CN115785168B

CN115785168B - Method for preparing 4-demethoxydaunorubicin hydrochloride

Info

Publication number: CN115785168B
Application number: CN202211011213.5A
Authority: CN
Inventors: 刘世领; 陆建军; 刘洪斌; 时彬
Original assignee: Zhejiang Arthur Pharmaceutical Co ltd
Current assignee: Zhejiang Arthur Pharmaceutical Co ltd
Priority date: 2022-08-22
Filing date: 2022-08-22
Publication date: 2023-11-07
Anticipated expiration: 2042-08-22
Also published as: CN115785168A

Abstract

According to the application, daunorubicin is taken as a reaction initiator, trifluoroacetic anhydride is added into daunorubicin or a suspension of pharmaceutically acceptable salt thereof for reaction to obtain a double-protection intermediate, and 4-methoxyl upper methyl of daunorubicin is selectively removed based on the double-protection intermediate for further reaction to prepare idarubicin or pharmaceutically acceptable salt thereof. The application adopts the intermediate with double protecting groups, improves the selectivity of removing 4-methoxyl, obviously reduces the impurity content in the final product and improves the quality of idarubicin hydrochloride. Meanwhile, the method does not need hydrolysis, simplifies post-treatment operation procedures, and greatly reduces synthesis cost.

Description

Method for preparing 4-demethoxydaunorubicin hydrochloride

Technical Field

The application relates to a chemical synthesis method of anthracyclines, in particular to a method for preparing idarubicin hydrochloride based on daunorubicin hydrochloride.

Background

Idarubicin hydrochloride is an anthracycline compound with a structure of formula 1, and the chemical name is: 4-demethoxydaunorubicin hydrochloride is a cell cycle nonspecific anticancer drug which can inhibit DNA synthesis and interfere with RNA polymerase, is used for treating tumors, is a first-line drug for treating acute non-lymphoblastic leukemia, and has the following structural formula:

the prior art discloses a two-step method for preparing idarubicin hydrochloride, which is characterized in that a glycosyl donor and a demethoxy anthracycline compound are respectively prepared to prepare idarubicin through glycosylation reaction. For example, in "journal of chinese antibiotics, 2006, 31 (3): 181-183' discloses a semisynthesis route of idarubicin hydrochloride, which is characterized in that daunorubicin hydrochloride is subjected to acid hydrolysis to obtain 2,3, 6-trideoxy-3-aminohexose and tetracyclic anthrone structures, and glycosyl donor 2,3, 6-deoxy-3-aminohexose chloro compounds and tetracyclic anthrone structure compounds with 4-methoxyl groups removed are obtained through further reaction; and carrying out glycosylation reaction on the glycosyl donor and the anthrone structural compound under the action of silver salt, and carrying out deprotection to form salt to obtain the idarubicin hydrochloride. This route has the following disadvantages: the glycol is required to use a solvent benzene for protecting the C-13 ketocarbonyl; the glycosylation reaction has the problem of stereoselectivity, and the reaction condition is harsh; long reaction steps, low yield and high cost.

CN102757470B discloses a synthetic route for preparing idarubicin hydrochloride based on daunorubicin hydrochloride, which comprises protecting the 3 '-amino group of daunorubicin with trifluoroacetyl to obtain 3' -trifluoroacetyl daunorubicin, and then subjecting to anhydrous MgCl ₂ Removing methyl on 4-methoxyl of anthracycline to obtain 4-demethyl-3 '-trifluoroacetyl daunorubicin, removing 4-phenolic hydroxyl and 3' -amino protecting group through three-step reaction to obtain idarubicin, and salifying to obtain idarubicin hydrochloride. The inventor of the application finds that raw materials are not reacted completely in the process of removing the 4-methyl of the anthracycline, and a large number of 7-glycosidic bond-broken impurities A and B occur in the process of repeating the method, and the structural formula is as follows, so that the separation and the purification are very difficult, the yield is low, the cost is high, and the method is not suitable for industrial production.

