CN104177396A

CN104177396A - Entecavir intermediates and preparation methods thereof

Info

Publication number: CN104177396A
Application number: CN201310198175.3A
Authority: CN
Inventors: 应律; 陈清泉; 胡俊斌
Original assignee: Zhejiang Xing Yue Medicine Science And Technology Co Ltd
Current assignee: Zhejiang Xing Yue Medicine Science And Technology Co Ltd
Priority date: 2013-05-23
Filing date: 2013-05-23
Publication date: 2014-12-03

Abstract

The invention discloses an entecavir intermediate and a preparation method thereof. A provided preparation method for an entecavir intermediate compound 5 comprises the following steps: performing ring-opening reaction on a compound 6 and a compound 7 in an aprotic organic solvent, so as to obtain the compound 5. A provided preparation method for an entecavir intermediate compound 6 is characterized by comprising the following steps: performing Sharpless chiral epoxidation reaction on a compound 8, so as to obtain the compound 6. The preparation methods are cheap and easily available in raw materials, mild in reaction conditions, relatively high in product yield, good in atom economy, friendly to environment, and suitable for industrialized production.

Description

Entecavir midbodies and preparation method thereof

Technical field

The present invention relates to entecavir midbodies and preparation method thereof.

Background technology

Nucleotide analog is as the important compound of a class, in the concern widely having obtained in pharmaceutical chemistry field.Large quantities of significant medicines have been brought up in relative research, especially in antiviral field.A considerable amount of anti-AIDS drugs and anti-hbv drug are all benefited 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, and needs of patients needs for a long time or in most cases to carry out throughout one's life virus and suppresses.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 exceedes 80% at present.In nucleoside medicine, Entecavir relies on its significant 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.This drug patent expired in 2008, but because its synthetic difficulty is huge, its activeconstituents (API) existing market price is high, and manufacturer is few.

The bulk drug of Entecavir, because its synthetic difficulty is large, has caused widely and has paid close attention in scientific circles.Therefore synthetic method research about Entecavir also 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 people such as Shen Guobing and this paper are quoted, there is detailed introduction.Other relevant documents also have a lot, for example 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, the pertinent literature that quote WO2012006964A1 and these documents the inside.

The larger problem that current most synthetic routes exist, such as equivalent uses more expensive raw material and the reagent such as Dess-Martin reagent or two firpene borines, and severe reaction conditions, purification procedures complexity, need the expensive means of purification such as chromatographic column separation, atom utilization is low, and aftertreatment is seriously polluted, is not suitable for large-scale industrial production.Wherein a comparatively practical production line is WO2005118585 report, and its synthetic route is shown below.This route also has its corresponding defect, and such as the raw material production difficulties such as phenyldimethylchlorosilane cause, price is high, cost is higher; And the use of high toxicity reagent such as boron trifluoride; And the intermediate of the overwhelming majority is all the purification difficult that oily liquids causes in process of production.

Chinese patent CN101050216A has reported the synthetic route similar to WO2005118585, but decrease on production cost, has adopted diphenyl methyl chloro silane that price is lower as starting raw material.But because two phenyl ring caused huge steric effect that is connected with Siliciumatom, make this route in the end when deprotection base, still cannot avoid using the boron trifluoride of high malicious high pollution, and be unfavorable for suitability for industrialized production.

Summary of the invention

Technical problem to be solved by this invention is more expensive in order to overcome existing Entecavir preparation method reaction raw materials price, be difficult to obtain, severe reaction conditions, product yield is lower, post-processing operation is loaded down with trivial details, atom utilization is low, and environmental pollution is seriously not suitable for the defects such as suitability for industrialized production, and entecavir midbodies and preparation method thereof is provided.Preparation method's raw material of the present invention is cheap and easy to get, reaction conditions gentleness, and product yield is higher.Atom economy is good, and environmental friendliness is suitable for suitability for industrialized production.

The preparation method who the invention provides a kind of entecavir midbodies compound 5, it comprises the following steps: in aprotic organic solvent, compound 6 and compound 7 are carried out to ring-opening reaction, obtain compound 5;

Wherein, 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 can be 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 can be one or more; Described every class refers to above-mentioned C ₁～C ₃alkyl, halogen and C ₁～C ₃one in alkoxyl group.

Described R ₂₁be preferably following arbitrary substituting group:

Y is for connecting or not connecting substituent 3～9 carbon carbon atoms, thereby forms and replace or the saturated or undersaturated silicon-carbon ring of unsubstituted 4～10 yuan with Si; Or Y, for connecting or not connecting substituently, adds 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:

or

In substituting group IIa, n is that 0～2, p is that 0～2, q is that 1～2, X and Y are independently carbon, oxygen or nitrogen separately, R ₃the position of substitution be the position that can replace arbitrarily except Siliciumatom on heterocycle; R ₃can be monosubstituted or polysubstituted, work as R ₃when polysubstituted, substituting group can be identical or different, R ₃be selected from methyl, ethyl, propyl group or sec.-propyl; In the time that n is 0, X is carbon, and in the time that p is 0, Y is carbon.

Described substituting group IIa is preferably following arbitrary substituting group:

P ₂for stable hydroxy-protective group under acidic conditions conventional in this area, in the present invention particularly preferably the C that alkoxyl group replaces ₁～C ₆alkyl (preferably methoxyl methyl or ethoxymethyl) or trimethyl silicane ethoxymethyl; Wherein said alkoxyl group is C ₁～C ₆alkoxyl group.R ₄for one or more substituting groups, R ₅for one or two substituting group, R ₄be selected from hydrogen, halogen, C ₁～C ₆straight or branched alkyl (preferable methyl, ethyl, propyl group, sec.-propyl or the tertiary butyl) and nitro in one or more; R ₅be selected from hydrogen, halogen, C ₁～C ₆straight or branched alkyl (preferable methyl, ethyl, propyl group, sec.-propyl or the tertiary butyl) and nitro in one or two.R ₆for hydrogen, or one or more C that is selected from ₁～C ₆straight or branched alkoxyl group (preferably methoxyl group), C ₁～C ₆straight or branched alkyl (preferable methyl) and the substituting group of halogen atom (as fluorine, chlorine or bromine).

Prepare the method for compound 5, under the condition preferably existing at alkali, carry out.

Preparing in the method for compound 5, the method of described ring-opening reaction and condition all can be ordinary method and the condition of such reaction in 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 N, dinethylformamide, dimethyl sulfoxide (DMSO), acetonitrile, tetrahydrofuran (THF), one or more in N-Methyl pyrrolidone and 2-methyltetrahydrofuran.Described organic solvent is 1mL/g～100mL/g with the volume mass of described compound 6 than preferably, and that better is 3mL/g～20mL/g.Described compound 7 is preferably 0.5～10 with the molar ratio of described compound 6, and better is 1～3.The time of described ring-opening reaction is generally 0.5 hour～24 hours till can no longer carrying out by detection reaction, and better is 3 hours～20 hours.The temperature of described ring-opening reaction is preferably 0～150 DEG C, and better is 25 DEG C～120 DEG C.

Preparing compound 5 preferably in method, described alkali is preferably lithium hydroxide and/or lithium hydride.The molar ratio of described alkali and compound 6 is preferably 0.01～10, and better is 0.05～5.

Preparing in the method for entecavir midbodies compound 5, described compound 6 can be prepared by following method, and it comprises the following steps: in organic solvent, compound 8 is carried out to the reaction of Sharpless chiral epoxy, obtain compound 6;

Again successively according to the described method of preparing compound 5, the described method of preparing compound 4, the described method of preparing compound 3, the described method of preparing compound 2 and the described method of preparing Entecavir 1 make Entecavir 1;

Wherein, P ₂and R ₂definition all the same described in.

Preparing in the method for compound 6, the method of described Sharpless chiral epoxy reaction and condition can be ordinary method and the condition of such reaction in 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, compound 8 and superoxide are carried out to the reaction of Sharpless chiral epoxy, obtain compound 6.

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 described compound 8 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 molar ratio of described chiral ligand and described compound 8 is preferably 0.0001～1, and better is 0.001～0.3.The molar ratio of described tetraisopropoxy titanium and described compound 8 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.The molar ratio of described superoxide and described compound 8 is preferably 0.5～10, and better is 1～5.The time of described chiral epoxy reaction is generally 0.25 hour～24 hours till can no longer carrying out by detection reaction, and better is 1 hour～16 hours.The temperature of described chiral epoxy reaction is preferably-78 DEG C～25 DEG C, and better is-60 DEG C～0 DEG C.

