CN110305001A - A kind of synthetic method of epirubicin intermediate daunomycinone - Google Patents

A kind of synthetic method of epirubicin intermediate daunomycinone Download PDF

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CN110305001A
CN110305001A CN201810259489.2A CN201810259489A CN110305001A CN 110305001 A CN110305001 A CN 110305001A CN 201810259489 A CN201810259489 A CN 201810259489A CN 110305001 A CN110305001 A CN 110305001A
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霍领雁
时江华
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Lunan Pharmaceutical Group Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
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    • C07C45/65—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
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    • C07C46/00—Preparation of quinones
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    • C07—ORGANIC CHEMISTRY
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    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/72—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 spiro-condensed with carbocyclic rings
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Abstract

The invention belongs to medical synthesis fields, and in particular to a kind of chemical synthesis process of epirubicin intermediate daunomycinone.The present invention is with 2,5- dihydroxy-benzyl alcohol for Material synthesis daunomycinone, and the route raw material is low in cost, and reaction condition is mild, convenient post-treatment, and total recovery is high, has preferable industrial applications prospect.

Description

A kind of synthetic method of epirubicin intermediate daunomycinone
Technical field
The invention belongs to medical synthesis fields, and in particular to a kind of synthetic method of epirubicin intermediate daunomycinone.
Background technique
Epirubicin also known as Epi-ADM belong to Anthraquinones antibiotic, and structural formula is as follows:
Epirubicin is by Pfizer's exploitation for treating the anthracene nucleus antineoplastic antibiotic of breast cancer, lung cancer, liver cancer, It lists within 1984, lists in the U.S. in Europe within 1999.Treatment leukaemia, lymthoma and various solid tumors (including breast cancer, Non-small cell tumour, cervix cancer and head and neck cancer) in have a wide range of applications.Its mechanism of action is to be directly embedded into DNA core alkali pair Between, transcription is interfered, the formation of mRNA is prevented, to inhibit the synthesis of DNA and RNA.In addition, Epi-ADM is different to topology Structure enzyme II also has inhibiting effect.It is effective to a variety of transplanted tumors for a cell cycle nonspecific agent (CCNSA).With adriamycin phase Than curative effect is equal or slightly higher, but smaller to the toxicity of heart.
The preparation of epirubicin at present mainly using the daunorubicin obtained that ferments as raw material, is made into through molecular design Product.But the disadvantages of resulting raw material of fermenting is there are low efficiency, and impurity is more and poor repeatability, this will result directly in epirubicin finished product Impurity is more, poor repeatability, generally requires resin post separation, this significantly increases the production cycle, constitutes potential prestige to drug safety The side of body, pure chemistry synthesis epirubicin have become a new breakthrough point.
Daunomycinone is an important intermediate of epirubicin, is mostly to be made with daunorubicin fermentation liquor recovery processing, changes The report for learning synthetic method is less.Its structural formula is as follows:
Summary of the invention
For overcome the deficiencies in the prior art, the purpose of the present invention is to provide a kind of epirubicin intermediate daunomycinones Chemical synthesis process, specific technical solution are as follows:
A kind of synthetic method of epirubicin intermediate daunomycinone, synthetic route are as follows:
Wherein, the step of intermediate 1 being prepared by 2,5- dihydroxy-benzyl alcohol are as follows: 2,5- dihydroxy-benzyl alcohol is dissolved in organic solvent In, diisopropylethylamine and chloromethyl methyl ether are added under nitrogen protection, to end of reaction, cooling will be anti-for stirring at 35~70 DEG C It answers liquid to pour into 5% sodium bicarbonate solution, stirs, stand liquid separation, water phase is used methylene chloride or chloroform to extract again, collected organic Phase is successively washed with water, saturated salt solution, and the dry organic phase of anhydrous sodium sulfate is collected by filtration organic phase reduced pressure, stone is added Oily ether mashing, filters, is dried under reduced pressure to obtain intermediate 1.
The step of intermediate 2 are prepared by intermediate 1 are as follows: intermediate 1 is placed in a reaction flask, is added dissolved with N, bis- ring of N'- The organic solvent of hexyl-N- methyl carbodiimides iodide is protected from light at 25~55 DEG C, evaporating solvent under reduced pressure, residue It is dissolved in n-hexane, washes, water phase n-hexane extraction, collect organic phase and, suction filtration dry with anhydrous sodium sulfate, filtrate decompression Concentration, residue methylene chloride and n-hexane mixed solvent recrystallize to obtain intermediate 2.
The step of intermediate 3 are prepared by intermediate 2 are as follows: acid 11 is dissolved in organic solvent, -78 DEG C, is delayed under nitrogen protection Slowly instill lithium hexamethyldisilazide tetrahydrofuran solution, be added dissolved with intermediate 2 organic solvent, -78~-50 DEG C It is stirred to react 1~3h, -30~-20 DEG C is warming up to and is stirred to react 15~22h, end of reaction pours into reaction solution in hydrochloric acid, different Propyl ether extraction, collects organic phase, dry with magnesium sulfate, is dissolved in methylene chloride after evaporating solvent under reduced pressure, uses saturated sodium bicarbonate Solution washing, water phase are extracted with isopropyl ether, collect organic phase, and magnesium sulfate is dry, is concentrated under reduced pressure up to intermediate 3.
The step of intermediate 4 are prepared by intermediate 3 are as follows: intermediate 3 is placed in a reaction flask, is added at room temperature organic molten Thionyl chloride is added under nitrogen protection in agent, and tin tetrachloride is added after being cooled to room temperature in heating reflux reaction 12h, stirs at 20 DEG C Reaction 1h is mixed, is cooled to 0 DEG C, trash ice is added, water phase is collected in liquid separation, and water phase is extracted with dichloromethane, and organic phase is collected, with saturation Sodium bicarbonate solution and saturated sodium chloride solution are successively washed, and anhydrous magnesium sulfate is dry, are concentrated under reduced pressure to obtain 4 crude product of intermediate, and four The mixed solution of hydrogen furans and n-hexane recrystallizes to obtain intermediate 4.
The step of intermediate 5 are prepared by intermediate 4 are as follows: under nitrogen protection, tetrahydrofuran is sequentially added into reaction vessel Solution, N, N- diethylaniline borane, the solution of the tetrahydrofuran of (R) -2- methyl CBS- oxazaborolidine, 15~25 DEG C of temperature control, It is slowly added to the tetrahydrofuran solution of intermediate 4, insulation reaction, control temperature is lower than 25 DEG C, methanol is slowly added dropwise, stirs, subtract Pressure concentration is added methylene chloride, sulfuric acid is added dropwise at 15~25 DEG C, stirs, add moisture liquid, organic phase uses water and saturated sodium-chloride again Solution successively washs, and anhydrous sodium sulfate is dry, filters, and filtrate decompression is concentrated to dryness, and tetrahydrofuran and ether mixed solution are tied again Crystalline substance obtains intermediate 5.
The step of intermediate 6 are prepared by intermediate 5 are as follows: intermediate 5 is dissolved in tetrahydrofuran solvent, under nitrogen protection, It is cooled to 0 DEG C, is instilled after dimethyl sulfoxide-sodium hydride to be dissolved in the mixed solution of dimethyl sulfoxide and tetrahydrofuran, stirring is anti-at room temperature It answers, extractant and saturated ammonium chloride solution stirring is added in end of reaction, stands liquid separation, and water phase is washed with extractant, collects Organic phase, organic phase are washed with water, and anhydrous sodium sulfate is dry, and intermediate 6 is concentrated under reduced pressure to obtain.
The step of intermediate 7 are prepared by intermediate 6 are as follows: be dissolved in intermediate 6 in the mixed solution of tetrahydrofuran and water, room Temperature is lower to be added aluminium amalgam, and stirred under nitrogen atmosphere filters out solid, and filter cake is washed with a small amount of tetrahydrofuran, and filtrate decompression concentration adds Enter ether solution, stir, stand, liquid separation, organic phase is dry with anhydrous sodium sulfate, and evaporating solvent under reduced pressure, product recrystallizes again Obtain intermediate 7.
The step of intermediate 8 are prepared by intermediate 7 are as follows: intermediate 7 is added into three-necked flask, is dissolved with methylene chloride, 0 Under DEG C nitrogen protection, triethylamine, trim,ethylchlorosilane is added dropwise, stirring terminates to reaction, and methylene chloride dilute reaction solution will react Liquid pours into ice water, and extraction, organic phase water, saturated salt solution successively washs, and anhydrous sodium sulfate is dry, filters up to intermediate 8。
The step of intermediate 9 are prepared by intermediate 8 are as follows: alchlor is added portionwise in the dichloromethane solution of intermediate 8, It is cooled to 0 DEG C, is slowly dropped into the dichloromethane solution of compound 12,0 DEG C of stirring 30min is warmed to room temperature 6~8h of stirring naturally, Reaction solution is poured into 0 DEG C of dilute hydrochloric acid, 0 DEG C of stirring 10min, stirs 0.5~1h, liquid separation, water phase methylene chloride at room temperature Organic phase is collected in extraction, and saturated sodium bicarbonate solution washing, anhydrous sodium sulfate is dry, 9 crude product of intermediate is concentrated under reduced pressure to obtain, weight Crystallize to obtain intermediate 9.
