CN101130542B - Synthesis method of antiviral nucleoside analogue - Google Patents
Synthesis method of antiviral nucleoside analogue Download PDFInfo
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- CN101130542B CN101130542B CN2006100884648A CN200610088464A CN101130542B CN 101130542 B CN101130542 B CN 101130542B CN 2006100884648 A CN2006100884648 A CN 2006100884648A CN 200610088464 A CN200610088464 A CN 200610088464A CN 101130542 B CN101130542 B CN 101130542B
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
The invention discloses a synthesizing method of entikawei with antiviral activity, which relates to the intermediate to prepare entikawei and making method of the intermediate.
Description
Technical field
The present invention relates to the synthetic method of nucleoside analog, be specifically related to have the synthetic method of the compound Entecavir of antiviral activity, the invention still further relates to and be used to the method for preparing the intermediate of Entecavir and prepare these intermediates.
Background technology
Entecavir (entecavir) is a kind of carbocyclic ring guanosine-analogue, chemical name: [1S-(1 α, 3 α, 4 β)]-2-amino-1,9-dihydro-9-[4-hydroxyl-3-methylol-2-methylene cyclopentyl]-the fast quinoline of 6H--6-ketone; Molecular formula: C
12H
15O
3N
5, molecular weight 277.3; Chemical structural formula is as follows:
Entecavir is as a kind of medicine of effective anti-hepatitis B virus, this compound and monohydrate thereof and sodium salt may be used to the treatment of hepatitis B, see U.S. Pat 5206244 about Entecavir and as the report head of antiviral purposes; CN1310999 and CN1658844 have described the Entecavir low dose pharmaceutical compositions and have been used for the treatment of hepatitis b virus infected.JOC1985,50,755, CN1061972, WO9809964, CN1747959 etc. have described its preparation method, and its core is first synthesizing epoxy cyclopentane compounds, directly open the oxygen ring with guanine derivatives then and synthesize carbocyclic nucleoside, this reaction scheme has following shortcoming:
1. the ring-opening reaction productive rate is low: for example the productive rate of WO9809964 report about 50%, JOC1985, the productive rates of 50,755 reports are 27%.
2. ring-opening reaction product separation purification difficult need be used repeatedly column chromatography, and the ring-opening reaction product is that steric isomer mixes, even through after repeatedly silica gel column chromatography is purified, still is difficult to each other separate, and influences the purity of final product.For example to need repeatedly just to obtain behind the silica gel column chromatography purity be 92% product to WO9809964 report ring-opening reaction product.
3. the amino on the guanine needs protection in subsequent reactions; the protective reaction difficulty; unstable products; separate numerous and diverse and need to use column chromatography for example the amino on the WO9809964 report guanine be difficult to finish with the reaction of MMT protection; product needs to use silica gel column chromatography in the process of follow-up purification, and is easy to decompose at silicagel column.
4.CN1747959 in method used the precursor of silane as hydroxyl, after the basic structure of having finished target molecule synthetic, need using very, intensive oxidizing condition and strong acid and strong base condition are converted into hydroxyl with silane group, influenced the purity and the productive rate of target product, and need be with the special resins chromatography method target product of purifying.
Therefore, directly use the low-cost height of reaction scheme complex process yield in the process that reality is used of guanine open loop to be not suitable for suitability for industrialized production.
Summary of the invention
The object of the present invention is to provide the synthetic method of Entecavir, this method helps the industrial production of repetition and mass-producing and obtains to be suitable for medicinal product with low cost.
Another object of the present invention is to be provided for the intermediate of synthetic Entecavir, and the synthetic method of these intermediates.