CN107698634B discloses a method for preparing idarubicin hydrochloride by removing methoxy at 4-position of anthracycline compound with metallic nickel catalyst/organophosphine ligand/silane reducer. However, the inventors of the present application found that the 7-position sugar epoxy group is extremely easily removed under the nickel catalyst/organophosphine ligand/silane reducing agent in the above synthesis process, and an intermediate from which only the 4-position methoxy group is removed cannot be obtained, which is not practical in production.

Disclosure of Invention

In order to solve the problems, in particular to solve the problems that a great amount of impurities are generated by cleavage of a 7-glycosidic bond in the process of removing methyl in 4-methoxy of an anthracycline and the yield of a target compound is low, the application provides a method for preparing 4-demethoxydaunorubicin hydrochloride.

The application takes daunorubicin hydrochloride as a reaction initiator, wherein the structure of the daunorubicin hydrochloride is shown as a formula 1, and the daunorubicin hydrochloride is as follows:

the application provides a method for selectively removing methyl on 4-methoxyl group of daunorubicin anthracycline, which comprises the following steps:

adding trifluoroacetic anhydride into daunorubicin salt suspension to react to obtain a double-protection intermediate with a structure of formula 2, namely an intermediate 2:

wherein the daunorubicin salt is a pharmaceutically acceptable salt, and in particular embodiments of the application, daunorubicin hydrochloride is used. The suspension is a suspension of daunorubicin salt in a solvent, preferably dichloromethane, and the suspension is a suspension of daunorubicin hydrochloride. The double protection means that the amino group at the 3 '-position of the aminoglycoside group at the 7-position on the anthracycline forms 3' -trifluoroacetamide with trifluoroacetic anhydride, and the hydroxyl group at the 4 '-position of the glycoside forms 4' -trifluoroacetate with trifluoroacetic anhydride.

Wherein, the reaction conditions for preparing the intermediate 2 are as follows: cooling the methylene dichloride suspension of daunorubicin salt to 0-10 ℃, preferably cooling to 0 ℃ (ice water bath), adding trifluoroacetic anhydride into the methylene dichloride suspension of daunorubicin salt, and further maintaining stirring until complete reaction, wherein the stirring time is 15 minutes-1 hour. The molar ratio of daunorubicin hydrochloride to trifluoroacetic anhydride is 1 (2-4), preferably 1 (2-3), based on the mass of daunorubicin hydrochloride.

Reacting intermediate 2 with a composition containing Lewis acid under anhydrous condition, and selectively removing methyl on 4-methoxyl of anthracycline; to give a compound having the structure of formula 3, hereinafter referred to as intermediate 3:

wherein the Lewis acid containing composition comprises anhydrous MgX ₂ KX, tetrabutylammonium halide, wherein X is halogen. Based on the double-protection intermediate with the structure of formula 2, the mol ratio of the intermediate 2 to anhydrous magnesium chloride, anhydrous potassium iodide and tetrabutylammonium iodide is 1 (1-2.5): 0.8-1.2): 0.5-1.2.

Preferably, the lewis acid-containing composition further comprises a molecular sieve. Based on the weight of the compound with the structure of formula 3, the weight ratio of the compound to the molecular sieve is 1 (0.5-1.5)

The reaction temperature with Lewis acid is 55-65 ℃ and the reaction is carried out for 1-3 hours under the condition of stirring.

The second part of the application provides an application in selectively removing methyl on 4-methoxyl of daunorubicin anthracycline and further preparing idarubicin hydrochloride.

The method for preparing idarubicin hydrochloride further comprises the following steps:

reacting the intermediate 3 with a trifluoromethylsulfonating agent to obtain an intermediate having a structure of formula 4, hereinafter referred to as intermediate 4:

in the reaction for preparing intermediate 4, the trifluoromethanesulfonic acid reagent is trifluoromethanesulfonic anhydride, and the reaction is carried out under alkaline conditions. Intermediate 3 is first dissolved in pyridine and reacted with trichloromethane sulfonic anhydride under sterically hindered amine and catalyst conditions to afford intermediate 4. In particular, in a particular embodiment of the application, the sterically hindered amine is a tertiary amine, preferably N, N-diisopropylethylamine; the catalyst is 4-dimethylaminopyridine.

