichloride, ferric trichloride, or boron trifluoride, which can also yield intermediate 4.

[0071] Preferably, the solvent for this reaction is selected from dichloromethane, chloroform, toluene, or 1,2-dichloroethane; more preferably, it is dichloromethane.

[0072] Preferably, the molar ratio of intermediate 3, thionyl chloride and Lewis acid is 1:3 to 6:3 to 6, and more preferably 1:4.5:4.

[0073] Preparation of intermediate 5 in step (e):

[0074]

[0075] Under nitrogen protection, the reaction solvent, reducing agent N,N-diethylaniline borane, and chiral catalyst (R)-2-methylCBS-oxazolium borane organic solution were added sequentially to the reaction vessel. The temperature was controlled at 15–25°C. The organic solution of intermediate 4 was slowly added, and the reaction was maintained at a constant temperature below 25°C. Methanol was slowly added dropwise, and the mixture was stirred and concentrated under reduced pressure. Dichloromethane was added, and sulfuric acid was added dropwise at 15–25°C. The mixture was stirred, and water was added to liquidate the organic phase. The organic phase was then washed sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The filtrate was recrystallized from a mixed solution of tetrahydrofuran and diethyl ether to obtain intermediate 5.

[0076] In a preferred embodiment, the reducing agent N,N-diethylanilineborane can also be 2-methylpyridineborane.

[0077] Preferably, the solvent used in this reaction is selected from one of tetrahydrofuran, dichloromethane, and chloroform.

[0078] Preferably, the molar ratio of intermediate 4 to reducing agent is 1:1.

[0079] Preferably, the mass of (R)-2-methyl-CBS oxazolborane added is 1 to 5% of the mass of intermediate 4.

[0080] Preparation of intermediate 6 in step (f):

[0081]

[0082] Intermediate 5 was dissolved in tetrahydrofuran solvent. Under nitrogen protection, the mixture was cooled to 0°C. Sodium dimethyl sulfoxide was dissolved in a mixed solution of dimethyl sulfoxide and tetrahydrofuran and added dropwise. The mixture was stirred at room temperature. After the reaction was complete, an extraction solvent and a saturated ammonium chloride solution were added and stirred. The mixture was allowed to stand and separated. The aqueous phase was washed with the extraction solvent, and the organic phase was collected. The organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate 6.

[0083] Preferably, the molar ratio of intermediate 5 to the sodium salt of dimethyl sulfoxide is 1:3 to 5, and more preferably 1:4.17.

[0084] Preferably, after the reaction is completed, an extraction solvent and a saturated ammonium chloride solution are added to the reaction system and stirred. The organic solvent is dichloromethane, ethyl acetate, or chloroform, and more preferably dichloromethane.

[0085] Preparation of intermediate 7 in step (g):

[0086]

[0087] Intermediate 6 was dissolved in a mixed solution of tetrahydrofuran and water. Aluminum amalgam reducing agent was added at room temperature. The mixture was stirred under nitrogen protection, and the solid was filtered off. The filter cake was washed with a small amount of tetrahydrofuran. The filtrate was concentrated under reduced pressure, and an aqueous solution of diethyl ether was added. The mixture was stirred, allowed to stand, and separated. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The crude product was recrystallized to obtain intermediate 7.

[0088] In a preferred embodiment, zinc amalgam or zinc powder can be used as a reducing agent in the above steps to obtain intermediate 7.

[0089] Preferably, the molar ratio of intermediate 6 to reducing agent is 1:15 to 25, and more preferably 1:18 to 22.

[0090] Preferably, after the reaction is complete, the crude intermediate 7 needs to be recrystallized and purified. The recrystallization solvent is selected from one of the following: a mixed solution of dichloromethane and isopropyl ether, a mixed solution of dichloromethane and diethyl ether, or a mixed solution of chloroform and diethyl ether. More preferably, the recrystallization solvent is a mixed solution of dichloromethane and isopropyl ether.

[0091] The use of an intermediate compound 7 in the synthesis of daunorubicin.