New synthetic method provided by the invention comprises:
Route 1:
1. at first be that nitrogenous nucleophilic reagent is opened the oxirane ring in the compound 1, gets the compound 2 of 1 hydroxyl with compound 1 and nitrogenous nucleophilic reagent reaction.Wherein P is the blocking group of hydroxyl, and NG is the nitrogenous remaining residue in nucleophilic reagent reaction back, and available nitrogenous nucleophilic reagent comprises azido acid salt, ammonia, and phthalic imidine and salt thereof and organic amine be benzene methanamine or allylamine for example.Reaction can be at alkaline condition, carry out under acidic conditions or the neutrallty condition, for example phthalic imidine and salt thereof and oxirane ring carry out under alkaline condition, the organic amine for example reaction of benzene methanamine and allylamine and oxirane ring can carry out under the condition that silk acid in Louis exists, and azido acid salt can carry out ring-opening reaction under nearly neutral condition; The solvent that reaction is used is selected polar aprotic solvent or protonic solvent and water for use according to the difference of nucleophilic reagent, the ring-opening reaction of phthalic imidine is generally carried out in polar aprotic solvent such as DMF or DMSO, and the reaction of azido acid salt is generally carried out in alcohol, water or pure water mixed solution; Temperature of reaction is generally in room temperature to 180 ℃.
2. the hydroxyl in the oxygenated compound 2 can obtain compound 3.Oxygenant can be selected chromic acid, potassium permanganate, sodium bromate, DMSO/DCC, DMSO/SOCL for use
2, DMSO/TFA, DESS-MARTIN reagent or the like, preferred PCC, PDC, DESS-MARTIN reagent is DESS-MARTIN reagent more preferably.The condition of oxidizing reaction can be undertaken by the condition of known oxidizing reaction.
3. compound 3 is converted into the outer carbon-to-carbon double bond of ring by the methylenation reaction with the carbonyl in the molecule, thereby obtains compound 4.Methylenation reagent such as NYSTED reagent or TOBBE reagent are used in the methylenation reaction usually, are catalyzer with the titanium tetrachloride, carry out to the temperature range of room temperature at-78 ℃.
4. the nitrogen-containing functional group NG in the compound 4 is converted into amino and obtains compound 5.For example, azido-can become amino by reduction, and phthalimide-based can be used hydrazine, phenylhydrazine or organic amine such as n-Butyl Amine 99, and quadrols etc. are sloughed phthaloyl and are obtained amino, and the allyl amido can obtain amino with the palladium catalyst deprotection.
The preparation method of compound 1 can be with reference to J.CHEM.SOC.PERKIN.TRANS.1; 549 (1988).At first with cyclopentadiene sodium and benzyl chloride methyl ether reaction condensation, pass through asymmetric hydroboration oxidizing reaction then, epoxidation reaction obtains with last protection hydroxyl.
The blocking group of hydroxyl as herein described can be selected the blocking group that not influenced by subsequent reactions arbitrarily for use.Suitable blocking group can be with reference to the protective groups in organic synthesis that GREENE showed, for example benzyl, trityl, trialkyl silica, benzoyl etc., preferred benzyl.Hydroxyl can be with reference to U.S. Pat 5206244 by the detailed preparation method of the compound 1 of benzyl protection.
The special case of the above-mentioned route 1 of route 2:()
1. compound 1 ' reacts open loop with phthalic imidine or its salt and obtains compound 2 ' in aprotic polar solvent.Wherein Bn is a benzyl, and reaction is generally made solvent with DMF, and temperature of reaction is made catalyzer with sodium hydride or lithium hydride between room temperature to 150 ℃, preferably use phthalic imidine or its sylvite or lithium salts to react.
2. the hydroxyl in the oxygenated compound 2 ' can obtain compound 3 '.Oxygenant can adopt chromic acid preparation, potassium permanganate, sodium bromate, DMSO/DCC, DMSO/SOCL
2, DMSO/TFA, DESS-MARTIN reagent or the like.The reaction conditions gentleness of PCC, PDC, DESS-MARTIN reagent, especially DESS-MARTIN reagent in these reagent, the transformation efficiency height is handled easily.Compound 3 ' can not carry out purifying and is directly used in next step reaction.
3. compound 3 ' is converted into the outer carbon-to-carbon double bond of ring by the methylenation reaction with the carbonyl that contains in the molecule, thereby obtains compound 4 '.Methylenation reagent such as NYSTED reagent or TOBBE reagent are used in the methylenation reaction usually, are catalyzer with the titanium tetrachloride, carry out to the temperature range of room temperature at-78 ℃.
4. with the phthalimide-based hydrazine in the compound 4 ', phenylhydrazine or organic amine such as n-Butyl Amine 99, quadrols etc. are sloughed phthaloyl and are obtained compound 5 '.
