CN104017016B - The preparation method of the intermediate of one class Entecavir, and intermediate - Google Patents

Abstract

The invention discloses the preparation method of the intermediate of a class Entecavir, and intermediate.The preparation method of the intermediate of the Entecavir as shown in formula IV or IV ' is comprised the steps of：In solvent, in the presence of Bronsted acid, compound V is carried out into the as follows reaction for sloughing amino protecting group and hydroxyl protecting group, you can.The preparation method raw material of the present invention is cheap and easy to get, and reaction condition is gentle, side reaction is few, high income, environmental pollution are little, and intermediate is easy to purifies and separates, is suitable to industrialized production.

Description

The preparation method of the intermediate of one class Entecavir, and intermediate

Technical field

The present invention is specifically related to the preparation method of the intermediate of a class Entecavir, and intermediate.

Background technology

Nucleotide analog is used as an important chemical type, the extensive pass for having obtained inside pharmaceutical chemistry Note.Relative research has created large quantities of significant medicines, especially in antiviral field.It is a great deal of Anti-AIDS and anti-hbv drug both be from the further investigation in the field.

There are 3.5 hundred million～4.0 hundred million hepatitis type B virus (HBV) the infecteds in the whole world, wherein there is nearly 1,000,000 patient to die from every year Cirrhosis and liver cancer that HBV infection causes.There are more than 1.2 hundred million HBV infection persons in China, account for more than the 1/3 of the world total, occupy generation The 1st, boundary, chronic hepatitis B (hepatitis B) patient 30,000,000, and also this numeral is just in rising trend at present.Chronic second Hepatovirus infection does not also have the method that can cure completely till now, and patient needs long-term or lifelong（Majority of case Under）Carry out HIV suppression.The clinical guidelines recommended therapy course for the treatment of is at least 1 year.Nucleoside medicine in the medicine of current hepatitis B Occupation rate of market cross 80%.In nucleoside medicine, Entecavir relies on its obvious curative effect and good anti-drug resistance, from Since 2007, having substituted Lamivudine becomes the anti-hepatic-B virus medicine of a line.Entecavir is by U.S.'s Bristol Myers Squibb Company develops, and on March 29th, 2005, approval was listed U.S. FDA.State food drug surveilance is obtained on November 15th, 2005 Management board SFDA ratifies Discussion on Chinese Listed.Drug patent expired in 2008.Because its synthesis difficulty is huge, its active component （API）Price is high at present, and manufacturer is few.

The bulk drug of Entecavir causes extensive concern in scientific circles because its huge synthesis challenge.With regard to grace Therefore synthetic methodology research for card Wei obtained deep development.Wherein more representational synthetic route is in the institute such as Shen Guobing Write《Entecavir route is illustrated》（749-752 page of 10 phase of volume 38 of Chinese Journal of Pharmaceuticals 2007）And the paper is drawn There is detailed review paper in document.Other related documents such as, but not limited to CN1861602A, CN101050216A、CN101182322A、CN101210015A、CN101235034A、CN101245067A、 CN101531660A、CN101723945A、CN101756890A、CN101759698A、CN101781301A、 CN101805339A、CN101830856A、CN101838207A、CN101838270A、CN101863842A、 CN101891741A、CN101906113A、CN102002023A、CN102225938A、CN102229608A、 DE102009060194A1、EP2433941A1、SG171963A1、TW201118097A、US2006106216A1、 Draw inside US2010286089A1, WO2011102806A1, WO2011150513A1, WO2012006964A1 and these documents Other documents.

The larger problem that current most synthetic routes are present, such as equivalent use Dess-Martin reagents, two pinanes The raw material costly such as alkene borine and reagent, experiment condition are harsh, and separating step is complicated, needs silica gel chromatograph post separation contour The means of purification of cost, is not suitable for big production.

A wherein comparatively practical production line（WO2005118585）It is as follows.There is the route reaction to receive The features such as rate is high, working condition is gentle, purification step is simple, is adapted to amplify production.But also there is its corresponding defect, such as one A little reagents such as phenyldimethylchlorosilane production difficulty cause high price, high toxicity reagent such as boron trifluoride use, And the intermediate of the overwhelming majority is all purification difficult caused by oily liquids institute in process of production.

The synthetic route similar to which in document CN101050216A has been made to be discussed in detail, and has larger changing on cost Enter, the relatively low diphenyl methyl chloro silane of price is employed as initiation material.But it is because that two phenyl ring are connected with silicon atom Caused by huge steric effect cause still avoid using the borontrifluoride of high poison high pollution during the last deprotection of the route Boron.

The content of the invention

The technical problem to be solved is to overcome the synthesising method reacting condition of existing Entecavir severe Carve, yield is high, environmental pollution is larger and expensive starting materials caused by the defect such as production cost is huge, and provide a class grace For the preparation method of the intermediate of card Wei, and intermediate.The preparation method raw material of the present invention is cheap and easy to get, reaction condition temperature Little with, few side reaction, high income, environmental pollution, intermediate is easy to purifies and separates, is suitable to industrialized production.

Present invention firstly provides the system of a kind of intermediate of Entecavir as shown in formula IV or its dynamic isomer IV ' Preparation Method, which comprises the steps of：In solvent, in the presence of Bronsted acid, compound V is carried out as follows sloughing amino The reaction of protection group and hydroxyl protecting group, you can；

Wherein, R^aFor C₁~C₄Straight chained alkyl（It is preferred that methyl）；R^bRepresent phenyl ring on one or more selected from halogen atom, The substituent or H of methoxyl group or methyl；R^cFor methyl；R₂The substituent being as follows：

Wherein, R₂₁For substituted or unsubstituted pyridine radicals or substituted or unsubstituted C₆~C₁₀Aryl, described replacement Pyridine radicals in substituent be C₁~C₃Alkyl, halogen and C₁~C₃One or more in alkoxyl, per the number of class substituent For one or more；Described substituted C₆~C₁₀Substituent in aryl is C₁～C₃Alkyl, halogen and C₁~C₃In alkoxyl One or more, the number per class substituent is one or more；

Y is 3 ~ 9 carbon for connecting or being not connected to other substituents, so as to form substituted or unsubstituted 4 ~ 10 yuan with Si Saturation or undersaturated silicon-carbon ring；Or, Y is to connect or be not connected to other substituents, and sum is the carbon atom of 3 ~ 9 and miscellaneous Atom, so as to the saturation that substituted or unsubstituted 4 ~ 10 yuan are formed with Si or undersaturated carbon sila ring, the hetero atom is O, S Or N, heteroatomic number is 1 ~ 3；Substituent in described replacement is C₁~C₃Alkyl；Described silicon-carbon ring or carbon sila ring For a ring or and two rings together（For example

Described R₂Preferably following arbitrary substituent：

In substituent IVa, n be 0 ~ 2, p be 0 ~ 2, q be independently carbon, oxygen or nitrogen for 1 ~ 2, X and Y, R₄For C₁~C₃Alkyl, And R₄For one or more substituents；When n is 0, X is carbon, and when p is 0, Y is carbon.

The more preferably following arbitrary substituents of substituent IVa：

Described R₂₁Preferably following arbitrary substituent：

In the present invention, the method and condition of the described reaction for sloughing amino protecting group and hydroxyl protecting group can be ability The conventional method and condition of this two classes reaction of domain, following conditions specifically preferred according to the invention：Described preferred solvents for organic molten Agent, water or their mixture, wherein described organic solvent is preferably dichloromethane, methyl alcohol, ethanol, isopropanol, tertiary fourth One or more in alcohol, tetrahydrofuran, acetonitrile, DMF and dimethyl sulfoxide (DMSO).The volume mass ratio of the solvent and compound V Preferably 2ml/g ~ 20ml/g, more preferably 5ml/g ~ 15ml/g.Described Bronsted acid be preferably hydrochloric acid, sulfuric acid, nitric acid, One or more in trifluoroacetic acid and methanesulfonic acid.Bronsted acid is preferably 0.1 ~ 100 with the mol ratio of compound V, more preferably For 1 ~ 20.Till the time of described reaction can be no longer carried out by detection reaction, generally 0.5 ~ 36 hour.Described reaction Temperature be preferably 0 ~ 100 DEG C, more preferably 20 ~ 80 DEG C.The described reaction for sloughing amino protecting group and hydroxyl protecting group Can carry out simultaneously.

In the present invention, above-claimed cpd V can be prepared by following methods：

Under inert gas shielding, in organic solvent, in the presence of titanium tetrabromide or titanium tetrachloride, compound VI and will receive Si Te（Nysted）Reagent carries out methylenation, you can；

Wherein, R^a、R^b、R^cAnd R₂Definition be the same as those described above.

Wherein, described Na Site（Nysted）The reagent that reagent is known in the art, its structure are as follows：

In the present invention, the method and condition of described methylenation can be the conventional method of this kind of reaction in this area And condition, following conditions specifically preferred according to the invention：Described organic solvent be preferably tetrahydrofuran, 2- methyltetrahydrofurans, One or more in ether and t-butyl methyl ether.The volume mass of described organic solvent and compound VI than preferably 2 ~ 50, more preferably 5 ~ 20.Described inert gas is preferably argon gas.Described Na Site（Nysted）Reagent and compound VI Mol ratio be preferably 0.5 ~ 10, more preferably 1 ~ 5.The mol ratio of described titanium tetrabromide or titanium tetrachloride and compound VI Preferably 0.1 ~ 10, more preferably 1 ~ 5.The time of described methylenation can be by detecting that behavior is no longer entered in reaction Only, generally 0.5 ~ 24 hour, more preferably 1 ~ 12 hour.The temperature of described methylenation is preferably -78 ~ 50 DEG C, more preferably -45 ~ 25 DEG C.