The step of epirubicin intermediate daunomycinone is prepared by intermediate 9 are as follows: intermediate 9 is dissolved in methylene chloride, nitrogen Under gas shielded, 2~8 DEG C are cooled to, instills the dichloromethane solution of dimethyl boron bromide, 2~8 DEG C are stirred to react, and reaction terminates Reaction solution is poured into afterwards in the mixed solution of saturated sodium bicarbonate and tetrahydrofuran, stirring stands liquid separation, water phase methylene chloride Organic phase is collected in extraction, washs organic phase with saturated sodium chloride solution, organic phase is collected in liquid separation, and anhydrous sodium sulfate drying is organic Phase is concentrated under reduced pressure up to epirubicin intermediate daunomycinone.
Preferably, in the step of preparing intermediate 1 by 2,5- dihydroxy-benzyl alcohol, the organic solvent be methylene chloride, One of chloroform, acetonitrile or DMF, it is further preferred that the organic solvent is methylene chloride；2,5- dihydroxy-benzyl alcohol, two The molar ratio of wopropyl ethyl amine and chloromethyl methyl ether is 1:3~6:2~4, more preferably 1:3.8:2.8.
Preferably, in the step of preparing intermediate 2 by intermediate 1, the organic solvent be tetrahydrofuran, n-hexane, One of toluene or acetonitrile, it is further preferred that the organic solvent is tetrahydrofuran or n-hexane；Intermediate 1 and N, N'- The molar ratio of dicyclohexyl-N- methyl carbodiimides iodide is 1:1~3, more preferably 1:2；The reaction temperature It is 30~40 DEG C.
Preferably, in the step of preparing intermediate 3 by intermediate 2, the organic solvent of the dissolving acid 11 or intermediate 2 is Tetrahydrofuran, n-hexane, hexamethylene, normal heptane or ether, it is further preferred that the organic solvent be tetrahydrofuran or just oneself Alkane；The molar ratio of acid 11, intermediate 2 and lithium hexamethyldisilazide is 1:1~3:2~4, more preferably 1:2~2.5: 2.5~3.5.
Preferably, in the step of preparing intermediate 4 by intermediate 3, the organic solvent is methylene chloride, chloroform, toluene Or 1,2- dichloroethanes, it is further preferred that the organic solvent is methylene chloride；Intermediate 3, thionyl chloride and tin tetrachloride Molar ratio is 1:3~6:3~6, more preferably 1:4.5:4.
Preferably, in the step of preparing intermediate 5 by intermediate 4, intermediate 4 and N, mole of N- diethylaniline borane Than for 1:1；The mass ratio of intermediate 4 and (R) -2- methyl-CBS- oxazaborolidine is 1:1%~5%.
Preferably, in the step of preparing intermediate 6 by intermediate 5, the molar ratio of intermediate 5 and dimethyl sulfoxide-sodium hydride is 1: 3~5, preferably 1:4.17；Extractant is methylene chloride, chloroform or ethyl acetate, preferably methylene chloride after completion of the reaction.
Preferably, in the step of preparing intermediate 7 by intermediate 6, the molar ratio of intermediate 6 and aluminium amalgam be 1:15~ 25, more preferably 1:18~22；Recrystallization solvent is methylene chloride and isopropyl ether mixed solvent, and methylene chloride and ether mix Solvent or chloroform and ether mixed solvent；It is further preferred that recrystallization solvent is methylene chloride and isopropyl ether mixed solvent.
Preferably, in the step of preparing intermediate 8 by intermediate 7, the molar ratio of intermediate 7 and trim,ethylchlorosilane is 1: 2~3, more preferably 1:2.2.
Preferably, in the step of preparing intermediate 9 by intermediate 8, the recrystallization process is first by product dichloro Methane and isopropyl ether recrystallization, then with ethyl alcohol and Diethyl ether recrystallization；The molar ratio of intermediate 8 and compound 12 is 1:1, intermediate 8 and the molar ratio of alchlor be 1:3~6, more preferably 1:3~4.
Preferably, in the step of preparing daunomycinone by intermediate 9, the molar ratio of intermediate 9 and dimethyl boron bromide is 1:2 ~2.5, more preferably 1:2.
The present invention is initial substance by 2,5- dihydroxy-benzyl alcohol, and preparation synthesis epirubicin important intermediate daunomycinone should Route raw material is low in cost, and reaction condition is mild, convenient post-treatment, and total recovery is high, has preferable industrial applications prospect.
Specific embodiment
Content in order to better understand the present invention further illustrates skill of the invention below by specific embodiment Art scheme, but these embodiments are not intended to limit the present invention.
In following embodiment, raw material 2,5- dihydroxy-benzyl alcohol, sour 11 compounds and compound 12 can use following methods Preparation can also be prepared using other methods, and raw material sources are not limited condition by the present invention.
2,5- dihydroxy-benzyl alcohol can be prepared by the following method:
The concentrated hydrochloric acid 50ml of 2,5- dimethoxy-benzyl alcohol 10g and 35% is taken to mix, room temperature mechanical stirring 48h is placed on ice water In bath, Na is added portionwise while stirring2CO3It neutralizes, is filtered after so that pH value is adjusted to 2-3, filtrate is extracted with ethyl acetate (100ml × 3) It takes, merges organic phase, decompression steams ethyl acetate after organic phase is dried, filtered with anhydrous sodium sulfate, obtains 6.38g light yellow solid As 2,5- dihydroxy-benzyl alcohol.
The method that sour 11 compounds can refer to document Liebigs Ann.Chem.1987,515-520 is prepared.
Compound 12 can be prepared by following methods:
4- methoxyl group phthalic acid 24.2g, methylene chloride 240ml are added in a reservoir, thionyl chloride is slowly added dropwise 17.9ml, after completion of dropwise addition, back flow reaction 5h under nitrogen protection；Compound 12 is concentrated under reduced pressure to obtain.
The preparation of 1 intermediate 1 of embodiment
2,5- dihydroxy-benzyl alcohol (14.0g, 0.1mol) is dissolved in 1.4L methylene chloride, nitrogen protection, diisopropyl is added Base ethamine (62.8mL, 0.38mol) and chloromethyl methyl ether (21.3mL, 0.28mol) are kept stirring reflux 22h；End of reaction, Cooling, reaction solution is poured into the sodium bicarbonate solution that 1.4L mass fraction is 5%, stir about 10min, liquid separation, and water phase is with two Chloromethanes (3 × 500ml) extraction, collects and merges organic phase, successively uses 1.4L water washing, and 1.4L saturated common salt water washing is organic Phase, organic phase are dried, filtered with anhydrous sodium sulfate again, and filtrate is concentrated under reduced pressure to give brown oil, and 70ml petroleum ether is added Be beaten about 30min, filter, be dried under reduced pressure white solid is intermediate 1, molar yield 97.8%, HPLC purity 98.2%.
The preparation of 2 intermediate 1 of embodiment
2,5- dihydroxy-benzyl alcohol (14.0g, 0.1mol) is dissolved in 1L chloroform, nitrogen protection, diisopropyl is added Ethamine (90.9mL, 0.55mol) and chloromethyl methyl ether (26.6mL, 0.35mol) keep 48 DEG C of stirring 16h；End of reaction, drop Temperature is poured into reaction solution in the sodium bicarbonate solution that 1.4L mass fraction is 5%, stir about 10min, liquid separation, water phase chloroform (3 × 500ml) extraction, collects and merges organic phase, successively uses 1L water washing, 1L saturated common salt water washing organic phase, organic phase is again It being dried, filtered with anhydrous sodium sulfate, filtrate is concentrated under reduced pressure to give brown oil, and 40ml petroleum ether is added and is beaten about 30min, Filter, be dried under reduced pressure white solid is intermediate 1, molar yield 95.5%, HPLC purity 97.3%.
The preparation of 3 intermediate 1 of embodiment
2,5- dihydroxy-benzyl alcohol (14.0g, 0.1mol) is dissolved in 1L acetonitrile, nitrogen protection, diisopropylethylamine is added (49.6mL, 0.3mol) and chloromethyl methyl ether (30.4mL, 0.4mol) keeps 60 DEG C of stirring 15h；End of reaction, cooling, will be anti- Answer liquid pour into 1.4L mass fraction be 5% sodium bicarbonate solution in, stir about 10min, liquid separation, water phase with chloroform (3 × It 500ml) extracts, collects and merge organic phase, successively use 1L water washing, 1L saturated common salt water washing organic phase, organic phase uses nothing again Aqueous sodium persulfate dries, filters, and filtrate is concentrated under reduced pressure to give brown oil, and 40ml petroleum ether is added and is beaten about 30min, takes out Filter, be dried under reduced pressure white solid is intermediate 1, molar yield 86.4%, HPLC purity 94.6%.
The preparation of 4 intermediate 1 of embodiment
2,5- dihydroxy-benzyl alcohol (14.0g, 0.1mol) is dissolved in 1LDMF, nitrogen protection, diisopropylethylamine is added (99.2mL, 0.6mol) and chloromethyl methyl ether (15.2mL, 0.2mol) keeps 80 DEG C of stirring 20h；End of reaction, cooling, will be anti- Answer liquid pour into 1.4L mass fraction be 5% sodium bicarbonate solution in, stir about 10min, liquid separation, water phase with methylene chloride (3 × It 500ml) extracts, collects and merge organic phase, successively use 1.5L water washing, 1.5L saturated common salt water washing organic phase, organic phase is again It being dried, filtered with anhydrous sodium sulfate, filtrate is concentrated under reduced pressure to give brown oil, and 80ml petroleum ether is added and is beaten about 30min, Filter, be dried under reduced pressure white solid is intermediate 1, molar yield 82.5%, HPLC purity 95.3%.