In the reaction, the molar ratio of the intermediate 3 to the trifluoromethanesulfonic anhydride, the N, N-diisopropylethylamine and the 4-dimethylaminopyridine is based on the mass of the intermediate 3: 1 (1-2): 3-10): 0.1-2. The reaction condition is room temperature, and the stirring reaction is carried out for 1-2 hours at 25 ℃.

Reduction of intermediate 4 to remove the 4-position substitution of the anthracycline to give an intermediate having the structure of formula 5, hereinafter referred to as intermediate 5:

specifically, the intermediate 4 is dissolved in dimethylformamide, triethylamine formate, palladium acetate and 1,1' -bis (diphenylphosphine) ferrocene are added under the protection of argon, and the mixture is heated to 45-55 ℃ and stirred for 10-20 hours. In this reaction, based on the amount of intermediate 4, the molar ratio of intermediate 4 to triethylamine formate, palladium acetate, 1' -bis (diphenylphosphine) ferrocene is: 1 (1.5-3) (0.1-0.5).

The intermediate with the structure of formula 5 is further used for removing the protection of the amino group at the 3' position under alkaline condition, and further reacted with acid to obtain idarubicin hydrochloride.

Specifically, the intermediate 4 is added into tetrahydrofuran and water, naOH solution is dripped at the temperature of 25-30 ℃ until the amino group on the glycoside is completely deprotected, dichloromethane is used for extraction, the pH is further adjusted to 3-4 by hydrochloric acid, and the idarubicin hydrochloride is obtained by filtering.

In the application, the reaction product containing the intermediate obtained in each step is separated and purified by extraction and recrystallization. The recrystallized intermediate is further analyzed by liquid chromatography or the intermediate of each step is further purified and separated by liquid chromatography.

In the present application, the selective removal means that the reaction is selectively performed only for the 4-position and the glycosidic bond is not removed in the 7-position during the removal of the methyl group at the 4-position on the anthracycline and during the removal of the 4-position substitution on the anthracycline.

Compared with the prior art, the application adopts the double-protecting-group intermediate 2 to remove the 4-methoxyl group of the anthracycline compound, improves the selectivity of removing the 4-methoxyl group, obviously reduces the contents of impurities A and B in the final product, and improves the quality of idarubicin hydrochloride. Meanwhile, compared with the prior art, as sodium bicarbonate is needed to be used for selectively hydrolyzing the trifluoroacetyl to form the single-protection trifluoroacetyl intermediate in the prior art, the method does not need to hydrolyze, simplifies post-treatment operation procedures, and greatly reduces synthesis cost.

Drawings

Fig. 1: the reaction scheme of the application is schematically shown.

Fig. 2: HPLC chromatogram of example 1 intermediate 2.

Fig. 3: HPLC chromatogram of example 4 intermediate 3.

Fig. 4: comparative example single protection intermediate product nuclear magnetic spectrum.

Fig. 5: example 1 nuclear magnetic spectrum of intermediate 2 product.

Detailed Description

In order to make the objects, technical solutions and advantages of the present application more clear and clear, the present application will be further described in detail below with reference to the accompanying drawings and examples. It should be understood that the specific embodiments described herein are for purposes of illustration only and are not intended to limit the scope of the application.

Example 1: preparation of intermediate 2

20g of daunorubicin hydrochloride (1) are suspended in 800ml of dichloromethane and cooled to 0 ℃. 14ml of trifluoroacetic anhydride was added dropwise to the dichloromethane suspension, the mixture was kept at 0℃for an additional 30 minutes, added to 600ml of distilled water and stirred, the separated organic layer was concentrated to give 24.7g of intermediate 2 in 96.8% yield and 95.80% purity by HPLC, as shown in FIG. 2.