Preparing in the method for compound 6, described compound 8 can be prepared by following method, and it comprises the following steps: in solvent, under acidic conditions, compound 9 is removed to the reaction of hydroxyl protecting group, obtain compound 8;

Again successively according to the described method of preparing compound 6, the described method of preparing compound 5, the described method of preparing compound 4, the described method of preparing compound 3, the described method of preparing compound 2 and the described method of preparing Entecavir 1 make Entecavir 1;

Wherein, P ₂and R ₂definition all the same described in; P ₁for the hydroxyl protecting group that can be hydrolyzed under acidic conditions conventional in this area, its acid resistance compares P ₂a little less than, be preferably wherein R ₈for hydrogen, or C ₁～C ₆straight or branched alkyl (preferable methyl, ethyl or propyl group); R ₉for C ₁～C ₆straight or branched alkyl (preferable methyl, ethyl or propyl group), trimethyl silicon based, triethyl is silica-based, trityl group or t-Butyldimethylsilyl.

Preparing in the method for compound 8; the method of the described reaction that removes hydroxyl protecting group and condition can be ordinary method and the condition of such reaction in this area; the present invention is following condition particularly preferably: described preferred solvents be organic solvent and/or water, wherein said organic solvent is preferably methylene dichloride, methyl alcohol; ethanol; Virahol, the trimethyl carbinol, tetrahydrofuran (THF); acetonitrile, one or more in DMF and dimethyl sulfoxide (DMSO).Described solvent is 2mL/g～20mL/g with the volume mass of described compound 9 than preferably, and that better is 5mL/g～15mL/g.Described protonic acid is preferably hydrochloric acid, sulfuric acid, nitric acid, one or more in trifluoroacetic acid, methylsulfonic acid and tosic acid.The molar ratio of described protonic acid and described compound 9 is preferably 0.01～100, and better is 0.1～20.The time of described reaction is generally 0.5 hour～24 hours till can no longer carrying out by detection reaction.The temperature of described reaction is preferably 0～100 DEG C, and better is 20 DEG C～80 DEG C.

Preparing in the method for compound 8, described compound 9 can be prepared by following method, and it comprises the following steps: in aprotic organic solvent, under alkaline condition, compound 10 is carried out to reacting of upper hydroxyl protecting group with hydroxyl protection reagent, obtain compound 9;

Again successively according to the described method of preparing compound 8, the described method of preparing compound 6, the described method of preparing compound 5, the described method of preparing compound 4, the described method of preparing compound 3, the described method of preparing compound 2 and the described method of preparing Entecavir 1 make Entecavir 1;

Wherein P ₁, P ₂and R ₂all same as above.

Described hydroxyl protection reagent is hydroxyl protection reagent conventional in this area, in the present invention particularly preferably the C that alkoxy replaces ₁～C ₆haloalkane (preferably methoxyl methyl or ethoxymethyl) or trimethyl silicane ethoxymethyl haloalkane, wherein, described alkoxyl group is C ₁～C ₆alkoxyl group; Described halogen is chlorine, bromine or iodine; R ₄for one or more substituting groups, R ₅for one or two substituting group, R ₄be selected from hydrogen, halogen, C ₁～C ₆straight or branched alkyl (preferable methyl, ethyl, propyl group, sec.-propyl or the tertiary butyl) and nitro in one or more; R ₅be selected from hydrogen, halogen, C ₁～C ₆straight or branched alkyl (preferable methyl, ethyl, propyl group, sec.-propyl or the tertiary butyl) and nitro in one or two.

Preparing in the method for compound 9; the method of described upper hydroxyl protection radical reaction and condition 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 N; dinethylformamide, dimethyl sulfoxide (DMSO); acetonitrile, tetrahydrofuran (THF), one or more in 2-methyltetrahydrofuran and N-Methyl pyrrolidone.Described organic solvent is 1mL/g～100mL/g with the volume mass of described compound 10 than preferably, and that better is 3mL/g～20mL/g.Described alkali is preferably DMAP, triethylamine, diisopropylethylamine, salt of wormwood, one or more in sodium carbonate, cesium carbonate, potassium hydride KH and sodium hydride; Better is sodium hydride; Described potassium hydride KH or sodium hydride are preferably quality percentage composition to be 10%～90% be scattered in potassium hydride KH or the sodium hydride reagent in mineral oil, better are scattered in potassium hydride KH or the sodium hydride reagent in mineral oil for quality percentage composition is 60%; Described quality percentage composition refers to that the quality of potassium hydride KH or sodium hydride accounts for the percentage composition of potassium hydride KH or sodium hydride and mineral oil mixture total mass.The molar ratio of described alkali and described compound 10 is preferably 0.5～10, and better is 1～5.The molar ratio of described hydroxyl protection reagent and described compound 10 is preferably 0.5～10, and better is 1～3.The time of the reaction of described upper hydroxyl protecting group is generally 0.5 hour～72 hours till can no longer carrying out by detection reaction, and better is 1 hour～36 hours.The temperature of the reaction of described upper hydroxyl protecting group is preferably-20 DEG C～80 DEG C, and better is-20 DEG C～50 DEG C.

Preparing in the method for compound 9, described compound 10 can be prepared by following method, and it comprises the following steps: in organic solvent, under the effect of reductive agent, ester compound 11 is carried out to reduction reaction, obtain compound 10;

Again successively according to the described method of preparing compound 9, the described method of preparing compound 8, the described method of preparing compound 6, the described method of preparing compound 5, the described method of preparing compound 4, the described method of preparing compound 3, the described method of preparing compound 2 and the described method of preparing Entecavir 1 make Entecavir 1;

Wherein, R ₂and P ₁all same as above; R ₁₀for 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.

Preparing in the method for compound 10, described organic solvent is not affect the conventional solvent of this type of reduction reaction that reaction is carried out, for example methylene dichloride, toluene, 1, one or more in 2-ethylene dichloride, tetrahydrofuran (THF) and 2-methyltetrahydrofuran.Described organic solvent is 3mL/g～20mL/g with the volume mass of described compound 11 than preferably, and that better is 5mL/g～12mL/g.

Preparing in the method for compound 10, the consumption of described reductive agent can be the conventional amount used of this type of reduction reaction of this area, be for example 1～5 times of described compound 11, the present invention is following ranges particularly preferably: the molar ratio of described reductive agent and described compound 11 is preferably 1.1～3.In the time that reductive agent is sodium borohydride, described reduction reaction is carried out under the existence of lithium chloride and/or lithiumbromide, and the molar ratio of described lithium chloride and/or lithiumbromide and described compound 11 is preferably 0.1～2.

Preparing in the method for compound 10, the temperature of described reduction reaction is preferably-78 DEG C～100 DEG C, and better is-20 DEG C～40 DEG C.The time of described reduction reaction is generally 0.5 hour～12 hours till can no longer carrying out by detection reaction.

Preparing in the method for compound 10, described compound 11 can be prepared by following method, and it comprises the following steps: in organic solvent, under the condition that acid exists, compound 12 is carried out to reacting of upper hydroxyl protecting group with hydroxyl protection reagent, obtain compound 11;

Again successively according to the described method of preparing compound 10, the described method of preparing compound 9, the described method of preparing compound 8, the described method of preparing compound 6, the described method of preparing compound 5, the described method of preparing compound 4, the described method of preparing compound 3, the described method of preparing compound 2, the described method of preparing Entecavir 1 makes Entecavir 1;

Wherein R ₂, R ₁₀and P ₁definition all same as above; Wherein R ₈for hydrogen, or C ₁～C ₆straight or branched alkyl (preferable methyl, ethyl or propyl group); R ₉for C ₁～C ₆straight or branched alkyl (preferable methyl, ethyl or propyl group), trimethyl silicon based, triethyl is silica-based, trityl group or t-Butyldimethylsilyl.

Preparing in the method for compound 11, the described reaction of carrying out upper protecting group can be nucleophilic substitution reaction or linked reaction.

Described hydroxyl protection reagent is the hydroxyl protecting group that can be hydrolyzed under the acidic conditions of routine in this area, is preferably wherein R ₈for hydrogen, or C ₁～C ₆straight or branched alkyl (preferable methyl, ethyl or propyl group); R ₉for C ₁～C ₆straight or branched alkyl (preferable methyl, ethyl or propyl group), trimethyl silicon based, triethyl is silica-based, trityl group or t-Butyldimethylsilyl.

