CN103739603B - Preparation method of entecavir - Google Patents
Preparation method of entecavir Download PDFInfo
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- CN103739603B CN103739603B CN201310736913.5A CN201310736913A CN103739603B CN 103739603 B CN103739603 B CN 103739603B CN 201310736913 A CN201310736913 A CN 201310736913A CN 103739603 B CN103739603 B CN 103739603B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
Abstract
The invention belongs to the technical field of pharmaceutical preparation, and specifically relates to a preparation method of a hepatitis B therapeutic entecavir. The method comprises the following steps: (1) under a nitrogen condition, carrying out reaction on Zn, tetrahydrofuran and CH2Br2 to obtain a NYSted reagent; (2) adding Ente-8, CH2Cl2 and NYSted into a reaction pot to prepare Ente-9; (3) adding THF (Tetrahydrofuran), CeRh2Ga, methanol and Ente-9 into a reaction bottle, stirring and adding HCl(3N) to obtain Ente-10; and (4) adding Ente-10 and dichloromethane into the reaction pot, dropwise adding CH2Cl2 liquor of BCl3, carrying out reaction to obtain an Entecavir coarse product, and refining to obtain a pure product. Compared with the prior art, the preparation method of entecavir provided by the invention has the characteristics of high yield, good product purity, simple operation of posttreatment, environment-friendliness, adaptability to industrialized product and the like.
Description
Technical field
The invention belongs to technical field of medicine preparation, it particularly relates to the preparation side of a kind of hepatitis B therapeutic medicament entecavir
Method.
Background technology
Whole world hepatitis B virus surface antigen (HBsAg) positive about 3.5 hundred million, is distributed mainly on Asia, Africa and Latin America
Area.China HBsAg (+) person there are about 1.2 hundred million, wherein 30,000,000 is Chronic Hepatitis B.The chronic viral hepatitis B of 10%～30%
Patient can develop into liver cirrhosis through 10-30, and the patient of about 1%～5% can develop into hepatocarcinoma through 20～40 years.According to statistics, entirely
Ball there are about 800,000 people every year, and to die from HBV infection diseases related, accounts for the 9th of disease death reason.HBsAg (+) mother
Parent can make infections in infants HBV by vertical transmission, and wherein more than 90% becomes chronic HBsAg carriers, thus serious shadow
Ring follow-on health.Therefore, effectively treat chronic viral hepatitis B, reduce the task of top priority that HBV infection rate is for we.
Entecavir chemical name is 2-amino-1,9-dihydro-9-[(1S, 3R, 4S)-4-hydroxyl-3-(methylol)-2-methylene ring penta
Base]-6H-purine-6-one, belong to guanosine analog, inhibited to hepatitis B virus (HBV) polymerase.Its energy
Enough becoming active triphosphate by phosphorylation, triphosphate is 15 hours in the intracellular half-life.By with HBV
The natural substrate triphosphoric acid NSC 22837 competition of polymerase, Entecavir triphosphate can suppress virus polymerase (to reverse
Record enzyme) all three activity: 1) startup of HBV polymerase；2) formation of pregenomic mRNA reverse transcription minus strand；3)
The synthesis of HBV DNA normal chain.Entecavir triphosphate is 0.0012 μM to the inhibition constant (Ki) of HBV DNA polymerase,
α, β, δ DNA polymerase and mitochondrion γ DNA polymerase inhibitory action to cell are more weak, and Ki value is 18 as 160 μMs.
Transfecting the mankind HepG of wild type hepatitis B virus2In cell, Entecavir presses down 50% viral DNA synthesis desired concn
(EC50) it is 0.004 μM.Grace replaces the Wei EC to lamivudine resistance Strain50Median be 0.26 μM.To North America soil
Dialling studying for a long period of time of Mus to show, Weekly administration 0.5mg/kg Entecavir (being equivalent to the dosage of human body 1.0mg) can be by therein
It is lower up to 3 years as long as that the viral DNA of 3 marmots is maintained at detection limit.The animal of 3 years it is up in the treatment of this medicine of any use
In, do not find the change of HBV polymerase generation drug resistance dependency.In vitro study: find in test cell line, lamivudine
Entecavir is afraid of that phenotype sensitivity reduces by 8 to 30 times by the Strain of drug resistance.
