CN106749446B

CN106749446B - A kind of intermediate of epirubicin hydrochloride compound V

Info

Publication number: CN106749446B
Application number: CN201710016791.0A
Authority: CN
Inventors: 刁玉林; 张贵民
Original assignee: Lunan Pharmaceutical Group Corp
Current assignee: Lunan Pharmaceutical Group Corp
Priority date: 2017-01-10
Filing date: 2017-01-10
Publication date: 2019-10-29
Anticipated expiration: 2037-01-10
Also published as: CN106749446A

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 that existing epirubicin hydrochloride synthetic route generates is avoided simultaneously to meet water unstable, easily decompose, the relatively low problem of whole route yield, for better energy-saving and emission-reduction, this route has used the reagent low in cost being easy to get；Removable selective protection means are used simultaneously, and generation impurity is few, purity is high, high income.

Description

A kind of intermediate of epirubicin hydrochloride compound V

Technical field

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

Background technique

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- arabopyranose bases)-O-] -6,8,11- trihydroxy -8- glycolyl -1- Methoxyl group -7,8,9,10- tetrahydro aphthacene -5,12- dione hydrochlorides, structure are as follows:

For the isomer of adriamycin, mechanism of action is directly embedded between DNA core alkali pair, interferes transcription, resistance The only formation of tumour cell mRNA, to inhibit the synthesis of DNA and RNA.In addition, epirubicin hydrochloride is to topoisomeraseⅡ There is inhibiting effect.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 inhibiting effect to kinds of tumors, can be used for breast cancer, pernicious leaching Bar tumor, soft tissue sarcoma and gastric cancer.Also there is anti-tumor activity to malignant mela noma and colon cancer.Combining with other anticarcinogens makes With can be used for treating lung cancer and oophoroma.Therefore play the part of more and more important role in human anti-tumor's clinical application, clinic needs It measures and increases year by year.

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

Using 4 '-epirubicin as raw material, methyl formate and bromine effect under reaction obtain brominated product, then successively with It is prepared into bromo ketone intermediate after propylene oxide, hydrogen bromide hydrolysis, finally successively with sodium bicarbonate, sodium hydroxide and sodium chloride water Epirubicin hydrochloride is hydrolyzed to obtain in solution.Used such as propylene oxide organic solvent is to producer's body and mind in this method Health generates high risks, and the waste liquid generated is difficult to handle, huge to environmental pressure；Meanwhile last hydrolysis stage uses The condition that multi-step, difference pH are hydrolyzed, it is difficult to accurate control, thus high requirement is proposed to the technology of operator, so, The technique production 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 requires more harsh when the water content and reaction of erythromycin, finds that the slight change of water content is in actual application The defect that 4 '-epirubicin residual quantities can be caused excessive, end product quality are 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 it all uses first with the processing method of sodium triacetoxy borohydride reduction amination, later again by the intermediate bromine of generation The mode that change, sodium formate hydrolyze obtains final product epirubicin hydrochloride, and the more traditional organic synthesis reagent of the reagent cost is high, and Applied reagent is difficult to save under workshop condition, is easy to happen industrial accident, 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 technical requirements are high, environmental pollution is serious, high production cost, and the preparation method of epirubicin hydrochloride generates in the prior art Intermediate is high for moisture requirement, easily decomposes, and is unfavorable for carrying out industrialized production.

Summary of the invention

In view of the deficiencies in the prior art, the present invention is provided a kind of new intermediate compound V and is synthesized using the intermediate The variation route of epirubicin hydrochloride.This route is simple, cheap, efficient, in order to preferably reduce production cost and reduce to environment Pollution, this route used the organic reagent of economy, less pollution substantially, and the intermediate that the preparation method generates is for water Divide and require low, stability height, mass yield is high.

The present invention is realized especially by following technical solution:

A kind of intermediate of epirubicin hydrochloride compound is shown in formula V, and structural formula is as follows:

A kind of preparation method of midbody compound V, includes the following steps:

Methanol, acidic catalyst, esterifying reagent B is added in step 1., and generating daunorubicin hydrochloride II has ketal structure Non- separation of intermediates compound ii -1, with trifluoroacetic anhydride in the intermediate structure sugar moiety active amino carry out Protection generates the unsegregated midbody compound III with amino trifluoroacetic acid ester structure；Step 2. is in 1,5- diaza-bicyclo The lower further dehydration of (4,3,0) nonyl- 5- alkene (DBN) catalysis, is oxidized to carbonyl for the alcoholic extract hydroxyl group of amino sugar structure, generation does not separate Midbody compound IV；Step 3. using selective reduction agent D by the carbonyl reduction in amino sugar as hydroxyl, be converted into have with The opposite intermediate V of daunorubicin amino sugar structure 4-OH configuration；

Wherein, step 1. compound ii synthesis compound III includes following synthetic route:

It includes following synthetic route that step 2. compound III, which synthesizes compounds Ⅳ:

Step 3. compounds Ⅳ synthesis compound V includes the following steps:

Step 1. compound ii synthesis compound III specifically comprises the following steps: in organic solvent A, and methanol, acid is added Property catalyst, esterifying reagent B, daunorubicin hydrochloride II, react 2~3 hours, generate have ketal structure non-separation of intermediates Compound ii -1, backward reaction system in trifluoroacetic anhydride is added, be stirred to react 1~1.5 hour, generate have amino trifluoro The midbody compound III of acetic acid ester structure.

The temperature reacted described in step 1 with esterifying reagent B is 0~10 DEG C.

Organic solvent A described in step 1 be selected from arene, fat hydrocarbon, alicyclic hydrocarbon type, halogenated hydrocarbons, alcohols, alkanes, One of ethers, amides, diol, derivatives class and esters solvent are a variety of；More preferable benzene, toluene, hexamethylene, the tert-butyl alcohol, Methylene chloride, 1,4- dioxane, ether, acetone, trichloro ethylene, tetrahydrofuran, methyl tertiary butyl ether(MTBE), ethyl acetate and DMF One of or it is a variety of；Further preferably methanol or methylene chloride or 1,4- dioxane.

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

The dosage of organic solvent A described in step 1. are as follows: (following part (W/V, g/mL) table in terms of weight g/ volume mL Show), daunorubicin hydrochloride: organic solvent A=1:50~70, preferably 1:60.

The dosage of organic solvent B described in step 1. are as follows: daunorubicin hydrochloride: esterifying reagent B=1:1~4, preferably 1:2 (W/V, g/mL).

Trifluoroacetic anhydride dosage described in step 1. are as follows: daunorubicin hydrochloride: trifluoroacetic anhydride=1:1~4, preferably 1:2 (W/V, g/mL).

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

Described in step 2 with the temperature of 1,5- diaza-bicyclo (4,3,0) nonyl- 5- alkene reaction be preferably -75 DEG C~0 DEG C, it is optimal It is selected as -70 DEG C~-40 DEG C.

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

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 of palmitic acid, acrylic acid are a variety of；Further preferably formic acid, acetic acid, propionic acid, butyric acid, octanoic acid, adipic acid, second two One of acid, malonic acid, succinic acid and maleic acid；Most preferably glacial acetic acid and malonic acid.

Preferably, step 2 specifically: organic solvent A is added into three neck glass reaction bottles.Open stirring, temperature control -70 ~-40 DEG C, it is slowly added to the organic solvent A solution of trifluoroacetic anhydride, is stirred to react in -70~-40 DEG C 1~1.5 hour.To anti- Answer the organic solvent A solution that intermediate of epirubicin hydrochloride III is slowly added dropwise in liquid；Addition finishes, and stirring after twenty minutes, is added dropwise The organic solvent A solution of 1,5- diaza-bicyclo (4,3,0) nonyl- 5- alkene, addition finish, and stirring after ten minutes, is added organic acid C's Organic solvent A solution is stirred to react 0.5 hour.The dosage of the organic solvent A are as follows: 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 trifluoroacetic anhydride are as follows: intermediate III: trifluoroacetic anhydride: methylene chloride= 1:0.5~0.8:2.4~3 (W/W/V, g/g/mL).

The organic solvent A is preferably methylene chloride.

The organic acid C is preferably formic acid, acetic acid, propionic acid, butyric acid, octanoic acid, adipic acid, ethanedioic acid, malonic acid, succinic acid One of with maleic acid；Most preferably glacial acetic acid and malonic acid.

