CN106749447A - A kind of intermediate of epirubicin hydrochloride compound - Google Patents

A kind of intermediate of epirubicin hydrochloride compound Download PDF

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CN106749447A
CN106749447A CN201710016793.XA CN201710016793A CN106749447A CN 106749447 A CN106749447 A CN 106749447A CN 201710016793 A CN201710016793 A CN 201710016793A CN 106749447 A CN106749447 A CN 106749447A
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solution
reaction
stirring
acid
dichloromethane
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CN106749447B (en
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张贵民
刁玉林
孟凡波
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Lunan Pharmaceutical Group Corp
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Lunan Pharmaceutical Group Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/24—Condensed ring systems having three or more rings
    • C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/06—Separation; Purification

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, is easily decomposed, the relatively low problem of overall route yield, for more preferable energy-saving and emission-reduction, this route uses the reagent being easy to get with low 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 is as follows：
It is the isomer of adriamycin, mechanism of action is directly embedded between DNA core alkali pair, disturbs transcription, resistance The only formation of tumour cell mRNA, so as to suppress the synthesis of DNA and RNA.Additionally, epirubicin hydrochloride is to topoisomeraseⅡ There is inhibitory action.It is a cell cycle nonspecific agent (CCNSA), it is effective to various transplanted tumors.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, can be used for breast cancer, pernicious pouring 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 can be used for treat lung cancer and oophoroma.Therefore play the part of more and more important role in human anti-tumor's clinical practice, clinic is needed 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：
Be raw material with 4 '-EPIDNR, reaction obtains brominated product under methyl formate and bromine effect, then successively with Bromo ketone intermediate is prepared into after expoxy propane, hydrogen bromide hydrolysis, finally successively with sodium acid carbonate, NaOH and sodium chloride water Solution is hydrolyzed to obtain epirubicin hydrochloride.Used such as expoxy propane organic solvent is to producer's body and mind in this method Health produces high risks, and the waste liquid for producing to be difficult to process, huge to environmental pressure；Meanwhile, last hydrolysis stage is used Multi-step, the condition of difference pH hydrolysis, it is difficult to precise control, thus technology to operator proposes high requirement, 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 defect that 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 various epirubicin hydrochlorides, and composition principle is not quite similar, but Substantially all employ first with the processing method of sodium triacetoxy borohydride reduction amination, the intermediate bromine that will be generated again afterwards Change, the mode of sodium formate hydrolysis obtains final product epirubicin hydrochloride, the more traditional organic synthesis reagent of the reagent cost is high, and Institute is difficult to preserve using reagent under workshop condition, is susceptible to industrial accident, is unsuitable for industrialized production reality.
Therefore, it is problematic in that in epirubicin hydrochloride preparation method in sum, or yield is low, impurity big, or Person's technical requirements are high, environmental pollution is serious, production cost is high, and in the prior art epirubicin hydrochloride preparation method generation 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, of the invention to provide 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 has used the organic reagent of economy, 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 is realized especially by following technical scheme：
A kind of intermediate of epirubicin hydrochloride compound, is that structural formula is as follows shown in formula II -1：
The preparation method of a kind 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 generate with ketal structure midbody compound II -1；
Compound ii synthesis compound ii -1 specifically includes following steps：In organic solvent A, methyl alcohol, acidity is added to urge Agent, esterifying reagent B, daunorubicin hydrochloride II, react 2~3 hours, and 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, methyl alcohol, 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 includes following steps：It is to add in three neck glass reaction bottles Enter organic solvent A and daunorubicin hydrochloride II.Stirring is opened, 5~10 DEG C of temperature control after 10~15 minutes, checks material dissolution feelings Condition, continues 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, adds esterifying reagent B；Addition is finished, and is stirred 2~3 hours.Preferably, the organic solvent A Consumption be：(part is represented with (W/V, g/mL) below), daunorubicin hydrochloride in terms of weight g/ volumes mL：Organic solvent A= 1:50~70, preferably 1:60；The organic solvent A be preferably one kind in methyl alcohol, dichloromethane and 1,4- dioxane or It is various.
The acidic catalyst methanol solution consumption of the addition is：Daunorubicin hydrochloride：Methyl alcohol：Acidic catalyst=1: 177~200:1~3 (W/V/W, g/mL/g), acidic catalyst is preferably camphorsulfonic acid or p-methyl benzenesulfonic acid.
Preferably, the consumption 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 for preparing epirubicin hydrochloride using the intermediate II -1, including following step simultaneously Suddenly：Step 1. compound ii prepares unseparated compound ii -1 and synthesizes compound III again；Step 2. compound III is further Dehydration, carbonyl is oxidized to 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. generates intermediate VI to the protection of amino in sloughing the structure of intermediate V with highly basic；Step 5. exists Bromination and acid hydrolytic reaction are carried out under sour environment successively, corresponding bromo ketone intermediate is generated, then sent out in sodium formate solution Unboiled water solution, is substituted by bromine alcoholic extract hydroxyl group and finally obtains target product epirubicin hydrochloride I.
Preferably, its specific synthetic route is as follows：
Step 1. compound ii prepares unseparated compound ii -1 and synthesizes compound III again and specifically includes following steps： In organic solvent A, the methanol solution of acidic catalyst is added, after stirring 1 hour, add daunorubicin hydrochloride II and 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 State the temperature reacted with esterifying reagent B and be preferably 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 kind in ethers, amide-type, diol, derivatives class and esters solvent；It preferably is selected from benzene, toluene, hexamethylene, methyl alcohol, ethanol, uncle Butanol, dichloromethane, Isosorbide-5-Nitrae-dioxane, ether, acetone, trichloro ethylene, tetrahydrofuran, methyl tertiary butyl ether(MTBE), ethyl acetate With one or more in DMF；More preferably methyl alcohol or dichloromethane or 1,4- dioxane.
The acidic catalyst methanol solution consumption of addition is described in step 1：(with bottom in terms of weight g/ volume mL/ weight g Divide and represented with (W/V/W, g/mL/g)), daunorubicin hydrochloride：Methyl alcohol：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 consumption of organic solvent A described in step 1 is：In terms of weight g/ volumes mL ((W/V, g/mL) table is partly used below Show), daunorubicin hydrochloride：Organic solvent A=1:50~70, preferably 1:60.