Preparing in the method for compound 11, described organic solvent is preferably one or more in aromatic hydrocarbon solvent, halogenated hydrocarbon solvent and alkane solvents; Described aromatic hydrocarbon solvent is preferably toluene; Described halogenated hydrocarbon solvent is preferably methylene dichloride and/or ethylene dichloride; Described alkane solvents is preferably one or more in normal hexane, Skellysolve A, sherwood oil and normal heptane; Described organic solvent is 3mL/g～20mL/g with the volume mass of described compound 12 than preferably, and that better is 5mL/g～15mL/g.Described acid is preferably organic acid, the preferred tosic acid of described organic acid.The molar ratio of described acid and described compound 12 is preferably 0.01～10, and better is 0.01～1.The molar ratio of described hydroxyl protection reagent and described compound 12 is preferably 1～100, and better is 1～20.

Preparing in the method for compound 11, the temperature of the reaction of described upper hydroxyl protecting group is preferably-20 DEG C～100 DEG C, and better is-20 DEG C～40 DEG C.The time of the reaction of described upper hydroxyl protecting group is generally 0.5 hour～12 hours till can no longer carrying out by detection reaction.

Preparing in the method for compound 11, described compound 12 can be prepared by following method, and it comprises the following steps:

Step (1): in organic solvent, by compound 13 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 ₁₀oH carries out esterification, obtains compound 12;

Again successively according to the described method of preparing compound 11, the described method of preparing compound 10, the described method of preparing compound 9, the described method of preparing compound 8, the described method of preparing compound 6, the described method of preparing compound 5, the described method of preparing compound 4, the described method of preparing compound 3, the described method of preparing compound 2 and the described method of preparing Entecavir 1 make Entecavir 1;

Wherein, R ₂and R ₁₀definition all same as above;

In the step (1) of preparing compound 12, 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 Virahol, methyl alcohol, ethanol, water, DMF, dimethyl sulfoxide (DMSO), acetonitrile, one or more in tetrahydrofuran (THF), 2-methyltetrahydrofuran and N-Methyl pyrrolidone.Described organic solvent is 1mL/g～100mL/g with the volume mass of described compound 13 than preferably, and that better is 3mL/g～20mL/g.Described (1R, 2R)-2-amino-1-(4-nitrophenyl) propane-1, the molar ratio of 3-glycol and described compound 13 is preferably 0.25～10, better is 0.4～3.The time of described reaction is generally 0.25 hour～72 hours till can no longer carrying out by detection reaction, and better is 0.5 hour～24 hours.The temperature of described reaction is preferably 0～150 DEG C, and better is 25 DEG C～80 DEG C.

In the step (2) of preparing compound 12, 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 solvent.Described organic solvent is 1mL/g～100mL/g with the volume mass of described compound 13 than preferably, and that better is 3mL/g～20mL/g.The weight percentage of the described vitriol oil can be 60%～98%(as 98%wt).The molar ratio of the described vitriol oil and described compound 13 is preferably 0.01～100, and better is 0.05～30.The time of described reaction is generally 0.5 hour～72 hours till can no longer carrying out by detection reaction, and better is 1 hour～48 hours.The temperature of described reaction is preferably-20 DEG C～100 DEG C, and better is-10 DEG C～60 DEG C.

Preparing in the method for compound 12, described compound 13 can make by following method, and it comprises the following steps: in solvent, it is reacting of hydroxyl that compound 14 and reductive agent are carried out to carbonyl reduction, obtains compound 13;

Again successively according to the described method of preparing compound 12, the described method of preparing compound 11, the described method of preparing compound 9, the described method of preparing compound 8, the described method of preparing compound 6, the described method of preparing compound 5, the described method of preparing compound 4, the described method of preparing compound 3, the described method of preparing compound 2 and the described method of preparing Entecavir 1 make Entecavir 1;

Wherein, R ₂definition same as above.

Preparing in the method for compound 13, described carbonyl reduction is ordinary method and the condition that the method for reaction of hydroxyl and condition all can be this class reaction of this area, 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).Described solvent is 1mL/g～100mL/g with the volume mass of described compound 14 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 molar ratio of reductive agent and compound 14 is preferably 0.5～10, better is 1～3, described alcohol organic solvent can be Virahol, methyl alcohol, ethanol, one or more in 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 molar ratio of reductive agent and compound 14 is preferably 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 hour～12 hours, better is 0.5 hour～10 hours.Described carbonyl reduction is that the temperature of the reaction of hydroxyl is preferably-78 DEG C～120 DEG C, and better is-60 DEG C～60 DEG C.

Preparing in the method for compound 13, described compound 14 can be prepared by following method, and it comprises the following steps: in solvent, under the effect of alkali, compound 15 is carried out to isomerization reaction, obtain compound 14;

Again successively according to the described method of preparing compound 13, the described method of preparing compound 12, the described method of preparing compound 11, the described method of preparing compound 9, the described method of preparing compound 8, the described method of preparing compound 6, the described method of preparing compound 5, the described method of preparing compound 4, the described method of preparing compound 3, the described method of preparing compound 2 and the described method of preparing Entecavir 1 make Entecavir 1;

Wherein, R ₂definition same as above.

Preparing in the method for compound 14, the method for described isomerization 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 solvent can be Virahol, methyl alcohol, ethanol, the trimethyl carbinol, propyl carbinol, N, dinethylformamide, dimethyl sulfoxide (DMSO), acetonitrile, tetrahydrofuran (THF), one or more in 2-methyltetrahydrofuran, N-Methyl pyrrolidone and water.Described solvent is 1mL/g～100mL/g with the volume mass of described compound 15 than preferably, and that better is 3mL/g～20mL/g.Described alkali is preferably triethylamine, diisopropylethylamine, 1,8-diazabicylo [5.4.0], 11 carbon-7-alkene, sodium carbonate, salt of wormwood, cesium carbonate, Quilonum Retard, potassium hydroxide, lithium hydroxide, one or more in sodium hydroxide and cesium hydroxide.The molar ratio of described alkali and described compound 15 is preferably 0.5～10, and better is 1～3.The time of described isomerization reaction is generally 0.25 hour～72 hours till can no longer carrying out by detection reaction, and better is 0.5 hour～12 hours.The temperature of described isomerization reaction is preferably-50 DEG C～100 DEG C, and better is-10 DEG C～80 DEG C.

Preparing in the method for compound 14, described compound 15 can be prepared by following method, and it comprises the following steps: in the mixing solutions of organic solvent and water, under the effect of alkali, compound 16 is carried out to hydrolysis reaction as follows, obtain compound 15;

Again successively according to the described method of preparing compound 14, the described method of preparing compound 13, the described method of preparing compound 12, the described method of preparing compound 11, the described method of preparing compound 9, the described method of preparing compound 8, the described method of preparing compound 6, the described method of preparing compound 5, the described method of preparing compound 4, the described method of preparing compound 3, the described method of preparing compound 2 and the described method of preparing Entecavir 1 make Entecavir 1;

Wherein, R ₂definition same as above.

Preparing in the method for compound 15, the method of described hydrolysis 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 can be Virahol, methyl alcohol, ethanol, the trimethyl carbinol, propyl carbinol, N, dinethylformamide, dimethyl sulfoxide (DMSO), acetonitrile, one or more in tetrahydrofuran (THF) and N-Methyl pyrrolidone.Described organic solvent is 0.5mL/g～100mL/g with the volume mass of described compound 16 than preferably, and that better is 1mL/g～20mL/g.Described water is 0.25mL/g～100mL/g with the volume mass of described compound 16 than preferably, and that better is 0.5mL/g～20mL/g.Described alkali is preferably triethylamine, diisopropylethylamine, 1,8-diazabicylo [5.4.0], 11 carbon-7-alkene, sodium carbonate, salt of wormwood, cesium carbonate, Quilonum Retard, potassium hydroxide, lithium hydroxide, one or more in sodium hydroxide and cesium hydroxide.The molar ratio of described alkali and described compound 16 is preferably 0.5～100, and better is 1～50.The time of described hydrolysis reaction is generally 0.25 hour～72 hours till can no longer carrying out by detection reaction, and better is 0.5 hour～12 hours.The temperature of described hydrolysis reaction is preferably-10 DEG C～150 DEG C, and better is 0～120 DEG C.

Preparing in the method for compound 15, described compound 16 can make by following method, and it comprises the following steps: in organic solvent, under the effect of alkali, compound 17 and dichloroacetyl chloride are carried out to addition reaction as follows, obtain compound 16;

Again successively according to the described method of preparing compound 15, the described method of preparing compound 14, the described method of preparing compound 13, the described method of preparing compound 12, the described method of preparing compound 11, the described method of preparing compound 9, the described method of preparing compound 8, the described method of preparing compound 6, the described method of preparing compound 5, the described method of preparing compound 4, the described method of preparing compound 3, the described method of preparing compound 2 and the described method of preparing Entecavir 1 make Entecavir 1,

Wherein, R ₂definition same as above.