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

The organic solvent A solution usage of 1,5- diaza-bicyclo (4,3,0) the nonyl- 5- alkene are as follows: III: 1,5- phenodiazine of intermediate Two rings (4,3,0) nonyl- 5- alkene: methylene chloride=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 are as follows: intermediate III: organic acid C: organic solvent A=1:0.85 ~0.9:10~14 (W/V/V, g/mL/mL).

Preferably, TLC is detected: with chloroform/isopropanol (volume ratio 96/4) for solvent, detecting III spot of intermediate It should disappear substantially, III Rf ≈ 0.3 of intermediate, IV Rf ≈ 0.8 of intermediate.Reaction solution is warming up to 0~10 DEG C, organic phase is successively used After purified water, 0.1mol/L hydrochloric acid solution, the washing of 2% sodium bicarbonate solution, concentration in vacuo to certain volume (intermediate III: the volume of the concentrated liquid=1:10 (W/V, g/mL)) n-hexane crystallization, is added under stirring, is obtained among solid after filtering drying Body compounds Ⅳ.Preferably, the n-hexane additional amount are as follows: intermediate III: n-hexane=1:10 (W/V, g/mL).

Step 3. compounds Ⅳ synthesis compound V specifically comprise 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, being converted into has and daunorubicin amino sugar knot The opposite intermediate V of structure 4-OH configuration.

The temperature reacted described in step 3 with reducing agent D is preferably -75 DEG C~0 DEG C, most preferably -60 DEG C~-30 DEG C.

Organic solvent A described in step 3 be selected from arene, fat hydrocarbon, alicyclic hydrocarbon type, halogenated hydrocarbons, alcohols, alkanes, One of ethers, amides, diol, derivatives class and esters solvent are a variety of；More preferable benzene, toluene, hexamethylene, the tert-butyl alcohol, Methylene chloride, 1,4- dioxane, ether, acetone, trichloro ethylene, tetrahydrofuran, methyl tertiary butyl ether(MTBE), ethyl acetate and DMF One of or it is a variety of；Further preferably methylene chloride or acetone.

Reducing agent D described in step 3 is selected from sodium hydride, tetrahydrochysene lithium aluminium, sodium borohydride, lithium hydride, double methoxyethoxy aluminium hydrogen One of compound, lithium triethylborohydride, sodium cyanoborohydride are a variety of；In can preferably the making of the selective reduction agent The isomer impurities of mesosome V are preferably minimized, V 85% or more purity of intermediate.

The application provides a kind of method for preparing epirubicin hydrochloride using the intermediate V simultaneously, includes the following steps: Steps 1 and 2 and 3 are as described above；Step 4. is sloughed in V structure of intermediate with highly basic and generates intermediate VI to the protection of amino； Step 5. successively carries out bromination and acid hydrolytic reaction under acidic environment, generates corresponding bromo ketone intermediate, then in sodium formate It is hydrolyzed in solution, bromine is substituted by alcoholic extract hydroxyl group and finally obtains target product epirubicin hydrochloride I.Its specific synthetic route is such as Shown in lower:

Step 4: the preparation specific steps of midbody compound VI are as follows: in purified water, by midbody compound V and alkali E Reaction 0.5 hour, obtains midbody compound VI；The temperature reacted with alkali E is preferably 0 DEG C~20 DEG C, most preferably 0 DEG C~ 10℃。

Alkali E described in step 4 is selected from one of sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate and sodium bicarbonate, Most preferably sodium hydroxide.

Step 5: the preparation specific steps of midbody compound I are as follows: carry out bromination reaction first under acidic environment, convert For the Bromo-intermediates VI -1 with ketal structure, the intermediate of this structure carries out acid hydrolytic reaction in acidic environment, removal Ketal structure generates corresponding bromo ketone intermediate VI -2 to the protection of carbonyl, hydrolyzes in sodium formate solution thereafter, Bromine is substituted by alcoholic extract hydroxyl group, and at 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 are described in further detail are as follows:

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

It is added in enough reducing agent F and suitable saturation aqueous slkali G adjusting reaction after excessive bromine quenching reaction, is added Liquid pH to 4.5~5.0, most preferably pH are 4.7.

Inorganic acid H aqueous solution is added, adjusts pH=1.3~1.5, optimal selection pH=1.5 is stirred in 25 DEG C~35 DEG C heat preservations Mix reaction 2~2.5 hours.

Aqueous sodium formate solution, adjusting pH value to 3.0~3.5, optimal selection 3.2,25~35 DEG C of sodium formate water of temperature control are added Solution 1~3 hour, it is final to obtain I crude product solution of target compound epirubicin hydrochloride.Aqueous sodium formate solution mass concentration (the g/ It g) 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 of ethers, amides, diol, derivatives class, esters solvent and phenol are a variety of；More preferable benzene, toluene, hexamethylene, uncle Butanol, methylene chloride, Isosorbide-5-Nitrae-dioxane, ether, acetone, trichloro ethylene, tetrahydrofuran, methyl tertiary butyl ether(MTBE), ethyl acetate With one of DMF or a variety of；Further preferably methanol or Isosorbide-5-Nitrae-dioxane or acetone or ethyl acetate or acetone With ethyl acetate mixed solvent (the two volume ratio is 1:3).

The reducing agent F is selected from one of sodium sulfite, sodium hydrogensulfite, ferrous sulfate, sodium nitrite and oxalic acid, most It is preferred that sodium sulfite.

The alkali G is selected from one of sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide and sodium bicarbonate, 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 described in further detail in following part:

Step 1, the preparation of midbody compound III:

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

The dosage of the organic solvent A are as follows: (following part is indicated with (W/V, g/mL)), hydrochloric acid in terms of weight g/ volume mL Daunorubicin: organic solvent A=1:50~70, preferably 1:60；The organic solvent A is preferably methanol, methylene chloride and 1, One of 4- dioxane is a variety of.

The acidic catalyst methanol solution dosage of the addition are as follows: 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.

The dosage of the esterifying reagent B are as follows: 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 trifluoroacetic anhydride dosage are as follows: daunorubicin hydrochloride: trifluoroacetic anhydride=1:1~4, preferably 1:2 (W/V, g/ mL)。

End of reaction is added methanol (daunorubicin hydrochloride: methanol=1:20~40 (W/V, g/mL)) into reaction solution, stirs After mixing 10~15 minutes, 8% sodium bicarbonate solution is added and adjusts pH value to 7.0~8.0.15 DEG C~25 DEG C of temperature of control, heat preservation It is stirred to react 3~5 hours.TLC detection: with chloroform/isopropanol (volume ratio 96/4) for solvent, detection raw material spot is answered It is basic to disappear.Midbody compound III Rf ≈ 0.3, daunorubicin hydrochloride Rf ≈ 0.Liquid separation is stood, lower layer's organic phase is collected.Vacuum It is concentrated under state certain volume (daunorubicin hydrochloride: the volume of the concentrated liquid=1:10 (W/V, g/mL)), is added under stirring N-hexane crystallization obtains solid midbody compound III after filtering drying.Preferably, the n-hexane additional amount are as follows: hydrochloric acid is soft red Mycin: 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 are slowly added to trifluoro The organic solvent A solution of acetic anhydride is stirred to react 1~1.5 hour in -70~-40 DEG C.

The organic solvent A is preferably methylene chloride.

The dosage of the organic solvent A are as follows: intermediate III: organic solvent A=1:20~40, preferably 1:40 (W/V, g/ mL)。

The organic solvent A solution of intermediate of epirubicin hydrochloride III is slowly added dropwise into reaction solution for end of reaction；It has been added Finish, after twenty minutes, the organic solvent A solution of 1,5- diaza-bicyclo (4,3,0) nonyl- 5- alkene is added dropwise in stirring, and addition finishes, stirring 10 After minute, the organic solvent A solution of organic acid C is added, is stirred to react 0.5 hour.The organic solvent A is preferably dichloromethane Alkane.The organic acid C is preferably formic acid, acetic acid, propionic acid, butyric acid, octanoic acid, adipic acid, ethanedioic acid, malonic acid, succinic acid and horse Come one of sour；Most preferably glacial acetic acid and malonic acid.