Present invention also offers the midbody compound of the Entecavir as shown in Formula V or VI, or as shown in formula IV The midbody compound of Entecavir or its dynamic isomer IV '：

Wherein, R^a、R^b、R^cAnd R₂Definition be the same as those described above.

In the present invention, Entecavir or its dynamic isomer can be prepared by following methods：

A kind of preparation method of Entecavir or its dynamic isomer I ' shown in formula I, which comprises the steps of：It is organic In solvent, in the presence of reducing agent, compound II is carried out into the as follows reaction that ester is reduced to alcohol, you can；

Wherein, R^aFor C₁~C₄Straight chained alkyl（It is preferred that methyl）；Described reducing agent is diisobutyl aluminium hydride, aluminum hydride Lithium, red aluminum（It is double（2- methoxy ethoxies）Sodium aluminum hydride）Or sodium borohydride, when reducing agent is sodium borohydride, the reaction Carry out in the presence of lithium chloride and/or lithium bromide.

In the present invention, the species of described organic solvent is not particularly limited, and does not affect to react the such reduction reaction for carrying out Conventional solvent is applicable, such as in dichloromethane, toluene, 1,2- dichloroethanes, tetrahydrofuran and 2- methyltetrahydrofurans One or more.The volume mass of described organic solvent and compound II or II ' than preferably 3 ~ 20ml/g, more preferably For 5 ~ 12ml/g.

In the present invention, the consumption of reducing agent can be the conventional amount used of the such reduction reaction in this area, for example, compound II Or 1 ~ 5 times of II ', following ranges specifically preferred according to the invention：The mol ratio of described reducing agent and compound II or II ' is preferably For 1.1 ~ 3.When reducing agent is sodium borohydride, the reaction is carried out in the presence of lithium chloride and/or lithium bromide, described chlorine The mol ratio for changing lithium and/or lithium bromide with compound II or II ' is preferably 0.1 ~ 2.

In the present invention, the temperature of the above-mentioned reaction that ester is reduced to alcohol is preferably -78 ~ 100 DEG C, more preferably -20 ~ 40℃.The time of the above-mentioned reaction that ester is reduced to alcohol can be by, till detecting that reaction is no longer carried out, generally 0.5 ~ 12 is little When.

In the present invention, after the Entecavir or its dynamic isomer I ' being obtained by above-mentioned preparation method shown in formula I, , can be carried out in Formulas I or I ' compound structures at 60 ~ 100 DEG C after for example adding water by the conventional post processing mode in this area The reaction of one hydrone, filters（Such as filtered with diatomite）, by filtrate crystallisation by cooling, you can obtain the entecavir with a crystallization water Wei compound or its tautomerism compound, it is as follows：

In the present invention, above-claimed cpd II or its dynamic isomer II ' can be prepared by following methods：

In solvent, compound III or its dynamic isomer III ' are carried out into Tamao-Fleming oxidation reactions, you can；

Wherein, R^aIt is as defined above described；R₁ForY is 3 ~ 9 carbon for connecting or being not connected to other substituents, So as to the saturation that substituted or unsubstituted 4 ~ 10 yuan are formed with Si or undersaturated silicon-carbon ring；Or, Y is for connection or is not connected to which His substituent, sum is carbon atom and the hetero atom of 3 ~ 9, so as to substituted or unsubstituted 4 ~ 10 yuan of saturation is formed with Si Or undersaturated carbon sila ring, the hetero atom is O, S or N, and heteroatomic number is 1 ~ 3；Replacement in described replacement Base is C₁~C₃Alkyl；Described silicon-carbon ring or carbon sila ring are a ring or and two rings together（For exampleOr

Described R₁Preferably following arbitrary substituent：

In substituent IVa, n be 0 ~ 2, p be 0 ~ 2, q be independently carbon, oxygen or nitrogen for 1 ~ 2, X and Y, R₄For C₁~C₃Alkyl, And R₄For one or more substituents；When n is 0, X is carbon, and when p is 0, Y is carbon.

The more preferably following arbitrary substituents of substituent IVa：

In the present invention, described Tamao-Fleming oxidation reactions are the classical name reactions of this area, said method and Condition can be the conventional method and condition of the such Tamao-Fleming oxidation reactions in this area, for example, may be referred to document (Fleming,I;Barbero,A;Walter,D;Chem Rev, 1997,97,2063-2192) in method carry out.

For above-mentioned Tamao-Fleming oxidation reactions, method specifically preferred according to the invention and condition：

Described Tamao-Fleming oxidation reactions are preferably comprised the steps of：

In solvent, in the presence of alkali and fluorination reagent, compound III or III ' and oxidant are carried out into Tamao- Fleming oxidation reactions.

Wherein, described preferred solvents in water, methyl alcohol, tetrahydrofuran, ethanol and DMF Plant or several.The volume mass of solvent and compound III or III ' is than preferably 1 ~ 300ml/g, more preferably 3 ~ 100ml/ g.Described alkali is preferably triethylamine, diisopropylethylamine (Hunig base）, saleratus, sodium acid carbonate and caesium bicarbonate In one or several.The mol ratio of described alkali and compound III or III ' is preferably 0.5 ~ 30, more preferably 0.8 ~ 15.Described oxidant be preferably hydrogen peroxide, Peracetic acid, tert-Butanol peroxide, metachloroperbenzoic acid, chlorine, bromine, One or more in iodine, N- dichloro-succinic acids Asia acid amides, N- bromosuccinic acids Asia acid amides and N- iodos succinic acid Asia acid amides.Institute The concentration of the hydrogen peroxide stated is preferably mass percent 1% to 60%.Described oxidant and compound III or III ' mole Than being preferably 0.8 ~ 30, more preferably 1 ~ 20.Described fluorination reagent is preferably sodium fluoride, cesium fluoride, potassium fluoride, fluorination One or more in hydrogen and boron trifluoride.Fluorination reagent is preferably 0.8 ~ 30 with the mol ratio of compound III or III ', more It is good for 1 ~ 10.The time of described Tamao-Fleming oxidation reactions can be by till detecting that reaction is no longer carried out.Described The temperature of Tamao-Fleming oxidation reactions is preferably -20 DEG C ~ 120 DEG C（More preferably 0 ~ 80 DEG C）.

In the present invention, above-claimed cpd III or III ' are prepared by following methods：

In solvent, in the presence of Bronsted acid, compound IV or its dynamic isomer IV ' are hydrolyzed reaction, will R₂In R₂₁Substituent replaces with hydroxyl；

R₁And R^aDefinition be the same as those described above, R₂For R₁In hydroxyl replace with R₂₁Substituent, i.e.,

Except R₂₁Outward, the same R of each group definition₁Described in；

R₂₁For substituted or unsubstituted pyridine radicals or substituted or unsubstituted C₆~C₁₀Aryl, described substituted pyridine Substituent in base is C₁~C₃Alkyl, halogen and C₁~C₃One or more in alkoxyl, the number per class substituent are one Or it is multiple；Described substituted C₆~C₁₀Substituent in aryl is C₁~C₃Alkyl, halogen and C₁~C₃One kind in alkoxyl or Various, the number per class substituent is one or more.

Preferably, described R₂₁For following arbitrary substituent：

Prepare in the method for above-claimed cpd III or its dynamic isomer III ', described solvent can be to common are machine Solvent or water, or their mixture, described organic solvent can be dichloromethane, 1,2- dichloroethanes, tetrahydrofuran, 2- One or more in methyltetrahydrofuran, acetonitrile, methyl alcohol, ethanol, isopropanol, toluene and t-butyl methyl ether.The solvent with The volume mass of compound IV or IV ' is than preferably 1 ~ 20ml/g.Described Bronsted acid can for hydrochloric acid, sulfuric acid, trifluoroacetic acid, One or more in nitric acid, methanesulfonic acid and TFMS.Bronsted acid with the mol ratio of compound IV or IV ' is preferably 0.1~20.Till the time of described reaction can be no longer carried out by detection reaction, generally 0.5 ~ 24 hour.Described reaction Temperature be preferably -20 ~ 80 DEG C, with acid species change.

