CN108473523B - Preparation method of epirubicin hydrochloride and intermediate thereof - Google Patents

Abstract

The invention discloses a preparation method of epirubicin hydrochloride and an intermediate thereof. The method comprises the following steps: in an organic solvent, under the action of alkali, the compound 4 and trifluoromethanesulfonic anhydride undergo esterification reaction as shown below to prepare a compound 4'. The preparation method has the advantages of short route, high yield, easily obtained reaction raw materials, no need of other expensive reagents, low cost, mild reaction conditions, simple operation and contribution to industrial production.

Description

Preparation method of epirubicin hydrochloride and intermediate thereof

Technical Field

The invention belongs to a chemical synthesis process of a drug, and particularly relates to a preparation method of epirubicin hydrochloride and an intermediate thereof.

Background

Epirubicin hydrochloride also known as epirubicin hydrochloride, chemical name (8S, 10S) -10- [ (3 '-amino-2', 3 ', 6' -trideoxy-alpha-L-arabinopyranosyl) oxy]-6, 8, 11-trihydroxy-8-hydroxyethyl-1-methoxy-7, 8, 9, 10-tetrahydrotetracene-5, 12-dione hydrochloride of formula C₂₇H₃₀ClNO₁₁Molecular weight 579.15, CAS registry number 56690-09-1. It is an anthracycline antitumor antibiotic developed by Famazepine (present pfeiffer) and used for treating breast cancer, lung cancer and liver cancer, and is marketed in Europe in 1984 and in the United states in 1999, and the structural formula is as follows:

the synthetic routes of epirubicin hydrochloride mainly include the following:

1. DE2510866 discloses a synthesis method of epirubicin hydrochloride. The method has 11 steps of reaction, and the yield of the crude epirubicin hydrochloride product is only 8.6 percent, the route is long, and the yield is low.

2. Polish Journal of Chemistry, 2005, 79 (2): 349-359 discloses a synthetic method of epirubicin hydrochloride. The method has 10 steps of reaction, and the yield of the crude epirubicin hydrochloride product is 22%, the route is long, and the yield is low. Meanwhile, the reaction raw materials of the method are not easy to obtain and need to be prepared through two steps of reactions, so that the synthetic route of epirubicin hydrochloride is prolonged to 12 steps.

3. WO2006096665 discloses a method for synthesizing epirubicin hydrochloride. The method has 7 steps of reaction, although the reaction route is shortened compared with the method 1 and the method 2, the yield of the crude epirubicin hydrochloride is 26 percent, and the yield is low. In addition, in the method, the temperature oxidation of dimethyl sulfoxide and trifluoroacetic anhydride is carried out at a low temperature of-70 ℃, which is difficult to realize industrially and is not beneficial to industrial production.

4. A method for synthesizing epirubicin hydrochloride is disclosed in WO9629335a 1. The yield of epirubicin hydrochloride in the method is 41%, but the epirubicin hydrochloride still has 11 steps of reaction and long route.

5. WO9629335A1 discloses a preparation method of epirubicin hydrochloride. The method uses doxorubicin hydrochloride as a raw material, dissolves in N, N-dimethylformamide with high boiling point and difficult recovery, uses triethyl orthoformate as a dihydroxyl protective agent, uses trifluoroacetic acid as a catalyst, and performs dihydroxyl protection to obtain a compound 29, wherein due to the strong acidity of the trifluoroacetic acid, a product of the reaction in the step can be returned to the raw material, so that the yield is not high, the patent does not report the yield, the patent operation is repeated, and the yield is lower than 70%; reacting a compound 29 with trifluoroacetic anhydride, adding sodium bicarbonate, and reacting in two steps to obtain a compound 30, wherein the yield is not reported in the patent, and the yield is lower than 85% by repeating the patent operation; the compound 30 reacts with trifluoromethanesulfonic anhydride to activate the hydroxyl group on the sugar, and then expensive silicon protection is carried out to obtain a compound 31; 31 reacting with triethylamine formate, reacting for 2 days under the action of potassium fluoride, and removing silicon protection to obtain a compound 32; the compound 32 is firstly desugared in an aqueous solution of sodium hydroxide at 5 ℃ to carry out hydroxyl and amino protection, and then is subjected to post-treatment to obtain a solid, and then the double-hydroxyl protection is removed in methanol-hydrochloric acid to obtain a crude epirubicin hydrochloride product, the whole route is subjected to 9-step reaction, the crude epirubicin hydrochloride product is obtained with 31% yield according to patent reports, and the yield is low.

Therefore, the epirubicin hydrochloride preparation method disclosed in the prior art generally has the defects of long route, low yield, difficult obtainment of reaction raw materials, high cost, harsh reaction conditions, complex operation, difficult realization of industrial production and the like, and expensive reagents such as silicon and the like are required. Therefore, the above technical problems need to be solved.

Disclosure of Invention

The invention aims to solve the technical problems of long route, low yield, expensive reaction raw materials, difficult obtainment, high cost, harsh reaction conditions, complex operation, difficult realization of industrial production and the like in the existing epirubicin hydrochloride preparation method, and provides a preparation method and an intermediate thereof. The preparation method has the advantages of short route, high yield, easily obtained reaction raw materials, no need of other expensive reagents, low cost, mild reaction conditions, simple operation and contribution to industrial production.

The invention mainly solves the technical problems through the following technical scheme.

The invention provides a preparation method of a compound 4', which comprises the following steps: in an organic solvent, under the action of alkali, carrying out esterification reaction on the compound 4 and trifluoromethanesulfonic anhydride as shown in the specification to obtain a compound 4';

in the method for preparing the compound 4', the esterification reaction preferably comprises the following steps: and mixing the compound 4, an organic solvent and a base, and adding trifluoromethanesulfonic anhydride to perform the esterification reaction. Preferably, the esterification reaction needs to be carried out at the temperature of-5 ℃ to 0 ℃ and trifluoromethanesulfonic anhydride is added.

In the preparation method of the compound 4', the organic solvent can be a solvent conventional in such reactions in the field, and is preferably a halogenated hydrocarbon solvent. The halogenated hydrocarbon solvent is preferably dichloromethane, more preferably anhydrous dichloromethane. The base may be a base conventional in such reactions in the art, preferably an organic base. The organic base is preferably pyridine, more preferably anhydrous pyridine. The trifluoromethanesulfonic anhydride is preferably used in the form of an organic solution of trifluoromethanesulfonic anhydride. In the organic solution of trifluoromethanesulfonic anhydride, the amounts of trifluoromethanesulfonic anhydride and organic solvent used are not particularly limited. The said way of adding trifluoromethanesulfonic anhydride is preferably dropwise. The dropping speed is not particularly limited as long as the temperature of the reaction system is controlled to be between-5 ℃ and 0 ℃. The base may be used in an amount conventional in such reactions in the art, preferably in a molar ratio to compound 4 of from 3:1 to 10:1, more preferably from 5:1 to 8: 1. The triflic anhydride may be used in an amount conventional in the art for such reactions, preferably in a molar ratio to compound 4 of from 1:1 to 5:1, more preferably from 2:1 to 3: 1. The amount of the organic solvent is not particularly limited as long as the reaction is not affected, and preferably, the volume-to-mass ratio of the organic solvent to the compound 4 is 5mL/g to 20 mL/g. The esterification reaction temperature is preferably-5 ℃ to 0 ℃. The progress of the esterification reaction can be monitored by detection methods conventional in the art (e.g., TLC, HPLC or GC), and is generally the end point of the reaction when compound 4 is eliminated. The time for the esterification reaction is preferably 0.5 hour to 3 hours, more preferably 1 hour.

In a preferred embodiment of the present invention, the preparation method of the compound 4' can also be performed under a gas atmosphere. The gas in the gas shield can be a protective gas conventional in the field of organic synthesis, and preferably is N₂。

In the method for producing the compound 4', the method may further comprise a post-treatment operation after the completion of the esterification reaction. The post-processing operation preferably comprises the steps of: and (3) adding an alkane solvent into the reaction liquid after the esterification reaction is finished, separating out solids, and filtering to obtain the catalyst. The alkane solvent can be an alkane solvent which is conventional in the organic field, and preferably is n-heptane. The amount of the alkane solvent is not particularly limited, and it is preferable that no solid is precipitated.

In a preferred embodiment of the present invention, the esterification reaction can be directly followed without post-treatment.

The preparation method of the compound 4' preferably further comprises the following steps: in an organic solvent, under the catalysis of acid and/or acid salt, carrying out condensation reaction shown in the specification on a compound 3 and triisopropyl orthoformate to obtain a compound 4;

in the method for preparing the compound 4, the condensation reaction preferably includes the steps of: suspending the compound 3 in an organic solvent, adding an acid and/or an acid salt, triisopropyl orthoformate, and carrying out the condensation reaction.