Preparation finishes, TLC detection: with chloroform/isopropanol (volume ratio 96/4) for solvent, detecting III spot of intermediate Point should disappear substantially, III Rf ≈ 0.3 of intermediate, IV Rf ≈ 0.8 of intermediate.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 solution, 2% sodium bicarbonate solution, concentration in vacuo to certain volume is (intermediate Body III: the volume of the concentrated liquid=1:10 (W/V, g/mL)), n-hexane crystallization is added under stirring, filter it is dry after in solid Intermediate compounds therefor IV.Preferably, the n-hexane additional amount are as follows: 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 are added dropwise Reducing agent D ethanol solution, addition finishes, after being stirred to react 0.5~1 hour, acetone is added into reaction solution, continues to stir 20~40 minutes.

The organic solvent A is preferably methylene chloride or acetone.

The dosage of the organic solvent A are as follows: 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；Further preferably sodium borohydride.Selection Property reducing agent preferably can be such that the isomer impurities of intermediate V are preferably minimized.

The dosage of the ethanol solution of the reducing agent D are as follows: intermediate IV: reducing agent D: dehydrated alcohol=1:0.02~ 0.04:80~100 (W/W/V, g/g/mL).

Acetone is added into reaction solution for end of reaction, continues stirring 20~40 minutes, the dosage of the acetone are as follows: intermediate Body IV: acetone=1:1~3 (W/V, g/mL).Reaction solution is warming up to 0~10 DEG C, TLC detection: with chloroform/isopropanol (volume ratio 96/4) is solvent, and detection IV spot of intermediate should disappear substantially, III Rf ≈ 0.3 of intermediate, IV Rf ≈ of intermediate 0.8, V Rf ≈ 0.25 of intermediate.Methylene chloride 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 is mutually with dichloromethane solution extraction 3 Secondary (intermediate IV: methylene chloride=1:30~40 (W/V, g/mL)) merges organic phase, concentration in vacuo to certain volume (intermediate IV: the volume of the concentrated liquid=1:10 (W/V, g/mL)) n-hexane crystallization is added under stirring, filter it is dry after must consolidate Body midbody compound V.Preferably, the n-hexane additional amount are as follows: 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, be stirred to react 0.5 hour, TLC detection: with chloroform/isopropanol (volume ratio=96/4) for solvent, in detection V spot of mesosome should disappear substantially, V Rf ≈ 0.25 of intermediate, VI Rf ≈ 0 of intermediate.

The purifying water consumption are as follows: 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 are as follows: intermediate V: sodium hydroxide=1:0.25~0.4 (W/W, g/g).The addition amount of sodium hydroxide can also With statement are as follows: intermediate V: sodium hydroxide: purified water=1:0.25~0.4:10~14 (W/W/V, g/g/mL).

End of reaction, into reaction solution be added methanol dichloromethane solution (intermediate V: methanol: methylene chloride=1: 40~60:8~10 (W/V/V, g/mL/mL)), stirring is opened, and 0.5mol/L sodium bicarbonate solution is added dropwise and adjusts pH value to 7.6 ~7.8.Finally pH value is adjusted to 8.0~8.2 with 0.5mol/L sodium carbonate liquor.Liquid separation is stood, organic phase, vacuum state are collected Under be concentrated into certain volume (intermediate V: the volume of the concentrated liquid=1:10 (W/V, g/mL)), under stirring be added n-hexane analysis Crystalline substance obtains solid midbody compound VI after filtering drying.Preferably, the n-hexane additional amount are as follows: intermediate V: n-hexane= 1:10 (W/V, g/mL).

Step 5, the preparation of epirubicin hydrochloride I:

Into three neck glass reaction bottles, addition organic solvent A, intermediate VI, which are opened, stirs, and 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, reducing agent F is added into reaction solution Solution, stirring 10~15 minutes after, with alkali G adjust PH be 4.5~5.0, after being stirred to react 10~15 minutes, with 7% it is inorganic It is 1.3~1.5 that sour H solution, which adjusts PH, is reacted 2~2.5 hours in 25 DEG C~35 DEG C insulated and stirreds.Reaction terminates, and is added 25% Aqueous sodium formate solution, adjusting 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 I crude product solution of object epirubicin hydrochloride.

The organic solvent A dosage being added into three neck glass reaction bottles are as follows: 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 are as follows: the organic solvent A of the hydrogen bromide of intermediate VI: 4% 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 are as follows: 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 usage: intermediate VI: reducing agent F: purified water=1:0.05~0.07:0.5~0.7 (W/ W/V, g/g/mL).The wherein reducing agent F solution concentration are as follows: 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 finishes, methylene chloride and purified water are added in reaction solution (intermediate VI: purified water: methylene chloride= 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: methylene chloride=1:30~40 (W/V, g/mL)) merges organic phase, concentration in vacuo to certain volume (intermediate VI: the volume of the concentrated liquid=1:10 (W/V, g/mL)) n-hexane crystallization is added under stirring, filter it is dry after must consolidate Body epirubicin hydrochloride I.Preferably, the additional amount of the n-hexane are as follows: 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 mature processing method to the pollutant of generation, produce Raw environmental pollution is small.Holistic approach is easy to operation, not harsh to practitioner's technical requirements, meanwhile, each reaction step Reacting balance, easily controllable, the intermediate of generation is loose to moisture requirement and generation impurity is few, and purity is high, quality is stablized, yield It is high.

The intermediate that the prior art generates is prone to keto-acid and enol form interconversion, in the transition state with enol-type structure Mesosome is extremely unstable, vulnerable in air moisture (such as: in air humidity biggish summer, original process intermediate I is to centre The conversion yield of body II is extremely unstable, and humidity and yield are in obvious negatively correlated situation, i.e. humidity is bigger, and conversion ratio is lower, the summer Season yield is 30%-40%；Other step conversion ratios conversion ratio in high humility also can be reduced accordingly), the influence of temperature And the progress of reaction is hindered, or even be converted into other impurities, directly affect product yield and product purity.And the present invention is by primitive nail Triethylenetetraminehexaacetic acid ester is directly reacted with raw material to protect ketone group, inhibit the tautomerism between ketone group and enol-type structure, protected Card reaction is gone on smoothly.

The route for the synthetic hydrochloric acid epirubicin that the prior art provides is using 4 '-epirubicin as raw material, after bromination PH is adjusted with 5% sodium formate solution first, then with, with excessive bromine, the sodium formate that this method introduces is dense in solution of sodium bisulfite Contracting step (i.e. before hydrobromic acid hydrolysing step) can cause the considerable damage of material, generate the sticky insoluble impurity of dark brown, greatly Ground reduces product yield, and the concentration continuous time is long, and energy consumption and manpower consumption are high.And this technique is directly with the sulfurous acid of recipe quantity In hydrogen sodium and after excessive bromine again in such a way that saturated sodium bicarbonate solution adjusts pH, gained reaction solution system intermediate, which can be stablized, to be deposited , above-mentioned impurity will not be generated under the conditions of same concentration, it can be by yield (mass yield, i.e. chemical combination of original process 40% or so VI to VI -1 step of converting yield of object) it is promoted to 95% or more；On this basis, crude product is through the mass yield before pillar layer separation It is promoted to 85% or more 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, the present invention is efficient, and economical, production operation is simple, complies fully with the requirement of industrialized production.

Specific embodiment

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

Embodiment one

The preparation of midbody compound III:

Methylene chloride and daunorubicin hydrochloride (daunorubicin hydrochloride: dichloro are added into tri- neck glass reaction bottle of 1000mL Methane=1:60 (W/V, g/mL)).It opens and stirs, after 5 DEG C of temperature control, 10~15 minutes, check material dissolution situation, if not completely Dissolution then continues to stir；If being completely dissolved, feed liquid is cooled to 0 DEG C, the methanol solution (hydrochloric acid of camphorsulfonic acid is added thereto Daunorubicin: methanol: camphorsulfonic acid=1:177:1 (W/V/W, g/mL/g)), after stirring 1 hour, trimethyl orthoformate is added (daunorubicin hydrochloride: trimethyl 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 are answered, trifluoroacetic anhydride is added into bottle, and (daunorubicin hydrochloride: trifluoroacetic anhydride=1:2 (W/V, g/mL) is added It finishes, stirs 1 hour.

Methanol (daunorubicin hydrochloride: methanol=1:30 (W/V, g/mL)) is added into reaction solution in end of reaction, stirring 10 After minute, 8% sodium bicarbonate solution is added and adjusts pH value to 7.0~8.0.15 DEG C~25 DEG C of temperature of control, insulated and stirred reaction 3 ~5 hours.TLC detection: 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, lower layer's organic phase is collected.It is dense under vacuum state It is reduced to certain volume (daunorubicin hydrochloride: the volume of the concentrated liquid=1:10 (W/V, g/mL)), n-hexane (salt is added under stirring Sour daunorubicin: n-hexane=1:10 (W/V, g/mL)) crystallization, solid midbody compound III is obtained after filtering drying, quality is received Rate 95.6%.Purity 95.5%.