The preparation of 5 intermediate 2 of embodiment
Intermediate 1 (18.0g, 78.9mmol, HPLC purity 98.2%) is placed in 500mL reaction flask, is added dissolved with N, The tetrahydrofuran solution 270mL of N'- dicyclohexyl-N- methyl carbodiimides iodide (54.7g, 158mol), at 30 DEG C, nitrogen Gas shielded is protected from light stirring 3h, evaporating solvent under reduced pressure, and residue is dissolved in 200mL n-hexane, washs three with water (100mL × 3) Secondary, water phase 150ml n-hexane extraction collects organic phase and, suction filtration dry with anhydrous sodium sulfate, filtrate decompression concentration, with two Chloromethanes and n-hexane mixed solvent recrystallize to obtain intermediate 2, molar yield 96.0%, HPLC purity 98.4%.
The preparation of 6 intermediate 2 of embodiment
Intermediate 1 (15.0g, 65.7mmol, HPLC purity 98.2%) is placed in 500mL reaction flask, is added dissolved with N, The hexane solution 200mL of N'- dicyclohexyl-N- methyl carbodiimides iodide (34.1g, 98.55mmol), at 40 DEG C, Nitrogen protection, is protected from light stirring 3h, evaporating solvent under reduced pressure, and residue is dissolved in 150mL n-hexane, is washed with water (80mL × 3) Three times, water phase 100mL n-hexane extraction, collects organic phase and, suction filtration dry with anhydrous sodium sulfate, and filtrate decompression concentration is used Methylene chloride and n-hexane mixed solvent recrystallize to obtain intermediate 2, molar yield 94.3%, HPLC purity 97.8%.
The preparation of 7 intermediate 2 of embodiment
Intermediate 1 (15.0g, 65.7mmol, HPLC purity 98.2%) is placed in 500mL reaction flask, is added dissolved with N, The toluene solution 300mL of N'- dicyclohexyl-N- methyl carbodiimides iodide (68.2g, 197.1mmol), at 25 DEG C, nitrogen Gas shielded is protected from light stirring 3h, evaporating solvent under reduced pressure, and residue is dissolved in 240mL n-hexane, washs three with water (120mL × 3) Secondary, water phase 200mL n-hexane extraction collects organic phase and, suction filtration dry with anhydrous sodium sulfate, filtrate decompression concentration, with two Chloromethanes and n-hexane mixed solvent recrystallize to obtain intermediate 2, molar yield 93.1%, HPLC purity 96.4%.
The preparation of 8 intermediate 2 of embodiment
Intermediate 1 (15.0g, 65.7m mol, HPLC purity 98.2%) is placed in 500mL reaction flask, is added dissolved with N, The acetonitrile solution 200mL of N'- dicyclohexyl-N- methyl carbodiimides iodide (22.7g, 65.7mmol), at 55 DEG C, nitrogen Protection is protected from light stirring 3h, evaporating solvent under reduced pressure, and residue is dissolved in 150mL n-hexane, is washed three times with water (80mL × 3), Water phase 100mL n-hexane extraction, collects organic phase and, suction filtration dry with anhydrous sodium sulfate, and dichloromethane is used in filtrate decompression concentration Alkane and n-hexane mixed solvent recrystallize to obtain intermediate 2, molar yield 83.6%, HPLC purity 94.7%.
The preparation of 9 intermediate 3 of embodiment
11 (5.0g, 24.7mmol) of acid are dissolved in 200mL n-hexane, are slowly instilled under -78 DEG C, nitrogen protection After 20min, it is molten that 50mL is added dissolved with the tetrahydrofuran solution of lithium hexamethyldisilazide (8.27g, 49.4mmol) in 130mL There is the hexane solution of intermediate 2 (12.5g, 37.0mmol, HPLC purity 98.4%).1h is stirred at -78~-50 DEG C, is heated up To -30 DEG C of stirring 20h, end of reaction pours into reaction solution in 300mL 1mol/L hydrochloric acid, with the ether of 150mL × 3 extraction three It is secondary, collect organic phase, organic phase MgSO4Dry, residue is dissolved in 250mL methylene chloride by evaporating solvent under reduced pressure, is used The saturated sodium bicarbonate solution of 125mL × 3 washs three times, and the water phase ether of 150mL × 3 extracts three times, collects and merges organic phase, MgSO4It is dry, be concentrated under reduced pressure off-white powder is intermediate 3, molar yield 89.2%, HPLC purity 96.4%.
The preparation of 10 intermediate 3 of embodiment
11 (10.0g, 49.4mmol) of acid are dissolved in 400mL tetrahydrofuran, are slowly dripped under -78 DEG C, nitrogen protection Enter 200mL dissolved with the tetrahydrofuran solution of lithium hexamethyldisilazide (29.9g, 148mmol), after 20min, 83mL is added Dissolved with the tetrahydrofuran solution of intermediate 2 (41.6g, 123mmol, HPLC purity 98.4%).3h is stirred at -78~-50 DEG C, is risen Temperature to -20 DEG C of stirring 15h, end of reaction pours into reaction solution in 600mL 1mol/L hydrochloric acid, with the ether of 300mL × 3 extraction three It is secondary, it collects organic phase and uses MgSO4Dry, residue is dissolved in 500mL methylene chloride, with 250mL × 3 by evaporating solvent under reduced pressure Saturated sodium bicarbonate solution washs three times, and the water phase ether of 300mL × 3 extracts three times, collects and merges organic phase, MgSO4It is dry, Be concentrated under reduced pressure off-white powder is intermediate 3, molar yield 91.3%, HPLC purity 97.2%.
The preparation of 11 intermediate 3 of embodiment
11 (5.0g, 24.7mmol) of acid are dissolved in 200mL hexamethylene, are slowly instilled under -78 DEG C, nitrogen protection After 20min, 50mL is added dissolved with the tetrahydrofuran solution of lithium hexamethyldisilazide (16.54g, 98.8mmol) in 200mL Dissolved with the cyclohexane solution of intermediate 2 (8.4g, 24.7mmol, HPLC purity 98.4%).2h is stirred at -78~-50 DEG C, is heated up To -25 DEG C of stirring 22h, end of reaction pours into reaction solution in 400mL 1mol/L hydrochloric acid, with the ether of 200mL × 3 extraction three It is secondary, collect organic phase, organic phase MgSO4Dry, residue is dissolved in 400mL methylene chloride by evaporating solvent under reduced pressure, is used The saturated sodium bicarbonate solution of 180mL × 3 washs three times, and the water phase ether of 200mL × 3 extracts three times, collects and merges organic phase, MgSO4It is dry, be concentrated under reduced pressure off-white powder is intermediate 3, molar yield 80.2%, HPLC purity 93.5%.
The preparation of 12 intermediate 3 of embodiment
11 (5.0g, 24.7mmol) of acid are dissolved in 200mL normal heptane, are slowly instilled under -78 DEG C, nitrogen protection After 20min, 100mL is added dissolved with the tetrahydrofuran solution of lithium hexamethyldisilazide (8.27g, 49.4mmol) in 200mL Dissolved with the n-heptane solution of intermediate 2 (25.0g, 74.1mmol, HPLC purity 98.4%).2h is stirred at -78~-50 DEG C, is risen Temperature to -25 DEG C of stirring 22h, end of reaction pours into reaction solution in 400mL 1mol/L hydrochloric acid, with the ether of 200mL × 3 extraction three It is secondary, collect organic phase, organic phase MgSO4Dry, residue is dissolved in 400mL methylene chloride by evaporating solvent under reduced pressure, is used The saturated sodium bicarbonate solution of 180mL × 3 washs three times, and the water phase ether of 200mL × 3 extracts three times, collects and merges organic phase, MgSO4It is dry, be concentrated under reduced pressure off-white powder is intermediate 3, molar yield 87.6%, HPLC purity 94.8%.
The preparation of 13 intermediate 3 of embodiment
11 (10.0g, 49.4mmol) of acid are dissolved in 400mL ether, are slowly instilled under -78 DEG C, nitrogen protection After 20min, it is molten that 83mL is added dissolved with the tetrahydrofuran solution of lithium hexamethyldisilazide (29.9g, 148mmol) in 200mL There is the diethyl ether solution of intermediate 2 (41.6g, 123mmol, HPLC purity 98.4%).3h is stirred at -78~-50 DEG C, be warming up to - 20 DEG C of stirring 15h, end of reaction pour into reaction solution in 600mL 1mol/L hydrochloric acid, three times with the extraction of the ether of 300mL × 3, receive Collection organic phase simultaneously uses MgSO4Dry, residue is dissolved in 500mL methylene chloride by evaporating solvent under reduced pressure, with the saturated carbon of 250mL × 3 Three times, the water phase ether of 300mL × 3 extracts three times for sour hydrogen sodium solution washing, collects and merges organic phase, MgSO4It is dry, it depressurizes dense Contract off-white powder is intermediate 3, molar yield 88.5%, HPLC purity 95.2%.
