CN104017012A

CN104017012A - Entecavir intermediates and preparation method thereof

Info

Publication number: CN104017012A
Application number: CN201310062864.1A
Authority: CN
Inventors: 陈清泉; 胡俊斌; 应律
Original assignee: Zhejiang Xing Yue Medicine Science And Technology Co Ltd
Current assignee: Zhejiang Xing Yue Medicine Science And Technology Co Ltd
Priority date: 2013-02-28
Filing date: 2013-02-28
Publication date: 2014-09-03

Abstract

The invention discloses Entecavir intermediates and a preparation method thereof. The preparation method of an Entecavir intermediate represented by a formula XII shown in descriptions comprises the following step of enabling a compound XIII to be subjected to isomerization reaction in the presence of alkali in a solvent. The invention further discloses an Entecavir intermediate compound represented by a formula XV, XIV or XIII shown in descriptions. The preparation method disclosed by the invention has the advantages that raw materials are cheap and are easily obtained, reaction conditions are mild, side reactions are few, the yield is high, the pollution to the environment is little, and the intermediates are easily purified and separated, so that the preparation method is applicable to industrial 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 as an important chemical type, in the concern widely having obtained of pharmaceutical chemistry the inside.Large quantities of significant medicines have been brought up in relative research, especially in antiviral field.A considerable amount of anti-AIDS and anti-hbv drug all come from the further investigation in this field.

There are 3.5 hundred million～4.0 hundred million hepatitis B virus (HBV) the infecteds in the whole world, wherein has every year nearly 1,000,000 patients to die from HBV and infects the liver cirrhosis and the liver cancer that cause.There are 1.2 hundred million above HBV the infecteds in China, account for the more than 1/3 of the world total, occupy the 1st, the world, chronic hepatitis B (hepatitis B) patient 3,000 ten thousand examples, and also this numeral is just in rising trend at present.Chronic hepatitis B virus infection does not also have the method that can cure completely till now, needs of patients long-term or throughout one's life (in most cases) carry out virus inhibition.Clinical guidelines recommended therapy course for the treatment of is minimum is 1 year.In the medicine of hepatitis B, the share of market of nucleoside medicine crosses 80% at present.In nucleoside medicine, Entecavir relies on its obvious curative effect and good anti-drug resistance, and since two thousand seven, substituting lamivudine becomes the anti-hepatic-B virus medicine of a line.Entecavir is developed by Bristol-Myers Squibb Co. of the U.S., and U.S. FDA is in approval listing on March 29th, 2005.Obtain the SFDA of State Food and Drug Administration approval Discussion on Chinese Listed on November 15th, 2005.Drug patent expired in 2008.Because its synthetic difficulty is huge, price is high at present for its activeconstituents (API), and manufacturer is few.

The bulk drug of Entecavir is because its huge synthetic challenge has caused concern widely in scientific circles.Therefore synthetic method research about Entecavir obtained deep development.In the document that " diagram of Entecavir route " (Chinese Journal of Pharmaceuticals 38 10 phase of volume 749-752 pages in 2007) that wherein more representational synthetic route is shown at Shen Guobing etc. and this paper are quoted, there is detailed review paper.Other relevant documents are 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, US2010286089A1, WO2011102806A1, WO2011150513A1, other document that quote WO2012006964A1 and these documents the inside.

The larger problem that current most synthetic routes exist, is used Dess-Martin reagent, more expensive raw material and the reagent such as two firpene borines such as equivalent, experiment condition harshness, separating step complexity, needs the expensive means of purification such as silica gel chromatographic column separation, is not suitable for large production.

Wherein a comparatively practical production line (WO2005118585) is shown below.This route has the features such as reaction yield is high, working condition is gentle, purification step is simple, is applicable to amplifying producing.But also have its corresponding defect, such as some reagent such as phenyldimethylchlorosilane produces that difficulty causes that price is high, the use of high toxicity reagent such as boron trifluoride and in process of production the intermediate of the overwhelming majority be all the purification difficult that oily liquids causes.

The synthetic route similar to it done detailed introduction in document CN101050216A, has larger improvement on cost, adopted diphenyl methyl chloro silane that price is lower as starting raw material.But because two phenyl ring are connected with Siliciumatom and still cannot avoid using the boron trifluoride of high malicious high pollution when caused huge steric effect makes the last deprotection of this route.

Summary of the invention

The defects such as technical problem to be solved by this invention is that synthesising method reacting condition harshness, the yield in order to overcome existing Entecavir is not high, environmental pollution is large and the expensive production cost causing of raw material is huge, and the preparation method of the intermediate of a class Entecavir is provided, and intermediate.Preparation method's raw material of the present invention is cheap and easy to get, and reaction conditions gentleness, side reaction is few, yield is high, environmental pollution is little, and intermediate is easy to purifies and separates, is suitable for suitability for industrialized production.

First the present invention provides a kind of preparation method of the intermediate suc as formula the Entecavir shown in XII, and it comprises the following step:

In solvent, under the effect of alkali, compounds X III is carried out to isomerization reaction as follows;

R ₂substituting group for as follows:

Wherein, R ₂₁for replacing or unsubstituted pyridyl or replacement or unsubstituted C ₆～C ₁₀aryl, the substituting group in the pyridyl of described replacement is C ₁～C ₃alkyl, halogen and C ₁～C ₃one or more in alkoxyl group, the substituent number of every class is one or more; The C of described replacement ₆～C ₁₀substituting group in aryl is C ₁～C ₃alkyl, halogen and C ₁～C ₃one or more in alkoxyl group, the substituent number of every class is one or more;

Y is for connecting or not connecting other substituent 3～9 carbon, thereby forms and replace or the saturated or undersaturated silicon-carbon ring of unsubstituted 4～10 yuan with Si; Or, other are substituent in order to connect or not connect for Y, add up to carbon atom and the heteroatoms of 3～9, thereby form and replace or the saturated or undersaturated carbon sila ring of unsubstituted 4～10 yuan with Si, described heteroatoms is O, S or N, and heteroatomic number is 1～3; Substituting group in described replacement is C ₁～C ₃alkyl; Described silicon-carbon ring or carbon sila ring be a ring or and together two rings (for example ).

Described R ₂be preferably following arbitrary substituting group:

In substituting group IVa, n is that 0～2, p is that 0～2, q is that 1～2, X and Y are independently carbon, oxygen or nitrogen, R ₄for C ₁～C ₃alkyl, and R ₄for one or more substituting groups; In the time that n is 0, X is carbon, and in the time that p is 0, Y is carbon.

What substituting group IVa was better is following arbitrary substituting group:

Described R ₂₁be preferably following arbitrary substituting group:

Wherein, the method of described isomerization reaction and condition all can be ordinary method and the condition of this class reaction of this area, the present invention is following condition particularly preferably: described solvent can be one or more in Virahol, methyl alcohol, ethanol, the trimethyl carbinol, propyl carbinol, DMF, dimethyl sulfoxide (DMSO), acetonitrile, tetrahydrofuran (THF), 2-methyltetrahydrofuran, N-Methyl pyrrolidone and water.Described solvent is 1ml/g～100ml/g with the volume mass of compounds X III than preferably, and that better is 3ml/g～20ml/g.Described alkali can be triethylamine, diisopropylethylamine, 1, one or more in 8-diazabicylo [5.4.0] 11 carbon-7-alkene, sodium carbonate, salt of wormwood, cesium carbonate, Quilonum Retard, potassium hydroxide, lithium hydroxide, sodium hydroxide and cesium hydroxide.The mol ratio of described alkali and compounds X III can be 0.5～10, and better is 1～3.The time of described isomerization reaction is generally 0.25～72 hour till can no longer carrying out by detection reaction, and better is 0.5～12 hour.The temperature of described isomerization reaction is preferably-50～100 DEG C, and better is-10～80 DEG C.

