CN106749447B

CN106749447B - A kind of intermediate of epirubicin hydrochloride compound

Info

Publication number: CN106749447B
Application number: CN201710016793.XA
Authority: CN
Inventors: 张贵民; 刁玉林; 孟凡波
Original assignee: Lunan Pharmaceutical Group Corp
Current assignee: Lunan Pharmaceutical Group Corp
Priority date: 2017-01-10
Filing date: 2017-01-10
Publication date: 2018-02-13
Anticipated expiration: 2037-01-10
Also published as: CN106749447A

Abstract

The present invention provides new intermediate and the variation route using the intermediate synthetic hydrochloric acid epirubicin.This route is simple, cheap, efficient, the intermediate for avoiding existing epirubicin hydrochloride synthetic route generation simultaneously is met water unstable, easily decomposed, the problem of overall route yield is relatively low, for more preferable energy-saving and emission-reduction, this route has used the cheap reagent being easy to get of cost；Removable selective protection means are employed simultaneously, and generation impurity is few, and purity is high, high income.

Description

A kind of intermediate of epirubicin hydrochloride compound

Technical field

The invention belongs to the field of chemical synthesis, and in particular to a kind of intermediate of epirubicin hydrochloride compound.

Background technology

Epirubicin hydrochloride also known as Farmorubine Hydrochloride, belong to Anthraquinones antibiotic, chemical name：(8S,10S)-10- [(3 '-amino -2 ', 3 ', 6 '-three deoxidation-α-L- arabopyranoses bases)-O-] -6,8,11- trihydroxy -8- glycolyls -1- Methoxyl group -7,8,9,10- tetrahydrochysene aphthacene -5,12- dione hydrochlorides, its structure are as follows：

For the isomer of adriamycin, mechanism of action is directly embedded between DNA core alkali pair, disturbs transcription, resistance Only tumour cell mRNA formation, so as to suppress DNA and RNA synthesis.In addition, epirubicin hydrochloride is to topoisomeraseⅡ There is inhibitory action.It is effective to a variety of transplanted tumors for a cell cycle nonspecific agent (CCNSA).Clinical efficacy and adriamycin phase Deng or it is slightly higher but smaller to cardiac toxic, single drug has wide spectrum inhibitory action to kinds of tumors, available for breast cancer, pernicious leaching Bar knurl, soft tissue sarcoma and stomach cancer.Also there is antitumor activity to malignant mela noma and colon cancer.Combining with other anticarcinogens makes With available for treatment lung cancer and oophoroma.Therefore play the part of more and more important role in human anti-tumor's clinical practice, clinic needs Measure and increase year by year.

Patent JP2007261976A provides a kind of route of synthetic hydrochloric acid epirubicin, and specific synthetic route is as follows：

Using 4 '-EPIDNR as raw material, under methyl formate and bromine effect reaction obtain brominated product, then successively with Bromo ketone intermediate is prepared into after expoxy propane, hydrogen bromide hydrolysis, finally successively with sodium acid carbonate, sodium hydroxide and sodium chloride water Epirubicin hydrochloride is hydrolyzed to obtain in solution.Used such as expoxy propane organic solvent is to producer's body and mind in this method Health produces high risks, and caused waste liquid is difficult to handle, huge to environmental pressure；Meanwhile last hydrolysis stage uses Multi-step, the condition of different pH hydrolysis, it is difficult to accurate control, thus high requirement is proposed to the technology of operator, so, The technique productions cost is huge, and environmental pollution is serious, is unfavorable for carrying out industrialized production.And the technique is soft to raw material 4 '-table Humidity requirement is more harsh when the water content of erythromycin and reaction, and the slight change that water content is found in actual application is The defects of 4 '-EPIDNR residual quantity can be caused excessive, end product quality is difficult to ensure that, loss of material rate is high.

Patent US20070142309 provides the synthetic route of a variety of epirubicin hydrochlorides, and composition principle is not quite similar, but Substantially all employ first with the processing method of sodium triacetoxy borohydride reduction amination, afterwards again by the intermediate bromine of generation Change, the mode of sodium formate hydrolysis obtain final product epirubicin hydrochloride, and the more traditional organic synthesis reagent of the reagent cost is high, and Applied reagent is difficult to preserve under workshop condition, and industrial accident easily occurs, and is unsuitable for industrialized production reality.

Therefore, it is problematic in that in epirubicin hydrochloride preparation method in summary, or yield is low, impurity is big, or Person's technical requirements are high, environmental pollution is serious, production cost is high, and the preparation method generation of epirubicin hydrochloride in the prior art Intermediate is high for moisture requirement, easily decomposes, and is unfavorable for carrying out industrialized production.

The content of the invention

In view of the deficiencies in the prior art, the present invention is provided a kind of new intermediate compound II -1 and closed using the intermediate The variation route of hydrochloric acid epirubicin.This route is simple, cheap, efficient, in order to preferably reduce production cost and reduce to ring The pollution in border, this route have used economy, the organic reagent of less pollution substantially, the intermediate of the preparation method generation for Moisture requirement is low, and stability is high, and mass yield is high.

The present invention realizes especially by following technical scheme：

A kind of intermediate of epirubicin hydrochloride compound, it is that structural formula is as follows shown in formula II -1：

A kind of preparation method of midbody compound II -1, it is characterised in that preparation method comprises the following steps：Add first Alcohol, acidic catalyst, esterifying reagent B, make daunorubicin hydrochloride II generation with ketal structure midbody compound II -1；

Compound ii synthesis compound ii -1 specifically comprises the following steps：In organic solvent A, methanol is added, acidity is urged Agent, esterifying reagent B, daunorubicin hydrochloride II, react 2~3 hours, midbody compound II of the generation with ketal structure- 1.The temperature with esterifying reagent B reactions is preferably 0~10 DEG C.

The organic solvent A be selected from arene, fat hydrocarbon, alicyclic hydrocarbon type, halogenated hydrocarbons, alcohols, alkanes, ethers, One kind in amide-type, diol, derivatives class and esters solvent.

The organic solvent A is selected from benzene, toluene, hexamethylene, methanol, ethanol, the tert-butyl alcohol, dichloromethane, Isosorbide-5-Nitrae-dioxy six One or more in ring, ether, acetone, trichloro ethylene, tetrahydrofuran, methyl tertiary butyl ether(MTBE), ethyl acetate and DMF；Enter one Step is preferably dichloromethane or 1,4- dioxane.

The esterifying reagent B is selected from Ethyl formate, methyl formate, methyl acetate, ethyl acetate, triethyl orthoformate, chlorine One or more in Ethyl formate and propyl formate；Preferably triethyl orthoformate or trimethyl orthoformate.

Preferably, compound ii synthesis compound ii -1 specifically comprises the following steps：To add into three neck glass reaction bottles Enter organic solvent A and daunorubicin hydrochloride II.Open stirring, after 5~10 DEG C, 10~15 minutes of temperature control, check material dissolution feelings Condition, continue to stir if not being completely dissolved；If being completely dissolved, feed liquid is cooled to 0~5 DEG C, adds the first of acidic catalyst Alcoholic solution, after stirring 1 hour, add esterifying reagent B；Addition finishes, and stirs 2~3 hours.Preferably, the organic solvent A Dosage be：(represented in terms of weight g/ volumes mL with lower part with (W/V, g/mL)), daunorubicin hydrochloride：Organic solvent A= 1:50~70, preferably 1:60；The organic solvent A be preferably methanol, dichloromethane and one kind in 1,4- dioxane or It is a variety of.

The acidic catalyst methanol solution dosage of the addition is：Daunorubicin hydrochloride：Methanol：Acidic catalyst=1: 177~200:1~3 (W/V/W, g/mL/g), acidic catalyst are preferably camphorsulfonic acid or p-methyl benzenesulfonic acid.

Preferably, the dosage of the esterifying reagent B is：Daunorubicin hydrochloride：Esterifying reagent B=1:1~4, preferably 1:2 (W/V, g/mL)；The esterifying reagent B is preferably trimethyl orthoformate or triethyl orthoformate.

The application provides a kind of method that epirubicin hydrochloride is prepared using the intermediate II -1, including following step simultaneously Suddenly：Step 1. prepares unseparated compound ii -1 with compound ii and synthesizes compound III again；Step 2. compound III is further Dehydration, is oxidized to carbonyl by the alcoholic extract hydroxyl group of amino sugar structure, generates unsegregated midbody compound IV；Step 3. is with selectivity Carbonyl reduction in amino sugar is hydroxyl by reducing agent D, is converted into opposite with daunorubicin amino sugar structure 4-OH configurations Intermediate V；Step 4. is sloughed in the structure of intermediate V with highly basic and intermediate VI is generated to the protection of amino；Step 5. exists Bromination and acid hydrolytic reaction are carried out under sour environment successively, generates corresponding bromo ketone intermediate, then sent out in sodium formate solution Unboiled water solution, bromine is substituted by alcoholic extract hydroxyl group and finally obtains target product epirubicin hydrochloride I.

Preferably, its specific synthetic route is as follows：

Step 1. compound ii, which prepares unseparated compound ii -1 and synthesizes compound III again, to be specifically comprised the following steps： In organic solvent A, the methanol solution of acidic catalyst is added, after stirring 1 hour, daunorubicin hydrochloride II is added and is tried with esterification Agent B, react 2~3 hours, generation with ketal structure non-separation of intermediates compound ii -1, backward reaction system in add Enter TFAA, stirring reaction 1~1.5 hour, midbody compound III of the generation with amino trifluoroacetic acid ester structure.Institute It is preferably 0~10 DEG C to state with the temperature of esterifying reagent B reactions.

Organic solvent A described in step 1 be selected from arene, fat hydrocarbon, alicyclic hydrocarbon type, halogenated hydrocarbons, alcohols, alkanes, One kind in ethers, amide-type, diol, derivatives class and esters solvent；It preferably is selected from benzene, toluene, hexamethylene, methanol, ethanol, uncle Butanol, dichloromethane, Isosorbide-5-Nitrae-dioxane, ether, acetone, trichloro ethylene, tetrahydrofuran, methyl tertiary butyl ether(MTBE), ethyl acetate With the one or more in DMF；More preferably methanol or dichloromethane or 1,4- dioxane.

The acidic catalyst methanol solution dosage added described in step 1 is：(with bottom in terms of weight g/ volume mL/ weight g Divide and represented with (W/V/W, g/mL/g)), daunorubicin hydrochloride：Methanol：Acidic catalyst=1:177~200:1~3, acidity is urged Agent is preferably camphorsulfonic acid or p-methyl benzenesulfonic acid.

Esterifying reagent B described in step 1 is selected from Ethyl formate, methyl formate, methyl acetate, ethyl acetate, primitive nail triethylenetetraminehexaacetic acid One or more in ester, ethyl chloroformate and propyl formate；More preferably triethyl orthoformate or trimethyl orthoformate.

The dosage of organic solvent A described in step 1 is：(with lower part (W/V, g/mL) table in terms of weight g/ volumes mL Show), daunorubicin hydrochloride：Organic solvent A=1:50~70, preferably 1:60.

The dosage of organic solvent B described in step 1 is：Daunorubicin hydrochloride：Esterifying reagent B=1:1~4, preferably 1:2 (W/V, g/mL).