Owing to Entecavir has plurality of advantages, it is widely used to the treatment of the diseases such as hepatocarcinoma, under existing preparation method also
Seem that supply falls short of demand.Chinese patent (CN101781301A) provides for a kind of method preparing Entecavir, to reducing
Pollute.But its effect is not the most notable, and especially productivity is the highest, and purity is poor.
Summary of the invention
In order to solve above-mentioned technical problem, the invention provides a kind of yield high, good product purity, post-processing operation is simple, ring
Border is friendly, is suitable for the preparation method of the Entecavir of industrialized production.
The preparation method of Entecavir of the present invention, concretely comprising the following steps of described method:
1) under nitrogen atmosphere, Zn is joined in oxolane, be cooled to-40 DEG C, add CH2Br2, insulation, stirring
Lower addition TiCl4, warm naturally to 5 DEG C, insulation reaction 4 days, obtain NYSted reagent；
2) nitrogen protection, at room temperature adds (2R, 3S, 5S)-5-[2-[[(4-methoxyphenyl) benzhydryl] ammonia in reactor
Base]-6-benzyloxy-9H-purine-9-base]-3-benzyloxy-2-[(benzyloxy) methyl] Ketocyclopentane and anhydrous CHCl3, add anhydrous three
Ethamine, Li, 4-methoxyl group-triphenylchloromethane and dimethylamino naphthyridine, stirring, 20 DEG C of lucifuge reaction 24h, silica gel column chromatography,
Obtain Ente-8；
3) under nitrogen atmosphere, in retort, Ente-8 and CH is added2Cl2, stirring, add NYSted reagent, room temperature
Stirring reaction 5h, joins in the mixed solution of saturated sodium bicarbonate and chloroform by reactant liquor, stirring 30min, centrifuge,
Separatory, water layer chloroform extraction three times, merge organic layer, wash three times with saturated nacl aqueous solution, anhydrous sodium sulfate is dried,
Filtering, rotation is evaporated off solvent and obtains residue, and column chromatography is refining to obtain Ente-9；
4) in reaction bulb, add THF, methanol and Ente-9, stirring, add HCl, be heated to 50 DEG C, react 1h, instead
Should be complete, it is down to room temperature, is 7 with NaOH regulation pH value, extracts 3 times by ethyl acetate, merge organic layer, with saturated
Sodium chloride solution washs 3 times, and anhydrous sodium sulfate is dried, and filters, and rotation is evaporated off solvent and obtains residue, pulls an oar to obtain Ente-10 with ether；
5) under nitrogen atmosphere, in retort, add Ente-10 and dichloromethane, stirring, be cooled to-80 DEG C, drip BCl3
CH2Cl2Solution, is warming up to-40 DEG C, reacts 3h, after reaction terminates, drips methanol, and rotation is evaporated off solvent and obtains Entecavir
Crude product, refined, produce sterling.
The preparation method of Entecavir of the present invention, the concrete preparation method of described NYSted reagent is: at the atmosphere of nitrogen
Under enclosing, 68.9g Zn is joined in 0.6L oxolane, be cooled to-40 DEG C, add 24mL CH2Br2, insulation, stirring
Lower addition 24mL TiCl4, warm naturally to 5 DEG C, insulation reaction 4 days, prepare product.
