WO2017120729A1 - Method and intermediate for the preparation of epirubicin hydrochloride - Google Patents

Abstract

The present invention discloses a method and an intermediate for the preparation of an epirubicin hydrochloride. The method comprises the following step: in an organic solvent and under an action of an alkali, subjecting compound 4 and a trifluoromethanesulfonic anhydride to an esterification shown below to obtain compound 4'. The preparation method of the present invention has the advantages of short reaction routes, high yield, ready availability of reaction raw materials, no need to use other expensive reagents, low costs, mild reaction conditions, and simple operations, facilitating industrial production.

Description

 Method for preparing epirubicin hydrochloride and its intermediates

 The invention belongs to a process for chemically synthesizing a medicament, in particular to a preparation method of epirubicin hydrochloride and an intermediate thereof. Background technique

Epirubicin hydrochloride, also known as epirubicin hydrochloride, chemical name (8 & 105 10-[(3'-amino-2',3',6'-tripleoxy-α-J-arabinopyranosyl) oxygen -6,8,11-trihydroxy-8-hydroxyethyl-1-methoxy-7,8,9, 10-tetrahydrotetracene-5,12-dione hydrochloride, molecular formula C ₂₇ H ₃ .C1N0 _U , molecular weight 579.15, CAS registration number 56390-09-1. It is famasiapu strong

Anthracycline anti-tumor antibiotics developed for the treatment of breast cancer, lung cancer and liver cancer (now Pfizer), listed in Europe in 1984 and listed in the US in 1999.

 The synthetic routes of epirubicin hydrochloride are mainly as follows:

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

 2. Polish Journal of Chemistry, 2005, 79(2): 349-359 discloses a method for synthesizing epirubicin hydrochloride. The method has a total of 10 steps of reaction, and the crude product yield of epirubicin hydrochloride is 22%, the route is long, and the yield is low. At the same time, the reaction raw materials of the method are not easily obtained, and are prepared by a two-step reaction, so that the synthetic route of epirubicin hydrochloride is extended to 12 steps.

 3. WO2006096665 discloses a method for synthesizing epirubicin hydrochloride. The method has a total of seven steps of reaction. Although the reaction route is shortened compared with the methods 1 and 2, the crude yield of epirubicin hydrochloride is 26%, and the yield is low. Further, in this method, the sulphur oxidation in which dimethyl sulfoxide and trifluoroacetic acid are involved is required to be carried out at a low temperature of -70 ° C, which is industrially difficult to achieve, and is disadvantageous for industrial production.

 4. A method for synthesizing epirubicin hydrochloride is disclosed in W09629335A1. The yield of epirubicin hydrochloride is 41%, but there are still 11 steps and the route is long.

5. A method for preparing epirubicin hydrochloride is disclosed in W09629335A1. Doxorubicin hydrochloride As a raw material, it is soluble in hydrazine, dimethyl-dimethylformamide, which is difficult to recover by boiling point, triethyl orthoformate as a bishydroxy protecting agent, and trifluoroacetic acid as a catalyst to carry out bishydroxyprotection to obtain compound 29, due to trifluoroacetic acid. Strong acidity, will return the product of this step to the raw material, so the yield is not high, the patent does not report the yield, repeat the patent operation, the yield is less than 70%; Compound 29 first reacts with trifluoroacetic anhydride, then adds carbonic acid Sodium hydride, two-step reaction gives compound 30, the patent does not report the yield, repeated patent operation, the yield is less than 85%; compound 30 is first reacted with trifluoromethanesulfonic anhydride to activate the hydroxyl group on the sugar, and then the more expensive silicon protection Compound 31; 31 is first reacted with triethylamine formate, and then reacted with potassium fluoride for 2 days, and deprotected by silicon to obtain compound 32; compound 32 is firstly de-sugared in aqueous sodium hydroxide solution at 5 °C. Protected by hydroxyl and amino groups, after treatment with solid, and then deprotected with dihydroxyl in methanol-hydrochloric acid to obtain crude epirubicin hydrochloride. The whole route has 9 steps.

 It can be seen that in the preparation method of epirubicin hydrochloride disclosed in the prior art, the route is long, the yield is low, the reaction raw materials are not easily obtained, and expensive reagents such as silicon are required, the cost is high, the reaction conditions are harsh, and the operation is complicated. It is difficult to achieve defects such as industrial production. Therefore, the above technical problems need to be solved urgently. Summary of the invention

The technical problem to be solved by the present invention is to overcome the existing long route in the preparation method of epirubicin hydrochloride, the yield is low, the reaction raw material is expensive, difficult to obtain, high in cost, harsh in reaction conditions, complicated in operation, and difficult In order to achieve defects such as industrial production, a preparation method of epirubicin hydrochloride and an intermediate thereof are provided. The preparation method of the invention has the advantages of short route, high yield, easy availability of reaction raw materials, no need to use other expensive reagents, low cost, mild reaction conditions, simple operation and favorable industrial production.

 The present invention mainly solves the above technical problems by the following technical solutions.

 The invention provides a preparation method of the compound 4', which comprises the following steps: in an organic solvent, the compound 4 and the trifluoromethanesulfonic anhydride are subjected to an esterification reaction as shown below under the action of a base to obtain a compound 4 ';

In the preparation method of the compound 4', the esterification reaction preferably comprises the following steps: after the compound 4, the organic solvent and the base are mixed, trifluoromethanesulfonic anhydride is added to carry out the esterification reaction. Preferably, the esterification reaction requires the addition of trifluoromethanesulfonic anhydride at a temperature of -5 V -0 V.

 In the preparation method of the compound 4', the organic solvent may be a conventional solvent for such a reaction in the art, and is preferably a halogenated hydrocarbon solvent. The halogenated hydrocarbon solvent is preferably dichloromethane, more preferably anhydrous methylene chloride. The base may be a conventional base for such reaction 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 the trifluoromethanesulfonic anhydride, the amount of the trifluoromethanesulfonic anhydride and the organic solvent may not be specifically limited. The manner of adding trifluoromethanesulfonic anhydride is preferably dropwise. The speed of the dropwise addition may be not particularly limited as long as the temperature of the reaction system is controlled to be between -5 ° C and 0 ° C. The amount of the base to be used may be a conventional amount for such a reaction in the art, and preferably, the molar ratio thereof to the compound 4 is from 3:1 to 10:1, more preferably from 5:1 to 8:1. The amount of the trifluoromethanesulfonic anhydride used may be a conventional amount for such a reaction in the art, and preferably, the molar ratio thereof to the compound 4 is 1: 1-5: 1, more preferably 2: 1-3. : 1. The amount of the organic solvent to be used is not particularly limited as long as the reaction is not affected, and preferably, the volume-to-mass ratio of the compound to the compound 4 is from 5 mL/g to 20 mL/g. The temperature of the esterification reaction is preferably from -5 ° C to 0 ° C. The progress of the esterification reaction can be monitored by conventional detection methods in the art (e.g., TLC, HPLC or GC), generally as the end of the reaction when Compound 4 disappears. The period of the esterification reaction is preferably from 0.5 to 3 hours, more preferably 1 hour.

In a preferred embodiment of the invention, the method of preparing the compound 4' can also be carried out in gas protection. The gas in the gas protection may be a conventional protective gas in the field of organic synthesis, preferably N ₂ . In the method for producing the compound 4', after the esterification reaction is completed, the post-treatment operation may be further included. The post-treatment operation preferably comprises the steps of: adding a terpene hydrocarbon solvent to the reaction liquid after completion of the esterification reaction, precipitating the solid, and filtering. The terpene hydrocarbon solvent may be a conventional terpene hydrocarbon solvent in the organic field, preferably n-glycol. The amount of the terpene hydrocarbon solvent to be used may be not particularly limited, so that no solid precipitation is preferable.

 In a preferred embodiment of the present invention, after the esterification reaction is completed, the subsequent reaction can be carried out directly without post-treatment.

 The method for preparing the compound 4' preferably further comprises the steps of: exemplifying the compound 3 and the triisopropyl orthoformate in the organic solvent under the catalysis of an acid and/or an acid salt; a condensation reaction to produce the compound 4;

In the preparation method of the compound 4, the condensation reaction preferably comprises the steps of: suspending the compound 3 in an organic solvent, adding an acid and/or an acid salt, triisopropyl orthoformate, and performing the Condensation reaction.