In the preparation method of the compound 4, the acid or acid salt can be an acid or acid salt conventional in such reactions in the art, and the acid is preferably an organic acid, more preferably camphorsulfonic acid; the acid salt is preferably pyridine hydrochloride and/or pyridine p-methylbenzenesulfonate. The organic solvent is preferably an anhydrous organic solvent. The organic solvent may be an organic solvent conventional in the art for such reactions, and preferably an ether solvent and/or a halogenated hydrocarbon solvent. The ether solvent is preferably tetrahydrofuran and/or 2-methyltetrahydrofuran. The halogenated hydrocarbon solvent is preferably dichloromethane. The molar ratio of triisopropyl orthoformate to compound 3 is preferably from 4:1 to 10:1, more preferably from 5:1 to 6: 1. The amount of the acid and/or the acid salt (if the acid and the acid salt are used for catalysis together, the amount refers to the total amount of the acid and the acid salt) is a catalytic amount, preferably, the amount is 0.01 to 0.2 percent, and more preferably, 0.05 to 0.08 percent of the mass of the compound 3. The amount of the organic solvent is not particularly limited as long as the reaction is not affected, and preferably, the volume-to-mass ratio of the organic solvent to the compound 3 is 1mL/g to 50mL/g, more preferably 5mL/g to 20 mL/g. The condensation reaction temperature is preferably 25 ℃ to the solvent reflux temperature under normal pressure. The progress of the condensation reaction can be monitored by detection methods conventional in the art (e.g., TLC, HPLC or GC), and is generally the end point of the reaction when compound 3 disappears. The condensation reaction preferably comprises a first stage reaction and a second stage reaction, wherein the temperature of the first stage reaction is preferably 25-30 ℃; the temperature of the second stage reaction is preferably the reflux temperature of the solvent under normal pressure. The time of the condensation reaction is preferably 1 to 6 hours, wherein the first stage reaction time is preferably 0.5 to 5 hours, and the second stage reaction time is preferably 0.5 to 3 hours.

After the condensation reaction, the reaction preferably further comprises a post-treatment operation. The method and conditions for the operation of said work-up may be those conventional for work-up in the field of organic synthesis, and preferably comprise the following steps: after completion of the condensation reaction, water and a base (for example, 22.7mL of water and 0.2g of sodium bicarbonate) are added to the reaction solution, an organic solvent for extraction (for example, ethyl acetate) is added to extract the mixture into layers (in the case of extraction, the organic phase is generally washed with water (114 mL. times.2), the aqueous phases are combined, and the organic solvent for extraction (for example, ethyl acetate) is washed (227 mL. times.2)), all the organic phases are combined, the organic solvent is removed (for example, by reduced pressure rotary evaporation), and the mixture is dried (for example, under vacuum at 35 ℃ C. to constant weight) to obtain compound 4. The base may be one conventional in the art for such post-reaction treatments, and is preferably sodium bicarbonate. The temperature of the mixture of the reaction solution after the condensation reaction, water and alkali is preferably 20 ℃ to 40 ℃, and more preferably 25 ℃ to 30 ℃.

After the completion of the condensation reaction, the reaction solution after the completion of the condensation reaction may be preferably treated with an organic acid having a pKa value of 3 to 5(25 ℃). The organic acid is preferably one or more of formic acid, acetic acid, n-propionic acid, n-butyric acid, citric acid, fumaric acid and tartaric acid. The amount of the organic acid to be used is not particularly limited as long as it does not affect the reaction, and preferably, it is used in a molar ratio of 5:1 to 20:1, more preferably 10:1 to 20:1, to the compound 3. The temperature of the organic acid treatment is preferably 10 ℃ to 30 ℃. The organic acid treatment time is preferably 10 hours to 20 hours, more preferably 15 hours to 18 hours.

The method may further comprise the step of mixing the reaction solution after the completion of the condensation reaction with water and an alkali, before treating the reaction solution after the completion of the condensation reaction with an organic acid. The base may be one conventional in the art for such post-reaction treatments, preferably sodium bicarbonate. The relationship between the amounts of water and alkali used is not particularly limited. The temperature of the mixture of the reaction solution after the condensation reaction, water and alkali is preferably 20 ℃ to 40 ℃, and more preferably 25 ℃ to 30 ℃.

In the method for producing the compound 4, when the reaction solution after the completion of the condensation reaction is treated with an organic acid having a pKa value of 3 to 5(25 ℃), the post-treatment preferably includes the steps of: to the reaction solution treated with an organic acid having a pKa value of 3 to 5(25 ℃), an aqueous sodium hydrogencarbonate solution (for example, 67.8g of sodium hydrogencarbonate plus 784mL of water) is added, an organic solvent for extraction (for example, ethyl acetate) is added to extract the layers (in the case of extraction, the organic phase is generally washed with water (114 mL. times.2), the aqueous phases are combined, the organic solvent for extraction (for example, ethyl acetate) is washed (227 mL. times.2)), all the organic phases are combined, the organic solvent is removed (for example, by reduced pressure rotary evaporation), and the mixture is dried (for example, vacuum drying at 35 ℃ C. to constant weight) to obtain compound 4. Wherein the temperature of mixing the reaction solution treated with the organic acid having a pKa value of 3 to 5(25 ℃) with an aqueous sodium bicarbonate solution is preferably-5 ℃ to 0 ℃.

The preparation method of the compound 4' preferably further comprises the following steps: in an organic solvent A, carrying out acylation reaction on a compound 2 and trifluoroacetic anhydride, and then treating a reaction solution after the acylation reaction with alkali in the solvent to obtain a compound 3;

in the process for preparing compound 3, the acylation reaction preferably comprises the steps of: suspending the compound 2 in the organic solvent A, adding trifluoroacetic anhydride, and performing the acylation reaction, wherein the acylation reaction is preferably performed by adding the trifluoroacetic anhydride at a temperature of 0-25 ℃ (for example, 10-25 ℃).

In the preparation method of the compound 3, the organic solvent A is preferably an anhydrous organic solvent. The organic solvent A may be an organic solvent conventional in the art for such reactions, preferably an ether solvent and/or a halogenated hydrocarbon solvent. The ether solvent is preferably tetrahydrofuran and/or 2-methyltetrahydrofuran. The halogenated hydrocarbon solvent is preferably dichloromethane. The molar ratio of trifluoroacetic anhydride to compound 2 is preferably 3:1 to 10:1, more preferably 4:1 to 6: 1. The amount of the organic solvent A is not particularly limited as long as the reaction is not affected, and preferably, the volume-to-mass ratio of the organic solvent A to the compound 2 is 5mL/g to 30mL/g, more preferably 5mL/g to 10 mL/g. The temperature of the acylation reaction is preferably 0 ℃ to 25 ℃, more preferably 10 ℃ to 20 ℃. The progress of the acylation reaction can be monitored by detection methods conventional in the art (e.g., TLC, HPLC or GC), and is generally the end point of the reaction when compound 2 is eliminated. The time of the acylation reaction is preferably 3 hours to 10 hours, more preferably 4 hours to 6 hours.

In the method for producing compound 3, the treatment of the reaction solution after the completion of the acylation reaction with a base preferably comprises the steps of: after the acylation reaction is completed, the reaction mixture is added with a base and an organic solvent B, and then water is added to carry out the reaction. The organic solvent B may be a solvent conventional in such reactions in the art, preferably one or more of an ether solvent, a halogenated hydrocarbon solvent, an ester solvent and an alcohol solvent, and more preferably a mixed solvent of one or more of an ether solvent, a halogenated hydrocarbon solvent and an ester solvent and an alcohol solvent. The ether solvent is preferably tetrahydrofuran and/or 2-methyltetrahydrofuran. The halogenated hydrocarbon solvent is preferably dichloromethane. The ester solvent is preferably ethyl acetate. The alcohol solvent is preferably methanol.

In the method for producing compound 3, in the above-mentioned operation of treating the reaction solution after the completion of the acylation reaction with a base, the base is preferably an inorganic base. The inorganic base is preferably one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and sodium phosphate. The base may be used in an amount conventional in such reactions in the art, preferably in a molar ratio of 15-25:1 to compound 2. The amounts of water and organic solvent B may be those conventionally used in such reactions in the art. The relationship between the amount of the mixed solvent of water and the organic solvent B and the amount of the compound 2 is not particularly limited as long as the reaction is not affected. The temperature of the alkali treatment of the reaction solution after the end of the acylation reaction is preferably 30 ℃ to 35 ℃. The time for treating the reaction solution after the completion of the acylation reaction with the base is preferably 10 hours to 25 hours, more preferably 15 hours to 20 hours.

In the method for producing compound 3, after the reaction solution after the completion of the acylation reaction is treated with a base, it is preferable that the method further comprises a post-treatment operation. The post-treatment method and conditions may be conventional in the field of reaction post-treatment in organic synthesis, and preferably include the steps of: adding hydrochloric acid aqueous solution (obtained by mixing 14.2mL of concentrated hydrochloric acid and 150mL of water) into the reaction solution after the reaction of acylation is completed and alkali treatment, separating the layers, washing the organic phase with water, combining the aqueous phases, washing the combined aqueous phases with an organic solvent for extraction (such as ethyl acetate), combining all the organic phases, washing with an aqueous acid solution with a pH value of 4.0, washing with water, removing the organic solvent (such as reduced pressure rotary evaporation), and drying (such as vacuum drying at 35 ℃ to constant weight). The acid in the aqueous acid solution having a pH of 4.0 may be an acid which is conventional in the art as long as the pH of the aqueous acid solution is controlled to 4.0. The temperature of mixing the reaction solution after the end of the acylation reaction with the aqueous solution of hydrochloric acid and the reaction solution after the end of the alkali treatment is preferably-5 ℃ to 0 ℃.

The invention also provides a preparation method of the compound 5, which comprises the following steps: in an organic solvent, under the action of alkali, carrying out nucleophilic substitution reaction on the compound 4' prepared by the preparation method and formic acid to prepare a compound 5;

in the method for preparing the compound 5, the nucleophilic substitution reaction preferably comprises the steps of: the nucleophilic substitution reaction is carried out by adding a mixed solution of a base, formic acid and an organic solvent to a mixed solution of the compound 4' and the organic solvent. The amount of the organic solvent in the mixed solution of the compound 4' and the organic solvent and the mixed solution of the base, the formic acid and the organic solvent is not particularly limited as long as the reaction is not affected.