The preparation method of Entecavir of the present invention, the concrete preparation method of described Ente-8 is: protect at nitrogen, room temperature
Lower toward addition 40g (2R, 3S, 5S)-5-[2-[[(4-methoxyphenyl) benzhydryl] amino]-6-benzyloxy in 500mL two neck flask
-9H-purine-9-base]-3-benzyloxy-2-[(benzyloxy) methyl] Ketocyclopentane and anhydrous 400mL CHCl3, add 16mL anhydrous three
Ethamine, 2g Li, 27g 4-methoxyl group-triphenylchloromethane and 2g dimethylamino naphthyridine, magnetic agitation, 20 DEG C of lucifuge reaction 24h；
Add 10mL anhydrous triethylamine, 13.8g 4-methoxyl group-triphenylchloromethane and 0.9g dimethylamino naphthyridine, then room temperature lucifuge is anti-
Answer 12h, TLC monitoring reaction completely；It is concentrated to give weak yellow foam shape solid, silica gel column chromatography, concentrates, be vacuum dried to produce
Product.
The preparation method of Entecavir of the present invention, the concrete preparation method of described Ente-9 is: under nitrogen atmosphere, to
Retort adds 30g Ente-8 and 0.6LCH2Cl2, stirring, add 0.6L NYSted reagent, reaction 5h is stirred at room temperature,
Reactant liquor is joined in the mixed solution of 1.3L saturated sodium bicarbonate and 1.3L chloroform, stir 30min.Centrifuge,
Separatory, water layer each 0.41L chloroform extraction three times, merge organic layer, with each 0.68L saturated nacl aqueous solution washing three
Secondary, anhydrous sodium sulfate is dried, and filters, and rotation is evaporated off solvent and obtains residue, and column chromatography is refining to obtain product.
The preparation method of Entecavir of the present invention, the concrete preparation method of described Ente-10 is: add in reaction bulb
190mL oxolane, 1.2g CeRh2Ga, 190mL methanol and 18.9g Ente-9, stirring, add 3mol/l HCl 95ml,
Being heated to 50 DEG C, react 1h, react complete, be down to room temperature, regulating pH value with the NaOH of 1mol/l is 7, with every time
3L ethyl acetate is extracted 3 times, merges organic layer, washs 3 times with each 300ml saturated nacl aqueous solution, and anhydrous sodium sulfate is done
Dry, to filter, rotation is evaporated off solvent and obtains residue, pulls an oar to obtain product with ether.
The preparation method of Entecavir of the present invention, the concrete preparation method of described Entecavir is: under nitrogen atmosphere,
In retort, add 6.9g Ente-10,207mL dichloromethane, stirring, be cooled to-80 DEG C, drip 1.2mol/l BCl3's
Dichloromethane solution 138mL, is warming up to-40 DEG C, reacts 3h, after reaction terminates, drips 1.04L methanol, and rotation is evaporated off molten
Agent obtains thick product.
The preparation method of Entecavir of the present invention, described Entecavir is to deposit with anhydrous form or the form containing water of crystallization
?.
Compared with prior art, it is high that the preparation method of Entecavir of the present invention has yield, good product purity, post processing
Simple to operate, environmental friendliness, it is suitable for the features such as industrialized production.
Detailed description of the invention
Below in conjunction with specific embodiment, preparation method of the present invention is described further, but protection scope of the present invention
It is not limited to this.
Embodiment 1
The preparation of NYSted reagent (zinc-titanium tetrachloride-methylene bromide complex): under the atmosphere of nitrogen, 68.9g Zn is added
Enter in 0.6L THF (oxolane), be cooled to-40 DEG C, add 24mL CH2Br2.Insulation, adds 24mL under stirring
TiCl4.Warm naturally to 5 DEG C, insulation reaction 4 days, stand-by (attention: in course of reaction, THF is readily volatilized, need to suitably mend
Add THF).TLC detection (chloroform: methanol=5:1) reacts complete.