The consumption 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 consumption is described in step 1.：Daunorubicin hydrochloride：TFAA=1:1~4, preferably 1：2 (W/V, g/mL).
Reaction is finished, to addition methyl alcohol (daunorubicin hydrochloride in reaction solution：Methyl alcohol=1:20~40 (W/V, g/mL)), stir After mixing 10~15 minutes, 8% sodium bicarbonate solution is added to adjust pH value to 7.0~8.0.15 DEG C~25 DEG C of temperature of control, insulation Stirring reaction 3~5 hours.TLC is detected：With chloroform/isopropanol (volume ratio 96/4) as solvent, detection raw material spot should It is basic to disappear.Midbody compound III Rf ≈ 0.3, daunorubicin hydrochloride Rf ≈ 0.A point liquid is stood, lower floor's organic phase is collected.Vacuum Certain volume (daunorubicin hydrochloride is concentrated under state：The volume of concentrate=1:10 (W/V, g/mL)), added under stirring N-hexane crystallization, suction filtration obtains solid midbody compound III 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 includes following steps：In organic solvent A, trifluoroacetic acid is added Acid anhydride, addition is finished, stirring reaction 1~1.5 hour, is subsequently adding midbody compound III and 1,5- diaza-bicyclo (4,3,0) nonyl- 5- alkene reactions 0.5 hour, carbonyl is oxidized to by the alcoholic extract hydroxyl group of amino sugar structure, backward reaction system in add organic acid C, stir Reaction 0.5 hour is mixed, midbody compound IV is generated.
It is preferably -75 DEG C~0 DEG C described in step 2 with the temperature of 1,5- diaza-bicyclos (4,3,0) nonyl- 5- alkene reactions, it is optimal 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 one or more in DMF；More preferably dichloromethane.
The consumption 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 includes 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, 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 The isomer impurities of intermediate V that can preferably make of selective reduction agent are preferably minimized, 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, Methyl alcohol, 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 is concretely comprised the following steps：In purified water, by midbody compound V one Determine to be reacted 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.
Alkali E described in step 4 is selected from the one kind in NaOH, potassium hydroxide, calcium hydroxide, sodium carbonate and sodium acid carbonate, Most preferably NaOH.
Step 5：The preparation of midbody compound I is concretely comprised the following steps：Carry out bromination reaction first under sour environment, convert It is the Bromo-intermediates VI -1 with ketal structure, the intermediate of this structure carries out acid hydrolytic reaction in sour environment, removal 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 describe 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 To the organic solvent A solution that bromine is added dropwise in reaction solution during answering；The temperature of the organic solvent A solution reaction with hydrogen bromide Preferably 0 DEG C~30 DEG C, most preferably 10 DEG C~20 DEG C.
It is quenched after reacting with excessive bromine in the enough reducing agent F of addition, adds appropriate saturation aqueous slkali G to adjust reaction 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 are 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) 20~30% are preferably.
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 one or more in DMF；More preferably methyl alcohol, 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 reducing agent F is selected from the one kind in sodium sulfite, sodium hydrogensulfite, ferrous sulfate, natrium nitrosum and oxalic acid, most It is preferred that sodium sulfite.
The alkali G is selected from the one kind in NaOH, 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 described in further detail in following part：
Step 1, the preparation of midbody compound III：
To addition organic solvent A and daunorubicin hydrochloride II in three neck glass reaction bottles.Open and stir, 5~10 DEG C of temperature control, After 10~15 minutes, material dissolution situation is checked, continue to stir if not being completely dissolved；If being completely dissolved, feed liquid is lowered the temperature To 0~5 DEG C, the methanol solution of acidic catalyst is added, after stirring 1 hour, add esterifying reagent B；Addition is finished, stirring 2 ~3 hours；Stirring is finished, and controls 3~10 DEG C of reacting liquid temperature, and to TFAA is added in bottle, addition is finished, and stirring 1~ 1.5 hours.
The consumption of the organic solvent A is：(part is represented with (W/V, g/mL) below), hydrochloric acid in terms of weight g/ volumes mL Daunorubicin：Organic solvent A=1:50~70, preferably 1:60；The organic solvent A is preferably methyl alcohol, dichloromethane and 1, One or more in 4- dioxane.
The acidic catalyst methanol solution consumption of the addition is：Daunorubicin hydrochloride：Methyl alcohol：Acidic catalyst=1: 177~200:1~3 (W/V/W, g/mL/g), acidic catalyst is preferably camphorsulfonic acid or p-methyl benzenesulfonic acid.
The consumption 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 consumption is：Daunorubicin hydrochloride：TFAA=1:1~4, preferably 1：2 (W/V, g/ mL)。
Reaction is finished, to addition methyl alcohol (daunorubicin hydrochloride in reaction solution：Methyl alcohol=1:20~40 (W/V, g/mL)), stir After mixing 10~15 minutes, 8% sodium bicarbonate solution is added to adjust pH value to 7.0~8.0.15 DEG C~25 DEG C of temperature of control, insulation Stirring reaction 3~5 hours.TLC is detected：With chloroform/isopropanol (volume ratio 96/4) as solvent, detection raw material spot should It is basic to disappear.Midbody compound III Rf ≈ 0.3, daunorubicin hydrochloride Rf ≈ 0.A point liquid is stood, lower floor's organic phase is collected.Vacuum Certain volume (daunorubicin hydrochloride is concentrated under state：The volume of concentrate=1:10 (W/V, g/mL)), added under stirring N-hexane crystallization, suction filtration obtains solid midbody compound III 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：
To adding organic solvent A in 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, in -70~-40 DEG C of stirring reactions 1~1.5 hour.
The organic solvent A is preferably dichloromethane.