TFAA dosage is described in step 1.：Daunorubicin hydrochloride：TFAA=1:1~4, preferably 1：2 (W/V, g/mL).

Reaction is finished, and methanol (daunorubicin hydrochloride is added into reaction solution：Methanol=1:20~40 (W/V, g/mL)), stir After mixing 10~15 minutes, add 8% sodium bicarbonate solution and adjust pH value to 7.0~8.0.Control 15 DEG C~25 DEG C of temperature, insulation Stirring reaction 3~5 hours.TLC is detected：With chloroform/isopropanol (volume ratio 96/4) for solvent, detection raw material spot should It is basic to disappear.Midbody compound III Rf ≈ 0.3, daunorubicin hydrochloride Rf ≈ 0.Liquid separation is stood, collects lower floor's organic phase.Vacuum Certain volume (daunorubicin hydrochloride is concentrated under state：The volume of concentrate=1:10 (W/V, g/mL)), add under stirring N-hexane crystallization, filter and solid midbody compound III is obtained after drying.Preferably, the n-hexane addition is：Hydrochloric acid is soft red Mycin：N-hexane=1:10 (W/V, g/mL).

Step 2. compound III synthesis compounds Ⅳ specifically comprises the following steps：In organic solvent A, trifluoroacetic acid is added Acid anhydride, addition finish, stirring reaction 1~1.5 hour, then add midbody compound III and 1,5- diaza-bicyclo (4,3,0) nonyl- 5- alkene reactions 0.5 hour, the alcoholic extract hydroxyl group of amino sugar structure is oxidized to carbonyl, backward reaction system in add organic acid C, stir Reaction 0.5 hour is mixed, generates midbody compound IV.

It is optimal with preferably -75 DEG C~0 DEG C of the temperature of 1,5- diaza-bicyclos (4,3,0) nonyl- 5- alkene reactions described in step 2 Elect -70 DEG C~-40 DEG C as.

Organic acid C described in step 2 is selected from formic acid, acetic acid, propionic acid, butyric acid, octanoic acid, adipic acid, ethanedioic acid, malonic acid, fourth Diacid, maleic acid, tartaric acid, benzoic acid, phenylacetic acid, phthalic acid, terephthalic acid (TPA), valeric acid, caproic acid, capric acid, stearic acid, One or more in palmitic acid, acrylic acid.More preferably formic acid, acetic acid, propionic acid, butyric acid, octanoic acid, adipic acid, second two One kind in acid, malonic acid, succinic acid and maleic acid；Most preferably glacial acetic acid and malonic acid.

Organic solvent A described in step 2 be selected from arene, fat hydrocarbon, alicyclic hydrocarbon type, halogenated hydrocarbons, alcohols, alkanes, One or more in ethers, amide-type, diol, derivatives class, esters solvent and phenol；More preferably benzene, toluene, hexamethylene, uncle Butanol, dichloromethane, 1,4- dioxane, ether, acetone, trichloro ethylene, tetrahydrofuran, methyl tertiary butyl ether(MTBE), ethyl acetate With the one or more in DMF；More preferably dichloromethane.

The dosage of organic solvent A described in step 2 is：Intermediate III：Organic solvent A=1:20~40, preferably 1:40(W/ V, g/mL).

Step 3. compounds Ⅳ synthesis compound V specifically comprises the following steps：In organic solvent A, by intermediate IV with Reducing agent D reacts 0.5~1 hour, is hydroxyl by the carbonyl reduction in amino sugar, and being converted into has and daunorubicin amino sugar knot The opposite intermediate V of structure 4-OH configurations.

The temperature with reducing agent D reactions is preferably -75 DEG C~0 during step 3. compounds Ⅳ synthesis compound V DEG C, it is most preferably -60 DEG C~-30 DEG C.

The reducing agent D is selected from sodium hydride, tetrahydrochysene lithium aluminium, hydroboration during step 3. compounds Ⅳ synthesis compound V One or more in sodium, lithium hydride, double methoxyethoxy alanates, lithium triethylborohydride, sodium cyanoborohydride；It is described Selective reduction agent preferably can be preferably minimized the isomer impurities of intermediate V, the purity more than 85% of intermediate V.

Organic solvent A described in step made above is selected from arene, fat hydrocarbon, alicyclic hydrocarbon type, halogenated hydrocarbons, alcohol One kind in class, alkanes, ethers, amide-type, diol, derivatives class, esters solvent and phenol；More preferably benzene, toluene, hexamethylene, Methanol, ethanol, the tert-butyl alcohol, dichloromethane, Isosorbide-5-Nitrae-dioxane, ether, acetone, trichloro ethylene, tetrahydrofuran, methyl tertbutyl One or more in ether, ethyl acetate and DMF；More preferably dichloromethane or acetone.

Step 4：The preparation of midbody compound VI concretely comprises the following steps：In purified water, by midbody compound V one Determine to react 0.5 hour with alkali E at temperature, obtain midbody compound VI；Described temperature is preferably 0 DEG C~20 DEG C, further excellent Elect 0 DEG C~10 DEG C as.

The one kind of alkali E in sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate and sodium acid carbonate described in step 4, Most preferably sodium hydroxide.

Step 5：The preparation of midbody compound I concretely comprises the following steps：Carry out bromination reaction first under sour environment, convert For the Bromo-intermediates VI -1 with ketal structure, the intermediate of this structure carries out acid hydrolytic reaction in sour environment, removes Ketal structure generates corresponding bromo ketone intermediate VI -2 to the protection of carbonyl, is hydrolyzed in sodium formate solution thereafter, Bromine is substituted by alcoholic extract hydroxyl group, and into salt in hydrochloric acid-methanol solution, it is final to obtain target product epirubicin hydrochloride I.

Step 5：The preparation specific steps of midbody compound I be described in further detail for：

In organic solvent A, by the organic solvent A solution reaction 2~3 hours of midbody compound VI and hydrogen bromide；Instead The organic solvent A solution of bromine is added dropwise during answering into reaction solution；The described and temperature of the organic solvent A solution reaction of hydrogen bromide Preferably 0 DEG C~30 DEG C, most preferably 10 DEG C~20 DEG C.

Add in enough reducing agent F after reaction is quenched with excessive bromine, add appropriate saturation aqueous slkali G regulation reactions Liquid pH to 4.5~5.0, most preferably pH are 4.7.

The inorganic acid H aqueous solution is added, pH=1.3~1.5 is adjusted, optimal selection pH=1.5, is stirred in 25 DEG C~35 DEG C insulations Mix reaction 2~2.5 hours.

Add aqueous sodium formate solution, regulation pH value to 3.0~3.5, optimal selection 3.2,25~35 DEG C of sodium formate water of temperature control Solution 1~3 hour, it is final to obtain the crude product solution of target compound epirubicin hydrochloride I.Aqueous sodium formate solution mass concentration (the g/ G) it is preferably 20~30%.

Organic solvent A described in step 5 be selected from arene, fat hydrocarbon, alicyclic hydrocarbon type, halogenated hydrocarbons, alcohols, alkanes, One or more in ethers, amide-type, diol, derivatives class, esters solvent and phenol；More preferably benzene, toluene, hexamethylene, uncle Butanol, dichloromethane, Isosorbide-5-Nitrae-dioxane, ether, acetone, trichloro ethylene, tetrahydrofuran, methyl tertiary butyl ether(MTBE), ethyl acetate With the one or more in DMF；More preferably methanol, or Isosorbide-5-Nitrae-dioxane, or acetone, or ethyl acetate, or acetone (the two volume ratio is 1 with ethyl acetate mixed solvent:3).

The one kind of the reducing agent F in sodium sulfite, sodium hydrogensulfite, ferrous sulfate, natrium nitrosum and oxalic acid, most It is preferred that sodium sulfite.

The one kind of the alkali G in sodium hydroxide, potassium hydroxide, calcium hydroxide, ammoniacal liquor and sodium acid carbonate, most preferably ammonia Water.

The inorganic acid H is selected from phosphoric acid, sulfuric acid, perchloric acid, boric acid, nitric acid, hydrochloric acid and hydrobromic acid one kind, most preferably salt Acid；The inorganic acid concentration is preferably 6~8%.

Wherein following compound is novel substance：

Above step is being described in further detail with lower part：

Step 1, the preparation of midbody compound III：

Organic solvent A and daunorubicin hydrochloride II are added into three neck glass reaction bottles.Open and stir, 5~10 DEG C of temperature control, After 10~15 minutes, material dissolution situation is checked, continues to stir if not being completely dissolved；If being completely dissolved, feed liquid is cooled To 0~5 DEG C, the methanol solution of acidic catalyst is added, after stirring 1 hour, adds esterifying reagent B；Addition finishes, stirring 2 ~3 hours；Stirring finishes, and controls 3~10 DEG C of reacting liquid temperature, TFAA is added into bottle, and addition finishes, and stirring 1~ 1.5 hour.

The dosage of the organic solvent A is：(represented in terms of weight g/ volumes mL with lower part with (W/V, g/mL)), hydrochloric acid Daunorubicin：Organic solvent A=1:50~70, preferably 1:60；The organic solvent A is preferably methanol, dichloromethane and 1, One or more in 4- dioxane.

The dosage of the esterifying reagent B is：Daunorubicin hydrochloride：Esterifying reagent B=1:1~4, preferably 1:2 (W/V, g/ mL)；The esterifying reagent B is preferably triethyl orthoformate or trimethyl orthoformate.

The TFAA dosage is：Daunorubicin hydrochloride：TFAA=1:1~4, preferably 1：2 (W/V, g/ mL)。

Reaction is finished, and methanol (daunorubicin hydrochloride is added into reaction solution：Methanol=1:20~40 (W/V, g/mL)), stir After mixing 10~15 minutes, add 8% sodium bicarbonate solution and adjust pH value to 7.0~8.0.Control 15 DEG C~25 DEG C of temperature, insulation Stirring reaction 3~5 hours.TLC is detected：With chloroform/isopropanol (volume ratio 96/4) for solvent, detection raw material spot should It is basic to disappear.Midbody compound III Rf ≈ 0.3, daunorubicin hydrochloride Rf ≈ 0.Liquid separation is stood, collects lower floor's organic phase.Vacuum Certain volume (daunorubicin hydrochloride is concentrated under state：The volume of concentrate=1:10 (W/V, g/mL)), add under stirring N-hexane crystallization, filter and solid midbody compound III is obtained after drying.

Preferably, the n-hexane addition is：Daunorubicin hydrochloride：N-hexane=1:10 (W/V, g/mL).

Step 2, the preparation of midbody compound IV：

Organic solvent A is added into three neck glass reaction bottles.Stirring is opened, temperature control -70~-40 DEG C, is slowly added to trifluoro The organic solvent A solution of acetic anhydride, in -70~-40 DEG C of stirring reactions 1~1.5 hour.

The organic solvent A is preferably dichloromethane.

The dosage of the organic solvent A is：Intermediate III：Organic solvent A=1:20~40, preferably 1:40 (W/V, g/ mL)。

The dosage of the organic solvent A solution of the TFAA is：Intermediate III：TFAA：Dichloromethane= 1：0.5~0.8：2.4~3 (W/W/V, g/g/mL).