In the present invention, the intermediate of the described Entecavir as shown in Formula IV can be prepared by following methods：

In the present invention, the intermediate of the Entecavir as shown in Formula IV can be obtained by following methods：It is non-proton organic molten In agent, in the presence of alkali, compound VII and compound VI ' are carried out into the reaction of upper amino protecting group as follows, i.e., Can；

Wherein, X is halogen（Such as chlorine, bromine or iodine）, R^aFor C₁~C₄Straight chained alkyl（It is preferred that methyl）；R^bRepresent on phenyl ring One or more substituents or H selected from halogen atom, methoxyl group or methyl；R^cFor methyl；R₂The substituent being as follows：

Wherein, R₂₁For substituted or unsubstituted pyridine radicals or substituted or unsubstituted C₆~C₁₀Aryl, described replacement Pyridine radicals in substituent be C₁~C₃Alkyl, halogen and C₁~C₃One or more in alkoxyl, per the number of class substituent For one or more；Described substituted C₆~C₁₀Substituent in aryl is C₁~C₃Alkyl, halogen and C₁~C₃In alkoxyl One or more, the number per class substituent is one or more；

Y is 3 ~ 9 carbon for connecting or being not connected to other substituents, so as to form substituted or unsubstituted 4 ~ 10 yuan with Si Saturation or undersaturated silicon-carbon ring；Or, Y is to connect or be not connected to other substituents, and sum is the carbon atom of 3 ~ 9 and miscellaneous Atom, so as to the saturation that substituted or unsubstituted 4 ~ 10 yuan are formed with Si or undersaturated carbon sila ring, the hetero atom is O, S Or N, heteroatomic number is 1 ~ 3；Substituent in described replacement is C₁~C₃Alkyl；Described silicon-carbon ring or carbon sila ring For a ring or and two rings together（For exampleOr

Described R₂Preferably following arbitrary substituent：

In substituent IVa, n be 0 ~ 2, p be 0 ~ 2, q be independently carbon, oxygen or nitrogen for 1 ~ 2, X and Y, R₄For C₁~C₃Alkyl, And R₄For one or more substituents；When n is 0, X is carbon, and when p is 0, Y is carbon.

The more preferably following arbitrary substituents of substituent IVa：

Described R₂₁Preferably following arbitrary substituent：

In the present invention, the method and condition that described upper amino protecting group reacts can be the normal of this two classes reaction of this area Rule method and condition, following conditions specifically preferred according to the invention：Described aprotic organic solvent can be the conventional non-matter in this area Sub- organic solvent, such as DMF, dimethyl sulfoxide (DMSO), acetonitrile, tetrahydrofuran, 2- methyltetrahydrofurans and N- methyl One or more in pyrrolidones.The volume mass of described organic solvent and compound VII than preferably 1ml/g ~ 100ml/g, preferable 3ml/g ~ 20ml/g.Described alkali be preferably DMAP, triethylamine, diisopropylethylamine, One or more in potassium carbonate, sodium carbonate and cesium carbonate.The mol ratio of described alkali and compound VII is preferably 0.5 ~ 10, preferably 1 ~ 5.The mol ratio of described compound VI ' and compound VII is preferably 0.5 ~ 10, more preferably 1 ~ 3. Till the time of the reaction of described upper amino protecting group can be no longer carried out by detection reaction, generally 0.5 ~ 72 hour, more It is good for 1 ~ 24.The temperature of the reaction of described upper amino protecting group is preferably 0 ~ 150 DEG C, more preferably 25 ~ 80 DEG C.

In the present invention, above-claimed cpd VII can be prepared by following methods：

In aprotic organic solvent, compound VIII and oxidant are carried out into oxidation reaction as follows, you can；

Wherein, R^a、R^bAnd R₂Definition be the same as those described above.

In the present invention, the method and condition of above-mentioned oxidation reaction can be the conventional method and bar of this kind of reaction in this area Part, following conditions specifically preferred according to the invention：Described aprotic organic solvent be preferably dichloromethane, n-hexane, toluene and One or more in ethyl acetate.The volume mass of described aprotic organic solvent and compound VIII than preferably 1 ~ 100, preferably 3 ~ 20.Described oxidant is preferably sodium metaperiodate, potassium metaperiodate, cesium periodate, sodium chlorate, chloric acid One or more in potassium, sodium hypochlorite and postassium hypochlorite.Described oxidant with the mol ratio of compound VIII is preferably 0.5 ~ 10, more preferably 1 ~ 3.Described oxidation reaction is carried out preferably in the presence of alkali, and described alkali is preferably carbonic acid Hydrogen potassium, one or more in sodium acid carbonate and caesium bicarbonate.Described alkali is preferably 0.5 with the mol ratio of compound VIII ~ 10, preferably 1 ~ 5.The time of described oxidation reaction can be by, till detecting that reaction is no longer carried out, generally 0.5 ~ 72 is little When, more preferably 1 ~ 24 hour.The temperature of described oxidation reaction is preferably -20 ~ 80 DEG C, more preferably 0 ~ 60 DEG C.

In the present invention, the intermediate of the Entecavir as shown in Formula VIII can be obtained by following methods：It is non-proton organic In solvent, in the presence of alkali, compound IX and VIII ' are carried out into ring-opening reaction as follows, you can；

Wherein, R^aFor C₁~C₄Straight chained alkyl（It is preferred that methyl）；R^bOne or more on phenyl ring are represented selected from halogen atom, The substituent or H of methoxyl group or methyl；R₂The substituent being as follows：

Wherein, R₂₁For substituted or unsubstituted pyridine radicals or substituted or unsubstituted C₆~C₁₀Aryl, described replacement Pyridine radicals in substituent be C₁～C₃Alkyl, halogen and C₁～C₃One or more in alkoxyl, per the number of class substituent Mesh is one or more；Described substituted C₆~C₁₀Substituent in aryl is C₁～C₃Alkyl, halogen and C₁～C₃Alkoxyl In one or more, the number per class substituent is one or more；

Y is 3 ~ 9 carbon for connecting or being not connected to other substituents, so as to form substituted or unsubstituted 4 ~ 10 yuan with Si Saturation or undersaturated silicon-carbon ring；Or, Y is to connect or be not connected to other substituents, and sum is the carbon atom of 3 ~ 9 and miscellaneous Atom, so as to the saturation that substituted or unsubstituted 4 ~ 10 yuan are formed with Si or undersaturated carbon sila ring, the hetero atom is O, S Or N, heteroatomic number is 1 ~ 3；Substituent in described replacement is C₁～C₃Alkyl；Described silicon-carbon ring or carbon sila Ring is a ring or and two rings together（For exampleOr

Described R₂Preferably following arbitrary substituent：

In substituent IVa, n be 0 ~ 2, p be 0 ~ 2, q be independently carbon, oxygen or nitrogen for 1 ~ 2, X and Y, R₄For C₁~C₃Alkyl, And R₄For one or more substituents；；When n is 0, X is carbon, and when p is 0, Y is carbon.

The more preferably following arbitrary substituents of substituent IVa：

Described R₂₁Preferably following arbitrary substituent：

Wherein, the method and condition of described ring-opening reaction can be the conventional method and condition of this kind of reaction in this area, Following conditions specifically preferred according to the invention：Described aprotic organic solvent can be the conventional aprotic organic solvent in this area, such as In N,N-dimethylformamide, dimethyl sulfoxide (DMSO), acetonitrile, tetrahydrofuran, 1-METHYLPYRROLIDONE and 2- methyltetrahydrofurans One or more.The volume mass of described organic solvent and compound IX than preferably 1ml/g ~ 100ml/g, preferably 3ml/g~20ml/g.Described alkali is preferably lithium hydroxide and/or lithium hydride.The mol ratio of described alkali and compound IX compared with It is good for 0.01 ~ 10, more preferably 0.05 ~ 5.The mol ratio of described compound VIII ' and compound IX is preferably 0.5 ~ 10, more preferably 1 ~ 3.The time of described ring-opening reaction can be by, till detecting that reaction is no longer carried out, generally 0.5 ~ 72 is little When, more preferably 3 ~ 48 hours.The temperature of described ring-opening reaction is preferably 0 ~ 150 DEG C, more preferably 25 ~ 120 DEG C.

In the present invention, above-claimed cpd IX can be prepared by following methods：

In organic solvent, compounds X is carried out into Sharpless chiral epoxy reactions, you can；

Wherein, R^aAnd R₂Definition be the same as those described above.

Wherein, the method and condition of described Sharpless chiral epoxies reaction can be the normal of this kind of reaction in this area Rule method and condition, such as can refer to document (Pfenninger, A.Synthesis1986,89）In method and condition carry out, can For following methods：In organic solvent, in the presence of tetraisopropoxy titanium and chiral ligand, compounds X and peroxide are entered Row Sharpless chiral epoxies react, you can.

Following conditions specifically preferred according to the invention：Described organic solvent can be dichloromethane and/or 1,2- dichloroethanes.Institute The volume mass of the organic solvent stated and compounds X is than preferably 1ml/g ~ 100ml/g, more preferably 3ml/g ~ 20ml/g. Described chiral ligand is preferably（2S, 3S）- ethyl tartrate or（2S, 3S）- tartaric acid diisopropyl ester.Hand-type part with The mol ratio of compounds X is preferably 0.0001 ~ 1, more preferably 0.001 ~ 0.3.Tetraisopropoxy titanium and compounds X mole Than being preferably 0.0001 ~ 1, more preferably 0.001 ~ 0.3.Described peroxide is preferably tert-Butanol peroxide, peroxidating One or more in hydrogen, Peracetic acid and metachloroperbenzoic acid.Described peroxide is preferable with the mol ratio of compounds X For 0.5 ~ 10, more preferably 1 ~ 5.Till the time of described chiral epoxy reaction can be no longer carried out by detection reaction, Generally 0.25 ~ 12 hour, more preferably 0.5 ~ 8 hour.The temperature of described chiral epoxy reaction is preferably -78 ~ 25 DEG C, more preferably -60 ~ 0 DEG C.