In the preparation method of the compound 5, the formic acid is preferably anhydrous formic acid. The organic solvent may be an organic solvent conventional in the art for such reactions, preferably a halogenated hydrocarbon solvent. The halogenated hydrocarbon solvent is preferably dichloromethane (e.g., anhydrous dichloromethane). The base may be one conventional in the art for such reactions, preferably triethylamine. The base may be used in an amount conventional in the art, preferably in a molar ratio of 1:1 to 5:1, more preferably 1:1 to 3:1, with formic acid. The molar ratio of the compound 4' to formic acid is preferably from 1:10 to 1:15, more preferably 1: 12.5. The amount of the solvent is not particularly limited as long as the reaction is not affected, and preferably the volume-to-mass ratio of the solvent to formic acid is 1mL/g to 50mL/g, more preferably 1mL/g to 30 mL/g. The temperature of the nucleophilic substitution reaction may be a temperature conventional in such reactions in the art, preferably from 20 ℃ to 25 ℃. The progress of the nucleophilic substitution reaction can be monitored by detection methods conventional in the art (e.g., TLC, HPLC or GC), and is generally the end point of the reaction when compound 4' is eliminated. The time for the nucleophilic substitution reaction is preferably 10 hours to 20 hours, more preferably 15 hours to 20 hours.

In the method for producing compound 5, after the nucleophilic substitution reaction is completed, it is preferable that the method further comprises a post-treatment operation. The method and conditions for the operation of said work-up may be those conventional for work-up in the field of organic synthesis, and preferably comprise the following steps: after the completion of the nucleophilic substitution reaction, a base (for example, sodium bicarbonate) and water are added to the reaction solution, layers are separated, the organic phase is washed with an aqueous acid solution (for example, an aqueous 8% acetic acid solution) (for example, 300mL × 2), the aqueous acid layers are combined, the organic solvent for extraction is washed with an organic solvent (the organic solvent for extraction is generally the same as the organic solvent used for the nucleophilic substitution reaction, for example, dichloromethane)), all the organic phases are combined, an aqueous alkaline solution (for example, 5% sodium bicarbonate, 300mL) is washed with an aqueous alkaline solution, the organic solvent for extraction is generally the same as the organic solvent used for the nucleophilic substitution reaction, for example, dichloromethane), all the organic phases are combined, washed with water, and the organic solvent is removed (for example, reduced pressure rotary evaporation), whereby compound 5 is obtained.

In the preparation method of the compound 5, after the compound 4 'is prepared according to the preparation method, preferably, the compound 4' and formic acid are subjected to the nucleophilic substitution reaction under the action of alkali without post-treatment to prepare the compound 5; more preferably, the nucleophilic substitution reaction is carried out by directly adding the mixed solution of the base, formic acid and organic solvent without post-treatment.

The present invention also provides a process for the preparation of compound 5', comprising the steps of: in a solvent, under the action of alkali, carrying out deprotection reaction shown in the specification on the compound 5 prepared by the preparation method to prepare a compound 5';

in the method for preparing the compound 5', the deprotection reaction preferably comprises the following steps: mixing the compound 5 with a solvent, and adding alkali to carry out deprotection reaction; preferably, the deprotection reaction needs to be carried out at the temperature of-25 ℃ to-5 ℃ by adding alkali.

In the preparation method of the compound 5', the solvent can be a solvent conventional in the reaction in the field, and preferably a halogenated hydrocarbon solvent and/or C₁-C₄The alcohol solvent of (1). The halogenated hydrocarbon solvent is preferably dichloromethane. Said C₁-C₄The alcohol solvent of (b) is preferably one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol. The base may be a base conventional in such reactions in the art, preferably an inorganic base. The inorganic base is preferably sodium hydroxide and/or potassium hydroxide. The base is preferably used in the form of an aqueous base solution. The molar concentration of the aqueous solution of the base is not particularly limited as long as it does not affect the reaction, and it is preferable that the molar concentration of the aqueous solution of the base is not specifically limitedThe molar concentration of the aqueous alkali solution is 1mol/L-3 mol/L. The amount of the base used is not particularly limited as long as the reaction is not affected, and preferably, the mass ratio of the compound 5 to the base is 1:1 to 1:3, more preferably 1: 2. The amount of the solvent to be used is not particularly limited as long as the reaction is not affected. The temperature of the deprotection reaction is preferably-25 ℃ to-5 ℃. The progress of the deprotection reaction can be monitored by detection methods conventional in the art (e.g., TLC, HPLC or GC), and is generally terminated when compound 5 disappears. The deprotection reaction time is preferably 5 hours to 20 hours, more preferably 8 hours to 15 hours.

After the deprotection reaction is completed, it is preferable to further include a post-treatment operation. The post-treatment operation may be a post-treatment operation conventional in the art for such reactions in the preparation of epirubicin hydrochloride, and the present invention preferably comprises the following steps: adding organic acid and inorganic base into the reaction solution after the deprotection reaction, extracting with organic solvent (the organic solvent can be conventional organic solvent for extraction in the field, preferably halogenated hydrocarbon solvent) (extracting twice or more), extracting aqueous phase with organic solvent (the organic solvent can be conventional organic solvent for extraction in the field, preferably halogenated hydrocarbon solvent or halogenated hydrocarbon solvent and C)₁-C₄Mixing alcoholic solvent (such as dichloromethane: methanol ═ 4: 1(v/v))), combining all organic phases, washing with water, and removing organic solvent (such as rotary evaporation under reduced pressure). In the post-treatment operation, the organic acid may be an organic acid conventional in such post-reaction treatments in the art, preferably acetic acid. The organic acid is preferably used in the form of an aqueous solution of an organic acid. The mass fraction of the organic acid in the aqueous solution of an organic acid is preferably 5% to 15%, more preferably 8%. The inorganic base may be an inorganic base conventional in the art for such post-reaction treatments, and is preferably sodium bicarbonate. The amount of the organic acid and the inorganic acid may be those conventionally used in such post-reaction treatments in the art, and may not be particularly limited herein.

In the method for producing the compound 5 ', after the compound 5 is produced by the production method described above, the deprotection reaction is preferably carried out in a solvent without any post-treatment under the action of a base to produce the compound 5'.

The invention also provides a preparation method of the epirubicin hydrochloride compound 1, which comprises the following steps: in a solvent, under the action of hydrochloric acid, carrying out deprotection reaction shown in the specification on the compound 5' prepared by the preparation method to prepare a compound 1;

in the preparation method of the compound 1, the solvent can be a solvent which is conventional in the reaction in the field, and preferably a halogenated hydrocarbon solvent and/or C₁-C₄The alcohol solvent of (1). The halogenated hydrocarbon solvent is preferably dichloromethane. Said C₁-C₄The alcohol solvent of (b) is preferably one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol. The hydrochloric acid preferably takes part in the reaction in the form of an aqueous hydrochloric acid solution. The molar concentration of the aqueous hydrochloric acid solution is not particularly limited as long as it does not affect the reaction, and preferably, the molar concentration of the aqueous hydrochloric acid solution is 2mol/L to 4 mol/L. The amount of the hydrochloric acid is not particularly limited as long as it does not affect the reaction, and preferably, it is used in a molar ratio of 26:1 to 52:1 with respect to the compound 5'. The amount of the solvent to be used is not particularly limited as long as the reaction is not affected. The temperature of the deprotection reaction is preferably 0 to 25 ℃. The progress of the deprotection reaction can be monitored by detection methods conventional in the art (e.g., TLC, HPLC or GC), and is generally terminated when compound 5' disappears. The deprotection reaction time is preferably 3 hours to 15 hours, more preferably 5 hours to 10 hours.

In the method for producing compound 1, after the completion of the deprotection reaction, it is preferable that the method further comprises a post-treatment operation. The method and conditions for the post-treatment may be those conventional in the field of organic synthesis, and preferably include the steps of: and (3) demixing the reaction solution after the deprotection reaction is finished, washing the water phase by using an organic solvent (such as dichloromethane) for extraction, combining the organic phase and the water phase, combining the water phase to obtain a crude epirubicin hydrochloride aqueous solution, and then carrying out column chromatography separation and purification. The separation and purification method can be a method which is conventional in the field of epirubicin hydrochloride separation and purification, such as the separation and purification method of epirubicin hydrochloride disclosed in patent IT01237202 and US4861870, and Chinese patent application with application number CN201510744980.0 and application date 2015, 11 and 5, the entire contents of the aforementioned patent applications are incorporated herein.

In a preferred embodiment of the present invention, after compound 5' is prepared according to the above preparation method, hydrochloric acid is preferably added directly without post-treatment to carry out the deprotection reaction to prepare compound 1.

The invention also provides a preparation method of the compound 4, which comprises the following steps: in an organic solvent, under the catalysis of acid and/or acid salt, carrying out condensation reaction shown in the specification on a compound 3 and triisopropyl orthoformate to obtain a compound 4;

wherein, the preparation method of the compound 4 has the same conditions as the above.

The invention also provides a preparation method of the compound 5, which comprises the following steps: in an organic solvent, under the action of alkali, carrying out nucleophilic substitution reaction on the compound 4' and formic acid as shown in the specification to obtain a compound 5;

wherein, the preparation method of the compound 5 has the same conditions as the above.

The present invention also provides a process for the preparation of compound 5', comprising the steps of: in a solvent, under the action of alkali, carrying out deprotection reaction on the compound 5 as shown in the specification to obtain a compound 5';

the conditions of the deprotection method are the same as those described above.

The invention also provides a preparation method of the epirubicin hydrochloride compound 1, which comprises the following steps: in a solvent, under the action of hydrochloric acid, carrying out deprotection reaction on a compound 5' as shown in the specification to prepare a compound 1;

the conditions of the deprotection method are the same as those described above.

The invention also provides a compound shown in the formula 4, a compound shown in the formula 4 ', a compound shown in the formula 5 or a compound shown in the formula 5':

in the present invention, in the structures of the respective compounds

The configuration of the attached carbon atoms is racemic or non-racemic. When it is non-racemic, it is in the S or R configuration.