The preparation of Ente-8: nitrogen is protected, adds (2R, 3S, 5S)-5-[2-[[(4-methoxyl group under room temperature in 500mL two neck flask
Phenyl) benzhydryl] amino]-6-benzyloxy-9H-purine-9-base]-3-benzyloxy-2-[(benzyloxy) methyl] Ketocyclopentane (40g) and anhydrous
CHCl3(400mL) anhydrous triethylamine (16mL), Li (2g), 4-methoxyl group-triphenylchloromethane (27g) and dimethylamino, are added
Pyridine (2g), magnetic agitation, 20 DEG C of lucifuge reaction 24h.Add anhydrous triethylamine (10mL), 4-methoxyl group-triphenylchloromethane
(13.8g) with dimethylamino naphthyridine (0.9g), then reaction 12h, the TLC monitoring of room temperature lucifuge (silica gel plate triethylamine pretreatment,
V(CHC13)/(CH3OH)=50/1, add 2 triethylamines) reaction is completely.It is concentrated to give 69g weak yellow foam shape solid, silicagel column
Chromatography (petroleum ether and ethyl acetate by volume ratio 5/1,3/1 are the quick eluting of eluant respectively), concentrates, is vacuum dried
40.3g white solid, i.e. Ente-8.
Ente-9 (2-[(4-methoxyphenyl) (diphenyl) methyl] amino-6-benzyloxy-9 hydrogen-9-{ (1S, 3R, 4S) 4-benzyloxy-3-[(4-
Methoxyphenyl) (diphenyl) methoxyl group] methyl-2-methene-cyclopenta-purine) preparation: under nitrogen atmosphere, to reaction
Tank adds 30g Ente-8 and 0.6LCH2Cl2, stirring, add 0.6L NYSted reagent, reaction 5h is stirred at room temperature, will be anti-
Answer liquid to join in the mixed solution of 1.3L saturated sodium bicarbonate and 1.3L chloroform, stir 30min.Centrifuge, separatory,
Water layer each 0.41L chloroform extraction three times, merges organic layer, with each 0.68L saturated nacl aqueous solution washing three times.Nothing
Aqueous sodium persulfate is dried, and filters, and rotation is evaporated off solvent and obtains residue, and column chromatography is refining to obtain 19g product, yield about 65%.
Ente-10 (2-amino-1,9-dihydro-9-[(1S, 3R, 4S)-4-benzyloxy-3-(methylol)-2-methylene cyclopenta]-6H-purine-6-
Ketone) preparation: in reaction bulb add 190mL THF, 190mL methanol and 18.9g Ente-9, stirring, add 95ml HCl (3
Mol/l), it is heated to 50 DEG C, reacts 1h.React complete.Being down to room temperature, regulating pH value with the NaOH of 1mol/l is 7.
Extract 3 times by each 3L ethyl acetate.Merge organic layer, wash 3 times with each 300ml saturated nacl aqueous solution.Anhydrous
Sodium sulfate is dried, and filters, and rotation is evaporated off solvent and obtains residue, pulls an oar to obtain 5.1g product with ether, yield about 65%.
Entecavir (2-amino-1,9-dihydro-9-[(1S, 3R, 4S)-4-hydroxyl-3-(methylol)-2-methylene cyclopenta]-6H-purine-6-
Ketone) preparation: under nitrogen atmosphere, in retort add 4.9g Ente-10,148mL dichloromethane, stirring.Cooling
To-80 DEG C, drip 1.2mol/l BCl3Dichloromethane solution 138mL.It is warming up to-40 DEG C, reacts 3h.After reaction terminates,
Dropping 0.84L methanol, rotation is evaporated off solvent and obtains thick product 2.94g.Yield about 70%.
Refining of product: in reaction bulb, adds 2.9g Entecavir crude product, adds 56mL deionized water, adds 0.25g
Activated carbon, temperature rising reflux 30min, while hot sucking filtration, filtrate is slowly stirred down, natural cooling, separates out solid, sucking filtration, filter cake
Entecavir fine work 2.2g is obtained, detection in 30 DEG C of drying under reduced pressure.Elementary analysis consists of Cl2H15N5O3·H2O； (C=1, DMF: methanol=50:50)；MS:[M+H]+=m/z 278, [M+Na]+=m/z 300.Concrete data ginseng
Be shown in Table 1, table 2, table 3.