In the present invention, the intermediate of Entecavir represented by a formula X can be obtained by following methods：

Step（1）：In organic solvent, by compounds X I and（1R,2R）- 2- amino -1-（4- nitrobenzophenones）Propane -1,3- Glycol is reacted；

Step（2）：In organic solvent, in the presence of the concentrated sulfuric acid, by step（1）The material for obtaining and R^aOH is esterified Reaction, you can；

Wherein, R^aFor C₁~C₄Straight chained alkyl（It is preferred that methyl）；

R₂The substituent being as follows：

Wherein, R₂₁For substituted or unsubstituted pyridine radicals or substituted or unsubstituted C₆~C₁₀Aryl, described replacement Pyridine radicals in substituent be C₁～C₃Alkyl, halogen and C₁～C₃One or more in alkoxyl, per the number of class substituent Mesh is one or more；Described substituted C₆~C₁₀Substituent in aryl is C₁～C₃Alkyl, halogen and C₁～C₃Alkoxyl In one or more, the number per class substituent is one or more；

Y is 3 ~ 9 carbon for connecting or being not connected to other substituents, so as to form substituted or unsubstituted 4 ~ 10 yuan with Si Saturation or undersaturated silicon-carbon ring；Or, Y is to connect or be not connected to other substituents, and sum is the carbon atom of 3 ~ 9 and miscellaneous Atom, so as to the saturation that substituted or unsubstituted 4 ~ 10 yuan are formed with Si or undersaturated carbon sila ring, the hetero atom is O, S Or N, heteroatomic number is 1 ~ 3；Substituent in described replacement is C₁～C₃Alkyl；Described silicon-carbon ring or carbon sila Ring is a ring or and two rings together（For exampleOr

Described R₂Preferably following arbitrary substituent：

In substituent IVa, n be 0 ~ 2, p be 0 ~ 2, q be independently carbon, oxygen or nitrogen for 1 ~ 2, X and Y, R₄For C₁~C₃Alkyl, And R₄For one or more substituents；When n is 0, X is carbon, and when p is 0, Y is carbon.

The more preferably following arbitrary substituents of substituent IVa：

Described R₂₁Preferably following arbitrary substituent：

Step（1）In, the method and condition of described reaction can be the conventional method and condition of this kind of reaction in this area, Following conditions specifically preferred according to the invention：Described organic solvent can be isopropanol, methyl alcohol, ethanol, water, N, N- dimethyl formyls One or more in amine, dimethyl sulfoxide (DMSO), acetonitrile, tetrahydrofuran, 2- methyltetrahydrofurans and 1-METHYLPYRROLIDONE.It is described Organic solvent and compounds X I volume mass than preferably 1ml/g ~ 100ml/g, more preferably 3ml/g ~ 20ml/g.Institute State（1R,2R）- 2- amino -1-（4- nitrobenzophenones）Propane -1, the mol ratio of 3- glycol and compounds X I is preferably 0.25 ~ 10, more preferably 0.4 ~ 3.The time of described reaction can be by, till detecting that reaction is no longer carried out, generally 0.25 ~ 72 is little When, more preferably 0.5 ~ 24 hour.The temperature of described reaction is preferably 0 ~ 150 DEG C, more preferably 25 ~ 80 DEG C.

Step（2）In, the method and condition of described esterification can be the conventional method of this kind of reaction in this area and Condition, following conditions specifically preferred according to the invention：Described organic solvent can be C₁~C₄Alkylol.Described organic solvent and chemical combination The volume mass of thing XI is than preferably 1ml/g ~ 100ml/g, more preferably 3ml/g ~ 20ml/g.The quality of the described concentrated sulfuric acid Percentage can be 60% ~ 98%（Such as 98%wt）.The described concentrated sulfuric acid is preferably 0.01 ~ 100 with the mol ratio of compounds X I, more It is good for 0.05 ~ 30.Till the time of described reaction can be no longer carried out by detection reaction, generally 0.5 ~ 72 hour, more It is good for 1 ~ 48 hour.The temperature of described reaction is preferably -20 ~ 100 DEG C, more preferably -10 ~ 60 DEG C.

In the present invention, above-claimed cpd XI can be prepared by following methods：

In solvent, compounds X II is carried out into the reaction that carbonyl reduction is hydroxyl with reducing agent, you can；

Wherein, R₂It is as defined above described.

Wherein, described carbonyl reduction can be the routine of this kind of reaction in this area for the method and condition of the reaction of hydroxyl Method and condition, following conditions specifically preferred according to the invention：Described preferred solvents for alcohol organic solvent and/or water；Or One or more in toluene, dichloromethane and tetrahydrofuran.The volume mass of solvent and compounds X II is than preferably 1ml/ G ~ 100ml/g, more preferably 3ml/g ~ 20ml/g.When solvent is alcohol organic solvent and/or water, described reducing agent can be LiBH₄、CsBH₄、KBH₄And NaBH₄In one or more, the mol ratio of reducing agent and compounds X II can be 0.5 ~ 10, more preferably For 1 ~ 3, described alcohol organic solvent can be one or more in isopropanol, methyl alcohol, ethanol, the tert-butyl alcohol and n-butanol. When solvent is one or more in toluene, dichloromethane and tetrahydrofuran, described reducing agent can be lithium aluminium hydride reduction, two different Butyl aluminum hydride or red aluminum（Double (2- methoxy ethoxies) sodium aluminum hydrides））, reducing agent with the mol ratio of compounds X II can be 0.5 ~ 10, more preferably 1 ~ 3.Described carbonyl reduction can be by detecting that behavior is no longer entered in reaction for the time of the reaction of hydroxyl Only, generally 0.25 ~ 12 hour, more preferably 0.5 ~ 10 hour.Described carbonyl reduction is preferable for the temperature of the reaction of hydroxyl For -78 ~ 120 DEG C, more preferably -60 ~ 60 DEG C.

In the present invention, the intermediate of the Entecavir as shown in Formula X II can be obtained by following methods：

In solvent, in the presence of alkali, compounds X III is carried out into isomerization reaction as follows, you can；

R₂The substituent being as follows：

Wherein, R₂₁For substituted or unsubstituted pyridine radicals or substituted or unsubstituted C₆~C₁₀Aryl, described replacement Pyridine radicals in substituent be C₁～C₃Alkyl, halogen and C₁～C₃One or more in alkoxyl, per the number of class substituent Mesh is one or more；Described substituted C₆~C₁₀Substituent in aryl is C₁~C₃Alkyl, halogen and C₁~C₃In alkoxyl One or more, the number per class substituent is one or more；

Y is 3 ~ 9 carbon for connecting or being not connected to other substituents, so as to form substituted or unsubstituted 4 ~ 10 yuan with Si Saturation or undersaturated silicon-carbon ring；Or, Y is to connect or be not connected to other substituents, and sum is the carbon atom of 3 ~ 9 and miscellaneous Atom, so as to the saturation that substituted or unsubstituted 4 ~ 10 yuan are formed with Si or undersaturated carbon sila ring, the hetero atom is O, S Or N, heteroatomic number is 1 ~ 3；Substituent in described replacement is C₁～C₃Alkyl；Described silicon-carbon ring or carbon sila Ring is a ring or and two rings together（For exampleOr

Described R₂Preferably following arbitrary substituent：

In substituent IVa, n be 0 ~ 2, p be 0 ~ 2, q be independently carbon, oxygen or nitrogen for 1 ~ 2, X and Y, R₄For C₁~C₃Alkyl, And R₄For one or more substituents；When n is 0, X is carbon, and when p is 0, Y is carbon.

The more preferably following arbitrary substituents of substituent IVa：

Described R₂₁Preferably following arbitrary substituent：

Wherein, the method and condition of described isomerization reaction can be the conventional method and bar of this kind of reaction in this area Part, following conditions specifically preferred according to the invention：Described solvent can be isopropanol, methyl alcohol, ethanol, the tert-butyl alcohol, n-butanol, N, N- bis- One kind in NMF, dimethyl sulfoxide (DMSO), acetonitrile, tetrahydrofuran, 2- methyltetrahydrofurans, 1-METHYLPYRROLIDONE and water Or it is various.The volume mass of described solvent and compounds X III than preferably 1ml/g ~ 100ml/g, more preferably 3ml/g ~ 20ml/g.Described alkali can be triethylamine, diisopropylethylamine, 11 carbon -7- alkene of 1,8- diazabicylos [5.4.0], carbonic acid One or more in sodium, potassium carbonate, cesium carbonate, lithium carbonate, potassium hydroxide, lithium hydroxide, NaOH and cesium hydroxide.Institute The alkali stated can be 0.5 ~ 10, more preferably 1 ~ 3 with the mol ratio of compounds X III.The time of described isomerization reaction can pass through Till detection reaction is no longer carried out, generally 0.25 ~ 72 hour, more preferably 0.5 ~ 12 hour.Described isomerization reaction Temperature is preferably -50 ~ 100 DEG C, more preferably -10 ~ 80 DEG C.