Preparing in the method for compound 16, 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 normal hexane, toluene, dimethylbenzene, trimethylbenzene, benzene, chlorobenzene, sherwood oil, tetrahydrofuran (THF), 2-methyltetrahydrofuran, one or more in Skellysolve A and normal heptane.Described organic solvent is 1mL/g～100mL/g with the volume mass of described compound 17 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 molar ratio of described alkali and described compound 17 is preferably 0.5～100, and better is 1～50.The molar ratio of described dichloroacetyl chloride and described compound 17 is preferably 0.5～10, and better is 0.8～3.The time of described addition reaction is generally 0.25 hour～72 hours till can no longer carrying out by detection reaction, and better is 0.5 hour～24 hours.The temperature of described addition reaction is preferably-50 DEG C～100 DEG C, and better is-30 DEG C～30 DEG C.

Preparing in the method for compound 16, described compound 17 can make 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;

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

Preparing in the method for compound 17, the method of described nucleophilic substitution 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 is preferably tetrahydrofuran (THF), sherwood oil, 2-methyltetrahydrofuran, normal hexane, one or more in Skellysolve A and normal heptane.Described organic solvent and described 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 as described in cyclopentadiene alkaline earth salt and as described in compound R ₂the molar 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 hour～72 hours till can no longer carrying out by detection reaction, and better is 0.5 hour～24 hours.The temperature of described nucleophilic substitution reaction is preferably-78 DEG C～50 DEG C, and better is-60 DEG C～30 DEG C.

After making entecavir midbodies compound 5, can also prepare entecavir midbodies compound 4, it comprises the following steps: in solvent, under acidic conditions, compound 5 is carried out to transketalation with compound 18 and react, obtain compound 4;

Prepare again Entecavir 1;

Wherein, R ₂, R ₆and P ₂definition all same as above, R ₇for hydrogen atom or C ₁～C ₆straight or branched alkyl; R ₁₁for C ₁～C ₈straight or branched alkyl, or C ₁～C ₈cycloalkyl; R ₁₂for C ₁～C ₈straight or branched alkyl, or C ₁～C ₈cycloalkyl.

Preparing in the method for compound 4, described transketalation reaction is for the ordinary method of such reaction occurs in this area, particularly preferably following reaction conditions and method in the present invention:

Preparing in the method for compound 4, the preferred non-protonic solvent of described solvent, one or more in the preferred halogenated hydrocarbon solvent of described non-protonic solvent, aromatic hydrocarbon solvent, ether solvent and alkane solvents; The preferred chlorinated hydrocarbon solvent of described halogenated hydrocarbon solvent; The described preferred methylene dichloride of chlorinated hydrocarbon solvent and/or ethylene dichloride; The preferred toluene of described aromatic hydrocarbon solvent; The preferred tetrahydrofuran (THF) of described ether solvent and/or 2-methyltetrahydrofuran; One or more in the preferred normal hexane of described alkane solvents, normal heptane and sherwood oil.

Preparing in the method for compound 4, described acidic conditions can be realized by acidic substance, and described acidic substance are one or more in organic acid, mineral acid and strong acid weak base salt; The preferred strong acid weak base salt of described acidic substance, described acidic conditions is preferably realized by strong acid weak base salt, realizes described transketalation reaction by strong acid weak base salt.The preferred tosic acid of described organic acid and/or methylsulfonic acid; One or more in the preferred hydrochloric acid of described mineral acid, sulfuric acid and phosphoric acid; Described strong acid weak base salt refers to that strong acid reacts the aobvious weakly acidic salt forming with weak base, preferably one or more in para-methylbenzenepyridinsulfonate sulfonate (PPTS), tosic acid triethylamine salt, methylsulfonic acid pyridinium salt and methylsulfonic acid triethylamine salt, further preferred para-methylbenzenepyridinsulfonate sulfonate (PPTS) and methylsulfonic acid pyridinium salt, more further preferred para-methylbenzenepyridinsulfonate sulfonate.The molar ratio of described acidic substance and described compound 5 is preferably 0.01～5; Described solvent is 1mL/g～20mL/g with the volume mass of described compound 5 than preferably.As described R ₁₁for C ₁～C ₈straight or branched alkyl time, described C ₁～C ₈the preferred C of straight or branched alkyl ₁～C ₆straight or branched alkyl, further preferably C ₁～C ₄straight or branched alkyl, more further preferably ethyl; As described R ₁₁for C ₁～C ₈cycloalkyl time, described C ₁～C ₈the preferred C of cycloalkyl ₁～C ₆cycloalkyl; As described R ₁₂for C ₁～C ₈straight or branched alkyl time, described C ₁～C ₈the preferred C of straight or branched alkyl ₁～C ₆straight or branched alkyl, further preferably C ₁～C ₄straight or branched alkyl, more further preferably ethyl; As described R ₁₂for C ₁～C ₈cycloalkyl time, described C ₁～C ₈the preferred C of cycloalkyl ₁～C ₆cycloalkyl; Compound shown in described compound 18 is preferably as follows, that is:

Wherein, R ₇for hydrogen atom, or C ₁～C ₆straight or branched alkyl.

Described compound 5 is preferably 0.5～10 with the molar ratio of described compound 18.The time of described reaction is generally 1 hour～24 hours till can no longer carrying out by detection to reaction.The temperature of described reaction is preferably-20 DEG C～80 DEG C.

After making entecavir midbodies compound 4, can also prepare entecavir midbodies compound 3, it comprises the following steps: it comprises the following steps: in solvent, compound 4 is carried out to reduction reaction, obtain compound 3;

Prepare again Entecavir 1;

Wherein R ₂, P ₂and R ₇definition all same as above; R ₆for hydrogen, or one or more C that is selected from ₁～C ₆straight or branched alkoxyl group (preferably methoxyl group), C ₁～C ₆straight or branched alkyl (preferable methyl) and the substituting group of halogen atom (as fluorine, chlorine or bromine).

Prepare the method for above-claimed cpd 3, under the condition preferably existing in acid, carry out; Better can also carry out under the condition of acid and additive existence, described additive is preferably selected from one or more in 2,6 di tert butyl 4 methyl phenol, butylated hydroxy anisole (BHA), butylated hydroxytoluene (BHT), Tenox PG (PG), Tert. Butyl Hydroquinone (TBHQ), Resorcinol and 2.6-dinitro-p-cresol.The effect of described additive is to prevent that raw material, product or its Intermediates from high temperature degrading.

Preparing in the method for above-claimed cpd 3, described preferred solvents be anhydrides preferred solvents described in anhydrides solvent be diacetyl oxide and/or benzoyl oxide;

Preparing in the method for above-claimed cpd 3, the time of described reaction can, by till detecting and no longer carrying out to reaction, be generally 1 hour～72 hours.The temperature of described reaction changes with sour kind, is preferably 20 DEG C～180 DEG C.

In the preferably method of preparing above-claimed cpd 3, described acid is preferably organic acid and/or mineral acid, described organic acid is preferably Glacial acetic acid, described mineral acid is preferably hydrochloric acid, described hydrochloric acid is hydrochloric acid reagent conventional in this area, be generally mass percent and be 1%～37% aqueous hydrochloric acid, the concentrated hydrochloric acid that preferred mass per-cent is 37%, described mass percent refers to that the quality of hydrogenchloride accounts for the per-cent of aqueous hydrochloric acid total mass.Described solvent is 1mL/g～20mL/g with the volume mass of described compound 4 than preferably.In the preferably method of the above-mentioned entecavir midbodies compound 3 of preparation, the molar ratio of described acid and described compound 4 is preferably 1～200.

In the better method of preparing above-claimed cpd 3, the molar ratio of described additive and described compound 4 is preferably 0.1～100, and better is 0.5～30.

After making entecavir midbodies compound 3, can also prepare entecavir midbodies compound 2, it comprises the following steps: in solvent, under sour effect, by compound 3 reaction that is hydrolyzed, obtain compound 2;

Prepare again Entecavir 1;

R ₂definition ditto described in, R ₁for y is for connecting or not connecting substituent 3～9 carbon atoms, thereby forms and replace or the saturated or undersaturated silicon-carbon ring of unsubstituted 4～10 yuan with Si; Or Y, for connecting or not connecting substituently, adds 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: with wherein, R ₃the position of substitution be the position that can replace arbitrarily except Siliciumatom on heterocycle; R ₃can be monosubstituted or polysubstituted, work as R ₃when polysubstituted, substituting group can be identical or different, R ₃be selected from methyl, ethyl, propyl group or sec.-propyl;

In substituting group Ia, n is that 0～2, p is that 0～2, q is that 1～2, X and Y are independently carbon, oxygen or nitrogen separately; In the time that n is 0, X is carbon, and in the time that p is 0, Y is carbon.