Reaction finishes, and the organic solvent A solution of intermediate of epirubicin hydrochloride III is slowly added dropwise into reaction solution；Add Finish, after stirring 20 minutes, the organic solvent A solution of 1,5- diaza-bicyclos (4,3,0) nonyl- 5- alkene is added dropwise, addition finishes, stirring 10 After minute, organic acid C organic solvent A solution, stirring reaction 0.5 hour are added.

The organic solvent A is preferably dichloromethane.

The organic acid C is preferably formic acid, acetic acid, propionic acid, butyric acid, octanoic acid, adipic acid, ethanedioic acid, malonic acid, succinic acid With one kind in maleic acid；Most preferably glacial acetic acid and malonic acid.

The organic solvent A solution of the intermediate III is：Intermediate III：Organic solvent A=1:5~8 (W/V, g/mL).

The organic solvent A solution usage of 1,5- diaza-bicyclos (4,3,0) the nonyl- 5- alkene is：Intermediate III：1,5- phenodiazines Two rings (4,3,0) nonyl- 5- alkene：Dichloromethane=1：0.84~0.9：5~8 (W/W/V, g/g/mL).

The dosage of the organic solvent A solution of the organic acid C is：Intermediate III：Organic acid C：Organic solvent A=1：0.85 ~0.9：10~14 (W/V/V, g/mL/mL).

Reaction finishes, TLC detections：With chloroform/isopropanol (volume ratio 96/4) for solvent, the spot of intermediate III is detected Point should disappear substantially, the Rf ≈ 0.3 of intermediate III, the Rf ≈ 0.8 of intermediate IV.Reaction solution is warming up to 0~10 DEG C, organic phase is successively After being washed with purified water, 0.1mol/L hydrochloric acid solutions, 2% sodium bicarbonate solution, concentration in vacuo to certain volume is (middle Body III：The volume of concentrate=1:10 (W/V, g/mL)), n-hexane crystallization is added under stirring, filter after drying in solid Intermediate compounds therefor IV.Preferably, the n-hexane addition is：Intermediate III：N-hexane=1:10 (W/V, g/mL).

Step 3, the preparation of midbody compound V：

Organic solvent A, intermediate IV are added into three neck glass reaction bottles.Stirring is opened, temperature control -60~-30 DEG C, is added dropwise Reducing agent D ethanol solution, addition finishes, stirring reaction 0.5~1 hour.

The organic solvent A is preferably dichloromethane or acetone.

The dosage of the organic solvent A is：Intermediate IV：Organic solvent A=1:40~50 (W/V, g/mL).

The reducing agent D is preferably sodium hydride or tetrahydrochysene lithium aluminium or sodium borohydride；More preferably sodium borohydride.Selection Property reducing agent preferably can be preferably minimized the isomer impurities of intermediate V.

The dosage of the ethanol solution of the reducing agent D is：Intermediate IV：Reducing agent D：Absolute ethyl alcohol=1:0.02~ 0.04:80~100 (W/W/V, g/g/mL).

After reaction terminates, acetone is added into reaction solution, continues stirring 20~40 minutes, the dosage of the acetone is：In Mesosome IV：Acetone=1:1~3 (W/V, g/mL).Reaction solution is warming up to 0~10 DEG C, TLC detections：With chloroform/isopropanol (volume ratio 96/4) is solvent, and the detection spot of intermediate IV should disappear substantially, the Rf ≈ 0.3 of intermediate III, the Rf ≈ of intermediate IV 0.8, the Rf ≈ 0.25 of intermediate V.Dichloromethane and purified water are added in reaction solution (intermediate IV：Purified water：Dichloromethane Alkane=1：40~60：30~40 (W/V/V, g/mL/mL)), liquid separation is stood after stirring, water intaking mutually extracts 3 with dichloromethane solution Secondary (intermediate IV：Dichloromethane=1：30~40 (W/V, g/mL)), merge organic phase, concentration in vacuo to certain volume (intermediate IV：The volume of concentrate=1:10 (W/V, g/mL)), n-hexane crystallization is added under stirring, filtering must consolidate after drying Body midbody compound V.

Preferably, the n-hexane addition is：Intermediate IV：N-hexane=1:10 (W/V, g/mL).

Step 4, the preparation of midbody compound VI：

Purified water, intermediate V are added into three neck glass reaction bottles.Stirring is opened, 0~10 DEG C of temperature control, alkali E is added dropwise, adds Enter to finish, stirring reaction 0.5 hour.

It is described purifying water consumption be：Intermediate V：Purified water=1:40~60 (W/V, g/mL).

Preferably, the alkali E is sodium hydroxide solution (sodium hydroxide：Purified water=0.25~0.4:10~14 (W/V, g/ G/mL)), dosage is：Intermediate V：Sodium hydroxide=1:0.25~0.4 (W/W, g/g).The addition amount of sodium hydroxide also may be used To be expressed as：Intermediate V：Sodium hydroxide：Purified water=1:0.25~0.4:10~14 (W/W/V, g/g/mL).

Preparation finishes, TLC detections：With chloroform/isopropanol (volume ratio=96/4) for solvent, intermediate V is detected Spot should disappear substantially, the Rf ≈ 0.25 of intermediate V, the Rf ≈ 0 of intermediate VI.The dichloromethane that methanol is added into reaction solution is molten Liquid (intermediate V：Methanol：Dichloromethane=1：40~60：8~10 (W/V/V, g/mL/mL)), stirring is opened, and be added dropwise 0.5mol/L sodium bicarbonate solutions adjust pH value to 7.6~7.8.Finally pH value is adjusted to 8.0 with 0.5mol/L sodium carbonate liquors ~8.2.Liquid separation is stood, collects organic phase, concentration in vacuo to certain volume (intermediate V：The volume of concentrate=1:10 (W/V, g/mL)), n-hexane crystallization is added under stirring, filters after drying to obtain solid midbody compound VI.Preferably, institute Stating n-hexane addition is：Intermediate V：N-hexane=1:10 (W/V, g/mL).

Step 5, the preparation of epirubicin hydrochloride I：

Organic solvent A is added into three neck glass reaction bottles, intermediate VI opens stirring, 15 DEG C of temperature control, into reaction solution The organic solvent A solution of 4% hydrogen bromide is added dropwise, is added dropwise, after stirring 20~30 minutes, having for bromine is added dropwise into reaction solution Solvent solution A, is added dropwise, and insulated and stirred is reacted 2~2.5 hours.After reaction terminates, reducing agent F is added into reaction solution Solution, be 4.5~5.0 with alkali G regulations PH after stirring 10~15 minutes, stirring reaction is after 10~15 minutes, with 7% it is inorganic Sour H solution regulation PH is 1.3~1.5, is reacted 2~2.5 hours in 25 DEG C~35 DEG C insulated and stirreds.Reaction terminates, and adds 25% Aqueous sodium formate solution, regulation PH is 3.0~3.5, and 25~35 DEG C of sodium formates of temperature control hydrolyze 1~3 hour, final target chemical combination The crude product solution of thing epirubicin hydrochloride I.

The organic solvent A dosage that is added into three neck glass reaction bottles is：Intermediate VI：Organic solvent A=1:40 ~60 (W/V, g/mL), the organic solvent A are preferably methanol or Isosorbide-5-Nitrae-dioxane.

The organic solvent A solution usage of described 4% hydrogen bromide is：Intermediate VI：The organic solvent A of 4% hydrogen bromide Solution=1：4~8 (W/V, g/mL), the organic solvent A are preferably methanol or Isosorbide-5-Nitrae-dioxane.

The organic solvent A solution usage of the bromine is：Intermediate VI：Bromine：Isosorbide-5-Nitrae-dioxane=1:0.2~0.5:5~8 (W/W/V, g/g/mL), the organic solvent A are preferably methanol or Isosorbide-5-Nitrae-dioxane.

The reducing agent F solution usages：Intermediate VI：Reducing agent F：Purified water=1:0.05~0.07:0.5~0.7 (W/ W/V, g/g/mL).Wherein described reducing agent F solution concentrations are：Reducing agent F：Purified water=0.05~0.07:0.5~0.7 (W/ V, g/mL).The reducing agent F solution is preferably sodium sulfite solution.

Preparation is finished, and dichloromethane and purified water are added in reaction solution into (intermediate VI：Purified water：Dichloromethane= 1：40~60：30~40 (W/V/V, g/mL/mL)), liquid separation is stood after stirring, water intaking is mutually extracted three times with dichloromethane solution (intermediate VI：Dichloromethane=1：30~40 (W/V, g/mL)), merge organic phase, concentration in vacuo to certain volume (intermediate VI：The volume of concentrate=1:10 (W/V, g/mL)), n-hexane crystallization is added under stirring, filtering must consolidate after drying Body epirubicin hydrochloride I.Preferably, the addition of the n-hexane is：Intermediate VI：N-hexane=1:10 (W/V, g/mL).

Advantages of the present invention：

Used various reagents are cheap and easy to get, and have more ripe processing method to caused pollutant, production Raw environmental pollution is small.Holistic approach is easy to operation, not harsh to practitioner's technical requirements, meanwhile, each reactions steps Reacting balance, easily controllable, the intermediate of generation is loose to moisture requirement and generation impurity is few, and purity is high, steady quality, yield It is high.

The intermediate of prior art generation is prone to keto-acid and enol form change, in the transition state with enol-type structure Mesosome is extremely unstable, moisture easily in by air (such as：In the summer that air humidity is larger, former process intermediates I are to centre The conversion yield of body II is extremely unstable, and humidity is in obvious negatively correlated situation with yield, i.e. humidity is bigger, and conversion ratio is lower, the summer Season, yield was 30%-40%；Other step conversion ratios conversion ratio in the case of high humility also can be reduced accordingly), the influence of temperature And the progress of reaction is hindered, or even other impurities are converted into, directly affect product yield and product purity.It is and of the invention by primitive nail Triethylenetetraminehexaacetic acid ester can be protected with raw material directly reaction to ketone group, is suppressed the tautomerism between ketone group and enol-type structure, is protected Card reaction is smoothed out.

The route for the synthetic hydrochloric acid epirubicin that prior art provides is using 4 '-EPIDNR as raw material, after bromination terminates PH is adjusted with 5% sodium formate solution first, then so that, with excessive bromine, the sodium formate that this method introduces is dense in solution of sodium bisulfite Contracting step can cause the considerable damage of material (i.e. before hydrobromic acid hydrolysing step), generate the sticky insoluble impurity of dark brown, greatly Ground reduces product yield, and the concentration continuous time is grown, and energy consumption and manpower consumption are high.And this technique is directly with the sulfurous acid of recipe quantity In hydrogen sodium and excessive bromine after again by saturated sodium bicarbonate solution adjust pH in a manner of, gained reaction solution system intermediate can stablize deposit , above-mentioned impurity will not be produced under the conditions of same concentration, can be by yield (mass yield, i.e. chemical combination of former technique 40% or so The step of converting yield of thing VI to VI -1) it is promoted to more than 95%；On this basis, crude product is through the mass yield before pillar layer separation More than 85% is promoted to by original 40%-60%, and concentration time is substantially shorter after process modification, directly saves people The consumption of power, the energy and material resources.