In the preparation method of the compound 4, the acid or acid salt may be a conventional acid or acid salt of the reaction in the art, and the acid is preferably an organic acid, more preferably camphorsulfonate. The acid salt is preferably a pyridine hydrochloride salt and/or a pyridine p-toluenesulfonate. The organic solvent is preferably an anhydrous organic solvent. The organic solvent may be a conventional organic solvent for such a reaction in the art, preferably an ether solvent and/or a 3⁄4 hydrocarbon solvent. The ether solvent is preferably tetrahydrofuran and/or 2-methyltetrahydrofuran. The halogenated hydrocarbon solvent is preferably dichloromethane. The molar ratio of the triisopropyl orthoformate to the 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 acid salt (if the acid and the acid salt are co-catalyzed, the amount used herein refers to the total amount of the acid and the acid salt) is a catalytic amount, preferably, the mass is a compound. 3% by mass of 0.01% to 0.2%, more preferably 0.05% to 0.08%. The amount of the organic solvent to be used is not particularly limited as long as it does not affect the progress of the reaction, and preferably, the volume-to-mass ratio of the solvent to the compound 3 is from 1 mL/g to 50 mL/g, more preferably from 5 mL/g to 20 mL. /g. The temperature of the condensation reaction is preferably from 25 ° C to the reflux temperature of the solvent at normal pressure. The progress of the condensation reaction can be monitored by conventional detection methods in the art (e.g., TLC, HPLC or GC), generally as the end of the reaction when Compound 3 disappears. Preferably, the condensation reaction comprises a first-stage reaction and a second-stage reaction, wherein the temperature of the first-stage reaction is preferably from 25 ° C to 30 ° C _; the second-stage reaction The temperature is preferably the solvent reflux temperature at normal pressure. The time of the condensation reaction is preferably from 1 to 6 hours, wherein the first stage reaction time is preferably 0.5 The second stage reaction time is preferably from 0.5 hours to 3 hours, in hours to 5 hours.

 Preferably, after the end of the condensation reaction, a post-treatment operation is further included. The method and conditions for the post-treatment operation may be a conventional method and condition for post-treatment in the field of organic synthesis, and preferably include the following steps: adding water, a base (for example, 22.7 mL of water) to the reaction liquid after the end of the condensation reaction , 0.2g sodium bicarbonate), added to the extraction with an organic solvent (such as ethyl acetate) extraction layering (extraction, the general operation is the organic phase washed with water (114mLx2), combined with the aqueous phase, extraction with organic solvents (such as ethyl acetate) Wash (227 mL x 2)), combine all the organic phases, remove the organic solvent (for example, steam under reduced pressure), and dry (for example, vacuum drying at 35 ° C to constant weight) to obtain Compound 4. Wherein the base can be a post-treatment conventional base in the art for such reaction, preferably sodium bicarbonate. The temperature at which the reaction liquid after the completion of the condensation reaction is mixed with water and alkali is preferably from 20 ° C to 40 ° C, preferably from 25 ° C to 30 ° C.

 After completion of the condensation reaction, preferably, the reaction liquid after completion of the condensation reaction may be treated with an organic acid having a pKa value of 3-5 (25 ° C). 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 progress of the reaction, and preferably, the molar ratio thereof to the compound 3 is 5:1 to 20:1, more preferably 10:1 to 20 : 1. The temperature of the organic acid treatment is preferably from 10 ° C to 30 ° C. The organic acid treatment time is preferably from 10 hours to 20 hours, more preferably from 15 hours to 18 hours.

 Before the reaction liquid after completion of the condensation reaction is treated with an organic acid, it is preferred to further comprise a step of mixing the reaction liquid after completion of the condensation reaction with water or a base. The base can be a post-treatment conventional base in the art for such reactions, preferably sodium bicarbonate. The relationship between the amount of water and the amount of the base may not be specifically limited. The temperature at which the reaction liquid after completion of the condensation reaction is mixed with water and alkali is preferably 20 ° C to 40 ° C, preferably 25 ° C to 30 ° C.

 In the preparation method of the compound 4, when the reaction liquid after the end of the condensation reaction is treated with an organic acid having a pKa value of 3-5 (25 ° C), the post-treatment operation preferably includes The following steps: To the reaction solution treated with an organic acid having a pKa value of 3-5 (25 ° C), an aqueous solution of sodium hydrogencarbonate (for example, 67.8 g of sodium hydrogencarbonate plus 784 mL of water) is added, and an organic solvent for extraction is added (for example, Ethyl acetate) extraction stratification (extraction, the organic phase is usually washed with water (114 mL x 2), the aqueous phase is combined, the extraction is washed with an organic solvent (such as ethyl acetate) (227 mL> < 2), and all organic phases are combined. The organic solvent is removed (e.g., under reduced pressure) and dried (e.g., dried under vacuum at 35 ° C to constant weight) to afford compound 4. The temperature at which the reaction solution treated with the organic acid having a pKa value of 3-5 (25 ° C) is mixed with the aqueous sodium hydrogencarbonate solution is preferably -5 ° C - 0 ° C.

The method for preparing the compound 4' preferably further comprises the steps of: acylating the compound 2 with trifluoroacetic anhydride in the organic solvent A, and then, in the solvent, after the acylation reaction is completed. The reaction solution is treated with a base to obtain the compound 3;

 2 3 In the preparation method of the compound 3, the acylation reaction preferably comprises the steps of: suspending the compound 2 in the organic solvent A, and then adding trifluoroacetic anhydride to carry out the acylation reaction, preferably, The acylation reaction requires the addition of trifluoroacetic anhydride at a temperature between 0 ° C and 25 ° C (e.g., 10 ° C to 25 ° C).

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

 In the preparation method of the compound 3, the treatment of the reaction liquid after completion of the acylation reaction with a base preferably includes the following steps: adding a base and an organic solvent B to the reaction liquid after completion of the acylation reaction, and adding water , carry out the reaction. The organic solvent B may be a conventional solvent for such a reaction in the art, preferably one or more of an ether solvent, a 3⁄4 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 with 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 the compound 3, in the operation of treating the reaction liquid after 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 hydrogencarbonate, potassium hydrogencarbonate and sodium phosphate. The amount of the base to be used may be a conventional amount for such a reaction in the art, and preferably, the molar ratio thereof to the compound 2 is from 15 to 25:1. The amount of water and organic solvent B used may be a conventional amount for such reactions in the art. The relationship between the mixed solvent of the 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 at which the reaction solution after the completion of the acylation reaction is treated with a base is preferably from 30 ° C to 35 ° C. The time at which the reaction solution after the completion of the acylation reaction is treated with a base is preferably 10 hours to 25 hours, more preferably 15 hours to 20 hours.

 In the method for producing the compound 3, after the reaction solution after completion of the acylation reaction is finished with an alkali, it is preferable to further include a post-treatment operation. The method and conditions for the post-treatment may be the conventional methods and conditions for post-treatment in the field of organic synthesis, and preferably include the following steps: adding to the reaction solution after the end of the acylation reaction is completed with a base, An aqueous solution of hydrochloric acid (14.2 mL of concentrated hydrochloric acid and 150 mL of water is mixed), the layers are separated, the organic phase is washed with water, and the aqueous phase is combined with an organic solvent (for example ethyl acetate) for extraction, and all the organic phases are combined with an acid having a pH of 4.0. The aqueous solution is washed, washed with water, and the organic solvent is removed (for example, under reduced pressure), and dried (for example, vacuum drying at 35 ° C to constant weight). The acid in the aqueous acid solution having a pH of 4.0 may be a conventional acid in the art as long as the pH in the aqueous acid solution is controlled to 4.0. The temperature at which the reaction liquid after completion of the acylation reaction is mixed with the aqueous hydrochloric acid solution after completion of the alkali treatment is preferably -5 °C - 0 °C.

 The invention also provides a preparation method of the compound 5, which comprises the following steps: in the organic solvent, the compound 4' and the formic acid prepared according to the preparation method as described above are subjected to the following steps under the action of a base; Nucleophilic substitution reaction to produce compound 5;

In the preparation method of the compound 5, the nucleophilic substitution reaction preferably comprises the steps of: adding a mixed solution of a base, a formic acid and an organic solvent to a mixed solution of the compound 4' and an organic solvent; Nucleophilic substitution reaction. The amount of the organic solvent in the mixed solution of the compound 4' and the organic solvent and the mixed solution of the alkali, 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 a conventional organic solvent for such a reaction in the art, preferably a 3⁄4 generation hydrocarbon solvent. The 3⁄4 generation hydrocarbon solvent is preferably methylene chloride (for example, anhydrous dichloromethane). The base may be a conventional base for such reactions in the art, preferably triethylamine. The base may be used in an amount conventionally used in the art, and preferably, the molar ratio thereof to formic acid is 1:1-5:1, more preferably 1:1-3:1. The molar ratio of the compound 4' and the formic acid is preferably 1:10-1:15, more preferably 1:12.5. The amount of the solvent to be used is not particularly limited as long as it does not affect the progress of the reaction. Preferably, the volume-to-mass ratio of the solvent to the formic acid is from 1 mL/g to 50 mL/g, more preferably from 1 mL/g to 30 mL/g. . The temperature of the nucleophilic substitution reaction may be a conventional temperature for such a reaction in the art, preferably from 20 ° C to 25 ° C. The process of the nucleophilic substitution reaction can be carried out Conventional detection methods in the field are monitored (eg, TLC, HPLC, or GC), typically as the endpoint of the reaction when Compound 4' disappears. The time of the nucleophilic substitution reaction is preferably from 10 hours to 20 hours, more preferably from 15 hours to 20 hours.

 In the preparation method of the compound 5, after the completion of the nucleophilic substitution reaction, it is preferred to further include a post-treatment operation. The method and conditions of the post-treatment operation may be a conventional method and condition for post-treatment in the field of organic synthesis, and preferably include the following steps: adding a base to the reaction solution after the end of the nucleophilic substitution reaction (for example Sodium bicarbonate) and water, layered, the organic phase is washed with an aqueous acid solution (for example, 8% aqueous acetic acid) (for example, 300 mL×2), and the aqueous acid layer is combined, and the extraction is carried out with an organic solvent (the organic solvent for extraction is generally reacted with a nucleophilic substitution reaction). The organic solvent used is the same, for example, methylene chloride, combined with all the above organic phases, washed with an aqueous alkali solution (for example, 5% sodium hydrogencarbonate, 300 mL), and the aqueous alkali solution is washed with an organic solvent for extraction (the organic solvent for extraction is generally The nucleophilic substitution reaction uses the same organic solvent, for example, methylene chloride. The organic phase is combined, washed with water, and the organic solvent is removed (for example, under reduced pressure) to obtain compound 5.