The preparation of 14 intermediate 4 of embodiment
By being placed in a reaction flask for intermediate 3 (15.0g, 36.4mmol, HPLC purity 97.2%), it is added at room temperature 225mL methylene chloride, is added thionyl chloride (11.2mL, 0.164mol) under nitrogen protection, and heating reflux reaction 12h is cooled to Tin tetrachloride (27.0mL, 0.146mol) is added after room temperature, 1h is stirred at 20 DEG C, end of reaction is cooled to 0 DEG C, is added Water phase is collected in 225g trash ice, liquid separation, and water phase is extracted three times with methylene chloride 120mL × 3 at 0 DEG C, collects and merge organic phase, point NaHCO is not saturated with 400mL3Solution and the washing of 400mL saturated sodium chloride solution, the anhydrous MgSO of organic phase4It is dry, it depressurizes dense Contracting, obtains 4 crude product of intermediate, molar yield 96.4%, HPLC purity 87.1%；4 crude product of intermediate uses tetrahydrofuran and just oneself again The mixed solution that alkane volume ratio is 1:3 recrystallizes, and obtains intermediate 4, molar yield 88.3%, HPLC purity 99.3%.mp:158 DEG C, [α] 20D=+48.4 (c=0.48, CHCl3)]。
The preparation of 15 intermediate 4 of embodiment
By being placed in a reaction flask for intermediate 3 (15.0g, 36.4mmol, HPLC purity 97.2%), it is added at room temperature 225mL chloroform, is added thionyl chloride (12.6mL, 0.173mol) under nitrogen protection, and heating reflux reaction 12h is cooled to room temperature Tin tetrachloride (25.5mL, 0.218mol) is added afterwards, 1h is stirred at 20 DEG C, end of reaction is cooled to 0 DEG C, and 225g is added Water phase is collected in trash ice, liquid separation, and water phase is extracted three times with the methylene chloride of 120mL × 3 at 0 DEG C, collects and merge organic phase, use respectively 400mL is saturated NaHCO3Solution and the washing of 400mL saturated sodium chloride solution, the anhydrous MgSO of organic phase4It is dry, it is concentrated under reduced pressure, obtains 4 crude product of intermediate, molar yield 95.0%, HPLC purity 86.4%；4 crude product of intermediate uses tetrahydrofuran and n-hexane volume again Than the mixed solution recrystallization for 1:3, intermediate 4, molar yield 84.0%, HPLC purity 98.9% are obtained.Mp:157 DEG C, [α] 20D=+48.5 (c=0.48, CHCl3)]。
The preparation of 16 intermediate 4 of embodiment
By being placed in a reaction flask for intermediate 3 (15.0g, 36.4mmol, HPLC purity 97.2%), it is added at room temperature Thionyl chloride (8.0mL, 0.109mol) is added under nitrogen protection, heating reflux reaction 12h, after being cooled to room temperature in 225mL toluene It is added tin tetrachloride (25.5mL, 0.218mol), 1h is stirred at 20 DEG C, end of reaction is cooled to 0 DEG C, and it is broken that 225g is added Water phase is collected in ice, liquid separation, and water phase is extracted three times with the methylene chloride of 120mL × 3 at 0 DEG C, collects and merge organic phase, use respectively 400mL is saturated NaHCO3Solution and the washing of 400mL saturated sodium chloride solution, the anhydrous MgSO of organic phase4It is dry, it is concentrated under reduced pressure, obtains 4 crude product of mesosome, molar yield 90.1%, HPLC purity 85.7%；4 crude product of intermediate uses tetrahydrofuran and n-hexane volume ratio again It is recrystallized for the mixed solution of 1:3, obtains intermediate 4, molar yield 80.4%, HPLC purity 98.0%.Mp:156 DEG C, [α] 20D =+48.4 (c=0.48, CHCl3)]。
The preparation of 17 intermediate 4 of embodiment
By being placed in a reaction flask for intermediate 3 (15.0g, 36.4mmol, HPLC purity 97.2%), it is added at room temperature Thionyl chloride (15.9mL, 0.218mol) is added under nitrogen protection in 225mL1,2- dichloroethanes, heating reflux reaction 12h, cold But to addition tin tetrachloride (12.8mL, 0.109mol) after room temperature, 1h is stirred at 20 DEG C, end of reaction is cooled to 0 DEG C, 225g trash ice is added, water phase is collected in liquid separation, and water phase is extracted three times at 0 DEG C with the methylene chloride of 120mL × 3, and collection merges organic Phase is saturated NaHCO with 400mL respectively3Solution and the washing of 400mL saturated sodium chloride solution, the anhydrous MgSO of organic phase4It is dry, subtract Pressure concentration, obtains 4 crude product of intermediate, molar yield 92.1%, HPLC purity 83.6%；4 crude product of intermediate use again tetrahydrofuran and The mixed solution that n-hexane volume ratio is 1:3 recrystallizes, and obtains intermediate 4, molar yield 81.3%, HPLC purity 96.3%.mp: 158 DEG C, [α] 20D=+48.5 (c=0.48, CHCl3)]。
The preparation of 18 intermediate 5 of embodiment
80mL tetrahydrofuran is added under nitrogen protection into reaction flask, opens stirring, N, N- diethylaniline borane is added Catalyst (R) -2- methyl-CBS- oxazaborolidine ((R)-MeCBS) (0.22g, 2%) is dissolved in by (5.0mL, 27.9mmol) 80ml tetrahydrofuran, cocurrent be added reaction flask in, 15~25 DEG C of reaction solution temperature control, with constant pressure funnel be added dropwise 220mL dissolved with The tetrahydrofuran solution of (11.0g, 27.9mmol, the HPLC purity 99.3%) of intermediate 4, it is ensured that 2~3h is dripped off, insulation reaction 10-20min；End of reaction, control temperature are lower than 25 DEG C, 32mL methanol are slowly added dropwise, and stir 15min, are concentrated under reduced pressure, are added 300mL methylene chloride, the sulfuric acid of 15~25 DEG C of temperature control dropwise addition 160mL 2mol/L, there is foam appearance, stirs 15min, adds 160mL Water, liquid separation, organic phase successively use 250mL water washing, and the washing of 250mL saturated sodium chloride solution, anhydrous sodium sulfate is dry, filter, Filtrate decompression is concentrated to dryness, then with tetrahydrofuran and ether volume ratio be 2:3 mixed solution recrystallization, obtain intermediate 5, mole receive Rate 94.2%, HPLC purity 98.8%.
The preparation of 19 intermediate 5 of embodiment
80mL tetrahydrofuran is added under nitrogen protection into reaction flask, opens stirring, N, N- diethylaniline borane is added Catalyst (R) -2- methyl-CBS- oxazaborolidine ((R)-MeCBS) (0.55g, 5%) is dissolved in by (5.0mL, 27.9mmol) 80ml tetrahydrofuran, cocurrent be added reaction flask in, 15~25 DEG C of reaction solution temperature control, with constant pressure funnel be added dropwise 220mL dissolved with The tetrahydrofuran solution of (11.0g, 27.9mmol, the HPLC purity 99.3%) of intermediate 4, it is ensured that 2~3h is dripped off, insulation reaction 10-20min；End of reaction, control temperature are lower than 25 DEG C, 32mL methanol are slowly added dropwise, and stir 15min, are concentrated under reduced pressure, are added 300mL methylene chloride, the sulfuric acid of 15~25 DEG C of temperature control dropwise addition 160mL 2mol/L, there is foam appearance, stirs 15min, adds 160mL Water, liquid separation, organic phase successively use 250mL water washing, and the washing of 250mL saturated sodium chloride solution, anhydrous sodium sulfate is dry, filter, Filtrate decompression is concentrated to dryness, then with tetrahydrofuran and ether volume ratio be 2:3 mixed solution recrystallization, obtain intermediate 5, mole receive Rate 92.7%, HPLC purity 97.2%.
The preparation of 20 intermediate 6 of embodiment
Intermediate 5 (9.51g, 24mmol, HPLC purity 98.8%) is dissolved in 500mL tetrahydrofuran, under nitrogen protection, drop 0.1mol dimethyl sulfoxide-sodium hydride is dissolved in the mixed solution of 50mL dimethyl sulfoxide and tetrahydrofuran and instills reaction flask by temperature to 0 DEG C In, 30min end of reaction is stirred at room temperature, 1.25L methylene chloride is added and 2.0L saturated ammonium chloride solution stirs 5min, it is quiet Liquid separation is set, water phase is washed twice with the methylene chloride of 1.25L × 2, merges organic phase, with 1.0L water washing organic phase, with anhydrous sulphur The dry organic phase of sour sodium, filtering, filtrate are concentrated under reduced pressure, and intermediate 6, molar yield 98.0%, HPLC purity 96.7% are obtained.
The preparation of 21 intermediate 6 of embodiment
Intermediate 5 (9.51g, 24mmol, HPLC purity 98.8%) is dissolved in 500mL tetrahydrofuran, under nitrogen protection, drop 0.12mol dimethyl sulfoxide-sodium hydride is dissolved in the mixed solution of 50mL dimethyl sulfoxide and tetrahydrofuran and instills reaction flask by temperature to 0 DEG C In, 30min end of reaction is stirred at room temperature, 1250mL chloroform is added and 2.0L saturated ammonium chloride solution stirs 5min, stands Liquid separation, water phase twice, merges organic phase 1.0L water washing with the chloroform of 1.25L × 2, dry with anhydrous sodium sulfate, decompression Concentration, obtains intermediate 6, molar yield 96.1%, HPLC purity 95.4%.