To sum up, efficiently, economical, production operation is simple, complies fully with the requirement of industrialized production by the present invention.

Embodiment

Be explained further the present invention below in conjunction with specific embodiment, but embodiment invention is not done in itself it is any type of Limit.

Embodiment one

The preparation of midbody compound III：

Dichloromethane and daunorubicin hydrochloride (daunorubicin hydrochloride are added into the neck glass reaction bottles of 1000mL tri-：Dichloro Methane=1:60 (W/V, g/mL)).Open stirring, after 5 DEG C, 10~15 minutes of temperature control, material dissolution situation is checked, if incomplete Dissolving then continues to stir；If being completely dissolved, feed liquid is cooled to 0 DEG C, adds the methanol solution (hydrochloric acid of camphorsulfonic acid thereto Daunorubicin：Methanol：Camphorsulfonic acid=1:177:1 (W/V/W, g/mL/g)), after stirring 1 hour, add trimethyl orthoformate (daunorubicin hydrochloride：Triethyl orthoformate=1:2 (W/V, g/mL))；Addition finishes, and stirs 2 hours；Stirring finishes, and control is anti- 5 DEG C of liquid temperature degree is answered, TFAA (daunorubicin hydrochloride is added into bottle：TFAA=1：2 (W/V, g/mL), add Finish, stir 1 hour.

Reaction is finished, and methanol (daunorubicin hydrochloride is added into reaction solution：Methanol=1:30 (W/V, g/mL)), stirring 10 After minute, add 8% sodium bicarbonate solution and adjust pH value to 7.0~8.0.Control 15 DEG C~25 DEG C of temperature, insulated and stirred reaction 3 ~5 hours.TLC is detected：With chloroform/isopropanol (volume ratio 96/4) for solvent, detection raw material spot should disappear substantially. Midbody compound III Rf ≈ 0.3, daunorubicin hydrochloride Rf ≈ 0.Liquid separation is stood, collects lower floor's organic phase.It is dense under vacuum state It is reduced to certain volume (daunorubicin hydrochloride：The volume of concentrate=1:10 (W/V, g/mL)), n-hexane (salt is added under stirring Sour daunorubicin：N-hexane=1:10 (W/V, g/mL)) crystallization, filter and solid midbody compound III is obtained after drying, quality is received Rate 95.6%.Purity 95.5%.

Embodiment two

The preparation of midbody compound III：

Isosorbide-5-Nitrae-dioxane and daunorubicin hydrochloride (daunorubicin hydrochloride are added into the neck glass reaction bottles of 1000mL tri-： Isosorbide-5-Nitrae-dioxane=1:70 (W/V, g/mL)).Open stirring, after 10 DEG C, 10~15 minutes of temperature control, check material dissolution feelings Condition, continue to stir if not being completely dissolved；If being completely dissolved, feed liquid is cooled to 5 DEG C, adds the first of camphorsulfonic acid thereto Alcoholic solution (daunorubicin hydrochloride：Methanol：Camphorsulfonic acid=1:177:1 (W/V/W, g/mL/g)), after stirring 1 hour, add former Trimethyl orthoformate (daunorubicin hydrochloride：Trimethyl orthoformate=1:1 (W/V, g/mL))；Addition finishes, and stirs 3 hours；Stirring Finish, control 10 DEG C of reacting liquid temperature, TFAA (daunorubicin hydrochloride is added into bottle：TFAA=1：4(W/ V, g/mL)), addition finishes, and stirs 1.5 hours.

Reaction is finished, and methanol (daunorubicin hydrochloride is added into reaction solution：Methanol=1:40 (W/V, g/mL)), stirring 10 After minute, add 8% sodium bicarbonate solution and adjust pH value to 7.0~8.0.Control 15 DEG C~25 DEG C of temperature, insulated and stirred reaction 3 ~5 hours.TLC is detected：With chloroform/isopropanol (volume ratio 96/4) for solvent, detection raw material spot should disappear substantially. Midbody compound III Rf ≈ 0.3, daunorubicin hydrochloride Rf ≈ 0.Liquid separation is stood, collects lower floor's organic phase.It is dense under vacuum state It is reduced to certain volume (daunorubicin hydrochloride：The volume of concentrate=1:10 (W/V, g/mL)), n-hexane (salt is added under stirring Sour daunorubicin：N-hexane=1:10 (W/V, g/mL)) crystallization, filter and solid midbody compound III is obtained after drying, quality is received Rate 93.7%.Purity 95.4%.

Embodiment three

The preparation of midbody compound III：

Tetrahydrofuran and daunorubicin hydrochloride (daunorubicin hydrochloride are added into the neck glass reaction bottles of 1000mL tri-：Tetrahydrochysene Furans=1:50 (W/V, g/mL)).Open stirring, after 8 DEG C, 10~15 minutes of temperature control, material dissolution situation is checked, if incomplete Dissolving then continues to stir；If being completely dissolved, feed liquid is cooled to 3 DEG C, adds the methanol solution (hydrochloric acid of camphorsulfonic acid thereto Daunorubicin：Methanol：Camphorsulfonic acid=1:177:1 (W/V/W, g/mL/g)), after stirring 1 hour, add trimethyl orthoformate (daunorubicin hydrochloride：Trimethyl orthoformate=1:5 (W/V, g/mL))；Addition finishes, and stirs 3 hours；Stirring finishes, and control is anti- 3 DEG C of liquid temperature degree is answered, TFAA (daunorubicin hydrochloride is added into bottle：TFAA=1：5 (W/V, g/mL)), add Finish, stir 1.5 hours.

Reaction is finished, and methanol (daunorubicin hydrochloride is added into reaction solution：Methanol=1:20 (W/V, g/mL)), stirring 15 After minute, add 8% sodium bicarbonate solution and adjust pH value to 7.0~8.0.Control 15 DEG C~25 DEG C of temperature, insulated and stirred reaction 3 ~5 hours.TLC is detected：With chloroform/isopropanol (volume ratio 96/4) for solvent, detection raw material spot should disappear substantially. Midbody compound III Rf ≈ 0.3, daunorubicin hydrochloride Rf ≈ 0.Liquid separation is stood, collects lower floor's organic phase.It is dense under vacuum state It is reduced to certain volume (daunorubicin hydrochloride：The volume of concentrate=1:10 (W/V, g/mL)), n-hexane (salt is added under stirring Sour daunorubicin：N-hexane=1:10 (W/V, g/mL)) crystallization, filter and solid midbody compound III is obtained after drying, quality is received Rate 92.4%.Purity 95.0%.

Example IV

The preparation of midbody compound III：

Normal heptane and daunorubicin hydrochloride (daunorubicin hydrochloride are added into the neck glass reaction bottles of 1000mL tri-：Normal heptane =1:40 (W/V, g/mL)).Open stirring, after 15 DEG C, 10~15 minutes of temperature control, material dissolution situation is checked, if completely molten Xie Ze continues to stir；If being completely dissolved, feed liquid is cooled to 11 DEG C, adds the methanol solution (hydrochloric acid of camphorsulfonic acid thereto Daunorubicin：Methanol：Camphorsulfonic acid=1:200:3 (W/V/W, g/mL/g)), after stirring 1 hour, add triethyl orthoformate (daunorubicin hydrochloride：Triethyl orthoformate=1:7 (W/V, g/mL))；Addition finishes, and stirs 3 hours；Stirring finishes, and control is anti- 15 DEG C of liquid temperature degree is answered, TFAA (daunorubicin hydrochloride is added into bottle：TFAA=1：7 (W/V, g/mL)), add Enter to finish, stir 1.5 hours.

Reaction is finished, and methanol (daunorubicin hydrochloride is added into reaction solution：Methanol=1:50 (W/V, g/mL)), stirring 15 After minute, add 8% sodium bicarbonate solution and adjust pH value to 8.5.15 DEG C~25 DEG C of temperature is controlled, it is small that insulated and stirred reacts 3~5 When.TLC is detected：With chloroform/isopropanol (volume ratio 96/4) for solvent, detection raw material spot should disappear substantially.It is middle Body compound III Rf ≈ 0.3, daunorubicin hydrochloride Rf ≈ 0.Liquid separation is stood, collects lower floor's organic phase.Concentration in vacuo is extremely Certain volume (daunorubicin hydrochloride：The volume of concentrate=1:15 (W/V, g/mL)), n-hexane is added under stirring, and (hydrochloric acid is soft Erythromycin：N-hexane=1:8 (W/V, g/mL)) crystallization, filter and solid midbody compound III, mass yield are obtained after drying 90.0%.Purity 93.7%.

Embodiment five

The preparation of midbody compound IV：

Dichloromethane (intermediate III is added into the neck glass reaction bottles of 1000mL tri-：Dichloromethane：1：40 (W/V, g/ mL)).Unlatching is stirred, -40 DEG C of temperature control, is slowly added to the dichloromethane solution (intermediate III of TFAA：TFAA： Dichloromethane=1：0.8：2.4 (W/W/V, g/g/mL)), after -40 DEG C of stirring reactions 1 hour, it is slowly added dropwise into reaction solution The dichloromethane solution of intermediate of epirubicin hydrochloride III, (intermediate III：Dichloromethane=1:5 (W/V, g/mL))；Add Finish, after stirring 20 minutes, the dichloromethane solution (intermediate III of 1,5- diaza-bicyclos (4,3,0) nonyl- 5- alkene is added dropwise：1,5- bis- The ring of nitrogen two (4,3,0) nonyl- 5- alkene：Dichloromethane=1：0.84：5 (W/W/V, g/g/mL)), addition finishes, after stirring 10 minutes, Add the dichloromethane solution (intermediate III of glacial acetic acid：Glacial acetic acid：Dichloromethane=1：0.85：10 (W/V/V, g/mL/mL)), Stirring reaction 0.5 hour.

TLC is detected：With chloroform/isopropanol (volume ratio 96/4) for solvent, detection intermediate III spot should be basic Disappear, the Rf ≈ 0.3 of intermediate III, the Rf ≈ 0.8 of intermediate IV.Reaction solution is warming up to 0~10 DEG C, organic phase is successively with purifying After water, 0.1mol/L hydrochloric acid solutions, the washing of 2% sodium bicarbonate solution, concentration in vacuo to certain volume (intermediate III： The volume of concentrate=1:10 (W/V, g/mL)), n-hexane (intermediate III is added under stirring：N-hexane=1:10 (W/V, g/ ML)) crystallization, filter and solid midbody compound IV, mass yield 93.2% are obtained after drying.Purity 86.2%, relevant material (in Intermediate compounds therefor III) content<8.0%.

