CN109942647A

CN109942647A - A kind of synthetic method of epirubicin intermediate epirubicin

Info

Publication number: CN109942647A
Application number: CN201811405052.1A
Authority: CN
Inventors: 霍领雁; 时江华
Original assignee: Lunan Pharmaceutical Group Corp
Current assignee: Lunan Pharmaceutical Group Corp
Priority date: 2018-11-23
Filing date: 2018-11-23
Publication date: 2019-06-28
Anticipated expiration: 2038-11-23
Also published as: CN109942647B

Abstract

The invention belongs to organic synthesis fields, specifically disclose a kind of synthetic method of epirubicin intermediate epirubicin.The present invention is with (2R; 6S) -6- methoxyl group -2- methyl -6H- pyrans -3- ketone is starting material; through reduction double bond, halogenated, ammonification, chiral resolution, intermediate VI is obtained after trifluoroacetyl group protects amino, chloro again, intermediate VI and daunomycinone, which are coupled, obtains epirubicin intermediate epirubicin through sodium borohydride reduction, de- trifluoroacetyl group again.The fully synthetic route of the present invention has many advantages, such as that step is short, reaction condition is mild, high income, convenient post-treatment, has preferable industrial prospect.

Description

A kind of synthetic method of epirubicin intermediate epirubicin

Technical field

The invention belongs to organic synthesis fields, and in particular to a kind of synthesis side of epirubicin intermediate epirubicin Method.

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, 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.

Epirubicin is the chiral isomer of daunorubicin, and the important intermediate of synthesis epirubicin, chemistry close At method report it 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 body surface among a kind of epirubicin is soft red mould The chemical synthesis process of element, specific technical solution are as follows:

A kind of synthetic method of the epirubicin with structural formula X, includes the following steps,

Formula VIII compound obtains the compound of Formula X structure, i.e. epirubicin through basic hydrolysis amido bond, and reaction equation is such as Under:

Preferably, the alkali is selected from NaOH, KOH, ammonium hydroxide, K₂CO₃、Na₂CO₃One of, reaction temperature is 0~10 ℃。

Preferably, the compound with Formula VIII structure is obtained with the ketone group of 4 ' position of reducing agent reduction-type VII compound, instead Answer formula as follows:

It is further preferred that used reducing agent is sodium borohydride, reaction temperature is -5~10 DEG C.

Preferably, daunomycinone reacts the chemical combination for obtaining and having Formula VII structure with Formula IV compound under the effect of the catalyst Object, reaction equation are as follows:

It is further preferred that catalyst used in this reaction be selected from 3a molecular sieve/mercury oxide/mercuric bromide and 4a molecular sieve/ One group in silver trifluoromethanesulfonate, used solvent in tetrahydrofuran, methylene chloride, toluene and ethyl acetate one Kind.

Preferably, Formula V compound reacts the compound for obtaining and having Formula IV structure with chlorinating agent, and reaction equation is as follows:

It is further preferred that chlorinating agent used by this reaction is selected from chloroacetic chloride/thionyl chloride, chloroacetic chloride/dibrominated zinc With one group in boron chloride, used organic solvent is selected from one or more of methylene chloride, tetrahydrofuran and ether.

Preferably, formula IV compound obtains the compound with Formula V structure through trifluoroacetic anhydride amidation, and reaction equation is such as Under:

It is further preferred that the molar ratio of this reaction compound of formula IV and trifluoroacetic anhydride is 1: 0.75~1.5.

Preferably, formula III a compound is split under the action of chiral reagent, then obtained through adjusting PH with base with formula IV knot The compound of structure, reaction equation are as follows:

It is further preferred that chiral reagent used by this reaction is selected from l-tyrosine, L-Glutimic acid and L- dibenzoyl One of tartaric acid；Used organic solvent is selected from one of methanol, ethyl alcohol, isopropanol and tert-butyl alcohol.

Preferably, Formula II compound reacts the compound for obtaining and having formula III structure, formula III compound with aminating agent It is dissolved in water, then adjusts pH=9~10 through alkali, organic solvent extraction is dry, formula III a compound is concentrated under reduced pressure to obtain, reaction equation is such as Under:

It is further preferred that aminating agent used by this reaction is protobromide ketone dimethyl sulphide/tricyclohexyl phosphine/bromination Ammonium/potassium phosphate；Organic solvent is selected from one of methylene chloride, ethyl acetate and chloroform.

Preferably, the compound for obtaining and there is Formula II structure, process route choosing are reacted after compound of formula I dissolution with halide From route b-1 or b-2,

When X is Br in Formula II compound, route b-1 is selected；When X is I in Formula II compound, route b-2 is selected.

Preferably, it is obtained after the dissolution of (2S, 6R) -2- methyl -6- methoxyl group -6H- pyrans -3- ketone through reducing agent reduction double bond Compound with Formulas I structure, reaction equation are as follows:

It is further preferred that solvent used in this reaction is in methylene chloride, chloroform, ethyl acetate and tetrahydrofuran It is one or more；Reducing agent is palladium-containing catalyst, preferably Pd/C and Pd (PPh₃)₄/ZnCl₂In one group；Reaction temperature is room Temperature.

The synthetic method of the further preferred formula X compound of the following contents:

Formula VIII compound prepares epirubicin through basic hydrolysis amido bond, and reaction equation is as follows:

After Formula VIII compound is hydrolyzed with aqueous slkali, then successively through persalt tune pH, organic solvent washing, water phase alkali soluble Liquid tune pH, liquid separation concentration obtain the compound of Formula X structure, i.e. epirubicin.

Preferably, alkali is selected from NaOH, KOH, Na₂CO₃、K₂CO₃, one of ammonium hydroxide.

Preferably, hydrochloric acid tune pH range is 3~6.

Preferably, adjusting PH with base range is 7.0~9.5.

Organic solvent is selected from one of methylene chloride, ethyl acetate, chloroform.

In a preferred embodiment, amido bond is hydrolyzed using NaOH, hydrochloric acid tune pH is 5, Na₂CO₃Adjusting pH is 8.2, is made It is washed with methylene chloride.

Preferably, Formula VIII compound is obtained with 4 ' position ketone group of reducing agent reduction-type VII compound, reaction equation is as follows:

The crude compound with Formula VIII structure is obtained with the ketone group of 4 ' position of sodium borohydride reduction Formula VII compound, slightly Product are recrystallized to give Formula VIII compound highly finished product through mixed solvent.

It is further preferred that the molar ratio of Formula VII compound and sodium borohydride is 1: 0.25~1.0.

It is further preferred that the mixed solvent of recrystallization are as follows: the mixed solution of methylene chloride, ethyl acetate and n-hexane.

It is further preferred that the volume ratio of recrystallization in the mixed solvent methylene chloride, ethyl acetate and n-hexane is 1: 0.4 ~0.8: 1~1.5.

In a preferred embodiment, the molar ratio of Formula VII compound and sodium borohydride is 1: 0.5；Reaction temperature is -5 ~0 DEG C；The volume ratio 1: 0.6: 1.2 of methylene chloride, ethyl acetate and n-hexane.

Preferably, Formula IV compound reacts preparation formula VII compound with daunomycinone under the action of catalyst, and reaction equation is such as Under:

After daunomycinone is dissolved, reacts and had with Formula IV compound under the action of 3a molecular sieve, mercury oxide, mercuric bromide There is the crude compound of Formula VII structure, Formula VII crude compound is recrystallized through mixed solvent, obtains the purification of Formula VII compound Product.

It is further preferred that the molar ratio of daunomycinone and mercury oxide is 1: 4~5；The molar ratio of daunomycinone and mercuric bromide is 1: 0.5~0.8；The molar ratio of daunomycinone and Formula IV compound is 1: 3.

It is further preferred that daunomycinone and mercury oxide molar ratio are 1: 4.8；The molar ratio of daunomycinone and mercuric bromide is 1: 0.72, the molar ratio of daunomycinone and Formula IV compound is 1: 3.

Preferably, Formula V compound, chlorinating agent are dissolved in organic solvent, are stirred to react, end of reaction is concentrated under reduced pressure To the dry compound for obtaining and there is Formula IV structure.

It is further preferred that the molar ratio of Formula V compound and chlorinating agent is 1: 2~3.

In a preferred embodiment, the molar ratio of Formula V compound and chlorinating agent is 1: 3.