In the present invention, above-claimed cpd XIII is prepared by following methods：

In the mixed solution of organic solvent and water, in the presence of alkali, compounds X IV is carried out into hydrolysis as follows anti- Should, you can；

Wherein, R₂It is as defined above described.

Wherein, the method and condition of described hydrolysis can be the conventional method and condition of this kind of reaction in this area, Following conditions specifically preferred according to the invention：Described organic solvent can be isopropanol, methyl alcohol, ethanol, the tert-butyl alcohol, n-butanol, N, N- One or more in dimethylformamide, dimethyl sulfoxide (DMSO), acetonitrile, tetrahydrofuran and 1-METHYLPYRROLIDONE.Described has The volume mass of machine solvent and compounds X IV is than preferably 0.5ml/g ~ 100ml/g, more preferably 1ml/g ~ 20ml/g.Institute The volume mass of the water stated and compounds X IV is than preferably 0.25ml/g ~ 100ml/g, more preferably 0.5ml/g ~ 20ml/g. Described alkali can be triethylamine, diisopropylethylamine, 11 carbon -7- alkene of 1,8- diazabicylos [5.4.0], sodium carbonate, carbonic acid One or more in potassium, cesium carbonate, lithium carbonate, potassium hydroxide, lithium hydroxide, NaOH and cesium hydroxide.Described alkali Mol ratio with compounds X IV is preferably 0.5 ~ 100, more preferably 1 ~ 50.The time of described hydrolysis can be by inspection Till survey reaction is no longer carried out, generally 0.25 ~ 72 hour, more preferably 0.5 ~ 12 hour.The temperature of described hydrolysis Preferably -10 ~ 150 DEG C, more preferably 0 ~ 120 DEG C.

In the present invention, above-claimed cpd XIV can be prepared by following methods：

In organic solvent, in the presence of alkali, compounds X V and dichloroacetyl chloride are carried out into addition reaction as follows, ；

Wherein, R₂It is as defined above described.

Wherein, the method and condition of described addition reaction can be the conventional method and condition of this kind of reaction in this area, Following conditions specifically preferred according to the invention：

Described organic solvent is preferably n-hexane, toluene, dimethylbenzene, trimethylbenzene, benzene, chlorobenzene, petroleum ether, tetrahydrochysene furan Mutter, one or more in 2- methyltetrahydrofurans, pentane and normal heptane.The volume mass ratio of organic solvent and compounds X V Preferably 1ml/g ~ 100ml/g, more preferably 3ml, g ~ 20ml/g.Described alkali is preferably diisopropylethylamine, 1,8- One or more in 11 carbon -7- alkene of diazabicylo [5.4.0], triethylamine and pyridine.Described alkali is with compounds X V's Mol ratio can be 0.5 ~ 100, more preferably 1 ~ 50.Described dichloroacetyl chloride can be 0.5 ~ 10 with the mol ratio of compounds X V, More preferably 0.8 ~ 3.The time of described addition reaction can be by, till detecting that reaction is no longer carried out, generally 0.25 ~ 72 is little When, more preferably 0.5 ~ 24 hour.The temperature of described addition reaction is preferably -50 ~ 100 DEG C, more preferably -30 ~ 30 DEG C.

In the present invention, above-claimed cpd XV can be prepared by following either method：

Under inert gas shielding, in organic solvent, by compound R₂The alkali metal salt of X and cyclopentadiene（Such as cyclopentadiene Sodium）Or the alkali salt of cyclopentadiene carries out nucleophilic substitution as follows, you can；

Wherein, X be F, Cl, Br, OTf orR₂It is as defined above described.

Wherein, the method and condition of described nucleophilic substitution can be the conventional method and bar of this kind of reaction in this area Part, following conditions specifically preferred according to the invention：Described organic solvent is preferably tetrahydrofuran, petroleum ether, 2- methyl tetrahydrochysene furans Mutter, one or more in n-hexane, pentane and normal heptane.Solvent and compound R₂The volume mass ratio of X is preferably 1ml/g ~ 100ml/g, more preferably 3ml/g ~ 20ml/g.The alkali metal salt of described cyclopentadiene（Such as sodium cyclopentadiene）Or ring The alkali salt and compound R of pentadiene₂The mol ratio of X is preferably 0.5 ~ 10, more preferably 0.8 ~ 3.Described nucleophilic The time of substitution reaction can be by, till detecting that reaction is no longer carried out, generally 0.25 ~ 72 hour, more preferably 0.5 ~ 24 is little When.The temperature of described nucleophilic substitution is preferably -78 ~ 50 DEG C, more preferably -60 ~ 30 DEG C.

Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can be combined, and obtain final product the present invention each preferably Example.

Agents useful for same of the present invention and raw material are commercially available.

The present invention positive effect be：The preparation method raw material of the present invention is cheap and easy to get, and reaction condition is gentle, secondary Reaction less, high income, environmental pollution it is little, intermediate is easy to purifies and separates, is suitable to industrialized production.

Specific embodiment

The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to described reality Among applying a scope.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or according to business Product specification is selected.

Example 1

Example 1-a

R^a=Me

In dichloromethane (1000ml) solution of as above initial compounds (50.0g, 164mmol), ice-water bath keeps 0 ~ 5 Degree Celsius, it is slowly added to diisobutyl aluminium hydride（2M toluene solutions, 180mL）.Reaction is dropped after being kept for 4 hours at 0 ~ 5 degree Celsius Temperature arrives -20 degrees Celsius, and is slowly added to methyl alcohol（50ml）.The mixed liquor for obtaining adds distilled water after being evaporated organic solvent 2000ml.The suspension for obtaining is filtered through diatomite after being heated to 80 degrees Celsius, and it is Celsius that the filtrate for obtaining is slow cooling to 0 Degree.The crystalline powdery solid for obtaining is collected by filtration（39.7g, yield 82%）, as required target product.

¹H NMR(400MHz,DMSO-d₆):δ10.57(br s,1H)7.69(s,1H)6.41(br s,2H)5.36(m, 1H)5.12(m,1H)4.89(s,1H)4.83(m,1H)4.58(m,1H)4.22(m,1H)3.55(m,2H)2.52(m,1H)2.21 (m,1H)2.04(m,1H)

¹³C NMR(100MHz,DMSO-d₆):δ156.8,153.4,151.4,151.2,135.9,116.2,109.2, 70.3,62.9,55.0,54.0,39.2

ESI-MS：278.1[M+H]⁺

1 embodiment 1-b of table is to embodiment 1-g（In addition to table conditional, other conditions are with example 1-a）

Example 2

Example 2-a

R^a=Me,

In the water of the initial compounds as shown in above formula (65.0g, 173mmol)（1300mL）Saleratus is added in solution （51.9g,519mmol）, potassium fluoride（20g,345mmol）.The mixed liquor for obtaining is slowly added to 30% hydrogen peroxide under 70 degrees Celsius （110g,865mmol）.Mixed liquor after completion of dropping is incubated under 70 degrees Celsius and adds acetic acid after stirring 3 hours （115mL）, and continue 70 degrees Celsius of insulation and stir 30 minutes.Mixed liquor is slow cooling to 5 degrees Celsius Jing after diatomite filtration. The powder crystal for obtaining is collected by filtration to be scattered in 1000mL distilled water again after 5 degrees Celsius are distilled water washing, heats It is allowed to be completely dissolved to 95 degrees Celsius.The clear liquid for obtaining is slow cooling to 5 degrees Celsius.The powder crystal for obtaining is collected by filtration simultaneously It is dried and is required target compound（48.0g, yield 91%）.

¹H-NMR(400MHz,CD₃OD)δ7.80(s,1H),5.44-5.39(m,1H),5.14(s,1H),4.70(s,1H), 4.30-4.28(m,1H),3.67(s,3H),2.69(s,1H),2.31-2.24(m,1H),2.14-2.08(m,1H);

¹³C-NMR(400MHz,CD₃OD)δ170.0,159.8,155.6,153.8,152.2,140.0,117.7,112.0, 73.8,57.4,53.6,52.3,41.3

ESI-MS：306.1[M+H]⁺

Conventional method of the method that reaction can be used for Tamao-Fleming oxidation reactions, bibliography (Fleming,I;Barbero,A;Walter,D;Chem Rev,1997,97,2063-2192).

2 embodiment 2-b of table is to embodiment 2-l（In addition to table conditional, other conditions are with example 2-a）

Example 3

Example 3-a

R^aFor methyl.

In the dichloromethane of as above initial compounds (105.0g, 241mmol)（1050mL）Methanesulfonic acid is added in solution （10.5ml）.The brown liquid for obtaining is slowly dropped in the aqueous solution of potassium hydroxide after stirring 2 hours under 25 degrees Celsius（2M, 2L）.The mixed liquor for obtaining adds acetic acid to pH=6 ~ 7 after being evaporated organic solvent.The solid dry as institute for obtaining is collected by filtration The target compound for needing（77.7g, yield 86%）.

¹H-NMR(400MHz,CD₃OD)δ7.80(s,1H),5.30(s,1H),5.02(s,1H),4.34-4.26(m,1H), 3.67(s,3H),3.08(d,1H),2.84(m,1H),2.39-3.37(m,1H),2.17-2.13(m,1H),1.85-1.45(m, 4H),1.25-1.05(m,2H);

¹³C-NMR(400MHz,CD₃OD)δ170.0,156.5,155.2,153.9,153.1,117.4,112.1,59.7, 52.3,45.8,39.4,28.3,22.4,18.7,8.4；

ESI-MS：376.1[M+H]⁺

3 embodiment 3-b of table is to embodiment 3-r（In addition to table conditional, other conditions are with example 3-a）

Example 4

Example 4-a

R^aFor methyl.