In the present invention, prepare above-claimed cpd XIII by following method:

In the mixing solutions of organic solvent and water, under the effect of alkali, compounds X IV is carried out to hydrolysis reaction as follows;

Wherein, R ₂definition ditto described in.

Wherein, the method of described hydrolysis reaction and condition all can be ordinary method and the condition of this class reaction of this area, the present invention is following condition particularly preferably: described organic solvent can be one or more in Virahol, methyl alcohol, ethanol, the trimethyl carbinol, propyl carbinol, DMF, dimethyl sulfoxide (DMSO), acetonitrile, tetrahydrofuran (THF) and N-Methyl pyrrolidone.Described organic solvent is 0.5ml/g～100ml/g with the volume mass of compounds X IV than preferably, and that better is 1ml/g～20ml/g.Described water is 0.25ml/g～100ml/g with the volume mass of compounds X IV than preferably, and that better is 0.5ml/g～20ml/g.Described alkali can be triethylamine, diisopropylethylamine, 1, one or more in 8-diazabicylo [5.4.0] 11 carbon-7-alkene, sodium carbonate, salt of wormwood, cesium carbonate, Quilonum Retard, potassium hydroxide, lithium hydroxide, sodium hydroxide and cesium hydroxide.The mol ratio of described alkali and compounds X IV is preferably 0.5～100, and better is 1～50.The time of described hydrolysis reaction is generally 0.25～72 hour till can no longer carrying out by detection reaction, and better is 0.5～12 hour.The temperature of described hydrolysis reaction is preferably-10～150 DEG C, and better is 0～120 DEG C.

In the present invention, can prepare above-claimed cpd XIV by following method:

In organic solvent, under the effect of alkali, compounds X V and dichloroacetyl chloride are carried out to addition reaction as follows;

Wherein, R ₂definition ditto described in.

Wherein, the method for described addition reaction and condition all can be ordinary method and the condition of this class reaction of this area, and the present invention is following condition particularly preferably

Described organic solvent is preferably one or more in normal hexane, toluene, dimethylbenzene, trimethylbenzene, benzene, chlorobenzene, sherwood oil, tetrahydrofuran (THF), 2-methyltetrahydrofuran, Skellysolve A and normal heptane.Organic solvent is 1ml/g～100ml/g with the volume mass of compounds X V than preferably, and that better is 3ml, g～20ml/g.Described alkali is preferably diisopropylethylamine, 1, one or more in 8-diazabicylo [5.4.0] 11 carbon-7-alkene, triethylamine and pyridine.The mol ratio of described alkali and compounds X V can be 0.5～100, and better is 1～50.The mol ratio of described dichloroacetyl chloride and compounds X V can be 0.5～10, and better is 0.8～3.The time of described addition reaction is generally 0.25～72 hour till can no longer carrying out by detection reaction, and better is 0.5～24 hour.The temperature of described addition reaction is preferably-50～100 DEG C, and better is-30～30 DEG C.

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

Under protection of inert gas, in organic solvent, by compound R ₂an alkali metal salt (as cyclopentadiene sodium) of X and cyclopentadiene or the alkaline earth salt of cyclopentadiene carry out nucleophilic substitution reaction as follows;

Wherein, X be F, Cl, Br, OTf or , R ₂definition ditto described in.

Wherein, the method of described nucleophilic substitution reaction and condition all can be ordinary method and the condition of this class reaction of this area, and the present invention is following condition particularly preferably: described organic solvent is preferably one or more in tetrahydrofuran (THF), sherwood oil, 2-methyltetrahydrofuran, normal hexane, Skellysolve A and normal heptane.Solvent and compound R ₂the volume mass of X is 1ml/g～100ml/g than preferably, and that better is 3ml/g～20ml/g.An alkali metal salt (as cyclopentadiene sodium) of described cyclopentadiene or alkaline earth salt and the compound R of cyclopentadiene ₂the mol ratio of X is preferably 0.5～10, and better is 0.8～3.The time of described nucleophilic substitution reaction is generally 0.25～72 hour till can no longer carrying out by detection reaction, and better is 0.5～24 hour.The temperature of described nucleophilic substitution reaction is preferably-78～50 DEG C, and better is-60～30 DEG C.

The present invention also provide suc as formula shown in XV, XIV or XIII the midbody compound of Entecavir:

Wherein, R ₂definition ditto described in.

In the present invention, Entecavir or its tautomer can be prepared by following method:

A kind of preparation method suc as formula the Entecavir shown in I or its tautomer I ', it comprises the following step: in organic solvent, under the effect of reductive agent, Compound I I or its tautomer II ' are carried out to the as follows reaction that ester is reduced to alcohol;

Wherein, R ^afor C ₁～C ₄straight chained alkyl (preferable methyl); Described reductive agent is diisobutyl aluminium hydride, lithium aluminum hydride, red aluminium (two (2-methoxy ethoxy) sodium aluminum hydride) or sodium borohydride, and in the time that reductive agent is sodium borohydride, described reaction is carried out under the existence of lithium chloride and/or lithiumbromide.

In the present invention, the kind of described organic solvent is not particularly limited, do not affect the conventional solvent of reaction this type of reduction reaction of carrying out all applicable, for example methylene dichloride, toluene, 1, one or more in 2-ethylene dichloride, tetrahydrofuran (THF) and 2-methyltetrahydrofuran.The volume mass of described organic solvent and Compound I I or II ' is 3～20ml/g than preferably, and that better is 5～12ml/g.

In the present invention, the consumption of reductive agent can be the conventional amount used of this type of reduction reaction of this area, for example, be Compound I I or II ' 1～5 times, and the present invention is following ranges particularly preferably: the mol ratio of described reductive agent and Compound I I or II ' is preferably 1.1～3.In the time that reductive agent is sodium borohydride, described reaction is carried out under the existence of lithium chloride and/or lithiumbromide, and the mol ratio of described lithium chloride and/or lithiumbromide and Compound I I 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, and better is-20～40 DEG C.The time of the above-mentioned reaction that ester is reduced to alcohol is generally 0.5～12 hour till can no longer carrying out by detection reaction.

In the present invention, make suc as formula the Entecavir shown in I or its tautomer I ' by above-mentioned preparation method after, can pass through the post processing mode of this area routine, for example, after adding water, carry out the reaction of a upper water molecules on formula I or I ' compound structure at 60～100 DEG C, filter (as used diatomite filtration), by filtrate crystallisation by cooling, get final product with the entecavir compound prepared of a crystal water or its tautomerism compound, as follows:

or

In the present invention, can prepare above-claimed cpd II or its tautomer II ' by following method:

In solvent, compound III or its tautomer III ' are carried out to Tamao-Fleming oxidizing reaction;

Wherein, R ^adefinition ditto described in; R ₁for , Y is for connecting or not connecting other substituent 3～9 carbon, thereby forms and replace or the saturated or undersaturated silicon-carbon ring of unsubstituted 4～10 yuan with Si; Or, other are substituent in order to connect or not connect for Y, add up to carbon atom and the heteroatoms of 3～9, thereby form and replace or the saturated or undersaturated carbon sila ring of unsubstituted 4～10 yuan with Si, described heteroatoms is O, S or N, and heteroatomic number is 1～3; Substituting group in described replacement is C ₁～C ₃alkyl; Described silicon-carbon ring or carbon sila ring be a ring or and together two rings (for example or ).