[0092] A synthetic method for preparing daunolide using intermediate 7 is disclosed. Intermediate 7 is protected with a hydroxyl group to obtain intermediate 8. Intermediate 8 reacts with compound 12 to form a cyclization, and then the MOM protecting group is removed to obtain daunolide. The synthetic route is as follows:

[0093]

[0094] Specifically, the synthesis of daunorubicin from intermediate 7 includes the following steps:

[0095] (h) Intermediate 7 reacts with a substituent protecting agent to give intermediate 8, as shown in the following reaction formula:

[0096]

[0097] The substituent protecting agent used in this reaction is one of trimethylchlorosilane, tert-butyldimethylchlorosilane, or triisopropylchlorosilane, with the corresponding R being TMS, TBS, and TIPS, respectively. The solvent used in this reaction is dichloromethane, tetrahydrofuran, chloroform, or toluene, preferably dichloromethane. The molar ratio of intermediate 7 to the substituent protecting agent is 1:2 to 3, preferably 1:2.2.

[0098] (i) Intermediate 8 reacts with 3-methoxy-1,2-dibenzoyl chloride under Lewis acid catalysis to form a ring, and then the protecting group is removed under acidic conditions to obtain intermediate 9, as shown in the following reaction formula:

[0099]

[0100] The solvent used in this reaction is dichloromethane or tetrahydrofuran. The Lewis acid is selected from aluminum trichloride, tin tetrachloride, ferric chloride, and boron trifluoride, preferably aluminum trichloride. The reaction temperature is 0–10°C. The molar ratio of intermediate 8 to Lewis acid is 1:3–6, preferably 1:3–4; the molar ratio of intermediate 8 to compound 12 is 1:1; the acid used in the acid hydrolysis process is hydrochloric acid, acetic acid, or dilute sulfuric acid. After the reaction, the crude intermediate 9 needs to be purified by recrystallization. The recrystallization process involves recrystallizing the crude intermediate 9 first with a mixed solution of dichloromethane and isopropyl ether, and then recrystallizing it again with a mixed solution of ethanol and diethyl ether.

[0101] (j) Intermediate 9 reacts in the presence of dimethylboron bromide, and then hydrolyzes in sodium bicarbonate solution to generate compound 10, which is the epirubicin intermediate daunolide. The reaction formula is as follows:

[0102]

[0103] The solvent used in this reaction is dichloromethane, the reaction temperature is 2-8℃, and the molar ratio of intermediate 9 to dimethylboron bromide is 1:2-2.5, preferably 1:2.

[0104] The following section details the preparation of daunorubicin from intermediate compound 7.

[0105] Preparation of intermediate 8 in step (h):

[0106]

[0107] Add intermediate 7 to a three-necked flask and dissolve it in an organic solvent. Under nitrogen protection at 0°C, add triethylamine and trimethylchlorosilane dropwise and stir until the reaction is complete. Then add organic solvent to dilute the reaction solution. Pour the reaction solution into ice water and extract. Wash the organic phase with water and saturated brine in sequence, dry it with anhydrous sodium sulfate, and filter to obtain intermediate 8.

[0108] In another preferred embodiment, intermediate 7 is reacted with tert-butyldimethylchlorosilane or triisopropylchlorosilane in toluene-chloroform or tetrahydrofuran, which can protect the two hydroxyl groups in intermediate 7.

[0109] Preferably, the organic solvent for this reaction is dichloromethane, tetrahydrofuran, chloroform, or toluene, and more preferably dichloromethane.

[0110] Preferably, the molar ratio of intermediate 7 to the substituent protecting agent is 1:2 to 3, more preferably 1:2.2.

[0111] Step (i) Preparation of intermediate 9:

[0112]

[0113] Intermediate 8 was dissolved in an organic solvent, and Lewis acid aluminum trichloride was added in portions. The mixture was cooled to 0°C, and a solution of compound 12 in dichloromethane or tetrahydrofuran was slowly added dropwise. The mixture was stirred at 0°C for 30 min, and then allowed to rise naturally to room temperature and stirred for 6–8 h. The reaction solution was poured into a dilute acid at 0°C, stirred at 0°C for 10 min, and then stirred at room temperature for 0.5–1 h. The mixture was separated, and the aqueous phase was extracted with dichloromethane. The organic phase was collected, washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude intermediate 9. Intermediate 9 was then recrystallized.

[0114] In a preferred embodiment, the Lewis acid may also be ferric chloride, tin tetrachloride, or boron trifluoride.

[0115] Preferably, the organic solvent used in this reaction is dichloromethane or tetrahydrofuran.

[0116] Preferably, the reaction temperature is 0–10°C.