The consumption of the organic solvent A is：Intermediate III：Organic solvent A=1:20~40, preferably 1:40 (W/V, g/ mL)。
The consumption 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 is finished, to the organic solvent A solution that intermediate of epirubicin hydrochloride III is slowly added dropwise in reaction solution；Add Finish, after stirring 20 minutes, the organic solvent A solution of 1,5- diaza-bicyclo (4,3,0) nonyl- 5- alkene is added dropwise, addition is finished, stirring 10 After minute, the organic solvent A solution of organic acid C, 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 the 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 consumption 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 is finished, TLC detections：With chloroform/isopropanol (volume ratio 96/4) as 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)), addition n-hexane crystallization under stirring, suction filtration is obtained in solid after drying 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：
To addition organic solvent A, intermediate IV in three neck glass reaction bottles.Stirring is opened, temperature control -60~-30 DEG C are 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 consumption 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 The isomer impurities of intermediate V that can preferably make of property reducing agent are preferably minimized.
The consumption 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, to acetone is added in reaction solution, continue to stir 20~40 minutes, the consumption 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 to (intermediate IV in reaction solution：Purified water：Dichloromethane Alkane=1：40~60：30~40 (W/V/V, g/mL/mL)), a point liquid is stood after stirring, water intaking 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)), add n-hexane crystallization, suction filtration to consolidate after drying under stirring 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：
To addition purified water, intermediate V in three neck glass reaction bottles.Stirring is opened, 0~10 DEG C of temperature control is added dropwise alkali E, plus 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 (NaOH：Purified water=0.25~0.4:10~14 (W/V, g/ G/mL)), consumption is：Intermediate V：NaOH=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：NaOH：Purified water=1:0.25~0.4:10~14 (W/W/V, g/g/mL).
Preparation is finished, TLC detections：With chloroform/isopropanol (volume ratio=96/4) as solvent, intermediate V is detected Spot should disappear substantially, the Rf ≈ 0.25 of intermediate V, the Rf ≈ 0 of intermediate VI.To being added in reaction solution, the dichloromethane of methyl alcohol is molten Liquid (intermediate V：Methyl alcohol：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 to 8.0 is adjusted with 0.5mol/L sodium carbonate liquors ~8.2.A point liquid is stood, organic phase, concentration in vacuo to certain volume (intermediate V is collected：The volume of concentrate=1:10 (W/V, g/mL)), add n-hexane crystallization, suction filtration to obtain solid midbody compound VI after drying under stirring.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：
Stirring, 15 DEG C of temperature control, in reaction solution are opened to organic solvent A, intermediate VI is added in three neck glass reaction bottles It is added dropwise the organic solvent A solution of 4% hydrogen bromide, completion of dropping after stirring 20~30 minutes, has to bromine is added dropwise in reaction solution Machine solvent orange 2 A solution, completion of dropping, insulated and stirred is reacted 2~2.5 hours.After reaction terminates, to addition reducing agent F in reaction solution After solution, stirring 10~15 minutes, it is 4.5~5.0 to adjust PH with alkali G, and 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 are hydrolyzed 1~3 hour, final target chemical combination The crude product solution of thing epirubicin hydrochloride I.
It is described to be to the organic solvent A consumption added in three neck glass reaction bottles：Intermediate VI：Organic solvent A=1:40 ~60 (W/V, g/mL), the organic solvent A is preferably methyl alcohol 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 is preferably methyl alcohol 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 is preferably methyl alcohol 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.
The alkali G is selected from the one kind in NaOH, 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%.
Preparation is finished, and dichloromethane and purified water are added into (intermediate VI in reaction solution：Purified water：Dichloromethane= 1：40~60：30~40 (W/V/V, g/mL/mL)), a point liquid is stood after stirring, water intaking is 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)), add n-hexane crystallization, suction filtration to consolidate after drying under stirring 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：
The various reagents for being used are cheap and easy to get, and pollutant to producing has more ripe processing method, produces Raw environmental pollution is small.Holistic approach is easy to operation, not harsh to practitioner's technical requirements, meanwhile, each reactions steps Reacting balance, it is easy to control, 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, easily by the moisture in air (for example：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 bigger in substantially negative correlation situation, i.e. humidity with yield, and conversion ratio is lower, the summer Season yield be 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 carrying out of reaction is hindered, or even other impurities are converted into, directly affect product yield and product purity.And the present invention is by primitive nail Triethylenetetraminehexaacetic acid ester can be protected with raw material direct reaction to ketone group, suppress the tautomerism between ketone group and enol-type structure, be protected Card reaction is smoothed out.
Prior art provide synthetic hydrochloric acid epirubicin route with 4 '-EPIDNR be raw material, after bromination terminates PH is adjusted with 5% sodium formate solution first, then so that in solution of sodium bisulfite and excessive bromine, the sodium formate that the method is introduced is dense 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 the way of saturated sodium bicarbonate solution regulation pH, gained reaction solution system intermediate can be stablized be deposited , 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, the present invention is efficiently, economical, and production operation is simple, complies fully with the requirement of industrialized production.
Specific embodiment
The present invention is explained further below in conjunction with specific embodiment, but embodiment does not do any type of to invention in itself Limit.
Embodiment one
The preparation of midbody compound III：
To addition dichloromethane and daunorubicin hydrochloride (daunorubicin hydrochloride in the neck glass reaction bottles of 1000mL tri-：Dichloro Methane=1:60 (W/V, g/mL)).Stirring is opened, 5 DEG C of temperature control after 10~15 minutes, checks material dissolution situation, if incomplete Dissolving then continues to stir；If being completely dissolved, feed liquid is cooled to 0 DEG C, is added thereto to the methanol solution (hydrochloric acid of camphorsulfonic acid Daunorubicin：Methyl alcohol：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 is finished, and is stirred 2 hours；Stirring is finished, and control is anti- 5 DEG C of liquid temperature degree is answered, to addition TFAA (daunorubicin hydrochloride in bottle：TFAA=1：2 (W/V, g/mL), add Finish, stir 1 hour.
Reaction is finished, to addition methyl alcohol (daunorubicin hydrochloride in reaction solution：Methyl alcohol=1:30 (W/V, g/mL)), stirring 10 After minute, 8% sodium bicarbonate solution is added to adjust 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 is detected：With chloroform/isopropanol (volume ratio 96/4) as solvent, detection raw material spot should disappear substantially. Midbody compound III Rf ≈ 0.3, daunorubicin hydrochloride Rf ≈ 0.A point liquid is stood, lower floor's organic phase is collected.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, solid midbody compound III is obtained after suction filtration drying, quality is received Rate 95.6%.Purity 95.5%.