Preferably, the preparation of Formula V compound:

Formula IV compound is dissolved in organic solvent, trifluoroacetic anhydride, end of reaction, to reaction solution are slowly dropped into after cooling Middle addition methanol, sodium bicarbonate aqueous solution tune pH stir liquid separation, and water phase is extracted with dichloromethane, and merge organic phase, organic phase warp Aqueous hydrochloric acid solution washing, dry, filtering, concentration obtain the compound with Formula V structure.

It is further preferred that organic solvent is selected from one of methylene chloride, chloroform, ethyl acetate and tetrahydrofuran； The temperature that cools down is -10~5 DEG C；PH=7.0~9.0.

In a preferred embodiment, the molar ratio of formula IV compound and trifluoroacetic anhydride is 1: 1, and organic solvent uses two Chloromethanes, cooling temperature are -5~0 DEG C.

Preferably, the preparation of formula IV compound:

Chiral reagent is dissolved in alcoholic solution, (2S, 4S, 6R) -4- amino -6- methoxyl group -2- methyl-tetrahydro pyrrole is added dropwise It mutters mixture (the formula III a compound of -3- ketone and (2S, 4R, 6R) -4- amino -6- methoxyl group -2- methyl-tetrahydro pyrans -3- ketone Crude product) solution, drop is complete, is heated to reflux 2~3h, stops heating, is down to room temperature, filters, and filter cake is eluted with alcoholic solution, dry (2S, 4S, 6R) -4- amino -6- methoxyl group -2- methyl-tetrahydro pyrans -3- ketone chirality hydrochlorate.Again by above-mentioned (2S, 4S, 6R) -4- Amino -6- methoxyl group -2- methyl-tetrahydro pyrans -3- ketone chirality hydrochlorate is dissolved in the aqueous solution of alcohol, under the conditions of -5~5 DEG C, uses alkali Solution adjusts pH to 10~11.It is extracted with ethyl acetate, organic layer is dry with anhydrous sodium sulfate, and formula IV chemical combination is concentrated under reduced pressure to obtain Object.

It is further preferred that the molar ratio of formula III a compound and chiral reagent is 1: 0.5~0.9；Alkali be selected from NaOH, KOH, Ammonium hydroxide, Na₂CO₃And K₂CO₃One of；Alcoholic solution is selected from one of methanol, ethyl alcohol, isopropanol, ethylene glycol and tert-butyl alcohol.

In a preferred embodiment, the molar ratio of formula III a compound and chiral reagent is 1: 0.7, and alkali uses K₂CO₃。 In a further advantageous embodiment, the molar ratio of formula III a compound and chiral reagent is 1: 0.9, and alkali uses NaOH.

Preferably, the preparation of formula III a compound:

Protobromide ketone dimethyl sulphide, Formula II compound, ammonium bromide, potassium phosphate and three hexamethylenes are sequentially added into acetonitrile solution Base phosphine, heating reaction, end of reaction are concentrated to dryness, and acetone is added into condensate residue, dissolves by heating, filters out insoluble Object removes acetone under reduced pressure, methylene chloride is then added, and with 15% ethanol solution of hydrogen chloride tune pH=1~2, solid is precipitated, takes out Filter, vacuum drying obtain the compound with formula III structure.Formula III compound is dissolved in water, with aqueous slkali adjust pH=9~ 10, formula III a crude compound is concentrated under reduced pressure to obtain in organic solvent extraction, dry organic phase.

It is further preferred that the dosage of protobromide ketone dimethyl sulphide is the 5%~9% of Formula II compound mole, ammonium bromide Dosage be 2~5 times of Formula II compound mole, the dosage of potassium phosphate is 2~5 times of Formula II compound mole, tricyclic The dosage of hexyl phosphine is the 10% of Formula II compound mole；The alkali is selected from ammonium hydroxide, KOH, NaOH, Na₂CO₃And K₂CO₃In It is a kind of.

In a preferred embodiment, the dosage of protobromide ketone dimethyl sulphide is the 7% of Formula II compound mole, bromination The molar ratio of ammonium and Formula II compound is 3: 1, and the molar ratio of potassium phosphate and Formula II compound is 4: 1, the dosage of tricyclohexyl phosphine It is the 10% of Formula II compound mole, alkali uses sodium carbonate, and organic solvent uses methylene chloride.

Preferably, the preparation of Formula II compound:

Compound of formula I is dissolved in organic solvent A, is slowly added to halide at room temperature, is stirred to react, end of reaction, mistake Filter, filtrate decompression concentration, concentrate are dissolved with organic solvent B, and salting liquid, stirring is added, and liquid separation, water phase is extracted with organic solvent B It takes, merges organic phase and drying, filter out desiccant, filtrate is through being concentrated under reduced pressure the compound for obtaining and having Formula II structure.

When the halide is bromine, using the synthetic route of step b-1), organic solvent A is ether, organic solvent B choosing From one of ethyl acetate and methylene chloride, salting liquid is saturated sodium bisulfite solution.

It is further preferred that the molar ratio of compound of formula I and bromine is 1: 1~2；

It is further preferred that the molar ratio of compound of formula I and bromine is 1: 1.1~1.3.

In a preferred embodiment, organic solvent A uses ether, and organic solvent B uses methylene chloride, compound of formula I Molar ratio with bromine is 1: 1.3.

When the halide is iodide, using the synthetic route of step b-2), organic solvent A be selected from methanol, ethyl alcohol and One of isopropanol, organic solvent B are selected from one of ethyl acetate and methylene chloride, and salting liquid is mass fraction 10% Hypo solution.

It is further preferred that compound of formula I and NH₄The molar ratio of I is 1: 1.05~1.50, and compound of formula I and Oxone's rubs You are than being 1: 1.05~1.50.

In a preferred embodiment, organic solvent A uses ethyl alcohol, and organic solvent B uses methylene chloride, compound of formula I Molar ratio with Oxone is 1: 1.3, compound of formula I and NH₄The molar ratio of I is 1: 1.3.

Preferably, the preparation of compound of formula I:

Starting material (2R, 6S) -6- methoxyl group -2- methyl -6H- pyrans -3- ketone is dissolved in organic solvent, reduction is added Agent, stirring, atmospheric pressure at room reaction, end of reaction, filtering, filtrate is through being concentrated under reduced pressure the compound for obtaining and having Formulas I structure.

It is further preferred that reducing agent is Pd/C, the dosage of palladium is (2S, 6R) -6- methoxyl group -2- methyl -6H- pyrans -3- The 0.25%~2.5% of ketone quality.

In a preferred embodiment, organic solvent is tetrahydrofuran, and the dosage of palladium is (2S, 6R) -6- methoxyl group -2- The 1.0% of methyl -6H- pyrans -3- ketone quality.

In an embodiment preferably, the synthetic method of Formula X compound the following steps are included:

With (2R, 6S) -6- methoxyl group -2- methyl -6H- pyrans -3- ketone be starting material, through reduction double bond, halogenating reaction, Amination substitution reaction, obtains Formula IV compound, formula after amino, chlorine methoxyl group displacement are protected in trifluoroacetylation again at chiral resolution VI compound is coupled to obtain Formula VII compound with daunomycinone again, ketone group of the Formula VII compound through 4 ' position of sodium borohydride reduction, de- three Acetyl fluoride base obtains epirubicin,

Its synthetic route is as follows:

The present invention achieve it is following the utility model has the advantages that

(1) process route is short, easily operated, at low cost, has preferable industrial prospect.

(2) reaction condition is mild, convenient post-treatment.

(3) yield purity is high.Reduction double bond and the yield purity of halogenating reaction are above 90%.

(4) epirubicin purity made from is up to 99.3%, largest single impurity 0.5%.

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.

The preparation method of starting material (2R, 6S) -6- methoxyl group -2- methyl -6H- pyrans -3- ketone of the present invention can refer to text Offer H Guo, GA O ' Doherty, De Novo Asymmetric Synthsis of Anthrax Tetrasaccharide And Related Tetrasaccharide [J] .Journal of Organic Chemistry, 2008,73 (14): 5211- 5220, daunomycinone can be commercially available by commercial channel.Compound Oxone molecular formula are as follows: KHSO₅·0.5KHSO₄· 0.5K₂SO₄。

The preparation of 1 compound of formula I of embodiment

Starting material (2R, 6S) -6- methoxyl group -2- methyl -6H- pyrans -3- ketone (15g, 105.5mmol) is dissolved in 45ml It in ethyl acetate, is added 10% palladium carbon (1.5g), opens stirring, nitrogen is replaced three times, and hydrogen is replaced three times, atmospheric pressure at room, hydrogenation Overnight, end of reaction, filtering, filtrate are concentrated under reduced pressure into fraction and are no longer flowed out, and weak yellow liquid 15.1g, as Formulas I chemical combination are obtained Object, HPLC purity: 99.2%, molar yield: 99.5%.