Embodiment two

The preparation of midbody compound III:

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

Methanol (daunorubicin hydrochloride: methanol=1:40 (W/V, g/mL)) is added into reaction solution in end of reaction, stirring 10 After minute, 8% sodium bicarbonate solution is added and adjusts pH value to 7.0~8.0.15 DEG C~25 DEG C of temperature of control, insulated and stirred reaction 3 ~5 hours.TLC detection: 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, lower layer's organic phase is collected.It is dense under vacuum state It is reduced to certain volume (daunorubicin hydrochloride: the volume of the concentrated liquid=1:10 (W/V, g/mL)), n-hexane (salt is added under stirring Sour daunorubicin: n-hexane=1:10 (W/V, g/mL)) crystallization, solid midbody compound III is obtained after filtering drying, quality is received Rate 93.7%.Purity 95.4%.

Embodiment three

The preparation of midbody compound III:

Tetrahydrofuran and daunorubicin hydrochloride (daunorubicin hydrochloride: tetrahydro are added into tri- neck glass reaction bottle of 1000mL Furans=1:50 (W/V, g/mL)).It opens and stirs, after 8 DEG C of temperature control, 10~15 minutes, check material dissolution situation, if not completely Dissolution then continues to stir；If being completely dissolved, feed liquid is cooled to 3 DEG C, the methanol solution (hydrochloric acid of camphorsulfonic acid is added thereto Daunorubicin: methanol: camphorsulfonic acid=1:177:1 (W/V/W, g/mL/g)), after stirring 1 hour, trimethyl orthoformate is added (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 are answered, trifluoroacetic anhydride (daunorubicin hydrochloride: trifluoroacetic anhydride=1:5 (W/V, g/mL)) is added into bottle, is added It finishes, stirs 1.5 hours.

Methanol (daunorubicin hydrochloride: methanol=1:20 (W/V, g/mL)) is added into reaction solution in end of reaction, stirring 15 After minute, 8% sodium bicarbonate solution is added and adjusts pH value to 7.0~8.0.15 DEG C~25 DEG C of temperature of control, insulated and stirred reaction 3 ~5 hours.TLC detection: 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, lower layer's organic phase is collected.It is dense under vacuum state It is reduced to certain volume (daunorubicin hydrochloride: the volume of the concentrated liquid=1:10 (W/V, g/mL)), n-hexane (salt is added under stirring Sour daunorubicin: n-hexane=1:10 (W/V, g/mL)) crystallization, solid midbody compound III is obtained after filtering 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: normal heptane are added into tri- neck glass reaction bottle of 1000mL =1:40 (W/V, g/mL)).It opens and stirs, after 15 DEG C of temperature control, 10~15 minutes, check material dissolution situation, if completely molten Xie Ze continues to stir；If being completely dissolved, feed liquid is cooled to 11 DEG C, the methanol solution (hydrochloric acid of camphorsulfonic acid is added thereto Daunorubicin: methanol: camphorsulfonic acid=1:200:3 (W/V/W, g/mL/g)), after stirring 1 hour, triethyl orthoformate is added (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 are answered, trifluoroacetic anhydride (daunorubicin hydrochloride: trifluoroacetic anhydride=1:7 (W/V, g/mL)) is added into bottle, adds Enter to finish, stir 1.5 hours.

Methanol (daunorubicin hydrochloride: methanol=1:50 (W/V, g/mL)) is added into reaction solution in end of reaction, stirring 15 After minute, 8% sodium bicarbonate solution is added and adjusts pH value to 8.5.15 DEG C~25 DEG C of temperature of control, insulated and stirred reaction 3~5 are small When.TLC detection: with chloroform/isopropanol (volume ratio 96/4) for solvent, detection raw material spot should disappear substantially.It is intermediate Body compound III Rf ≈ 0.3, daunorubicin hydrochloride Rf ≈ 0.Liquid separation is stood, lower layer's organic phase is collected.Concentration in vacuo is extremely Certain volume (daunorubicin hydrochloride: the volume of the concentrated liquid=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, solid midbody compound III, mass yield are obtained after filtering drying 90.0%.Purity 93.7%.

Embodiment five

The preparation of midbody compound IV:

Methylene chloride (intermediate III: methylene chloride: 1:40 (W/V, g/ is added into tri- neck glass reaction bottle of 1000mL mL)).Open stirring, -40 DEG C of temperature control, be slowly added to trifluoroacetic anhydride dichloromethane solution (intermediate III: trifluoroacetic anhydride: Methylene chloride=1:0.8:2.4 (W/W/V, g/g/mL)), after -40 DEG C are stirred to react 1 hour, it is slowly added dropwise into reaction solution The dichloromethane solution of intermediate of epirubicin hydrochloride III, (intermediate III: methylene chloride=1:5 (W/V, g/mL))；It has been added Finish, after twenty minutes, dichloromethane solution (intermediate III: 1,5- bis- of 1,5- diaza-bicyclo (4,3,0) nonyl- 5- alkene is added dropwise in stirring Two ring of nitrogen (4,3,0) nonyl- 5- alkene: methylene chloride=1:0.84:5 (W/W/V, g/g/mL)), addition finishes, it stirs after ten minutes, The dichloromethane solution (intermediate III: glacial acetic acid: methylene chloride=1:0.85:10 (W/V/V, g/mL/mL)) of glacial acetic acid is added, It is stirred to react 0.5 hour.

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

Embodiment six

The preparation of midbody compound IV:

Ethyl acetate (intermediate III: ethyl acetate: 1:20 (W/V/V, g/ is added into tri- neck glass reaction bottle of 1000mL mL/mL)).Stirring is opened, -70 DEG C of temperature control, is slowly added to the ethyl acetate solution (intermediate III: trifluoroacetic acid of trifluoroacetic anhydride Acid anhydride: ethyl acetate=1:0.5:3 (W/W/V, g/g/mL)), after -70 DEG C are stirred to react 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))；It has been added Finish, after twenty minutes, ethyl acetate solution (intermediate III: 1,5- bis- of 1,5- diaza-bicyclo (4,3,0) nonyl- 5- alkene is added dropwise in stirring Two ring of nitrogen (4,3,0) nonyl- 5- alkene: ethyl acetate=1:0.9:8 (W/W/V, g/g/mL)), addition finishes, it stirs after ten minutes, The ethyl acetate solution (intermediate III: malonic acid: ethyl acetate=1:0.9:14 (W/V/V, g/mL/mL)) of malonic acid is added, It is stirred to react 0.5 hour.

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

Embodiment seven

The preparation of midbody compound IV:

DMF (intermediate III: DMF=1:50 (W/V/V, g/mL/mL)) is added into tri- neck glass reaction bottle of 1000mL.It opens Stirring is opened, -30 DEG C of temperature control, is slowly added to the DMF solution (intermediate III: trifluoroacetic anhydride: DMF=1:0.4:4 of trifluoroacetic anhydride (W/W/V, g/g/mL)), after -30 DEG C are stirred to react 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 twenty minutes, 1,5- phenodiazine is added dropwise in stirring Two rings (4,3,0) nonyl- 5- alkene DMF solution (III: 1,5- diaza-bicyclo of intermediate (4,3,0) nonyl- 5- alkene: DMF=1:0.95: 10 (W/W/V, g/g/mL)), addition finishes, and after ten minutes, the DMF solution (intermediate III: malonic acid: DMF of formic acid is added in stirring =1:0.9:16 (W/V/V, g/mL/mL)), it is stirred to react 0.5 hour.

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

Embodiment eight

The preparation of midbody compound V:

The methylene chloride, (intermediate IV: methylene chloride=1:40 of intermediate IV are added into tri- neck glass reaction bottle of 1000mL (W/V, g/mL)).Stirring is opened, -60 DEG C of temperature control, the ethanol solution of sodium borohydride is added dropwise, (intermediate IV: sodium borohydride: anhydrous Ethyl alcohol=1:0.02:100 (W/W/V, g/g/mL)), addition finishes, and after being stirred to react 0.5 hour, acetone is added into reaction solution (intermediate IV: acetone=1:1 (W/V, g/mL)) continues stirring 20 minutes.