Described R ₁be preferably following arbitrary substituting group:

In the present invention; described Tamao-Fleming oxidizing reaction is the classical name reaction of this area, and aforesaid method and condition all can be ordinary method and the condition of this type of Tamao-Fleming oxidizing reaction of this area, for example; can reference (Fleming, I; Barbero, A; Walter, D; Chem Rev, 1997,97,2063-2192) in method carry out.

For above-mentioned Tamao-Fleming oxidizing reaction, the present invention is method and condition particularly preferably:

Described Tamao-Fleming oxidizing reaction preferably comprises the following step:

In solvent, under the effect of alkali and fluorination reagent, compound III or its tautomer III ' and oxygenant are carried out to Tamao-Fleming oxidizing reaction.

Wherein, described preferred solvents is one or more in water, methyl alcohol, tetrahydrofuran (THF), ethanol and DMF.The volume mass of solvent and compound III or III ' is 1～300ml/g than preferably, and that better is 3～100ml/g.Described alkali is preferably one or several in triethylamine, diisopropylethylamine (Hunig base), saleratus, sodium bicarbonate and cesium bicarbonate.The mol ratio of described alkali and compound III or III ' is preferably 0.5～30, and better is 0.8～15.Described oxygenant is preferably one or more in hydrogen peroxide, Peracetic Acid, peroxy tert-butyl alcohol, metachloroperbenzoic acid, chlorine, bromine, iodine, the sub-acid amides of N-chlorosuccinic acid, the sub-acid amides of N-bromosuccinic acid and the sub-acid amides of N-iodo succinic acid.The concentration of described hydrogen peroxide is preferably mass percent 1% to 60%.The mol ratio of described oxygenant and compound III or III ' is preferably 0.8～30, and better is 1～20.Described fluorination reagent is preferably one or more in Sodium Fluoride, cesium fluoride, Potassium monofluoride, hydrogen fluoride and boron trifluoride.The mol ratio of fluorination reagent and compound III or III ' is preferably 0.8～30, and better is 1～10.Till the time of described Tamao-Fleming oxidizing reaction can no longer carry out by detection reaction.The temperature of described Tamao-Fleming oxidizing reaction is preferably-20 DEG C～120 DEG C (better is 0～80 DEG C).

In the present invention, prepare above-claimed cpd III or its tautomer III ' by following method:

In solvent, under the effect of protonic acid, by compound IV or its tautomer IV ' reaction that is hydrolyzed, by R ₂in R ₂₁substituting group replaces with hydroxyl;

R ₁and R ^adefinition all the same described in, R ₂for R ₁in hydroxyl replace with R ₂₁substituting group,

Except R ₂₁outward, all same R of each group definition ₁described in;

R ₂₁for replacing or unsubstituted pyridyl or replacement or unsubstituted C ₆～C ₁₀aryl, the substituting group in the pyridyl of described replacement is C ₁～C ₃alkyl, halogen and C ₁～C ₃one or more in alkoxyl group, the substituent number of every class is one or more; The C of described replacement ₆～C ₁₀substituting group in aryl is C ₁～C ₃alkyl, halogen and C ₁～C ₃one or more in alkoxyl group, the substituent number of every class is one or more.

Preferably, described R ₂₁for following arbitrary substituting group:

Prepare in the method for above-claimed cpd III or its tautomer III ', described solvent can be and common are machine solvent or water, or their mixture, described organic solvent can be methylene dichloride, 1, one or more in 2-ethylene dichloride, tetrahydrofuran (THF), 2-methyltetrahydrofuran, acetonitrile, methyl alcohol, ethanol, Virahol, toluene and t-butyl methyl ether.The volume mass of described solvent and compound IV or IV ' is 1～20ml/g than preferably.Described protonic acid can be one or more in hydrochloric acid, sulfuric acid, trifluoroacetic acid, nitric acid, methylsulfonic acid and trifluoromethanesulfonic acid.The mol ratio of protonic acid and compound IV or IV ' is preferably 0.1～20.The time of described reaction is generally 0.5～24 hour till can no longer carrying out by detection reaction.The temperature of described reaction is preferably-20～80 DEG C and changes with sour kind.

In the present invention, intermediate or its tautomer IV ' suc as formula the Entecavir shown in IV can obtain by following preparation method: in solvent, under the effect of protonic acid, compound V is carried out to deaminize protecting group as follows and the reaction of hydroxyl protecting group;

Wherein, R ^afor C ₁～C ₄straight chained alkyl (preferable methyl); R ^brepresent one or more substituting group or the H that are selected from halogen atom, methoxyl group or methyl on phenyl ring; R ^cfor methyl; R ₂definition ditto described in, be substituting group as follows:

Y is for connecting or not connecting other substituent 3～9 carbon, thereby forms and replace or the saturated or undersaturated silicon-carbon ring of unsubstituted 4～10 yuan with Si; Or, other are substituent in order to connect or not connect for Y, add up to carbon atom and the heteroatoms of 3～9, thereby form and replace or the saturated or undersaturated carbon sila ring of unsubstituted 4～10 yuan with Si, described heteroatoms is O, S or N, and heteroatomic number is 1～3; Substituting group in described replacement is C ₁～C ₃alkyl; Described silicon-carbon ring or carbon sila ring be a ring or and together two rings (for example or ).

Described R ₂be preferably following arbitrary substituting group:

Described R ₂₁be preferably following arbitrary substituting group:

In the present invention; the method of described deaminize protecting group and the reaction of hydroxyl protecting group and condition all can be ordinary method and the condition of this two classes reaction of this area; the present invention is following condition particularly preferably: described preferred solvents be organic solvent, water or their mixture, wherein said organic solvent is preferably one or more in methylene dichloride, methyl alcohol, ethanol, Virahol, the trimethyl carbinol, tetrahydrofuran (THF), acetonitrile, DMF and dimethyl sulfoxide (DMSO).Described solvent is 2ml/g～20ml/g with the volume mass of compound V than preferably, and that better is 5ml/g～15ml/g.Described protonic acid is preferably one or more in hydrochloric acid, sulfuric acid, nitric acid, trifluoroacetic acid and methylsulfonic acid.The mol ratio of protonic acid and compound V is preferably 0.1～100, and better is 1～20.The time of described reaction is generally 0.5～36 hour till can no longer carrying out by detection reaction.The temperature of described reaction is preferably 0～100 DEG C, and better is 20～80 DEG C.Described deaminize protecting group and the reaction of hydroxyl protecting group can be carried out simultaneously.

In the present invention, can prepare above-claimed cpd V by following method:

Under protection of inert gas, in organic solvent, under the effect of titanium tetrabromide or titanium tetrachloride, compound VI and Na Site (Nysted) reagent are carried out to methylenation;

Wherein, R ^a, R ^b, R ^cand R ₂definition all the same described in.