Substituting group Ia is preferably following arbitrary substituting group:

P ₂for stable hydroxy-protective group under acidic conditions conventional in this area, in the present invention particularly preferably the C that alkoxyl group replaces ₁～C ₆alkyl (preferably methoxyl methyl or ethoxymethyl) or trimethyl silicane ethoxymethyl; Wherein said alkoxyl group is C ₁～C ₆alkoxyl group, R ₄for one or more substituting groups, R ₅for one or two substituting group, R ₄be selected from hydrogen, halogen, C ₁～C ₆straight or branched alkyl (preferable methyl, ethyl, propyl group, sec.-propyl or the tertiary butyl) and nitro in one or more; R ₅be selected from hydrogen, halogen, C ₁～C ₆straight or branched alkyl (preferable methyl, ethyl, propyl group, sec.-propyl or the tertiary butyl) and nitro in one or two.

Preparing in the method for above-claimed cpd 2, described solvent can be conventional organic solvent and/or water; Described organic solvent can be methylene dichloride, 1,2-ethylene dichloride, tetrahydrofuran (THF), 2-methyltetrahydrofuran, acetonitrile, methyl alcohol, ethanol, Virahol, one or more in toluene and t-butyl methyl ether.Described solvent is 1mL/g～20mL/g with the volume mass of described compound 3 than preferably.Described acid can be protonic acid or Lewis acid, is preferably protonic acid; Described protonic acid is preferably hydrochloric acid, sulfuric acid, trifluoroacetic acid, nitric acid, one or more in methylsulfonic acid and trifluoromethanesulfonic acid; Described Lewis acid is preferably boron trifluoride and/or titanium tetrachloride.Described hydrochloric acid is hydrochloric acid reagent conventional in this area, be generally mass percent and be 1%～37% aqueous hydrochloric acid, preferred mass per-cent is 37% concentrated hydrochloric acid, and described mass percent refers to that the quality of hydrogenchloride accounts for the per-cent of aqueous hydrochloric acid total mass.Described sulfuric acid is sulphate reagent conventional in this area, is generally mass percent and is 1%～98% aqueous sulfuric acid, the vitriol oil that preferred mass per-cent is 98%, and described mass percent refers to that the quality of sulfuric acid accounts for the per-cent of aqueous sulfuric acid total mass.The molar ratio of described acid and described compound 3 is preferably 1～200.The time of described reaction is generally 0.5 hour～24 hours till can no longer carrying out by detection to reaction.The temperature of described reaction changes with sour kind, is preferably 0 DEG C～120 DEG C, and better is 10 DEG C～80 DEG C.

After making entecavir midbodies compound 2, can also prepare Entecavir 1, it comprises the following steps: in solvent, compound 2 is carried out to Tamao-Fleming oxidizing reaction, obtain Entecavir as shown in Equation 1;

Wherein, R ₁for y is for connecting or not connecting substituent 3～9 carbon atoms, thereby forms and replace or the saturated or undersaturated silicon-carbon ring of unsubstituted 4～10 yuan with Si; Or Y, for connecting or not connecting substituently, adds 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

Substituting group Ia is 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) and the pertinent literature quoted in method carry out.

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

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

In solvent, under the effect of alkali and fluorination reagent, compound 2 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.Described solvent is 1mL/g～300mL/g with the volume mass of described compound 2 than preferably, and that better is 3mL/g～100mL/g.Described alkali is preferably one or more in triethylamine, diisopropylethylamine (Hunig base), saleratus, sodium bicarbonate and cesium bicarbonate.The molar ratio of described alkali and described compound 2 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.Described hydrogen peroxide is the aqueous solution of hydrogen peroxide; The concentration of described hydrogen peroxide is preferably mass percent 1%～60%.The molar ratio of described oxygenant and described compound 2 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 molar ratio of described fluorination reagent and described compound 2 is preferably 0.8～30, and better is 1～10.The time of described Tamao-Fleming oxidizing reaction can by detect to reaction no longer carry out till.The temperature of described Tamao-Fleming oxidizing reaction is preferably-20 DEG C～120 DEG C, and better is 0～80 DEG C.

In the present invention, under different acid-base conditions, also can there is tautomer as follows in the structural formula of described Entecavir:

In the present invention, making after Entecavir as shown in Equation 1 by above-mentioned preparation method, can pass through the post processing mode of this area routine, for example add water and be heated at 60 DEG C～100 DEG C, filter (as used diatomite filtration), by filtrate crystallisation by cooling, what get final product with crystal water is entecavir compound prepared, and its structure is as follows:

The preparation method of the compound 6 described in the present invention also provides, it comprises the following steps: in organic solvent, compound 8 is carried out to the reaction of Sharpless chiral epoxy, obtain compound 6;

R ₂and P ₂definition all the same described in, each reaction conditions is with identical described in the above-mentioned method of preparing compound 5.

The present invention also provides compound 2, compound 3, compound 4, compound 5, compound 6, compound 8, compound 9, compound 10 or compound 11;

Wherein, each substituent definition is all same as above.

" alkyl " described in the present invention means the representative examples of saturated aliphatic alkyl of side chain or straight chain, such as " C ₁～C ₃alkyl " refer to that containing carbon number is 1,2 or 3 side chain or the representative examples of saturated aliphatic alkyl of straight chain, for example methyl, ethyl, n-propyl or sec.-propyl.

Generation group after described " alkoxyl group " means alkyl and be connected with Sauerstoffatom, i.e. " RO-", R is alkyl, such as " C ₁～C ₃alkoxyl group " refer to that containing carbon number is the generation group after 1,2 or 3 alkyl is connected with Sauerstoffatom, for example methoxyl group, oxyethyl group, positive propoxy or isopropoxy.

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.

Room temperature in the present invention refers to envrionment temperature, is 10 DEG C～35 DEG C.

Positive progressive effect of the present invention is: preparation method's raw material of the present invention is cheap and easy to get, reaction conditions gentleness, and reaction conversion ratio is high, and post-processing operation is easy, product yield is high, and purity is good, and Atom economy is good, environmental friendliness, production cost is low, 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.

Embodiment 1

Embodiment 1-1 is at compound 2(R ₁for ) add saleratus (260g, 2600mmol), Potassium monofluoride (100g, 1720mmol) in water (6500mL) solution of (30.1g, 86.5mmol).The mixed solution obtaining slowly adds 30% hydrogen peroxide (550g, 4320mmol) under 70 degrees Celsius.Mixed solution after dropwising is incubated and stirs and after 3 hours, adds acetic acid (1150mL) 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 2500mL 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 dry required target compound 121.3g, the yield 89% of being that obtain.

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] ⁺。

According to the identical method Preparation Example 1-2～embodiment 1-4 of embodiment 1-1, specific experiment condition and product structure appraising datum are in table 1.

Table 1 embodiment 1-2 to embodiment 1-4(is except table conditional, and other conditions are with embodiment 1-1)

Embodiment 2

Embodiment 2-1

Compound 3-1(R ₂for p ₂for benzyl) add the vitriol oil (8.2ml, 98%) in methylene dichloride (82mL) solution of (82.0g, 165mmol).The brown liquid obtaining stirs in the aqueous solution that slowly splashes into potassium hydroxide after 2 hours (2M, 1.6L) under 25 degrees Celsius.After the mixed solution evaporate to dryness organic solvent obtaining, add acetic acid to regulate pH=6～7.Filter to collect the solid obtaining and be dried and be required target compound 2-1(R ₁for ) 50g, yield 87%.

¹H?NMR(400MHz,CDCl ₃):δ7.64(s,1H),5.30(s,2H),5.16-5.10(m,1H),3.88-3.72(m,2H),3.56-3.46(m,1H),2.52-2.38(m,1H),2.17-1.92(m,2H),1.90-1.75(m,1H),1.73-1.54(m,4H),1.00-0.70(m,4H);

¹³C?NMR(100MHz,CD ₃OD):δ159.4,155.2,153.9,153.1,129.1,117.4,112.1,63.2,59.7,44.1,30.1,19.5,17.1,8.6,

ESI-MS：348.1[M+H] ⁺。

According to the identical method Preparation Example 2-2～embodiment 2-8 of embodiment 2-1, specific experiment condition and product structure appraising datum are in table 2.