Product elemental analysis calculated C,51.75; h,3.78; o,26.68, C,51.74; h,3.78; o,26.69.

Nuclear magnetic spectrum of intermediate 2, 1H NMR (DMSO-d 6): δ1.11 (3H, d, j=6.5 Hz), 1.66-1.72 (2H, m), 2.01-2.20 (2H, m), 2.30 (3H, s), 2.81-2.94 (2H, m), 3.95 (3H, s), 4.32-4.39 (1H, m), 4.60 (1H, dd, j=13.0 Hz,6.0 Hz), 4.92-4.96 (1H, m), 5.24 (1H, m), 5.40 (1H, d, j=2 Hz), 5.57 (1H, dd, j=8.5 Hz,1.5 Hz), 7.80-7.87 (2H, m), 9.60 (1H, d, j=7 Hz), 13.18 (1H, 96, 1H).

The HPLC profile of example 1 intermediate 2 is shown in fig. 2 and the HPLC data is shown in table 1 below:

table 1: HPLC data for intermediate 2 of example 1

Example 2: preparation of intermediate 2

20g of daunorubicin hydrochloride (1) are suspended in 800ml of dichloromethane and cooled to 10 ℃. 14ml of trifluoroacetic anhydride were added dropwise to the dichloromethane suspension, the mixture was kept at 0℃for a further 30 minutes, added to 600ml of distilled water and stirred, the separated organic layer was concentrated to give 24.3g of intermediate 2 in 95.2% yield and 94.66% HPLC purity.

Example 3: preparation of intermediate 2

20g of daunorubicin hydrochloride (1) are suspended in 800ml of dichloromethane and cooled to 0 ℃.18 ml of trifluoroacetic anhydride was added dropwise to the dichloromethane suspension, the mixture was kept at 0℃for another 30 minutes, added to 600ml of distilled water and stirred, the separated organic layer was concentrated to give 25.1g of intermediate 2 in 98% yield and 93.42% purity by HPLC.

Example 4: preparation of intermediate 3

20g of intermediate 2 are dissolved in 500ml of tetrahydrofuran. 6.6g of anhydrous magnesium chloride, 10g of tetrabutylammonium iodide, 4.6g of anhydrous potassium iodide and 20g of molecular sieve are stirred at 60 ℃ for 2 hours, the filtrate is filtered, added to ice water and acidified to pH2.5 with trifluoroacetic acid, the mixture is extracted with 2X150ml of dichloromethane, the organic layer is dried over anhydrous MgSO4 and the solvent is distilled off under reduced pressure to give 15.9g of intermediate 3 in 94% yield and 96.72% HPLC purity, as shown in FIG. 3.

The nuclear magnetic spectrum of intermediate 3 is shown below, 1H NMR (DMSO-d 6): δ1.15 (3H, d, J=6.5 Hz), 1.53-1.61 (2H, m), 2.05-2.13 (2H, m), 2.28 (3H, s), 2.97 (2H, s), 3.52 (1H, m), 4.05 (1H, m), 4.24 (1H, m), 4.93 (1H, m), 5.00 (1H, m), 5.26 (1H, m), 5.57 (1H, d, J=4 Hz), 7.40 (1H, dd, J=8.2 Hz,1.4 Hz), 7.79 (1H, dd, J=7.5 Hz,1.4 Hz), 7.82-7.86 (1H, m), 9.09 (1H, d, J=7 Hz), 12.01 (1H, s), 12.86 (1H, 1S), 13.43 (1H, s)

The HPLC profile of example 4 intermediate 3 is shown in fig. 3 and the HPLC data is shown in table 2 below:

table 2: HPLC data for intermediate 3 of example 1

Example 5: preparation of intermediate 3

20g of intermediate 2 are dissolved in 500ml of tetrahydrofuran. 5.6g of anhydrous magnesium chloride, 10g of tetrabutylammonium iodide, 4.6g of anhydrous potassium iodide and 20g of molecular sieve are stirred at 60℃for 2 hours, the filtrate is filtered off, added to ice water and acidified to pH2.5 with trifluoroacetic acid, the mixture is extracted with 2X150ml of dichloromethane, the organic layer is dried over anhydrous MgSO4 and the solvent is distilled off under reduced pressure to give 15.3g of intermediate 3 in a yield of 90% and an HPLC purity of 96.79%.