In the invention, the synthetic route of the preparation method of the epirubicin hydrochloride compound 1 is as follows:

the above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The reagents and starting materials used in the present invention are commercially available.

In the present invention, if the temperature is not indicated, the operation is carried out at room temperature, which is ambient temperature, generally 10 ℃ to 30 ℃.

In the present invention, the temperature of the added materials, the temperature of the mixture of the materials, etc. are the temperature of the reaction system (or the reaction solution).

In the present invention, the term "without post-treatment" generally means that the reaction solution after the completion of the reaction is not subjected to post-treatment.

The positive progress effects of the invention are as follows:

(1) the compound 2 is subjected to two-step reaction to obtain a compound 3, the yield is more than 96%, and the purity is more than 97% without crystallization or column chromatography; the compound 3 is subjected to two-step reaction to obtain a compound 4, the yield is more than 98%, and the purity is more than 90% without crystallization or column chromatography. The compound 4 is obtained by the compound 2 through four-step reaction, the yield is high, a high-purity product can be obtained without crystallization or column chromatography, and the operation is simple. In addition, in the method for preparing the compound 4 by using the compound 2 as a raw material, the amino group is protected firstly, so that the damage of strong acid (such as trifluoroacetic acid) generated in the process to the protection of the dihydroxyl group can be avoided, and the yield and the purity of the compound 3 are improved.

(2) The compound 4 reacts with trifluoromethanesulfonic anhydride to obtain a compound 4 ', and due to the special structure of the compound 4', the compound can directly react with formic acid to obtain a compound 5 under the action of alkali without post-reaction treatment and hydroxyl protection, so that the cost is saved, and the operation steps are reduced. When the compound 5 is deprotected under alkaline and acidic conditions, the concentration of alkali and acid and the reaction temperature are optimized, and after alkaline deprotection, the acid deprotection is directly carried out without post-reaction treatment to obtain the epirubicin hydrochloride, the yield of the two-step reaction is more than 90%, the purity of the final product epirubicin hydrochloride is more than 85%, the operation steps are reduced, and the product yield and purity are improved.

(3) The preparation method has the advantages of short route, easily obtained reaction raw materials, no need of other expensive reagents, low cost, mild reaction conditions, simple operation, yield of more than 65 percent, purity of more than 85 percent, high yield and purity, and contribution to industrial production.

Detailed Description

The doxorubicin hydrochloride of the present invention is provided by Zhejiang Haizheng pharmaceutical industry, Inc.

The purity of compound 3, compound 4-1, compound 4-2, compound 4 ', compound 5 ', compound 29, compound 30, compound 32 and compound 30 ' described in the present invention was determined by HPLC normalization, chromatographic conditions: fortis H₂O column (4.6 mm. times.250 mm, 5 um); mobile phase: 20mmol/L potassium dihydrogen phosphate solution (pH 4.0) (A), acetonitrile (B), gradient elution (0 → 8min, A95%; 8 → 15min, A95% → 25%; 15 → 56min, A25%; 56 → 60min, A25% → 95%; 60 → 65min, A95%); detection wavelength: 245 nm; the column temperature is 40 ℃; the flow rate was 1.0 ml/min.

The purity of the crude doxorubicin hydrochloride and epirubicin hydrochloride in the invention is measured by an HPLC normalization method, and the chromatographic conditions refer to USP38-NF 33.

The concentration of the epirubicin hydrochloride is measured by an HPLC method, the epirubicin hydrochloride in a sample is diluted to a proper concentration, and the concentration of the epirubicin hydrochloride in the sample is obtained by a regression equation.

The regression equation was derived from the standard curve. Drawing a standard curve: precisely weighing a certain amount of epirubicin hydrochloride reference substance, placing the reference substance in a volumetric flask, adding a mobile phase for dissolving to a constant volume, and taking the reference substance as a reference substance stock solution. Precisely measuring a proper amount of stock solution, diluting with a mobile phase to prepare series of standard solutions with the concentrations of 26.3, 52.6, 105.2, 210.4, 315.6, 420.8 and 526.0 mu g/mL, respectively injecting samples, and performing linear regression by taking the epirubicin hydrochloride peak area A (mAU x min) as an ordinate and the concentration c (mu g/mL) as an abscissa to obtain a regression equation: a ═ 0.1186c-0.0469, R²When the average molecular weight is 0.9994, the linear relationship is good in the range of 26.3 to 526.0 [ mu ] g/mL.

The purities mentioned in the examples below all refer to HPLC purities.

EXAMPLE 1 Synthesis of Compound 3

Chemical combinationSubstance 2(30g, 51.8mmol) was suspended in anhydrous tetrahydrofuran (300ml) and trifluoroacetic anhydride (65.3g, 310.8mmol) was added at 15 ℃. The reaction was continued at 15 ℃ for 4 h and sodium bicarbonate (108.8g, 1295mmol), ethyl acetate (300ml) and methanol (30ml) were added and finally water (150ml) was added. Stirring at 30 deg.C for 16 hr, cooling to-5 deg.C, adding hydrochloric acid (14.2ml concentrated hydrochloric acid and 150ml water), stirring, separating layers, washing organic phase with water (150ml × 2), mixing water phases, washing with ethyl acetate (150ml × 2), mixing organic phases, washing with acid aqueous solution (150ml) with pH of 4.0, and washing with water (150 ml). The organic phase was spin dried under reduced pressure and dried at 35 ℃ under vacuum to constant weight to give compound 3(32.4g, yield 98%), mp 171-173 ℃, purity 98.5%. Q-TOF ESI-MS (m/z): 662[ M + Na ]]⁺；¹H NMR(400MHz，DMSO-d₆)δ：14.03(br s，1H，11-OH)，13.26(s，1H，6-OH)，9.08(d，J＝7.4Hz，1H，3′-NH)，7.88～7.93(m，2H，1-H，2-H)，7.62～7.67(m，1H，3-H)，5.47(s，1H，1′-H)，5.26(d，J＝3.1Hz，1H，7-H)，4.99(d，J＝5.9Hz，1H，4′-OH)，4.93～4.97(m，1H，5′-H)，4.84(t，J＝6.0Hz，1H，3′-H)，4.58(d，J＝6.0Hz，2H，14-CH₂)，4.16～4.25(m，1H，9-OH)，4.00～4.07(m，1H，4′-H)，3.98(s，3H，-OCH₃)，3.52(d，J＝4.3Hz，1H，14-OH)，2.96～3.04(m，1H，10-H_β)，2.90～2.96(m，1H，10-H_α)，2.17～2.25(m，1H，8-H_β)，2.03～2.15(m，2H，8-H_α，2′-H_β)，1.48(dd，J＝4.3，16.2Hz，1H，2′-H)，1.13(d，J＝6.5Hz，3H，-CH₃)；¹³C NMR(400MHz，DMSO-d₆)δ：214.00(C-13)，186.13，186.25(C-5，C-12)，160.68(C-4)，156.08(C-6)，155.20，155.56，155.92，156.28(C-6′)，154.47(C-11)，136.09(C-2)，134.45，135.33(C-6α，C-12α)，134.07(C-10α)，119.59，119.78(C-1，C-3)，118.86(C-4α)，111.49，114.35，117.22，120.09(CF₃)，110.44，110.57(C-5α，C-11α)，100.03(C-1′)，74.81(C-9)，69.85(C-7)，66.92(C-5′)，66.43(C-4′)，63.76(C-14)，56.51(OCH₃)，47.00(C-3′)，36.45(C-8)，31.94(C-10)，28.73(C-2′)，16.92(CH₃)。

EXAMPLE 2 Synthesis of Compound 4

Compound 3(32.4g, 50.7mmol) was suspended in anhydrous tetrahydrofuran (226.4ml), camphorsulfonic acid (16.2mg) was added, triisopropyl orthoformate (57.9g, 304.2mmol) was added, and the reaction was continued at 25 ℃ for 0.5 hour and under reflux for 1.8 hours. The temperature was reduced to 30 ℃ and water (22.7ml) was added to the mixture, followed by addition of sodium hydrogencarbonate (0.2g) and stirring for 1 hour. Acetic acid (43.9ml) was added thereto, and the mixture was stirred at 30 ℃ for 16 hours. The temperature was reduced to-5 ℃ and an aqueous sodium bicarbonate solution (784 ml water in 67.8g sodium bicarbonate) was added and stirred for 1 hour. Ethyl acetate (114ml) was added, the layers were separated and the organic layer was washed with water (114 ml. times.2). The aqueous phases were combined and washed with ethyl acetate (227 ml. times.2). The organic phases were combined and washed with water (114 ml). The organic phase was evaporated to dryness and dried in a vacuum oven at 35 ℃ to constant weight to give compound 4(35.4g, 98.5% yield) with a purity of 91.2%. Compound 4 was analyzed by HPLC, and the results are shown in Table 1.

In table 1, numerals 1, 2, 3 and 4 are peak marks indicating information on retention time, peak height, peak area, relative area, etc. of each component in compound 4 obtained in example 2.

TABLE 1

In this, peak No. 2 represents compound 4.