Embodiment six

The preparation of midbody compound IV：

Ethyl acetate (intermediate III is added into the neck glass reaction bottles of 1000mL tri-：Ethyl acetate：1：20 (W/V/V, g/ mL/mL)).Unlatching is stirred, -70 DEG C of temperature control, is slowly added to the ethyl acetate solution (intermediate III of TFAA：Trifluoroacetic acid Acid anhydride：Ethyl acetate=1：0.5：3 (W/W/V, g/g/mL)), after -70 DEG C of stirring reactions 1 hour, it is slowly added dropwise into reaction solution The ethyl acetate solution of intermediate of epirubicin hydrochloride III, (intermediate III：Ethyl acetate=1:8 (W/V, g/mL))；Add Finish, after stirring 20 minutes, the ethyl acetate solution (intermediate III of 1,5- diaza-bicyclos (4,3,0) nonyl- 5- alkene is added dropwise：1,5- bis- The ring of nitrogen two (4,3,0) nonyl- 5- alkene：Ethyl acetate=1：0.9：8 (W/W/V, g/g/mL)), addition finishes, after stirring 10 minutes, Add the ethyl acetate solution (intermediate III of malonic acid：Malonic acid：Ethyl acetate=1：0.9：14 (W/V/V, g/mL/mL)), Stirring reaction 0.5 hour.

TLC is detected：With chloroform/isopropanol (volume ratio 96/4) for solvent, detection intermediate III spot should be basic Disappear, the Rf ≈ 0.3 of intermediate III, the Rf ≈ 0.8 of intermediate IV.Reaction solution is warming up to 0~10 DEG C, organic phase is successively with purifying After water, 0.1mol/L hydrochloric acid solutions, the washing of 2% sodium bicarbonate solution, concentration in vacuo to certain volume (intermediate III： The volume of concentrate=1:10 (W/V, g/mL)), n-hexane (intermediate III is added under stirring：N-hexane=1:10 (W/V, g/ ML)) crystallization, filter and solid midbody compound IV, mass yield 93.1% are obtained after drying.Purity 85.5%, relevant material (in Intermediate compounds therefor III) content<8.0%.

Embodiment seven

The preparation of midbody compound IV：

DMF (intermediates III are added into the neck glass reaction bottles of 1000mL tri-：DMF=1：50 (W/V/V, g/mL/mL)).Open Open stirring, -30 DEG C of temperature control, be slowly added to the DMF solution (intermediate III of TFAA：TFAA：DMF=1：0.4：4 (W/W/V, g/g/mL)), after -30 DEG C of stirring reactions 1.5 hours, intermediate of epirubicin hydrochloride is slowly added dropwise into reaction solution III DMF solution, (intermediate III：DMF=1:10 (W/V, g/mL))；Addition finishes, and after stirring 20 minutes, 1,5- phenodiazines are added dropwise DMF solution (the intermediate III of two rings (4,3,0) nonyl- 5- alkene：1,5- diaza-bicyclos (4,3,0) nonyl- 5- alkene：DMF=1：0.95： 10 (W/W/V, g/g/mL)), addition finishes, and after stirring 10 minutes, adds the DMF solution (intermediate III of formic acid：Malonic acid：DMF =1：0.9：16 (W/V/V, g/mL/mL)), stirring reaction 0.5 hour.

TLC is detected：With chloroform/isopropanol (volume ratio 96/4) for solvent, detection intermediate III spot should be basic Disappear, the Rf ≈ 0.3 of intermediate III, the Rf ≈ 0.8 of intermediate IV.Reaction solution is warming up to 0~10 DEG C, organic phase is successively with purifying After water, 0.1mol/L hydrochloric acid solutions, the washing of 2% sodium bicarbonate solution, concentration in vacuo to certain volume (intermediate III： The volume of concentrate=1:15 (W/V, g/mL)), n-hexane (intermediate III is added under stirring：N-hexane=1:7 (W/V, g/ ML)) crystallization, filter and solid midbody compound IV, mass yield 91.7% are obtained after drying.Purity 84.1%, relevant material (in Intermediate compounds therefor III) content<8.0%.

Embodiment eight

The preparation of midbody compound V：

The dichloromethane, (intermediate IV of intermediate IV are added into the neck glass reaction bottles of 1000mL tri-：Dichloromethane=1:40 (W/V, g/mL)).Unlatching is stirred, -60 DEG C of temperature control, and the ethanol solution of sodium borohydride, (intermediate IV is added dropwise：Sodium borohydride：It is anhydrous Ethanol=1:0.02:100 (W/W/V, g/g/mL)), addition finishes, and stirring reaction adds acetone into reaction solution after 0.5 hour (intermediate IV：Acetone=1:1 (W/V, g/mL)), continue stirring 20 minutes.

Reaction solution is warming up to 0~10 DEG C, TLC detections：With chloroform/isopropanol (volume ratio 96/4) for solvent, The detection spot of intermediate IV should disappear substantially, the Rf ≈ 0.3 of intermediate III, the Rf ≈ 0.8 of intermediate IV, the Rf ≈ 0.25 of intermediate V. Dichloromethane and purified water are added in reaction solution (intermediate IV：Purified water：Dichloromethane=1：60：30 (W/V/V, g/ ML/mL)), liquid separation is stood after stirring, water intaking mutually extracts (intermediate IV three times with dichloromethane solution：Dichloromethane=1：30 (W/V, g/mL)), merge organic phase, concentration in vacuo to certain volume (intermediate IV：The volume of concentrate=1:10(W/ V, g/mL)), intermediate V compounds are detected, purity 87.3%, n-hexane (intermediate IV are added under stirring：N-hexane= 1:10 (W/V, g/mL)) crystallization, filter and solid midbody compound V, mass yield 93.9% are obtained after drying.Purity 99.7%, The relevant content of material midbody compound I<0.6%.

Embodiment nine

The preparation of midbody compound V：

The acetone, (intermediate IV of intermediate IV are added into the neck glass reaction bottles of 1000mL tri-：Acetone=1:50 (W/V, g/ mL)).Unlatching is stirred, -30 DEG C of temperature control, and the ethanol solution of tetrahydrochysene lithium aluminium, (intermediate IV is added dropwise：Tetrahydrochysene lithium aluminium：Absolute ethyl alcohol= 1:0.04:80 (W/W/V, g/g/mL)), addition finishes, and stirring reaction adds acetone (intermediate into reaction solution after 1 hour Ⅳ：Acetone=1:2 (W/V, g/mL)), continue stirring 20 minutes.

Reaction solution is warming up to 0~10 DEG C, TLC detections：With chloroform/isopropanol (volume ratio 96/4) for solvent, The detection spot of intermediate IV should disappear substantially, the Rf ≈ 0.3 of intermediate III, the Rf ≈ 0.8 of intermediate IV, the Rf ≈ 0.25 of intermediate V. Dichloromethane and purified water are added in reaction solution (intermediate IV：Purified water：Dichloromethane=1：40：40 (W/V/V, g/ ML/mL)), liquid separation is stood after stirring, water intaking mutually extracts (intermediate IV three times with dichloromethane solution：Dichloromethane=1：40 (W/V, g/mL)), merge organic phase, concentration in vacuo to certain volume (intermediate IV：The volume of concentrate=1:10(W/ V, g/mL)), intermediate V compounds are detected, purity 88.1%, n-hexane (intermediate IV are added under stirring：N-hexane= 1:10 (W/V, g/mL)) crystallization, filter and solid midbody compound V, mass yield 92.7% are obtained after drying.Purity 99.6%, The relevant content of material midbody compound I<0.6%.

Embodiment ten

The preparation of midbody compound V：

The tetrahydrofuran, (intermediate IV of intermediate IV are added into the neck glass reaction bottles of 1000mL tri-：Tetrahydrofuran=1:60 (W/V, g/mL)).Unlatching is stirred, -75 DEG C of temperature control, and the ethanol solution of sodium cyanoborohydride, (intermediate IV is added dropwise：Cyano group boron hydrogen Change sodium：Absolute ethyl alcohol=1:0.06:70 (W/W/V, g/g/mL)), addition finishes, and stirring reaction adds after 1 hour into reaction solution Enter acetone (intermediate IV：Acetone=1:4 (W/V, g/mL)), continue stirring 20 minutes.

Reaction solution is warming up to 0~10 DEG C, TLC detections：With chloroform/isopropanol (volume ratio 96/4) for solvent, The detection spot of intermediate IV should disappear substantially, the Rf ≈ 0.3 of intermediate III, the Rf ≈ 0.8 of intermediate IV, the Rf ≈ 0.25 of intermediate V. Dichloromethane and purified water are added in reaction solution (intermediate IV：Purified water：Dichloromethane=1：30：50 (W/V/V, g/ ML/mL)), liquid separation is stood after stirring, water intaking mutually extracts (intermediate IV three times with dichloromethane solution：Dichloromethane=1：50 (W/V, g/mL)), merge organic phase, concentration in vacuo to certain volume (intermediate IV：The volume of concentrate=1:15(W/ V, g/mL)), intermediate V compounds are detected, purity 88.3%, n-hexane (intermediate IV are added under stirring：N-hexane= 1:12 (W/V, g/mL)) crystallization, filter and solid midbody compound V, mass yield 92.5% are obtained after drying.Purity 99.5%, The relevant content of material midbody compound I<0.6%.

Embodiment 11

The preparation of midbody compound V：

The hexamethylene, (intermediate IV of intermediate IV are added into the neck glass reaction bottles of 1000mL tri-：Hexamethylene=1:40(W/ V, g/mL)).Unlatching is stirred, 5 DEG C of temperature control, and the ethanol solution of lithium triethylborohydride, (intermediate IV is added dropwise：Boron triethyl hydrogenates Lithium：Absolute ethyl alcohol=1:0.02:100 (W/W/V, g/g/mL)), addition finishes, and stirring reaction is after 1.5 hours, into reaction solution Add acetone (intermediate IV：Acetone=1:4 (W/V, g/mL)), continue stirring 20 minutes.

Reaction solution is warming up to 0~10 DEG C, TLC detections：With chloroform/isopropanol (volume ratio 96/4) for solvent, The detection spot of intermediate IV should disappear substantially, the Rf ≈ 0.3 of intermediate III, the Rf ≈ 0.8 of intermediate IV, the Rf ≈ 0.25 of intermediate V. Dichloromethane and purified water are added in reaction solution (intermediate IV：Purified water：Dichloromethane=1：50：50 (W/V/V, g/ ML/mL)), liquid separation is stood after stirring, water intaking mutually extracts (intermediate IV three times with dichloromethane solution：Dichloromethane=1：50 (W/V, g/mL)), merge organic phase, concentration in vacuo to certain volume (intermediate IV：The volume of concentrate=1:8 (W/V, G/mL)), intermediate V compounds are detected, purity 87.8%, n-hexane (intermediate IV are added under stirring：N-hexane=1:8 (W/V, g/mL)) crystallization, filter and solid midbody compound V, mass yield 89.1% are obtained after drying.Purity 98.4%, it is relevant The content of material midbody compound I<0.6%.

Embodiment 12

The preparation of midbody compound VI：

The purified water, (intermediate V of intermediate V are added into the neck glass reaction bottles of 1000mL tri-：Purified water=1:60(W/ V, g/mL)).Stirring is opened, 0 DEG C of temperature control, sodium hydroxide solution, (intermediate V is added dropwise：Sodium hydroxide：Purified water=1:0.25: 10 (W/W/V, g/g/mL)), addition finishes, stirring reaction 0.5 hour, TLC detections：With chloroform/isopropanol (volume ratio= 96/4) it is solvent, the detection spot of intermediate V should disappear substantially, the Rf ≈ 0.25 of intermediate V, the Rf ≈ 0 of intermediate VI.