 In the preparation method of the compound 5, after the compound 4' is obtained according to the preparation method as described above, preferably, the compound 4' and the formic acid are directly subjected to the action of a base without post-treatment. The nucleophilic substitution reaction is carried out 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 an organic solvent without post-treatment.

 The present invention also provides a process for the preparation of the compound 5', which comprises the steps of: deprotecting the compound 5 obtained according to the preparation method as described above under the action of a base in a solvent. , obtaining compound 5';

In the preparation method of the compound 5', the deprotection reaction preferably comprises the following steps: after mixing the compound 5 with a solvent, adding a base to carry out the deprotection reaction; preferably, the The deprotection reaction is controlled by adding a base at a temperature of -25 °C to -5 °C.

In the preparation method of the compound 5', the solvent may be a conventional solvent for such a reaction in the art, preferably a halogenated hydrocarbon solvent and/or an alcohol solvent of dC ₄ . The halogenated hydrocarbon solvent is preferably dichloromethane. The alcohol solvent of d- is preferably methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol. One or more of them. The base may be a conventional base for 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 solution of a base. The molar concentration of the aqueous solution of the base is not particularly limited as long as it does not affect the progress of the reaction. Preferably, the molar concentration of the aqueous alkali solution is from 1 mol/L to 3 mol/L. The amount of the base to be used is not particularly limited as long as it does not affect the progress of the reaction. Preferably, the mass ratio of the compound 5 to the base is 1:1-1:3, more preferably 1:2. The amount of the solvent to be used may not be specifically limited as long as it does not affect the progress of the reaction. The temperature of the deprotection reaction is preferably -25 5 °C. The progress of the deprotection reaction can be monitored by conventional detection methods in the art (e.g., TLC, HPLC or GC), generally as the end of the reaction when Compound 5 disappears. The time of the deprotection reaction is preferably from 5 hours to 20 hours, more preferably from 8 hours to 15 hours.

After the end of the deprotection reaction, it is preferred to further include a post-treatment operation. The post-treatment operation may be a conventional post-treatment operation for preparing such a reaction in epirubicin hydrochloride, and the present invention preferably comprises the following steps: in the reaction liquid after the end of the deprotection reaction, The organic acid and the inorganic base are sequentially added, and the organic solvent (the organic solvent may be extracted by a conventional organic solvent in the art, preferably a halogenated hydrocarbon solvent) may be extracted (extractable two or more times). The aqueous phase is extracted with an organic solvent (the organic solvent may be a conventional organic solvent for extraction in the art, preferably a halogenated hydrocarbon solvent or a mixed solvent of a halogenated hydrocarbon solvent and a dC ₄ alcohol solvent (for example). Dichloromethane: Methanol = 4: 1 (v/v))), all organic phases are combined, washed with water, and the organic solvent is removed (for example, steam distillation under reduced pressure). In the post-treatment operation, the organic acid may be a post-treatment conventional organic acid, preferably acetic acid, for such reactions in the art. 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 the organic acid is preferably from 5% to 15%, more preferably 8%. The inorganic base can be post-treated to a conventional inorganic base, preferably sodium bicarbonate, for such reactions in the art. The amount of the organic acid and the inorganic acid to be used may be a conventional amount for such post-treatment in the art, and is not specifically limited herein.

 In the preparation method of the compound 5', after the compound 5 is obtained according to the preparation method as described above, preferably, the removal is carried out directly in a solvent under the action of a base without post-treatment. The reaction was protected to prepare compound 5'.

 The invention also provides a preparation method of epirubicin hydrochloride compound 1, which comprises the following steps: in the solvent, under the action of hydrochloric acid, the compound 5' obtained according to the above preparation method is subjected to the deprotection reaction shown below. , obtaining compound 1 ;

In the preparation method of the compound 1, the solvent may be a conventional solvent for such a reaction in the art, and is preferably a halogenated hydrocarbon solvent and/or an alcohol solvent of dC ₄ . The halogenated hydrocarbon solvent is preferably dichloromethane. The alcohol solvent of dC ₄ is preferably one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol. The hydrochloric acid preferably participates in the reaction in the form of an aqueous solution of hydrochloric acid. The molar concentration of the aqueous hydrochloric acid solution is not particularly limited as long as it does not affect the progress of the reaction. Preferably, the aqueous hydrochloric acid solution has a molar concentration of 2 mol/L to 4 mol/L. The amount of the hydrochloric acid to be used is not particularly limited as long as it does not affect the progress of the reaction, and preferably, the molar ratio thereof to the compound 5' is from 26:1 to 52:1. The amount of the solvent to be used may not be specifically limited as long as it does not affect the progress of the reaction. The temperature of the deprotection reaction is preferably from 0 to 25 °C. The progress of the deprotection reaction can be monitored by conventional detection methods in the art (e.g., TLC, HPLC or GC), generally as the end of the reaction when compound 5' disappears. The time of the deprotection reaction is preferably from 3 hours to 15 hours, more preferably from 5 hours to 10 hours.

 In the preparation method of the compound 1, after the completion of the deprotection reaction, it is preferred to further include a post-treatment operation. The method and conditions for the post-treatment may be the conventional methods and conditions for post-treatment in the field of organic synthesis, and preferably include the following steps: the reaction solution after the end of the deprotection reaction is layered, and the aqueous phase is extracted with an organic solvent. (for example, dichloromethane), the organic phase is combined, washed with water, and the aqueous phase is combined to obtain a crude aqueous solution of epirubicin hydrochloride, which is then separated and purified by column chromatography. The method for separating and purifying can be a conventional method for separating and purifying epirubicin hydrochloride in the field, for example, a method for separating and purifying epirubicin hydrochloride disclosed in patents IT01237202 and US4861870, and the application number is CN201510744980.0, the application date is Chinese Patent Application, Nov. 5, 2015, the entire contents of which is incorporated herein by reference.

 In a preferred embodiment of the present invention, after the compound 5' is obtained according to the above production method, preferably, the hydrochloric acid is directly added to the deprotection reaction without post-treatment to obtain the compound 1.

 The invention also provides a preparation method of the compound 4, which comprises the following steps: in the organic solvent, the compound 3 and the triisopropyl orthoformate are subjected to a condensation reaction as shown below under the catalysis of an acid and/or an acid salt; , the compound 4 is prepared;

 4

 Here, the conditions of the preparation method of the compound 4 are the same as described above.

The invention also provides a preparation method of the compound 5, which comprises the following steps: in an organic solvent, in a base Under the action, the compound 4' and the formic acid are subjected to a nucleophilic substitution reaction as shown below to prepare a compound.

Wherein, the conditions of the preparation method of the compound 5 are the same as described above.

 The invention also provides a preparation method of the compound 5', which comprises the following steps: in a solvent, under the action of a base, the compound 5 is subjected to a deprotection reaction as shown below to obtain a compound 5';

 The conditions of the deprotection method are as described above.

 The present invention also provides a preparation method of epirubicin hydrochloride compound 1, which comprises the following steps: in a solvent, under the action of hydrochloric acid, the compound 5' is subjected to a deprotection reaction as shown below to obtain a compound 1;

 The conditions of the deprotection method are as described above.

The present invention also provides a compound of Formula 4, a compound of Formula 4', a compound of Formula 5, or a compound of Formula 5':

In the present invention, the configuration of the "one" attached carbon atom in the structure of each compound is racemic or non-racemic. When it is non-racemic, it is in the S configuration or the R configuration.

 Ben

The above preferred conditions can be arbitrarily combined without departing from the ordinary knowledge in the art, that is, preferred embodiments of the present invention. The reagents and starting materials used in the present invention are commercially available.

 In the present invention, if temperature is not specified, it means operating at room temperature, and the room temperature means ambient temperature, generally 10 ° C - 30 ° C o

 In the present invention, the temperature of the added materials, the mixing temperature of the materials, and the like refer to the temperature of the reaction system (or the reaction liquid).

 In the present invention, the post-treatment without treatment generally means that the reaction liquid after the completion of the reaction is not post-treated.

 The positive effects of the present invention are:

 (1) Compound 2 is reacted in two steps to obtain compound 3, the yield is more than 96%, and the purity is more than 97% without crystallization or column chromatography; Compound 3 is reacted in two steps to obtain compound 4, and the yield is more than 98%, Crystallization or column chromatography with a purity greater than 90%. The compound 4 is obtained from the compound 2 in four steps, and the yield is high, and high purity product is obtained without crystallization or column chromatography, and the operation is simple. Further, in the method of preparing the compound 4 using the compound 2 as a raw material, the protection of the amino group first avoids the destruction of the dihydroxy group by the strong acid (e.g., trifluoroacetic acid) produced in the process, and improves the yield and purity of the compound 3.