Wherein, described Na Site (Nysted) reagent is reagent well known in the art, and its structure is as follows:

In the present invention, the method of described methylenation and condition all can be ordinary method and the condition of this class reaction of this area, and the present invention is following condition particularly preferably: described organic solvent is preferably one or more in tetrahydrofuran (THF), 2-methyltetrahydrofuran, ether and t-butyl methyl ether.Described organic solvent is 2～50 with the volume mass of compound VI than preferably, and better is 5～20.Described rare gas element is preferably argon gas.Described Na Site (Nysted) reagent and the mol ratio of compound VI are preferably 0.5～10, and better is 1～5.The mol ratio of described titanium tetrabromide or titanium tetrachloride and compound VI is preferably 0.1～10, and better is 1～5.The time of described methylenation is generally 0.5～24 hour till can no longer carrying out by detection reaction, and better is 1～12 hour.The temperature of described methylenation is preferably-78～50 DEG C, and better is-45～25 DEG C.

In the present invention, can make by following method suc as formula the intermediate of the Entecavir shown in VI: in aprotic organic solvent, under the effect of alkali, by compound VI I and compound VI ' carry out the reaction of upper amino protecting group as follows;

Wherein, X is halogen (as chlorine, bromine or iodine), R ^afor C ₁～C ₄straight chained alkyl (preferable methyl); R ^brepresent the one or more halogen atoms that are selected from phenyl ring, the substituting group of methoxyl group or methyl or H; R ^cfor methyl; R ₂substituting group for as follows:

Described R ₂be preferably following arbitrary substituting group:

Described R ₂₁be preferably following arbitrary substituting group:

In the present invention; the method of described upper amido protecting radical reaction and condition all can be ordinary method and the condition of this two classes reaction of this area; the present invention is following condition particularly preferably: described aprotic organic solvent can be the aprotic organic solvent of this area routine; as one or more in DMF, dimethyl sulfoxide (DMSO), acetonitrile, tetrahydrofuran (THF), 2-methyltetrahydrofuran and N-Methyl pyrrolidone.Described organic solvent is 1ml/g～100ml/g with the volume mass of compound VI I than preferably, better 3ml/g～20ml/g.Described alkali is preferably one or more in DMAP, triethylamine, diisopropylethylamine, salt of wormwood, sodium carbonate and cesium carbonate.The mol ratio of described alkali and compound VI I is preferably 0.5～10, is preferably 1～5.Described compound VI ' with the mol ratio of compound VI I be preferably 0.5～10, better is 1～3.The time of the reaction of described upper amino protecting group is generally 0.5～72 hour till can no longer carrying out by detection reaction, and better is 1～24.The temperature of the reaction of described upper amino protecting group is preferably 0～150 DEG C, and better is 25～80 DEG C.

In the present invention, can prepare above-claimed cpd VII by following method:

In aprotic organic solvent, compound VI II and oxygenant are carried out to oxidizing reaction as follows;

Wherein, R ^a, R ^band R ₂definition all the same described in.

In the present invention, the method of above-mentioned oxidizing reaction and condition all can be ordinary method and the condition of this class reaction of this area, and the present invention is following condition particularly preferably: described aprotic organic solvent is preferably one or more in methylene dichloride, normal hexane, toluene and ethyl acetate.Described aprotic organic solvent is 1～100 with the volume mass of compound VI II than preferably, is preferably 3～20.Described oxygenant is preferably one or more in sodium periodate, potassium periodate, cesium periodate, sodium chlorate, Potcrate, clorox and potassium hypochlorite.The mol ratio of described oxygenant and compound VI II is preferably 0.5～10, and better is 1～3.Described oxidizing reaction is preferably carried out under the effect of alkali, and described alkali is preferably one or more in saleratus, sodium bicarbonate and cesium bicarbonate.The mol ratio of described alkali and compound VI II is preferably 0.5～10, is preferably 1～5.The time of described oxidizing reaction is generally 0.5～72 hour till can no longer carrying out by detection reaction, and better is 1～24 hour.The temperature of described oxidizing reaction is preferably-20～80 DEG C, and better is 0～60 DEG C.

In the present invention, can make by following method suc as formula the intermediate of the Entecavir shown in VIII: in aprotic organic solvent, under the effect of alkali, Compound I X and VIII ' are carried out to ring-opening reaction as follows;

Wherein, R ^afor C ₁～C ₄straight chained alkyl (preferable methyl); R ^brepresent the one or more halogen atoms that are selected from phenyl ring, the substituting group of methoxyl group or methyl or H; R ₂substituting group for as follows:

Described R ₂be preferably following arbitrary substituting group:

In substituting group IVa, n is that 0～2, p is that 0～2, q is that 1～2, X and Y are independently carbon, oxygen or nitrogen, R ₄for C ₁～C ₃alkyl, and R ₄for one or more substituting groups; ; In the time that n is 0, X is carbon, and in the time that p is 0, Y is carbon.

Described R ₂₁be preferably following arbitrary substituting group:

Wherein, the method of described ring-opening reaction and condition all can be ordinary method and the condition of this class reaction of this area, the present invention is following condition particularly preferably: described aprotic organic solvent can be the aprotic organic solvent of this area routine, as one or more in DMF, dimethyl sulfoxide (DMSO), acetonitrile, tetrahydrofuran (THF), N-Methyl pyrrolidone and 2-methyltetrahydrofuran.Described organic solvent is 1ml/g～100ml/g with the volume mass of Compound I X than preferably, is preferably 3ml/g～20ml/g.Described alkali is preferably lithium hydroxide and/or lithium hydride.The mol ratio of described alkali and Compound I X is preferably 0.01～10, and better is 0.05～5.Described compound VI II ' is preferably 0.5～10 with the mol ratio of Compound I X, and better is 1～3.The time of described ring-opening reaction is generally 0.5～72 hour till can no longer carrying out by detection reaction, and better is 3～48 hours.The temperature of described ring-opening reaction is preferably 0～150 DEG C, and better is 25～120 DEG C.

In the present invention, can prepare above-claimed cpd IX by following method:

In organic solvent, compounds X is carried out to the reaction of Sharpless chiral epoxy;

Wherein, R ^aand R ₂definition all the same described in.

Wherein, the method of described Sharpless chiral epoxy reaction and condition can be ordinary method and the condition of this class reaction of this area, as can reference literature (Pfenninger, A.Synthesis1986,89) method in and condition are carried out, and can be following method: in organic solvent, under the effect of tetraisopropoxy titanium and chiral ligand, compounds X and superoxide are carried out to the reaction of Sharpless chiral epoxy.

The present invention is following condition particularly preferably: described organic solvent can be methylene dichloride and/or 1,2-ethylene dichloride.Described organic solvent is 1ml/g～100ml/g with the volume mass of compounds X than preferably, and that better is 3ml/g～20ml/g.Described chiral ligand is preferably (2S, 3S)-diethyl tartrate or (2S, 3S)-tartrate diisopropyl ester.The mol ratio of hand-type part and compounds X is preferably 0.0001～1, and better is 0.001～0.3.The mol ratio of tetraisopropoxy titanium and compounds X is preferably 0.0001～1, and better is 0.001～0.3.Described superoxide is preferably one or more in peroxy tert-butyl alcohol, hydrogen peroxide, Peracetic Acid and metachloroperbenzoic acid.Described superoxide and the mol ratio of compounds X are preferably 0.5～10, and better is 1～5.The time of described chiral epoxy reaction is generally 0.25～12 hour till can no longer carrying out by detection reaction, and better is 0.5～8 hour.The temperature of described chiral epoxy reaction is preferably-78～25 DEG C, and better is-60～0 DEG C.