' H NMR (400MHz, CDCl3) δ: 1.26 (d, J=6.5Hz, 3H, CH₃C-5), 1.82~2.57 (m, 4H, C- 2H, C-3H), 3.41 (s, 3H, CH₃O), 4.54 (q, J=6.5Hz, C-5H), 4.82 (m, 4H, C-1H)

ESI-MS (M/Z)=167.17 [M+Na]⁺。

The preparation of 2 compound of formula I of embodiment

Starting material (2R, 6S) -6- methoxyl group -2- methyl -6H- pyrans -3- ketone (15g, 105.5mmol) is dissolved in 45ml In solvent (methylene chloride 25ml+ tetrahydrofuran 20ml), 4.1gPd (PPh is added₃)₄With 5.7g ZnCl₂, open stirring, under normal pressure, Overnight, end of reaction filters, and filtrate decompression is concentrated into fraction and no longer flows out for room temperature reaction, obtains weak yellow liquid 15.1g, as Compound of formula I, HPLC purity: 98.1%, molar yield: 99.2%.

ESI-MS (M/Z)=167.17 [M+Na]⁺。

The preparation of 3 compound of formula I of embodiment

Starting material (2R, 6S) -6- methoxyl group -2- methyl -6H- pyrans -3- ketone (15g, 105.5mmol) is dissolved in 45ml It in tetrahydrofuran, is added 15% palladium carbon (0.25g), opens stirring, nitrogen is replaced three times, and hydrogen is replaced three times, room temperature hydrogen under normal pressure Change overnight, end of reaction, filtering, filtrate decompression is concentrated into fraction and no longer flows out, and obtains weak yellow liquid 14.4g, as Formulas I chemical combination Object, HPLC purity: 96.7%, molar yield: 94.8%.

ESI-MS (M/Z)=167.17 [M+Na]⁺。

The preparation of 4 compound of formula I of embodiment

Starting material (2R, 6S) -6- methoxyl group -2- methyl -6H- pyrans -3- ketone (15g, 105.5mmol) is dissolved in 45ml In solvent (chloroform 20ml+ ethyl acetate 25ml), 6.5g Pd (PPh is added₃)₄With 6.5g ZnCl₂, open stirring, under normal pressure, room Overnight, end of reaction filters, and filtrate decompression is concentrated into fraction and no longer flows out for temperature reaction, obtains weak yellow liquid 13.8g, as Formulas I Compound, HPLC purity: 92.6%, molar yield: 90.7%.

ESI-MS (M/Z)=167.17 [M+Na]⁺。

The preparation of 5 Formula II compound of embodiment (X Br)

Compound of formula I (14.2g, 98.5mmol) is dissolved in 200ml ether, be slowly dropped at room temperature bromine (18.1g, 113.3mmol, 1.15eq), it is added dropwise, is stirred to react.End of reaction, filtering, filtrate decompression concentration, concentrate acetic acid second Ester dissolution, is added 115ml saturated aqueous sodium sulfite, stirs 10min, liquid separation, and water phase is extracted with ethyl acetate, and merges organic It is mutually and dry, desiccant is filtered out, filtrate is concentrated to dryness to obtain 21.7g faint yellow solid, the as compound of Formula II structure, HPLC purity: 94.7%, molar yield: 98.7%.

' H NMR (400MHz, CDCl3) δ: 1.35 (d, J=6.4Hz, 3H, CH₃C-5), 2.01 (m, 1H, C-2H), 2.94 (m, 1H, C-2H), 3.43 (s, 3H, CH₃O), 4.56 (q, J=6.4Hz, 1H, C-5H), 4.97 (m, 1H, C-1H), 5.13 (dd, J=12.4Hz, J '=6.0Hz, 1H, C-3H)

ESI-MS (M/Z)=246.06 [M+Na]⁺。

The preparation of 6 Formula II compound of embodiment (X Br)

Compound of formula I (14.2g, 98.5mmol) is dissolved in 200ml ether, be slowly dropped at room temperature bromine (20.4g, 128.1mmol, 1.3eq), it is added dropwise, is stirred to react.End of reaction, filtering, filtrate decompression concentration, concentrate dichloromethane Alkane dissolution, is added 10% sodium thiosulfate solution of 115ml, stirs 10min, liquid separation, and water phase is extracted with dichloromethane, and merges Organic phase and drying, filter out desiccant, and filtrate is concentrated to dryness to obtain 21.6g faint yellow solid, the as change of Formula II structure Object is closed, HPLC purity: 96.8%, molar yield: 98.3%.

ESI-MS (M/Z)=246.06 [M+Na]⁺。

The preparation of 7 Formula II compound of embodiment (X Br)

Compound of formula I (14.2g, 98.5mmol) is dissolved in 200ml ether, be slowly dropped at room temperature bromine (31.4g, 197.0mmol, 2.0eq), it is added dropwise, is stirred to react, end of reaction, filtering, filtrate decompression concentration, concentrate dichloromethane Alkane dissolution, is added 115ml saturated aqueous sodium sulfite, stirs 10min, liquid separation, and water phase is extracted with dichloromethane, and merges organic It is mutually and dry, desiccant is filtered out, filtrate is concentrated to dryness to obtain 19.9g faint yellow solid, the as compound of Formula II structure, HPLC purity: 91.2%, molar yield: 90.7%.

ESI-MS (M/Z)=246.06 [M+Na]⁺。

The preparation of 8 Formula II compound of embodiment (X I)

Compound of formula I (14.2g, 98.5mmol) is dissolved in 200ml methanol, is slowly added to NH at room temperature₄I (15.0g, 103.4mmol, 1.05eq) and Oxone (31.8g, 103.4mmol, 1.05eq), addition finishes, it is stirred to react, end of reaction, Filtering, filtrate decompression concentration, concentrate are dissolved with ethyl acetate, and the sodium thiosulfate that 115ml mass fraction 10% is added is water-soluble Liquid stirs 10min, liquid separation, and water phase is extracted with ethyl acetate, and merges organic phase and drying, filters out desiccant, and filtrate is dense through depressurizing It is reduced to dry 24.5g faint yellow solid, the as compound of Formula II structure, HPLC purity: 93.1%, molar yield: 92.1%.

' H NMR (400MHz, CDCl3) δ: 1.35 (d, J=6.4Hz, 3H, CH₃C-5), 2.01 (m, 1H, C-2H), 2.94 (m, 1H, C-2H), 3.43 (s, 3H, CH₃O), 4.82 (q, J=6.4Hz, 1H, C-5H), 4.97 (m, 1H, C-1H), 5.13 (dd, J=12.4Hz, J '=6.0Hz, 1H, C-3H)

ESI-MS (M/Z)=292.96 [M+Na]⁺。

The preparation of 9 Formula II compound of embodiment (X I)

Compound of formula I (14.2g, 98.5mmol) is dissolved in 200ml ethyl alcohol, is slowly added to NH at room temperature₄I (18.6g, 128.1mmol, 1.3eq) and Oxone (39.4g, 128.1mmol, 1.3eq), addition finishes, and is stirred to react, end of reaction, mistake Filter, filtrate decompression concentration, concentrate are dissolved with methylene chloride, and the sodium thiosulfate solution of 115ml mass fraction 10% is added, 10min, liquid separation are stirred, water phase is extracted with dichloromethane, and merges organic phase and drying, filters out desiccant, filtrate is through being concentrated under reduced pressure It is extremely dry to obtain 25.2g faint yellow solid, the as compound of Formula II structure, HPLC purity: 94.9%, molar yield: 94.6%.

ESI-MS (M/Z)=292.96 [M+Na]⁺。

The preparation of 10 Formula II compound of embodiment (X I)

Compound of formula I (14.2g, 98.5mmol) is dissolved in 200ml isopropanol, is slowly added to NH at room temperature₄I (21.4g, 147.8mmol, 1.5eq) and Oxone (45.4g, 147.8mmol, 1.5eq), addition finishes, and is stirred to react, reaction It finishes, filters, filtrate decompression concentration, concentrate is dissolved with methylene chloride, and the sodium thiosulfate of 115ml mass fraction 10% is added Aqueous solution stirs 10min, liquid separation, and water phase is extracted with dichloromethane, and merges organic phase and drying, filters out desiccant, filtrate is through subtracting Pressure is concentrated to dryness to obtain 24.3g faint yellow solid, the as compound of Formula II structure, HPLC purity: 90.3%, molar yield: 91.5%.