Embodiment two
The preparation of midbody compound III：
To addition Isosorbide-5-Nitrae-dioxane and daunorubicin hydrochloride (daunorubicin hydrochloride in the neck glass reaction bottles of 1000mL tri-： Isosorbide-5-Nitrae-dioxane=1:70 (W/V, g/mL)).Stirring is opened, 10 DEG C of temperature control after 10~15 minutes, checks material dissolution feelings Condition, continues to stir if not being completely dissolved；If being completely dissolved, feed liquid is cooled to 5 DEG C, is added thereto to the first of camphorsulfonic acid Alcoholic solution (daunorubicin hydrochloride：Methyl alcohol：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 is finished, and is stirred 3 hours；Stirring Finish, control 10 DEG C of reacting liquid temperature, to addition TFAA (daunorubicin hydrochloride in bottle：TFAA=1：4(W/ V, g/mL)), addition is finished, and is stirred 1.5 hours.
Reaction is finished, to addition methyl alcohol (daunorubicin hydrochloride in reaction solution：Methyl alcohol=1:40 (W/V, g/mL)), stirring 10 After minute, 8% sodium bicarbonate solution is added to adjust 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 is detected：With chloroform/isopropanol (volume ratio 96/4) as solvent, detection raw material spot should disappear substantially. Midbody compound III Rf ≈ 0.3, daunorubicin hydrochloride Rf ≈ 0.A point liquid is stood, lower floor's organic phase is collected.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, solid midbody compound III is obtained after suction filtration drying, quality is received Rate 93.7%.Purity 95.4%.
Embodiment three
The preparation of midbody compound III：
To addition tetrahydrofuran and daunorubicin hydrochloride (daunorubicin hydrochloride in the neck glass reaction bottles of 1000mL tri-：Tetrahydrochysene Furans=1:50 (W/V, g/mL)).Stirring is opened, 8 DEG C of temperature control after 10~15 minutes, checks material dissolution situation, if incomplete Dissolving then continues to stir；If being completely dissolved, feed liquid is cooled to 3 DEG C, is added thereto to the methanol solution (hydrochloric acid of camphorsulfonic acid Daunorubicin：Methyl alcohol：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 is finished, and is stirred 3 hours；Stirring is finished, and control is anti- 3 DEG C of liquid temperature degree is answered, to addition TFAA (daunorubicin hydrochloride in bottle：TFAA=1：5 (W/V, g/mL)), add Finish, stir 1.5 hours.
Reaction is finished, to addition methyl alcohol (daunorubicin hydrochloride in reaction solution：Methyl alcohol=1:20 (W/V, g/mL)), stirring 15 After minute, 8% sodium bicarbonate solution is added to adjust 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 is detected：With chloroform/isopropanol (volume ratio 96/4) as solvent, detection raw material spot should disappear substantially. Midbody compound III Rf ≈ 0.3, daunorubicin hydrochloride Rf ≈ 0.A point liquid is stood, lower floor's organic phase is collected.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, solid midbody compound III is obtained after suction filtration drying, quality is received Rate 92.4%.Purity 95.0%.
Example IV
The preparation of midbody compound III：
To addition normal heptane and daunorubicin hydrochloride (daunorubicin hydrochloride in the neck glass reaction bottles of 1000mL tri-：Normal heptane =1:40 (W/V, g/mL)).Stirring is opened, 15 DEG C of temperature control after 10~15 minutes, checks material dissolution situation, if completely not molten Xie Ze continues to stir；If being completely dissolved, feed liquid is cooled to 11 DEG C, is added thereto to the methanol solution (hydrochloric acid of camphorsulfonic acid Daunorubicin：Methyl alcohol：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 is finished, and is stirred 3 hours；Stirring is finished, and control is anti- 15 DEG C of liquid temperature degree is answered, to addition TFAA (daunorubicin hydrochloride in bottle：TFAA=1：7 (W/V, g/mL)), plus Enter to finish, stir 1.5 hours.
Reaction is finished, to addition methyl alcohol (daunorubicin hydrochloride in reaction solution：Methyl alcohol=1:50 (W/V, g/mL)), stirring 15 After minute, 8% sodium bicarbonate solution is added to adjust pH value to 8.5.15 DEG C~25 DEG C of temperature of control, insulated and stirred reaction 3~5 is small When.TLC is detected：With chloroform/isopropanol (volume ratio 96/4) as solvent, detection raw material spot should disappear substantially.It is middle Body compound III Rf ≈ 0.3, daunorubicin hydrochloride Rf ≈ 0.A point liquid is stood, lower floor's organic phase is collected.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, obtain solid midbody compound III, mass yield after suction filtration drying 90.0%.Purity 93.7%.
Embodiment five
The preparation of midbody compound IV：
To addition dichloromethane (intermediate III in the neck glass reaction bottles of 1000mL tri-：Dichloromethane：1：40 (W/V, g/ mL)).Stirring is opened, -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)), in after -40 DEG C of stirring reactions 1 hour, to being slowly added dropwise in 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-bicyclo (4,3,0) nonyl- 5- alkene is added dropwise：1,5- bis- Nitrogen two ring (4,3,0) nonyl- 5- alkene：Dichloromethane=1：0.84：5 (W/W/V, g/g/mL)), addition is finished, 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) as 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, suction filtration obtains solid midbody compound IV, mass yield 93.2% after drying.Purity 86.2%, relevant material (in Intermediate compounds therefor III) content<8.0%.
Embodiment six
The preparation of midbody compound IV：
To addition ethyl acetate (intermediate III in the neck glass reaction bottles of 1000mL tri-：Ethyl acetate：1：20 (W/V/V, g/ mL/mL)).Stirring is opened, -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)), in after -70 DEG C of stirring reactions 1 hour, to being slowly added dropwise in 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-bicyclo (4,3,0) nonyl- 5- alkene is added dropwise：1,5- bis- Nitrogen two ring (4,3,0) nonyl- 5- alkene：Ethyl acetate=1：0.9：8 (W/W/V, g/g/mL)), addition is finished, 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) as 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, suction filtration obtains solid midbody compound IV, mass yield 93.1% after drying.Purity 85.5%, relevant material (in Intermediate compounds therefor III) content<8.0%.