 (2) Compound 4 is reacted with trifluoromethanesulfonic anhydride to obtain compound 4'. Due to the special structure of 4', it can be directly reacted with formic acid under the action of a base to obtain compound 5 without reaction and hydroxy group protection, thereby saving Cost, reduced operational steps. When compound 5 is deprotected under alkaline and acidic conditions, the concentration of alkali and acid and the temperature of the reaction are optimized, and after alkaline deprotection, the acid deprotection is directly carried out without reaction and the epirubicin hydrochloride is obtained. The yield of the reaction is more than 90%, and the purity of the final product of epirubicin hydrochloride is more than 85%, which reduces the operation steps and improves the product yield and purity.

 (3) The preparation method of the invention has short route, easy to obtain reaction raw materials, no need to use other expensive reagents, low cost, mild reaction conditions, simple operation, yield greater than 65%, purity greater than 85%, high yield and purity , is conducive to industrial production. detailed description

 The doxorubicin hydrochloride described in the present invention is provided by Zhejiang Hisun Pharmaceutical Co., Ltd.

The purity of the compound 3, the compound 4, the compound 4-1, the compound 4-2, the compound 4', the compound 5, the compound 5', the compound 29, the compound 30, the compound 32 and the compound 30' in the present invention is normalized by HPLC. method was measured, chromatographic conditions: Fortis H ₂ 0 column (4.6mm X 250mm, 5um); mobile phase: 20mmol / L potassium dihydrogen phosphate solution (pH 4.0) (A), acetonitrile (B), gradient ( 0→8 min, A 95%; 8→15 min, A 95%→25%; 15

→56 min, A 25%; 56→60 min, A 25%→95%; 60→65 min, A 95%); Detection wavelength: 245 nm; Column temperature 40 °C; Flow rate 1.Oml/mino In the present invention, the purity of the crude doxorubicin hydrochloride and the crude epirubicin hydrochloride is determined by HPLC normalization method, and the chromatographic conditions are referred to USP38-F33.

 In the present invention, the concentration of epirubicin hydrochloride is determined by HPLC, and the sample is diluted to a suitable concentration in epirubicin hydrochloride, and the concentration of epirubicin hydrochloride in the sample is obtained by a regression equation.

The regression equation is derived from the standard curve. Standard curve drawing: Precisely weigh a certain amount of epirubicin hydrochloride reference substance in a volumetric flask, add mobile phase to dissolve and volume, and use it as a reference stock solution. Accurately measure the appropriate amount of stock solution, and dilute with the mobile phase to prepare a series of standard solutions with concentrations of 26.3, 52.6, 105.2, 210.4, 315.6, 420.8, and 526.0 g/mL, respectively, and inject them separately, with a peak area of epirubicin hydrochloride ( mAUxmin) is the ordinate, the concentration c (^g/mL) is the abscissa, and the linear regression is performed. The regression equation is obtained: =0.1186c-0.0469, R ² =0.9994, showing a linear relationship in the range of 26.3 to 526.0μ _§ /ιηί good.

 The purity referred to in the following examples all refers to HPLC purity.

 Example 1 Synthesis of Compound 3

 Compound 2 (30 g, 51.8 mmol) was suspended in anhydrous tetrahydrofuran (300 ml), trifluoroacetic anhydride (65.3 g, 310.8 mmol) was added at 15 ° C. The reaction was continued for 4 hours at 15 ° C, and sodium hydrogencarbonate (108.8) was added. g, 1295 mmol), ethyl acetate (300 ml) and methanol (30 ml), and finally water (150 ml). Stir at 30 ° C for 16 hours, cool to -5 ° C, add hydrochloric acid (14.2 ml of concentrated hydrochloric acid and 150 ml of water), stir the layers, wash the organic phase with water (150mlx2), and combine with water, ethyl acetate (150mlx2) The organic phase was washed with an aqueous acid solution (150 ml) of pH 4.0 and washed with water (150 ml). The organic phase was dried under reduced pressure, dried under vacuum at 35 ° C to constant weight to give compound 3 (32.4 g, yield 98%), mp 171 - 173 ° C, purity 98.5%. Q-TOF ESI-MS( /z): 662[M+Na]+; 1H MR(400 MHz, DMSO-i3⁄4) δ: 14.03(br s, IH, 11 -OH), 13.26(s, IH, 6 -OH), 9.08 (d, J=7.4 Hz, IH,

3 - H), 7.88 to 7.93 (m, 2H, 1-H, 2-H), 7.62 to 7.67 (m, IH, 3-H), 5.47 (s, IH, l '-H), 5.26 (d , J=3.1 Hz, IH, 7-H), 4.99(d, J=5.9 Hz, IH, 4 -OH), 4.93 to 4.97(m, IH, 5 -H), 4.84(t, J=6.0 Hz , IH, 3 -H), 4.58 (d, J = 6.0 Hz, 2H, 14-CH ₂ ), 4.16 to 4.25 (m, IH, 9-OH), 4.00 to 4.07 (m, IH,

4 -H), 3.98(s, 3H, -OCH ₃ ), 3.52 (d, J=4.3 Hz, IH, 14-OH), 2.96 to 3.04 (m, IH, 10-Η _β ), 2.90 to 2.96 ( m, IH, 10-H _a ), 2.17 to 2.25 (m, IH, 8-Η _β ), 2.03 to 2.15 (m, 2H, 8-Η _α; 2'-Η _β ), 1.48 (dd, J= 4.3, 16.2 Hz, IH, 2 -H), 1.13 (d, J = 6.5 Hz, 3H, -CH ₃ ); ¹³ C MR (400 MHz, DMSO-i3⁄4) 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-6a, C-12a), 134.07 (C-10a), 119.59, 119.78 (C-1, C-3), 118.86 (C-4a), 111.49, 114.35, 117.22, 120.09 (CF ₃ ), 110.44, 110.57 (C-5a, Cl la), 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 (OCH ₃ ), 47.00 (C-3 '), 36.45 (C-8), 31.94 (C-10), 28.73 (C-2'), 16.92 ( CH ₃ ). Synthesis of Compound 4 of Example 2

 Compound 3 (32.4 g, 50.7 mmol) was suspended in anhydrous tetrahydrofuran (226.4 ml), and camphorsulfonic acid (1. 2 mg) was added, and triisopropyl orthoformate (57.9 g, 304.2 mmol) was added, and the reaction was carried out at 25 ° C for 0.5 hour. The reaction was continued for 1.8 hours under reflux. The temperature was lowered to 30 ° C, water (22.7 ml) was added, sodium hydrogencarbonate (0.2 g) was added, and the mixture was stirred for 1 hour. Acetic acid (43.9 ml) was added and stirred at 30 ° C for 16 hours. The temperature was lowered to -5 ° C, and an aqueous sodium hydrogencarbonate solution (67.8 g of sodium hydrogen carbonate and 784 ml of water) was added and stirred for 1 hour. Ethyl acetate (114 ml) was added, the layers were separated, and the organic phase was washed with water (114mlx2). The combined aqueous phases were washed with ethyl acetate (227 ml x 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 ° C to constant weight to give compound 4 (35.4 g, yield 98.5%), purity 91.2%. Compound 4 was subjected to HPLC analysis, and the results are shown in Table 1.

 In Table 1, numerals 1, 2, 3 and 4 are peak numbers indicating the retention time, peak height, peak area, and relative area of each component in the compound 4 obtained in Example 2.

 Table 1

 Among them, the peak No. 2 indicates the compound 4.

Compound 4 is theoretically a pair of epimers, and the two main peaks appearing in the HPLC analysis are separated by silica gel column chromatography to obtain compound 4-1 and compound 4-2, respectively, for mass spectrometry, nuclear magnetic resonance and HPLC analysis revealed that both mass spectra have ESI-MS( /z): molecular ion peak of 732 [M+Na] ⁺ ; nuclear magnetic resonance spectrum of compound 4-1: 1H MR (400 MHz, DMSO-i3⁄4) δ : 13.94 ~ 14.00(m, IH, 11 -OH), 13.19(s, IH, 6-OH), 8.93(d, J=7.3 Hz, IH, 3'-NH), 7.86 to 7.89(m, 2H, 1-H, 2-H), 7.60 to 7.63 (m, IH, 3-H), 5.86 (s, IH, 15-H), 5.25 (d, J = 2.8 Hz, l'-H), 5.00 〜 </ RTI></RTI><RTIgt_; , IH, 5'-H), 4.04 to 4.06 (m, IH, 3'-H), 3.97 (s, 3H, -OCH ₃ ), 3.92 to 3.95 (m, IH, 4'-H), 3.49 ( Br s, IH, 16-H), 3.34 (d, J=18.0 Hz, IH, 10-Η _β ), 2.81 (d J=17.9 Hz, IH, 10-Η _α ), 2.36 to 2.42 (m, IH , 8-Η _β ), 2.25 〜 2.29(m, IH, 8-Η _α ), 1.99 〜 2.13(m, 2H, 2'-CH ₂ ), 1.11 〜 1.14(m, 9H, 5'-CH ₃ , I6-CH3, I6-CH3); Nuclear magnetic resonance spectrum of compound 4-2: 1H MR (400 MHz, DMSO-i3⁄4) δ: 14.00 (s, IH, 11 -OH), 13.14 (s, IH, 6-OH), 9.03 (d, J = 7.2 Hz, IH 3'-H), 7.84 to 7.88 (m, 2H, 1-H, 2-H), 7.59 (d, J=7.3 Hz, IH, 3-H), 5.86(s, IH, 15-H), 5.37(d, J=2.4 Hz, IH, l'-H), 4.97 (d, J=4.3 Hz, IH, 7-H), 4.94 (d, J=4.0 Hz, IH, 4'-OH), 4.46(s, 2H, 14-CH ₂ ), 4.10 to 4.13 (m, IH, 5'-H), 4.02 to 4.06 (m, IH, 3'-H), 3.97 (s, 3H, -OCH ₃ ), 3.88 to 3.94 (m, IH, 4'-H), 3.54 (br s, IH, 16-H), 3.17 (d, J = 18.2 Hz, IH, 10-Η _β ), 2.90 (d, J = 18.2 Hz, IH 10-Η _α ), 2.55 to 2.67 (m, IH, 8-Η _β ), 2.05 to 2.15 (m, 2H, 8-Η _α , 2'-Η _β ), 1.91 to 2.02 (m, IH, 2' - Η _α ), 1.02 to 1.18 (m, 9H, 5'-CH ₃ , 16-CH3, 16-CH ₃ ), which are known to be a pair of epimers by mass spectrometry and nuclear magnetic resonance spectroscopy. The results of HPLC analysis of Compound 4-1 and Compound 4-2 are shown in Table 2 or Table 3.