Embodiment 2
The preparation of NYSted reagent (zinc-titanium tetrachloride-methylene bromide complex): under the atmosphere of nitrogen, 68.9g Zn is added
Enter in 0.6L THF (oxolane), be cooled to-40 DEG C, add 24mL CH2Br2.Insulation, adds 24mL under stirring
TiCl4.Warm naturally to 5 DEG C, insulation reaction 4 days, stand-by (attention: in course of reaction, THF is readily volatilized, need to suitably mend
Add THF).TLC detection (chloroform: methanol=5:1) reacts complete.
The preparation of Ente-8: nitrogen is protected, adds (2R, 3S, 5S)-5-[2-[[(4-methoxyl group under room temperature in 500mL two neck flask
Phenyl) benzhydryl] amino]-6-benzyloxy-9H-purine-9-base]-3-benzyloxy-2-[(benzyloxy) methyl] Ketocyclopentane (40g) and anhydrous
CHCl3(400mL) anhydrous triethylamine (16mL), Li (2g), 4-methoxyl group-triphenylchloromethane (27g) and dimethylamino, are added
Pyridine (2g), magnetic agitation, 20 DEG C of lucifuge reaction 24h.Add anhydrous triethylamine (10mL), 4-methoxyl group-triphenylchloromethane
(13.8g) with dimethylamino naphthyridine (0.9g), then reaction 12h, the TLC monitoring of room temperature lucifuge (silica gel plate triethylamine pretreatment,
V(CHC13)/(CH3OH)=50/1, add 2 triethylamines) reaction is completely.It is concentrated to give 69g weak yellow foam shape solid, silicagel column
Chromatography (petroleum ether and ethyl acetate by volume ratio 5/1,3/1 are the quick eluting of eluant respectively), concentrates, is vacuum dried
40.3g white solid, i.e. Ente-8.
Ente-9 (2-[(4-methoxyphenyl) (diphenyl) methyl] amino-6-benzyloxy-9 hydrogen-9-{ (1S, 3R, 4S) 4-benzyloxy-3-[(4-
Methoxyphenyl) (diphenyl) methoxyl group] methyl-2-methene-cyclopenta-purine) preparation: under nitrogen atmosphere, to reaction
Tank adds 30g Ente-8 and 0.6LCH2Cl2, stirring, add 0.6L NYSted reagent, reaction 5h is stirred at room temperature, will be anti-
Answer liquid to join in the mixed solution of 1.3L saturated sodium bicarbonate and 1.3L chloroform, stir 30min.Centrifuge, separatory,
Water layer each 0.41L chloroform extraction three times, merges organic layer, with each 0.68L saturated nacl aqueous solution washing three times.Nothing
Aqueous sodium persulfate is dried, and filters, and rotation is evaporated off solvent and obtains residue, and column chromatography is refining to obtain 19g product, yield about 65%.
Ente-10 (2-amino-1,9-dihydro-9-[(1S, 3R, 4S)-4-benzyloxy-3-(methylol)-2-methene cyclopenta]-6H-purine
-6-ketone) preparation: in reaction bulb add 190mL THF, 1.2g CeRh2Ga, 190mL methanol and 18.9g Ente-9,
Stirring, adds 95ml HCl (3mol/l), is heated to 50 DEG C, reacts 1h.React complete.It is down to room temperature, with 1mol/l's
NaOH regulation pH value is 7.Extract 3 times by each 3L ethyl acetate.Merge organic layer, with the saturated chlorination of each 300ml
Sodium solution washs 3 times.Anhydrous sodium sulfate is dried, and filters, and rotation is evaporated off solvent and obtains residue, pulls an oar to obtain 7g product with ether,
Yield about 90%.