Example 6: preparation of intermediate 3

20g of intermediate 2 are dissolved in 500ml of tetrahydrofuran. 6.6g of anhydrous magnesium chloride, 10g of tetrabutylammonium iodide, 4.6g of anhydrous potassium iodide and 20g of molecular sieve are stirred at 55℃for 3 hours, the filtrate is filtered off, added to ice water and acidified to pH2.5 with trifluoroacetic acid, the mixture is extracted with 2X150ml of dichloromethane, the organic layer is dried over anhydrous MgSO4 and the solvent is distilled off under reduced pressure to give 15.5g of intermediate 3 in a yield of 91% and an HPLC purity of 95.65%.

Example 7: preparation of intermediate 4

15g of intermediate 3 are dissolved in 400ml of pyridine. 20.7g diisopropylethylamine and 4.5g 4-dimethylaminopyridine were added and the mixture was cooled to 0 ℃. 10.4g of trifluoromethanesulfonic anhydride was added, and the mixture was stirred at room temperature for 1 hour. Then 650ml of 10% hydrochloric acid, 0.8kg of ice and 800ml of dichloromethane were added. The organic layer was washed twice with 500ml of distilled water, separated and the dichloromethane was removed under reduced pressure, and the organic phase was concentrated and passed through a column to give 14.8g of intermediate 4 in 81% yield and 97.26% purity by HPLC.

Example 8: preparation of intermediate 5

12g of intermediate 4 was dissolved in 100ml of dimethylformamide and 7.1g of triethylamine formate, 35mg of palladium acetate and 0.9g of 1,1' -bis (diphenylphosphine) ferrocene were added with stirring under argon atmosphere, and the mixture was heated to 50℃and stirred for 16 hours. Cooling, filtering, adding 100ml water and 200ml dichloromethane into the filtrate, stirring and separating, washing the organic phase with 100ml x 2 times water, concentrating the organic phase, and passing through a column to obtain 8.8g intermediate 5, wherein the yield is 92% and the HPLC purity is 99.33%.

Example 9: preparation of idarubicin hydrochloride

8g of intermediate 5 are added to 80ml of tetrahydrofuran and 160ml of water, 24ml of 1.0N NaOH solution is added dropwise at 30 ℃, stirring is carried out for 30 minutes after the dripping is finished, 160ml of dichloromethane is added for extraction, 8ml of hydrogen chloride methanol solution is added to the organic phase for regulating the pH to 3-4, stirring is carried out for 30 minutes, and filtering is carried out, thus obtaining 6.3g of idarubicin hydrochloride, the yield is 88%, and the HPLC purity is 99.73%.

Comparative example 1:

the single protected intermediate, N-trifluoroacetamide daunorubicin, was prepared by the same procedure as in example 2 of CN102757470B, by substitution of the amino and hydroxy groups on the glycoside with trifluoroacetic anhydride and further hydrolysis of sodium bicarbonate solution. The specific method comprises the following steps: 20g of daunorubicin hydrochloride was suspended in 400ml of Dichloromethane (DCM) and cooled to 0deg.C. 28ml of trifluoroacetic anhydride was added to 45ml of DCM solution while stirring vigorously for 1 hour. The mixture was kept at 0℃for an additional 30 minutes, added to 750ml of distilled water and stirred. The organic layer is removed. 400ml of saturated sodium bicarbonate solution was added to the organic layer and kept at room temperature while vigorously stirring for 15-25 hours to hydrolyze 4'O-3' N-di-trifluoroacetyl daunorubicin. After the hydrolysis, the organic layer was separated and the solvent was completely evaporated under reduced pressure. After evaporation, 20g of daunorubicin N-trifluoroacetamide of 93% purity was obtained, as shown in the following structural formula.