The preparation of 22 intermediate 6 of embodiment
Intermediate 5 (9.51g, 24mmol, HPLC purity 98.8%) is dissolved in 500mL tetrahydrofuran, under nitrogen protection, drop 0.072mol dimethyl sulfoxide-sodium hydride is dissolved in the mixed solution of 50mL dimethyl sulfoxide and tetrahydrofuran and instills reaction by temperature to 0 DEG C In bottle, 30min end of reaction is stirred at room temperature, 1250mL ethyl acetate and the stirring of 2.0L saturated ammonium chloride solution is added 5min stands liquid separation, and water phase is washed twice with the ethyl acetate of 1.25L × 2, merges organic phase 1.0L water washing, with anhydrous sulphur Sour sodium is dry, is concentrated under reduced pressure, obtains intermediate 6, molar yield 91.9%, HPLC purity 95.6%.
The preparation of 23 intermediate 7 of embodiment
Intermediate 6 (9.13g, 23.5mmol, HPLC purity 96.7%) is dissolved in the mixed of 250mL tetrahydrofuran and 25mL water It closes in solution, nitrogen protection, aluminium amalgam (11.9g, 0.43mol) is added at room temperature, stir 90min, filter out solid, filter Cake is washed with a small amount of tetrahydrofuran, and the mixed solution of 200mL ether and 50mL water is added into concentrate for filtrate decompression concentration, Stirring stands, separates water phase, and organic phase is dry with anhydrous sodium sulfate, evaporating solvent under reduced pressure, and concentrate is again through methylene chloride and different Propyl ether volume ratio is that the mixed solution of 1:1.8 recrystallizes to obtain intermediate 7, molar yield 91.6%, HPLC purity 99.6%.[α] 20D=+8.0 (c=1.78, chloroform)
The preparation of 24 intermediate 7 of embodiment
Intermediate 6 (9.13g, 23.5mmol, HPLC purity 96.7%) is dissolved in the mixed of 250mL tetrahydrofuran and 25mL water It closes in solution, nitrogen protection, aluminium amalgam (10.0g, 0.36mol) is added at room temperature, stir 90min, filter out solid, filter Cake is washed with a small amount of tetrahydrofuran, and the mixed solution of 200mL ether and 50mL water is added into concentrate for filtrate decompression concentration, Stirring is stood, and separates water phase, organic phase is dry with anhydrous sodium sulfate, and evaporating solvent under reduced pressure, concentrate is again through methylene chloride and second Ether volume ratio is that the mixed solution of 1:1.8 recrystallizes to obtain intermediate 7, molar yield 86.4%, HPLC purity 99.0%.[α]20D =+8.0 (c=1.78, chloroforms)
The preparation of 25 intermediate 7 of embodiment
Intermediate 6 (9.13g, 23.5mmol, HPLC purity 96.7%) is dissolved in the mixed of 250mL tetrahydrofuran and 25mL water It closes in solution, nitrogen protection, aluminium amalgam (16.0g, 0.58mol) is added at room temperature, stir 90min, filter out solid, filter Cake is washed with a small amount of tetrahydrofuran, and the mixed solution of 200mL ether and 50mL water is added into concentrate for filtrate decompression concentration, Stirring is stood, and separates water phase, organic phase is dry with anhydrous sodium sulfate, and evaporating solvent under reduced pressure, concentrate is again through chloroform and ether body Product is than being that the mixed solution of 1:2.3 recrystallizes to obtain intermediate 7, molar yield 89.5%, HPLC purity 99.2%.[α] 20D=+ 8.1 (c=1.78, chloroforms)
The preparation of 26 intermediate 8 of embodiment
Intermediate 7 (7.0g, 21.5mmol, HPLC purity 99.6%) is added into three-necked flask, with 42mL methylene chloride Dissolution, 0 DEG C, under nitrogen protection, be added dropwise triethylamine (6.0mL, 43mmol), be then added dropwise again trim,ethylchlorosilane (6.00mL, 47.3mmol), 1~2h is stirred to react at 0 DEG C, reaction terminates, and the dilution of 100mL methylene chloride, reaction are added into reaction system Liquid pours into 100mL ice water, and organic phase is collected in extraction, successively twice with the water washing of 100mL × 2, the saturated salt solution of 100mL × 2 Wash twice, organic phase is dry with anhydrous sodium sulfate, filter, filtrate decompression be concentrated to dryness intermediate 8, molar yield are 98.7%, HPLC purity 98.4%.
The preparation of 27 intermediate 8 of embodiment
Intermediate 7 (7.0g, 21.5mmol, HPLC purity 99.6%) is added into three-necked flask, with 42mL methylene chloride Dissolution, 0 DEG C, under nitrogen protection, be added dropwise triethylamine (6.0mL, 43mmol), be then added dropwise again trim,ethylchlorosilane (8.1mL, 64.5mmol), 1~2h is stirred to react at 0 DEG C, reaction terminates, and the dilution of 100mL methylene chloride, reaction are added into reaction system Liquid pours into 100mL ice water, and organic phase is collected in extraction, successively twice with the water washing of 100mL × 2, the saturated salt solution of 100mL × 2 Wash twice, organic phase is dry with anhydrous sodium sulfate, filter, filtrate decompression be concentrated to dryness intermediate 8, molar yield are 96.5%, HPLC purity 98.2%.
The preparation of 28 intermediate 9 of embodiment
The dichloromethane solution of intermediate 8 (10.1g, 21.5mmol, HPLC purity 98.4%) is added into reaction flask, point Batch be added alchlor (8.6g, 64.5mmol), be cooled to 0 DEG C, be slowly dropped into 30mL dissolved with compound 12 (5.0g, Dichloromethane solution 21.5mmol), 0 DEG C of stirring 30min, is warmed to room temperature naturally, stirs 6-8h, the 70mL that reaction solution is poured into Mass fraction is in 3%HCl solution, and 0.5~1h is stirred at room temperature in 0 DEG C of insulated and stirred 10min, stands liquid separation, separates organic phase, Water phase is extracted with 40mL methylene chloride, collects organic phase, and organic phase is washed with 100mL saturated sodium bicarbonate solution, anhydrous slufuric acid Sodium is dry, is concentrated under reduced pressure, and concentrate is recrystallized through the mixed solution that methylene chloride and isopropyl ether volume ratio are 1:4, then uses ethyl alcohol Mixed solution recrystallization with ether volume ratio is 1:5, obtains intermediate 9.Molar yield 93.9%, HPLC purity 99.7%.
The preparation of 29 intermediate 9 of embodiment
The dichloromethane solution of intermediate 8 (10.1g, 21.5mmol, HPLC purity 98.4%) is added into reaction flask, point Batch be added alchlor (17.2g, 129mmol), be cooled to 0 DEG C, be slowly dropped into 30mL dissolved with compound 12 (5.0g, Dichloromethane solution 21.5mmol), 0 DEG C of stirring 30min, is warmed to room temperature naturally, stirs 6-8h, the 70mL that reaction solution is poured into Mass fraction is in 3%HCl solution, and 0.5~1h is stirred at room temperature in 0 DEG C of insulated and stirred 10min, stands liquid separation, separates organic phase, Water phase is extracted with 40mL methylene chloride, collects organic phase, and organic phase is washed with 100mL saturated sodium bicarbonate solution, anhydrous slufuric acid Sodium is dry, is concentrated under reduced pressure, and concentrate is recrystallized through the mixed solution that methylene chloride and isopropyl ether volume ratio are 1:4, then uses ethyl alcohol Mixed solution recrystallization with ether volume ratio is 1:5, obtains intermediate 9.Molar yield 93.4%, HPLC purity 99.5%.
The preparation of 30 daunomycinone of embodiment
Intermediate 9 (9.3g, 19.1mmol, HPLC purity 99.7%) is dissolved in 120mL methylene chloride, under nitrogen protection, It is cooled to 2-8 DEG C, 20mL is instilled dissolved with the dichloromethane solution of dimethyl boron bromide (4.6g, 38.2mmol), keeps the temperature 2-8 DEG C 2h is stirred, reaction solution is poured into the mixed solution of 80mL saturated sodium bicarbonate solution and 120ml tetrahydrofuran, stirs 15min, point Liquid, the water phase methylene chloride of 80mL × 3 extract three times, collect and merge organic phase, organic phase 160mL saturated common salt water washing, Anhydrous sodium sulfate is dry, and daunomycinone, molar yield 98.2%, HPLC purity 99.5% is concentrated under reduced pressure to obtain.