Table 2 embodiment 2-2 to embodiment 2-8(is except table conditional, and other conditions are with embodiment 2-1)

Embodiment 3

Embodiment 3-1

2,6 di tert butyl 4 methyl phenol (100g, 454mmol) adds compound 4-1(R after melting completely under 80 degrees Celsius ₂for p ₂for benzyl, R ₆for hydrogen atom, R ₇for methyl) in aceticanhydride (390mL) solution of (65g, 94mmol), and add Glacial acetic acid (40mL).The mixed solution obtaining stirs after 8 hours and cools to 50 degrees Celsius under 80 degrees Celsius, and adds methyl alcohol (780mL) and salt aqueous acid (6N, 390mL).The mixed solution obtaining stirs after 72 hours and cools to 25 degrees Celsius under 50 degrees Celsius.In the mixed solution obtaining, add n-hexane extraction (300mL × 2).After first alcohol and water mixed phase phase evaporate to dryness organic solvent, add the aqueous solution (3N) of potassium hydroxide to regulate pH=7.Filter to collect the white solid obtaining and be dried and be required target compound 3-1(R ₂for p ₂for benzyl) 38g, yield 82%.

¹H?NMR(400MHz,CDCl ₃):δ8.68(d,1H),7.64(s,1H),7.55-7.26(m,8H),5.30(s,2H),5.16-5.10(m,1H),4.38(s,2H),3.72-3.62(m,2H),3.56-3.46(m,1H),2.72-2.58(m,1H),2.17-1.92(m,2H),1.90-1.75(m,1H),1.73-1.54(m,4H),1.00-0.70(m,2H);

¹³C?NMR(100MHz,CD ₃OD):δ168.2,159.4,155.2,153.9,153.1,150.1,139.6,138.6,133.8,129.5,129.0,128.8,128.6,122.6,117.4,112.1,74.3,73.6,59.7,45.5,34.6,20.8,19.1,7.9;

ESI-MS：499.2[M+H] ⁺。

According to the identical method Preparation Example 3-2～embodiment 3-8 of embodiment 3-1, specific experiment condition and product structure appraising datum are in table 3.

Table 3 embodiment 3-2 to embodiment 3-8(is except table conditional, and other conditions are with embodiment 3-1)

Embodiment 4

Embodiment 4-1

Compound 5-1(R ₂for p ₂for benzyl, R ₆for hydrogen atom) add diethoxy methyl alcohol ethyl ester (12mL, 75mmol) in methylene dichloride (450mL) solution of (45g, 72.3mmol).The reaction solution obtaining adds tosic acid (4.5g, 0.0261mol) under 0 degree Celsius.This reaction solution stirs and after 12 hours, adds saturated sodium bicarbonate aqueous solution (100mL) under 25 degrees Celsius.The organic phase that stratification obtains is after dried over sodium sulfate, and the white solid that evaporate to dryness organic solvent obtains is required target compound 4-1(R ₂for p ₂for benzyl, R ₆for hydrogen atom, R ₇for methyl) 48g, yield 96%.

¹H?NMR(400MHz,CDCl ₃):δ8.68(d,1H),7.55-7.19(m,14H),5.55(s,2H),4.83(s,2H),4.39-4.31(m,3H),3.72-3.52(m,2H),3.35-3.21(m,2H),2.88-2.72(m,1H),2.27-2.16(m,2H),2.01(s,3H),1.75-1.44(m,5H),1.13-0.85(m,2H);

¹³C?NMR(100MHz,CD ₃OD):δ170.3,168.2,161.6,158.4,154.3,150.1,139.6,137.4,135.3,133.8,128.7,128.6,128.6,128.3,128.3,128.2,128.2,122.6,117.8,116.2,82.1,73.7,69.0,68.7,67.6,60.4,46.7,27.8,21.0,20.3,11.4,6.4

ESI-MS：693.3[M+H] ⁺。

According to the identical method Preparation Example 4-2～embodiment 4-8 of embodiment 4-1, specific experiment condition and product structure appraising datum are in table 4.

Table 4 embodiment 4-2 to embodiment 4-8(is except table conditional, and other conditions are with embodiment 4-1)

Embodiment 5

Embodiment 5-1

Compound 6-1(R ₂for p ₂for benzyl, R ₆for hydrogen atom) (130g, 341mmol), DMF 1300mL, adds O-6-benzyl guanine (90.4g, 375mmol) and lithium hydroxide (8.18g, 341mmol).The liquid that is suspended obtaining stirs after 12 hours under 95 degrees Celsius, is concentrated to 200mL 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 (200mL) through 200g filtered through silica gel, and silica gel is through the further drip washing of 1000mL ethyl acetate.Merge all ethyl acetate phase evaporate to dryness organic solvents that leach.The white solid obtaining is required target compound 5-1(R ₂for p ₂for benzyl, R ₆for hydrogen atom) 180g, yield 85%.

¹H?NMR(400MHz,CDCl ₃):δ8.68(d,1H),7.55-7.19(m,14H),5.55(s,2H),5.00(s,1H),4.83(s,2H),4.74-4.64(m,1H),4.33(d,2H),4.26-4.17(m,1H),3.55-3.37(m,2H),3.35-3.21(m,2H),2.88-2.72(m,1H),2.27-2.16(m,2H),1.75-1.44(m,5H),1.13-0.85(m,2H);

¹³C?NMR(100MHz,CD ₃OD):δ168.2,161.6,158.4,154.3,150.1,139.6,137.4,135.3,133.8,128.7,128.6,128.6,128.3,128.3,128.2,128.2,122.6,116.2,82.2,73.7,69.0,68.4,65.3,62.9,48.7,20.3,20.2,11.4,6.1

ESI-MS：623.3[M+H] ⁺。

According to the identical method Preparation Example 5-2～embodiment 5-8 of embodiment 5-1, specific experiment condition and product structure appraising datum are in table 5.

Table 5 embodiment 5-2 to embodiment 5-8(is except table conditional, and other conditions are with embodiment 5-1)

Embodiment 6

Embodiment 6-1

In 2100mL methylene dichloride, add tetraisopropoxy titanium (64mL, 223mmol) and be cooled to subzero 30 degrees Celsius.Add compound 8-1(R in this solution the inside ₂for p ₂for benzyl) (409g, 1.12mol) and (2S, 3S)-tartrate diisopropyl ester (62g, 265mmol).The mixed solution obtaining slowly adds anhydrous peroxy tert-butyl alcohol (toluene solution of 2.5M, 500mL) stir 1 hour under subzero 30 degrees Celsius after.Keep temperature of reaction after 3 hours, in reaction solution, slowly to add Sulfothiorine (2M, 350mL) 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 × 2), 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 white powder that evaporate to dryness organic solvent obtains is required target compound intermediate 6-1(R ₂for p ₂for benzyl) 380g, yield 89%.

¹H?NMR(400MHz,CDCl ₃):δ8.68(d,1H),7.55-7.26(m,8H),4.43(s,2H),3.72(s,1H),3.47(s,1H),3.33-3.27(m,2H),3.05(d,1H),2.66(t,1H),2.38-2.26(m,1H),1.91-1.85(m,2H),1.73-1.54(m,4H),1.00-0.70(m,2H);

¹³C?NMR(100MHz,CD ₃OD):δ168.2,150.1,138.6,133.8,129.5,129.0,128.8,128.6,122.6,81.7,73.8,73.3,61.8,61.2,43.1,21.8,20.8,7.2,-1.3;

ESI-MS：382.2[M+H] ⁺。

According to the identical method Preparation Example 6-2～embodiment 6-8 of embodiment 6-1, specific experiment condition and product structure appraising datum are in table 6.

Table 6 embodiment 6-2 to embodiment 6-8(is except table conditional, and other conditions are with embodiment 6-1)

Embodiment 7

Embodiment 7-1

Compound 9-1(R ₂for p ₁for p ₂for benzyl) 123g(0.28mol) be dissolved in 600mL ethanol, and add tosic acid 6g(0.0348mol).The reaction solution obtaining stirs after 12 hours and cools to 0 degree Celsius under 25 degrees Celsius, and adds 100mL saturated sodium bicarbonate aqueous solution.After the mixed solution evaporate to dryness methyl alcohol obtaining, extract by t-butyl methyl ether (200mL × 3).Merge organic phase process dried over sodium sulfate.The white powder obtaining after evaporate to dryness organic solvent is required target compound intermediate 8-1(R ₂for p ₂for benzyl) 90g, yield 88%.