ESI-MS (M/Z)=292.96 [M+Na]⁺。

The preparation of 11 formula III a compound of embodiment

Protobromide ketone dimethyl sulphide (1.11g, 5.4mmol, 0.07eq), Formula II are sequentially added in acetonitrile (200ml) It closes object (20.0g, 89.7mmol), ammonium bromide (26.4g, 269.1mmol, 3eq), potassium phosphate (76.2g, 358.8mmol, 4eq), With tricyclohexyl phosphine (2.52g, 9mmol, 0.1eq), it is heated to 55 DEG C and is stirred to react 15 hours, end of reaction is concentrated under reduced pressure into It is dry, 300ml acetone is added into condensate residue, after being heated to 50 DEG C, filters out insoluble matter, decompression is spin-dried for acetone, is then added Solid is precipitated with 15% ethanol solution of hydrogen chloride tune pH=1~2 in 200ml methylene chloride, filters, and 50 DEG C of vacuum drying are had There is the compound of formula III structure, formula III compound is dissolved in 30ml water, then adjusts pH=9~10 through 32% aqueous sodium carbonate, Methylene chloride (50ml × 2) extraction merges organic phase, and anhydrous sodium sulfate is dry, is concentrated to dryness to obtain formula III a compound 15.5g, HPLC purity: 88.9%, molar yield: 88.4%.

' H NMR (400MHz, CDCl3) δ: 1.33 (d, J=6.4Hz, 3H, CH3C-5), 1.91 (m, 1H, C-2H), 2.90 (m, 1H, C-2H), 3.44 (s, 3H, CH₃O), 4.38 (q, J=6.4Hz, 1H, C-5H), 4.85 (m, 1H, C-1H), 4.98 (dd, J=12.5Hz, J '=6.0Hz, 1H, C-3H), 8.03 (brs, 2H, NH₂).

ESI-MS (M/Z)=182.18 [M+Na]⁺。

The preparation of 12 formula III a compound of embodiment

Protobromide ketone dimethyl sulphide (1.66g, 8.1mmol, 0.09eq), Formula II are sequentially added in acetonitrile (200ml) It closes object (20.0g, 89.7mmol), ammonium bromide (44.0g, 448.5mmol, 5eq), potassium phosphate (95.2g, 448.5mmol, 5eq) With tricyclohexyl phosphine (2.52g, 9mmol, 0.1eq), it is heated to 55 DEG C and is stirred to react 15 hours, end of reaction is concentrated under reduced pressure into It is dry, 300ml acetone is added into condensate residue, after being heated to 50 DEG C, filters out insoluble matter, decompression is spin-dried for acetone, is then added Solid is precipitated with 15% ethanol solution of hydrogen chloride tune pH=1~2 in 200ml chloroform, filters, and 50 DEG C of vacuum drying are had There is the compound of formula III structure, formula III compound is dissolved in 30ml water, then adjusts pH=9~10 through 32% aqueous sodium carbonate, Methylene chloride (50ml × 2) extraction merges organic phase, and anhydrous sodium sulfate is dry, is concentrated to dryness to obtain formula III a compound 14.7g, HPLC purity: 86.1%, molar yield: 83.7%.

ESI-MS (M/Z)=182.18 [M+Na]⁺。

The preparation of 13 formula III a compound of embodiment

Protobromide ketone dimethyl sulphide (0.92g, 4.5mmol, 0.05eq), Formula II are sequentially added in acetonitrile (200ml) It closes object (20.0g, 89.7mmol), ammonium bromide (17.6g, 179.4mmol, 2eq), potassium phosphate (38.1g, 179.4mmol, 2eq) With tricyclohexyl phosphine (2.52g, 9mmol, 0.1eq), it is heated to 55 DEG C and is stirred to react 15 hours, end of reaction is concentrated under reduced pressure into It is dry, 300ml acetone is added into condensate residue, after being heated to 50 DEG C, filters out insoluble matter, decompression is spin-dried for acetone, is then added Solid is precipitated with 15% ethanol solution of hydrogen chloride tune pH=1~2 in 200ml ethyl acetate, filters, and 50 DEG C of vacuum drying are had There is the compound of formula III structure, formula III compound is dissolved in 30ml water, then adjusts pH=9~10 through 32% aqueous sodium carbonate, Methylene chloride (50ml × 2) extraction merges organic phase, and anhydrous sodium sulfate is dry, is concentrated to dryness to obtain formula III a compound 14.3g, HPLC purity: 83.6%, molar yield: 81.3%.

ESI-MS (M/Z)=182.18 [M+Na]⁺。

The preparation of 14 formula IV compound of embodiment

16.4g (0.9eq) l-tyrosine is dissolved in 150ml methanol, (2S, 4S, 6R) -4- amino -6- methoxyl group-is added dropwise The mixture of 2- methyl-tetrahydro pyrans -3- ketone and (2S, 4R, 6R) -4- amino -6- methoxyl group -2- methyl-tetrahydro pyrans -3- ketone (16g, 0.1mol, 1eq) acetonitrile solution 30ml, drop finish, and are heated to reflux 2~3h, stop heating, are down to room temperature, and insulated and stirred 2~ 3h, filtering, filter cake elutes with methanol, dry (2S, 4S, 6R) -4- amino -6- methoxyl group -2- methyl-tetrahydro pyrans -3- ketone - L-tyrosine salt 24.2g, yield 71.2%.

It is again that above-mentioned (2S, 4S, 6R) -4- amino -6- methoxyl group -2- methyl-tetrahydro pyrans -3- ketone-l-tyrosine salt is molten In the aqueous solution of methanol, under the conditions of -5~5 DEG C, pH to 10~11 is adjusted with the NaOH solution of 6mmol/ml.Use ethyl acetate (200ml × 3) extraction, organic layer are dried, filtered with anhydrous sodium sulfate, are concentrated to dryness to obtain white solid 7.7g, total recovery: 48.4%, as IV compound, measure ee value 99.91%.

ESI-MS (M/Z)=182.18 [M+Na]⁺。

The preparation of 15 formula IV compound of embodiment

9.0g (0.7eq) L-Glutimic acid is dissolved in 150ml ethyl alcohol, (2S, 4S, 6R) -4- amino -6- methoxy is added dropwise Base -2- methyl-tetrahydro pyrans -3- ketone is mixed with (2S, 4R, 6R) -4- amino -6- methoxyl group -2- methyl-tetrahydro pyrans -3- ketone Object (16g, 0.1mol, 1eq) ethanol solution 30ml is closed, drop finishes, and is heated to reflux 2~3h, stops heating, is down to room temperature, heat preservation is stirred 2~3h is mixed, is filtered, filter cake ethanol rinse, dry (2S, 4S, 6R) -4- amino -6- methoxyl group -2- methyl-tetrahydro pyrans - 3- ketone-L-Glutimic acid salt 23.7g, yield 67.8%.

Again by above-mentioned (2S, 4S, 6R) -4- amino -6- methoxyl group -2- methyl-tetrahydro pyrans -3- ketone-L-Glutimic acid salt It is dissolved in the aqueous solution of ethyl alcohol, under the conditions of -5~5 DEG C, with the K of 6mmol/ml₂CO₃Solution adjusts pH to 10~11.With acetic acid second Ester (200ml × 3) extraction, organic layer are dried, filtered with anhydrous sodium sulfate, are concentrated to dryness to obtain white solid 7.3g, total to receive Rate: 46.0%, as IV compound measure ee value 99.93%.

ESI-MS (M/Z)=182.18 [M+Na]⁺。

The preparation of 16 formula IV compound of embodiment

17.9g (0.5eq) L- (-)-dibenzoyl tartaric acid is dissolved in 150ml isopropanol, (2S, 4S, 6R) -4- is added dropwise Amino -6- methoxyl group -2- methyl-tetrahydro pyrans -3- ketone and (2S, 4R, 6R) -4- amino -6- methoxyl group -2- methyl-tetrahydro pyrrole Mutter mixture (16g, 0.1mol, 1eq) acetonitrile solution 30ml of -3- ketone, and drop finishes, and is heated to reflux 2~3h, stops heating, is down to Room temperature, 2~3h of insulated and stirred, filtering, filter cake elutes with isopropanol, dry (2S, 4S, 6R) -4- amino -6- methoxyl group -2- Methyl-tetrahydro pyrans -3- ketone-L- (-)-dibenzoyl tartaric acid salt 22.1g, yield 65.1%.