The preparation of 1 intermediate 1 of comparative example
2,5- dihydroxy-benzyl alcohol (14.0g, 0.1mol) is dissolved in 1.4L normal heptane, nitrogen protection, diisopropyl is added Ethamine (62.8mL, 0.38mol) and chloromethyl methyl ether (21.3mL, 0.28mol) are kept stirring reflux 22h；End of reaction, drop Temperature is poured into reaction solution in the sodium bicarbonate solution that 1.4L mass fraction is 5%, stir about 10min, liquid separation, water phase dichloro Methane (3 × 500ml) extraction, collects and merges organic phase, and organic phase successively uses 1.4L water washing, 1.4L saturated common salt water washing, Anhydrous sodium sulfate dries organic phase, filtering, and filtrate is concentrated under reduced pressure to give brown oil, and the mashing of 70ml petroleum ether is added about 30min, filter, be dried under reduced pressure white solid is intermediate 1, molar yield 68.5%, HPLC purity 92.3%.
The preparation of 2 intermediate 1 of comparative example
2,5- dihydroxy-benzyl alcohol (14.0g, 0.1mol) is dissolved in 1.4L methylene chloride, nitrogen protection, diisopropyl is added Base ethamine (33.0mL, 0.2mol) and chloromethyl methyl ether (38.0mL, 0.5mol) are kept stirring reflux 22h；End of reaction, drop Temperature is poured into reaction solution in the sodium bicarbonate solution that 1.4L mass fraction is 5%, stir about 10min, liquid separation, water phase dichloro Methane (3 × 500ml) extraction, collects and merges organic phase, and organic phase successively uses 1.4L water washing, 1.4L saturated common salt water washing, Anhydrous sodium sulfate dries organic phase, filtering, and filtrate is concentrated under reduced pressure to give brown oil, and the mashing of 70ml petroleum ether is added about 30min, filter, be dried under reduced pressure white solid is intermediate 1, molar yield 55.2%, HPLC purity 93.8%.
The preparation of 3 intermediate 2 of comparative example
Intermediate 1 (18.0g, 78.9m mol, HPLC purity 98.2%) is placed in 1000mL reaction flask, be added dissolved with The tetrahydrofuran solution 500mL of N, N'- dicyclohexyl-N- methyl carbodiimides iodide (137g, 394.5mol), 30 DEG C Under, nitrogen protection is protected from light stirring 3h, and evaporating solvent under reduced pressure, residue is dissolved in 200mL n-hexane, with water (100mL × 3) Three times, water phase 150ml n-hexane extraction, collects organic phase and, suction filtration dry with anhydrous sodium sulfate, filtrate decompression are dense for washing Contracting, recrystallizes to obtain intermediate 2, molar yield 90.6%, HPLC with the mixed solvent that methylene chloride and n-hexane volume ratio are 1:3 Purity 78.5%.
The preparation of 4 intermediate 3 of comparative example
11 (5.0g, 24.7mmol) of acid are dissolved in 200mL n-hexane, are slowly instilled under -78 DEG C, nitrogen protection After 20min, it is molten that 50mL is added dissolved with the tetrahydrofuran solution of lithium hexamethyldisilazide (20.60g, 123mmol) in 200mL There is the tetrahydrofuran solution of intermediate 2 (33.3g, 98.4mmol, HPLC purity 98.4%).1h is stirred at -78~-50 DEG C, is risen Temperature to -30 DEG C of stirring 20h, end of reaction pours into reaction solution in 300mL 1mol/L hydrochloric acid, with the ether of 150mL × 3 extraction three It is secondary, it collects organic phase and uses MgSO4Dry, residue is dissolved in 250mL methylene chloride, with 125mL × 3 by evaporating solvent under reduced pressure Saturated sodium bicarbonate solution washs three times, and the water phase ether of 150mL × 3 extracts three times, collects and merges organic phase, MgSO4It is dry, Be concentrated under reduced pressure off-white powder is intermediate 3, molar yield 75.1%, HPLC purity 81.8%.
The preparation of 5 intermediate 4 of comparative example
By being placed in a reaction flask for intermediate 3 (15.0g, 36.4mmol, HPLC purity 97.2%), it is added at room temperature 225mL methylene chloride, is added thionyl chloride (5.0mL, 72.8mmol) under nitrogen protection, and heating reflux reaction 12h is cooled to room Tin tetrachloride (13.5mL, 72.8mmol) is added after temperature, 1h is stirred at 20 DEG C, end of reaction is cooled to 0 DEG C, is added Water phase is collected in 225g trash ice, liquid separation, and water phase is extracted three times with methylene chloride 120mL × 3 at 0 DEG C, collects and merge organic phase, have Machine is mutually successively saturated NaHCO with 400mL3Solution and the washing of 400mL saturated sodium chloride solution, anhydrous MgSO4It is dry, it is concentrated under reduced pressure, Obtain 4 crude product of intermediate, molar yield 78.3%, HPLC purity 76.8%；4 crude product of intermediate uses tetrahydrofuran and n-hexane body again Product is recrystallized than the mixed solution for being 1:3, obtains intermediate 4, molar yield 60.9%, HPLC purity 90.7%.Mp:157 DEG C, [α] 20D=+48.1 (c=0.48, CHCl3)]。
The preparation of 6 intermediate 4 of comparative example
By being placed in a reaction flask for intermediate 3 (15.0g, 36.4mmol, HPLC purity 97.2%), it is added at room temperature 225mL methylene chloride, is added thionyl chloride (25.0mL, 364mmol) under nitrogen protection, and heating reflux reaction 12h is cooled to room Tin tetrachloride (13.5mL, 72.8mmol) is added after temperature, 1h is stirred at 20 DEG C, end of reaction is cooled to 0 DEG C, is added Water phase is collected in 225g trash ice, liquid separation, and water phase is extracted three times with methylene chloride 120mL × 3 at 0 DEG C, collects and merge organic phase, have Machine is mutually successively saturated NaHCO with 400mL3Solution and the washing of 400mL saturated sodium chloride solution, anhydrous MgSO4It is dry, it is concentrated under reduced pressure, Obtain 4 crude product of intermediate, molar yield 79.6%, HPLC purity 62.7%；4 crude product of intermediate uses tetrahydrofuran and n-hexane body again Product is recrystallized than the mixed solution for being 1:3, obtains intermediate 4, molar yield 50.7%, HPLC purity 82.3%.Mp:156 DEG C, [α] 20D=+48.4 (c=0.48, CHCl3)]。
The preparation of 7 intermediate 5 of comparative example
80mL tetrahydrofuran is added under nitrogen protection into reaction flask, opens stirring, N, N- diethylaniline borane is added Catalyst (R) -2- methyl-CBS- oxazaborolidine ((R)-MeCBS) (0.22g, 2%) is dissolved in by (2.5mL, 13.9mmol) 80ml tetrahydrofuran, cocurrent be added reaction flask in, 15~25 DEG C of reaction solution temperature control, with constant pressure funnel be added dropwise 220mL dissolved with The tetrahydrofuran solution of (11.0g, 27.9mmol, the HPLC purity 99.3%) of intermediate 4, it is ensured that 2~3h is dripped off, insulation reaction 10-20min, control temperature are lower than 25 DEG C, 32mL methanol are slowly added dropwise, and stir 15min, are concentrated under reduced pressure, 300mL dichloromethane is added Alkane, the sulfuric acid of 15~25 DEG C of temperature control dropwise addition 160mL 2mol/L, there is foam appearance, stirs 15min, adds 160mL water, stands and divides Liquid, organic phase 250mL water washing, the washing of 250mL saturated sodium chloride solution, anhydrous sodium sulfate is dry, filters, and filtrate decompression is dense It is reduced to dry, the mixed solution that tetrahydrofuran and ether volume ratio are 2:3 recrystallizes, obtain intermediate 5, molar yield 90.1%, HPLC purity 56.3%.
The preparation of 8 intermediate 6 of comparative example
Intermediate 5 (9.51g, 24mmol, HPLC purity 98.8%) is dissolved in 500mL tetrahydrofuran, under nitrogen protection, drop 0.05mol dimethyl sulfoxide-sodium hydride is dissolved in the mixed solution of 50mL dimethyl sulfoxide and tetrahydrofuran and instills reaction flask by temperature to 0 DEG C In, 30min end of reaction is stirred at room temperature, 1250mL methylene chloride is added and 2.0L saturated ammonium chloride solution stirs 5min, Liquid separation is stood, water phase is washed twice with the methylene chloride of 1.25L × 2, is merged organic phase with 1.0L water washing and is used anhydrous sodium sulfate It is dry, it is concentrated under reduced pressure, obtains intermediate 6, molar yield 76.6%, HPLC purity 89.7%.
The preparation of 9 intermediate 7 of comparative example
Intermediate 6 (9.13g, 23.5mmol, HPLC purity 96.7%) is dissolved in the mixed of 250mL tetrahydrofuran and 25mL water It closes in solution, nitrogen protection, aluminium amalgam (6.6g, 0.24mol) is added at room temperature, stir 90min, filter out solid, filter Cake is washed with a small amount of tetrahydrofuran, and filtrate decompression concentration is added the mixed solution of 200mL ether and 50mL water, stirs, stands, Separate water phase, organic phase is dry with anhydrous sodium sulfate, evaporating solvent under reduced pressure, then through methylene chloride and isopropyl ether volume ratio is 1: 1.8 mixed solution recrystallizes to obtain intermediate 7, molar yield 76.8%, HPLC purity 87.9%.[α] 20D=+7.9 (c= 1.78, chloroform)
The preparation of 10 intermediate 8 of comparative example
Intermediate 7 (7.0g, 21.5mmol, HPLC purity 99.6%) is added into three-necked flask, with 42mL methylene chloride Dissolution, 0 DEG C, under nitrogen protection, be added dropwise triethylamine (6.0mL, 43mmol), be then added dropwise again trim,ethylchlorosilane (13.5mL, 107.5mmol), 1~2h is stirred to react at 0 DEG C, reaction terminates, and the dilution of 100mL methylene chloride is added, and reaction solution pours into 100mL In ice water, organic phase is collected in extraction, and organic phase successively uses the water washing of 100mL × 2 twice, the saturated common salt water washing of 100mL × 2 Twice, anhydrous sodium sulfate is dry, filters, filtrate decompression is drying to obtain intermediate 8, molar yield 92.7%, HPLC purity 78.6%.