Route 3:
Wherein, L is a leavings group arbitrarily, is generally chlorine, bromine or iodine; R is amino or can be converted into amino group, the amino of for example having protected, and nitro, nitroso-group, diazoes etc., R can also be hydrogen, hydrogen can react with diazonium salt and become diazo, and then is reduced into amino; X is hydroxyl or the group that can change into hydroxyl arbitrarily, for example halogen and the hydroxyl protected.The amino of having protected can be the amino of BOC, Fmoc, CBZ protection; the amino of acyl group (phthaloyl, benzoyl, ethanoyl, trifluoroacetyl group etc.) protection; the amino that also has the alkyl protection, for example benzene methanamine base, benzhydrylamine base, allyl group amido etc.The hydroxyl of having protected can be acyl group (benzoyl, ethanoyl) protection, also has the alkyl protection, for example benzyloxy, methoxyl group etc.
1. methylene radical cyclopentane compounds 5 and 6 bit strips are had the pyrimidine derivatives coupling of leavings group, the amino on the methylene radical cyclopentane compounds 5 is connected on 6 of pyrimidine ring and obtains compound 6, and wherein P is a hydroxy-protective group;
6 bit strips have the pyrimidine derivatives structure of leavings group to be shown below:
Compound 5 carries out in alcohols and DMF isopolarity solvent He in the presence of the acid binding agent usually with the linked reaction of pyrimidine derivatives, acid binding agent is generally organic amine, temperature of reaction between room temperature to 180 ℃, if L is a chlorine or bromine, can also use cuprous iodide as the catalyzer accelerated reaction usually;
2. the R on the pyrimidine ring is converted into amino and can obtains compound 7, according to the character of R group, concrete transform mode is had nothing in common with each other; If R then needs protecting group is sloughed for the amino of protection; If R is a nitro, nitroso-group, diazo then can obtain amino with the reductive method; If R is H, then needs earlier R to be become diazo, and then be reduced into amino;
3. compound 7 is carried out ring closure reaction with strong acid catalysis in alkyl orthoformate and can obtain purine compound 8;
4. the X on the purine compound 8 is converted into hydroxyl and obtains compound 9;
5. obtain the final product Entecavir after sloughing blocking groups all on the compound 9.Can slough benzyl with boron trichloride, use the Iodotrimethylsilane demethylating, slough trityl, slough benzoyl and ethanoyl, slough the protected silane base with tetrabutyl ammonium fluoride with alkali with hydrochloric acid.
The special case of route 4:(route 3)
1. compound 5 reacts in polar solvent with 2-amino-5-nitro-3-hydroxyl-6-chloropyrimide and obtains compound 10, preferred polar solvent is ethanol, propyl carbinol and DMF, and do acid binding agent with organic amine, preferred acid binding agent is diisopropylethylamine and triethylamine, reaction is carried out with nitrogen protection and under reflux temperature, and wherein P is a hydroxy-protective group;
2. the nitro in the compound 10 obtains di-amino-pyrimidine midbody compound 11 after reducing, and common reduction nitro becomes amino method easily to change compound 10 into 11, as SnCl
2/ HCl, NaBH
4/ CoCl
2, Fe/HCl and sodium hyposulfate, preferred sodium hyposulfate.
3. compound 11 does not generally need to separate to purify and just ring closure reaction generation compound 9 can take place under the catalysis of strong acid in alkyl orthoformate, preferred trimethyl orthoformate of alkyl orthoformate and triethyl orthoformate, strong acid is selected concentrated hydrochloric acid usually for use, and temperature of reaction is usually between room temperature and 100 ℃.
4. compound 9 promptly obtains Entecavir after sloughing protecting group.
The special case of route 5:(route 3)
1. compound 5 and 2; 5-diamino-4; the 6-dichloro pyrimidine reacts in polar solvent and obtains compound 12; preferred solvent is ethanol, propyl carbinol and DMF; and do acid binding agent with organic amine; preferred acid binding agent is diisopropylethylamine and triethylamine, and reaction is carried out with nitrogen protection and under the reflux temperature of solvent.
2. ring closure reaction generation compound 13 takes place in compound 12 under the catalysis of strong acid in alkyl orthoformate, preferred trimethyl orthoformate of alkyl orthoformate and triethyl orthoformate, strong acid is selected concentrated hydrochloric acid usually for use, and temperature of reaction is usually between room temperature and 100 ℃.