Again by above-mentioned (2S, 4S, 6R) -4- amino -6- methoxyl group -2- methyl-tetrahydro pyrans -3- ketone-L- (-)-hexichol first Acyl tartrate is dissolved in the aqueous solution of isopropanol, under the conditions of -5~5 DEG C, adjusts pH to 10 with 25%~28% ammonia spirit ~11.It is extracted with ethyl acetate (200ml × 3), organic layer is dried, filtered with anhydrous sodium sulfate, is concentrated to dryness white Solid 7.2g, total recovery: 45.2%, as IV compound measure ee value 99.82%.

ESI-MS (M/Z)=182.18 [M+Na]⁺。

The preparation of 17 Formula V compound of embodiment

Formula IV compound (15.0g, 76.7mmol) is dissolved in tetrahydrofuran, is slowly dropped into after being cooled to -10~-5 DEG C Trifluoroacetic anhydride (8.12ml, 57.5mmol) is added dropwise and continues to be stirred to react about 1h, and TLC is detected after completion of the reaction, Xiang Fanying 2ml methanol is added in liquid and 1h, liquid separation is stirred at room temperature, water phase is extracted with methylene chloride with 5% sodium bicarbonate aqueous solution tune pH ≈ 7.0 It takes, merges organic phase, organic phase washs through aqueous hydrochloric acid solution (0.1N, 60ml), water washing (50ml × 2), anhydrous slufuric acid twice Sodium is dry, filter, is concentrated to dryness compound 18.8g, the HPLC purity for obtaining and having Formula V structure: 95.8%, it mole receives Rate: 96.3%, mp.165.2~166.5 DEG C.

' H NMR (400MHz, CDCl3) δ: 1.31 (d, J=6.5Hz, 3H, CH3C-5), 1.89 (m, 1H, C-2), 2.88 (m, 1H, C-2), 3.43 (s, 3H, CH₃O), 4.37 (q, J=6.5Hz, 1H, C-5H), 4.83 (m, 1H, C-1H), 4.95 (dd, J =12.6Hz, J '=6.0Hz, 1H, C-3H), 8.21 (brs, 1H, NH)

ESI-MS (M/Z)=278.19 [M+Na]⁺。

The preparation of 18 Formula V compound of embodiment

Formula IV compound (15.0g, 76.7mmol) is dissolved in methylene chloride, is slowly dropped into three after being cooled to -5~0 DEG C Fluoroacetic acid acid anhydride (10.8ml, 76.7mmol) is added dropwise and continues to be stirred to react about 1h, and TLC is detected after completion of the reaction, to reaction solution With 5% sodium bicarbonate aqueous solution tune pH ≈ 7.5 1h, liquid separation is stirred at room temperature, water phase is extracted with methylene chloride in middle addition 2ml methanol It takes, merges organic phase, organic phase washs through aqueous hydrochloric acid solution (0.1N, 60ml), water washing (50ml × 2), anhydrous slufuric acid twice Sodium is dry, filter, is concentrated to dryness compound 19.2g, the HPLC purity for obtaining and having Formula V structure: 97.2%, it mole receives Rate: 98.5%, mp.165.2~166.5 DEG C.

' H NMR (400MHz, CDCl3) δ: 1.31 (d, J=6.5Hz, 3H, CH3C-5), 1.89 (m, 1H, C-2), 2.88 (m, lH, C-2), 3.43 (s, 3H, CH₃O), 4.37 (q, J=6.5Hz, 1H, C-5H), 4.83 (m, 1H, C-1H), 4.95 (dd, J =12.6Hz, J '=6.0Hz, 1H, C-3H), 8.21 (brs, 1H, NH)

ESI-MS (M/Z)=278.19 [M+Na]⁺。

The preparation of 19 Formula V compound of embodiment

Formula IV compound (15.0g, 76.7mmol) is dissolved in chloroform, is slowly dropped into trifluoro after being cooled to 0~5 DEG C Acetic anhydride (16.2ml, 115.1mmol) is added dropwise and continues to be stirred to react about 1h, and TLC is detected after completion of the reaction, to reaction solution With 5% sodium bicarbonate aqueous solution tune pH ≈ 9.0 1h, liquid separation is stirred at room temperature, water phase is extracted with methylene chloride in middle addition 2ml methanol It takes, merges organic phase, organic phase washs through aqueous hydrochloric acid solution (0.1N, 60ml), water washing (50ml × 2), anhydrous slufuric acid twice Sodium is dry, filter, is concentrated to dryness compound 18.4g, the HPLC purity for obtaining and having Formula V structure: 92.7%, it mole receives Rate: 94.2%, mp.165.2~166.5 DEG C.

ESI-MS (M/Z)=278.19 [M+Na]⁺。

The preparation of 20 Formula IV compound of embodiment

By Formula V compound (12g, 47.0mmol), chloroacetic chloride (7.4g, 94.0mmol, 2eq) and thionyl chloride (0.1ml) It being placed in a reaction flask, about 18h is stirred at room temperature, end of reaction is concentrated to dryness, solid 11.85g, as Formula IV compound are obtained, HPLC purity: 95.7%, molar yield: 97.2%.

' H NMR (400MHz, CDCl3) δ: 1.33 (d, J=6.4Hz, 3H, CH3C-5), 1.98 (m, 1H, C-2), 2.95 (m, 1H, C-2), 4.46 (q, J=6.4Hz, 1H, C-5H), 4.95 (m, 1H, C-1H), 5.04 (dd, J=12.6Hz, J '= 6.0Hz, 1H, C-3H), 8.18 (brs, 1H, NH)

ESI-MS (M/Z)=271.58 [M+Na]⁺。

The preparation of 21 Formula IV compound of embodiment

By Formula V compound (12g, 47.0mmol), chloroacetic chloride (11.1g, 141.0mmol, 3eq) and thionyl chloride (0.2ml) is placed in a reaction flask, and about 18h is stirred at room temperature, and end of reaction is concentrated to dryness, and obtains solid 12.0g, as Formula IV Compound, HPLC purity: 96.9%, molar yield: 98.3%.

ESI-MS (M/Z)=271.58 [M+Na]⁺。

The preparation of 22 Formula IV compound of embodiment

Formula V compound (2.55g, 10mmol) is dissolved in 30ml anhydrous ether, nitrogen protection, is cooled to 0 DEG C, is added dropwise three The dichloromethane solution 16ml of boron chloride (2.93g, 25mmol), is added dropwise, and continues to be stirred to react 2 hours, end of reaction, to 50ml methylene chloride is added in system, successively uses purified water (100ml), NaHCO₃Saturated solution washs (100ml), and organic phase is used Na₂SO₄It drying, filtering, organic phase decompression is concentrated to dryness, solid 2.53g, as Formula IV compound are obtained, HPLC purity: 96.2%, Molar yield: 97.6%.

ESI-MS (M/Z)=271.58 [M+Na]⁺。

The preparation of 23 Formula IV compound of embodiment

By Formula V compound (12g, 47.0mmol) and ZnBr₂(0.22g, 0.02eq) is dissolved in 40ml tetrahydrofuran, is added dropwise Chloroacetic chloride (7.4g, 2eq), is added dropwise, and heats reaction system to 40 DEG C, is stirred to react 30min, temperature of reaction system is down to 0~5 DEG C, continue to be stirred to react 5h, end of reaction filters, and filtrate decompression is concentrated to dryness, and obtains solid 11.7g, as Formula IV chemical combination Object, HPLC purity: 96.5%, molar yield: 96.1%.

ESI-MS (M/Z)=271.58 [M+Na]⁺。

The preparation of 24 Formula VII compound of embodiment

Daunomycinone (3.1g, 7.68mmol, 1eq) is dissolved in 100ml anhydrous ethyl acetate solution, powdery 3a is sequentially added Molecular sieve, mercury oxide (6.7g, 30.75mmol, 4.0eq), mercuric bromide (1.38g, 3.84mmol, 0.5eq) are protected from light at 40 DEG C and stir It mixes 0.5 hour.It is slowly dropped into the anhydrous ethyl acetate solution 36ml dissolved with Formula IV compound (6.0g, 23.0mmol) again, about 6 is small When drip off, continue after being added dropwise stirring 5 hours, 40 DEG C of evaporating solvent under reduced pressure, into residue be added 200ml methylene chloride it is molten Liquid, filtering, filtrate through be concentrated under reduced pressure obtain Formula VII crude compound, crude product volume ratio be 1: 2.5 dehydrated alcohol and just oneself Alkane mixed solvent recrystallization, obtains Formula VII compound highly finished product 3.9g, HPLC purity: 87.7%, molar yield: 82.0%.