In the tetrahydrofuran of as above initial compounds (250.0g, 312mmol)（1000mL）Hydrochloric acid is added in solution（1M, 1500mL）.After the brown liquid for obtaining is stirred 12 hours under 65 degrees Celsius, 25 degrees Celsius are cooled to, tetrahydrochysene furan is distilled off Mutter.The clear liquid for obtaining is extracted through t-butyl methyl ether（200mL X2）.The water for obtaining mutually is slowly dropped into the aqueous solution of potassium hydroxide （2M）To pH=6 ~ 7.The solid for obtaining the target compound being dried needed for being is collected by filtration（129g, yield 95%）.

¹H-NMR(400MHz,CD₃OD)δ8.68(d,1H),7.80(s,1H),7.46(t,1H),7.38(d,1H),7.18 (t,1H),5.30(s,1H),5.02(s,1H),4.34-4.26(m,1H),3.67(s,3H),3.08(d,1H),2.84(m, 1H),2.39-2.37(m,1H),2.17-2.13(m,1H),1.85-1.55(m,4H),1.25-1.05(m,2H);

¹³C-NMR(400MHz,CD₃OD)δ170.0,157.9,156.5,155.2,153.9,153.1,149.4,140.1, 133.8,128.2,122.8,117.4,112.1,59.7,52.3,47.8,32.0,24.5,19.3,7.6;;

ESI-MS：437.2[M+H]⁺

4 embodiment 4-b of table is to embodiment 4-r（In addition to table conditional, other conditions are with example 4-a）

Example 5

Example 5-a

R^aFor methyl.

Nysted reagents under argon gas protection atmosphere（1200mL, 2M, tetrahydrofuran solution）Four are added under 0 ~ 5 degree Celsius Titanium chloride（240ml, 1M, dichloromethane solution）.The brownish red troubled liquor for obtaining is lowered the temperature after stirring 2 hours under 25 degrees Celsius To 0 degree Celsius, and it is slowly added to compound shown in above formula（192g,240mmol）.The mixture for obtaining is little in 0 degree Celsius of stirring 6 When after be slowly added into the saturated solution of sodium bicarbonate that is stirred vigorously under nitrogen atmosphere protection（2000mL）In.The mixture for obtaining As a child filtered through diatomite in 25 degrees Celsius of stirrings 1, filter cake is through dichloromethane（1000mL）Stir and wash.The water phase of merging and It is organic to be added to salt（600g）Layering is filtered after saturation.Detached organic phase is evaporated organic solvent after magnesium sulfate drying Obtain target product crude product（163g, yield 85%）

¹H-NMR(400MHz,CD₃OD)δ8.68(d,1H),8.1(s,1H),7.60-7.10(m,20H),6.70(d,2H), 5.30(s,1H),5.24(s,2H),5.02(s,1H),4.34-4.26(m,1H),3.75(s,3H),3.67(s,3H),3.08 (d,1H),2.84(m,1H),2.39-2.37(m,1H),2.17-2.13(m,1H),1.85-1.45(m,4H),1.25-1.05 (m,2H);

¹³C-NMR(400MHz,CD₃OD)δ170.0,159.9,157.9,156.5,155.2,153.9,153.1,149.4, 148.0,140.2,140.1,137.1,133.8,132.5,130.9,130.5,129.8,129.7,129.3,129.1, 128.2,122.8,117.4,115.8,112.1,74.9.73.0,71.1,57.6,52.3,47.7,31.5,24.5,19.2, 7.6

ESI-MS：799.3[M+H]⁺

5 embodiment 5b-5r of table（In addition to table conditional, other conditions are with example 5-a）

Example 6

Example 6-a

R^aFor methyl.

In the N,N-dimethylformamide of the initial compounds (230g, 436mmol) shown in above formula（1050mL）Middle addition DMAP（80g, 654mmol）With 4- methoxyphenyls-diphenyl methyl chloride（269g, 872mmol）.What is obtained is anti- Liquid is answered to be slowly added to sodium hydrate aqueous solution after stirring 36 hours under 25 degrees Celsius（0.5M,1000mL）.The turbid solution for obtaining T-butyl methyl ether extraction is added in body（600mL X3）.The t-butyl methyl ether of merging is concentrated to after sodium sulphate drying 750mL, and n-hexane is slowly added under 45 degrees Celsius（1200mL）And cool to -20 degrees Celsius.The pin for obtaining is collected by filtration Shape solid the target compound intermediate being dried needed for being（251g, yield 72%）.

¹H-NMR(400MHz,CD₃OD)δ8.68(d,1H),8.1(s,1H),7.60-7.10(m,20H),6.70(d,2H), 5.24(s,2H)4.34-4.26(m,1H),3.75(s,3H),3.67(s,3H),2.98(d,1H),2.84(m,1H),2.79- 2.77(m,1H),2.67-2.63(m,1H),1.85-1.45(m,4H),1.25-1.05(m,2H);

¹³C-NMR(400MHz,CD₃OD)δ208.2,170.0,167.9,159.9,156.5,153.9,153.1,149.4, 148.0,140.2,139.0,137.1,133.8,132.5,130.9,130.5,129.8,129.7,129.3,129.1, 128.2,122.8,117.4,115.8,78.5,74.9.73.0,57.6,55.4,51.9,31.9,20.8,15.8,3.3;

ESI-MS：801.3[M+H]⁺

6 embodiment 6-b to 6-r of table（In addition to table conditional, other conditions are with example 6-a）

Example 7

Example 7-a

R^aFor methyl.

In the dichloromethane of the initial compounds (270g, 482mmol) shown in above formula（1080mL）Saturation is added in solution Sodium bicarbonate solution（3240mL）And cool to 0 degree Celsius.It is slowly added to sodium metaperiodate solid（114g, 530mmol）.Obtain Reactant liquor stirred 2 as a child under 0 degree Celsius, was slowly added to hypo solution（1M,100mL）.The mixed liquor for obtaining is quiet After putting point liquid, water is extracted through dichloromethane（600mL X2）.Merge all of organic phase after sodium sulphate drying, concentrate 1200mL n-hexanes are slowly added to 600mL and under 35 degrees Celsius.Mixed liquor is collected by filtration after being slow cooling to -10 degrees Celsius The powder for obtaining dry, as required target compound intermediate（234g, yield 92%）.

¹H-NMR(400MHz,CD₃OD)δ8.68(d,1H),7.80(s,1H),7.60-7.15(m,8H),5.24(s,2H) 4.34-4.26 (m, 1H), 3.67 (s, 3H), 2.98 (d, 1H), 2.84 (s,1H), 2.79-2.77 (m, 1H), 2.67-2.63 (m, 1H),1.85-1.45(m,4H),1.25-1.05(m,2H);

¹³C-NMR(400MHz,CD₃OD)δ208.2,170.0,167.9,161.1,156.5,153.1,149.4,139.0, 137.1,133.8,129.8,129.7,129.3,128.2,122.8,117.4,78.5,74.9.55.4,51.9,31.9, 20.8,15.8,3.3;

ESI-MS：529.2[M+H]⁺

7 embodiment 7-b to 7-r of table（In addition to table conditional, other conditions are with example 7-a）

Example 8

Example 8-a

R^aFor methyl.

In the N,N-dimethylformamide of the initial compounds (250g, 784mmol) shown in above formula（1000mL）Middle addition O-6- benzyl guanines（227g, 941mmol）And lithium hydroxide（1.88g,78.4mmol）.The suspended liquid for obtaining is Celsius 95 After the lower stirring of degree 12 hours, Jing vacuum distillations are concentrated to 300mL.It is molten that the concentrate is slowly dropped to 1000mL sodium acid carbonate saturations In liquid.The solid of generation is collected by filtration and be dried after water washing with being distilled.The solid is dissolved in ethyl acetate（300mL）Afterwards through 300g silica gel is filtered, and silica gel is through the further drip washing of 1200mL ethyl acetate.Merge all ethyl acetate phases for leaching and be evaporated Organic solvent.The faint yellow solid for obtaining is required target compound intermediate（364g, yield 83%）.

¹H-NMR(400MHz,CD₃OD)δ8.68(d,1H),7.80(s,1H),7.60-7.15(m,8H),5.64(s,2H), 3.84-3.72(m,1H),3.74(d,1H),3.49(d,1H),3.67(s,3H),2.48(d,1H),2.24-2.16(m,1H), 1.89-1.45(m,6H),1.25-1.05(m,2H);

¹³C-NMR(400MHz,CD₃OD)δ174.6,167.9,161.1,156.5,153.1,149.4,139.0,137.1, 133.8,129.8,129.7,129.3,128.2,122.8,117.4,83.8,74.9,66.1,63.4,52.2,40.3,21.9, 21.6,16.4,4.1;

ESI-MS：561.2[M+H]⁺

8 embodiment 8-b to 8-r of table（In addition to table conditional, other conditions are with example 8-a）

Example 9

Example 9-a

R^aFor methyl.