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

Embodiment nine

The preparation of midbody compound V:

The acetone, (intermediate IV: acetone=1:50 (W/V, g/ of intermediate IV are added into tri- neck glass reaction bottle of 1000mL mL)).Stirring is opened, -30 DEG C of temperature control, the ethanol solution of tetrahydrochysene lithium aluminium is added dropwise, (intermediate IV: tetrahydrochysene lithium aluminium: dehydrated alcohol= 1:0.04:80 (W/W/V, g/g/mL)), addition finishes, and after being stirred to react 1 hour, acetone (intermediate is added into reaction solution IV: acetone=1:2 (W/V, g/mL)), continue stirring 20 minutes.

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

Embodiment ten

The preparation of midbody compound V:

The tetrahydrofuran, (intermediate IV: tetrahydrofuran=1:60 of intermediate IV are added into tri- neck glass reaction bottle of 1000mL (W/V, g/mL)).Stirring is opened, -75 DEG C of temperature control, the ethanol solution of sodium cyanoborohydride is added dropwise, (intermediate IV: cyano boron hydrogen Change sodium: dehydrated alcohol=1:0.06:70 (W/W/V, g/g/mL)), addition finishes, and after being stirred to react 1 hour, adds into reaction solution Enter acetone (intermediate IV: acetone=1:4 (W/V, g/mL)), continues stirring 20 minutes.

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

Embodiment 11

The preparation of midbody compound V:

The hexamethylene, (intermediate IV: hexamethylene=1:40 (W/ of intermediate IV are added into tri- neck glass reaction bottle of 1000mL V, g/mL)).Stirring is opened, 5 DEG C of temperature control, the ethanol solution of lithium triethylborohydride is added dropwise, (intermediate IV: boron triethyl hydrogenation Lithium: dehydrated alcohol=1:0.02:100 (W/W/V, g/g/mL)), addition finishes, after being stirred to react 1.5 hours, into reaction solution It is added acetone (intermediate IV: acetone=1:4 (W/V, g/mL)), continues stirring 20 minutes.

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

Embodiment 12

The preparation of midbody compound VI:

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

Dichloromethane solution (the intermediate V: methanol: methylene chloride=1:60:8 (W/V/ of methanol is added into reaction solution V, g/mL/mL)), stirring is opened, and 0.5mol/L sodium bicarbonate solution is added dropwise and adjusts pH value to 7.6~7.8.Finally use 0.5mol/L sodium carbonate liquor adjusts pH value to 8.0~8.2.Liquid separation is stood, organic phase is collected, concentration in vacuo is to certain Volume (intermediate V: the volume of the concentrated liquid=1:10 (W/V, g/mL)), be added under stirring n-hexane (intermediate V: just oneself Alkane=1:10 (W/V, g/mL)) crystallization, solid midbody compound VI, mass yield 94.6% are obtained after filtering 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: purified water=1:40 (W/ of intermediate V are added into tri- neck glass reaction bottle of 1000mL V, g/mL)).Stirring is opened, 10 DEG C of temperature control, sodium hydroxide solution is added dropwise, (intermediate V: sodium hydroxide: purified water=1:0.4: 14 (W/W/V, g/g/mL)), addition finishes, be stirred to react 0.5 hour, TLC detection: with chloroform/isopropanol (volume ratio= It 96/4) is solvent, detection V spot of intermediate should disappear substantially, V Rf ≈ 0.25 of intermediate, VI Rf ≈ 0 of intermediate.

Dichloromethane solution (the intermediate V: methanol: methylene chloride=1:40:10 (W/V/ of methanol is added into reaction solution V, g/mL/mL)), stirring is opened, and 0.5mol/L sodium bicarbonate solution is added dropwise and adjusts pH value to 7.6~7.8.Finally use 0.5mol/L sodium carbonate liquor adjusts pH value to 8.0~8.2.Liquid separation is stood, organic phase is collected, concentration in vacuo is to certain Volume (intermediate V: the volume of the concentrated liquid=1:10 (W/V, g/mL)), be added under stirring n-hexane (intermediate V: just oneself Alkane=1:10 (W/V, g/mL)) crystallization, solid midbody compound VI, mass yield 93.1% are obtained after filtering 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: purified water=1:70 (W/ of intermediate V are added into tri- neck glass reaction bottle of 1000mL V, g/mL)).Stirring is opened, 20 DEG C of temperature control, sodium bicarbonate solution is added dropwise, (intermediate V: sodium bicarbonate: purified water=1:1.5: 10 (W/W/V, g/g/mL)), addition finishes, be stirred to react 1 hour, TLC detection: with chloroform/isopropanol (volume ratio= It 96/4) is solvent, detection V spot of intermediate should disappear substantially, V Rf ≈ 0.25 of intermediate, VI Rf ≈ 0 of intermediate.

Dichloromethane solution (the intermediate V: methanol: methylene chloride=1:35:15 (W/V/ of methanol is added into reaction solution V, g/mL/mL)), stirring is opened, and 0.5mol/L sodium bicarbonate solution is added dropwise and adjusts pH value to 7.6~7.8.Finally use 0.5mol/L sodium carbonate liquor adjusts pH value to 8.0~8.2.Liquid separation is stood, organic phase is collected, concentration in vacuo is to certain Volume (intermediate V: the volume of the concentrated liquid=1:10 (W/V, g/mL)), be added under stirring n-hexane (intermediate V: just oneself Alkane=1:10 (W/V, g/mL)) crystallization, solid midbody compound VI, mass yield 92.1% are obtained after filtering 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: purified water=1:30 (W/ of intermediate V are added into tri- neck glass reaction bottle of 1000mL V, g/mL)).Stirring is opened, controls 25 DEG C, calcium hydroxide solution, (intermediate V: calcium hydroxide: purified water=1:1.1:10 is added dropwise (W/W/V, g/g/mL)), addition finishes, be stirred to react 1.5 hours, TLC detection: with chloroform/isopropanol (volume ratio= It 96/4) is solvent, detection V spot of intermediate should disappear substantially, V Rf ≈ 0.25 of intermediate, VI Rf ≈ 0 of intermediate.

Dichloromethane solution (the intermediate V: methanol: methylene chloride=1:65:15 (W/V/ of methanol is added into reaction solution V, g/mL/mL)), stirring is opened, and 0.5mol/L sodium bicarbonate solution is added dropwise and adjusts pH value to 7.6~7.8.Finally use 0.5mol/L sodium carbonate liquor adjusts pH value to 8.0~8.2.Liquid separation is stood, organic phase is collected, concentration in vacuo is to certain Volume (intermediate V: the volume of the concentrated liquid=1:12 (W/V, g/mL)), be added under stirring n-hexane (intermediate V: just oneself Alkane=1:8 (W/V, g/mL)) crystallization, solid midbody compound VI, mass yield 91.2% are obtained after filtering 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: methanol=1:40 (W/V, g/ of intermediate VI are added into tri- neck glass reaction bottle of 1000mL mL)).Stirring is opened, 15 DEG C of temperature control, the methanol solution (bromination of intermediate VI: 4% of 4% hydrogen bromide is added dropwise into reaction solution Methanol solution=1:4 (W/V, g/mL) of hydrogen), it is added dropwise, stirring after twenty 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)), is added dropwise, and insulated and stirred is reacted 2 hours.Reaction terminates Afterwards, sodium sulfite solution (intermediate VI: sodium hydrogensulfite: purified water=1:0.05:0.5 (W/W/V, g/ is added into reaction solution G/mL)), after ten minutes, adjusting pH with ammonium hydroxide is 4.5~5.0 for stirring, is stirred to react after ten minutes, with 7% hydrochloric acid solution tune Saving pH is 1.3~1.5, is reacted 2 hours in 25 DEG C~35 DEG C insulated and stirreds.Reaction terminates, and 25% aqueous sodium formate solution is added, Adjusting pH is 3.0~3.5, 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.