¹H-NMR (400MHz, DMSO-d₆) δ: 1.34 (d, J=6.5Hz, 3H, CH3C-5 ')；1.91~2.18 (m, 4H, CH₂- 2 ', CH₂-8)；2.33 (s, 3H, COCH₃)；2.93~2.98 (m, 2H, CH₂-10)；3.07~3.28 (S, 3H, OCH₃)； 4.52 (q, J=6.5Hz, 1H, H-5 ')；4.93 (dd, J=12.6Hz, J '=6.0Hz, 1H, H-3 '), 5.05 (brs, 1H, H- 7)；5.39 (1H, m, H-1 ')；5.59 (S, 1H, OH-9)；7.59~7.62 (m, 1H, H-3)；7.28~7.86 (m, 2H, H-1, H-2)；8.22 (S, 1H, NH)；13.36 (brs, 1H, Ar-OH)；13.55 (brs, 1H, Ar-OH)

ESI-MS (M/Z)=644.51 [M+Na]⁺。

The preparation of 25 VII compound of embodiment

Daunomycinone (3.1g, 7.68mmol, 1eq) is dissolved in 100ml anhydrous methylene chloride/toluene (1: 1) solution, successively 4a molecular sieve is added, silver trifluoromethanesulfonate (3.0g, 11.5mmol, 1.5eq), is protected from light lower stirring 0.5 hour by -30 DEG C of temperature control.Again It is slowly dropped into anhydrous methylene chloride/toluene (1: 1) solution 36ml dissolved with Formula IV compound (3.0g, 11.5mmol, 1.5eq), It drips off within about 1 hour, is added dropwise, heating reaction solution to room temperature continues to be stirred to react 5 hours, end of reaction, and 40 DEG C of decompressions are steamed Except solvent, 200ml dichloromethane solution is added into residue, filtering, it is thick that acquisition Formula VII compound is concentrated under reduced pressure in filtrate Product, dehydrated alcohol and n-hexane the mixed solvent recrystallization that crude product volume ratio is 1: 2.5, obtain Formula VII compound highly finished product 4.1g, HPLC purity: 90.1%, molar yield: 86.2%.

ESI-MS (M/Z)=644.51 [M+Na]⁺。

The preparation of 26 VII compound of embodiment

Daunomycinone (3.1g, 7.68mmol, 1eq) is dissolved in 100ml anhydrous methylene chloride/toluene (2: 1) solution, successively 4a molecular sieve is added, silver trifluoromethanesulfonate (4.0g, 15.4mmol, 2.0eq), is protected from light lower stirring 0.5 hour by -25 DEG C of temperature control.Again It is slowly dropped into anhydrous methylene chloride/toluene (2: 1) solution 36ml dissolved with Formula IV compound (4.0g, 15.4mmol, 2.0eq), It drips off within about 1 hour, is added dropwise, heating reaction solution to room temperature continues to be stirred to react 5 hours, end of reaction, and 40 DEG C of decompressions are steamed Except solvent, 200ml dichloromethane solution is added into residue, filtering, it is thick that acquisition Formula VII compound is concentrated under reduced pressure in filtrate Product, dehydrated alcohol and n-hexane the mixed solvent recrystallization that crude product volume ratio is 1: 2.5, obtain Formula VII compound highly finished product 4.3g, HPLC purity: 93.5%, molar yield: 89.5%.

ESI-MS (M/Z)=644.51 [M+Na]⁺。

The preparation of 27 VII compound of embodiment

Daunomycinone (3.1g, 7.68mmol, 1eq) is dissolved in 100ml anhydrous methylene chloride/toluene (1: 2) solution, successively 4a molecular sieve is added, silver trifluoromethanesulfonate (5.0g, 19.2mmol, 2.5eq), is protected from light lower stirring 0.5 hour by -30 DEG C of temperature control.Again It is slowly dropped into anhydrous methylene chloride/toluene (1: 2) solution 36ml dissolved with Formula IV compound (5.0g, 19.2mmol, 2.5eq), It drips off within about 1 hour, is added dropwise, heating reaction solution to room temperature continues to be stirred to react 5 hours, end of reaction, and 40 DEG C of decompressions are steamed Except solvent, 200ml dichloromethane solution is added into residue, filtering, it is thick that acquisition Formula VII compound is concentrated under reduced pressure in filtrate Product, dehydrated alcohol and n-hexane the mixed solvent recrystallization that crude product volume ratio is 1: 2.5, obtain Formula VII compound highly finished product 4.0g, HPLC purity: 87.2%, molar yield: 84.1%.

ESI-MS (M/Z)=644.51 [M+Na]⁺。

The preparation of 28 VIII compound of embodiment

By Formula VII compound (12g, 19.3mmol), 410ml methanol, 195ml methylene chloride is put into reaction flask, nitrogen Protection, cools to -5~0 DEG C, instills the ethanol solution of 80mL sodium borohydride (364mg, 9.6mmol, 0.5eq), about 30min is dripped off, and after insulation reaction 30min, 6.0ml acetone is added, with the dilute hydrochloric acid solution tune pH=4.0 of 0.1mol/L, liquid separation After collect organic phase, organic phase through pure water twice (200ml × 2), be concentrated under reduced pressure after Formula VIII crude compound, crude product Formula VIII compound essence is recrystallized to give with the methylene chloride, ethyl acetate, n-hexane mixed solvent that volume ratio is 1: 0.6: 1.2 Product 11.3g, HPLC purity: 91.8%, molar yield: 93.6%.

¹H-NMR (400MHz, DMSO-d₆) δ: 1.29 (d, J=6.4Hz, 3H, CH3C-5 ')；1.82~2.17 (m, 4H, CH₂- 2 ', CH₂-8)；2.32 (s, 3H, COCH₃)；2.94~2.99 (m, 2H, CH₂-10)；3.06~3.26 (S, 3H, OCH₃)； 3.56~3.67 (m, 1H, CH-4 ')；4.37~4.57 (m, 2H, H-5 ', H-3 ')；5.03 (brs, 1H, H-7)；5.27 (S, 1H, OH-4')；5.49 (1H, m, H-1 ')；5.59 (S, 1H, OH-9)；7.59~7.62 (m, 1H, H-3)；7.29~7.86 (m, 2H, H-1, H-2)；8.25 (S, 1H, NH)；13.37 (brs, 1H, Ar-OH)；13.56 (brs, 1H, Ar-OH)

ESI-MS (M/Z)=646.53 [M+Na]⁺。

The preparation of 29 VIII compound of embodiment

By Formula VII compound (12g, 19.3mmol), 410ml methanol, 195ml methylene chloride is put into reaction flask, nitrogen Protection, cools to 0~5 DEG C, instills the ethanol solution of 80ml sodium borohydride (728mg, 19.2mmol, 1.0eq), about 30min is dripped off, and after insulation reaction 30min, 6.0ml acetone is added, with the dilute hydrochloric acid solution tune pH=4.0 of 0.1mol/L, liquid separation After collect organic phase, organic phase through pure water twice (200ml × 2), be concentrated under reduced pressure after Formula VIII crude compound, crude product The purification of Formula VIII compound is recrystallized to give with the methylene chloride, ethyl acetate, n-hexane mixed solvent that volume ratio is 1: 0.4: 1 Product 11.1g, HPLC purity: 90.6%, molar yield: 92.4%.

ESI-MS (M/Z)=646.53 [M+Na]⁺。

The preparation of 30 VIII compound of embodiment

By Formula VII compound (12g, 19.3mmol), 410ml methanol, 195ml methylene chloride is put into reaction flask, nitrogen Protection, cools to 5~10 DEG C, instills the ethanol solution of 80ml sodium borohydride (182mg, 4.8mmol, 0.25eq), about 30min is dripped off, and after insulation reaction 30min, 6.0ml acetone is added, with the dilute hydrochloric acid solution tune pH=4.0 of 0.1mol/L, liquid separation After collect organic phase, organic phase through pure water twice (200ml × 2), be concentrated under reduced pressure after Formula VIII crude compound, crude product Formula VIII compound essence is recrystallized to give with the methylene chloride, ethyl acetate, n-hexane mixed solvent that volume ratio is 1: 0.8: 1.5 Product 10.7g, HPLC purity: 88.5%, molar yield: 89.1%.