 In Table 2, the numbers 1, 2, 3 and 4 are the peak numbers, indicating the retention time, peak height and peak area of each component in the compound 4-1 obtained by subjecting the compound 4 prepared in Example 2 by column chromatography. , relative area and other information.

 Table 2

 Among them, the peak No. 4 indicates the compound 4-1.

 In Table 3, the numbers 1, 2, 3 and 4 are the peak numbers, indicating the retention time, peak height and peak area of each component in the compound 4-2 obtained by subjecting the compound 4 prepared in Example 2 to fractional resolution by column chromatography. , relative area and other information.

 table 3

 Among them, the peak No. 3 indicates the compound 4-2.

 Synthesis of common orthoester protection products:

 According to the synthesis method of compound 4, compound 3 reacts with common orthoester to obtain a series of orthoester protection products. The yield is shown in Table 4 below:

 Table 4

Original acid ester name orthoester protection product yield Trimethyl orthoformate 80%

 Triethyl orthoformate 85%

 Tripropyl orthoformate 90%

 Trimethyl orthoacetate 97%

 Triethyl orthoacetate 98%

 Trimethyl orthopropionate 98%

 Triethyl orthopropionate 97%

 De-dihydroxy protection of common orthoester protection products:

 Compound 4 and orthoester protection compound with high yield (trimethyl orthoacetate protection product, triethyl orthoacetate protection product, trimethyl ortho-propionate protection product and triethyl ortho-propionate protection product) 5g each Soluble in methanol (100ml), add hydrochloric acid (lmol / L, 100ml), react at room temperature for 10 hours to obtain compound 3, the yield is shown in Table 5 below:

 table 5

 Example 3 Synthesis of Compound 4'

 Compound 4 (35.2g, 49.6mmol) was dissolved in anhydrous dichloromethane (321ml), anhydrous pyridine (19.7g, 249.4mmol was cooled to -5 ° C. Dilute anhydrous dichloromethane (30ml) The trifluoromethanesulfonic anhydride (28.1 g, 99.6 mmol) was further reacted for 1 hour at -5 °C for 30 minutes, and n-heptane was added to the reaction system to precipitate a solid, which was filtered to give the compound 4' (37.5 g, Yield 90%), purity 85%, ESI-MS (m/z): 864 [M+Na

 Example 4 Synthesis of Compound 5

Compound 4' (37.5 g, 44.6 mmol) was dissolved in anhydrous dichloromethane (321 ml), and a pre-prepared solution of triethylammonium triacetate (35.1 g of triethylamine, 20.5 g of anhydrous formic acid, Water dichloromethane 209 ml), stirred at 25 ° C for 16 hours, and the reaction was over. Add sodium bicarbonate (68.2g), add water (1000ml), layer, extract the organic phase, wash 8% aqueous solution of acetic acid (300ml*2), combine with aqueous acetic acid, dichloromethane (200*2ml), and combine organic The phases were washed with 5% sodium bicarbonate (300 ml), combined with aqueous sodium bicarbonate, dichloromethane (200ml*2ml), and the organic phase was washed with water (300*2ml). The organic phase was dried to give compound 5 (28.3 g, yield 86%). ESI-MS(w/z): 760[M+Na] ⁺ _o Example 5 Synthesis of Compound 5

 Compound 4' (37.5 g, 44.6 mmol) was dissolved in anhydrous dichloromethane (321 ml), and a pre-prepared solution of triethylammonium triacetate (112.8 g of triethylamine, 25.7 g of anhydrous formic acid, Water dichloromethane 209 ml), stirred at 25 ° C for 16 hours, the end of the reaction was turned over. Add sodium bicarbonate (68.2 g), add water (1000 ml), separate the layers, take the organic phase, wash with 8% aqueous acetic acid (300 ml * 2), combine with aqueous acetic acid, dichloromethane (200 * 2 ml), and combine organic The mixture was washed with 5% aqueous sodium hydrogencarbonate (300 mL), and then evaporated and evaporated. The organic phase was dried to give compound 5 (28.0 g, yield: 85%). ESI-MS ( /z): 760 [M+Na]+.

 Example 6 Synthesis of Compound 5

 Compound 4' (37.5 g, 44.6 mmol) was dissolved in anhydrous dichloromethane (321 ml), and a pre-prepared solution of triethylammonium triacetate (203.1 g of triethylamine, 30.8 g of anhydrous formic acid, no. Water dichloromethane 209 ml), stirred at 25 ° C for 16 hours, the end of the reaction was turned over. Add sodium bicarbonate (68.2 g), add water (1000 ml), separate the layers, take the organic phase, wash with 8% aqueous acetic acid (300 ml * 2), combine with aqueous acetic acid, dichloromethane (200 * 2 ml), and combine organic The mixture was washed with 5% aqueous sodium hydrogencarbonate (300 mL), and then evaporated and evaporated. The organic phase was dried to give compound 5 (27.3 g, yield 83%), purity 73%. ESI-MS ( /z): 760 [M+Na]+.

 Example 7 Synthesis of Compound 5

 Compound 4 (35.5 g, 50.0 mmol) was dissolved in anhydrous dichloromethane (321 ml), then EtOAc (25.7 g, Anhydrous dichloromethane (30 ml) diluted trifluoromethanesulfonic anhydride (35.3 g, 125 mmol) was added dropwise, and the reaction was continued for 30 minutes at -2 °C for 1 hour. A pre-prepared solution of triethylammonium triacetate (188.1 g of triethylamine, 28.7 g of anhydrous formic acid, 209 ml of anhydrous dichloromethane) was stirred at 20 to 25 ° C for 16 hours, and the reaction was over.

 Example 8 Synthesis of Compound 5'

 To the reaction mixture after the completion of the inversion reaction of Example 7, methanol (562 ml) was added, and the temperature was lowered to -20 °C. An aqueous solution of sodium hydroxide (894 ml of water, 56.0 g of sodium hydroxide, 1.6 mol/L) was added. After reacting at -20 ° C for 10 hours, 8% acetic acid aqueous solution (300 ml) was added dropwise, and sodium hydrogencarbonate (36 g) was added thereto, and the mixture was stirred for one hour, and the temperature was naturally raised. Dichloromethane (300 ml) was added, the layers were separated, and the aqueous phase was extracted with dichloromethane: methanol = 4:1 (300*2ml). The organic phase was combined, washed with water (300ml), and the organic phase was evaporated to give compound 5' (28.7 g, yield: 95%), mp. mp. mp., ESI-MS (m/z): 613 [M+Na]+.

 Example 9 Synthesis of Compound 5'

Compound 5 (28.3 g, 38.4 mmol) was dissolved in methanol (562 mL) and cooled to -25. Add sodium hydroxide to dissolve Liquid (707.5 ml water, 28.3 g sodium hydroxide, 1 mol/L). The mixture was reacted at -25 ° C for 10 hours, and an aqueous 8% acetic acid solution (525 ml) was added dropwise thereto, and sodium hydrogencarbonate (63 g) was added and stirred for one hour, and the temperature was naturally raised. Dichloromethane (300 ml) was added, the layers were separated, and the aqueous phase was extracted with methylene chloride:methanol = 4:1 (2*300ml). The organic phase was combined, washed with water (300ml), and the organic phase was evaporated to give compound 5' (22.4g, yield 95%), purity 86%, ESI-MS (m/z): 613[M+Na

 Example 10 Synthesis of Compound 5'

 Compound 5 (28.3 g, 38.4 mmol) was dissolved in ethanol (562 ml) and cooled to -15 °C. Aqueous sodium hydroxide solution (707.5 ml of water, 56.6 g of sodium hydroxide, 2 mol/L) was added. The reaction was carried out at -15 ° C for 10 hours, an aqueous solution of 8% acetic acid (1050 ml) was added dropwise, and sodium hydrogencarbonate (126 g) was added and stirred for one hour, and the temperature was naturally raised. Dichloromethane (300 ml) was added, the layers were separated, and the aqueous phase was extracted with methylene chloride:methanol = 4:1 (300*2ml). The organic phase was combined, washed with water (300ml), and the organic phase was evaporated to give compound 5' (21.2g, yield 90%), purity 85%. ESI-MS(m/z): 613[M+Na