[0117] Preferably, the molar ratio of intermediate 8 to Lewis acid is 1:3 to 6, and more preferably 1:3 to 4.

[0118] Preferably, the molar ratio of intermediate 8 to compound 12 is 1:1.

[0119] Preferably, the acid used in the acid hydrolysis process is hydrochloric acid, acetic acid, or dilute sulfuric acid.

[0120] Preferably, the crude intermediate 9 obtained after the reaction needs to be purified by recrystallization. The recrystallization process involves recrystallizing the crude intermediate 9 first with a mixed solution of dichloromethane and isopropyl ether, and then recrystallizing it again with a mixed solution of ethanol and diethyl ether.

[0121] Preparation of daunorubicin in step (j):

[0122]

[0123] Intermediate 9 was dissolved in dichloromethane. Under nitrogen protection, the mixture was cooled to 2–8 °C, and a dichloromethane solution of dimethylboron bromide was added dropwise. The mixture was stirred at 2–8 °C. After the reaction was completed, the reaction solution was poured into a mixed solution of saturated sodium bicarbonate and tetrahydrofuran. The mixture was stirred, allowed to stand, and separated. The aqueous phase was extracted with dichloromethane, and the organic phase was collected. The organic phase was washed with saturated sodium chloride solution, separated, and collected. The organic phase was dried with anhydrous sodium sulfate and concentrated under reduced pressure to obtain compound 10, epirubicin intermediate daunorubicin.

[0124] Preferably, the molar ratio of intermediate 9 to dimethylboron bromide is 1:2 to 2.5, and more preferably 1:2.

[0125] 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

[0126] 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.

[0127] 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 restrictions on the source of the raw materials.

[0128] 2,5-Dihydroxybenzyl alcohol can be prepared by the following method:

[0129]

[0130] 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.

[0131] N,N'-Dicyclohexyl-N-methylcarbodiimide iodide can be prepared by the method described in R. Scheffold, E. Saladin, Angew. Chem. 84 (1972) 158.

[0132] Compound 11 was prepared by the method described in the literature Liebigs Ann. Chem. 1987, 515-520.

[0133] Compound 12 can be prepared by the following methods:

[0134]

[0135] 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.

[0136] Preparation of Intermediate 1 in Example 1

[0137] 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%.

[0138] Intermediate 1 1 Analysis was performed using H-NMR and MS mass spectrometry.

[0139] 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)

[0140] ESI-MS (M / Z) = 251[M+Na] + .

[0141] Example 2: Preparation of intermediate 2 bromide

[0142] Intermediate 1 (18.0 g, 78.9 mmol, HPLC purity 98.2%) was dissolved in 500 mL of anhydrous dichloromethane and stirred in an ice-water bath for 10 min. Phosphorus tribromide (42.7 g, 157.8 mmol) was slowly added dropwise. After the addition was complete, the reaction mixture was continued in an ice-water bath for 1 h. The reaction solution was diluted with 2000 mL of dichloromethane, washed with water (250 mL × 3), washed with saturated brine (200 mL × 1), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain intermediate 2. The molar yield was 96.8%, and the HPLC purity was 98.1%.

[0143] Intermediate 2 bromide 1 Analysis was performed using H-NMR and MS mass spectrometry.

[0144] 1H NMR (400MHz, CDCl3): δ=6.69~6.72(m,2H,ArH); 6.65(s,1H,ArH); 6.05(s,2H,OCH2 O); 6.04(s,2H,OCH2O); 3.25(s,3H,OCH3); 3.24(s,3H,OCH3); 4.53(s,2H,CH2Br);

[0145] ESI-MS(M / Z) = 314[M+Na] + .

[0146] Example 3: Preparation of intermediate 2 iodide

[0147] 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%.

[0148] Intermediate 2 iodide 1 Analysis was performed using H-NMR and MS mass spectrometry.

[0149] 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);

[0150] ESI-MS(M / Z) = 361[M+Na] + .

[0151] Preparation of intermediate 3 in Example 4

[0152] Compound 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%.

[0153] Intermediate 3 1 Analysis was performed using H-NMR and MS mass spectrometry.

[0154] 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).

[0155] ESI-MS (M / Z) = 435[M+Na] + .

[0156] Preparation of intermediate 4 in Example 5

[0157] 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)).

[0158] Intermediate 4 1 Analysis was performed using H-NMR and MS mass spectrometry.