The reaction uses conventional Sharpless chiral epoxy reaction process Review literatures：（Pfenninger, A.Synthesis1986,89）

Tetraisopropoxy titanium is added in 2400mL dichloromethane（96mL, 335mmol）And it is cooled to subzero 30 degrees Celsius. The initiation material as shown in above formula is added inside the solution（507g,1.68mol）With（2S,3S）- tartaric acid diisopropyl ester（94g, 402mmol）.The mixed liquor for obtaining is slowly added to anhydrous tert-Butanol peroxide after stirring 1 hour under subzero 30 degrees Celsius（2.5M, Toluene solution, 800mL）.Reaction temperature is kept thiosulfuric acid to be slowly added in reactant liquor at subzero 20 ~ 30 degrees Celsius after 3 hours Sodium（2M, 500mL）.After completion of dropping, reactant liquor is slowly warmed up to 25 degrees Celsius and filters through diatomite.The filtrate Jing for obtaining After crossing stratification, isolated water is extracted through dichloromethane（1000mL X2）After merge all of dichloromethane.Close And organic phase further across saturated ammonium chloride（500mL）And saturated aqueous common salt（200mL）Jing sodium peroxydisulfates after substep washing It is dried.It is evaporated the pale yellow oily liquid that organic solvent obtains and is required target compound intermediate（488g, yield 91%）.

¹H-NMR(400MHz,CD₃OD)δ8.68(d,1H),7.60-7.35(m,3H),3.74(d,1H),3.49(d,1H), 3.67(s,3H),2.78(d,1H),2.51(d,1H),2.24-2.16(m,1H),1.89-1.45(m,6H),1.25-1.05(m, 2H);

¹³C-NMR(400MHz,CD₃OD)δ174.6,167.9,149.4,133.8,128.2,122.8,77.6,64.3, 63.8,52.2,40.3,21.9,21.6,16.4,4.1;

ESI-MS：320.1[M+H]⁺

9 embodiment 9-b to 9-r of table（In addition to table conditional, other conditions are with example 9-a）

Example 10

Raw material in the embodiment series is the equal amount of mixture of following two structures：

Example 10-a

R^aFor methyl.

In the initiation material as shown in above formula（520g, 1.80mol）2600 milliliters of isopropanols are dissolved in, and add (1R, 2R) -2- Amino -1- (4- nitrobenzophenones) propane -1,3- glycol（cas:716-61-0）（212g, 1.0mol）.The mixed solution for obtaining exists 25 degrees Celsius are slow cooling to after stirring 2 hours under 70 degrees Celsius.1200 millis are dissolved in after the solid drying for obtaining is collected by filtration Rise methyl alcohol and be slowly added to the concentrated sulfuric acid（98%, 120mL）.The mixed liquor for obtaining is stirred at room temperature 12 and was as a child slowly added to hydrogen Aqueous solution of sodium oxide（3M,3000mL）.The mixed liquor for obtaining is through n-hexane extraction（2000mL X2）.Organic phase is obtained by extraction Organic solvent is evaporated after dried over sodium sulfate, the pale yellow oily liquid for obtaining is required target compound intermediate （223g, yield 82%）.

¹H-NMR(400MHz,CD₃OD)δ8.68(d,1H),7.60-7.35(m,3H),5.59(s,1H),4.20(s,2H), 3.67(s,3H),3.18(d,1H),2.64(m,1H),2.49-2.47(m,1H),2.27-2.23(m,1H),1.85-1.45(m, 4H),1.05-1.25(m,2H);

¹³C-NMR(400MHz,CD₃OD)δ174.6,167.9,149.4,133.8,131.0,128.2,122.8,123.5, 66.3,52.3,44.4,29.0,21.6,17.3,16.5;

ESI-MS：304.1[M+H]⁺

10 embodiment 10-b to 10-r of table（In addition to table conditional, other conditions are with example 10-a）

Example 11

In the embodiment series, raw material is the equal amount of mixture of following two structures：

Product is the equal amount of mixture of following two structures：

Example 11-a

In the initiation material as shown in above formula（505g, 1.76mol）It is dissolved in 2600 milliliters of ethanol and adds hydroboration in batches Sodium（66.9g, 1.76mol）.The mixture for obtaining is stirred at room temperature 3 and as a child cooled to 0 degree Celsius, and adds 500 milliliters Saturated ammonium chloride solution.Mixed liquor adds ethyl acetate extraction after being evaporated organic solvent（2000mL X3）.Organic phase Jing of merging Supersaturation brine It（1000mL）It is dried through sodium sulphate again afterwards, is evaporated needed for the faint yellow solid that organic phase obtains is Target compound intermediate（482g, yield 95%）.

¹H-NMR(400MHz,CD₃OD)δ8.68(d,1H),7.60-7.35(m,3H),5.59(s,1H),4.20(s,2H), 3.28(d,1H),2.49-2.47(m,1H),2.34(s,1H),2.27-2.23(m,2H),1.85-1.45(m,4H),1.05- 1.25(m,2H);

¹³C-NMR(400MHz,CD₃OD)δ182.7,167.9,149.4,133.8,131.0,128.2,123.5,122.8, 66.3,46.9,29.0,21.6,17.0,16.5;

ESI-MS：290.1[M+H]⁺

11 embodiment 11-b to 11-r of table（In addition to table conditional, other conditions are with example 11-a）

Example 12

In the embodiment series, raw material is the equal amount of mixture of following two structures：

Product is the equal amount of mixture of following two structures：

Example 12-a

In the initiation material as shown in above formula（723g, 2.52mol）Be dissolved in 2600 milliliters of ethanol carbonic acid is added under 0 degree Celsius Sodium（534g, 5.04mol）.The mixture for obtaining is filtered after being stirred at room temperature 3 hours.The filtrate for obtaining adds watery hydrochloric acid（3M, 850mL）, after mixed liquor is evaporated organic solvent, addition ethyl acetate is beaten（2000mL X3）.The organic phase of merging is eaten through saturation Salt water washing（1000mL）It is dried through sodium sulphate again afterwards, is evaporated the faint yellow solid that organic phase obtains and is required targeted Compound intermediate（706g, yield 98%）.

¹H-NMR(400MHz,CD₃OD)δ9.68(s.1H),8.68(d,1H),7.60-7.35(m,3H),6.55(s,1H), 3.28(d,1H),2.49-2.47(m,1H),2.27-2.23(m,2H),1.85-1.45(m,4H),1.05-1.25(m,2H);

¹³C-NMR(400MHz,CD₃OD)δ192.9,182.7,167.9,156.7,149.4,133.8,129.2,128.2, 122.8,43.2,28.5,21.6,16.5,16.4;

ESI-MS：288.1[M+H]⁺

12 embodiment 12-b to 12-r of table（In addition to table conditional, other conditions are with example 12-a）

Example 13

In the series embodiment, product is the equal amount of mixture of following two compounds.

Example 13-a

In the initiation material as shown in above formula（491g, 1.52mol）The tert-butyl alcohol（982g）And water（1960g）In mixed solution Triethylamine 706g is instilled under 25 degrees Celsius.Drip off rear reactant liquor and be warming up to 85 degree and allow which to flow back, heating was down to 0 after about 60 minutes. It is evaporated organic solvent mixed liquor to be kept for 0 ~ 5 degree Celsius and be slowly added to concentrated hydrochloric acid（37%）Adjust pH ~ 6.Mixed liquor is through acetic acid second Ester is extracted（2600mL X3）.The organic phase of merging is dried through saturated common salt water washing, with sodium sulphate and is evaporated organic solvent and obtains The buff oily liquids for arriving is required target compound intermediate（327g, yield 75%）.

¹H-NMR(400MHz,CD₃OD)δ9.72(s.1H),8.68(d,1H),7.60-7.35(m,3H),6.00(s,1H), 5.59(s,1H),3.46(d,1H),3.08(m,1H),2.60(d,1H),1.85-1.45(m,4H),1.05-1.25(m,2H);

¹³C-NMR(400MHz,CD₃OD)δ201.5,183.1,167.9,149.4,134.2,133.8,129.1,128.2, 122.8,57.5,34.3,21.7,19.1,16.5;

ESI-MS：288.1[M+H]⁺

13 embodiment 13-b to 13-r of table（In addition to table conditional, other conditions are with example 13-a）

Example 14

Example 14-a

It is dissolved in 1800ml n-hexanes in the initiation material 254g (1.19mol) as shown in above formula, is cooled to 0 degree Celsius, Add dichloroacetyl chloride (390.5g, 2.65mol）, triethylamine (535g, 5.30mol) is added dropwise under maintaining 5 ~ 10 degrees Celsius, is dripped off Mixed liquor afterwards is stirred 14 hours under 25 degrees Celsius.Water is added in reaction mixture（1500ml）.The water that standing separation is obtained N-hexane is used mutually（500ml X3) extraction.The organic phase saturated common salt water washing of merging and it is dried over sodium sulfate after be evaporated it is organic Solvent obtains buff oily liquids and is required target compound intermediate（378g, yield 98%）.