Embodiment seven
The preparation of midbody compound IV：
To addition DMF (intermediates III in the neck glass reaction bottles of 1000mL tri-：DMF=1：50 (W/V/V, g/mL/mL)).Open Stirring is opened, -30 DEG C of temperature control is slowly added to the DMF solution (intermediate III of TFAA：TFAA：DMF=1：0.4：4 (W/W/V, g/g/mL)), in after -30 DEG C of stirring reactions 1.5 hours, to being slowly added dropwise intermediate of epirubicin hydrochloride in reaction solution III DMF solution, (intermediate III：DMF=1:10 (W/V, g/mL))；Addition is finished, and after stirring 20 minutes, 1,5- phenodiazines is 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 is finished, 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) as 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, suction filtration obtains solid midbody compound IV, mass yield 91.7% after drying.Purity 84.1%, relevant material (in Intermediate compounds therefor III) content<8.0%.
Embodiment eight
The preparation of midbody compound V：
To addition the dichloromethane, (intermediate IV of intermediate IV in the neck glass reaction bottles of 1000mL tri-：Dichloromethane=1:40 (W/V, g/mL)).Stirring is opened, -60 DEG C of temperature control is added dropwise the ethanol solution of sodium borohydride, (intermediate IV：Sodium borohydride：It is anhydrous Ethanol=1:0.02:100 (W/W/V, g/g/mL)), addition is finished, and stirring reaction is after 0.5 hour, to adding acetone in reaction solution (intermediate IV：Acetone=1:1 (W/V, g/mL)), continue to stir 20 minutes.
Reaction solution is warming up to 0~10 DEG C, TLC detections：With chloroform/isopropanol (volume ratio 96/4) as 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 to (intermediate IV in reaction solution：Purified water：Dichloromethane=1：60：30 (W/V/V, g/ ML/mL)), a point liquid is stood after stirring, water intaking extracts three (intermediates IV 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% adds n-hexane (intermediate IV under stirring：N-hexane= 1:10 (W/V, g/mL)) crystallization, obtain solid midbody compound V, mass yield 93.9% after suction filtration drying.Purity 99.7%, The relevant content of material midbody compound I<0.6%.
Embodiment nine
The preparation of midbody compound V：
To addition the acetone, (intermediate IV of intermediate IV in the neck glass reaction bottles of 1000mL tri-：Acetone=1:50 (W/V, g/ mL)).Stirring is opened, -30 DEG C of temperature control is added dropwise the ethanol solution of tetrahydrochysene lithium aluminium, (intermediate IV：Tetrahydrochysene lithium aluminium：Absolute ethyl alcohol= 1:0.04:80 (W/W/V, g/g/mL)), addition is finished, and stirring reaction is after 1 hour, to adding acetone (intermediate in reaction solution Ⅳ：Acetone=1:2 (W/V, g/mL)), continue to stir 20 minutes.
Reaction solution is warming up to 0~10 DEG C, TLC detections：With chloroform/isopropanol (volume ratio 96/4) as 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 to (intermediate IV in reaction solution：Purified water：Dichloromethane=1：40：40 (W/V/V, g/ ML/mL)), a point liquid is stood after stirring, water intaking extracts three (intermediates IV 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% adds n-hexane (intermediate IV under stirring：N-hexane= 1:10 (W/V, g/mL)) crystallization, obtain solid midbody compound V, mass yield 92.7% after suction filtration drying.Purity 99.6%, The relevant content of material midbody compound I<0.6%.
Embodiment ten
The preparation of midbody compound V：
To addition the tetrahydrofuran, (intermediate IV of intermediate IV in the neck glass reaction bottles of 1000mL tri-：Tetrahydrofuran=1:60 (W/V, g/mL)).Stirring is opened, -75 DEG C of temperature control is added dropwise the ethanol solution of sodium cyanoborohydride, (intermediate IV：Cyano group boron hydrogen Change sodium：Absolute ethyl alcohol=1:0.06:70 (W/W/V, g/g/mL)), addition is finished, and stirring reaction adds after 1 hour in reaction solution Enter acetone (intermediate IV：Acetone=1:4 (W/V, g/mL)), continue to stir 20 minutes.
Reaction solution is warming up to 0~10 DEG C, TLC detections：With chloroform/isopropanol (volume ratio 96/4) as 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 to (intermediate IV in reaction solution：Purified water：Dichloromethane=1：30：50 (W/V/V, g/ ML/mL)), a point liquid is stood after stirring, water intaking extracts three (intermediates IV 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% adds n-hexane (intermediate IV under stirring：N-hexane= 1:12 (W/V, g/mL)) crystallization, obtain solid midbody compound V, mass yield 92.5% after suction filtration drying.Purity 99.5%, The relevant content of material midbody compound I<0.6%.
Embodiment 11
The preparation of midbody compound V：
To addition the hexamethylene, (intermediate IV of intermediate IV in the neck glass reaction bottles of 1000mL tri-：Hexamethylene=1:40(W/ V, g/mL)).Stirring is opened, 5 DEG C of temperature control is added dropwise the ethanol solution of lithium triethylborohydride, (intermediate IV：Boron triethyl is hydrogenated Lithium：Absolute ethyl alcohol=1:0.02:100 (W/W/V, g/g/mL)), addition is finished, and stirring reaction is after 1.5 hours, in reaction solution Add acetone (intermediate IV：Acetone=1:4 (W/V, g/mL)), continue to stir 20 minutes.
Reaction solution is warming up to 0~10 DEG C, TLC detections：With chloroform/isopropanol (volume ratio 96/4) as 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 to (intermediate IV in reaction solution：Purified water：Dichloromethane=1：50：50 (W/V/V, g/ ML/mL)), a point liquid is stood after stirring, water intaking extracts three (intermediates IV 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% adds n-hexane (intermediate IV under stirring：N-hexane=1:8 (W/V, g/mL)) crystallization, obtain solid midbody compound V, mass yield 89.1% after suction filtration drying.Purity 98.4%, it is relevant The content of material midbody compound I<0.6%.
Embodiment 12
The preparation of midbody compound VI：
To addition the purified water, (intermediate V of intermediate V in 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 is added dropwise sodium hydroxide solution, (intermediate V：NaOH：Purified water=1:0.25: 10 (W/W/V, g/g/mL)), addition is finished, 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.