The preparation of 11 intermediate 9 of comparative example
The dichloromethane solution of intermediate 8 (10.1g, 21.5mmol, HPLC purity 98.4%) is added into reaction flask, point Batch be added alchlor (4.3g, 32.2mmol), be cooled to 0 DEG C, be slowly dropped into 30mL dissolved with compound 12 (5.0g, Dichloromethane solution 21.5mmol), 0 DEG C of stirring 30min, is warmed to room temperature naturally, stirs 6-8h, the 70mL that reaction solution is poured into Mass fraction is to keep the temperature 0 DEG C of stirring 10min in 3%HCl solution, 0.5~1h is stirred at room temperature, separates organic phase, water phase 40mL Methylene chloride extraction, collects organic phase, and organic phase is washed with 100mL saturated sodium bicarbonate solution, and anhydrous sodium sulfate is dry, decompression Concentration, the mixed solution that methylene chloride and isopropyl ether volume ratio are 1:4 recrystallize, then with ethyl alcohol and ether volume ratio are 1:5's Mixed solution recrystallization, obtains intermediate 9.Molar yield 90.5%, HPLC purity 81.3%.
The preparation of 12 daunomycinone of comparative example
Intermediate 9 (9.3g, 19.1mmol, HPLC purity 99.7%) is dissolved in 120mL methylene chloride, under nitrogen protection, It is cooled to 2-8 DEG C, 20mL is instilled dissolved with the dichloromethane solution of dimethyl boron bromide (11.5g, 95.5mmol), keeps the temperature 2-8 DEG C 2h is stirred, reaction solution is poured into the mixed solution of 80mL saturated sodium bicarbonate solution and 120ml tetrahydrofuran, stirs 15min, point Liquid, the water phase methylene chloride of 80mL × 3 extract three times, collect and merge organic phase, organic phase 160mL saturated common salt water washing, Anhydrous sodium sulfate is dry, and daunomycinone, molar yield 92.5%, HPLC purity 84.2% is concentrated under reduced pressure to obtain.
Intermediate 1 is analyzed with 1H-NMR and MS mass spectrum:
1H NMR(400MHz,CDCl3): δ=6.71~6.74 (m, 3H, ArH)；6.06(s,2H,OCH2O)；6.05(s, 2H,OCH2O)；3.27(s,3H,OCH3)；3.26(s,3H,OCH3)；4.84(s,2H,CH2OH)；2.87(s,1H,OH)
ESI-MS (M/Z)=251 [M+Na]+
Intermediate 2 is analyzed with 1H-NMR and MS mass spectrum:
1H NMR(400MHz,CDCl3): δ=6.68~6.71 (m, 2H, ArH)；6.64(s,1H,ArH)；6.05(s,2H, OCH2O)；6.04(s,2H,OCH2O)；3.26(s,3H,OCH3)；3.25(s,3H,OCH3)；4.35(s,2H,CH2I)；
ESI-MS (M/Z)=361 [M+Na]+
Intermediate 3 is analyzed with 1H-NMR and MS mass spectrum:
1H NMR(400MHz,CDCl3): δ=11.35 (brs, 1H, COOH)；6.77~6.79 (m, 2H, ArH)；6.70 (s,1H,ArH)；6.05(s,2H,OCH2O)；6.04(s,2H,OCH2O)；5.12(s,1H)；3.27(s,3H,OCH3)；3.26 (s,3H,OCH3)；3.09(d,Jgem=14.2Hz, 1H)；3.03(d,Jgem=14.2Hz, 1H)；2.92(d,Jgem=16.4Hz, 1H,CH2COOH)；2.70(d,Jgem=16.4Hz, 1H, CH2COOH)；0.97(s,9H,tBu).
ESI-MS (M/Z)=435 [M+Na]+。
Intermediate 4 is analyzed with 1H-NMR and MS mass spectrum:
1H NMR(400MHz,CDCl3): δ=7.04 (d, J=9.1Hz, 1H)；6.86 (d, J=9.1Hz, 1H)；6.04 (s,2H,OCH2O)；6.03(s,2H,OCH2O)；5.13(s,1H)；3.27(s,3H,OCH3)；3.26(s,3H,OCH3)；3.34 (d,Jgem=18.0Hz, 1H)；3.22(d,Jgem=18.2Hz, 1H)；2.90((s,2H)；0.97(s,9H,tBu).
ESI-MS (M/Z)=417 [M+Na]+。
Intermediate 5 is analyzed with 1H-NMR and MS mass spectrum:
1H NMR(400MHz,CDCl3): δ=7.73 (s, 2H, ArH)；6.05(s,2H,OCH2O)；6.03(s,2H, OCH2O)；5.30(s,1H)；5.21~5.25 (m, 1H)；3.28(s,3H,OCH3)；3.26(s,3H,OCH3)；3.25(dd,J =18.0Hz, 2.0Hz, 1H)；3.23 (d, J=9.0Hz, 1H, OH)；2.81 (d, J=18.0Hz, 1H)；2.43(m,1H)； 2.32(m,1H)；0.98(s,9H,tBu).
ESI-MS (M/Z)=419 [M+Na]+。
Intermediate 6 is analyzed with 1H-NMR and MS mass spectrum:
1H NMR(300MHz,DMSO-d6) δ=6.78 (d, J=8.6Hz, 1H, Ar-H)；6.77 (d, J=8.8Hz, 1H, Ar-H)；6.15(s,2H,OCH2O)；6.14(s,2H,OCH2O)；5.11~5.18 (m, 1H, 1-H)；3.87(S,1H, COCH2SO)；3.85(S,1H,3-OH)；3.78 (d, J=3.6Hz, 1H, 1-OH)；3.36(s,3H,OCH3)；3.34(s,3H, OCH3)；3.16(dd,Jgem=17.7Hz, J2b,4a=2.2Hz, 1H, 4a-H)；2.90(d,Jgem=17.7Hz, 1H, 4b-H)； 2.76(s,3H,SOCH3)；2.32~2.38 (m, 1H, 2b-H)；2.22(dd,Jgem=14.4Hz, J1a,2a=4.6Hz, 1H, 2a- H).
ESI-MS (M/Z)=411 [M+Na]+。
Intermediate 7 is analyzed with 1H-NMR and MS mass spectrum:
1H NMR(300MHz,DMSO-d6) δ=6.76 (d, J=8.6Hz, 1H, Ar-H)；6.75 (d, J=8.8Hz, 1H, Ar-H)；6.15(s,2H,OCH2O)；6.14(s,2H,OCH2O)；5.10~5.17 (m, 1H, 1-H)；3.84(S,1H,3-OH)； 3.78 (d, J=3.6Hz, 1H, 1-OH)；3.36(s,3H,OCH3)；3.34(s,3H,OCH3)；3.14(dd,Jgem=17.7Hz, J2b,4a=2.2Hz, 1H, 4a-H)；2.88(d,Jgem=17.7Hz, 1H, 4b-H)；2.46(s,3H,COCH3)；2.32~2.38 (m,1H,2b-H)；2.22(dd,Jgem=14.4Hz, J1a,2a=4.6Hz, 1H, 2a-H)
ESI-MS (M/Z)=349 [M+Na]+。
Intermediate 8 is analyzed with 1H-NMR and MS mass spectrum:
1H NMR(300MHz,DMSO-d6) δ=6.75 (d, J=8.6Hz, 1H, Ar-H), δ=6.74 (d, J=8.8Hz, 1H,Ar-H),6.13(s,2H,OCH2O),6.12(s,2H,OCH2), O 5.11~5.18 (m, 1H, 1-H), 3.36 (s, 3H, OCH3),3.34(s,3H,OCH3),3.13(dd,Jgem=17.7Hz, J2b,4a=2.2Hz, 1H, 4a-H), 2.86 (d, Jgem= 17.7Hz,1H,4b-H),2.44(s,3H,COCH3), 2.30~2.36 (m, 1H, 2b-H), 2.20 (dd, Jgem=14.4Hz, J1a,2a=4.6Hz, 1H, 2a-H), 0.09 (s, 9H, CH3).