In the present invention, can make by following method suc as formula the intermediate of the Entecavir shown in X:

Step (1): in organic solvent, by compounds X I and (1R, 2R)-2-amino-1-(4-nitrophenyl) propane-1,3-glycol reacts;

Step (2): in organic solvent, under the effect of the vitriol oil, material and R that step (1) is obtained ^aoH carries out esterification;

Wherein, R ^afor C ₁～C ₄straight chained alkyl (preferable methyl);

R ₂substituting group for as follows:

Described R ₂be preferably following arbitrary substituting group:

Described R ₂₁be preferably following arbitrary substituting group:

In step (1), the method of described reaction and condition all can be ordinary method and the condition of this class reaction of this area, the present invention is following condition particularly preferably: described organic solvent can be one or more in Virahol, methyl alcohol, ethanol, water, DMF, dimethyl sulfoxide (DMSO), acetonitrile, tetrahydrofuran (THF), 2-methyltetrahydrofuran and N-Methyl pyrrolidone.Described organic solvent is 1ml/g～100ml/g with the volume mass of compounds X I than preferably, and that better is 3ml/g～20ml/g.Described (1R, 2R)-2-amino-1-(4-nitrophenyl) propane-1, the mol ratio of 3-glycol and compounds X I is preferably 0.25～10, better is 0.4～3.The time of described reaction is generally 0.25～72 hour till can no longer carrying out by detection reaction, and better is 0.5～24 hour.The temperature of described reaction is preferably 0～150 DEG C, and better is 25～80 DEG C.

In step (2), the method for described esterification and condition all can be ordinary method and the condition of this class reaction of this area, and the present invention is following condition particularly preferably: described organic solvent can be C ₁～C ₄alkyl alcohol.Described organic solvent is 1ml/g～100ml/g with the volume mass of compounds X I than preferably, and that better is 3ml/g～20ml/g.The mass percent of the described vitriol oil can be 60%～98%(as 98%wt).The mol ratio of the described vitriol oil and compounds X I is preferably 0.01～100, and better is 0.05～30.The time of described reaction is generally 0.5～72 hour till can no longer carrying out by detection reaction, and better is 1～48 hour.The temperature of described reaction is preferably-20～100 DEG C, and better is-10～60 DEG C.

In the present invention, can prepare above-claimed cpd XI by following method:

In solvent, it is reacting of hydroxyl that compounds X II is carried out to carbonyl reduction with reductive agent;

Wherein, R ₂definition ditto described in.

Wherein, the method for the reaction that described carbonyl reduction is hydroxyl and condition all can be ordinary method and the condition of this area this class reaction, and the present invention is following condition particularly preferably: described preferred solvents be alcohol organic solvent and/or water; Or one or more in toluene, methylene dichloride and tetrahydrofuran (THF).Solvent is 1ml/g～100ml/g with the volume mass of compounds X II than preferably, and that better is 3ml/g～20ml/g.In the time that solvent is alcohol organic solvent and/or water, described reductive agent can be LiBH ₄, CsBH ₄, KBH ₄and NaBH ₄in one or more, the mol ratio of reductive agent and compounds X II can be 0.5～10, better is 1～3, described alcohol organic solvent can be one or more in Virahol, methyl alcohol, ethanol, the trimethyl carbinol and propyl carbinol.In the time that solvent is one or more in toluene, methylene dichloride and tetrahydrofuran (THF), described reductive agent can be lithium aluminum hydride, diisobutyl aluminium hydride or red aluminium (two (2-methoxy ethoxy) sodium aluminum hydride)), the mol ratio of reductive agent and compounds X II can be 0.5～10, and better is 1～3.Described carbonyl reduction be can no longer carry out by detection reaction the time of the reaction of hydroxyl till, be generally 0.25～12 hour, better is 0.5～10 hour.Described carbonyl reduction is that the temperature of the reaction of hydroxyl is preferably-78～120 DEG C, and better is-60～60 DEG C.

In the present invention, prepare above-claimed cpd XIII by following method:

Wherein, R ₂definition ditto described in.

Wherein, the method for described addition reaction and condition all can be ordinary method and the condition of this class reaction of this area, and the present invention is following condition particularly preferably:

Wherein, X be F, Cl, Br, OTf or , R ₂definition ditto described in.

Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can arbitrary combination, obtains the preferred embodiments of the invention.

Agents useful for same of the present invention and raw material be commercially available obtaining all.

Positive progressive effect of the present invention is: preparation method's raw material of the present invention is cheap and easy to get, and reaction conditions gentleness, side reaction is few, yield is high, environmental pollution is little, and intermediate is easy to purifies and separates, is suitable for suitability for industrialized production.

Embodiment

Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, according to ordinary method and condition, or selects according to catalogue.

Example 1

Example 1-a

R ^a=Me

In the as above methylene dichloride of initial compounds (50.0g, 164mmol) (1000ml) solution, ice-water bath keeps 0～5 degree Celsius, slowly adds diisobutyl aluminium hydride (2M toluene solution, 180mL).Reaction cools to-20 degrees Celsius 0～5 degree Celsius of maintenance after 4 hours, and slowly adds methyl alcohol (50ml).After the mixed solution evaporate to dryness organic solvent obtaining, add distilled water 2000ml.After the suspension liquid obtaining is heated to 80 degrees Celsius, through diatomite filtration, the filtrate obtaining is slow cooling to 0 degree Celsius.Filter and collect the crystalline powdery solid (39.7g, yield 82%) obtaining, be required target product.

¹H?NMR(400MHz,DMSO-d ₆):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-d ₆):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] ⁺

Table 1 embodiment 1-b to embodiment 1-g(is except table conditional, and other conditions are with example 1-a)

Example 2

Example 2-a

R ^a=Me，

In water (1300mL) solution of initial compounds (65.0g, 173mmol) as shown in above formula, add saleratus (51.9g, 519mmol), Potassium monofluoride (20g, 345mmol).The mixed solution obtaining slowly adds 30% hydrogen peroxide (110g, 865mmol) under 70 degrees Celsius.Mixed solution after dropwising is incubated and stirs and after 3 hours, adds acetic acid (115mL) under 70 degrees Celsius, and continues 70 degrees Celsius of insulations and stir 30 minutes.Mixed solution is slow cooling to 5 degrees Celsius after diatomite filtration.Filtration is collected the Powdered crystal obtaining and is again scattered in 1000mL distilled water after 5 degrees Celsius of distilled water washs, is heated to 95 degrees Celsius and makes it to dissolve completely.The clear liquid obtaining is slow cooling to 5 degrees Celsius.Filter and collect the Powdered crystal the dry required target compound (48.0g, yield 91%) that is that obtain.

¹H-NMR(400MHz,CD ₃OD)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,CD ₃OD)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] ⁺

The method of reacting operable is the conventional way of Tamao-Fleming oxidizing reaction, reference (Fleming, I; Barbero, A; Walter, D; Chem Rev, 1997,97,2063-2192).

Table 2 embodiment 2-b to embodiment 2-l(is except table conditional, and other conditions are with example 2-a)

Example 3

Example 3-a

r ^afor methyl.