¹H-NMR(400MHz,CD₃OD)δ8.68(d,1H),7.60-7.35(m,3H),6.00(s,1H),5.59(s,1H), 4.08(d,1H),3.68-3.57(m,1H),2.74(s,1H),1.85-1.45(m,4H),1.05-1.25(m,2H);

¹³C-NMR(400MHz,CD₃OD)δ183.1,167.9,149.4,138.0,133.8,129.2,128.2,122.8, 88.3,70.1,34.0,21.7,19.1,16.5;

ESI-MS：324.1[M+H]⁺

14 embodiment 14-b to 14-r of table（In addition to table conditional, other conditions are with example 14-a）

Example 15

Example 15-a

Sodium cyclopentadiene（165g, 1.87mol）It is dissolved in 1650ml tetrahydrofurans, is cooled under nitrogen protection subzero 50 degrees Celsius, it is added dropwise in the initiation material as shown in above formula（271g, 1.48mol）, it is little that temperature control reacts about 3 at subzero 45 degrees Celsius When.1000ml water quenchings are added to go out reaction after the completion of reaction.Evaporate remaining mixed liquor n-hexane after tetrahydrofuran（1500ml X3）Extraction.The organic phase of merging uses 0.5M hydrochloric acid successively（0.5M,500mL）With saturated common salt water washing, organic phase with sodium sulfate It is dried, filters, is spin-dried for organic solvent and obtains the target compound intermediate needed for oily bronzing liquid is（299g, yield 95%）.

¹H-NMR(400MHz,CD₃OD)δ8.68(d,1H),7.60-7.35(m,3H),6.62-6.52(m,4H),3.61 (s,1H),1.85-1.45(m,4H),1.05-1.25(m,2H);

¹³C-NMR(400MHz,CD₃OD)δ167.9,149.4,133.8,133.0,132.0,128.2,122.8,21.7, 19.1,16.5;

ESI-MS：214.1[M+H]⁺

15 embodiment 15-b to 15-r of table（In addition to table conditional, other conditions are with example 15-a）

Example 16R₂- X synthesizes

R₂The synthesis of-Cl has description in detail in the document in documents below and cited in them：

Russian Journal of General Chemistry2006,76,1261

Chemische Berichte1915,48,1238

Journal of Organometallic Chemistry1975,86,197

Journal of the American Chemical Society1946,68,485

Journal of the American Chemical Society2010,132,8270

Its general principle can be represented by formula illustrated below：

Wherein R-21 is corresponding aromatic ring yl lithium compound.Wherein W1, W2 are respectively independent-MgBr or-MgCl

Example 16-a

Synthetic method one

Step one：In 2- chloropyridines（1.15Kg, 10.2mol）Tetrahydrofuran（4600mL）Subzero 40 are kept to arrive in solution Subzero 50 degrees Celsius of dropwise additions butyl lithium（2.5M hexane solutions, 4200mL）.Reactant liquor after completion of dropping is slowly warmed up to 25 Degree Celsius and at such a temperature stir 2 hours.The brownish red reactant liquor for obtaining adds four chlorinations for being pre-chilled to subzero 50 degrees Celsius Silicon（1.7Kg,10mol）Tetrahydrofuran（6800mL）In solution.Control rate of addition keeps system subzero 40 to subzero 50 to take the photograph Family name's degree.The mixed liquor obtained after completion of dropping be slowly warmed up to 25 degrees Celsius and at such a temperature stir 12 hours after in blanket of nitrogen Enclose to push and filter the solid for generating.Filtrate be pre-chilled to subzero 50 degrees Celsius it is standby.

Step 2：1,3- dibromopropanes（2.2Kg,10.9mol）It is slowly added into suspension 264g magnesium chips in stirring（11mol） Tetrahydrofuran（17.6L）In.Control rate of addition keeps reaction temperature at subzero 40 ~ 50 degrees Celsius.It is incubated after completion of dropping Subzero 50 degrees Celsius are pre-chilled in subzero 40 ~ 50 degrees Celsius mixed liquors obtained after 2 hours, and add what is prepared by 2- chloropyridines Reaction mixture.Control rate of addition keeps reaction temperature at subzero 40 ~ 50 degrees Celsius.Slowly it is warmed up to 60 to take the photograph after completion of dropping Family name's degree simultaneously stirs 3 hours.Vacuum distillation concentration of reaction solution adds n-hexane to after 20 liters（20L）.It is filtered to remove the solid of generation. Distillation under pressure after filtrate concentration obtains colourless liquid and is required target compound intermediate（1.16Kg,62%）.

Synthetic method two

Example 16-b

Step one：1,3- dibromopropanes（2.2Kg,10.9mol）It is slowly added into suspension 264g magnesium chips in stirring（11mol） Tetrahydrofuran（17.6L）In.Control rate of addition keeps reaction temperature at subzero 40 ~ 50 degrees Celsius.It is incubated after completion of dropping Subzero 50 degrees Celsius are pre-chilled in subzero 40 ~ 50 degrees Celsius mixed liquors obtained after 2 hours.Four chlorinations are added dropwise in the reactant liquor Silicon（1.7Kg,10mol）.Control rate of addition keeps reaction temperature at subzero 40 ~ 50 degrees Celsius.Slowly heat up after completion of dropping Lower the temperature to 60 degrees Celsius and after stirring 3 hours and be pre-chilled to subzero 50 degrees Celsius.

Step 2：In 2- chloropyridines（1.15Kg, 10.2mol）Tetrahydrofuran（4600mL）Subzero 40 are kept to arrive in solution Subzero 50 degrees Celsius of dropwise additions butyl lithium（2.5M hexane solutions, 4200mL）.Reactant liquor after completion of dropping is slowly warmed up to 25 Degree Celsius and at such a temperature stir 2 hours.The brownish red reactant liquor for obtaining is pre-chilled to subzero 50 degrees Celsius, and is slowly added into Step one is prepared in reactant liquor.Control rate of addition keeps reaction temperature at subzero 40 ~ 50 degrees Celsius.Obtain after completion of dropping Mixed liquor be slowly warmed up to 25 degrees Celsius and at such a temperature stir 12 hours after, pressure distillation and concentration reactant liquor add to after 20 liters N-hexane（20L）.It is filtered to remove the solid of generation.Distillation under pressure after filtrate concentration obtains colourless liquid and is required targeted Compound intermediate（1.53Kg,82%）.

¹H-NMR(400MHz,CDCl₃)δ8.68(d,1H),7.60-7.35(m,3H),1.85-1.45(m,4H),1.05- 1.25(m,2H);

¹³C-NMR(400MHz,CDCl₃)167.9,149.4,133.8,128.2,122.8,17.6,12.5

16 embodiment 16-b to 16-r of table

Claims (7)

1. a kind of preparation method of the intermediate of the Entecavir as shown in formula IV or IV ', it is characterised in that comprise the steps of： In solvent, in the presence of Bronsted acid, compound V is carried out as follows sloughing the anti-of amino protecting group and hydroxyl protecting group Should, you can；

Wherein, R^aFor C₁～C₄Straight chained alkyl；R^bRepresent one or more on phenyl ring selected from halogen atom, methoxyl group or methyl Substituent or H；R^cFor methyl；R₂The arbitrary substituent being as follows：

Wherein, R₂₁For unsubstituted C₆Aryl, or be following arbitrary substituent：

2. preparation method as claimed in claim 1, it is characterised in that：Work as R^aFor C₁～C₄Straight chained alkyl when, described C₁~ C₄Straight chained alkyl be methyl.

3. preparation method as claimed in claim 1, it is characterised in that：Described solvent is organic solvent, water or theirs is mixed Compound, wherein described organic solvent be dichloromethane, methyl alcohol, ethanol, isopropanol, the tert-butyl alcohol, tetrahydrofuran, acetonitrile, DMF and One or more in dimethyl sulfoxide (DMSO)；Described Bronsted acid is in hydrochloric acid, sulfuric acid, nitric acid, trifluoroacetic acid and methanesulfonic acid Plant or various；Bronsted acid is 0.1～100 with the mol ratio of compound V；The temperature of described reaction is 0～100 DEG C.

4. preparation method as claimed in claim 3, it is characterised in that：Bronsted acid is 1～20 with the mol ratio of compound V；Institute The temperature of the reaction stated is 20～80 DEG C.

5. preparation method as claimed in claim 1, it is characterised in that：The compound V is prepared by following methods, then is prepared Compound IV：

Under inert gas shielding, in organic solvent, in the presence of titanium tetrabromide or titanium tetrachloride, by compound VI and Na Site Reagent carries out methylenation, you can；

Wherein, R^a、R^b、R^cAnd R₂Definition with described in claim 1.

6. preparation method as claimed in claim 5, it is characterised in that：In described methylenation：Described is organic molten Agent is one or more in tetrahydrofuran, 2- methyltetrahydrofurans, ether and t-butyl methyl ether；Described Nysted Reagent with The mol ratio of compound VI is 0.5～10；The mol ratio of described titanium tetrabromide or titanium tetrachloride and compound VI is 0.1～ 10；The temperature of described methylenation is -78～50 DEG C.

7. the midbody compound of the Entecavir as shown in Formula V or VI；Or the intermediate of the Entecavir as shown in formula IV Compound or its dynamic isomer IV '：

Wherein, R^a、R^b、R^cAnd R₂Definition with described in claim 1.