 Example 11 Synthesis of Compound 5'

 Compound 5 (28.3 g, 38.4 mmol) was dissolved in butanol (562 ml) and cooled to -5 °C. An aqueous potassium hydroxide solution (504 ml of water, 84.9 g of potassium hydroxide, 3 mol/L) was added. After reacting at -5 ° C for 10 hours, an aqueous solution of 8% acetic acid (1122 ml) was added dropwise, and sodium hydrogencarbonate (135 g) was added and stirred for one hour, and the temperature was naturally raised. Dichloromethane (300 ml) was added, the layers were separated, and the aqueous phase was extracted with methylene chloride:methanol = 4:1 (300*2ml). The organic phase was combined, washed with water (300ml), and evaporated to give compound 5' (21.2g, yield 90%), purity 84%, ESI-MS (m/z): 613[M+Na

 Example 12 Synthesis of epirubicin hydrochloride

Methanol (562 ml) was added to the reaction mixture after completion of the inversion reaction of Example 7, and the temperature was lowered to -20 °C. Aqueous sodium hydroxide solution (894 ml water, 56.0 g sodium hydroxide, 1.6 mol/L) was added. The reaction was carried out at -20 ° C for 10 hours, and hydrochloric acid (3 mol/L, 621 ml was heated to 10 ° C for 7 hours without further workup. The layers were separated, and the aqueous phase was washed with dichloromethane (562 ml X 2 ). , water (562ml X 2) wash. Combine the aqueous phase, get 3L of crude aqueous solution of epirubicin hydrochloride, purity 89.0%, dilute to the appropriate concentration, get the epirubicin hydrochloride in the crude aqueous solution of epirubicin hydrochloride by regression equation The concentration was 6.8 g/L, and the yield of crude epirubicin hydrochloride was 68% from doxorubicin hydrochloride. ESI-MS( /z): 544[M-HCl+H]+, 1H MR (400 MHz , DMSO δ: 13.96 (br s, 1H, 11 -OH), 13.15 (s, 1H, 6-OH), 8.08 (s, 3H, 3'-^ ₃ ), 7.82 to 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-CH ₂ ), 4.54 to 4.64(m, 2H, 5 -H,

3 -H), 3.14 to 3.34 (m, 4H, 9-OH, -OCH ₃ ), 2.93 to 2.97 (m, 2H, 10-CH ₂ ), 2.79 to 2.83 (m, 1H,

4 -H), 2.48 〜 2.50(m, 1H, 14-OH), 2.07 〜 2.18(m, 3H, 8- Η _β , 8-Η _α> 2'-Η _β ), 1.79-2.04(m, 1H , 2 -H _a ), 1.03-1.21 (m, 3H, -CH ₃ ); ¹³ C MR (400 MHz, DMSO 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-6a, C-12a), 134.59(C-10a), 120.03, 120.09 (C-1, C-3), 119.28 (C-4a), 110.86, 110.93(C-5a, C-lla), 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 (OCH ₃ ), 49.95 (C-3'), 36.86 (C-8), 34.18 (C-10), 32.46 (C-2'), 17.98 (CH ₃ ).

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

 In Table 6, the numerals 1-18 are the peak numbers, and indicate the retention time, peak height, peak area, and relative area of each component in the crude epirubicin hydrochloride obtained in Example 7.

 Table 6

 Among them, the peak No. 11 indicates epirubicin hydrochloride.

 Example 13 Synthesis of epirubicin hydrochloride

Compound 5' (22.4g, 36.5mmol) was dissolved in a mixed solvent of dichloromethane (562ml) and methanol (562ml). At 0 °C, hydrochloric acid (3mol/L, 316ml) was added and stirred at 0 °C. hour. The layers were separated and the aqueous phase was washed with dichloromethane (562 ml χ2). The organic phases were combined and washed with water (562 ml x 2). Combine the aqueous phase, obtain 3L of a crude aqueous solution of epirubicin hydrochloride, the purity is 89.0%, dilute to the appropriate concentration, and obtain the concentration of epirubicin hydrochloride in the crude aqueous solution of epirubicin hydrochloride by regression equation. At 6.7 g/L, the yield of crude epirubicin hydrochloride from the compound 5' was 95%.

 EXAMPLES Synthesis of Compound 3

 Compound 2 (30 g, 51.8 mmol) was suspended in anhydrous 2-methyltetrahydrofuran (300 ml), and trifluoroacetic anhydride (43.5 g, 207.2 mmol at 10 ° C for 4 hours) was added at 10 ° C, and sodium carbonate was added thereto. (82.4g, 777mmol), 2-methyltetrahydrofuran (300ml) and methanol (30ml), finally added water (150ml). Stir at 35°C for 16 hours, cool to 0°C, add hydrochloric acid (14.2ml concentrated hydrochloric acid and 150ml) The mixture was stirred and the organic phase was washed with water (150 ml×2), EtOAc (EtOAc) The mixture was dried under reduced pressure and dried under vacuum at 35 ° C to constant weight to give compound 3 (32.1 g, yield 97%), purity 98.2%.

 EXAMPLES Synthesis of Compound 4

 Compound 3 (32.1 g, 50.2 mmol) was suspended in anhydrous 2-methyltetrahydrofuran (226.4 ml), pyridine hydrochloride (25.7 mg) was added, and triisopropyl orthoformate (47.8 g, 251 mmol) was added at 30 ° C The reaction was carried out for 5 hours, and the reaction was continued under reflux for 0.5 hours. The temperature was lowered to 25 ° C, water (22.7 ml) was added, sodium hydrogencarbonate (0.2 g) was added, and the mixture was stirred for 1 hour. Propionic acid (38 ml) was added and stirred at 10 ° C for 15 hours. The temperature was lowered to 0 ° C, and a sodium hydrogencarbonate solution (67.8 g of sodium hydrogencarbonate and 784 ml of water) was added and stirred for 1 hour. Ethyl acetate (114 ml) was added, the layers were separated, and the organic phase was washed with water (114mlx2). The combined aqueous phases were washed with ethyl acetate (227 mL×2). The organic phases were combined and washed with water (114 ml). The organic phase was evaporated to dryness and dried in vacuo to dryness to 35 ° C to afford compound 4 (34.9 g, yield 98%), purity 90.2%.

 EXAMPLES Synthesis of Compound 5

Compound 4 (34.9 g, 49.2 mmol) was dissolved in anhydrous dichloromethane (321 ml), anhydrous pyridine (31.1 g, 393.6 mmol) was cooled to 0 ° C, and nitrogen was applied. Diluted trifluoromethanesulfonic anhydride (41.6 g, 147.6 mmol), and the reaction was continued for 1 hour at 0 ° C for 30 minutes. A pre-prepared solution of triethylammonium triacetate (156.8 g of triethylamine) was added. 28.7 g of anhydrous formic acid, 209 ml of anhydrous dichloromethane, stirred at 25 ° C for 16 hours, and the reaction was turned over. Add sodium hydrogencarbonate (68.2 g), add water (1000 ml), layer, and take organic phase, 8 The aqueous solution of acetic acid (300 ml*2) was washed, combined with aqueous acetic acid, washed with dichloromethane (200*2 ml), combined with organic phase, washed with 5% sodium hydrogencarbonate (300 ml), combined with aqueous sodium bicarbonate, The organic phase was washed with water (300*2 ml). The organic phase was dried to give compound 5 (30.3 g, yield: 92%), purity 87%. ESI-MS (w/z): 760 [M+Na] ⁺ _o

 EXAMPLES Synthesis of epirubicin hydrochloride

Compound 5' (22.4g, 36.5mmol) was dissolved in a mixed solvent of dichloromethane (562ml) and methanol (562ml), hydrochloric acid (2mol/L, 712ml) was added at 12°C, and stirred at 12°C for 7 hours. . The layers were separated and the aqueous phase was washed with dichloromethane (562 mL X2). The organic phases were combined and washed with water (562 ml X2). Combine the aqueous phase to obtain 3L of a crude aqueous solution of epirubicin hydrochloride. The purity was 88.2%, diluted to the appropriate concentration. The concentration of epirubicin hydrochloride in the crude aqueous solution of epirubicin hydrochloride was 6.6 g/L from the regression equation, and the yield of crude epirubicin hydrochloride from the compound 5' was 94. %.

 EXAMPLES Synthesis of Compound 3

 Compound 2 (30 g, 51.8 mmol) was suspended in anhydrous dichloromethane (300 ml), and then, at 25 ° C, trifluoroacetic anhydride (54.4 g, 259 mmol, 20 ° C, the reaction was continued for 4 hours, and potassium hydrogencarbonate was added. 107.2g, 1070.5mmol), tetrahydrofuran (300ml) and methanol (30ml), add water (150ml) for 30 minutes. Stir at 33 °C for 16 hours, cool to 0 ° C, add hydrochloric acid (14.2ml concentrated hydrochloric acid and 150ml) Mix with water. Stir the layers, wash the organic phase with water (150mlx2), wash the aqueous phase, dichloromethane (150mlx2), wash the organic phase, acid solution (150ml) with pH 4.0, wash with water (150ml) The organic phase was dried under reduced pressure and dried under vacuum at 35 ° C to constant weight to give compound 3 (32.5 g, yield 98%), purity 98.3%.