Further, based on the product N-trifluoroacetamide daunorubicin obtained by the above reaction, methyl group at the 4-methoxy group of the anthracycline was removed by the same method as in example 3 of CN102757470B to obtain a product having the same structure as that of the intermediate 3 of the present application. Specifically, 20g of 3' -protecting group-daunorubicin (IV) was dissolved in 450ml of tetrahydrofuran. 25g of anhydrous magnesium chloride and 20g of anhydrous potassium iodide were added to an environment which was not in contact with moisture in the atmosphere. The mixture was kept at 40 ℃ for 1.5 hours, added to ice water and acidified to ph2.5 with trifluoroacetic acid and the mixture was extracted with 2x150ml dichloromethane. The organic layer was removed, dried over anhydrous MgSO4, and then the solvent was evaporated under reduced pressure. 15.8g of daunorubicin (VI) are obtained as 4-demethyl-3' -protecting group with a purity of > 90%.

Comparison of the comparative example with the method of double protection of amino and hydroxyl groups on glycoside by trifluoroacetic anhydride in example 1 of the present application is shown in table 1: comparative examples are shown in the table against example 1.

Table 1: comparative example and example 1 Table

Comparison of the comparative example with the reaction of the application in example 4 with methyl removal at the 4-position is shown in Table 2: comparative examples are shown in the comparative table with example 4.

Table 2: comparative example and example 4 Table

The report values in the above table refer to information disclosed in CN102757470B, and the verification values in the above table are data obtained by repeating experiments according to the technical scheme disclosed in comparative document 1 by the inventor of the present application using the same experimental method and experimental apparatus as those of the examples, and testing the experimental products. As can be seen from the verification results of the table, the verification value is very different from the patent report value; the purity of the intermediate 3 prepared by the method is more definite than the reported value of the patent, the repeatability is high, and the yield is higher; the purity and selectivity are significantly improved over the verification values of the above patents.

In the present application, the HPLC represents high performance liquid chromatography (High Performance Liquid Chromatography \HPLC). The purity in the present application is measured based on HPLC, also indicated as HPLC purity or HPLC post-addition percentage for expressing purity. In the present application, the yield is based on the molar ratio of the reaction product to the theoretical product.

It is to be understood that the application is not limited in its application to the examples described above, but is capable of modification and variation in light of the above teachings by those skilled in the art, and that all such modifications and variations are intended to be included within the scope of the appended claims.

Claims

1. A process for preparing a compound having the structure of formula 3 comprising the steps of:

(1) Adding trifluoroacetic anhydride into daunorubicin or a suspension of pharmaceutically acceptable salt thereof to react to obtain a double-protection intermediate with a structure of formula 2:

(2) Firstly, under anhydrous condition, the intermediate with the structure of formula 2 is further reacted with a composition containing Lewis acid, methyl on 4-methoxyl of anthracycline is selectively removed, and then the intermediate with the structure of formula 3 is obtained by adding the intermediate into ice water and acidifying with trifluoroacetic acid:

2. the method of preparing a compound having the structure of formula 3 according to claim 1, wherein in step (1), the suspension of daunorubicin or a pharmaceutically acceptable salt thereof is a dichloromethane-based solvent suspension; in the step (1), firstly, cooling the suspension of daunorubicin or pharmaceutically acceptable salt thereof to 0-10 ℃, and then adding trifluoroacetic anhydride into the cooled suspension for heat preservation reaction; wherein the molar ratio of daunorubicin or a pharmaceutically acceptable salt thereof to trifluoroacetic anhydride is 1 (2-4) based on the amount of daunorubicin or a pharmaceutically acceptable salt thereof (1 eq.).

3. A process according to claim 2, wherein in step (1) the suspension of daunorubicin or a pharmaceutically acceptable salt thereof is first cooled to 0 ℃.

4. The method according to claim 2, wherein in the step (1), the molar ratio of daunorubicin or a pharmaceutically acceptable salt thereof to trifluoroacetic anhydride is 1 (2 to 3) based on the amount of daunorubicin or a pharmaceutically acceptable salt thereof.