[0159] 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).

[0160] ESI-MS (M / Z) = 417[M+Na] + .

[0161] Preparation of intermediate 5 in Example 6

[0162] 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%.

[0163] Intermediate 5 1 Analysis was performed using H-NMR and MS mass spectrometry.

[0164] 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).

[0165] ESI-MS (M / Z) = 419[M+Na] + .

[0166] Preparation of Intermediate 6 in Example 7

[0167] 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%.

[0168] Intermediate 6 1 Analysis was performed using H-NMR and MS mass spectrometry.

[0169] 1 H 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).

[0170] ESI-MS(M / Z) = 411[M+Na] + .

[0171] Preparation of intermediate 7 in Example 8

[0172] 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 by evaporation 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).

[0173] Intermediate 7 1 Analysis was performed using H-NMR and MS mass spectrometry.

[0174] 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).

[0175] ESI-MS (M / Z) = 349[M+Na] + .

[0176] Preparation of intermediate 8 in Example 9

[0177] 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%.

[0178] Intermediate 8 1 Analysis was performed using H-NMR and MS mass spectrometry.

[0179] 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).

[0180] ESI-MS (M / Z) = 494 [M + Na] + .

[0181] Preparation of Intermediate 9 in Example 10

[0182] 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%.

[0183] Intermediate 9 1 Analysis was performed using H-NMR and MS mass spectrometry.

[0184] 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).

[0185] ESI-MS (M / Z) = 509[M+Na] + .

[0186] Example 11 Preparation of daunorubicin

[0187] 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%.

[0188] daunoside 1 Analysis was performed using H-NMR and MS mass spectrometry.

[0189] 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).

[0190] ESI-MS(M / Z) = 421[M+Na] + .

Claims

1. A daunolide intermediate compound, the structural formula of which is shown in Formula 7:

2. A method for preparing the compound intermediate 7 as described in claim 1, characterized in that... The process includes the following steps: Intermediate 6 undergoes a reduction reaction in the presence of a catalyst to generate intermediate 7; the reaction formula is as follows:

3. The preparation method according to claim 2, characterized in that, The preparation method of the intermediate 7 compound includes the following steps: in a mixed solution of tetrahydrofuran and water, the intermediate 6 compound is reduced to the intermediate 7 compound under the action of a catalyst.

4. The preparation method according to claim 3, characterized in that, The catalyst is an aluminum amalgam, a zinc amalgam, or zinc powder.

5. The preparation method according to claim 3, characterized in that, The molar ratio of intermediate 6 to catalyst is 1:15 to 25.

6. The preparation method according to claim 2, characterized in that, The preparation method of intermediate 6 includes the following steps: intermediate 5 is ring-opened in the presence of sodium dimethyl sulfoxide, a strong affinity reagent, to generate intermediate 6; the reaction formula is as follows:

7. The preparation method according to claim 6, characterized in that, The reaction includes the following steps: intermediate 5 is ring-opened in tetrahydrofuran solvent under the action of sodium salt of dimethyl sulfoxide, a strong affinity reagent, to generate intermediate 6; wherein the molar ratio of intermediate 5 to sodium salt of dimethyl sulfoxide is 1:3 to 5.

8. The preparation method according to claim 6, characterized in that, Intermediate 5 is prepared by the following method: Intermediate 4 undergoes a chiral reduction reaction in the presence of a chiral catalyst and a reducing agent to generate intermediate 5; the reaction formula is shown below:

9. The preparation method according to claim 8, characterized in that, The chiral reduction reaction comprises the following steps: under nitrogen protection, intermediate 4 is chirally reduced to intermediate 5 in tetrahydrofuran, dichloromethane or chloroform, in the presence of a chiral catalyst (R)-2-methylCBS-oxazolium borane and a reducing agent borane.

10. The preparation method according to claim 9, characterized in that, The borane is N,N-diethylanilineborane or 2-methylpyridineborane.

11. The preparation method according to claim 9, characterized in that, The molar ratio of intermediate 4 to reducing agent is 1:1; the mass of (R)-2-methyl-CBS oxazolium borane added is 1 to 5% of the mass of intermediate 4.