3. compound 13 is hydrolyzed in containing the alkaline aqueous solution, obtains compound 9, and aqueous solution is generally the mixing solutions of water and alcohol compound, and highly basic is generally selected sodium hydroxide or potassium hydroxide for use, and temperature of reaction is a room temperature to 100 ℃.
4. compound 9 promptly obtains Entecavir after sloughing protecting group.
The special case of route 6:(route 3)
1. compound 5 and 2-amino-4, the 6-dichloro pyrimidine reacts in polar solvent and obtains compound 14, preferred polar solvent is ethanol, propyl carbinol and DMF, and do acid binding agent with organic amine, preferred acid binding agent is diisopropylethylamine or triethylamine, reaction is carried out with nitrogen protection and under reflux temperature, and wherein P is a hydroxy-protective group;
2. compound 14 is reflected in the aqueous alcohol solution and carries out with reaction obtains compound 15 to the chlorobenzene diazonium salt, and temperature of reaction generally is controlled at below the room temperature;
3. compound 15 obtains compound 12 through reduction.Reductive agent is generally selected NaBH for use
4/ THF, Zn/HCl and Sn/HCl, reaction solvent use organic alcohols usually;
4. ring closure reaction generation compound 13 takes place in compound 12 under the catalysis of strong acid in alkyl orthoformate, preferred trimethyl orthoformate of alkyl orthoformate and triethyl orthoformate, strong acid is selected concentrated hydrochloric acid usually for use, and temperature of reaction is usually between room temperature and 100 ℃;
5. compound 13 is hydrolyzed in containing the alkaline aqueous solution, obtains compound 9, and aqueous solution is generally the mixing solutions of water and alcohol compound, and highly basic is generally selected sodium hydroxide or potassium hydroxide for use, and temperature of reaction is no more than 100 ℃;
6. compound 9 promptly obtains Entecavir after sloughing protecting group.
The advantage of method provided by the present invention:
1. owing to avoided using the guanine open loop, reaction yield improves greatly, and compound 4 or 4 ' separating and purifying method are simple.
2. there are 9-N and two positions of 7-N that nucleophilic attack can take place during with the direct open loop of guanine on the guanine ring.Though the reaction preference of 9-N greater than 7-N, can not be got rid of the reaction product of 7-N fully, and with new synthetic route, because original amino finally only can change into 9-N, so there is not selective problems.
3. compound 4 or 4 ' steric isomer can separate with compound 4 or 4 ' at an easy rate, therefore can not bring diastereomer in final product.
4. because variation route is a resynthesis guanine after forming methylene radical,, simplified synthetic route so avoided the protection and the deprotection of 2-amino on the guanine.
5. it is higher to react the final product purity that obtains, and has avoided loaded down with trivial details resin chromatography to separate.
Embodiment
Embodiment 1:[1s-(1 α, 2 β, 3 α, 5 β)]-5-(phthalimide-based)-3-(benzyloxy)-2-[(benzyloxy) methyl] preparation of cyclopentanol (intermediate 2 ')
In the 5L there-necked flask, add 145g (0.98mol) phthalic imidine, 3.77gLiH and 765ml dry DMF, stir 10min.Restir 15min after being heated to 60 ℃, this moment, turbid solution became clarification.Slowly drip with 1.87L dry DMF dissolved 152g (0.49mol) [1s-(1 α, 2 α, 3 β, 5 α)]-3-(benzyloxy)-2-[(benzyloxy) methyl]-6-oxabicyclo [3.1.0] hexane (intermediate 1 '), stir 15min in 60 ℃.Be heated to 125 ℃, reaction 2h, TLC (second: just=1:3) showing that raw material disappears, with 28ml Glacial acetic acid termination reaction.Stir 10min.Add the 2.5L saturated aqueous common salt, with ethyl acetate 3 * 1.2L extraction, organic phase merges with the saturated common salt water washing once, and anhydrous sodium sulfate drying reclaims solvent.Residue oily matter silicagel column separates, and ethyl acetate/petroleum ether with 8% and 10% ethyl acetate/petroleum ether wash-out obtain 137.7g (0.3mol) colorless oil, yield: 61.5%.