The compound 4 is theoretically a pair of epimers, two main peaks appearing in HPLC analysis are separated by silica gel column chromatography to obtain a compound 4-1 and a compound 4-2, and mass spectra, nuclear magnetic hydrogen spectra and HPLC analysis are respectively carried out, and the mass spectra of the two compounds have ESI-MS (m/z): 732[ M + Na ]]⁺Molecular ion peak of (a); nuclear magnetic hydrogen spectrum of compound 4-1:¹H NMR(400MHz，DMSO-d₆)δ：13.94～14.00(m，1H，11-OH)，13.19(s，1H，6-OH)，8.93(d，J＝7.3Hz，1H，3′-NH)，7.86～7.89(m，2H，1-H，2-H)，7.60～7.63(m，1H，3-H)，5.86(s，1H，15-H)，5.25(d，J＝2.8Hz，1′-H)，5.00～5.02(m，1H，7-H)，4.89(d，J＝4.5Hz，1H，4′-OH)，4.33～4.55(m，2H，14-CH₂)，4.22(q，J＝6.2Hz，1H，5′-H)，4.04～4.06(m，1H，3′-H)，3.97(s，3H，-OCH₃)，3.92～3.95(m，1H，4′-H)，3.49(br s，1H，16-H)，3.34(d，J＝18.0Hz，1H，10-H_β)，2.81(d，J＝17.9Hz，1H，10-H_α)，2.36～2.42(m，1H，8-H_β)，2.25～2.29(m，1H，8-H_α)，1.99～2.13(m，2H，2′-CH₂)，1.11～1.14(m，9H，5′-CH₃，16-CH₃，16-CH₃) (ii) a Nuclear magnetic hydrogen spectrum of compound 4-2:¹H NMR(400MHz，DMSO-d₆)δ：14.00(s，1H，11-OH)，13.14(s，1H，6-OH)，9.03(d，J＝7.2Hz，1H，3′-NH)，7.84～7.88(m，2H，1-H，2-H)，7.59(d，J＝7.3Hz，1H，3-H)，5.86(s，1H，15-H)，5.37(d，J＝2.4Hz，1H，1′-H)，4.97(d，J＝4.3Hz，1H，7-H)，4.94(d，J＝4.0Hz，1H，4′-OH)，4.46(s，2H，14-CH₂)，4.10～4.13(m，1H，5′-H)，4.02～4.06(m，1H，3′-H)，3.97(s，3H，-OCH₃)，3.88～3.94(m，1H，4′-H)，3.54(br s，1H，16-H)，3.17(d，J＝18.2Hz，1H，10-H_β)，2.90(d，J＝18.2Hz，1H，10-H_α)，2.55～2.67(m，1H，8-H_β)，2.05～2.15(m，2H，8-H_α，2′-H_β)，1.91～2.02(m，1H，2′-H_α)，1.02～1.18(m，9H，5′-CH₃，16-CH₃，16-CH₃) The mass spectrum and nuclear magnetic hydrogen spectrum show that the two isomers are a pair of epimers. The results of HPLC analysis of Compound 4-1 and Compound 4-2 are shown in Table 2 or Table 3.

In table 2, numerals 1, 2, 3 and 4 are peak marks indicating information on retention time, peak height, peak area, relative area, etc. of each component in compound 4-1 obtained by column chromatography resolution of compound 4 prepared in example 2.

TABLE 2

Wherein, peak No. 4 represents Compound 4-1.

In table 3, numerals 1, 2, 3 and 4 are peak marks indicating information on retention time, peak height, peak area, relative area, etc. of each component in compound 4-2 obtained by column chromatography resolution of compound 4 prepared in example 2.

TABLE 3

Wherein, peak No. 3 represents Compound 4-2.

Synthesis of common orthoester protected products:

according to the synthesis method of the compound 4, the compound 3 reacts with common orthoester to obtain a series of orthoester protection products, and the yield is shown in the following table 4:

TABLE 4

Debishydroxy protection of common orthoester protection products:

5g of each of the compound 4 and the compounds having a high yield of orthoester protection (trimethyl orthoacetate protected product, triethyl orthoacetate protected product, trimethyl orthopropionate protected product and triethyl orthopropionate protected product) was dissolved in methanol (100ml), and hydrochloric acid (1mol/L, 100ml) was added to carry out a reaction at room temperature for 10 hours to obtain a compound 3, the yields of which are shown in Table 5 below:

TABLE 5

Reactants	Yield of dehydrodihydroxyl protection
		Compound 4	97％
Trimethyl orthoacetate protected product	20％
		Triethyl orthoacetate protection of the product	22％
Trimethyl orthopropionate protected product	11％
		Triethyl orthopropionate protection product	12％

EXAMPLE 3 Synthesis of Compound 4

Compound 4(35.2g, 49.6mmol) was dissolved in anhydrous dichloromethane (321ml), and anhydrous pyridine (19.7g, 249.4mmol) was added. The temperature is reduced to-5 ℃. Dropwise adding trifluoromethanesulfonic anhydride (28.1g, 99.6mmol) diluted with anhydrous dichloromethane (30ml), reacting for 30 minutes at-5 ℃ for 1 hour, adding n-heptane to the reaction system, separating out a solid, and filtering to obtain compound 4' (37.5g, yield 90%), purity 85%, ESI-MS (m/z): 864[ M + Na ]]⁺。

EXAMPLE 4 Synthesis of Compound 5

Compound 4' (37.5g, 44.6mmol) was dissolved in anhydrous dichloromethane (321ml), and a prepared triethylamine formic acid dichloromethane solution (triethylamine 45.1g, anhydrous formic acid 20.5g, anhydrous dichloromethane 209ml) was added thereto, and the mixture was stirred at 25 ℃ for 16 hours to terminate the reaction by inversion. Adding sodium bicarbonate (68.2g), adding water (1000ml) dropwise, separating layers, collecting organic phase, washing with 8% acetic acid water solution (300ml × 2), mixing acetic acid water solutions, washing with dichloromethane (200 × 2ml), mixing organic phases, washing with 5% sodium bicarbonate (300ml), mixing sodium bicarbonate water solutions, dichloromethane(200 ml. times.2 ml) wash, combine the organic phases and wash with water (300. times.2 ml). The organic phase was spin dried to give compound 5(28.3g, 86% yield) with 77% purity. ESI-MS (m/z): 760[ M + Na ]]⁺。

EXAMPLE 5 Synthesis of Compound 5

Compound 4' (37.5g, 44.6mmol) was dissolved in anhydrous dichloromethane (321ml), and a prepared triethylamine formic acid dichloromethane solution (triethylamine 112.8g, anhydrous formic acid 25.7g, anhydrous dichloromethane 209ml) was added thereto, and the mixture was stirred at 25 ℃ for 16 hours to terminate the reaction by inversion. Sodium bicarbonate (68.2g) was added, water (1000ml) was added dropwise, the layers were separated, the organic phase was taken, washed with 8% aqueous acetic acid (300ml x 2), combined aqueous acetic acid, dichloromethane (200 x 2ml), combined organic phase, 5% aqueous sodium bicarbonate (300ml), combined aqueous sodium bicarbonate, dichloromethane (200ml x 2ml), combined organic phase and water (300 x 2 ml). The organic phase was spin dried to give compound 5(28.0g, 85% yield) with 75% purity. ESI-MS (m/z): 760[ M + Na ]]⁺。

EXAMPLE 6 Synthesis of Compound 5

Compound 4' (37.5g, 44.6mmol) was dissolved in anhydrous dichloromethane (321ml), and a prepared triethylamine formic acid dichloromethane solution (203.1 g triethylamine, 30.8g anhydrous formic acid, 209ml anhydrous dichloromethane) was added thereto, and the mixture was stirred at 25 ℃ for 16 hours to terminate the reaction by inversion. Sodium bicarbonate (68.2g) was added, water (1000ml) was added dropwise, the layers were separated, the organic phase was taken, washed with 8% aqueous acetic acid (300ml x 2), combined aqueous acetic acid, dichloromethane (200 x 2ml), combined organic phase, 5% aqueous sodium bicarbonate (300ml), combined aqueous sodium bicarbonate, dichloromethane (200ml x 2ml), combined organic phase and water (300 x 2 ml). The organic phase was spin dried to give compound 5(27.3g, 83% yield) with a purity of 73%. ESI-MS (m/z): 760[ M + Na ]]⁺。

EXAMPLE 7 Synthesis of Compound 5

Compound 4(35.5g, 50.0mmol) was dissolved in anhydrous dichloromethane (321ml), and anhydrous pyridine (25.7g, 325mmol) was added. The temperature is reduced to-2 ℃. Trifluoromethanesulfonic anhydride (35.3g, 125mmol) diluted with dry dichloromethane (30ml) was added dropwise and the reaction was continued for 30 minutes at-2 ℃ for 1 hour. Adding prepared triethylamine formic acid dichloromethane solution (188.1 g of triethylamine, 28.7g of anhydrous formic acid and 209ml of anhydrous dichloromethane), stirring for 16 hours at 20-25 ℃, and finishing the overturning reaction.