¹H?NMR(400MHz,CDCl ₃):δ8.68(d,1H),7.55-7.26(m,8H),5.57(s,1H),4.43(s,2H),4.18-4.00(m,2H),3.33-3.27(m,2H),3.16(t,1H),2.98-2.86(m,1H),2.53-2.39(m,1H),2.33-2.20(m,1H),1.73-1.54(m,4H),1.00-0.70(m,2H);

¹³C?NMR(100MHz,CD ₃OD):δ168.2,150.1,139.6,138.6,133.8129.5,129.0,128.8,128.6,126.1,122.6,78.3,73.9,61.5,47.1,30.2,28.6,10.5,7.5;

ESI-MS：366.2[M+H] ⁺。

According to the identical method Preparation Example 7-2～embodiment 7-8 of embodiment 7-1, specific experiment condition and product structure appraising datum are in table 7.

Table 7 embodiment 7-2 to embodiment 7-8(is except table conditional, and other conditions are with embodiment 7-1)

Embodiment 8

Embodiment 8-1

Compound 10-1(R ₂for p ₁for ) 134g(0.39mol) be dissolved in 2000mLDMF(N, dinethylformamide) in, add sodium hydrogen (quality percentage composition 60% be scattered in the sodium hydride in mineral oil, 18.7g, 0.47mol), cool to 0 degree Celsius and drip benzyl bromine 55.2mL(0.2241mol).After dripping off, keeping below 5 degrees Celsius of reactions spends the night.Slowly add 2000mL cancellation reaction.The mixed solution obtaining extracts through 2000mL × 2 ethyl acetate, the ethyl acetate merging is through dried over sodium sulfate after washing (1000mL × 2) and saturated aqueous common salt (1000mL) washing, and the scarlet oily liquids that evaporate to dryness organic solvent obtains is required target compound intermediate 9-1(R ₂for p ₁for p ₂for benzyl) 157g, yield 92%.

¹H?NMR(400MHz,CDCl ₃):δ8.68(d,1H),7.55-7.26(m,8H),5.57(s,1H),4.43(s,2H),4.02-3.84(m,2H),3.33-3.27(m,2H),3.20-3.15(m,4H),2.98-2.86(m,1H),2.53-2.39(m,1H),2.33-2.20(m,1H),1.73-1.54(m,4H),1.31(s,6H),1.00-0.70(m,2H);

¹³C?NMR(100MHz,CD ₃OD):δ168.2,150.1,142.2,138.6,133.8129.5,129.0,128.8,128.6,122.6,119.5,100.2,78.3,73.9,66.1,48.5,42.8,28.6,24.5,20.8,10.5,7.5;

ESI-MS：438.2[M+H] ⁺。

According to the identical method Preparation Example 8-2～embodiment 8-8 of embodiment 8-1, specific experiment condition and product structure appraising datum are in table 8.

Table 8 embodiment 8-2 to embodiment 8-8(is except table conditional, and other conditions are with embodiment 8-1)

Embodiment 9

Embodiment 9-1

Compound 11-1(R ₂for r ₁₀for methyl, P ₁for ) 155g(0.41mol) be dissolved in 2800mL toluene, maintain 5 degrees Celsius of lower diisobutyl aluminium hydrides (toluene solution of 2M, 1L), under 5 degree, react 2 hours, saturated solution of sodium bicarbonate 1500mL slowly splashes under stirring, the mixed solution obtaining phase-splitting after diatomite filtration.Toluene extraction (700mL × 3) for water, merges all toluene phases that obtain, and the pale yellow oily liquid body that evaporate to dryness organic solvent obtains is required target compound intermediate 10-1(R ₂for r ₁₀for methyl, P ₁for ) 122g, yield 86%.

¹H?NMR(400MHz,CDCl ₃):δ8.68(d,1H),7.55-7.26(m,3H),5.78(s,1H),4.15-4.05(m,1H),3.84-3.75(m,1H),3.68-3.55(m,1H),3.42-3.31(m,2H),3.25-3.09(m,4H),2.85-2.71(m,1H),2.59-2.42(m,1H),2.32-2.17(m,1H),1.83-1.54(m,4H),1.31(s,6H),1.15-0.81(m,2H);

¹³C?NMR(100MHz,CD ₃OD):δ168.2,150.1,142.2,133.8,128.6,122.6,119.5,100.2,66.1,64.9,48.5,45.0,28.7,24.5,20.8,11.1,7.3;

ESI-MS：348.2[M+H] ⁺。

According to the identical method Preparation Example 9-2～embodiment 9-8 of embodiment 9-1, specific experiment condition and product structure appraising datum are in table 9.

Table 9 embodiment 9-2 to embodiment 9-8(is except table conditional, and other conditions are with embodiment 9-1)

Embodiment 10

Embodiment 10-1, wherein R ₂for r ₁₀for methyl

Compound 12-1(R ₂for r ₁₀for methyl) 109g(0.358mol) be dissolved in 1200mL toluene, add 4.4g(0.0256mol) tosic acid, drip 2-methoxyl group propylene 257g(3.564mol after being cooled to 0 degree Celsius).Temperature control below 5 degrees Celsius, stirring reaction 3 hours.Add saturated solution of sodium bicarbonate 1000mL, after phase-splitting, water extracts through toluene (400mL × 2).The toluene merging is through saturated nacl aqueous solution washing, and evaporate to dryness toluene obtains weak yellow liquid and is required target compound intermediate 11-1(R ₂for r ₁₀for methyl, P ₁for ) 128g, yield 95%.

¹H?NMR(400MHz,CDCl ₃):δ8.68(d,1H),7.55-7.26(m,3H),5.78(s,1H),3.92(s,2H),3.61(s,3H),3.51-3.42(m,1H),3.15(s,3H),2.69-2.55(m,1H),2.39-2.24(m,1H),2.13-2.00(m,1H),1.83-1.54(m,4H),1.31(s,6H),1.15-0.81(m,2H);

¹³C?NMR(100MHz,CD ₃OD):δ170.1,168.2,150.1,133.8,128.6,126.1,122.6,120.1，100.2,64.3,52.4,48.5,47.1,28.1,24.5,20.8,10.2,6.9;

ESI-MS：376.2[M+H] ⁺。

According to the identical method Preparation Example 10-2～embodiment 10-8 of embodiment 10-1, specific experiment condition and product structure appraising datum are in table 10.

Table 10 embodiment 10-2 to embodiment 10-8(is except table conditional, and other conditions are with embodiment 10-1)

Embodiment 11

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

Embodiment 11-1

R ₂= r ₁₀for methyl.

At compound 13-1(520g, 1.80mol) be dissolved in 2600 milliliters of Virahols, 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 × 2).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 12-1(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] ⁺。

According to the identical method Preparation Example 11-2～embodiment 11-18 of embodiment 11-1, specific experiment condition and product structure appraising datum are in table 11.

Table 11 embodiment 11-2 to 11-18(is except table conditional, and other conditions are with embodiment 11-1)

Embodiment 12

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:

Embodiment 12-1

R ₂＝

At compound 14-1(505g, 1.76mol as shown in above formula) be dissolved in 2600 milliliters of ethanol and add in batches sodium borohydride (66.9g, 1.76mol).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 × 3).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 13-1(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] ⁺。

According to the identical method Preparation Example 12-2～embodiment 12-18 of embodiment 12-1, specific experiment condition and product structure appraising datum are in table 12.

Table 12 embodiment 12-2 to 12-18(is except table conditional, and other conditions are with embodiment 12-1)

Embodiment 13

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

Embodiment 13-1

R ₂＝

At starting material compound 15-1(723g, 2.52mol as shown in above formula) be dissolved in 2600 milliliters of ethanol 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 × 3) 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 14-1(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] ⁺。

According to the identical method Preparation Example 13-2～embodiment 13-18 of embodiment 13-1, specific experiment condition and product structure appraising datum are in table 13.

Table 13 embodiment 13-2 to 13-18(is except table conditional, and other conditions are with embodiment 13-1)

Embodiment 14

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

Embodiment 14-1

R ₂=

At starting material compound 16-1(491g, 1.52mol as shown in above formula) the trimethyl carbinol (982g) and water (1960g) mixing solutions in splash into triethylamine 706g under 25 degrees Celsius.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 X 3).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 15-1(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] ⁺。

According to the identical method Preparation Example 14-2～embodiment 14-18 of embodiment 14-1, specific experiment condition and product structure appraising datum are in table 14.

Table 14 embodiment 14-2 to 14-18(is except table conditional, and other conditions are with embodiment 14-1)

Embodiment 15

Embodiment 15-1

R ₂=

Be dissolved in 1800ml normal hexane at starting material compound 17-1 254g (1.19 mol) as shown in above formula, be cooled to 0 degree Celsius, add dichloroacetyl chloride (390.5g, 2.65 mol), 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 (500mlX3) 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 16-1(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] ⁺。

According to the identical method Preparation Example 15-2～embodiment 15-18 of embodiment 15-1, specific experiment condition and product structure appraising datum are in table 15.