Survey: [α]
22 D=+34.8 ° of (C=1.0, CHCl
3)
1HNMR:δ7.71～7.82(4H，m)，δ7.26～7.32(10H，m)，δ4.72～4.75(1H，m)，δ4.51～4.53(4H，m)，δ4.43～4.46(1H，m)，δ3.7～4.0(2H，m)，δ3.64～3.66(1H，m)，δ2.48(1H，m)，δ2.35(1H，m)，δ2.16(2H，m)
MS(API-ES)(M+Na)
+＝480，
Embodiment 2:[1s-(1 α, 2 β, 3 α, 5 β)]-the 5-[phthalimide-based]-3-(benzyloxy)-2-[(benzyloxy) methyl] preparation of cyclopentanone (intermediate 3 ')
In the 3L there-necked flask, add Dess-Martin reagent 203g, add the anhydrous CH of 1.4L
2Cl
2Stir.With 137.7g intermediate 2 ' with the anhydrous CH of 890ml
2Cl
2Dissolving drops in the step suspension liquid, (the second: just=1:3) showing that raw material disappears stopped reaction of TLC behind the 20min.Earlier with NaHSO
3Saturated aqueous solution is washed 3 times, again with NaHCO
3Saturated aqueous solution is washed 3 times, and with saturated salt washing 3 times, organic layer dewaters and drains, and obtains 196g yellow oily compound at last.
Embodiment 3:1s-(1 α, 3 α, 4 β)-5-phthalimide-based-2-methylene radical-4-(benzyloxy)-3-[(benzyloxy) methyl] preparation of pentamethylene (intermediate 4 ')
In the 5L there-necked flask, add Nysted Reagent (Wt=20%) 1.46L and the anhydrous THF of 800ml, stir N
2Protection is cooled to-78 ℃.With 196g intermediate 3 ' with The addition of C H
2Cl
2Dissolving drops in the reaction.Get TiCl
4/ CH
2Cl
2(1:9) 393ml slowly drops in the reaction, and holding temperature is at-60 ℃～-78 ℃.Dropwise, mixture is kept reaction 15min under-78 ℃.Slowly be warming up to room temperature, continue to stir 1～3h, (second: just=1:4) showing that raw material disappears, reaction soln is atropurpureus to TLC.Pour this reaction soln into saturated NaHCO to 2.3L
3In, fully stirring, the white opacity thing can appear in this moment.With ethyl acetate extraction 3 times, saturated aqueous common salt is stripped once, and anhydrous sodium sulphate dewaters, and reclaims solvent and obtains intense violet color oily thing.Drain with oil pump again, obtain the light yellow oily compound of 188g.
1H?NMR：δ7.32～7.83(4H，m)，δ7.26～7.34(10H，m)，δ5.43(1H，m)，δ4.85(1H，s)，5.11(1H，s)，δ4.56～4.59(4H，m)，δ4.2(1H，m)，δ3.64～3.72(2H，m)，δ3.12(1H，m)，δ2.17～2.56(2H，m)
MS(API-ES)(M+Na)
+＝476，(M+H)
+＝454
Embodiment 4:1s-(1 α, 3 α, 4 β)-5-amido-2-methylene radical-4-(benzyloxy)-3-[(benzyloxy) methyl] preparation of pentamethylene (intermediate 5 ')
In the 2L there-necked flask, add 188g intermediate 4 ' and 930ml propyl carbinol, stirring and dissolving.Add the 93ml quadrol, be heated to 90 ℃ and refluxed 1 hour, (second: just=1:3) showing that raw material disappears, with 377ml washing, decompression and solvent recovery, chromatographic separation obtains 78.6g (0.24mol) oily matter to TLC, three step total recoverys: 80.0%.Survey: [α]
22 D=+13.0 ° of (C=1.0, CHCl
3)
1H?NMR：δ7.27～7.31(10H，m)，δ5.06(1H，s)，δ5.18(1H，s)，δ4.50～4.53(4H，m)，δ3.94～4.0(2H，m)，δ3.39～3.57(2H，m)，δ2.91(1H，m)，δ2.21(4H，m)
MS(API-ES)(M+H)
+＝324
Embodiment 5:1s-(1 α, 3 α, 4 β)-2-amino-6-[[4-benzyloxy-3-(benzyloxy) methyl-2-methylene radical cyclopentyl] amino]-preparation of 5-nitro-4 (3H)-pyrimidone
In the 1L there-necked flask, add 78.6g intermediate 5 ' (0.24mol) and 445ml propyl carbinol, stirring and dissolving, add the 13.4ml triethylamine, slowly add 11.5g2-amino-4-chloro-5-nitro-pyrimidine ketone (0.25mol), 90 ℃ of reflux are spent the night, and (methyl alcohol: methylene dichloride=1:20), raw material reaction finishes in the TLC detection.With the dilution of 1L methylene dichloride, 500ml uses anhydrous sodium sulfate drying after washing 1 time, reclaims solvent and obtains the 80g pale solid.