Methylene chloride and purified water are added in reaction solution (intermediate VI: purified water: methylene chloride=1:60:30 (W/ V/V, g/mL/mL)), stand liquid separation after stirring, water intaking mutually with dichloromethane solution extraction three times (intermediate VI: methylene chloride= 1:30 (W/V, g/mL)), merge organic phase, concentration in vacuo to certain volume (intermediate VI: the volume of the concentrated liquid=1:10 (W/V, g/mL)), n-hexane (intermediate VI: n-hexane=1:10 (W/V, g/mL)) crystallization is added under stirring, filters dry Solid epirubicin hydrochloride I, mass yield 94.1% are obtained after dry.Product is red powder, and purity 98.7% meets pharmacopeia and wants Ask: if any impurity peaks in test solution chromatogram, Doxorubicin ketone (relative retention time about 0.3) is by the peak area after correction It calculates (multiplied by correction factor 0.7), is not greater than contrast solution main peak area (1.0%), (relative retention time is about for Doxorubicin 0.8) peak area is not greater than contrast solution main peak area (1.0%), other single impurity peak areas are not greater than comparison liquid master 0.5 times (0.5%) of peak area, the sum of each impurity peak area are not greater than 2 times (2.0%) of comparison liquid main peak area.

Embodiment 17

The preparation of epirubicin hydrochloride I:

Isosorbide-5-Nitrae-dioxane, (intermediate VI: Isosorbide-5-Nitrae-dioxy six of intermediate VI are added into tri- neck glass reaction bottle of 1000mL Ring=1:60 (W/V, g/mL)).Stirring is opened, 0 DEG C of temperature control, Isosorbide-5-Nitrae-dioxane of 4% hydrogen bromide is added dropwise into reaction solution Solution (Isosorbide-5-Nitrae of the hydrogen bromide of intermediate VI: 4%-dioxane solution=1:8 (W/V, g/mL)), is added dropwise, and stirs 20 points Isosorbide-5-Nitrae-dioxane solution (intermediate VI: bromine: Isosorbide-5-Nitrae-dioxane=1:0.2:8 (W/ of bromine is added dropwise into reaction solution by Zhong Hou W/V, g/g/mL)), it is added dropwise, insulated and stirred is reacted 2.5 hours.After reaction, 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)) uses hydroxide after stirring 15 minutes It is 4.5~5.0 that potassium solution (intermediate V: potassium hydroxide: purified water=1:0.25:10 (W/W/V, g/g/mL)), which adjusts PH, is stirred Mix reaction after ten minutes, adjusting PH with 7% phosphoric acid solution is 1.3~1.5, small in 25 DEG C~35 DEG C insulated and stirred reactions 2.5 When.Reaction terminates, and 20% aqueous sodium formate solution is added, and adjusting 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 I crude product solution of target compound epirubicin hydrochloride.

Methylene chloride and purified water are added in reaction solution (intermediate VI: purified water: methylene chloride=1:40:40 (W/ V/V, g/mL/mL)), stand liquid separation after stirring, water intaking mutually with dichloromethane solution extraction three times (intermediate VI: methylene chloride= 1:40 (W/V, g/mL)), merge organic phase, concentration in vacuo to certain volume (intermediate VI: the volume of the concentrated liquid=1:10 (W/V, g/mL)), n-hexane (intermediate VI: n-hexane=1:10 (W/V, g/mL)) crystallization is added under stirring, filters dry Solid epirubicin hydrochloride I, mass yield 92.2% are obtained after dry.Product is red powder, and purity 98.1% meets pharmacopeia and wants Ask: if any impurity peaks in test solution chromatogram, Doxorubicin ketone (relative retention time about 0.3) is by the peak area after correction It calculates (multiplied by correction factor 0.7), is not greater than contrast solution main peak area (1.0%), (relative retention time is about for Doxorubicin 0.8) peak area is not greater than contrast solution main peak area (1.0%), other single impurity peak areas are not greater than comparison liquid master 0.5 times (0.5%) of peak area, the sum of each impurity peak area are not greater than 2 times (2.0%) of comparison liquid main peak area.

Embodiment 18

The preparation of epirubicin hydrochloride I:

The trichloro ethylene, (intermediate VI: trichloro ethylene=1:40 of intermediate VI are added into tri- neck glass reaction bottle of 1000mL (W/V, g/mL)).Stirring is opened, 30 DEG C of temperature control, the trichloro ethylene solution (intermediate of 4% hydrogen bromide is added dropwise into reaction solution The trichloro ethylene solution of VI: 4% hydrogen bromide=1:4 (W/V, g/mL)), it is added dropwise, stirs after twenty minutes, into reaction solution The trichloro ethylene solution (intermediate VI: bromine: trichloro ethylene=1:0.5:5 (W/W/V, g/g/mL)) of bromine is added dropwise, is added dropwise, protects Temperature is stirred to react 3 hours.After reaction, ferrous sulfate solution (intermediate VI: ferrous sulfate: purifying is added into reaction solution Water=1:0.05:0.5 (W/W/V, g/g/mL)), stirring after ten minutes, with potassium hydroxide solution (intermediate V: potassium hydroxide: Purified water=1:0.25:10 (W/W/V, g/g/mL)) adjust PH be 4.5~5.0, be stirred to react after ten minutes, with 7% phosphoric acid It is 1.3~1.5 that solution, which adjusts pH, is reacted 2 hours in 25 DEG C~35 DEG C insulated and stirreds.Reaction terminates, and 30% sodium formate is added Aqueous solution, adjusting pH is 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 I crude product solution of star.

Methylene chloride and purified water are added in reaction solution (intermediate VI: purified water: methylene chloride=1:65:45 (W/ V/V, g/mL/mL)), stand liquid separation after stirring, water intaking mutually with dichloromethane solution extraction three times (intermediate VI: methylene chloride= 1:45 (W/V, g/mL)), merge organic phase, concentration in vacuo to certain volume (intermediate VI: the volume of the concentrated liquid=1:8 (W/V, g/mL)), n-hexane (intermediate VI: n-hexane=1:12 (W/V, g/mL)) crystallization is added under stirring, filters dry Solid epirubicin hydrochloride I, mass yield 91.2% are obtained after dry.Product is red powder, and purity 97.8% meets pharmacopeia and wants Ask: if any impurity peaks in test solution chromatogram, Doxorubicin ketone (relative retention time about 0.3) is by the peak area after correction It calculates (multiplied by correction factor 0.7), is not greater than contrast solution main peak area (1.0%), (relative retention time is about for Doxorubicin 0.8) peak area is not greater than contrast solution main peak area (1.0%), other single impurity peak areas are not greater than comparison liquid master 0.5 times (0.5%) of peak area, the sum of each impurity peak area are not greater than 2 times (2.0%) of comparison liquid main peak area.

Embodiment 19

The preparation of epirubicin hydrochloride I:

The heptane, (intermediate VI: heptane=1:70 (W/V, g/ of intermediate VI are added into tri- neck glass reaction bottle of 1000mL mL)).Stirring is opened, 35 DEG C of temperature control, the n-heptane solution (bromination of intermediate VI: 4% of 4% hydrogen bromide is added dropwise into reaction solution N-heptane solution=1:2 (W/V, g/mL) of hydrogen), it is added dropwise, stirring after twenty 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)), is added dropwise, and insulated and stirred is reacted 1.5 hours.Reaction After, into reaction solution be added ferrous sulfate solution (intermediate VI: ferrous sulfate: purified water=1:0.09:0.9 (W/W/V, G/g/mL)), stirring after ten minutes, with potassium hydroxide solution (intermediate V: potassium hydroxide: purified water=1:0.2:6 (W/W/V, G/g/mL)) adjusting PH is 4.0~4.5, after being stirred to react 15 minutes, and adjusting PH with 12% phosphoric acid solution is 1.1~1.2, in 25 DEG C~35 DEG C insulated and stirreds are reacted 2 hours.Reaction terminates, and 35% aqueous sodium formate solution is added, and adjusting PH is 2.5~3.0, 25~35 DEG C of sodium formates of temperature control hydrolyze 1 hour, final to obtain I crude product solution of target compound epirubicin hydrochloride.

Methylene chloride and purified water are added in reaction solution (intermediate VI: purified water: methylene chloride=1:35:50 (W/ V/V, g/mL/mL)), stand liquid separation after stirring, water intaking mutually with dichloromethane solution extraction three times (intermediate VI: methylene chloride= 1:50 (W/V, g/mL)), merge organic phase, concentration in vacuo to certain volume (intermediate VI: the volume of the concentrated liquid=1:15 (W/V, g/mL)), n-hexane (intermediate VI: n-hexane=1:15 (W/V, g/mL)) crystallization is added under stirring, filters dry Solid epirubicin hydrochloride I, mass yield 90.0% are obtained after dry.Product is red powder, and purity 97.2% meets pharmacopeia and wants Ask: if any impurity peaks in test solution chromatogram, Doxorubicin ketone (relative retention time about 0.3) is by the peak area after correction It calculates (multiplied by correction factor 0.7), is not greater than contrast solution main peak area (1.0%), (relative retention time is about for Doxorubicin 0.8) peak area is not greater than contrast solution main peak area (1.0%), other single impurity peak areas are not greater than comparison liquid master 0.5 times (0.5%) of peak area, the sum of each impurity peak area are not greater than 2 times (2.0%) of comparison liquid main peak area.