EXAMPLE 8 Synthesis of 5' Compound

Methanol (562ml) was added to the reaction mixture after the end of the inversion reaction in example 7, and the temperature was lowered to-20 ℃. Aqueous sodium hydroxide (894ml water, 56.0g sodium hydroxide, 1.6mol/L) was added. After 10 hours of reaction at-20 ℃, 8% acetic acid aqueous solution (300ml) was added dropwise, sodium hydrogencarbonate (36g) was added thereto, and the mixture was stirred for one hour and naturally warmed. Dichloromethane (300ml) was added, the layers were separated, the aqueous phase was extracted with dichloromethane: methanol 4: 1(300 × 2ml), the organic phases were combined, washed with water (300ml), and the organic phase was evaporated to dryness to give compound 5' (28.7g, 95% yield) in 85% purity as compound 4, ESI-MS (m/z): 613[ M + Na ]]⁺。

EXAMPLE 9 Synthesis of Compound 5

Compound 5(28.3g, 38.4mmol) was dissolved in methanol (562ml) and cooled to-25 ℃. Aqueous sodium hydroxide (707.5ml water, 28.3g sodium hydroxide, 1mol/L) was added. After 10 hours of reaction at-25 ℃, 8% acetic acid aqueous solution (525ml) was added dropwise, sodium hydrogencarbonate (63g) was added thereto and stirred for one hour, and the temperature was naturally raised. Dichloromethane (300ml) was added, the layers were separated, the aqueous phase was extracted with dichloromethane: methanol 4: 1(2 × 300ml), the organic phases were combined, washed with water (300ml) and the organic phase was evaporated to dryness to give compound 5' (22.4g, 95% yield), 86% purity, ESI-MS (m/z): 613[ M + Na ]]⁺。

EXAMPLE 10 Synthesis of Compound 5

Compound 5(28.3g, 38.4mmol) was dissolved in ethanol (562ml) and cooled to-15 ℃. Aqueous sodium hydroxide (707.5ml water, 56.6g sodium hydroxide, 2mol/L) was added. After the reaction was carried out at-15 ℃ for 10 hours, 8% aqueous acetic acid (1050ml) was added dropwise thereto, sodium hydrogencarbonate (126g) was added thereto and the mixture was stirred for one hour, followed by natural warming. Dichloromethane (300ml) was added, the layers were separated, the aqueous phase was extracted with dichloromethane: methanol 4: 1(300 × 2ml), the organic phases were combined, washed with water (300ml) and the organic phase was evaporated to dryness to give compound 5' (21.2g, 90% yield), 85% purity, ESI-MS (m/z): 613[ M + Na ]]⁺。

EXAMPLE 11 Synthesis of Compound 5

Compound 5(28.3g, 38.4mmol) was dissolved in butanol (562ml) and cooled to-5 ℃. Aqueous potassium hydroxide (504ml water, 84.9g potassium hydroxide, 3mol/L) was added. After 10 hours of reaction at-5 ℃ C, 8% aqueous acetic acid (1122ml) was added dropwise thereto, followed by addition of sodium hydrogencarbonate (135g) and stirring for one hour, followed by natural warming. Dichloromethane (300ml) was added, the layers were separated, the aqueous phase was extracted with dichloromethane: methanol 4: 1(300 × 2ml), the organic phases were combined, washed with water (300ml) and the organic phase was evaporated to dryness to give compound 5' (21.2g, 90% yield), 84% purity, ESI-MS (m/z): 613[ M + Na ]]⁺。

EXAMPLE 12 Synthesis of epirubicin hydrochloride

Methanol (562ml) was added to the reaction mixture after the end of the inversion reaction in example 7, and the temperature was lowered to-20 ℃. Aqueous sodium hydroxide (894ml water, 56.0g sodium hydroxide, 1.6mol/L) was added. The reaction was carried out at-20 ℃ for 10 hours, and hydrochloric acid (3mol/L, 621ml) was added without any post-treatment. The temperature was raised to 10 ℃ and stirred for 7 hours. The layers were separated and the aqueous layer was washed with dichloromethane (562 ml. times.2). The organic phases were combined and washed with water (562 ml. times.2). And combining the water phases to obtain 3L of crude epirubicin hydrochloride aqueous solution with the purity of 89.0%, diluting to a proper concentration, obtaining the concentration of epirubicin hydrochloride in the crude epirubicin hydrochloride aqueous solution from a regression equation to be 6.8g/L, and obtaining the yield of the crude epirubicin hydrochloride from doxorubicin hydrochloride to be 68%. ESI-MS (m/z): 544[ M-HCl + H]⁺，¹H NMR(400MHz，DMSO-d₆)δ：13.96(br s，1H，11-OH)，13.15(s，1H，6-OH)，8.08(s，3H，3′-⁺NH₃)，7.82～7.85(m，2H，1-H，2-H)，7.58～7.60(m，1H，3-H)，5.77(s，1H，1′-H)，5.48(s，1H，7-H)，5.26(s，1H，4′-OH)，4.88(s，2H，14-CH₂)，4.54～4.64(m，2H，5′-H，3′-H)，3.14～3.34(m，4H，9-OH，-OCH₃)，2.93～2.97(m，2H，10-CH₂)，2.79～2.83(m，1H，4′-H)，2.48～2.50(m，1H，14-OH)，2.07～2.18(m，3H，8-H_β，8-H_α，2′-H_β)，1.79-2.04(m，1H，2′-H_α)，1.03-1.21(m，3H，-CH₃)；¹³C NMR(400MHz，DMSO-d₆)δ：214.52(C-13)，186.46，186.58(C-5，C-12)，161.11(C-4)，156.40(C-6)，154.82(C-11)，136.57(C-2)，134.79，135.41(C-6α，C-12α)，134.59(C-10α)，120.03，120.09(C-1，C-3)，119.28(C-4α)，110.86，110.93(C-5α，C-11α)，99.13(C-1′)，75.19(C-9)，72.81(C-7)，70.26(C-5′)，68.85(C-4′)，64.33(C-14)，56.98(OCH₃)，49.95(C-3′)，36.86(C-8)，34.18(C-10)，32.46(C-2′)，17.98(CH₃)。

The crude epirubicin hydrochloride prepared in example 7 was subjected to HPLC analysis, the results of which are shown in Table 6 below:

in Table 6, numerals 1 to 18 are peak marks indicating information on retention time, peak height, peak area, relative area, etc. of each component in the crude epirubicin hydrochloride prepared in example 7.

TABLE 6

Wherein, peak 11 represents epirubicin hydrochloride.

Example 13 Synthesis of epirubicin hydrochloride

Compound 5' (22.4g, 36.5mmol) was dissolved in a mixed solvent of methylene chloride (562ml) and methanol (562ml), and hydrochloric acid (3mol/L, 316ml) was added thereto at 0 ℃ and stirred at 0 ℃ for 7 hours. The layers were separated and the aqueous layer was washed with dichloromethane (562 ml. times.2). The organic phases were combined and washed with water (562 ml. times.2). And combining the water phases to obtain 3L of epirubicin hydrochloride crude water solution with the purity of 89.0%, diluting to a proper concentration, obtaining the concentration of epirubicin hydrochloride in the epirubicin hydrochloride crude water solution from a regression equation to be 6.7g/L, and obtaining the yield of the epirubicin hydrochloride crude product from the compound 5' to be 95%.

EXAMPLE 14 Synthesis of Compound 3

Compound 2(30g, 51.8mmol) was suspended in anhydrous 2-methyltetrahydrofuran (300ml), and trifluoroacetic anhydride (43.5g, 207.2mmol) was added at 10 ℃. The reaction was continued at 10 ℃ for 4 h and sodium carbonate (82.4g, 777mmol), 2-methyltetrahydrofuran (300ml) and methanol (30ml) were added and finally water (150ml) was added. Stirring at 35 deg.C for 16 hr, cooling to 0 deg.C, and adding hydrochloric acid (14.2ml concentrated hydrochloric acid and 150ml water). The layers were separated by stirring and the organic phase was washed with water (150 ml. times.2), the aqueous phases were combined, ethyl acetate (150 ml. times.2) was washed, the organic phases were combined, washed with aqueous acid (150ml) at pH 4.0 and with water (150 ml). The mixture was dried by spinning under reduced pressure at 35 ℃ under vacuum to constant weight to obtain compound 3(32.1g, 97% yield) with a purity of 98.2%.

EXAMPLE 15 Synthesis of Compound 4

Compound 3(32.1g, 50.2mmol) was suspended in anhydrous 2-methyltetrahydrofuran (226.4ml), pyridine hydrochloride (25.7mg) was added, triisopropyl orthoformate (47.8g, 251mmol) was added, reaction was carried out at 30 ℃ for 5 hours, and reaction was continued under reflux for 0.5 hour. The temperature was reduced to 25 ℃ and water (22.7ml) was added to the mixture, followed by addition of sodium hydrogencarbonate (0.2g) and stirring for 1 hour. Propionic acid (38ml) was added thereto, and the mixture was stirred at 10 ℃ for 15 hours. The temperature was reduced to 0 ℃ and sodium bicarbonate solution (67.8g sodium bicarbonate plus 784ml water) was added and stirred for 1 hour. Ethyl acetate (114ml) was added, the layers were separated and the organic layer was washed with water (114 ml. times.2). The aqueous phases were combined and washed with ethyl acetate (227 ml. times.2). The organic phases were combined and washed with water (114 ml). The organic phase was evaporated to dryness and dried in a vacuum oven at 35 ℃ to constant weight to give compound 4(34.9g, 98% yield) with 90.2% purity.

EXAMPLE 16 Synthesis of Compound 5

Compound 4(34.9g, 49.2mmol) was dissolved in anhydrous dichloromethane (321ml), and anhydrous pyridine (31.1g, 393.6mmol) was added. Cooling to 0 deg.C, and protecting with nitrogen. Trifluoromethanesulfonic anhydride (41.6g, 147.6mmol) diluted with anhydrous dichloromethane (30ml) was added dropwise over 30 minutes and the reaction was continued at 0 ℃ for 1 hour. A previously prepared triethylamine formic acid dichloromethane solution (156.8 g of triethylamine, 28.7g of anhydrous formic acid, 209ml of anhydrous dichloromethane) was added thereto, and the mixture was stirred at 25 ℃ for 16 hours to complete the reaction by inversion. Sodium bicarbonate (68.2g) was added, water (1000ml) was added dropwise, the layers were separated, the organic phase was taken, washed with 8% aqueous acetic acid (300ml x 2), combined aqueous acetic acid, dichloromethane (200 x 2ml), combined organic phase, 5% sodium bicarbonate (300ml), combined aqueous sodium bicarbonate, dichloromethane (200ml x 2ml), combined organic phase and water (300 x 2 ml). The organic phase was spin dried to give compound 5(30.3g, 92% yield) with 87% purity. ESI-MS (m/z): 760[ M + Na ]]⁺。

Example 17 Synthesis of epirubicin hydrochloride

Compound 5' (22.4g, 36.5mmol) was dissolved in a mixed solvent of methylene chloride (562ml) and methanol (562ml), and hydrochloric acid (2mol/L, 712ml) was added at 12 ℃ and stirred at 12 ℃ for 7 hours. The layers were separated and the aqueous layer was washed with dichloromethane (562 ml. times.2). The organic phases were combined and washed with water (562 ml. times.2). And combining the water phases to obtain 3L of crude epirubicin hydrochloride aqueous solution with the purity of 88.2%, diluting to a proper concentration, obtaining the concentration of epirubicin hydrochloride in the crude epirubicin hydrochloride aqueous solution from a regression equation to be 6.6g/L, and obtaining the yield of the crude epirubicin hydrochloride from the compound 5' to be 94%.