As above adding methylsulfonic acid (10.5ml) in the methylene dichloride of initial compounds (105.0g, 241mmol) (1050mL) solution.The brown liquid obtaining stirs in the aqueous solution that slowly splashes into potassium hydroxide after 2 hours (2M, 2L) under 25 degrees Celsius.After the mixed solution evaporate to dryness organic solvent obtaining, add acetic acid to pH=6～7.Filter and collect the solid the dry required target compound (77.7g, yield 86%) that is that obtain.

¹H-NMR(400MHz,CD ₃OD)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,CD ₃OD)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] ⁺

Table 3 embodiment 3-b to embodiment 3-r(is except table conditional, and other conditions are with example 3-a)

Example 4

Example 4-a

r ^afor methyl.

As above adding hydrochloric acid (1M, 1500mL) in the tetrahydrofuran (THF) of initial compounds (250.0g, 312mmol) (1000mL) solution.The brown liquid obtaining stirs after 12 hours under 65 degrees Celsius, cools to 25 degrees Celsius, and tetrahydrofuran (THF) is removed in distillation.The clear liquid obtaining is through t-butyl methyl ether extraction (200mL X2).The water obtaining slowly splashes into the aqueous solution (2M) of potassium hydroxide to pH=6～7.Filter and collect the solid the dry required target compound (129g, yield 95%) that is that obtain.

¹H-NMR(400MHz,CD ₃OD)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,CD ₃OD)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] ⁺

Table 4 embodiment 4-b to embodiment 4-r(is except table conditional, and other conditions are with example 4-a)

Example 5

Example 5-a

r ^afor methyl.

Nysted reagent (1200mL, 2M, tetrahydrofuran solution) under argon shield atmosphere adds titanium tetrachloride (240ml, 1M, dichloromethane solution) under 0～5 degree Celsius.The red-brown troubled liquor obtaining stirs after 2 hours and cools to 0 degree Celsius under 25 degrees Celsius, and slowly adds compound shown in above formula (192g, 240mmol).The mixture obtaining slowly joins vigorous stirring under nitrogen atmosphere protection 0 degree Celsius of stirring saturated solution of sodium bicarbonate (2000mL) after 6 hours is inner.The mixture obtaining stirs 1 at 25 degrees Celsius and as a child passed through diatomite filtration, and filter cake stirs and washes through methylene dichloride (1000mL).The water and the organic phase that merge add the saturated rear filtration layering of salt (600g).The organic phase separating is after dried over mgso, and evaporate to dryness organic solvent obtains target product crude product (163g, yield 85%)

¹H-NMR(400MHz,CD ₃OD)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,CD ₃OD)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] ⁺

Table 5 embodiment 5b-5r(is except table conditional, and other conditions are with example 5-a)

Example 6

Example 6-a

r ^afor methyl.

In the DMF (1050mL) of the initial compounds (230g, 436mmol) shown in above formula, add DMAP (80g, 654mmol) and 4-p-methoxy-phenyl-diphenyl methyl chloride (269g, 872mmol).The reaction solution obtaining stirs after 36 hours and slowly adds aqueous sodium hydroxide solution (0.5M, 1000mL) under 25 degrees Celsius.In the troubled liquor obtaining, add t-butyl methyl ether extraction (600mL X3).The t-butyl methyl ether merging is concentrated to 750mL after dried over sodium sulfate, and under 45 degrees Celsius, slowly adds normal hexane (1200mL) and cool to-20 degrees Celsius.Filter and collect the needle-like solid the dry required target compound intermediate (251g, yield 72%) that is that obtain.

¹H-NMR(400MHz,CD ₃OD)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,CD ₃OD)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] ⁺

Table 6 embodiment 6-b to 6-r(is except table conditional, and other conditions are with example 6-a)

Example 7

Example 7-a

r ^afor methyl.

In methylene dichloride (1080mL) solution of the initial compounds (270g, 482mmol) shown in above formula, add saturated sodium bicarbonate solution (3240mL) and cool to 0 degree Celsius.Slowly add sodium periodate solid (114g, 530mmol).The reaction solution obtaining stirred 2 as a child under 0 degree Celsius, slowly added hypo solution (1M, 100mL).After the mixed solution obtaining leaves standstill separatory, water is through dichloromethane extraction (600mL X2).Merge all organic phases after dried over sodium sulfate, be concentrated to 600mL and under 35 degrees Celsius, slowly add 1200mL normal hexane.Mixed solution is slow cooling to after-10 degrees Celsius and filters and collect the powder obtaining and be dried, and is required target compound intermediate (234g, yield 92%).

¹H-NMR(400MHz,CD ₃OD)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,CD ₃OD)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] ⁺

Table 7 embodiment 7-b to 7-r(is except table conditional, and other conditions are with example 7-a)

Example 8

Example 8-a

r ^afor methyl.

In the DMF (1000mL) of the initial compounds (250g, 784mmol) shown in above formula, add O-6-benzyl guanine (227g, 941mmol) and lithium hydroxide (1.88g, 78.4mmol).The liquid that is suspended obtaining stirs after 12 hours under 95 degrees Celsius, is concentrated to 300mL through underpressure distillation.This concentrated solution is slowly added drop-wise in 1000mL saturated solution of sodium bicarbonate.Filter and collect the solid that generates and with dry after distilled water wash.This solid is dissolved in after ethyl acetate (300mL) through 300g filtered through silica gel, and silica gel is through the further drip washing of 1200mL ethyl acetate.Merge all ethyl acetate phase evaporate to dryness organic solvents that leach.The faint yellow solid obtaining is required target compound intermediate (364g, yield 83%).

¹H-NMR(400MHz,CD ₃OD)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,CD ₃OD)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] ⁺

Table 8 embodiment 8-b to 8-r(is except table conditional, and other conditions are with example 8-a)

Example 9

Example 9-a

r ^afor methyl.

What this reaction was used is conventional Sharpless chiral epoxy reaction process Review literature: (Pfenninger, A.Synthesis1986,89)

In 2400mL methylene dichloride, add tetraisopropoxy titanium (96mL, 335mmol) and be cooled to subzero 30 degrees Celsius.Add starting raw material (507g, 1.68mol) and (2S, 3S)-tartrate diisopropyl ester (94g, 402mmol) as shown in above formula in this solution the inside.The mixed solution obtaining slowly adds anhydrous peroxy tert-butyl alcohol (2.5M, toluene solution, 800mL) stir 1 hour under subzero 30 degrees Celsius after.Keep temperature of reaction after 3 hours, in reaction solution, slowly to add Sulfothiorine (2M, 500mL) at subzero 20～30 degrees Celsius.Dropwise rear reaction solution and be slowly warmed up to 25 degrees Celsius and process diatomite filtration.The filtrate obtaining separates the water obtaining and after dichloromethane extraction (1000mL X2), merges all methylene dichloride after stratification.The organic phase merging is further dry through Sodium Persulfate after saturated ammonium chloride (500mL) and the washing of saturated aqueous common salt (200mL) substep.The pale yellow oily liquid body that evaporate to dryness organic solvent obtains is required target compound intermediate (488g, yield 91%).

¹H-NMR(400MHz,CD ₃OD)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,CD ₃OD)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] ⁺

Table 9 embodiment 9-b to 9-r(is except table conditional, and other conditions are with example 9-a)

Example 10

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

Example 10-a

r ^afor methyl.