Entecavir (2-amino-1,9-dihydro-9-[(1S, 3R, 4S)-4-hydroxyl-3-(methylol)-2-methene cyclopenta]-6H-purine
-6-ketone) preparation: under nitrogen atmosphere, in retort add 6.9g Ente-10,207mL dichloromethane, stirring.Fall
Temperature, to-80 DEG C, drips 1.2mol/l BCl3Dichloromethane solution 138mL.It is warming up to-40 DEG C, reacts 3h.After reaction terminates,
Dropping 1.04L methanol, rotation is evaporated off solvent and obtains thick product 4.1g.Yield about 70%.
Refining of product: in reaction bulb, adds 4g Entecavir crude product, adds 80mL deionized water, adds 0.32g and lives
Property charcoal, temperature rising reflux 30min, while hot sucking filtration, filtrate is slowly stirred down, natural cooling, separate out solid, sucking filtration, filter cake in
30 DEG C of drying under reduced pressure obtain Entecavir fine work 3g, detection.Elementary analysis consists of Cl2H15N5O3·H2O；
(C=1, DMF: methanol=50:50)；MS:[M+H]+=m/z 278, [M+Na]+=m/z 300.Concrete data see table 1,
Table 2, table 3.
Compared with prior art, it is high that the preparation method of Entecavir of the present invention has yield, good product purity, post processing
Simple to operate, environmental friendliness, it is suitable for the features such as industrialized production.Use CeRh2Ga (Xia Jizhou. the crystal field of cerium-containing compound grinds
Study carefully. Shangqiu Normal University journal .2008,3 (24)) as catalyst after, Ente-9 generates the conversion ratio of Ente-10 and is greatly improved,
And then improve the productivity of Entecavir.
Table 1: elemental analysis of samples is reported
Table 2: sample1HNMR determination data
Table 3: sample13CNMR determination data
Claims (6)
1. the preparation method of an Entecavir, it is characterised in that concretely comprising the following steps of described method:
1) under nitrogen atmosphere, Zn is joined in oxolane, be cooled to-40 DEG C, add CH2Br2, insulation, stirring
Lower addition TiCl4, warm naturally to 5 DEG C, insulation reaction 4 days, obtain NYSted reagent；
2) nitrogen protection, at room temperature adds (2R, 3S, 5S)-5-[2-[[(4-methoxyphenyl) benzhydryl] ammonia in reactor
Base]-6-benzyloxy-9H-purine-9-base]-3-benzyloxy-2-[(benzyloxy) methyl] Ketocyclopentane and anhydrous CHCl3, add anhydrous three
Ethamine, Li, 4-methoxyl group-triphenylchloromethane and dimethylamino naphthyridine, stirring, 20 DEG C of lucifuge reaction 24h, silica gel column chromatography,
Obtain Ente-8；
3) under nitrogen atmosphere, in retort, Ente-8 and CH is added2Cl2, stirring, add NYSted reagent, room temperature
Stirring reaction 5h, joins in the mixed solution of saturated sodium bicarbonate and chloroform by reactant liquor, stirring 30min, centrifuge,
Separatory, water layer chloroform extraction three times, merge organic layer, wash three times with saturated nacl aqueous solution, anhydrous sodium sulfate is dried,
Filtering, rotation is evaporated off solvent and obtains residue, and column chromatography is refining to obtain Ente-9；
4) in reaction bulb, 190mL oxolane, 1.2g CeRh are added2Ga, 190mL methanol and 18.9g Ente-9, stir
Mix, add 3mol/l HCl 95ml, be heated to 50 DEG C, react 1h, react complete, be down to room temperature, with the NaOH of 1mol/l
Regulation pH value is 7, extracts 3 times by each 3L ethyl acetate, merges organic layer, with each 300ml saturated nacl aqueous solution
Washing 3 times, anhydrous sodium sulfate is dried, and filters, and rotation is evaporated off solvent and obtains residue, pulls an oar to obtain Ente-10 with ether；
5) under nitrogen atmosphere, in retort, add Ente-10 and dichloromethane, stirring, be cooled to-80 DEG C, drip BCl3
CH2Cl2Solution, is warming up to-40 DEG C, reacts 3h, after reaction terminates, drips methanol, and rotation is evaporated off solvent and obtains Entecavir
Crude product, refined, produce sterling.