To the dichloromethane solution (intermediate V that methyl alcohol is added in reaction solution：Methyl alcohol：Dichloromethane=1：60：8(W/V/ V, g/mL/mL)), stirring is opened, and 0.5mol/L sodium bicarbonate solutions regulation pH value to 7.6~7.8 is added dropwise.Finally use 0.5mol/L sodium carbonate liquors adjust pH value to 8.0~8.2.A point liquid is stood, organic phase is collected, 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, obtain solid midbody compound VI, mass yield 94.6% after suction filtration drying.Purity 98.9%, maximum contaminant content<0.6%, total impurities content<3.0%.
Embodiment 13
The preparation of midbody compound VI：
To addition the purified water, (intermediate V of intermediate V in 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 is added dropwise sodium hydroxide solution, (intermediate V：NaOH：Purified water=1:0.4: 14 (W/W/V, g/g/mL)), addition is finished, 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.
To the dichloromethane solution (intermediate V that methyl alcohol is added in reaction solution：Methyl alcohol：Dichloromethane=1：40：10(W/V/ V, g/mL/mL)), stirring is opened, and 0.5mol/L sodium bicarbonate solutions regulation pH value to 7.6~7.8 is added dropwise.Finally use 0.5mol/L sodium carbonate liquors adjust pH value to 8.0~8.2.A point liquid is stood, organic phase is collected, 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, obtain solid midbody compound VI, mass yield 93.1% after suction filtration drying.Purity 98.8%, maximum contaminant content<0.6%, total impurities content<3.0%.
Embodiment 14
The preparation of midbody compound VI：
To addition the purified water, (intermediate V of intermediate V in 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 is added dropwise sodium bicarbonate solution, (intermediate V：Sodium acid carbonate：Purified water=1:1.5: 10 (W/W/V, g/g/mL)), addition is finished, 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.
To the dichloromethane solution (intermediate V that methyl alcohol is added in reaction solution：Methyl alcohol：Dichloromethane=1：35：15(W/V/ V, g/mL/mL)), stirring is opened, and 0.5mol/L sodium bicarbonate solutions regulation pH value to 7.6~7.8 is added dropwise.Finally use 0.5mol/L sodium carbonate liquors adjust pH value to 8.0~8.2.A point liquid is stood, organic phase is collected, 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, obtain solid midbody compound VI, mass yield 92.1% after suction filtration drying.Purity 98.2%, maximum contaminant content<0.6%, total impurities content<3.0%.
Embodiment 15
The preparation of midbody compound VI：
To addition the purified water, (intermediate V of intermediate V in the neck glass reaction bottles of 1000mL tri-：Purified water=1:30(W/ V, g/mL)).Stirring is opened, 25 DEG C are controlled, aqua calcis, (intermediate V is added dropwise：Calcium hydroxide：Purified water=1:1.1:10 (W/W/V, g/g/mL)), addition is finished, 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.
To the dichloromethane solution (intermediate V that methyl alcohol is added in reaction solution：Methyl alcohol：Dichloromethane=1：65：15(W/V/ V, g/mL/mL)), stirring is opened, and 0.5mol/L sodium bicarbonate solutions regulation pH value to 7.6~7.8 is added dropwise.Finally use 0.5mol/L sodium carbonate liquors adjust pH value to 8.0~8.2.A point liquid is stood, organic phase is collected, 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, obtain solid midbody compound VI, mass yield 91.2% after suction filtration drying.Purity 97.8%, maximum contaminant content<0.6%, total impurities content<3.0%.
Embodiment 16
The preparation of epirubicin hydrochloride I：
To addition the methyl alcohol, (intermediate VI of intermediate VI in the neck glass reaction bottles of 1000mL tri-：Methyl alcohol=1:40 (W/V, g/ mL)).Open stirring, 15 DEG C of temperature control, to the methanol solution (intermediate VI of the hydrogen bromide that 4% is added dropwise in reaction solution：4% bromination Methanol solution=1 of hydrogen：4 (W/V, g/mL)), completion of dropping, after stirring 20 minutes, to the methanol solution that bromine is added dropwise in reaction solution (intermediate VI：Bromine：Methyl alcohol=1:0.5:5 (W/W/V, g/g/mL)), completion of dropping, insulated and stirred is reacted 2 hours.Reaction terminates Afterwards, to addition sodium sulfite solution (intermediate VI in reaction solution：Sodium hydrogensulfite：Purified water=1:0.05:0.5 (W/W/V, g/ G/mL)), after stirring 10 minutes, it is 4.5~5.0 to adjust pH with ammoniacal liquor, and stirring reaction is adjusted after 10 minutes with 7% hydrochloric acid solution Section pH is 1.3~1.5, is reacted 2 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 are hydrolyzed 1 hour, final that target compound epirubicin hydrochloride I is thick Product solution.