Dichloromethane solution (the intermediate V of methanol is added into reaction solution：Methanol：Dichloromethane=1：60：8(W/V/ V, g/mL/mL)), stirring is opened, and 0.5mol/L sodium bicarbonate solutions are added dropwise and adjust pH value to 7.6~7.8.Finally use 0.5mol/L sodium carbonate liquors adjust pH value to 8.0~8.2.Liquid separation is stood, collects organic phase, concentration in vacuo is to certain Volume (intermediate V：The volume of concentrate=1:10 (W/V, g/mL)), n-hexane (intermediate V is added under stirring：Just oneself Alkane=1:10 (W/V, g/mL)) crystallization, filter and solid midbody compound VI, mass yield 94.6% are obtained after drying.Purity 98.9%, maximum contaminant content<0.6%, total impurities content<3.0%.

Embodiment 13

The preparation of midbody compound VI：

The purified water, (intermediate V of intermediate V are added into the neck glass reaction bottles of 1000mL tri-：Purified water=1:40(W/ V, g/mL)).Stirring is opened, 10 DEG C of temperature control, sodium hydroxide solution, (intermediate V is added dropwise：Sodium hydroxide：Purified water=1:0.4: 14 (W/W/V, g/g/mL)), addition finishes, stirring reaction 0.5 hour, TLC detections：With chloroform/isopropanol (volume ratio= 96/4) it is solvent, the detection spot of intermediate V should disappear substantially, the Rf ≈ 0.25 of intermediate V, the Rf ≈ 0 of intermediate VI.

Dichloromethane solution (the intermediate V of methanol is added into reaction solution：Methanol：Dichloromethane=1：40：10(W/V/ V, g/mL/mL)), stirring is opened, and 0.5mol/L sodium bicarbonate solutions are added dropwise and adjust pH value to 7.6~7.8.Finally use 0.5mol/L sodium carbonate liquors adjust pH value to 8.0~8.2.Liquid separation is stood, collects organic phase, concentration in vacuo is to certain Volume (intermediate V：The volume of concentrate=1:10 (W/V, g/mL)), n-hexane (intermediate V is added under stirring：Just oneself Alkane=1:10 (W/V, g/mL)) crystallization, filter and solid midbody compound VI, mass yield 93.1% are obtained after drying.Purity 98.8%, maximum contaminant content<0.6%, total impurities content<3.0%.

Embodiment 14

The preparation of midbody compound VI：

The purified water, (intermediate V of intermediate V are added into the neck glass reaction bottles of 1000mL tri-：Purified water=1:70(W/ V, g/mL)).Stirring is opened, 20 DEG C of temperature control, sodium bicarbonate solution, (intermediate V is added dropwise：Sodium acid carbonate：Purified water=1:1.5: 10 (W/W/V, g/g/mL)), addition finishes, stirring reaction 1 hour, TLC detections：With chloroform/isopropanol (volume ratio= 96/4) it is solvent, the detection spot of intermediate V should disappear substantially, the Rf ≈ 0.25 of intermediate V, the Rf ≈ 0 of intermediate VI.

Dichloromethane solution (the intermediate V of methanol is added into reaction solution：Methanol：Dichloromethane=1：35：15(W/V/ V, g/mL/mL)), stirring is opened, and 0.5mol/L sodium bicarbonate solutions are added dropwise and adjust pH value to 7.6~7.8.Finally use 0.5mol/L sodium carbonate liquors adjust pH value to 8.0~8.2.Liquid separation is stood, collects organic phase, concentration in vacuo is to certain Volume (intermediate V：The volume of concentrate=1:10 (W/V, g/mL)), n-hexane (intermediate V is added under stirring：Just oneself Alkane=1:10 (W/V, g/mL)) crystallization, filter and solid midbody compound VI, mass yield 92.1% are obtained after drying.Purity 98.2%, maximum contaminant content<0.6%, total impurities content<3.0%.

Embodiment 15

The preparation of midbody compound VI：

The purified water, (intermediate V of intermediate V are added into the neck glass reaction bottles of 1000mL tri-：Purified water=1:30(W/ V, g/mL)).Stirring is opened, controls 25 DEG C, aqua calcis, (intermediate V is added dropwise：Calcium hydroxide：Purified water=1:1.1:10 (W/W/V, g/g/mL)), addition finishes, stirring reaction 1.5 hours, TLC detections：With chloroform/isopropanol (volume ratio= 96/4) it is solvent, the detection spot of intermediate V should disappear substantially, the Rf ≈ 0.25 of intermediate V, the Rf ≈ 0 of intermediate VI.

Dichloromethane solution (the intermediate V of methanol is added into reaction solution：Methanol：Dichloromethane=1：65：15(W/V/ V, g/mL/mL)), stirring is opened, and 0.5mol/L sodium bicarbonate solutions are added dropwise and adjust pH value to 7.6~7.8.Finally use 0.5mol/L sodium carbonate liquors adjust pH value to 8.0~8.2.Liquid separation is stood, collects organic phase, concentration in vacuo is to certain Volume (intermediate V：The volume of concentrate=1:12 (W/V, g/mL)), n-hexane (intermediate V is added under stirring：Just oneself Alkane=1:8 (W/V, g/mL)) crystallization, filter and solid midbody compound VI, mass yield 91.2% are obtained after drying.Purity 97.8%, maximum contaminant content<0.6%, total impurities content<3.0%.

Embodiment 16

The preparation of epirubicin hydrochloride I：

The methanol, (intermediate VI of intermediate VI are added into the neck glass reaction bottles of 1000mL tri-：Methanol=1:40 (W/V, g/ mL)).Open stirring, 15 DEG C of temperature control, the methanol solution (intermediate VI of the hydrogen bromide of dropwise addition 4% into reaction solution：4% bromination Methanol solution=1 of hydrogen：4 (W/V, g/mL)), it is added dropwise, after stirring 20 minutes, the methanol solution of bromine is added dropwise into reaction solution (intermediate VI：Bromine：Methanol=1:0.5:5 (W/W/V, g/g/mL)), it is added dropwise, insulated and stirred is reacted 2 hours.Reaction terminates Afterwards, sodium sulfite solution (intermediate VI is added into reaction solution：Sodium hydrogensulfite：Purified water=1:0.05:0.5 (W/W/V, g/ G/mL)), it is 4.5~5.0 with ammoniacal liquor regulation pH after stirring 10 minutes, stirring reaction is adjusted after 10 minutes with 7% hydrochloric acid solution It is 1.3~1.5 to save pH, is reacted 2 hours in 25 DEG C~35 DEG C insulated and stirreds.Reaction terminates, and adds 25% aqueous sodium formate solution, It is 3.0~3.5 to adjust pH, and 25~35 DEG C of sodium formates of temperature control hydrolyze 1 hour, final that target compound epirubicin hydrochloride I is thick Product solution.

Dichloromethane and purified water are added in reaction solution (intermediate VI：Purified water：Dichloromethane=1：60：30(W/ V/V, g/mL/mL)), liquid separation is stood after stirring, water intaking mutually extracts (intermediate VI three times with dichloromethane solution：Dichloromethane= 1：30 (W/V, g/mL)), merge organic phase, concentration in vacuo to certain volume (intermediate VI：The volume of concentrate=1:10 (W/V, g/mL)), n-hexane (intermediate VI is added under stirring：N-hexane=1:10 (W/V, g/mL)) crystallization, filter dry Solid epirubicin hydrochloride I, mass yield 94.1% are obtained after dry.Product is red powder, purity 98.7%, meets that pharmacopeia will Ask：If any impurity peaks in need testing solution chromatogram, Doxorubicin ketone (relative retention time about 0.3) is by the peak area after correction Calculate (being multiplied by correction factor 0.7), cannot be greater than contrast solution main peak area (1.0%), (relative retention time is about for Doxorubicin 0.8) peak area cannot be greater than contrast solution main peak area (1.0%), and other single impurity peak areas cannot be greater than comparison liquid master 0.5 times (0.5%) of peak area, 2 times (2.0%) each impurity peak area and that cannot be greater than comparison liquid main peak area.

Embodiment 17

The preparation of epirubicin hydrochloride I：

Isosorbide-5-Nitrae-dioxane, (intermediate VI of intermediate VI are added into the neck glass reaction bottles of 1000mL tri-：Isosorbide-5-Nitrae-dioxy six Ring=1:60 (W/V, g/mL)).Open stirring, 0 DEG C of temperature control, Isosorbide-5-Nitrae-dioxane of the hydrogen bromide of dropwise addition 4% into reaction solution Solution (intermediate VI：Isosorbide-5-Nitrae-dioxane solution=1 of 4% hydrogen bromide：8 (W/V, g/mL)), it is added dropwise, stirs 20 points Zhong Hou, Isosorbide-5-Nitrae-dioxane solution (intermediate VI of bromine is added dropwise into reaction solution：Bromine：Isosorbide-5-Nitrae-dioxane=1:0.2:8(W/ W/V, g/g/mL)), it is added dropwise, insulated and stirred is reacted 2.5 hours.After reaction terminates, it is molten that ferrous sulfate is added into reaction solution Liquid (intermediate VI：Ferrous sulfate：Purified water=1:0.07:0.7 (W/W/V, g/g/mL)), after stirring 15 minutes, use hydroxide Potassium solution (intermediate V：Potassium hydroxide：Purified water=1:0.25:10 (W/W/V, g/g/mL)) regulation PH be 4.5~5.0, stir It is 1.3~1.5 with 7% phosphoric acid solution regulation PH after mixing reaction 10 minutes, it is small in 25 DEG C~35 DEG C insulated and stirred reactions 2.5 When.Reaction terminates, and adds 20% aqueous sodium formate solution, and regulation PH is 3.0~3.5, and 25~35 DEG C of sodium formate hydrolysis 3 of temperature control are small When, it is final to obtain the crude product solution of target compound epirubicin hydrochloride I.

Dichloromethane and purified water are added in reaction solution (intermediate VI：Purified water：Dichloromethane=1：40：40(W/ V/V, g/mL/mL)), liquid separation is stood after stirring, water intaking mutually extracts (intermediate VI three times with dichloromethane solution：Dichloromethane= 1：40 (W/V, g/mL)), merge organic phase, concentration in vacuo to certain volume (intermediate VI：The volume of concentrate=1:10 (W/V, g/mL)), n-hexane (intermediate VI is added under stirring：N-hexane=1:10 (W/V, g/mL)) crystallization, filter dry Solid epirubicin hydrochloride I, mass yield 92.2% are obtained after dry.Product is red powder, purity 98.1%, meets that pharmacopeia will Ask：If any impurity peaks in need testing solution chromatogram, Doxorubicin ketone (relative retention time about 0.3) is by the peak area after correction Calculate (being multiplied by correction factor 0.7), cannot be greater than contrast solution main peak area (1.0%), (relative retention time is about for Doxorubicin 0.8) peak area cannot be greater than contrast solution main peak area (1.0%), and other single impurity peak areas cannot be greater than comparison liquid master 0.5 times (0.5%) of peak area, 2 times (2.0%) each impurity peak area and that cannot be greater than comparison liquid main peak area.