EXAMPLE 18 Synthesis of Compound 3

Compound 2(30g, 51.8mmol) was suspended in anhydrous dichloromethane (300ml) and trifluoroacetic anhydride (54.4g, 259mmol) was added at 25 ℃. The reaction was continued at 20 ℃ for 4 hours and potassium bicarbonate (107.2g, 1070.5mmol), tetrahydrofuran (300ml) and methanol (30ml) were added and water (150ml) was added over 30 minutes. Stirring at 33 deg.C for 16 hr, cooling to 0 deg.C, and adding hydrochloric acid (14.2ml concentrated hydrochloric acid and 150ml water). The layers were separated by stirring and the organic phase was washed with water (150 ml. times.2), the aqueous phases were combined, dichloromethane (150 ml. times.2) was used, the organic phases were combined, washed with aqueous acid (150ml) at pH 4.0 and water (150 ml). The organic phase was spin-dried under reduced pressure and dried at 35 ℃ under vacuum to constant weight to give compound 3(32.5g, yield 98%) with 98.3% purity.

EXAMPLE 19 Synthesis of Compound 4

Compound 3(32.5g, 50.9mmol) was suspended in anhydrous dichloromethane (226.4ml), pyridine p-toluenesulfonate (21.1mg) was added, triisopropyl orthoformate (53.3g, 280mmol) was added, and the reaction was continued at 25 ℃ for 2.8 hours and under reflux for 3 hours. The temperature was reduced to 25 ℃ and water (22.7ml) was added to the mixture, followed by addition of sodium hydrogencarbonate (0.2g) and stirring for 1 hour. Butyric acid (93.4ml) was added thereto, and the mixture was stirred at 20 ℃ for 18 hours. The temperature was reduced to 0 ℃ and sodium bicarbonate solution (67.8g sodium bicarbonate plus 784ml water) was added and stirred for 1 hour. Dichloromethane (114ml) was added, the layers were separated and the organic phase was washed with water (114 ml. times.2). The aqueous phases were combined and washed with dichloromethane (227 ml. times.2). The organic phases were combined and washed with water (114 ml). The organic phase was evaporated to dryness and dried in a vacuum oven at 35 ℃ to constant weight to give compound 4(35.5g, 99% yield) with a purity of 91.5%.

EXAMPLE 20 Synthesis of epirubicin hydrochloride

Compound 5' (22.4g, 36.5mmol) was dissolved in a mixed solvent of methylene chloride (562ml) and methanol (562ml), and hydrochloric acid (4mol/L, 475ml) was added thereto at 25 ℃ and stirred at 25 ℃ for 7 hours. The layers were separated and the aqueous layer was washed with dichloromethane (562 ml. times.2). The organic phases were combined and washed with water (562 ml. times.2). And combining the water phases to obtain 3L of epirubicin hydrochloride crude water solution with the purity of 80.2%, diluting to a proper concentration, obtaining the concentration of epirubicin hydrochloride in the epirubicin hydrochloride crude water solution from a regression equation to be 6.3g/L, and obtaining the yield of the epirubicin hydrochloride crude product from the compound 5' to be 90%.

EXAMPLE 21 Synthesis of Compound 4

Compound 3(32.4g, 50.7mmol) was suspended in anhydrous tetrahydrofuran (226.4ml), camphorsulfonic acid (16.2mg) was added, triisopropyl orthoformate (57.9g, 304.2mmol) was added, and the reaction was continued at 30 ℃ for 0.5 hour and under reflux for 1.8 hours. The temperature was reduced to 30 ℃ and water (22.7ml) was added to the mixture, followed by addition of sodium hydrogencarbonate (0.2g) and stirring for 1 hour. Ethyl acetate (114ml) was added, the layers were separated and the organic layer was washed with water (114 ml. times.2). The aqueous phases were combined and washed with ethyl acetate (227 ml. times.2). The organic phases were combined and washed with water (114 ml). The organic phase was evaporated to dryness and dried in a vacuum oven at 35 ℃ to constant weight to give compound 4(35.2g, 98% yield) with 85.1% purity.

EXAMPLE 22 Synthesis of epirubicin hydrochloride

Compound 5(30.3g, 41.1mmol) was dissolved in dichloromethane (562ml), methanol (562ml) was added and the temperature was reduced to-20 ℃. Aqueous sodium hydroxide (443ml water, 28.3g sodium hydroxide, 1.6mol/L) was added. The reaction was carried out at-20 ℃ for 10 hours, and an aqueous hydrochloric acid solution (3mol/L, 380ml) was added without any post-treatment. The temperature was raised to 10 ℃ and stirred for 7 hours. The layers were separated and the aqueous layer was washed with dichloromethane (562 ml. times.2). The organic phases were combined and washed with water (562 ml. times.2). And combining the water phases to obtain 3L of epirubicin hydrochloride crude water solution with the purity of 89.0%, diluting to a proper concentration, and obtaining the epirubicin hydrochloride crude water solution with the concentration of 7.2g/L and the yield of 91% by a regression equation.

Comparative example 1 Synthesis of Compound 29

Compound 2(30g, 51.8mmol) was dissolved in N, N-dimethylformamide (600ml), and triethyl orthoformate (150ml) and trifluoroacetic acid (15ml) were added to stir at room temperature for 3 hours. Sodium bicarbonate (15g) and dichloromethane (600ml) were added successively, and finally water (150ml) was added dropwise over 30 minutes. After stirring at room temperature for 1 hour, the layers were separated and the organic phase was washed with water (150 ml. times.2), the aqueous phases were combined and washed with dichloromethane (300 ml. times.2), the organic phases were combined and washed with water (150 ml). The organic phase was spin dried under reduced pressure and dried under vacuum at 35 ℃ to constant weight to give compound 29(20.2g, yield 68%) with a purity of 80.3%.

Comparative example 2 Synthesis of Compound 30

Compound 29(20.2g, 33.7mmol) was dissolved in dichloromethane (600ml), N-methylmorpholine (46.9ml) was added and the temperature was reduced to 0 ℃. A solution of trifluoroacetic anhydride in dichloromethane was added (15ml of trifluoroacetic anhydride in 112.5ml of dichloromethane) and the reaction was continued at 0 ℃ for 3 hours. Sodium bicarbonate (56.3g) and methanol (562.5ml) were added and stirred for 20 minutes. Water (937.5ml), 0.25mol/L aqueous hydrochloric acid (937.5ml) and water (937.5 ml). The organic phase was spin dried under reduced pressure and dried at 35 ℃ under vacuum to constant weight to give compound 30(16.9g, 84% yield) with 75.0% purity.

Comparative example 3 Synthesis of Compound 32

Compound 30(19.1g, 32.0mmol) was dissolved in dichloromethane (1875ml) and pyridine (93.75ml) was added. The temperature was lowered to 0 ℃ and trifluoromethanesulfonic anhydride (9.4ml) diluted with dichloromethane (375ml) was added dropwise over 30 minutes at 0 ℃ for 1 hour. N, O-bis (trimethylsilyl) acetamide (BSA, 37.5ml) was added thereto, and the reaction was carried out at room temperature for 4 hours. 1mol/L of a triethylamine formate dichloromethane solution (1875ml) prepared in advance was added thereto, and the mixture was stirred at room temperature for 15 hours to terminate the tumbling reaction. A48% aqueous solution (187.5ml) of potassium fluoride was added, and methanol (375ml) was added thereto and the mixture was stirred at room temperature for 2 days. 0.5mol/L hydrochloric acid (1875ml), 3% sodium bicarbonate aqueous solution (1875ml), and water (1875 ml). The organic phase was dried over anhydrous sodium sulfate and rotary dried under reduced pressure to give compound 32(20.8g, yield 90%) with a purity of 65.0%.

Comparative example 4 Synthesis of epirubicin hydrochloride

Compound 32(20.8g, 28.8mmol) was added to a 0.1mol/L aqueous solution of sodium hydroxide (4688ml), and reacted at 5 ℃ for 3 hours. Chloroform (4688 ml. times.4), and the organic phase was dried over anhydrous sodium sulfate and then dried by spin-drying under reduced pressure. The solid was dissolved in methanol (1875ml), adjusted to pH 2 with hydrochloric acid and stirred for 30 minutes. Decompression drying at room temperature, pulping isopropyl ether to obtain crude epirubicin hydrochloride (9.0g, yield 30%) and purity 69%.