Dichloromethane and purified water are added to (intermediate VI in reaction solution：Purified water：Dichloromethane=1：60：30(W/ V/V, g/mL/mL)), a point liquid is stood after stirring, water intaking extracts three (intermediates VI 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, suction filtration do 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 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：
To addition Isosorbide-5-Nitrae-dioxane, (intermediate VI of intermediate VI in 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, to the Isosorbide-5-Nitrae-dioxane of the hydrogen bromide that 4% is added dropwise in reaction solution Solution (intermediate VI：Isosorbide-5-Nitrae-dioxane solution=1 of 4% hydrogen bromide：8 (W/V, g/mL)), completion of dropping stirs 20 points Zhong Hou, to Isosorbide-5-Nitrae-dioxane solution (intermediate VI that bromine is added dropwise in reaction solution：Bromine：Isosorbide-5-Nitrae-dioxane=1:0.2:8(W/ W/V, g/g/mL)), completion of dropping, insulated and stirred is reacted 2.5 hours.After reaction terminates, to being added in reaction solution, ferrous sulfate is molten 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 After mixing reaction 10 minutes, it is 1.3~1.5 to adjust PH with 7% phosphoric acid solution, 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 to (intermediate VI in reaction solution：Purified water：Dichloromethane=1：40：40(W/ V/V, g/mL/mL)), a point liquid is stood after stirring, water intaking extracts three (intermediates VI 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, suction filtration do 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 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：
To addition the trichloro ethylene, (intermediate VI of intermediate VI in the neck glass reaction bottles of 1000mL tri-：Trichloro ethylene=1:40 (W/V, g/mL)).Open stirring, 30 DEG C of temperature control, to the trichloro ethylene solution (intermediate of the hydrogen bromide that 4% is added dropwise in reaction solution Ⅵ：Trichloro ethylene solution=1 of 4% hydrogen bromide：4 (W/V, g/mL)), completion of dropping, after stirring 20 minutes, in 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)), completion of dropping is protected Warm stirring reaction 3 hours.After reaction terminates, to addition copperas solution (intermediate VI in 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 is 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 is 3.0~3.5, and 25~35 DEG C of sodium formates of temperature control are hydrolyzed 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 to (intermediate VI in reaction solution：Purified water：Dichloromethane=1：65：45(W/ V/V, g/mL/mL)), a point liquid is stood after stirring, water intaking extracts three (intermediates VI 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, suction filtration do 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 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：
To addition the heptane, (intermediate VI of intermediate VI in the neck glass reaction bottles of 1000mL tri-：Heptane=1:70 (W/V, g/ mL)).Open stirring, 35 DEG C of temperature control, to the n-heptane solution (intermediate VI of the hydrogen bromide that 4% is added dropwise in reaction solution：4% bromination N-heptane solution=1 of hydrogen：2 (W/V, g/mL)), completion of dropping, after stirring 20 minutes, to the n-heptane solution that bromine is added dropwise in reaction solution (intermediate VI：Bromine：Heptane=1:0.7:10 (W/W/V, g/g/mL)), completion of dropping, insulated and stirred is reacted 1.5 hours.Reaction After end, to addition copperas solution (intermediate VI in 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)) regulation PH is 4.0~4.5, and after 15 minutes, it is 1.1~1.2 to adjust PH with 12% phosphoric acid solution to stirring reaction, 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 are hydrolyzed 1 hour, final to obtain the crude product solution of target compound epirubicin hydrochloride I.
Dichloromethane and purified water are added to (intermediate VI in reaction solution：Purified water：Dichloromethane=1：35：50(W/ V/V, g/mL/mL)), a point liquid is stood after stirring, water intaking extracts three (intermediates VI 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, suction filtration do 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 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：
To addition the heptane, (intermediate VI of intermediate VI in the neck glass reaction bottles of 1000mL tri-：Heptane=1:70 (W/V, g/ mL)).Open stirring, 35 DEG C of temperature control, to the n-heptane solution (intermediate VI of the hydrogen bromide that 4% is added dropwise in reaction solution：4% bromination N-heptane solution=1 of hydrogen：2 (W/V, g/mL)), completion of dropping, after stirring 20 minutes, to the n-heptane solution that bromine is added dropwise in reaction solution (intermediate VI：Bromine：Heptane=1:0.7:10 (W/W/V, g/g/mL)), completion of dropping, insulated and stirred is reacted 1.5 hours.Reaction After end, to addition copperas solution (intermediate VI in 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)) regulation PH is 4.0~4.5, and after 15 minutes, it is 1.1~1.2 to adjust PH with 12% phosphoric acid solution to stirring reaction, 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 are hydrolyzed 1 hour, final to obtain the crude product solution of target compound epirubicin hydrochloride I.
Reaction terminates to add 250mL purified waters in backward reaction solution, after watery hydrochloric acid regulation pH to 3, 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, and purity 96.1% meets pharmacopoeial requirements：In need testing solution chromatogram if any Impurity peaks, Doxorubicin ketone (relative retention time about 0.3) by 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, it is molten that Doxorubicin (relative retention time about 0.8) peak area cannot be greater than control 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
Weigh 4 '-EPIDNR 6.7g plus 67mL methyl alcohol to dissolve at room temperature, after addition Isosorbide-5-Nitrae-dioxane 67mL again 6mL methyl formates and 0.73mL bromines are added, after reaction 1h, adds 2.16mL acidifying expoxy propane persistently to stir 30min, by this Reaction solution is concentrated into 65mL, and 740mL isopropanol crystallizations are added after concentration is finished after cooling, backward precipitation in add 150mL different Propanol rinse crystal, after crystal is fully dried, with 142mL water dissolves, adds the 146mL acetone solns of 4.2mL hydrogen bromides to enter Row acidifying, reacts 18h at room temperature, to the solution reaction 24h that 10g sodium formates and 42mL water are added in reaction solution, is adjusted with watery hydrochloric acid Section pH to 5, 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, by concentrate suction filtration after, separated with cationic ion-exchange resin, be concentrated to dryness after collecting principal component, final salt The solid of sour epirubicin I, mass yield is 59.7%, purity 90.1%.
Embodiment 22
Weigh 4 '-EPIDNR 6.7g plus 67mL methyl alcohol to dissolve at room temperature, after addition Isosorbide-5-Nitrae-dioxane 67mL again 6mL methyl formates and 0.73mL bromines are added, after reaction 1h, adds 2.16mL acidifying expoxy propane persistently to stir 30min, by this Reaction solution is concentrated into 65mL, and 740mL isopropanol crystallizations are added after concentration is finished after cooling, backward precipitation in add 150mL different Propanol rinse crystal, after crystal is fully dried, with 142mL water dissolves, adds the 146mL acetone solns of 4.2mL hydrogen bromides to enter Row acidifying, reacts 18h at room temperature, to the solution reaction 24h that 10g sodium formates and 42mL water are added in reaction solution, is adjusted with watery hydrochloric acid Section pH to 5, persistently stirs 24h afterwards.