Table 15 embodiment 15-2 to 15-18(is except table conditional, and other conditions are with embodiment 15-1)

Embodiment 16

Example 16-1

R ₂=

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 × 3) 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, filtration, is spin-dried for organic solvent and obtains oily sorrel liquid and be required target compound 17-1(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] ⁺

According to the identical method Preparation Example 16-2～embodiment 16-18 of embodiment 16-1, specific experiment condition and product structure appraising datum are in table 16.

Table 16 embodiment 16-2 to 16-18(is except table conditional, and other conditions are with example 16-1)

Embodiment 17 R ₂x 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?Chemistry?2006,?76,?1261

Chemische?Berichte?1915,?48,?1238

Journal?of?Organometallic?Chemistry?1975,?86,?197

Journal?of?the?American?Chemical?Society?1946,?68,?485

Journal?of?the?American?Chemical?Society?2010,?132,?8270

Its ultimate principle can be represented by following signal formula:

Wherein R-21 is corresponding aromatic ring yl lithium compound.Wherein W ₁, W ₂be respectively independently-MgBr or-MgCl.

Embodiment 17-1

R ₂=

Synthetic method one

Step 1: keep subzero 40 to drip butyllithium (2.5M hexane solution, 4200 mL) to subzero 50 degrees Celsius in tetrahydrofuran (THF) (4600mL) solution of 2-chloropyridine (1.15 Kg, 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 silicon tetrachloride (1.7 Kg, 10 mol) 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%).

Embodiment 17-1

Synthetic method two

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%).

R ₂=

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

According to the identical method Preparation Example 17-2～embodiment 17-18 of embodiment 17-1, specific experiment condition and product structure appraising datum are in table 17.

Table 17 embodiment 17-2 to 17-18(is except table conditional, and other conditions are with method one or the method two of example 17-1)

Claims

1. a preparation method for entecavir midbodies compound 5, is characterized in that comprising the following steps: in aprotic organic solvent, compound 6 and compound 7 are carried out to ring-opening reaction, obtain compound 5;

Wherein, R ₂substituting group for as follows:

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 substituent 3～9 carbon atoms, thereby forms and replace or the saturated or undersaturated silicon-carbon ring of unsubstituted 4～10 yuan with Si; Or Y, for connecting or not connecting substituently, adds 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 two rings together;

P ₂for the C that alkoxyl group replaces ₁～C ₆alkyl or trimethyl silicane ethoxymethyl; Wherein said alkoxyl group is C ₁～C ₆alkoxyl group, R ₄for one or more substituting groups, R ₅for one or two substituting group, R ₄be selected from hydrogen, halogen, C ₁～C ₆straight or branched alkyl and nitro in one or more; R ₅be selected from hydrogen, halogen, C ₁～C ₆straight or branched alkyl and nitro in one or two;

R ₆for hydrogen, or one or more C that is selected from ₁～C ₆straight or branched alkoxyl group, C ₁～C ₆straight or branched alkyl and the substituting group of halogen atom.

2. the preparation method of entecavir midbodies compound 5 as claimed in claim 1, is characterized in that: described R ₂for following arbitrary substituting group:

or

In substituting group IIa, n is that 0～2, p is that 0～2, q is that 1～2, X and Y are independently carbon, oxygen or nitrogen separately, R ₃for monosubstituted or polysubstituted, work as R ₃when polysubstituted, substituting group is identical or different, R ₃be selected from methyl, ethyl, propyl group or sec.-propyl; In the time that n is 0, X is carbon, and in the time that p is 0, Y is carbon.

3. the preparation method of entecavir midbodies as claimed in claim 2, is characterized in that: described substituting group IIa is following arbitrary substituting group:

4. the preparation method of entecavir midbodies compound 5 as claimed in claim 1, is characterized in that: described R ₂₁for following arbitrary substituting group:

5. the preparation method of entecavir midbodies compound 5 as claimed in claim 1, is characterized in that:

As described P ₂for the C of alkoxyl group replacement ₁～C ₆alkyl time, the C that described alkoxyl group replaces ₁～C ₆alkyl be methoxyl methyl or ethoxymethyl;

As described R ₄for C ₁～C ₆straight or branched alkyl time, described C ₁～C ₆straight or branched alkyl be methyl, ethyl, propyl group, sec.-propyl or the tertiary butyl;

As described R ₅for C ₁～C ₆straight or branched alkyl time, described C ₁～C ₆straight or branched alkyl be methyl, ethyl, propyl group, sec.-propyl or the tertiary butyl.

6. the preparation method of entecavir midbodies compound 5 as claimed in claim 1, is characterized in that:

As described R ₆for C ₁～C ₆straight or branched alkoxyl group time, described C ₁～C ₆straight or branched alkoxyl group be methoxyl group;

As described R ₆for C ₁～C ₆straight or branched alkyl time, described C ₁～C ₆straight or branched alkyl be methyl;

As described R ₆during for halogen atom, described halogen atom is fluorine, chlorine or bromine.

7. the preparation method of the entecavir midbodies compound 5 as described in claim 1～6, is characterized in that: under the condition that described ring-opening reaction exists at alkali, carry out; Described alkali is lithium hydroxide and/or lithium hydride; The molar ratio of described alkali and described compound 6 is 0.01～10.

8. the preparation method of entecavir midbodies compound 5 as claimed in claim 7, is characterized in that: the molar ratio of described alkali and described compound 6 is 0.05～5.

9. the preparation method of entecavir midbodies compound 5 as claimed in claim 1, is characterized in that: described aprotic organic solvent is DMF, dimethyl sulfoxide (DMSO), acetonitrile, tetrahydrofuran (THF), one or more in N-Methyl pyrrolidone and 2-methyltetrahydrofuran; Described compound 7 is 0.5～10 with the molar ratio of described compound 6; The temperature of described ring-opening reaction is 0～150 DEG C.

10. the preparation method of the entecavir midbodies compound 5 as described in claim 1 or 9, is characterized in that: described compound 7 is 1～3 with the molar ratio of described compound 6; The temperature of described ring-opening reaction is 25 DEG C～120 DEG C.

The preparation method of 11. entecavir midbodies compounds 5 as claimed in claim 1, it is characterized in that: by the described compound 6 of following method preparation, the method of the compound 6 described in preparation comprises the following steps: in organic solvent, compound 8 is carried out to the reaction of Sharpless chiral epoxy, obtain compound 6;

Prepare described compound 5 according to preparation method claimed in claim 1 again;

Wherein, P ₂definition as described in claim 1 or 5; R ₂definition as described in claim 1～4 any one.

The preparation method of 12. entecavir midbodies compounds 5 as claimed in claim 11, it is characterized in that: the reaction of preparing compound 6 comprises the following steps: in organic solvent, under the effect of tetraisopropoxy titanium and chiral ligand, compound 8 and superoxide are carried out to the reaction of Sharpless chiral epoxy, obtain compound 6.

The preparation method of 13. entecavir midbodies compounds 5 as claimed in claim 12, is characterized in that: preparing in the method for compound 6, described organic solvent is methylene dichloride and/or 1,2-ethylene dichloride; Described chiral ligand is (2S, 3S)-diethyl tartrate or (2S, 3S)-tartrate diisopropyl ester; The molar ratio of described chiral ligand and described compound 8 is 0.0001～1; The molar ratio of described tetraisopropoxy titanium and described compound 8 is 0.0001～1; Described superoxide is one or more in peroxy tert-butyl alcohol, hydrogen peroxide, Peracetic Acid and metachloroperbenzoic acid; The molar ratio of described superoxide and described compound 8 is 0.5～10; The temperature of described chiral epoxy reaction is preferably-78 DEG C～25 DEG C.

The preparation method of 14. entecavir midbodies compounds 5 as claimed in claim 13, is characterized in that: preparing in the method for compound 6, the molar ratio of described chiral ligand and described compound 8 is 0.001～0.3; The molar ratio of described tetraisopropoxy titanium and described compound 8 is 0.001～0.3; The molar ratio of described superoxide and described compound 8 is 1～5; The temperature of described chiral epoxy reaction is-60 DEG C～0 DEG C.

The preparation method of 15. 1 kinds of entecavir midbodies compounds 6, is characterized in that comprising the following steps: in organic solvent, compound 8 is carried out to the reaction of Sharpless chiral epoxy, obtain compound 6;

Wherein, P ₂definition as described in claim 1 or 5; R ₂definition as described in claim 1～4 any one, reaction conditions is as described in claim 11～14 any one.

16. 1 kinds suc as formula 6 or compound as shown in Equation 8,