ESI-MS (M/Z)=494 [M+Na]+。
Intermediate 9 is analyzed with 1H-NMR and MS mass spectrum:
1H NMR(300MHz,CDCl3) δ=8.03 (d, 1H, J=7.6Hz, 4-H)；7.80 (t, 1H, J=8.2Hz, 3- H)；7.42 (d, 1H, J=8.4Hz, 2-H)；6.35(s,2H,OCH2O)；6.28(s,2H,OCH2O)；5.32(brs,1H,10- H)；4.60(s,1H,8-OH)；4.06(s,3H,OCH3)；3.77(brs,1H,10-OH)；3.55(s,3H,OCH2OCH3)；3.49 (s,3H,OCH2OCH3)；3.06(AB,2H,JAB=18.6Hz, 7-H)；2.41(s,3H,COCH3)；2.35 (d, 1H, J= 14.6Hz,9-H)；2.17 (dd, 1H, J=4.8Hz, 9-H)
ESI-MS (M/Z)=509 [M+Na]+。
Daunomycinone is analyzed with 1H-NMR and MS mass spectrum:
1H NMR(300MHz,CDCl3) δ=14.01 (brs, 1H, 11-OH)；13.24(s,1H,6-OH)；8.04(d,1H, J=7.6Hz, 4-H)；7.81 (t, 1H, J=8.2Hz, 3-H)；7.42 (d, 1H, J=8.4Hz, 2-H)；5.30(brs,1H,10- H)；4.57(s,1H,8-OH)；4.05(s,3H,OCH3)；3.77(brs,1H,10-OH)；3.06(AB,2H,JAB=18.6Hz, 7-H)；2.41(s,3H,COCH3)；2.35 (d, 1H, J=14.6Hz, 9-H)；2.35 (dd, 1H, J=4.8Hz, 9-H)
ESI-MS (M/Z)=421 [M+Na]+。

Claims (10)

1. a kind of synthetic method of epirubicin intermediate daunomycinone, which is characterized in that synthetic route is as follows:
2. a kind of synthetic method of epirubicin intermediate daunomycinone according to claim 1, which is characterized in that by 2,5- Dihydroxy-benzyl alcohol prepares the step of intermediate 1 are as follows: 2,5- dihydroxy-benzyl alcohol is dissolved in organic solvent, is added two under nitrogen protection Wopropyl ethyl amine and chloromethyl methyl ether, reaction solution is poured into 5% sodium bicarbonate by stirring to end of reaction, cooling at 35~70 DEG C In solution, stirring stands liquid separation, and water phase uses methylene chloride or chloroform to extract again, collects organic phase, with water, saturated salt solution according to Secondary washing, the dry organic phase of anhydrous sodium sulfate, is collected by filtration organic phase reduced pressure, and petroleum ether mashing is added, filters, decompression is dry It is dry to obtain intermediate 1.
3. a kind of synthetic method of epirubicin intermediate daunomycinone according to claim 1, which is characterized in that by centre Body 1 prepares the step of intermediate 2 are as follows: is placed in a reaction flask intermediate 1, is added dissolved with N, the carbonization of N'- dicyclohexyl-N- methyl The organic solvent of diimine iodide is protected from light at 25~55 DEG C, and evaporating solvent under reduced pressure, residue is dissolved in n-hexane, water It washes, water phase n-hexane extraction, it is simultaneously dry with anhydrous sodium sulfate to collect organic phase, filters, filtrate decompression concentration, and residue is with two Chloromethanes and n-hexane mixed solvent recrystallize to obtain intermediate 2.
4. a kind of synthetic method of epirubicin intermediate daunomycinone according to claim 1, which is characterized in that by centre Body 2 prepares the step of intermediate 3 are as follows: acid 11 is dissolved in organic solvent, -78 DEG C, double front threes are slowly instilled under nitrogen protection The organic solvent dissolved with intermediate 2 is added in the tetrahydrofuran solution of base silicon substrate amido lithium, and -78~-50 DEG C are stirred to react 1~3h, It is warming up to -30~-20 DEG C and is stirred to react 15~22h, end of reaction pours into reaction solution in hydrochloric acid, and isopropyl ether extraction, collection has Machine phase, it is dry with magnesium sulfate, it is dissolved in methylene chloride after evaporating solvent under reduced pressure, is washed with saturated sodium bicarbonate solution, water phase is used Organic phase is collected in isopropyl ether extraction, and magnesium sulfate is dry, is concentrated under reduced pressure up to intermediate 3.
5. a kind of synthetic method of epirubicin intermediate daunomycinone according to claim 1, which is characterized in that by centre Body 3 prepares the step of intermediate 4 are as follows: is placed in a reaction flask intermediate 3, organic solvent is added at room temperature, adds under nitrogen protection Enter thionyl chloride, tin tetrachloride is added after being cooled to room temperature in heating reflux reaction 12h, is stirred to react 1h at 20 DEG C, is cooled to 0 DEG C, trash ice is added, water phase is collected in liquid separation, and water phase is extracted with dichloromethane, collect organic phase, with saturated sodium bicarbonate solution and Saturated sodium chloride solution is successively washed, and anhydrous magnesium sulfate is dry, and 4 crude product of intermediate, tetrahydrofuran and n-hexane is concentrated under reduced pressure to obtain Mixed solution recrystallize to obtain intermediate 4.
6. a kind of synthetic method of epirubicin intermediate daunomycinone according to claim 1, which is characterized in that by centre Body 4 prepares the step of intermediate 5 are as follows: under nitrogen protection, tetrahydrofuran solution, N, N- diethyl are sequentially added into reaction vessel Aniline borine, the solution of the tetrahydrofuran of (R) -2- methyl CBS- oxazaborolidine, is slowly added to intermediate 4 by 15~25 DEG C of temperature control Tetrahydrofuran solution, insulation reaction, control temperature be lower than 25 DEG C, methanol is slowly added dropwise, stir, be concentrated under reduced pressure, be added dichloro Sulfuric acid is added dropwise at 15~25 DEG C in methane, stirs, adds moisture liquid, organic phase is successively washed with water and saturated sodium chloride solution again, nothing Aqueous sodium persulfate is dry, filters, and filtrate decompression is concentrated to dryness, and tetrahydrofuran and ether mixed solution recrystallization obtain intermediate 5.
7. a kind of synthetic method of epirubicin intermediate daunomycinone according to claim 1, which is characterized in that by centre Body 5 prepares the step of intermediate 6 are as follows: intermediate 5 is dissolved in tetrahydrofuran solvent, under nitrogen protection, 0 DEG C is cooled to, by two First sulfoxide sodium salt instills after being dissolved in the mixed solution of dimethyl sulfoxide and tetrahydrofuran, is stirred to react at room temperature, and end of reaction is added Extractant and saturated ammonium chloride solution stirring, stand liquid separation, and water phase is washed with extractant, collect organic phase, and organic phase is used Water washing, anhydrous sodium sulfate is dry, and intermediate 6 is concentrated under reduced pressure to obtain.
8. a kind of synthetic method of epirubicin intermediate daunomycinone according to claim 1, which is characterized in that by centre Body 6 prepares the step of intermediate 7 are as follows: is dissolved in intermediate 6 in the mixed solution of tetrahydrofuran and water, aluminium mercury is added at room temperature Together, stirred under nitrogen atmosphere filters out solid, and filter cake is washed with a small amount of tetrahydrofuran, and it is water-soluble that ether is added in filtrate decompression concentration Liquid stirs, and stands, liquid separation, and organic phase is dry with anhydrous sodium sulfate, and evaporating solvent under reduced pressure, product recrystallizes to obtain intermediate 7 again.
9. a kind of synthetic method of epirubicin intermediate daunomycinone according to claim 1, which is characterized in that by centre Body 7 prepares the step of intermediate 8 are as follows: and intermediate 7 is added into three-necked flask, is dissolved with methylene chloride, under 0 DEG C of nitrogen protection, Triethylamine, trim,ethylchlorosilane is added dropwise, stirring terminates to reaction, and methylene chloride dilute reaction solution pours into reaction solution in ice water, Extraction, organic phase water, saturated salt solution successively wash, and anhydrous sodium sulfate is dry, filter up to intermediate 8.
10. a kind of synthetic method of epirubicin intermediate daunomycinone according to claim 1, which is characterized in that in Mesosome 8 prepares the step of intermediate 9 are as follows: alchlor is added portionwise in the dichloromethane solution of intermediate 8, is cooled to 0 DEG C, delays The slow dichloromethane solution for instilling compound 12,0 DEG C of stirring 30min are warmed to room temperature 6~8h of stirring naturally, reaction solution are poured into 0 DEG C dilute hydrochloric acid in, 0 DEG C of stirring 10min stirs 0.5~1h at room temperature, and liquid separation, water phase be extracted with dichloromethane, and collects organic Phase, saturated sodium bicarbonate solution washing, anhydrous sodium sulfate is dry, and 9 crude product of intermediate is concentrated under reduced pressure to obtain, recrystallizes to obtain intermediate 9； The step of epirubicin intermediate daunomycinone is prepared by intermediate 9 are as follows: intermediate 9 is dissolved in methylene chloride, under nitrogen protection, 2~8 DEG C are cooled to, instills the dichloromethane solution of dimethyl boron bromide, 2~8 DEG C are stirred to react, after reaction by reaction solution It pours into the mixed solution of saturated sodium bicarbonate and tetrahydrofuran, stirring stands liquid separation, and water phase is extracted with dichloromethane, and collects Organic phase washs organic phase with saturated sodium chloride solution, and organic phase is collected in liquid separation, and the dry organic phase of anhydrous sodium sulfate depressurizes dense It contracts up to epirubicin intermediate daunomycinone.
CN201810259489.2A 2018-03-27 2018-03-27 A kind of synthetic method of epirubicin intermediate daunomycinone Pending CN110305001A (en)

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