1H?NMR：δ10.63(1H，s)，δ9.53～9.55(1H，m)，δ7.26～7.36(10H，m)，δ5.2～5.3(1H，m)，δ5.05(1H，s)，δ5.12(1H，s)，δ4.47～4.50(4H，m)，δ3.96～3.98(1H，m)，δ3.40～3.60(2H，m)，δ2.49～2.51(2H，m)，δ2.17～2.56(2H，m)
Embodiment 6:1s-(1 α, 3 α, 4 β)-2-amino-9-[4-benzyloxy-3-(benzyloxy) methyl-2-methylene radical cyclopentyl]-1, the preparation of 9-dihydro-6H-purine-6-one
In the 3L there-necked flask, add 80g embodiment 5 gained compounds and 445ml propyl carbinol, stirring and dissolving.Add the 110g vat powder, be heated to 60 ℃, slowly add 445ml formic acid, react 2 hours postcooling, with being concentrated into dried with final vacuum in the 6N sodium hydroxide solution to room temperature.Residue is removed insolubles with methylene dichloride dissolving after-filtration, filtered liquid concentrates the back and adds the 445ml triethyl orthoformate, 44.6ml concentrated hydrochloric acid, be heated to 90 ℃, react and be neutralized to PH=7.0 with sodium hydroxide after 4 hours, obtain 45g pale solid thing (0.098mol) through ion exchange resin treatment, two step total recoverys: 56%.Survey mp:207-210 ℃.
1H?NMR：δ10.53(1H，s)，δ7.63～7.36(1H，s)，δ7.28～7.63(10H，m)，δ6.4(2H，s)，δ5.34～5.14(2H，m)，δ4.6(1H，m)，δ4.52～4.60(4H，m)，δ4.10(1H，m)，δ3.62～3.63(2H，m)，δ2.55(1H，m)，δ2.45～2.49(2H，m)
Embodiment 7: the preparation of Entecavir
In the 5L there-necked flask, add 45g embodiment 6 gained compounds and 600ml anhydrous methylene chloride.Under-78 ℃ and the nitrogen protection, add the dichloromethane solution 590ml of 1M boron trichloride, react and be warming up to-20 ℃ after 1 hour, again reaction mixture is cooled to-78 ℃ after reacting half an hour, slowly add 1.5L methyl alcohol.Add methyl alcohol 1.5L after the solvent removed in vacuo again, vacuum is removed methyl alcohol, use 700ml dissolved in distilled water residue then, solution is neutralized to neutrality with sodium hydroxide after with ethyl acetate extraction, to 140ml, there is solid to separate out solution concentration, obtain Entecavir crude product 20 grams (0.067mol) after the filtration, yield: 68.4%.