Be dissolved in 2600 milliliters of Virahols at starting raw material as shown in above formula (520g, 1.80 mol), and add (1R, 2R)-2-amino-1-(4-nitrophenyl) propane-1,3-glycol (cas:716-61-0) (212g, 1.0mol).The mixing solutions obtaining stirs after 2 hours and is slow cooling to 25 degrees Celsius under 70 degrees Celsius.Filter to collect after the solid obtaining is also dried and be dissolved in 1200 ml methanol and slowly add the vitriol oil (98%, 120mL).The mixed solution obtaining at room temperature stirs 12 and as a child slowly added aqueous sodium hydroxide solution (3M, 3000mL).The mixed solution obtaining is through n-hexane extraction (2000mL X2).Extraction obtains organic phase evaporate to dryness organic solvent after dried over sodium sulfate, and the pale yellow oily liquid body obtaining is required target compound intermediate (223g, yield 82%).

¹H-NMR(400MHz,CD ₃OD)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,CD ₃OD)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] ⁺

Table 10 embodiment 10-b to 10-r(is except table conditional, and other conditions are with example 10-a)

Example 11

In this 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

Be dissolved in 2600 milliliters of ethanol and add in batches sodium borohydride (66.9g, 1.76mol) at starting raw material (505g, 1.76mol) as shown in above formula.The mixture obtaining at room temperature stirs 3 and as a child cooled to 0 degree Celsius, and adds 500 milliliters of saturated ammonium chloride solutions.After mixed solution evaporate to dryness organic solvent, add ethyl acetate extraction (2000mL X3).The organic phase merging is passed through dried over sodium sulfate after saturated common salt water washing (1000mL) again, and the faint yellow solid that evaporate to dryness organic phase obtains is required target compound intermediate (482g, yield 95%).

¹H-NMR(400MHz,CD ₃OD)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,CD ₃OD)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] ⁺

Table 11 embodiment 11-b to 11-r(is except table conditional, and other conditions are with example 11-a)

Example 12

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

Example 12-a

Be dissolved in 2600 milliliters of ethanol at starting raw material (723g, 2.52mol) as shown in above formula and under 0 degree Celsius, add sodium carbonate (534g, 5.04mol).The mixture obtaining at room temperature stirs after 3 hours and filters.The filtrate obtaining adds dilute hydrochloric acid (3M, 850mL), adds ethyl acetate making beating (2000mL X3) after mixed solution evaporate to dryness organic solvent.The organic phase merging is passed through dried over sodium sulfate after saturated common salt water washing (1000mL) again, and the faint yellow solid that evaporate to dryness organic phase obtains is required target compound intermediate (706g, yield 98%).

¹H-NMR(400MHz,CD ₃OD)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,CD ₃OD)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] ⁺

Table 12 embodiment 12-b to 12-r(is except table conditional, and other conditions are with example 12-a)

Example 13

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

Example 13-a

In the trimethyl carbinol (982g) of starting raw material (491g, 1.52mol) as shown in above formula and water (1960g) mixing solutions, under 25 degrees Celsius, splash into triethylamine 706g.Drip off rear reaction solution be warming up to 85 degree allow its reflux, heat after approximately 60 minutes and be down to 0.Evaporate to dryness organic solvent mixed solution keeps 0～5 degree Celsius also slowly to add concentrated hydrochloric acid (37%) to regulate pH～6.Mixed solution is through ethyl acetate extraction (2600mL X3).The organic phase process saturated common salt water washing merging, the deep yellow oily liquid obtaining with dried over sodium sulfate evaporate to dryness organic solvent are required target compound intermediate (327g, yield 75%).

¹H-NMR(400MHz,CD ₃OD)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,CD ₃OD)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] ⁺

Table 13 embodiment 13-b to 13-r(is except table conditional, and other conditions are with example 13-a)

Example 14

Example 14-a

Be dissolved in 1800ml normal hexane at starting raw material 254g (1.19mol) as shown in above formula, be cooled to 0 degree Celsius, add dichloroacetyl chloride (390.5g, 2.65mol), maintain and under 5～10 degrees Celsius, drip triethylamine (535g, 5.30mol), the mixed solution after dripping off stirs 14 hours under 25 degrees Celsius.In reaction mixture, add water (1500ml).Normal hexane for water (500ml X3) extraction that standing separation obtains.The organic phase merging with saturated common salt water washing and after dried over sodium sulfate evaporate to dryness organic solvent obtain deep yellow oily liquid and be required target compound intermediate (378g, yield 98%).

¹H-NMR(400MHz,CD ₃OD)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,CD ₃OD)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] ⁺

Table 14 embodiment 14-b to 14-r(is except table conditional, and other conditions are with example 14-a)

Example 15

Example 15-a

Cyclopentadiene sodium (165g, 1.87mol) is dissolved in 1650ml tetrahydrofuran (THF), in nitrogen protection borehole cooling to subzero 50 degrees Celsius, drips at starting raw material (271g, 1.48mol) as shown in above formula, and temperature control was subzero 45 degrees Celsius of reactions approximately 3 hours.After having reacted, add the 1000ml shrend reaction of going out.Evaporate remaining normal hexane (1500ml X3) extraction for mixed solution after tetrahydrofuran (THF).The organic phase merging is used 0.5M hydrochloric acid (0.5M, 500mL) and saturated common salt water washing successively, organic phase dried over sodium sulfate, and filtration, is spin-dried for organic solvent and obtains oily sorrel liquid and be required target compound intermediate (299g, yield 95%).

¹H-NMR(400MHz,CD ₃OD)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,CD ₃OD)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] ⁺

Table 15 embodiment 15-b to 15-r(is except table conditional, and other conditions are with example 15-a)

Example 16 R ₂-X is synthetic

R ₂synthesizing of-Cl has detailed description in the document of being quoted with Publication about Document and they:

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 ultimate principle can be represented by following signal formula:

Wherein R-21 is corresponding aromatic ring yl lithium compound.Wherein be respectively independently-MgBr of W1, W2 or-MgCl

Example 16-a

Synthetic method one

Step 1: keep subzero 40 to drip butyllithium (2.5M hexane solution, 4200mL) to subzero 50 degrees Celsius in tetrahydrofuran (THF) (4600mL) solution of 2-chloropyridine (1.15Kg, 10.2mol).Reaction solution after dropwising is slowly warmed up to 25 degrees Celsius and at this temperature, stir 2 hours.The red-brown reaction solution obtaining adds in tetrahydrofuran (THF) (6800mL) solution of the silicon tetrachloride (1.7Kg, 10mol) that is pre-chilled to subzero 50 degrees Celsius.Controlling rate of addition keeps system subzero 40 to subzero 50 degrees Celsius.The mixed solution obtaining after dropwising is slowly warmed up to 25 degrees Celsius and at this temperature, stir after 12 hours and press down at nitrogen atmosphere the solid that filters generation.Filtrate be pre-chilled to subzero 50 degrees Celsius for subsequent use.

Step 2: 1,3-dibromopropane (2.2Kg, 10.9mol) slowly joins in the tetrahydrofuran (THF) (17.6L) of 264g magnesium chips (11mol) that suspend in stirring.Controlling rate of addition keeps temperature of reaction at subzero 40～50 degrees Celsius.Dropwise the mixed solution that rear insulation obtains after 2 hours at subzero 40～50 degrees Celsius and be pre-chilled to subzero 50 degrees Celsius, and add the reaction mixture of being prepared by 2-chloropyridine.Controlling rate of addition keeps temperature of reaction at subzero 40～50 degrees Celsius.Dropwise and be slowly warmed up to 60 degrees Celsius and stir 3 hours afterwards.After underpressure distillation concentration of reaction solution to 20 liter, add normal hexane (20L).Remove by filter the solid of generation.After filtrate is concentrated, pressure distillation obtains colourless liquid and is required target compound intermediate (1.16Kg, 62%).