 EXAMPLES Synthesis of Compound 4

 Compound 3 (32.5 g, 50.9 mmol) was suspended in anhydrous dichloromethane (226.4 ml), pyridine p-toluenesulfonate (21.1 mg) was added, and triisopropyl orthoformate (53.3 g, 280 mmol) was added at 25°. The reaction was carried out for 2.8 hours at C, and the reaction was continued for 3 hours under reflux. The temperature was lowered to 25 ° C, water (22.7 ml) was added, sodium hydrogencarbonate (0.2 g) was added, and the mixture was stirred for 1 hour. Butyric acid (93.4 ml) was added and stirred at 20 ° C for 18 hours. The temperature was lowered to 0 ° C, and a sodium hydrogencarbonate solution (67.8 g of sodium hydrogencarbonate and 784 ml of water) was added and stirred for 1 hour. Dichloromethane (114 ml) was added, the layers were separated and the organic phase was washed with water (114mlx2). The combined aqueous phases were washed with dichloromethane (227 ml x 2). The organic phases were combined and washed with water (114 ml). The organic phase was evaporated to dryness and dried in vacuo to a constant weight to afford compound 4 (35.5 g, yield 99%), purity 91.5%.

 EXAMPLES Synthesis of epirubicin hydrochloride

 Compound 5' (22.4 g, 36.5 mmol) was dissolved in a mixed solvent of dichloromethane (562 ml) and methanol (562 ml), and hydrochloric acid (4 mol/L, 475 ml) was added at 25 ° C, and stirred at 25 ° C. 7 hours. The layers were separated and the aqueous phase was washed with dichloromethane (562 ml X 2). Combine the organic phase and wash with water (562ml ><2). Combine the aqueous phase, obtain 3L of crude aqueous solution of epirubicin hydrochloride, the purity is 80.2%, dilute to the appropriate concentration, and the concentration of epirubicin hydrochloride in the aqueous solution of epirubicin hydrochloride is 6.3g/L by the regression equation. The yield of 5' crude crude epirubicin hydrochloride was 90%.

 EXAMPLES Synthesis of Compound 4

Compound 3 (32.4 g, 50.7 mmol) was suspended in anhydrous tetrahydrofuran (226.4 ml), and camphorsulfonic acid (1. 2 mg) was added, triisopropyl orthoformate (57.9 g, 304.2 mmol) was added, and the reaction was carried out at 30 ° C for 0.5 hour. The reaction was continued for 1.8 hours under reflux. The temperature was lowered to 30 ° C, water (22.7 ml) was added, sodium hydrogencarbonate (0.2 g) was added, and the mixture was stirred for 1 hour. Ethyl acetate (114 ml) was added, and the organic layer was washed with EtOAc EtOAc (EtOAcjjjjjjjjjjjj Compound 4 (35.2 g, yield 98%) was obtained with a purity of 85.1%. Example 22 Synthesis of epirubicin hydrochloride

 Compound 5 (30.3 g, 41.1 mmol) was dissolved in dichloromethane (562 mL). Aqueous sodium hydroxide solution (443 ml of water, 28.3 g of sodium hydroxide, 1.6 mol/L) was added. The reaction was carried out at -20 ° C for 10 hours, and an aqueous hydrochloric acid solution (3 mol/L, 380 ml) was directly added without the after-treatment. The temperature was raised to 10 ° C and stirred for 7 hours. The layers were washed with methylene chloride (562 ml x 2). Combine the organic phase and wash with water (562ml><2). The aqueous phase was combined to obtain 3L of a crude aqueous solution of epirubicin hydrochloride, the purity was 89.0%, and diluted to a suitable concentration. The concentration of epirubicin hydrochloride in the crude aqueous solution of epirubicin hydrochloride was 7.2 g/L by the regression equation. It is 91%.

 Comparative Example 1 Synthesis of Compound 29

 Compound 2 (30 g, 51.8 mmol) was dissolved in EtOAc EtOAc (EtOAc (EtOAc) Sodium hydrogencarbonate (15 g) and dichloromethane (600 ml) were added in that order, and finally water (150 ml) was added dropwise for 30 minutes. After stirring at room temperature for 1 hour, the organic layer was washed with water (150 ml×2). The organic phase was spin-dried under reduced pressure and dried under vacuum at 35 ° C to a constant weight to give compound 29 (20.2 g, yield 68%) with a purity of 80.3%.

 Comparative Example 2 Synthesis of Compound 30

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

 Comparative Example 3 Synthesis of Compound 32

Compound 30 (19.1g, 32.0mmol) was dissolved in of dichloromethane (1875ml) was added pyridine (93.75ml) ₀ cooled to 0 ° C, diluted with dropwise addition of trifluoromethanesulfonic anhydride of dichloromethane (375ml) (9.4ml ), the reaction was continued for 1 hour at 0 ° C for 30 minutes. Add hydrazine, hydrazine-bis (Wang methylsilyl; acetamide (BSA, 37.5 ml), react at room temperature for 4 hours. Add pre-prepared 1 mol/L solution of triethylammonium methoxide (1875 ml), stir at room temperature 15 After the completion of the inversion reaction, a 48% aqueous potassium fluoride solution (187.5 ml) was added, and methanol (375 ml) was added thereto, and the mixture was stirred at room temperature for 2 days. 0.5 mol/L hydrochloric acid (1875 ml) was washed, and 3% aqueous sodium hydrogencarbonate solution (1875 ml) was washed. The organic phase was dried over anhydrous sodium sulfate, and dried under reduced pressure to give compound 32 (20.8 g, yield: 90%), purity 65.0%.

 Comparative Example 4 Synthesis of epirubicin hydrochloride

Compound 32 (20.8 g, 28.8 mmol) was added to a 0.1 mol/L aqueous sodium hydroxide solution (4688 ml), and reacted at 5 ° C for 3 hours. The extract was extracted with chloroform (4688 ml X4), dried over anhydrous sodium sulfate and evaporated. The solid was dissolved in methanol (1875 ml), pH was adjusted to 2 with hydrochloric acid and stirred for 30 min. Dry at room temperature under reduced pressure, isopropyl ether was beaten to obtain hydrochloric acid The crude product of epirubicin (9.0 g, yield 30%), purity 69%.

 Contrast reality 5

Compound 30 (30.4 g, 49.6 mmol) was dissolved in anhydrous dichloromethane (3 mL), EtOAc (19.7 g, 249.4 mmol). Anhydrous dichloromethane (30 ml) diluted trifluoromethanesulfonic anhydride (28.1 g, 99.6 mmol) was added dropwise, and the reaction was continued for 30 minutes at -5 ° C for 30 minutes, and the previously prepared three were directly added without post-treatment. Dichloromethane acetate solution (62.7 g of triethylamine, 28.7 g of anhydrous formic acid, 209 ml of anhydrous dichloromethane), stirred at 25 ° C for 16 hours, added sodium bicarbonate (68.2 g), water was added dropwise (1000ml), layered, organic phase, 8% aqueous acetic acid (00ml*2), combined with aqueous acetic acid, dichloromethane (200*2ml), combined organic phase, 5% sodium bicarbonate (300ml) The combined aqueous sodium hydrogencarbonate solution, dichloromethane (200 ml * 2 ml) were washed, and the organic phases were combined and washed with water (300*2ml). The organic phase was dried to give compound 32 (30.8 g, yield 86%, Compound 30), purity 50%, ESI-MS (w/z): 746[M+Na]+.

 Comparative Example 6 Synthesis of epirubicin hydrochloride

 Compound 5 (21.2 g, 28.8 mmol) was added to a 0.1 mol/L aqueous sodium hydroxide solution (4688 ml), and reacted at 5 ° C for 3 hours. The mixture was extracted with chloroform (4688 ml×4), dried over anhydrous sodium sulfate and evaporated. The solid was dissolved in methanol (1875 ml), pH was adjusted to 2 with hydrochloric acid and stirred for 30 min. The mixture was decanted at room temperature under reduced pressure, and isopropyl ether was beaten to obtain crude epirubicin hydrochloride (18.0 g, yield 60%), purity 79%.

 While the invention has been described with respect to the preferred embodiments of the embodiments of the present invention modify. Accordingly, the scope of the invention is defined by the appended claims.

Claims

Rights request

 A method for producing a compound 4', which comprises the steps of: esterifying a compound 4 with trifluoromethanesulfonic anhydride under the action of a base in an organic solvent; Compound 4';

2. The preparation method according to claim 1, wherein the organic solvent is preferably a halogenated hydrocarbon solvent; and the halogenated hydrocarbon solvent is preferably dichloromethane. The base is anhydrous methylene chloride; the base is preferably an organic base; the organic base is preferably pyridine, more preferably anhydrous pyridine; the base is preferably better than the compound 4 The ground is 3:1-10:1, more preferably 5:1-8:1; the molar ratio of the trifluoromethanesulfonic anhydride to the compound 4 is preferably from 1:1 to 5:1, more preferably 2:1-3:1; the temperature of the esterification reaction is preferably -5 ° C to 0 ° C _; the esterification reaction preferably comprises the following steps: Compound 4, organic solvent and alkali After mixing, trifluoromethanesulfonic anhydride is added to carry out the esterification reaction; preferably, the esterification reaction is controlled to add trifluoromethanesulfonic anhydride at a temperature of -5 ° C to 0 ° C; The reaction is preferably carried out in gas protection; the gas is preferably N ₂ .