Embodiment 18

The preparation of epirubicin hydrochloride I：

The trichloro ethylene, (intermediate VI of intermediate VI are added into the neck glass reaction bottles of 1000mL tri-：Trichloro ethylene=1:40 (W/V, g/mL)).Open stirring, 30 DEG C of temperature control, the trichloro ethylene solution (intermediate of the hydrogen bromide of dropwise addition 4% into reaction solution Ⅵ：Trichloro ethylene solution=1 of 4% hydrogen bromide：4 (W/V, g/mL)), it is added dropwise, after stirring 20 minutes, into reaction solution Trichloro ethylene solution (the intermediate VI of bromine is added dropwise：Bromine：Trichloro ethylene=1:0.5:5 (W/W/V, g/g/mL)), it is added dropwise, protects Warm stirring reaction 3 hours.After reaction terminates, copperas solution (intermediate VI is added into reaction solution：Ferrous sulfate：Purifying Water=1:0.05:0.5 (W/W/V, g/g/mL)), after stirring 10 minutes, with potassium hydroxide solution (intermediate V：Potassium hydroxide： Purified water=1:0.25:10 (W/W/V, g/g/mL)) regulation PH be 4.5~5.0, stirring reaction is after 10 minutes, with 7% phosphoric acid Solution regulation pH is 1.3~1.5, is reacted 2 hours in 25 DEG C~35 DEG C insulated and stirreds.Reaction terminates, and adds 30% sodium formate The aqueous solution, regulation pH are 3.0~3.5, and 25~35 DEG C of sodium formates of temperature control hydrolyze 3 hours, final that target compound hydrochloric acid table is soft Than the crude product solution of star I.

Dichloromethane and purified water are added in reaction solution (intermediate VI：Purified water：Dichloromethane=1：65：45(W/ V/V, g/mL/mL)), liquid separation is stood after stirring, water intaking mutually extracts (intermediate VI three times with dichloromethane solution：Dichloromethane= 1：45 (W/V, g/mL)), merge organic phase, concentration in vacuo to certain volume (intermediate VI：The volume of concentrate=1:8 (W/V, g/mL)), n-hexane (intermediate VI is added under stirring：N-hexane=1:12 (W/V, g/mL)) crystallization, filter dry Solid epirubicin hydrochloride I, mass yield 91.2% are obtained after dry.Product is red powder, purity 97.8%, meets that pharmacopeia will Ask：If any impurity peaks in need testing solution chromatogram, Doxorubicin ketone (relative retention time about 0.3) is by the peak area after correction Calculate (being multiplied by correction factor 0.7), cannot be greater than contrast solution main peak area (1.0%), (relative retention time is about for Doxorubicin 0.8) peak area cannot be greater than contrast solution main peak area (1.0%), and other single impurity peak areas cannot be greater than comparison liquid master 0.5 times (0.5%) of peak area, 2 times (2.0%) each impurity peak area and that cannot be greater than comparison liquid main peak area.

Embodiment 19

The preparation of epirubicin hydrochloride I：

The heptane, (intermediate VI of intermediate VI are added into the neck glass reaction bottles of 1000mL tri-：Heptane=1:70 (W/V, g/ mL)).Open stirring, 35 DEG C of temperature control, the n-heptane solution (intermediate VI of the hydrogen bromide of dropwise addition 4% into reaction solution：4% bromination N-heptane solution=1 of hydrogen：2 (W/V, g/mL)), it is added dropwise, after stirring 20 minutes, the n-heptane solution of bromine is added dropwise into reaction solution (intermediate VI：Bromine：Heptane=1:0.7:10 (W/W/V, g/g/mL)), it is added dropwise, insulated and stirred is reacted 1.5 hours.Reaction After end, copperas solution (intermediate VI is added into reaction solution：Ferrous sulfate：Purified water=1:0.09:0.9 (W/W/V, G/g/mL)), after stirring 10 minutes, with potassium hydroxide solution (intermediate V：Potassium hydroxide：Purified water=1:0.2:6 (W/W/V, G/g/mL it is 4.0~4.5)) to adjust PH, and stirring reaction was 1.1~1.2 with 12% phosphoric acid solution regulation PH after 15 minutes, in 25 DEG C~35 DEG C insulated and stirreds are reacted 2 hours.Reaction terminates, and adds 35% aqueous sodium formate solution, and regulation PH is 2.5~3.0, 25~35 DEG C of sodium formates of temperature control hydrolyze 1 hour, final to obtain the crude product solution of target compound epirubicin hydrochloride I.

Dichloromethane and purified water are added in reaction solution (intermediate VI：Purified water：Dichloromethane=1：35：50(W/ V/V, g/mL/mL)), liquid separation is stood after stirring, water intaking mutually extracts (intermediate VI three times with dichloromethane solution：Dichloromethane= 1：50 (W/V, g/mL)), merge organic phase, concentration in vacuo to certain volume (intermediate VI：The volume of concentrate=1:15 (W/V, g/mL)), n-hexane (intermediate VI is added under stirring：N-hexane=1:15 (W/V, g/mL)) crystallization, filter dry Solid epirubicin hydrochloride I, mass yield 90.0% are obtained after dry.Product is red powder, purity 97.2%, meets that pharmacopeia will Ask：If any impurity peaks in need testing solution chromatogram, Doxorubicin ketone (relative retention time about 0.3) is by the peak area after correction Calculate (being multiplied by correction factor 0.7), cannot be greater than contrast solution main peak area (1.0%), (relative retention time is about for Doxorubicin 0.8) peak area cannot be greater than contrast solution main peak area (1.0%), and other single impurity peak areas cannot be greater than comparison liquid master 0.5 times (0.5%) of peak area, 2 times (2.0%) each impurity peak area and that cannot be greater than comparison liquid main peak area.

Embodiment 20

The preparation of epirubicin hydrochloride I：

Reaction terminates to add 250mL purified waters in backward reaction solution, after adjusting pH to 3 with watery hydrochloric acid, concentration, by concentrate After suction filtration, separated with cationic ion-exchange resin, be concentrated to dryness after collecting principal component, it is final to obtain the solid of epirubicin hydrochloride I, Mass yield 85.9%.Product is red powder, purity 96.1%, meets pharmacopoeial requirements：In need testing solution chromatogram if any Impurity peaks, Doxorubicin ketone (relative retention time about 0.3) press the calculated by peak area (being multiplied by correction factor 0.7) after correction, no Contrast solution main peak area (1.0%) must be more than, Doxorubicin (relative retention time about 0.8) peak area cannot be greater than compareing molten Liquid main peak area (1.0%), other single impurity peak areas cannot be greater than 0.5 times (0.5%) of comparison liquid main peak area, each miscellaneous 2 times (2.0%) mass peak area and that cannot be greater than comparison liquid main peak area.

Embodiment 21

Weighing 4 '-EPIDNR 6.7g adds 67mL methanol to dissolve at room temperature, adds after Isosorbide-5-Nitrae-dioxane 67mL again 6mL methyl formates and 0.73mL bromines are added, after reacting 1h, 2.16mL acidifying expoxy propane is added and persistently stirs 30min, by this Reaction solution is concentrated into 65mL, and 740mL isopropanol crystallizations are added after being concentrated after cooling, backward precipitation in add 150mL different Propanol rinse crystal, after crystal is fully dried, dissolved with 142mL water, the 146mL acetone solns for adding 4.2mL hydrogen bromides enter Row acidifying, reacts 18h at room temperature, and the solution reaction 24h of 10g sodium formates and 42mL water is added into reaction solution, is adjusted with watery hydrochloric acid PH to 5 is saved, persistently stirs 24h afterwards.Reaction terminates to add 250mL purified waters in backward reaction solution, and pH to 3 is adjusted with watery hydrochloric acid Afterwards, concentrate, after concentrate is filtered, separated with cationic ion-exchange resin, is concentrated to dryness after collecting principal component, it is final to obtain salt The sour solid of epirubicin I, mass yield 59.7%, purity 90.1%.

Embodiment 22

Weighing 4 '-EPIDNR 6.7g adds 67mL methanol to dissolve at room temperature, adds after Isosorbide-5-Nitrae-dioxane 67mL again 6mL methyl formates and 0.73mL bromines are added, after reacting 1h, 2.16mL acidifying expoxy propane is added and persistently stirs 30min, by this Reaction solution is concentrated into 65mL, and 740mL isopropanol crystallizations are added after being concentrated after cooling, backward precipitation in add 150mL different Propanol rinse crystal, after crystal is fully dried, dissolved with 142mL water, the 146mL acetone solns for adding 4.2mL hydrogen bromides enter Row acidifying, reacts 18h at room temperature, and the solution reaction 24h of 10g sodium formates and 42mL water is added into reaction solution, is adjusted with watery hydrochloric acid PH to 5 is saved, persistently stirs 24h afterwards.

React and dichloromethane and purified water are added in reaction solution (intermediate VI after terminating：Purified water：Dichloromethane= 1：35：50 (W/V/V, g/mL/mL)), liquid separation is stood after stirring, water intaking mutually extracts (intermediate VI three times with dichloromethane solution： Dichloromethane=1：50 (W/V, g/mL)), merge organic phase, concentration in vacuo to certain volume (intermediate VI：Concentrate Volume=1:15 (W/V, g/mL)), n-hexane (intermediate VI is added under stirring：N-hexane=1:15 (W/V, g/mL)) analysis Crystalline substance, filter and the solid of epirubicin hydrochloride I, mass yield 66.4% are obtained after drying.Product is red powder, and purity 90.2% is full Sufficient pharmacopoeial requirements：If any impurity peaks in need testing solution chromatogram, after Doxorubicin ketone (relative retention time about 0.3) is by correction Calculated by peak area (being multiplied by correction factor 0.7), cannot be greater than contrast solution main peak area (1.0%), Doxorubicin is (relative to protect Staying the time, about 0.8) peak area cannot be greater than contrast solution main peak area (1.0%), and other single impurity peak areas cannot be greater than 0.5 times (0.5%) of comparison liquid main peak area, it is each impurity peak area and cannot be greater than comparison liquid main peak area 2 times (2.0%).

Embodiment 23

Synthetic route

Specific preparation method：

The preparation of midbody compound III：

In the bottle glass reaction bulbs of 1000mL tri-, daunorubicin hydrochloride (5g, 8.63mmol) is suspended in dichloromethane (200mL；Intermediate II：Dichloromethane=1:40 (W/V, g/mL)) in, 0 DEG C is cooled under nitrogen protection, with vigorous stirring In trifluoacetic anhydride (7mL is added dropwise in 60min；Intermediate II：TFAA=1:1.4 (W/V, g/mL)) dichloromethane (15mL；Intermediate II：Dichloromethane=1:3 (W/V, g/mL)) solution, drop is complete, equality of temperature reaction 0.5h, it is pure to add 250mL afterwards Change water (intermediate II：Purified water=1:50 (W/V, g/mL)), fully shake up rear stratification and collect organic phase, add thereto Saturated sodium bicarbonate solution 200mL (intermediate IIs：Saturated sodium bicarbonate solution=1:40 (W/V, g/mL)), put after fully shaking up To room temperature, 15-24 hours are stirred vigorously, organic phase is separated to obtain after the completion of hydrolysis, 35 DEG C are dried under reduced pressure to constant weight, obtain intermediate III (4.1g, mass yield 82.0%), purity 85.5%.