Dichloromethane and purified water are added to (intermediate VI in reaction solution by reaction after terminating：Purified water：Dichloromethane= 1：35：50 (W/V/V, g/mL/mL)), a point liquid is stood after stirring, water intaking extracts three (intermediates VI 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, suction filtration obtains the solid of epirubicin hydrochloride I, mass yield 66.4% 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 About 0.8) peak area cannot be greater than contrast solution main peak area (1.0%) to stay the time, 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 being added dropwise over trifluoacetic anhydride (7mL in 60min；Intermediate II：TFAA=1:1.4 (W/V, g/mL)) dichloromethane (15mL；Intermediate II：Dichloromethane=1:3 (W/V, g/mL)) solution, drip and finish, equality of temperature reaction 0.5h adds 250mL pure afterwards Change water (intermediate II：Purified water=1:50 (W/V, g/mL)), fully shake up rear stratification and collect organic phase, it is added thereto to 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, it is stirred vigorously 15-24 hours, organic phase is separated to obtain after the completion of hydrolysis, 35 DEG C of drying under reduced pressure obtains intermediate III to constant weight (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 (intermediate III in 100mL dichloromethane： DMSO：Dichloromethane=1:1:20 (W/V/V, g/mL/mL)), it is sufficiently stirred for and the solution is cooled to -60 DEG C, add afterwards The oxalyl chloride and 5mL dichloromethane solutions (intermediate III of 1mL：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.The intermediate III of 5g is dissolved in (intermediate III in 50mL dichloromethane：Two Chloromethanes=1:10 (W/V, g/mL)), this solution was added into above-mentioned coolant in 20 minutes, temperature is maintained in the process - 60 ± 5 DEG C of degree, reacts 1 hour at this temperature, and 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)), 2 are stirred afterwards during this solution is added into reaction solution Minute, then to addition 300mL purified water (intermediates III in reaction solution：Purified water=1:60 (W/V, g/mL)), after being sufficiently stirred for Standing separation obtains organic phase, repeats this process 3 times, merges three gained organic phases, 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, in 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：Hydrochloric acid=1 of 1mol/L:32:63.8:0.43 (W/V/V/V, g/mL/mL/mL)), after being sufficiently stirred for 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 stream part, obtains 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-, by 3.0g intermediates V in being 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 the NaOH solution of 10mL 1.0mol/L (intermediate V：NaOH solution=1 of 1.0mol/L:3.3 (W/V, g/mL)), insulation reaction 30 minutes at the same temperature, this PH to 7.0 is adjusted with the hydrochloric acid solution of 1mol/L afterwards, the reaction solution is separated using preparative high performance liquid chromatography, collected It is concentrated to dryness after main peak stream part, 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)), suction filtration institute Must precipitate, and repeatedly 80mL acetone, the bromination of 80mL 0.25mol/L are dissolved in acetonitrile washing precipitation after sediment is dried (intermediate VI in the mixed liquor of aqueous solution of hydrogen and 8g sodium formates：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)), in 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, main peak stream part is collected, third is added after being concentrated under reduced pressure into and doing Ketone is recrystallized, 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, to drip and finish, 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 are added 562mL methyl alcohol (intermediate VI：Methyl alcohol=1:16 (W/V, g/mL)) after be cooled to -10~-5 DEG C, add the 1.6mol/L of 950g 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 warmed up to 10~15 DEG C anti- 7h is answered, reaction terminates rear stratification, and water mutually uses 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 Water phase, through NM100 macroporous absorbent resins adsorption and purification, [eluent is acetonitrile：The pH=4.5 aqueous solution (6：1) hydrochloric acid table], is obtained soft 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 It is 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 (10)

1. a kind of intermediate of epirubicin hydrochloride compound, 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 methyl alcohol, acidic catalyst, esterifying reagent B makes daunorubicin hydrochloride II generate the intermediate compound with ketal structure Thing II -1；
3. the preparation method according to claim .2, it is characterised in that compound ii synthesis compound ii -1 specifically include as Lower step：In organic solvent A, methyl alcohol, acidic catalyst, esterifying reagent B, daunorubicin hydrochloride II are added, reacted 2 hours, Midbody compound II -1 of the generation with ketal structure.
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 arene, aliphatic hydrocarbon In class, alicyclic hydrocarbon type, halogenated hydrocarbons, alcohols, alkanes, ethers, amide-type, diol, derivatives class, esters solvent and phenol one Kind.
7. 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 or more in ether, ethyl acetate and DMF.
8. the preparation method according to Claims 2 or 3, it is characterised in that the esterifying reagent B is selected from Ethyl formate, formic acid Methyl esters, methyl acetate, ethyl acetate, triethyl orthoformate, one or more in ethyl chloroformate and propyl formate；Preferably Triethyl orthoformate or trimethyl orthoformate.
9. purposes of the midbody compound in epirubicin is prepared according to claim 1.
10. purposes according to claim 10, it is characterised in that concrete application method is：With TFAA in the middle of this The active amino of sugar moiety is protected in the structure of body compound ii -1, generates unsegregated midbody compound III；Enter One step is dehydrated, and the alcoholic extract hydroxyl group of amino sugar structure is oxidized into carbonyl, generates unsegregated midbody compound IV；With selectivity also Carbonyl reduction in amino sugar is hydroxyl by former agent D, is converted into opposite with daunorubicin amino sugar structure 4-OH configurations Intermediate V；Intermediate VI is generated to the protection of amino in sloughing the structure of intermediate V with highly basic E；Under sour environment successively Bromination and acid hydrolytic reaction are carried out, corresponding bromo ketone intermediate is generated, then hydrolyzed in sodium formate solution, bromine is replaced Target product epirubicin hydrochloride I is finally obtained for alcoholic extract hydroxyl group.
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CN109293613A (en) * 2018-11-23 2019-02-01 鲁南制药集团股份有限公司 A kind of epirubicin midbody compound
CN109836465A (en) * 2017-11-24 2019-06-04 鲁南制药集团股份有限公司 A method of preparing epirubicin hydrochloride
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CN112574150A (en) * 2019-09-28 2021-03-30 鲁南制药集团股份有限公司 Epirubicin hydrochloride intermediate compound II
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CN109836465A (en) * 2017-11-24 2019-06-04 鲁南制药集团股份有限公司 A method of preparing epirubicin hydrochloride
CN109836404A (en) * 2017-11-24 2019-06-04 鲁南制药集团股份有限公司 Intermediate of epirubicin hydrochloride compound
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CN114149473A (en) * 2020-09-08 2022-03-08 鲁南制药集团股份有限公司 Synthetic method of epirubicin hydrochloride and intermediate thereof
CN114149473B (en) * 2020-09-08 2024-03-15 鲁南制药集团股份有限公司 Synthesis method of epirubicin hydrochloride and intermediate thereof

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