1H?NMR：δ10.57(1H，s)，δ7.69(1H，s)，δ6.41(10H，s)，δ5.36(1H，m)，δ5.(1H，m)，δ4.89(1H，s)，δ4.83(1H，m)，δ4.58(1H，m)，δ4.22(1H，m)，δ3.55(2H，m)，δ2.52(1H，m)，δ2.21(1H，m)，δ2.04(1H，m)
Embodiment 8: Entecavir refining
In the 1L there-necked flask, add 20g Entecavir crude product and 400ml distilled water, heating for dissolving.Add the 0.5g gac again,, claim heat filtering in 95 ℃ of insulated and stirred 30 minutes.Collect filtrate, be cooled to 0 ℃ of crystallization.Get the 16.5g Entecavir, yield L82.5%.Survey: mp:〉220 ℃, [α]
22 D=+34 ° of (C=0.30, H
2O).(document: mp=234～236 ℃, [α]
22 D=+33.2 °)
Embodiment 9:1s-(1 α, 3 α, 4 β)-2,5-diamino-6-[[4-benzyloxy-3-(benzyloxy) methyl-2-methylene radical cyclopentyl] amino]-preparation of 4-chloro-pyrimidine
2,5-diamino-4, and the 6-dichloro pyrimidine (1g, 5.6mmol), with triethylamine (3ml, 20mmol) and propyl carbinol (20ml, 0.34mol) dissolving, add compound 5 ' (1.1g again, 3.5mmol), follow the tracks of reaction (5% ethanol/methylene, Rf value=0.8) with TLC, 14 hours afterreactions of reflux finish.Stop heating, suction filtration, the washing with alcohol filter cake discards solid, and filtrate is drained, and separates with silica gel column chromatography, obtains the 0.42g target compound.
Embodiment 10:1s-(1 α, 3 α, 4 β)-2-amino-9-[4-benzyloxy-3-(benzyloxy) methyl-2-methylene radical cyclopentyl]-1, the preparation of 9-dihydro-6 chloro-purine
0.42g embodiment 9 gained compounds, ((0.5ml, 6.25mmol), TLC follows the tracks of reaction (5% ethanol/methylene, Rf value=0.5), stirring at normal temperature afterreaction end in 4 hours to add concentrated hydrochloric acid again for 9ml, 0.82mmol) dissolving to add trimethyl orthoformate.Stop to stir, add ethyl acetate (50ml) in the reaction solution, use NaHCO
3The aqueous solution (1N) neutralization reaction liquid is to pH value=7.Layering, organic layer dewaters with anhydrous sodium sulphate, drains, and separates with silica gel column chromatography, obtains the 0.2g target compound.
Embodiment 11:1s-(1 α, 3 α, 4 β)-2-amino-9-[4-benzyloxy-3-(benzyloxy) methyl-2-methylene radical cyclopentyl]-1, the preparation of 9-dihydro-6H-purine-6-one
Embodiment 10 products (0.2g, 0.84mmol) add NaOH solution (15ml, 0.5M), TLC follows the tracks of reaction (7.5% ethanol/methylene, Rf value=0.3), 6 hours afterreactions of 100 ℃ of stirring and refluxing are finished.Aftertreatment: between hydrochloric acid conditioned reaction liquid pH5-6, use ethyl acetate extraction three times, decompressing and extracting is separated with silica gel column chromatography, obtains the 80mg target compound.
Claims (15)
1. the preparation method of the following Entecavir of structural formula,
Comprise:
A. with methylene radical cyclopentane compounds 5
With 6 bit strips the pyrimidine derivatives coupling of leavings group is arranged,
Obtain compound 6
Wherein P is a hydroxy-protective group; L is a leavings group arbitrarily; R is the amino amino group that maybe can be converted into; X is hydroxyl or the group that can change into hydroxyl arbitrarily, and linked reaction and is reacted under the situation that acid binding agent exists in polar solvent, and temperature of reaction is between room temperature to 180 ℃;
B. be amino situation except R, the R on the pyrimidine ring of compound 6 be converted into amino obtain compound 7
C. compound 7 is carried out ring closure reaction with strong acid catalysis in alkyl orthoformate and obtain purine compound 8
D. be the situation of hydroxyl except X, the X on the purine compound 8 be converted into hydroxyl obtain compound 9
E. obtain Entecavir after sloughing the blocking group on the compound 9.
2. the preparation method of the described Entecavir of claim 1, wherein P is benzyl, trityl, trialkyl silica, benzoyl.
3. the preparation method of the described Entecavir of claim 1, wherein L is chlorine, bromine or iodine.
4. the preparation method of the described Entecavir of claim 1, wherein R is amino, amino, nitro, nitroso-group, diazo or the hydrogen protected.
5. the preparation method of the described Entecavir of claim 1, wherein X is hydroxyl, halogen or the hydroxyl protected.