Synthetic method two

Example 16-b

Step 1: 1,3-dibromopropane (2.2Kg, 10.9mol) slowly joins in the tetrahydrofuran (THF) (17.6L) of 264g magnesium chips (11mol) that suspend in stirring.Controlling rate of addition keeps temperature of reaction at subzero 40～50 degrees Celsius.Dropwise the mixed solution that rear insulation obtains after 2 hours at subzero 40～50 degrees Celsius and be pre-chilled to subzero 50 degrees Celsius.In this reaction solution, drip silicon tetrachloride (1.7Kg, 10mol).Controlling rate of addition keeps temperature of reaction at subzero 40～50 degrees Celsius.Dropwise and be slowly warmed up to 60 degrees Celsius and stir after 3 hours cooling and be pre-chilled to subzero 50 degrees Celsius afterwards.

Step 2: keep subzero 40 to drip butyllithium (2.5M hexane solution, 4200mL) to subzero 50 degrees Celsius in tetrahydrofuran (THF) (4600mL) solution of 2-chloropyridine (1.15Kg, 10.2mol).Reaction solution after dropwising is slowly warmed up to 25 degrees Celsius and at this temperature, stir 2 hours.The red-brown reaction solution obtaining is pre-chilled to subzero 50 degrees Celsius, and slowly joins in step 1 preparation feedback liquid.Controlling rate of addition keeps temperature of reaction at subzero 40～50 degrees Celsius.The mixed solution obtaining after dropwising is slowly warmed up to 25 degrees Celsius and at this temperature, stir after 12 hours, adds normal hexane (20L) after pressing distillation and concentration reaction solution to 20 liter.Remove by filter the solid of generation.After filtrate is concentrated, pressure distillation obtains colourless liquid and is required target compound intermediate (1.53Kg, 82%).

¹H-NMR(400MHz,CDCl ₃)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,CDCl ₃)167.9,149.4,133.8,128.2,122.8,17.6,12.5

Table 16 embodiment 16-b to 16-r

Claims

1. suc as formula a preparation method for the intermediate of the Entecavir shown in XII, it is characterized in that comprising the following step:

R2 is substituting group as follows:

Y is for connecting or not connecting other substituent 3～9 carbon, thereby forms and replace or the saturated or undersaturated silicon-carbon ring of unsubstituted 4～10 yuan with Si; Or, other are substituent in order to connect or not connect for Y, add up to carbon atom and the heteroatoms of 3～9, thereby form and replace or the saturated or undersaturated carbon sila ring of unsubstituted 4～10 yuan with Si, described heteroatoms is O, S or N, and heteroatomic number is 1～3; Substituting group in described replacement is C ₁～C ₃alkyl; Described silicon-carbon ring or carbon sila ring are a ring or and two rings together.

2. preparation method as claimed in claim 1, is characterized in that: described R ₂for following arbitrary substituting group:

3. preparation method as claimed in claim 2, is characterized in that: described substituting group IVa is following arbitrary substituting group:

4. the preparation method as described in claim 1～3 any one, is characterized in that: described R ₂₁for following arbitrary substituting group:

5. preparation method as claimed in claim 1, it is characterized in that: described solvent is one or more in Virahol, methyl alcohol, ethanol, the trimethyl carbinol, propyl carbinol, DMF, dimethyl sulfoxide (DMSO), acetonitrile, tetrahydrofuran (THF), 2-methyltetrahydrofuran, N-Methyl pyrrolidone and water; Described alkali is triethylamine, diisopropylethylamine, 1, one or more in 8-diazabicylo [5.4.0] 11 carbon-7-alkene, sodium carbonate, salt of wormwood, cesium carbonate, Quilonum Retard, potassium hydroxide, lithium hydroxide, sodium hydroxide and cesium hydroxide; The mol ratio of described alkali and compounds X III is 0.5～10; The temperature of described isomerization reaction is-50～100 DEG C.

6. preparation method as claimed in claim 1, is characterized in that: prepare described compounds X III by following method, then prepare compounds X II by the method for claim 1:

Wherein, R ₂definition with described in any one in claim 1～4.

7. preparation method as claimed in claim 1, it is characterized in that: in described hydrolysis reaction: described organic solvent is one or more in Virahol, methyl alcohol, ethanol, the trimethyl carbinol, propyl carbinol, DMF, dimethyl sulfoxide (DMSO), acetonitrile, tetrahydrofuran (THF) and N-Methyl pyrrolidone; Described alkali is triethylamine, diisopropylethylamine, 1, one or more in 8-diazabicylo [5.4.0] 11 carbon-7-alkene, sodium carbonate, salt of wormwood, cesium carbonate, Quilonum Retard, potassium hydroxide, lithium hydroxide, sodium hydroxide and cesium hydroxide; The mol ratio of described alkali and compounds X IV is 0.5～100; The temperature of described hydrolysis reaction is-10～150 DEG C.

8. preparation method as claimed in claim 6, is characterized in that: prepare described compounds X IV by following method, and then prepare compounds X III by the method described in claim 6, then prepare compounds X II by the method described in claim 1:

Wherein, R ₂definition with described in any one in claim 1～4.

9. preparation method as claimed in claim 6, it is characterized in that: in described addition reaction, described organic solvent is one or more in normal hexane, toluene, dimethylbenzene, trimethylbenzene, benzene, chlorobenzene, sherwood oil, tetrahydrofuran (THF), 2-methyltetrahydrofuran, Skellysolve A and normal heptane; Described alkali is diisopropylethylamine, 1, one or more in 8-diazabicylo [5.4.0] 11 carbon-7-alkene, triethylamine and pyridine; The mol ratio of described alkali and compounds X V is 0.5～100; The mol ratio of described dichloroacetyl chloride and compounds X V is 0.5～10; The temperature of described addition reaction is-50～100 DEG C.

10. preparation method as claimed in claim 8, it is characterized in that: prepare above-claimed cpd XV by following either method, prepare compounds X IV by method claimed in claim 8 again, prepare compounds X III by the method described in claim 6 again, then prepare compounds X II by the method described in claim 1:

Under protection of inert gas, in organic solvent, by compound R ₂an alkali metal salt of X and cyclopentadiene or the alkaline earth salt of cyclopentadiene carry out nucleophilic substitution reaction as follows;

Wherein, X be F, Cl, Br, OTf or

11. preparation methods as claimed in claim 10, is characterized in that: in described nucleophilic substitution reaction: described organic solvent is one or more in tetrahydrofuran (THF), sherwood oil, 2-methyltetrahydrofuran, normal hexane, Skellysolve A and normal heptane; An alkali metal salt of described cyclopentadiene or the alkaline earth salt of cyclopentadiene and compound R ₂the mol ratio of X is 0.5～10; The temperature of described nucleophilic substitution reaction is-78～50 DEG C.

12. preparation methods as described in claim 10 or 11, is characterized in that: an alkali metal salt of described cyclopentadiene is cyclopentadiene sodium.

13. suc as formula shown in XV, XIV or XIII the midbody compound of Entecavir:

wherein, R ₂definition with described in any one in claim 1～4.