2. the preparation method of Entecavir as claimed in claim 1, it is characterised in that the concrete system of described NYSted reagent
Preparation Method is: under the atmosphere of nitrogen, is joined in 0.6L oxolane by 68.9g Zn, is cooled to-40 DEG C, adds 24mL
CH2Br2, insulation, stirring is lower adds 24mL TiCl4, warm naturally to 5 DEG C, insulation reaction 4 days, prepare product.
3. the preparation method of Entecavir as claimed in claim 1, it is characterised in that the specifically side of preparation of described Ente-8
Method is: protect at nitrogen, adds 40g (2R, 3S, 5S)-5-[2-[[(4-methoxyphenyl) under room temperature in 500mL two neck flask
Benzhydryl] amino]-6-benzyloxy-9H-purine-9-base]-3-benzyloxy-2-[(benzyloxy) methyl] Ketocyclopentane and anhydrous 400mL
CHCl3, add 16mL anhydrous triethylamine, 2g Li, 27g 4-methoxyl group-triphenylchloromethane and 2g dimethylamino naphthyridine,
Magnetic agitation, 20 DEG C of lucifuge reaction 24h；Add 10mL anhydrous triethylamine, 13.8g 4-methoxyl group-triphenylchloromethane and 0.9g
Dimethylamino naphthyridine, then reaction 12h, the TLC monitoring reaction of room temperature lucifuge is completely；It is concentrated to give weak yellow foam shape solid, silica gel
Column chromatography, concentrates, is vacuum dried to obtain product.
4. the preparation method of Entecavir as claimed in claim 1, it is characterised in that the specifically side of preparation of described Ente-9
Method is: under nitrogen atmosphere, adds 30g Ente-8 and 0.6LCH in retort2Cl2, stirring, add 0.6L NYSted
Reagent, is stirred at room temperature reaction 5h, is joined by reactant liquor in the mixed solution of 1.3L saturated sodium bicarbonate and 1.3L chloroform, stir
Mix 30min；Centrifuge, separatory, water layer each 0.41L chloroform extraction three times, merge organic layer, use each 0.68L
Saturated nacl aqueous solution washs three times, and anhydrous sodium sulfate is dried, and filters, and rotation is evaporated off solvent and obtains residue, and column chromatography is refining to obtain product
Product.
5. the preparation method of Entecavir as claimed in claim 1, it is characterised in that the concrete preparation of described Entecavir
Method is: under nitrogen atmosphere, adds 6.9g Ente-10,207mL dichloromethane, stirring, be cooled to-80 DEG C in retort,
Dropping 1.2mol/l BCl3Dichloromethane solution 138mL, be warming up to-40 DEG C, react 3h, reaction terminate after, drip 1.04L
Methanol, rotation is evaporated off solvent and obtains thick product.
6. the preparation method of Entecavir as claimed in claim 1, it is characterised in that described Entecavir is with anhydrous shape
Formula or containing presented in water of crystallization.
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| CN101012228A (en) * | 2007-02-07 | 2007-08-08 | 上海阳帆医药科技有限公司 | Method of preparing antivirotic entecavir hydrate |
| CN101182322B (en) * | 2007-12-06 | 2011-04-06 | 福建广生堂药业有限公司 | Method for preparing antiviral drug of Entecavir |
| CN101235034A (en) * | 2008-02-28 | 2008-08-06 | 陆锦康 | Method for synthesizing entecavir |
| CN101723945B (en) * | 2008-10-17 | 2011-11-02 | 上海清松制药有限公司 | Method for preparing antiviral medicinal entecavir intermediate |
| CN102477036A (en) * | 2010-11-23 | 2012-05-30 | 上海永鸿实业集团化学科技有限公司 | Method for preparing Entecavir monohydrate |
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