Embodiment 20

The preparation of epirubicin hydrochloride I:

250mL purified water is added into reaction solution after reaction, after adjusting pH to 3 with dilute hydrochloric acid, concentration, by concentrate It after suction filtration, is separated with cation exchange resin, is concentrated to dryness after collecting principal component, it is final to obtain I solid of epirubicin hydrochloride, Mass yield 85.9%.Product is red powder, and purity 96.1% meets pharmacopoeial requirements: in test solution chromatogram if any Impurity peaks, Doxorubicin ketone (relative retention time about 0.3) is by the calculated by peak area (multiplied by correction factor 0.7) after correction, no It obtains and is greater than contrast solution main peak area (1.0%), it is molten that Doxorubicin (relative retention time about 0.8) peak area is not greater than control Liquid main peak area (1.0%), other single impurity peak areas are not greater than 0.5 times (0.5%) of comparison liquid main peak area, each miscellaneous The sum of mass peak area is not greater than 2 times (2.0%) of comparison liquid main peak area.

Embodiment 21

Weighing 4 '-epirubicin 6.7g adds 67mL methanol to dissolve at room temperature, is added after Isosorbide-5-Nitrae-dioxane 67mL again 6mL methyl formate and 0.73mL bromine is added, after reacting 1h, 2.16mL acidification propylene oxide is added and persistently stirs 30min, by this Reaction solution is concentrated into 65mL, and 740mL isopropanol crystallization is added after being concentrated after cooling, backward precipitating in addition 150mL it is different Propanol rinse crystal, by crystal it is sufficiently dry after, with the dissolution of 142mL water, be added the 146mL acetone soln of 4.2mL hydrogen bromide into Row acidification, reacts 18h at room temperature, the solution reaction of 10g sodium formate and 42mL water is added into reaction solution for 24 hours, with dilute hydrochloric acid tune PH to 5 is saved, lasting stirring later is for 24 hours.250mL purified water is added into reaction solution after reaction, pH to 3 is adjusted with dilute hydrochloric acid Afterwards, it is concentrated, after concentrate is filtered, is separated with cation exchange resin, is concentrated to dryness after collecting principal component, it is final to obtain salt Sour I solid of epirubicin, mass yield 59.7%, purity 90.1%.

Embodiment 22

Weighing 4 '-epirubicin 6.7g adds 67mL methanol to dissolve at room temperature, is added after Isosorbide-5-Nitrae-dioxane 67mL again 6mL methyl formate and 0.73mL bromine is added, after reacting 1h, 2.16mL acidification propylene oxide is added and persistently stirs 30min, by this Reaction solution is concentrated into 65mL, and 740mL isopropanol crystallization is added after being concentrated after cooling, backward precipitating in addition 150mL it is different Propanol rinse crystal, by crystal it is sufficiently dry after, with the dissolution of 142mL water, be added the 146mL acetone soln of 4.2mL hydrogen bromide into Row acidification, reacts 18h at room temperature, the solution reaction of 10g sodium formate and 42mL water is added into reaction solution for 24 hours, with dilute hydrochloric acid tune PH to 5 is saved, lasting stirring later is for 24 hours.

Methylene chloride and purified water are added in reaction solution after reaction (intermediate VI: purified water: methylene chloride= 1:35:50 (W/V/V, g/mL/mL)), stand liquid separation after stirring, water intaking mutually with dichloromethane solution extraction three times (intermediate VI: Methylene chloride=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: n-hexane=1:15 (W/V, g/mL)) analysis is added under stirring Crystalline substance obtains I solid of epirubicin hydrochloride, mass yield 66.4% after filtering drying.Product is red powder, and purity 90.2% is full Sufficient pharmacopoeial requirements: if any impurity peaks in test solution chromatogram, after Doxorubicin ketone (relative retention time about 0.3) is by correction Calculated by peak area (multiplied by correction factor 0.7), be not greater than contrast solution main peak area (1.0%), Doxorubicin is (opposite to protect Staying the time, about 0.8) peak area is not greater than contrast solution main peak area (1.0%), other single impurity peak areas are not greater than 0.5 times (0.5%) of comparison liquid main peak area, the sum of each impurity peak area are not greater than 2 times of comparison liquid main peak area (2.0%).

Embodiment 23

Synthetic route

Specific preparation method:

The preparation of midbody compound III:

In tri- bottle glass reaction flask of 1000mL, daunorubicin hydrochloride (5g, 8.63mmol) is suspended in methylene chloride (200mL；Intermediate II: methylene chloride=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: trifluoroacetic anhydride=1:1.4 (W/V, g/mL)) methylene chloride (15mL；Intermediate II: methylene chloride=1:3 (W/V, g/mL)) solution, drop is complete, and equality of temperature reacts 0.5h, and it is pure that 250mL is added later Change water (intermediate II: purified water=1:50 (W/V, g/mL)), sufficiently shakes up rear stratification and collect organic phase, be added thereto Saturated sodium bicarbonate solution 200mL (intermediate II: saturated sodium bicarbonate solution=1:40 (W/V, g/mL)), puts after sufficiently shaking up It to room temperature, is vigorously stirred 15-24 hours, separates to obtain organic phase 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 tri- neck glass reaction bottle of 500mL, 5mL DMSO is dissolved in 100mL methylene chloride (intermediate III: DMSO: methylene chloride=1:1:20 (W/V/V, g/mL/mL)), it is sufficiently stirred and the solution is cooled to -60 DEG C, be added later Oxalyl chloride and 5mL the dichloromethane solution (intermediate III: oxalyl chloride: methylene chloride=1:0.2:1 (W/V/V, g/mL/ of 1mL ML)), -60 DEG C of insulated and stirreds are reacted 40 minutes later.The intermediate III of 5g is dissolved in 50mL methylene chloride (intermediate III: two Chloromethanes=1:10 (W/V, g/mL)), this solution is added in 20 minutes into above-mentioned coolant liquid, maintains temperature in the process - 60 ± 5 DEG C of degree reacts 1 hour at this temperature, 7mL triethylamine (intermediate III: three is added in 10 minutes after reaction Ethamine=1:1.4 (W/V, g/mL)), this process keeps temperature≤- 60 DEG C.5mL glacial acetic acid is dissolved in 10mL methylene chloride (intermediate III: glacial acetic acid: methylene chloride=1:1:2 (W/V/V, g/mL/mL)), stirring 2 after this solution is added in reaction solution Minute, then 300mL purified water (intermediate III: purified water=1:60 (W/V, g/mL)) is added into reaction solution, after being sufficiently stirred Settle and separate 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 intermediate IV, quality yield 88.0%, purity 82.2% are obtained eventually.

The preparation of midbody compound V:

In tri- neck glass reaction bottle of 1000mL, 4.7g intermediate IV is dissolved in (intermediate in 180mL tetrahydrofuran IV: tetrahydrofuran=1:38.3 (W/V, g/mL)), open stirring after in 40 minutes be added 2.1g sodium triethylborohydride (in Mesosome IV: sodium triethylborohydride=1:1.5 (W/W, g/g)), it finishes, is stirred to react at 20 ± 2 DEG C 1 hour, reaction terminates This reaction solution is added to afterwards in the hydrochloric acid mixed solution of 150mL methylene chloride, 300mL purified water and 2mL 1mol/L (intermediate IV: Methylene chloride: purified water: hydrochloric acid=1:32:63.8:0.43 (W/V/V/V, g/mL/mL/mL) of 1mol/L), after being sufficiently stirred It stands, obtains organic phase, and organic phase 2 is washed with 300mL purified water (intermediate IV: purified water=1:63.8 (W/V, g/mL)) It is secondary, organic phase is concentrated to dryness to obtain V 4.6g of intermediate, 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 V 3.0g of intermediate, quality Yield 65.2%, purity 94%.