 The preparation method according to claim 1 or 2, wherein the method for preparing the compound 4' further comprises the steps of: catalyzing a compound in an organic solvent under the catalysis of an acid and/or an acid salt; 3 and triisopropyl orthoformate condensation reaction as shown below, to obtain the compound 4;

The preparation method according to claim 3, wherein in the method for preparing the compound 4, the acid is preferably an organic acid, more preferably camphorsulfonic acid, the acid form. The salt is preferably a pyridine hydrochloride and/or a pyridine p-toluenesulfonate; the organic solvent is preferably an ether solvent and/or a halogenated hydrocarbon solvent; The ground is tetrahydrofuran and/or 2-methyltetrahydrofuran; the halogenated hydrocarbon solvent is preferably dichloromethane; the molar ratio of triisopropyl orthoformate to compound 3 is preferably 4:1. More preferably, the mass of the acid and/or acid salt is from 0.01% to 0.2% by mass of the compound 3, more preferably 0.05% by weight - 5:1, more preferably from 5:1 to 6:1. 0.08% _; The temperature of the condensation reaction is preferably from 25 ° C to the reflux temperature of the solvent at normal pressure; the condensation reaction preferably includes a first-stage reaction and a second-stage reaction, wherein the first stage is The reaction temperature is preferably from 25 ° C to 30 ° C _; the temperature of the second-stage reaction is preferably the solvent reflux temperature at normal pressure; the condensation reaction preferably comprises the following steps: Suspension in an organic solvent, adding an acid and/or an acid salt, triisopropyl orthoformate, to carry out the condensation reaction; after the condensation reaction is completed, preferably further comprising a reaction after the end of the condensation reaction The operation of treating the liquid with an organic acid having a pKa value of 3 to 5; 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. Preferably, the molar ratio of the organic acid to the compound 3 is from 5:1 to 20:1, more preferably from 10:1 to 20:1; and the temperature of the organic acid treatment is preferably 10°. C -30 ° C.

 The preparation method according to claim 3 or 4, wherein the method for preparing the compound 4' further comprises the following steps: acylating the compound 2 with trifluoroacetic anhydride in the organic solvent A And then in the solvent, will be acylated 3;

 twenty three

The preparation method according to claim 5, wherein in the method for preparing the compound 3, the organic solvent A is preferably an ether solvent and/or a halogenated hydrocarbon solvent; The solvent is preferably tetrahydrofuran and/or 2-methyltetrahydrofuran; the halogenated hydrocarbon solvent is preferably dichloromethane; the trifluoroacetic anhydride and the compound 2 are preferably 3: 1-10:1, more preferably 4:1-6:1; the temperature of the acylation reaction is preferably from 0 ° C to 25 ° C, more preferably from 10 ° C to 20 ° C; The acylation reaction preferably comprises the steps of: suspending the compound 2 in an organic solvent A, and then adding trifluoroacetic anhydride to carry out the acylation reaction, preferably, the acylation reaction is controlled to a temperature of 0. Trifluoroacetic anhydride was added at °C-25 °C.

The preparation method according to claim 5 or 6, wherein the base is preferably an inorganic base; and the inorganic base is preferably sodium hydroxide, potassium hydroxide, sodium carbonate or carbonic acid. One or more of potassium, sodium hydrogencarbonate, potassium hydrogencarbonate and sodium phosphate; the molar ratio of the base to the compound 2 is preferably 15-25:1; the reaction solution after the acylation reaction is completed The temperature of the treatment with a base is preferably from 30 ° C to 35 ° C; the treatment of the reaction solution after completion of the acylation reaction with a base preferably comprises the following steps: adding the reaction solution after completion of the acylation reaction, The alkali and the organic solvent B are further added with water to carry out the reaction; the organic solvent B is preferably one or more of an ether solvent, a halogenated hydrocarbon solvent, an ester solvent and an alcohol solvent, more preferably One or more of an ether solvent, a halogenated hydrocarbon solvent, and an ester solvent a mixed solvent with an alcohol solvent; the ether solvent is preferably tetrahydrofuran and/or 2-methyltetrahydrofuran; the halogenated hydrocarbon solvent is preferably dichloromethane; the ester The solvent is preferably ethyl acetate; the alcohol solvent is preferably methanol.

 A method for producing a compound 5, which comprises the steps of: preparing a compound obtained by the production method according to at least one of claims 1 to 7 in an organic solvent under the action of a base 4' and formic acid are shown as pro

The preparation method according to claim 8, wherein in the preparation method of the compound 5, the formic acid is preferably anhydrous formic acid; and the organic solvent is preferably a halogenated hydrocarbon. The halogenated hydrocarbon solvent is preferably methylene chloride; the base is preferably triethylamine; the molar ratio of the base to formic acid is preferably 1: 1-5: More preferably, it is 1:1-3:1; the molar ratio of the compound 4' and formic acid is preferably 1:10-1:15, more preferably 1:12.5; the nucleophilic substitution The reaction preferably includes the following steps: The nucleophilic substitution reaction is carried out by adding a mixed solution of a base, a formic acid and an organic solvent to a mixed solution of the compound 4' and an organic solvent.

 The production method according to claim 8 or 9, wherein the compound 4' is obtained by the production method according to at least one of claims 1 to 7, without post-treatment, directly in the alkali Under the action, the compound 4' and the formic acid are subjected to the nucleophilic substitution reaction to prepare a compound 5.

 A process for the preparation of a compound 5', which comprises the steps of: preparing a compound according to the preparation method according to at least one of claims 8 to 10 in a solvent under the action of a base 5 performing a deprotection reaction as shown below to obtain a compound 5';

The method according to claim 11, wherein the solvent is preferably a halogenated hydrocarbon solution. And the alcohol solvent of dc ₄ ; the halogenated hydrocarbon solvent is preferably dichloromethane; the alcohol solvent of dC ₄ is preferably methanol, ethanol, n-propanol or different One or more of propanol, n-butanol, isobutanol and tert-butanol; the base is 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 solution of a base; the molar concentration of the aqueous solution of the base is preferably from 1 mol/L to 3 mol/L _; and the mass of the compound 5 and the base is preferably 1 : 1-1 : 3, more preferably 1: 2; the temperature of the deprotection reaction is preferably -25 5 ° C _; the deprotection reaction preferably comprises the following steps: After mixing with the solvent, the deprotection reaction is carried out by adding a base. Preferably, the deprotection reaction is carried out by adding a base at a temperature of -25 ° C to -5 ° C.

 The method according to claim 11 or 12, wherein after the compound 5 is produced according to the preparation method according to at least one of claims 8 to 10, directly in a solvent, without post-treatment, The deprotection reaction is carried out under the action of a base to prepare a compound 5'.

 A method for producing epirubicin hydrochloride compound 1, which comprises the steps of: preparing a solvent according to the preparation method according to at least one of claims 11-13 under the action of hydrochloric acid; The obtained compound 5' is subjected to a deprotection reaction as shown below to obtain a compound 1;

The method according to claim 14, wherein the solvent is preferably a halogenated hydrocarbon solvent and/or an alcohol solvent of dC ₄ ; and the halogenated hydrocarbon solvent is preferably Is dichloromethane; the alcohol solvent of dC ₄ is preferably one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tert-butanol; The hydrochloric acid preferably participates in the reaction in the form of an aqueous solution of hydrochloric acid; the molar concentration of the aqueous hydrochloric acid solution is preferably 2 m ₀ l / L - 4 mol / L _; the molar ratio of the hydrochloric acid to the compound 5' is preferably 26: 1-52: 1; The temperature of the deprotection reaction is preferably 0-25 V.

 The preparation method according to claim 14 or 15, wherein after the compound 5' is obtained by the production method according to at least one of claims 11 to 13, hydrochloric acid is directly added without post-treatment. The deprotection reaction was carried out to obtain Compound 1.

A method for producing a compound 4, which comprises the steps of: condensing compound 3 and triisopropyl orthoformate under the catalysis of an acid and/or an acid salt in an organic solvent as shown below; Reacting Compound 4;

Wherein the conditions of the preparation method of the compound 4 are the same as those in claim 3 or 4.

 18. A method for preparing a compound 5, which comprises the steps of: in an organic solvent, the compound 4' and the formic acid are subjected to a nucleophilic substitution reaction as shown below under the action of a base to obtain a compound 5;

Wherein, the conditions of the preparation method of the compound 5 are the same as those described in 8 or 9.

 A method for producing a compound 5', which comprises the following steps: in a solvent, a compound 5 is subjected to a deprotection reaction as shown below under the action of a base to obtain a compound 5';

 The conditions of the deprotection process are as described in claim 11 or 12.

 A method for preparing epirubicin hydrochloride compound 1, which comprises the steps of: deprotecting compound 5' as shown below under the action of hydrochloric acid in a solvent to obtain compound 1 ;

The conditions of the deprotection process are as described in claim 14 or 15.

 A compound of the formula 4, a compound of the formula 4', a compound of the formula 5 or a compound of the formula