12. The preparation method according to claim 8, characterized in that, The preparation method of intermediate 4 includes the following steps: intermediate 3 reacts with thionyl chloride to form an acyl chloride, which then undergoes a Friedel-Crafts acylation reaction under the action of a Lewis acid to generate intermediate 4; the reaction formula is as follows:

13. The preparation method according to claim 12, characterized in that, The preparation method of intermediate 4 specifically includes the following steps: intermediate 3 is reacted with thionyl chloride under nitrogen protection in an organic solvent and heated to reflux. After the reaction is completed, it is cooled to room temperature, and a Lewis acid is added to undergo a Friedel-Crafts acylation reaction to obtain intermediate 4.

14. The preparation method according to claim 13, characterized in that, The Lewis acid is one of aluminum trichloride, tin tetrachloride, ferric trichloride, or boron trifluoride.

15. The preparation method according to claim 13, characterized in that, The Lewis acid mentioned is tin tetrachloride.

16. The preparation method according to claim 13, characterized in that, The molar ratio of intermediate 3 to thionyl chloride is 1:3 to 6, and the molar ratio of intermediate 3 to Lewis acid is 1:3 to 6.

17. The preparation method according to claim 12, characterized in that, Intermediate 3 is prepared by reacting intermediate 2 with compound 11 in the presence of an organolithium reagent; the reaction formula is as follows:

18. The preparation method according to claim 17, characterized in that, The organolithium reagent is selected from one of n-butyllithium, sec-butyllithium, tert-butyllithium, phenyllithium, bis(trimethylsilylaminolithium) and diisopropylaminolithium.

19. The preparation method according to claim 17, characterized in that, The preparation method of intermediate 3 specifically includes the following steps: compound 11 is dissolved in an organic solvent, and an organolithium reagent is slowly added dropwise at -78°C under nitrogen protection. An organic solvent containing intermediate 2 is added, and the mixture is stirred at -78 to -50°C for 1 to 3 hours. The mixture is then heated to -30 to -20°C and stirred for 15 to 22 hours to obtain intermediate 3.

20. The preparation method according to claim 19, characterized in that, The organic solvent is selected from one of tetrahydrofuran, n-hexane, cyclohexane, n-heptane, or diethyl ether.

21. The preparation method according to claim 19, characterized in that, The molar ratio of compound 11, intermediate 2 and organolithium reagent is 1:1 to 3:2 to 4.

22. The preparation method according to claim 17, characterized in that, The preparation method of intermediate 2 is as follows: In the reaction solvent, intermediate 1 undergoes an affinity substitution reaction with a brominating or iodizing reagent to obtain intermediate 2; the reaction formula is as follows:

23. The preparation method according to claim 22, characterized in that, The brominating agent is hydrogen bromide, phosphorus tribromide, carbon tetrabromide, dibromotriphenylphosphine, or N,N-dicyclohexyl-N-methylcarbodiimide bromide; the iodizing agent is N,N-dicyclohexyl-N-methylcarbodiimide iodide.

24. The preparation method according to claim 22, characterized in that, The reaction solvent is selected from one of tetrahydrofuran, n-hexane, toluene, and acetonitrile.

25. The preparation method according to claim 22, characterized in that, The molar ratio of intermediate 1 to the brominizing agent or iodine agent is 1:1 to 3.

26. The preparation method according to claim 22, characterized in that, Intermediate 1 is prepared by reacting 2,5-dihydroxybenzyl alcohol with chloromethyl methyl ether in the presence of an acid-binding agent; the reaction formula is as follows:

27. The preparation method according to claim 26, characterized in that, The preparation method of intermediate 1 specifically includes the following steps: 2,5-dihydroxybenzyl alcohol and chloromethyl methyl ether are reacted in dichloromethane, chloroform or N,N-dimethylformamide at 35-70°C in the presence of acid-binding agents diisopropylethylamine or triethylaminepyridine to generate intermediate 1.

28. The preparation method according to claim 26, characterized in that, The molar ratio of 2,5-dihydroxybenzyl alcohol, acid binder, and chloromethyl methyl ether is 1:3 to 6:2 to 4.

29. Use of the compound of claim 1 for the synthesis of daunorubicin.

30. A method for preparing daunorubicin using the compound of claim 1, characterized in that, Specifically, the process includes the following steps: intermediate 7 is protected with a hydroxyl group to obtain intermediate 8; intermediate 8 reacts with compound 12 to form a cyclization; and then the MOM protecting group is removed to obtain daunolide. The synthetic route is as follows:

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