The preparation of midbody compound VI:

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

The preparation of epirubicin hydrochloride I:

In tri- neck glass reaction bottle of 1000mL, 2.1g intermediate VI is dissolved in 70mL DMF (intermediate VI: DMF= 1:33.3 (W/V, g/mL)) in, the backward solution in be added 2.8g bis- (n,N-dimethylacetamide) two bromo bromic acid hydrogen salt (intermediate VI: bis- (n,N-dimethylacetamide) two bromo bromic acid hydrogen salts=1:1.3 (W/W, g/g)), in 40 DEG C of insulation reactions 2 Hour, 350mL acetonitrile (intermediate VI: acetonitrile=1:167 (W/V, g/mL)) is added into reaction solution after reaction, filters institute It must precipitate, and be washed and precipitated with acetonitrile repeatedly, the bromination of 80mL acetone, 80mL 0.25mol/L is dissolved in after sediment is dried In the mixed liquor of aqueous solution of hydrogen and 8g sodium formate (intermediate VI: acetone: the aqueous solution of hydrogen bromide of 0.25mol/L: sodium formate=1: 38:38:3.8 (W/V/V/W, g/mL/mL/g)), it is stirred to react at 35 DEG C 30 hours, after reaction, yield 40.9% is pure Degree 60.2%.

Reaction solution is separated through preparative high performance liquid chromatography, main peak fraction is collected, third is added after being concentrated to dryness Ketone recrystallization, it is final to obtain 1.3g epirubicin hydrochloride, mass yield 61.9%, final mass yield 25.3%, purity 99.8%.

Embodiment 24

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

The preparation of epirubicin hydrochloride I:

In tri- neck glass reaction bottle of 1000mL, 35.2g intermediate VI (49.6mmol) is dissolved in the anhydrous dichloromethane of 321mL In alkane (intermediate VI: methylene chloride=1:9.1 (W/V, g/mL)), 19.7g anhydrous pyridine (249.4mmol is added；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 Sulphonic acid anhydride (99.6mmol) anhydrous methylene chloride (30mL) (intermediate VI: trifluoromethanesulfanhydride anhydride: anhydrous methylene chloride=1: 0.8:0.85 (W/W/V, g/g/mL)) solution, drop finishes, equality of temperature the reaction was continued 1h.Previously prepared triethylammonium formate is added Dichloromethane solution (triethylamine 62.7g, anhydrous formic acid 28.7g, anhydrous methylene chloride 209mL；Intermediate VI: triethylamine: 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 are added - 10~-5 DEG C are cooled to after 562mL methanol (intermediate VI: methanol=1:16 (W/V, g/mL)), the 1.6mol/L of 950g is added Sodium hydroxide solution (VI: 1.6mol/L sodium hydroxide solution of intermediate=1:27 (W/W, g/g)), equality of temperature react 6h.It is added 3mol/L hydrochloric acid 621mL (VI: 3mol/L hydrochloric acid of intermediate=1:17.6 (W/V, g/mL)) is stirred anti-after being warming up to 10~15 DEG C 7h is answered, after reaction stratification, water phase 562mL methylene chloride (intermediate VI: methylene chloride=1:16 (W/V, g/ ML it)) washes twice, merges organic phase, then washed twice with 562mL water (intermediate VI: water=1:16 (W/V, g/mL)), merge It is soft to obtain hydrochloric acid table through NM100 macroporous absorbent resin adsorption and purification [eluent is acetonitrile: pH=4.5 aqueous solution (6:1)] for water phase Than star crude product 16.8g, mass yield 47.7%, purity 90.1%.Crude product is through NM100 large pore resin absorption column chromatography [mobile phase For acetonitrile: pH=4.5 aqueous solution (1:7.3)] it purifies 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 epirubicin hydrochloride compound is shown in Formula V, structural formula is as follows:

。

2. a kind of preparation method of compound V described in claim 1, which is characterized in that preparation method includes the following steps: to walk Rapid 1 addition methanol, acidic catalyst, esterifying reagent B make daunorubicin hydrochloride II generation not separate centre with ketal structure Body compound II-1 is protected with active amino of the trifluoroacetic anhydride to sugar moiety in the intermediate structure, is generated not Isolated intermediate compound III；Step 2 is further dehydrated, and the alcoholic extract hydroxyl group of amino sugar structure is oxidized to carbonyl, generation does not separate Midbody compound IV；Step 3 using selective reduction agent D by the carbonyl reduction in amino sugar as hydroxyl, be converted into have with The opposite midbody compound V of daunorubicin amino sugar structure 4-OH configuration,

It includes following synthetic route that step 1 compound II, which synthesizes compound III:

It includes following synthetic route that step 2 compound III, which synthesizes compounds Ⅳ:

It includes following synthetic route that step 3 compounds Ⅳ, which synthesizes compound V:

。

3. preparation method according to claim 2, which is characterized in that step 1 compound ii synthesis compound III specifically includes Following steps: in organic solvent A, methanol, acidic catalyst, esterifying reagent B, daunorubicin hydrochloride II is added, reaction 2 is small When, generate have ketal structure non-separation of intermediates compound ii -1, backward reaction system in trifluoroacetic anhydride is added, stir Reaction 1 hour is mixed, the midbody compound III with amino trifluoroacetic acid ester structure is generated.

4. the preparation method according to Claims 2 or 3, which is characterized in that the temperature reacted with esterifying reagent B be 0~ 10℃。

5. the preparation method according to Claims 2 or 3, which is characterized in that the temperature reacted with esterifying reagent B is 5 DEG C.

6. preparation method according to claim 3, which is characterized in that the esterifying reagent B is selected from triethyl orthoformate or original Trimethyl orthoformate.

7. preparation method according to claim 2, which is characterized in that step 2 compound III synthesis compounds Ⅳ specifically includes Following steps: in organic solvent A, trifluoroacetic anhydride is added, addition finishes, is stirred to react 1 hour, intermediate is then added Object III and 1 is closed, the alcoholic extract hydroxyl group of amino sugar structure is oxidized to by 5- diaza-bicyclo (4,3,0) nonyl- 5- alkene reaction 0 .5 hours Carbonyl, backward reaction system in be added organic acid C, be stirred to react 0 .5 hour, generation midbody compound IV.

8. preparation method according to claim 7, which is characterized in that described and 1,5- diaza-bicyclo (4,3,0) nonyl- 5- The reaction temperature of alkene reaction is 0 DEG C~-75 DEG C.

9. preparation method according to claim 7, which is characterized in that described and 1,5- diaza-bicyclo (4,3,0) nonyl- 5- - 40 DEG C~-70 DEG C of the reaction temperature of alkene reaction.

10. preparation method according to claim 7, which is characterized in that the organic acid C is selected from formic acid, acetic acid, propionic acid, fourth It is acid, octanoic acid, adipic acid, ethanedioic acid, malonic acid, succinic acid, maleic acid, tartaric acid, benzoic acid, phenylacetic acid, phthalic acid, right One of phthalic acid, valeric acid, caproic acid, capric acid, stearic acid, palmitic acid, acrylic acid are a variety of.

11. preparation method according to claim 2, which is characterized in that step 3 compounds Ⅳ synthesis compound V specifically includes Following steps: in organic solvent A, midbody compound IV is reacted 0 .5 hours with reducing agent D, by the carbonyl in amino sugar It is reduced to hydroxyl, being converted into has the midbody compound V opposite with daunorubicin amino sugar structure 4-OH configuration.

12. preparation method according to claim 11, which is characterized in that the temperature reacted with reducing agent D be 0 DEG C~- 75℃。

13. preparation method according to claim 11, which is characterized in that the temperature reacted with reducing agent D is -30 DEG C ~-60 DEG C.

14. preparation method according to claim 11, which is characterized in that the reducing agent D be selected from sodium hydride, tetrahydrochysene lithium aluminium, One of sodium borohydride, lithium hydride, double methoxyethoxy alanates, lithium triethylborohydride, sodium cyanoborohydride are more Kind.

15. according to claim 3 or 7 or 11 preparation methods, which is characterized in that the organic solvent A be selected from arene, One of fat hydrocarbon, halogenated hydrocarbons, alcohols, ethers, amides, esters solvent and phenol.

16. according to claim 3 or 7 or 11 preparation methods, which is characterized in that the organic solvent A be selected from benzene, toluene, Hexamethylene, methanol, ethyl alcohol, the tert-butyl alcohol, methylene chloride, Isosorbide-5-Nitrae-dioxane, ether, acetone, trichloro ethylene, tetrahydrofuran, first One of base tertbutyl ether, ethyl acetate and DMF or a variety of.