The preparation of midbody compound IV：

In the neck glass reaction bottles of 500mL tri-, 5mL DMSO are dissolved in 100mL dichloromethane (intermediate III： DMSO：Dichloromethane=1:1:20 (W/V/V, g/mL/mL)), it is sufficiently stirred and the solution is cooled to -60 DEG C, adds afterwards 1mL oxalyl chloride and 5mL dichloromethane solutions (intermediate III：Oxalyl chloride：Dichloromethane=1:0.2:1 (W/V/V, g/mL/ ML)), -60 DEG C of insulated and stirreds are reacted 40 minutes afterwards.5g intermediate III is dissolved in 50mL dichloromethane (intermediate III：Two Chloromethanes=1:10 (W/V, g/mL)), this solution was added into above-mentioned coolant in 20 minutes, maintains temperature in the process - 60 ± 5 DEG C of degree, react 1 hour at this temperature, reaction added 7mL triethylamine (intermediates III after terminating in 10 minutes：Three Ethamine=1:1.4 (W/V, g/mL)), this process keeping temperature≤- 60 DEG C.5mL glacial acetic acid is dissolved in 10mL dichloromethane (intermediate III：Glacial acetic acid：Dichloromethane=1:1:2 (W/V/V, g/mL/mL)), stirring 2 after this solution is added in reaction solution Minute, then 300mL purified water (intermediates III are added into reaction solution：Purified water=1:60 (W/V, g/mL)), after being sufficiently stirred Standing separation obtains organic phase, repeats this process 3 times, merges gained organic phase three times, it is concentrated to dryness under vacuum conditions, most 4.4g intermediates IV, quality yield 88.0%, purity 82.2% are obtained eventually.

The preparation of midbody compound V：

In the neck glass reaction bottles of 1000mL tri-, 4.7g intermediates IV are dissolved in (intermediate in 180mL tetrahydrofurans Ⅳ：Tetrahydrofuran=1:38.3 (W/V, g/mL)), open stirring after added in 40 minutes 2.1g sodium triethylborohydrides (in Mesosome IV：Sodium triethylborohydride=1:1.5 (W/W, g/g)), finish, stirring reaction 1 hour at 20 ± 2 DEG C, reaction terminates This reaction solution is added to (intermediate IV in the hydrochloric acid mixed solution of 150mL dichloromethane, 300mL purified waters and 2mL 1mol/L afterwards： Dichloromethane：Purified water：1mol/L hydrochloric acid=1:32:63.8:0.43 (W/V/V/V, g/mL/mL/mL)), after being sufficiently stirred Stand, obtain organic phase, and with 300mL purified waters (intermediate IV：Purified water=1:63.8 (W/V, g/mL)) washing organic phase 2 It is secondary, organic phase is concentrated to dryness to obtain the 4.6g of intermediate V, mass yield 92.0%, purity 77.3% under vacuum conditions.By this Crude product is further purified with preparative high performance liquid chromatography, is concentrated to dryness after collecting main peak fraction, is obtained the 3.0g of intermediate V, quality Yield 65.2%, purity 94%.

The preparation of midbody compound VI：

In the neck glass reaction bottles of 500mL tri-, 3.0g intermediates V are completely dissolved in 200mL purified waters at 30 DEG C (intermediate V：Purified water=1:66.7 (W/V, g/mL)), the backward solution in add 10mL 1.0mol/L NaOH solution (intermediate V：1.0mol/L NaOH solution=1:3.3 (W/V, g/mL)), insulation reaction 30 minutes at the same temperature, this PH to 7.0 is adjusted with 1mol/L hydrochloric acid solution afterwards, the reaction solution is separated using preparative high performance liquid chromatography, is collected It is concentrated to dryness after main peak fraction, obtains 2.1g intermediates VI, mass yield 70.0%, purity 94.8%.

The preparation of epirubicin hydrochloride I：

In the neck glass reaction bottles of 1000mL tri-, 2.1g intermediates VI are dissolved in 70mL DMF (intermediates VI：DMF= 1:33.3 (W/V, g/mL)) in, the backward solution in add double (DMA) the two bromo bromic acid hydrogen salts of 2.8g (intermediate VI：Double (DMAC N,N' dimethyl acetamides) two bromo bromic acid hydrogen salt=1:1.3 (W/W, g/g)), in 40 DEG C of insulation reactions 2 Hour, reaction terminates to add 350mL acetonitrile (intermediates VI in backward reaction solution：Acetonitrile=1:167 (W/V, g/mL)), filter institute It must precipitate, and be washed and precipitated with acetonitrile repeatedly, 80mL acetone, 80mL 0.25mol/L bromination are dissolved in after sediment is dried (intermediate VI in the mixed liquor of aqueous solution of hydrogen and 8g sodium formates：Acetone：0.25mol/L aqueous solution of hydrogen bromide：Sodium formate=1: 38:38:3.8 (W/V/V/W, g/mL/mL/g)), stirring reaction 30 hours at 35 DEG C, after reaction terminates, yield 40.9% is pure Degree 60.2%.

Reaction solution is separated through preparative high performance liquid chromatography, collects main peak fraction, third is added after being concentrated under reduced pressure into and doing Ketone recrystallizes, final to obtain 1.3g epirubicin hydrochlorides, mass yield 61.9%, final mass yield 25.3%, purity 99.8%.

Embodiment 24

Intermediate II to VI preparation is identical with embodiment 23, changes the preparation of final step epirubicin hydrochloride I Method.

The preparation of epirubicin hydrochloride I：

In the neck glass reaction bottles of 1000mL tri-, 35.2g intermediates VI (49.6mmol) are dissolved in the anhydrous dichloromethanes of 321mL (intermediate VI in alkane：Dichloromethane=1:9.1 (W/V, g/mL)), add 19.7g anhydrous pyridines (249.4mmol；Intermediate Ⅵ：Anhydrous pyridine=1:7 (W/V, g/mL)).The solution is cooled to -5~0 DEG C, in dropwise addition fluoroform containing 28.1g in 30min Anhydrous methylene chloride (30mL) (intermediate VI of sulphonic acid anhydride (99.6mmol)：Trifluoromethanesulfanhydride anhydride：Anhydrous methylene chloride=1: 0.8:0.85 (W/W/V, g/g/mL)) solution, drop is complete, and equality of temperature continues to react 1h.Add previously prepared triethylammonium formate Dichloromethane solution (triethylamine 62.7g, anhydrous formic acid 28.7g, anhydrous methylene chloride 209mL；Intermediate VI：Triethylamine：It is anhydrous Formic acid：Anhydrous methylene chloride=1:1.8:0.82:6.0 (W/W/W/V, g/g/g/mL)), 20~25 DEG C of stirring 16h, add 562mL methanol (intermediate VI：Methanol=1:16 (W/V, g/mL)) after be cooled to -10~-5 DEG C, add 950g 1.6mol/L Sodium hydroxide solution (intermediate VI：1.6mol/L sodium hydroxide solution=1:27 (W/W, g/g)), equality of temperature reaction 6h.Add 3mol/L hydrochloric acid 621mL (intermediates VI：3mol/L hydrochloric acid=1:17.6 (W/V, g/mL)), stirred after being warming up to 10~15 DEG C anti- 7h is answered, reaction terminates rear stratification, aqueous phase 562mL dichloromethane (intermediate VI：Dichloromethane=1:16 (W/V, g/ ML)) wash twice, merge organic phase, then with 562mL water (intermediate VI：Water=1:16 (W/V, g/mL)) wash twice, merge Aqueous phase, through NM100 macroporous absorbent resins adsorption and purification, [eluent is acetonitrile：The pH=4.5 aqueous solution (6：1) it is soft], to obtain hydrochloric acid table Than star crude product 16.8g, mass yield 47.7%, purity 90.1%.Crude product is through NM100 large pore resin absorption column chromatogram [mobile phases For acetonitrile：The pH=4.5 aqueous solution (1：7.3)] purify again, obtain epirubicin hydrochloride sterling 15.1g, pillar layer separation yield 89.9%, final mass yield 42.9%, purity 94.7%.

Claims

1. a kind of intermediate of epirubicin hydrochloride compound, it is that structural formula is as follows shown in formula II -1：

2. the preparation method of the midbody compound described in a kind of claim 1, it is characterised in that preparation method includes following step Suddenly：

Adding methanol and acidic catalyst reacts daunorubicin hydrochloride II and esterifying reagent B, and generation has in ketal structure Intermediate compounds therefor II -1；The esterifying reagent B is selected from Ethyl formate, methyl formate, methyl acetate, ethyl acetate, orthoformic acid three Ethyl ester, the one or more in ethyl chloroformate and propyl formate；

3. preparation method according to claim 2, it is characterised in that compound ii synthesis compound ii -1 specifically includes as follows Step：In organic solvent A, methanol and acidic catalyst are added, daunorubicin hydrochloride II and esterifying reagent B are reacted 2 hours, Midbody compound II -1 of the generation with ketal structure；The organic solvent A is selected from arene, fat hydrocarbon, alicyclic One kind in class, halogenated hydrocarbons, alcohols, alkanes, ethers, amide-type, Isosorbide-5-Nitrae-dioxane and esters solvent.

4. preparation method according to claim 3, it is characterised in that the temperature of the reaction is 0~10 DEG C.

5. preparation method according to claim 3, it is characterised in that the temperature of the reaction is 5 DEG C.

6. preparation method according to claim 3, it is characterised in that the organic solvent A is selected from benzene, toluene, hexamethylene, first Alcohol, ethanol, the tert-butyl alcohol, dichloromethane, Isosorbide-5-Nitrae-dioxane, ether, acetone, trichloro ethylene, tetrahydrofuran, methyl tertbutyl One kind in ether, ethyl acetate and DMF.

7. the preparation method according to Claims 2 or 3, it is characterised in that the esterifying reagent B is triethyl orthoformate.

8. purposes of the midbody compound in epirubicin is prepared according to claim 1.

9. purposes according to claim 8, it is characterised in that concrete application method is：With TFAA to the intermediate The active amino of sugar moiety is protected in the structure of compound ii -1, generates unsegregated midbody compound III；Enter one Step dehydration, is oxidized to carbonyl by the alcoholic extract hydroxyl group of amino sugar structure, generates unsegregated midbody compound IV；With selective reduction Carbonyl reduction in amino sugar is hydroxyl by agent D, is converted into in opposite with daunorubicin amino sugar structure 4-OH configurations Mesosome V；Sloughed with highly basic E in the structure of intermediate V and intermediate VI is generated to the protection of amino；Enter successively under sour environment Row bromination and acid hydrolytic reaction, corresponding bromo ketone intermediate is generated, then hydrolyzed in sodium formate solution, bromine is substituted by Alcoholic extract hydroxyl group finally obtains target product epirubicin hydrochloride I；The reducing agent D be selected from sodium hydride, tetrahydrochysene lithium aluminium, sodium borohydride, One or more in lithium hydride, double methoxyethoxy alanates, lithium triethylborohydride, sodium cyanoborohydride；The alkali E One kind in sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate and sodium acid carbonate；Reaction scheme is as follows：