5. The method of claim 1, wherein in step (2), the lewis acid-containing composition comprises anhydrous magnesium chloride, anhydrous potassium iodide, tetrabutylammonium iodide, and optionally a molecular sieve; based on the double-protection intermediate with the structure of formula 2 (1 eq.), the mol ratio of the intermediate 2 to anhydrous magnesium chloride, anhydrous potassium iodide and tetrabutylammonium iodide is 1 (1-2.5): 0.8-1.2): 0.5-1.2.

6. The method of claim 1, wherein in step (2), the reaction conditions with the lewis acid-containing composition are: the temperature is 50-70 ℃, and the stirring reaction is carried out for 1-5 hours.

7. The method of claim 1, wherein in step (2), the reaction conditions with the lewis acid-containing composition are: the temperature is 55-65 ℃, and the stirring reaction is carried out for 1-3 hours.

8. Use of a process according to any one of claims 1-7 for the preparation of a compound having the structure of formula 3 for the preparation of idarubicin or a pharmaceutically acceptable salt thereof.

9. The use of the process for preparing a compound having the structure of formula 3 according to claim 8 for preparing idarubicin or a pharmaceutically acceptable salt thereof, further comprising the steps of:

(3) Removing the phenolic hydroxyl group at the 4-position of the anthracycline from the intermediate with the structure shown in formula 3 to obtain an intermediate with a structure shown in formula 5;

(4) The intermediate with the structure of formula 5 is used for removing the amino protecting group at the 3' -position of the glucoside under alkaline condition, and further salified with acid to obtain the idarubicin salt.

10. The use of the process for the preparation of a compound having the structure of formula 3 according to claim 9 for the preparation of idarubicin or a pharmaceutically acceptable salt thereof, wherein step (3) comprises dissolving intermediate 3 in pyridine, obtaining an intermediate of the structure of formula 4 by reaction with trichloromethane sulfonic anhydride under conditions of sterically hindered amine and catalyst;

further, the intermediate 4 is added into a reaction system of triethylamine formate, palladium acetate and 1,1' -bis (diphenylphosphine) ferrocene under the protection of argon gas to react to obtain an intermediate 5.

11. The use of the process for the preparation of a compound having the structure of formula 3 according to claim 10 for the preparation of idarubicin or a pharmaceutically acceptable salt thereof, wherein the molar ratio of intermediate 3 to triflic anhydride, sterically hindered amine and catalyst is: 1 (1-2): 3-10): 0.1-2.

12. The use of a process for the preparation of a compound having the structure of formula 3 according to claim 11, wherein the sterically hindered amine is N, N-diisopropylethylamine and the catalyst is 4-dimethylaminopyridine.

13. The use of the process for the preparation of a compound having the structure of formula 3 according to claim 10, in the preparation of idarubicin or a pharmaceutically acceptable salt thereof, wherein the molar ratio of intermediate 4 to triethylamine formate, palladium acetate, 1' -bis (diphenylphosphino) ferrocene in the reaction for the preparation of intermediate 5 is: 1 (1.5-3) (0.1-0.5); in the reaction for preparing the intermediate 5, the reaction temperature is 45-55 ℃, and the reaction is carried out for 10-20 hours under stirring.

14. The method for preparing the compound with the structure shown in the formula 3, which is applied to the preparation of idarubicin or pharmaceutically acceptable salt thereof, according to claim 9, wherein the step (4) is that the intermediate 5 is added into a mixed solvent of tetrahydrofuran and water, naOH solution is added, the mixture is extracted, and the organic phase is taken and filtered by hydrogen chloride to adjust the pH value to 3-4, so as to obtain idarubicin hydrochloride; wherein the mixing volume ratio of tetrahydrofuran and water is 1:1-2, dichloromethane is used for extraction, and the method of adjusting the pH by hydrogen chloride is to add a methanol solution of hydrogen chloride into an organic phase.