6. the preparation method of the described Entecavir of claim 1 comprises:
A. with methylene radical cyclopentane compounds 5
With 2-amino-5-nitro-4-hydroxyl-6-chloropyrimide in polar solvent, and under the situation that acid binding agent exists, react, obtain compound 10
Wherein P is a hydroxy-protective group;
B. diaminopyrimidine compounds 11 will be obtained behind the nitroreduction in the compound 10
C. with compound 11 in alkyl orthoformate under the catalysis of strong acid, ring closure reaction takes place generate compound 9
D. compound 9 promptly obtains Entecavir after sloughing protecting group.
7. the preparation method of the described Entecavir of claim 6, wherein the reductive agent described in the step b is SnCl
2/ HCl, NaBH
4/ CoCl
2, Fe/HCl or sodium hyposulfate.
8. the preparation method of the described Entecavir of claim 7, wherein the reductive agent described in the step b is a sodium hyposulfate.
9. the preparation method of the described Entecavir of claim 1 comprises:
A. with methylene radical cyclopentane compounds 5
With 2,5-diamino-4,6-dichloro pyrimidine and react under the situation that acid binding agent exists in polar solvent, obtain compound 12
Wherein P is a hydroxy-protective group;
B. ring closure reaction under the catalysis of strong acid, takes place and generates compound 13 in alkyl orthoformate in compound 12
C. compound 13 is hydrolyzed in containing the alkaline aqueous solution, obtains compound 9
D. compound 9 promptly obtains Entecavir after sloughing protecting group.
10. the preparation method of the described Entecavir of claim 1 comprises:
A. the methylene radical cyclopentane compounds 5
With 2-amino-4, the 6-dichloro pyrimidine reacts under the situation that acid binding agent exists in polar solvent, obtains compound 14
B. compound 14 with to the chlorobenzene diazonium salt, in aqueous alcohol solution, reaction obtains compound 15 below room temperature
C. obtain compound 12 with reductive agent reducing compound 15
D. ring closure reaction under the catalysis of strong acid, takes place and generates compound 13 in alkyl orthoformate in compound 12
E. compound 13 is hydrolyzed in containing the alkaline aqueous solution, obtains compound 9
F. compound 9 promptly obtains Entecavir after sloughing protecting group.
11. the preparation method of claim 1,6,9 or 10 described Entecavirs, wherein the P in the methylene radical cyclopentane compounds 5 is a benzyl.
12. the preparation method of claim 6,9 or 10 described Entecavirs, wherein polar solvent described in the step a is ethanol, propyl carbinol or DMF, and acid binding agent is diisopropylethylamine or triethylamine, and reaction is carried out with nitrogen protection and under reflux temperature.
13. the preparation method of claim 6,9 or 10 described Entecavirs, wherein said alkyl orthoformate is trimethyl orthoformate or triethyl orthoformate, and strong acid is concentrated hydrochloric acid, is reflected between the room temperature to 100 ℃.
14. the preparation method of claim 9 or 10 described Entecavirs, wherein said aqueous solution is the mixing solutions of water and alcohols, and highly basic is sodium hydroxide or potassium hydroxide, is reflected between the room temperature to 100 ℃.
15. the preparation method of the described Entecavir of claim 10, wherein the reductive agent described in the step c is NaBH
4/ THF, Zn/HCl or Sn/HCl, reaction solvent are organic alcohols.
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| CN2010101816428A Division CN101863842B (en) | 2006-08-24 | 2006-08-24 | Entecavir midbodies and synthesis method |
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| CN102336754B (en) * | 2010-07-15 | 2017-04-12 | 浙江奥翔药业股份有限公司 | Method for synthesizing entecavir and intermediate compound thereof |
| EP2597096A1 (en) | 2011-11-24 | 2013-05-29 | Esteve Química, S.A. | Process for preparing entecavir and intermediates thereof |
| CN103387587B (en) * | 2013-01-14 | 2015-12-09 | 重庆康施恩化工有限公司 | Entecavir midbodies and preparation method thereof |
| CN106749252B (en) * | 2017-01-23 | 2018-08-28 | 山东鲁抗医药股份有限公司 | A kind of method of purification of entecavir midbodies N8 |
| CN110759912A (en) * | 2018-07-25 | 2020-02-07 | 连云港润众制药有限公司 | Preparation method of entecavir intermediate |
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