ESI-MS (M/Z)=646.53 [M+Na]⁺。

The preparation of 31 epirubicin of embodiment

Formula VIII compound highly finished product 9.0g is suspended in 460ml purified water, is cooled to 0~5 DEG C, is instilled 3.5% sodium hydroxide solution 60ml, insulation reaction 50min, after reaction with hydrochloric acid tune pH=5.0, with 200ml dichloromethane Alkane washes twice, and collects water phase, 1200ml methylene chloride and 80ml methanol is added into water phase, with sodium carbonate liquor tune pH= 8.2, liquid separation is stood, organic phase is collected, organic phase is concentrated to dryness to obtain epirubicin 7.48g, molar yield 98.3%, HPLC purity 99.3%, largest single impurity: 0.5%.

¹H-NMR (400MHz, DMSO-d₆) δ: 1.26 (d, J=6.5Hz, 3H, CH3-C5 ')；1.70~2.16 (m, 4H, CH₂- 2 ', CH₂-8)；2.32 (s, 3H, COCH₃)；2.79~2.83 (m, 1H, CH-4 ')；2.93~2.98 (m, 2H, CH₂-10)； 3.04~3.24 (S, 3H, OCH₃)；4.34~4.54 (m, 2H, H-5 ', H-3 ')；5.02 (brs, 1H, H-7)；5.26 (S, 1H, 4'-OH)；5.35, (1H, m, H-1 ')；5.58 (S, 1H, OH-9)；7.58~7.61 (m, 1H, H-3)；7.28~7.85 (m, 2H, H-1, H-2)；8.05 (S, 2H, NH2)；13.36 (brs, 1H, Ar-OH)；13.54 (brs, 1H, Ar-OH)

ESI-MS (M/Z)=550.54 [M+Na]⁺。

The preparation of 32 epirubicin of embodiment

Formula VIII compound highly finished product 9.0g is suspended in 460ml purified water, is cooled to 5~10 DEG C, is instilled 3.5% potassium hydroxide solution 60ml, insulation reaction 50min, after reaction with hydrochloric acid tune pH=3.0, with 200ml acetic acid second Ester washes twice, and collects water phase, 1200ml ethyl acetate and 80ml methanol is added into water phase, with solution of potassium carbonate tune pH= 7.0, liquid separation is stood, organic phase is collected, organic phase is concentrated to dryness to obtain epirubicin 7.39g, molar yield 97.1%, HPLC purity 99.5%, largest single impurity: 0.4%.

¹H-NMR (400MHz, DMSO-d₆) δ: 1.26 (d, J=6.5Hz, 3H, CH3-C5 ')；1.70~2.16 (m, 4H, CH₂- 2 ', CH₂-8)；2.32 (s, 3H, COCH₃)；2.79~2.83 (m, 1H, CH-4 ')；2.93~2.98 (m, 2H, CH₂-10)； 3.04~3.24 (S, 3H, OCH₃)；4.34~4.54 (m, 2H, H-5 ', H-3 ')；5.02 (brs, 1H, H-7)；5.26 (S, 1H, 4'-OH)；5.35, (1H, m, H-1 ')；5.58 (S, 1H, OH-9)；7.58~7.61 (m, 1H, H-3)；7.28~7.85 (m, 2H, H-1, H-2)；8.05 (S, 2H, NH₂)；13.36 (brs, 1H, Ar-OH)；13.54 (brs, 1H, Ar-OH)

ESI-MS (M/Z)=550.54 [M+Na]+.

The preparation of 33 epirubicin of embodiment

Formula VIII compound highly finished product 9.0g is suspended in 460ml purified water, is cooled to 0~5 DEG C, ammonium hydroxide is instilled Solution 60ml, insulation reaction 50min are washed twice after reaction with hydrochloric acid tune pH=6.0 with 200ml chloroform, are collected 1200ml chloroform and 80ml methanol are added into water phase for water phase, quiet with 0.1mol/L sodium hydroxide solution tune pH=9.5 Liquid separation is set, organic phase is collected, organic phase is concentrated to dryness to obtain epirubicin 7.31g, molar yield 96.1%, HPLC purity 99.4%, largest single impurity: 0.3%.

ESI-MS (M/Z)=550.54 [M+Na]⁺。

The preparation of 1 compound of formula I of comparative example

Starting material (2R, 6S) -6- methoxyl group -2- methyl -6H- pyrans -3- ketone (15g, 105.5mmol) is dissolved in 45ml In methanol, 6.3g CuCl (63.3mmol, 0.6eq) and 8.8g NaBH is added₄(232.2mmol, 2.2eq) opens stirring, nitrogen Three times, overnight, 200ml water, ethyl acetate extraction are added into filtrate for end of reaction, filtering for atmospheric pressure at room, reaction for displacement (300ml × 2) merge organic phase, Na₂SO₄Dry, filtrate is concentrated to dryness, and obtains weak yellow liquid 13.3g, as Formulas I Compound, HPLC purity: 86.4%, molar yield: 87.6%.

ESI-MS (M/Z)=167.17 [M+Na]⁺。

The preparation of 2 Formula II compound of comparative example (X Br)

Compound of formula I (14.2g, 98.5mmol) is dissolved in 200ml ether, be slowly dropped at room temperature bromine (47.2g, 295.6mmol, 3.0eq), it is added dropwise, is stirred to react.End of reaction, filtering, filtrate decompression concentration, concentrate acetic acid second Ester dissolution, is added 115ml saturated aqueous sodium sulfite, stirs 10min, liquid separation, and water phase is extracted with ethyl acetate, and merges organic It is mutually and dry, desiccant is filtered out, filtrate is concentrated to dryness, and 18.2g faint yellow solid, as Formula II compound, HPLC are obtained Purity: 83.1%, molar yield: 82.9%.

ESI-MS (M/Z)=246.06 [M+Na]⁺。

The preparation of 3 Formula II compound of comparative example (X I)

Compound of formula I (14.2g, 98.5mmol) is dissolved in 200ml methanol, is slowly added to NH at room temperature₄I (14.3g, 98.5mmol, 1.0eq) and Oxone (30.3g, 98.5mmol, 1.0eq), addition finishes, and is stirred to react, end of reaction, it filters, Filtrate decompression concentration, concentrate are dissolved with ethyl acetate, and the sodium thiosulfate solution of 115ml mass fraction 10% is added, stirs 10min, liquid separation are mixed, water phase is extracted with ethyl acetate, and merges organic phase and drying, filters out desiccant, filtrate is through being concentrated under reduced pressure into It is dry, 22.4g faint yellow solid, the as compound of Formula II structure are obtained, HPLC purity: 86.3%, molar yield: 84.1%.

ESI-MS (M/Z)=292.96 [M+Na]⁺。

The preparation of 4 formula III a compound of comparative example

Protobromide ketone dimethyl sulphide (0.55g, 2.7mmol, 0.03eq), Formula II are sequentially added in acetonitrile (200ml) It closes object (20.0g, 89.7mmol), ammonium bromide (8.8g, 89.7mmol, 1eq), potassium phosphate (19.0g, 89.7mmol, 1eq), and Tricyclohexyl phosphine (2.52g, 9mmol, 0.1eq) is heated to 55 DEG C and is stirred to react 15 hours, and end of reaction is concentrated to dryness, 300ml acetone is added into condensate residue, after being heated to 50 DEG C, filters out insoluble matter, decompression is spin-dried for acetone, is then added Solid is precipitated with 15% ethanol solution of hydrogen chloride tune pH=1~2 in 200ml methylene chloride, filters, and 50 DEG C of vacuum drying are had There is the compound of formula III structure, formula III compound is dissolved in 30ml water, then adjusts pH=9~10 through 32% aqueous sodium carbonate, Methylene chloride (50ml × 2) extraction merges organic phase, and anhydrous sodium sulfate is dry, is concentrated to dryness, obtains formula III a compound 12.5g, HPLC purity: 74.9%, molar yield: 71.3%.

ESI-MS (M/Z)=182.18 [M+Na]⁺。

The preparation of 5 formula IV compound of comparative example

7.3g (0.4eq) l-tyrosine is dissolved in 150ml ethyl alcohol, (2S, 4S, 6R) -4- amino -6- methoxyl group-is added dropwise The mixture of 2- methyl-tetrahydro pyrans -3- ketone and (2S, 4R, 6R) -4- amino -6- methoxyl group -2- methyl-tetrahydro pyrans -3- ketone (16g, 0.1mol, 1eq) acetonitrile solution 30ml, drop finish, and are heated to reflux 2~3h, stop heating, are down to room temperature, and insulated and stirred 2~ 3h, filtering, filter cake ethanol rinse, dry (2S, 4S, 6R) -4- amino -6- methoxyl group -2- methyl-tetrahydro pyrans -3- ketone - L-tyrosine salt 19.3g, yield 56.8%.