Comparative example 5

Compound 30(30.4g, 49.6mmol) was dissolved in anhydrous dichloromethane (321ml), and anhydrous pyridine (19.7g, 249.4mmol) was added and the temperature was reduced to-5 ℃. Trifluoromethanesulfonic anhydride (28.1g, 99.6mmol) diluted with anhydrous dichloromethane (30ml) was added dropwise and the reaction was continued for a further 1 h at-5 ℃ over 30 min, and the solution of triethylamine formic acid in dichloromethane (62.7 g triethylamine, 28.7g anhydrous formic acid, 209ml anhydrous dichloromethane) prepared beforehand was added without work-up, stirred for 16 h at 25 ℃, sodium bicarbonate (68.2g) was added, water (1000ml) was added dropwise and the layers were separated, the organic phase was taken, washed with 8% aqueous acetic acid (00 ml. times.2), combined with aqueous acetic acid, dichloromethane (200. times.2 ml), combined with the organic phase, washed with 5% sodium bicarbonate (300ml), combined with aqueous sodium bicarbonate, dichloromethane (200. times.2 ml), combined with the organic phase and washed with water (300. times.2 ml). The organic phase was spin dried to give compound 32(30.8g, 86% yield based on compound 30), 50% purity, ESI-MS (m/z): 746[ M + Na ]]⁺。

Comparative example 6 Synthesis of epirubicin hydrochloride

Compound 5(21.2g, 28.8mmol) was added to a 0.1mol/L aqueous solution of sodium hydroxide (4688ml), and reacted at 5 ℃ for 3 hours. Chloroform (4688 ml. times.4), and the organic phase was dried over anhydrous sodium sulfate and then dried by spin-drying under reduced pressure. The solid was dissolved in methanol (1875ml), adjusted to pH 2 with hydrochloric acid and stirred for 30 minutes. And (3) carrying out decompression spin-drying at room temperature, and pulping isopropyl ether to obtain a crude epirubicin hydrochloride product (18.0g, yield 60%) with purity of 79%.

Although specific embodiments of the present invention have been described above, it will be appreciated by those skilled in the art that these are merely illustrative and that various changes or modifications may be made without departing from the principles and spirit of the invention. The scope of the invention is therefore defined by the appended claims.

Claims (14)

1. A process for the preparation of compound 5, characterized in that it comprises the following steps:

1) in an organic solvent, under the action of alkali, the compound 4 and trifluoromethanesulfonic anhydride are subjected to esterification reaction as shown in the following to obtain a compound 4'

2) In an organic solvent, under the action of alkali, the compound 4' and formic acid are subjected to nucleophilic substitution reaction as shown in the specification to prepare a compound 5

Wherein in the step 1), the organic solvent is a halogenated hydrocarbon solvent; the halogenated hydrocarbon solvent is dichloromethane; the alkali is organic alkali; the organic base is pyridine; the molar ratio of the alkali to the compound 4 is 3:1-10: 1; the molar ratio of the trifluoromethanesulfonic anhydride to the compound 4 is 1:1-5: 1; the temperature of the esterification reaction is-5 ℃ to 0 ℃; the esterification reaction comprises the following steps: mixing the compound 4, an organic solvent and alkali, and adding trifluoromethanesulfonic anhydride to perform the esterification reaction; the esterification reaction needs to be controlled at the temperature of-5-0 ℃, trifluoromethanesulfonic anhydride is added, and the esterification reaction is carried out under the protection of gas; the gas is N₂。

2. The method of claim 1, wherein compound 4 is prepared by a process comprising the following step 1'):

1') in an organic solvent, and under the catalysis of acid and/or acid salt, carrying out condensation reaction shown as the following on a compound 3 and triisopropyl orthoformate to obtain a compound 4

3. The process according to claim 2, wherein, in step 1'),

the acid is organic acid, and the acid salt is pyridine hydrochloride and/or pyridine p-methylbenzene sulfonate; the organic solvent is an ether solvent and/or a halogenated hydrocarbon solvent; the ether solvent is tetrahydrofuran and/or 2-methyltetrahydrofuran; the halogenated hydrocarbon solvent is dichloromethane; the molar ratio of triisopropyl orthoformate to the compound 3 is 4:1-10: 1; the mass of the acid and/or the acid salt is 0.01-0.2% of that of the compound 3; the temperature of the condensation reaction is 25 ℃ to the solvent reflux temperature under normal pressure; the condensation reaction comprises a first-stage reaction and a second-stage reaction, wherein the temperature of the first-stage reaction is 25-30 ℃; the temperature of the second stage reaction is the reflux temperature of the solvent under normal pressure; the condensation reaction comprises the following steps: suspending the compound 3 in an organic solvent, adding acid and/or acid salt and triisopropyl orthoformate, and carrying out the condensation reaction; after the condensation reaction is finished, further comprising the operation of treating the reaction liquid after the condensation reaction with an organic acid with a pKa value of 3-5; the organic acid is one or more of formic acid, acetic acid, n-propionic acid, n-butyric acid, citric acid, fumaric acid and tartaric acid; the molar ratio of the organic acid to the compound 3 is 5:1-20: 1; the temperature of the organic acid treatment is 10-30 ℃.

4. The process of claim 2, wherein compound 3 is prepared by a process comprising the following step 1 "):

1') subjecting the compound 2 and trifluoroacetic anhydride to acylation reaction in an organic solvent A, and then treating the reaction solution after the acylation reaction with alkali in the solvent to obtain the compound 3

5. The process according to claim 4, wherein in step 1 "), the organic solvent A is an ether solvent and/or a halogenated hydrocarbon solvent; the ether solvent is tetrahydrofuran and/or 2-methyltetrahydrofuran; the halogenated hydrocarbon solvent is dichloromethane; the molar ratio of the trifluoroacetic anhydride to the compound 2 is 3:1-10: 1; the temperature of the acylation reaction is 0-25 ℃; the acylation reaction comprises the following steps: suspending the compound 2 in an organic solvent A, adding trifluoroacetic anhydride, and carrying out the acylation reaction, wherein the temperature of the acylation reaction is controlled to be 0-25 ℃, and the trifluoroacetic anhydride is added.

6. The process according to claim 4, wherein, in step 1'),

the alkali is inorganic alkali; the inorganic base is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and sodium phosphate; the molar ratio of the alkali to the compound 2 is 15-25: 1; the temperature of the alkali treatment of the reaction liquid after the acylation reaction is 30-35 ℃; the alkali treatment of the reaction liquid after the acylation reaction comprises the following steps: adding alkali and an organic solvent B into the reaction liquid after the acylation reaction is finished, and adding water into the reaction liquid for reaction; the organic solvent B is one or more of an ether solvent, a halogenated hydrocarbon solvent, an ester solvent and an alcohol solvent; the ether solvent is tetrahydrofuran and/or 2-methyltetrahydrofuran; the halogenated hydrocarbon solvent is dichloromethane; the ester solvent is ethyl acetate; the alcohol solvent is methanol.

7. The method according to claim 1, wherein, in step 2),

the formic acid is anhydrous formic acid; the organic solvent is halogenated hydrocarbon solvent; the halogenated hydrocarbon solvent is dichloromethane; the alkali is triethylamine; the molar ratio of the alkali to the formic acid is 1:1-5: 1; the molar ratio of the compound 4' to the formic acid is 1:10-1: 15; the nucleophilic substitution reaction comprises the following steps: the nucleophilic substitution reaction is carried out by adding a mixed solution of a base, formic acid and an organic solvent to a mixed solution of the compound 4' and the organic solvent.

8. The process according to claim 1 or 7, wherein compound 5 is prepared by subjecting compound 4' and formic acid to said nucleophilic substitution reaction under the action of a base directly after step 1) without any post-treatment.

9. A process for the preparation of compound 5', characterized in that it comprises the following steps i) and 3):

step i): preparing compound 5 according to the preparation process of any one of claims 1 to 8;

step 3): carrying out deprotection reaction on the compound 5 prepared in the step i) in a solvent under the action of alkali to prepare a compound 5';

10. the method according to claim 9, wherein, in step 3),

the solvent is halogenated hydrocarbon solvent and/or C₁-C₄The alcohol solvent of (1); the halogenated hydrocarbon solvent is dichloromethane; said C₁-C₄The alcohol solvent is one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol; the alkali is inorganic alkali; the inorganic alkali is sodium hydroxide and/or potassium hydroxide; the alkali is used in the form of alkali aqueous solution; the base isThe molar concentration of the aqueous solution of (a) is 1mol/L-3 mol/L; the mass ratio of the compound 5 to the alkali is 1:1-1: 3; the temperature of the deprotection reaction is-25 ℃ to-5 ℃; the deprotection reaction comprises the following steps: and mixing the compound 5 with a solvent, and adding alkali to carry out deprotection reaction, wherein the temperature of the deprotection reaction needs to be controlled between-25 ℃ and-5 ℃ and the alkali is added.

11. The process according to claim 9 or 10, wherein compound 5' is produced by the deprotection reaction in a solvent under the action of a base without any post-treatment after producing compound 5 according to the process according to any one of claims 1 or 7.

12. A process for the preparation of epirubicin hydrochloride compound 1, characterized in that it comprises the following steps ii) and 4):

step ii): preparing compound 5' according to the process of any one of claims 9-11;

step 4): subjecting the compound 5' obtained in the step ii) to deprotection reaction in a solvent under the action of hydrochloric acid to obtain a compound 1;

13. the method according to claim 12, wherein, in step 4),

the solvent is halogenated hydrocarbon solvent and/or C₁-C₄The alcohol solvent of (1); the halogenated hydrocarbon solvent is dichloromethane; said C₁-C₄The alcohol solvent is one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol; the hydrochloric acid takes part in the reaction in the form of hydrochloric acid aqueous solution; the molar concentration of the hydrochloric acid aqueous solution is 2-4 mol/L; the mole of the hydrochloric acid and the compound 5The molar ratio is 26:1-52: 1; the temperature of the deprotection reaction is 0-25 ℃.

14. The production method according to claim 12 or 13, wherein the deprotection reaction is carried out by directly adding hydrochloric acid without any post-treatment after the step 4) to produce the compound 1.