(2S, 4S, 6R) -4- amino -6- methoxyl group -2- methyl-tetrahydro pyrans -3- ketone-l-tyrosine salt is dissolved in second again In the aqueous solution of alcohol, under the conditions of 25 DEG C, pH to 10~11 is adjusted with the NaOH solution of 6mmol/ml.With ethyl acetate (200ml × 3) it extracting, organic layer is dried, filtered with anhydrous sodium sulfate, is concentrated to dryness, white solid 6.3g is obtained, total recovery: 39.6%, As IV compound measures ee value 99.52%.

ESI-MS (M/Z)=182.18 [M+Na]⁺。

The preparation of 6 Formula V compound of comparative example

Formula IV compound (15.0g, 76.7mmol) is dissolved in 60ml methylene chloride, is slowly dripped after being cooled to -3~3 DEG C Enter trifluoroacetic anhydride (5.4mL, 38.4mmol), be added dropwise and continue to be stirred to react about 1h, TLC is detected after completion of the reaction, to anti- It answers and 2ml methanol is added in liquid with 5% sodium bicarbonate aqueous solution tune pH ≈ 9.5 1h, liquid separation, water phase methylene chloride is stirred at room temperature Extraction, merges organic phase, and organic phase washs through aqueous hydrochloric acid solution (0.1N, 60ml), water washing (50ml × 2), anhydrous sulphur twice Sour sodium is dry, filters, is concentrated to dryness, compound 16.1g, HPLC purity of the acquisition with Formula V structure: 83.6%, mole Yield: 82.7%, mp.165.2~166.5 DEG C.

ESI-MS (M/Z)=278.19 [M+Na]⁺。

The preparation of 7 Formula IV compound of comparative example

By Formula V compound (12g, 47.0mmol), chloroacetic chloride (11.1g, 141mmol, 3eq) and thionyl chloride (0.1ml) It being placed in a reaction flask, about 18h is stirred at room temperature, end of reaction is concentrated to dryness, solid 10.4g, as Formula IV compound are obtained, HPLC purity: 81.7%, molar yield: 85.5%.

ESI-MS (M/Z)=271.58 [M+Na]⁺。

The preparation of 8 Formula VII compound of comparative example

Daunomycinone (3.1g, 7.68mmol, 1eq) is dissolved in 100ml anhydrous tetrahydrofuran solution, powdery 3a is sequentially added Molecular sieve, mercury oxide (5.0g, 23.1mmol, 3eq), mercuric bromide (2.8g, 7.68mmol, 1eq) are protected from light at 40 DEG C and stir 0.5 Hour.It is slowly dropped into the anhydrous tetrahydrofuran solution (36ml) dissolved with Formula IV compound (6.0g, 23.0mmol) again, about 6 hours It drips off, continues stirring 5 hours after being added dropwise, it is molten that 200ml methylene chloride is added into residue for 40 DEG C of evaporating solvent under reduced pressure Liquid, filtering, filtrate, which is concentrated under reduced pressure, obtains Formula VII crude compound, the dehydrated alcohol and n-hexane that crude product volume ratio is 1: 2 Mixed solvent recrystallization, obtains Formula VII compound highly finished product 3.7g, HPLC purity: 80.7%, molar yield: 78.5%.

ESI-MS (M/Z)=644.51 [M+Na]⁺。

The preparation of 9 Formula VII compound of comparative example

Daunomycinone (3.1g, 7.68mmol, leq) is dissolved in 100ml anhydrous methylene chloride/toluene (1: 1) solution, successively 4a molecular sieve is added, silver trifluoromethanesulfonate (2.2g, 8.4mmol, 1.1eq), is protected from light lower stirring 0.5 hour by -30 DEG C of temperature control.Again It is slowly dropped into anhydrous methylene chloride/toluene (1: 1) solution 36ml dissolved with Formula IV compound (2.2g, 8.4mmol, 1.1eq), about It drips off within 1 hour, is added dropwise, heat reaction solution to room temperature, continue to be stirred to react 5 hours, end of reaction, 40 DEG C remove under reduced pressure 200ml dichloromethane solution, filtering are added into residue for solvent, and filtrate obtains Formula VII crude compound through being concentrated under reduced pressure, Dehydrated alcohol and n-hexane the mixed solvent recrystallization that crude product volume ratio is 1: 2.5, obtain Formula VII compound highly finished product 3.9g, HPLC purity: 82.7%, molar yield: 82.2%.

ESI-MS (M/Z)=644.51 [M+Na]⁺。

The preparation of 10 Formula VIII compound of comparative example

By Formula VII compound (12g, 19.3mmol), 410ml methanol, 195ml methylene chloride is put into reaction flask, nitrogen Protection, cools to -3~3 DEG C, instills the ethanol solution of 80ml sodium borohydride (730.2mg, 19.3mmol, 1eq), About 30min is dripped off, and after insulation reaction 30min, 6.0ml acetone is added, and with the dilute hydrochloric acid solution tune pH=4.0 of 0.1mol/L, is divided Organic phase is collected after liquid, organic phase obtains Formula VIII crude compound after pure water twice (200ml × 2), reduced pressure, slightly Product are recrystallized to give Formula VIII compound with the methylene chloride, ethyl acetate, n-hexane mixed solvent that volume ratio is 1: 0.6: 1.2 Highly finished product 9.8g, HPLC purity: 80.7%, molar yield: 81.5%.

ESI-MS (M/Z)=646.53 [M+Na]⁺。

The preparation of 11 epirubicin of comparative example

Formula VIII compound highly finished product 9.0g is suspended in 460ml purified water, 25 DEG C, instills 3.5% sodium hydroxide Solution 60ml, insulation reaction 50min are washed twice after reaction with hydrochloric acid tune pH=2.0 with 200ml methylene chloride, are collected 1200ml methylene chloride and 80ml methanol are added into water phase for water phase, with sodium carbonate liquor tune pH=10.0, stand liquid separation, receive Collect organic phase, organic phase is concentrated to dryness to obtain epirubicin 6.96g, molar yield 91.5%, HPLC purity 96.3%, most It is big single miscellaneous: 1.2%.

ESI-MS (M/Z)=550.54 [M+Na]⁺。

Claims

1. a kind of synthetic method of the epirubicin with structural formula X,

It is characterized in that, the described method comprises the following steps:

VIII compound of formula obtains the compound of Formula X structure, i.e. epirubicin through basic hydrolysis amido bond, and reaction equation is as follows:

2. synthetic method as described in claim 1, which is characterized in that the synthesis of VIII compound of formula includes the following steps:

The compound with VIII structure of formula is obtained with the ketone group of VII compound of reducing agent reduction-type, 4 ' position, reaction equation is as follows:

3. synthetic method as claimed in claim 2, which is characterized in that the synthesis of VII compound of formula includes the following steps:

Daunomycinone reacts to obtain the compound with VII structure of formula with VI compound of formula under the effect of the catalyst,

4. synthetic method as claimed in claim 3, which is characterized in that the synthesis of VI compound of formula includes the following steps:

V compound of formula reacts to obtain the compound with VI structure of formula with chlorinating agent, and reaction equation is as follows:

5. synthetic method as claimed in claim 4, which is characterized in that the synthesis of V compound of formula includes the following steps:

IV compound of formula obtains the compound with V structure of formula through trifluoroacetic anhydride amidation, and reaction equation is as follows:

6. synthetic method as claimed in claim 5, which is characterized in that the synthesis of IV compound of formula includes the following steps:

The chiral reagent of formula III a compound splits to obtain the compound with IV structure of formula, and reaction equation is as follows:

7. synthetic method as claimed in claim 6, which is characterized in that the synthesis of III a compound of formula includes the following steps:

II compound of formula reacts to obtain the compound with III a structure of formula with aminating agent, and reaction equation is as follows:

Wherein, X is selected from Br, I in II compound of formula.

8. synthetic method as claimed in claim 7, which is characterized in that the synthesis of II compound of formula includes the following steps:

React to obtain the compound with II structure of formula after type I compound dissolution with halide, process route be selected from route b-1 or B-2,

Wherein, when X is Br in II compound of formula, route b-1 is selected；When X is I in II compound of formula, route b-2 is selected.

9. synthetic method as claimed in claim 8, which is characterized in that the synthesis of type I compound includes the following steps:

It is obtained through reducing agent reduction double bond with structure shown in formula I after the dissolution of (2S, 6R) -2- methyl -6- methoxyl group -6H- pyrans -3- ketone Compound, reaction equation is as follows: