CN101148450A - Preparation method of nucleoside compound - Google Patents
Preparation method of nucleoside compound Download PDFInfo
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- CN101148450A CN101148450A CNA200710047774XA CN200710047774A CN101148450A CN 101148450 A CN101148450 A CN 101148450A CN A200710047774X A CNA200710047774X A CN A200710047774XA CN 200710047774 A CN200710047774 A CN 200710047774A CN 101148450 A CN101148450 A CN 101148450A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 30
- -1 nucleoside compound Chemical class 0.000 title claims abstract description 21
- 239000002777 nucleoside Substances 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 66
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- 230000007062 hydrolysis Effects 0.000 claims abstract description 13
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 13
- 238000007363 ring formation reaction Methods 0.000 claims abstract 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 238000009833 condensation Methods 0.000 claims description 5
- 230000005494 condensation Effects 0.000 claims description 5
- 239000002904 solvent Substances 0.000 claims description 4
- 150000008065 acid anhydrides Chemical class 0.000 claims description 3
- 230000002378 acidificating effect Effects 0.000 claims description 3
- 238000010511 deprotection reaction Methods 0.000 claims description 3
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 claims description 3
- 125000000879 imine group Chemical group 0.000 claims description 3
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 claims description 3
- 229910000103 lithium hydride Inorganic materials 0.000 claims description 3
- CCTHTLJWXPUNGT-UHFFFAOYSA-L nysted reagent Chemical compound C1CCOC1.Br[Zn]C[Zn]C[Zn]Br CCTHTLJWXPUNGT-UHFFFAOYSA-L 0.000 claims description 3
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 3
- FNIPRNMPSXNBDI-UHFFFAOYSA-N 3-azaspiro[5.5]undecane-2,4-dione Chemical compound C1C(=O)NC(=O)CC11CCCCC1 FNIPRNMPSXNBDI-UHFFFAOYSA-N 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 238000005822 methylenation reaction Methods 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- KNCYXPMJDCCGSJ-UHFFFAOYSA-N piperidine-2,6-dione Chemical compound O=C1CCCC(=O)N1 KNCYXPMJDCCGSJ-UHFFFAOYSA-N 0.000 claims description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims 2
- 239000003513 alkali Substances 0.000 claims 2
- 238000010719 annulation reaction Methods 0.000 claims 2
- 239000002585 base Substances 0.000 claims 2
- 239000007810 chemical reaction solvent Substances 0.000 claims 2
- 239000000413 hydrolysate Substances 0.000 claims 2
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims 1
- 230000001476 alcoholic effect Effects 0.000 claims 1
- 125000003368 amide group Chemical group 0.000 claims 1
- 238000005815 base catalysis Methods 0.000 claims 1
- 238000006482 condensation reaction Methods 0.000 claims 1
- VGGRCVDNFAQIKO-UHFFFAOYSA-N formic anhydride Chemical compound O=COC=O VGGRCVDNFAQIKO-UHFFFAOYSA-N 0.000 claims 1
- 125000000524 functional group Chemical group 0.000 claims 1
- 239000012046 mixed solvent Substances 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 12
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 abstract description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 abstract description 5
- 230000000840 anti-viral effect Effects 0.000 abstract description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 abstract 3
- 230000011987 methylation Effects 0.000 abstract 1
- 238000007069 methylation reaction Methods 0.000 abstract 1
- 230000003647 oxidation Effects 0.000 abstract 1
- 238000007254 oxidation reaction Methods 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 10
- 235000011167 hydrochloric acid Nutrition 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 239000012043 crude product Substances 0.000 description 5
- 238000003810 ethyl acetate extraction Methods 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 241000700721 Hepatitis B virus Species 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclopentanone Chemical compound O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000003252 repetitive effect Effects 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- YPDRJNPIGFCETD-UHFFFAOYSA-N 3-phenylmethoxy-2-(phenylmethoxymethyl)-6-oxabicyclo[3.1.0]hexane Chemical compound C12OC2CC(OCC=2C=CC=CC=2)C1COCC1=CC=CC=C1 YPDRJNPIGFCETD-UHFFFAOYSA-N 0.000 description 1
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 description 1
- RLAHWVDQYNDAGG-UHFFFAOYSA-N Methanetriol Chemical compound OC(O)O RLAHWVDQYNDAGG-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- XCIXKGXIYUWCLL-UHFFFAOYSA-N cyclopentanol Chemical compound OC1CCCC1 XCIXKGXIYUWCLL-UHFFFAOYSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- 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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a preparation method of a nucleoside compound, in particular to a preparation method of 2-amino-9- [ (1S, 3S, 4S) -4-hydroxy-3-hydroxymethyl-2-methylene amyl ] -1, 9-dihydro-6-H-purine-6-ketone, which takes [ 1S- (1 alpha, 2 beta, 3 alpha, 5 alpha) ] -3- (benzyloxy) -2- [ (benzyloxy) methyl ] -6-oxabicyclo [3.1.0] (compound shown in formula 2)) hexane as a starting material, obtains [ 1S- (1 alpha, 3 alpha, 4 beta) ] -5-succinimidyl-2-methylene-4- (benzyloxy) -3- [ (benzyloxy) methyl ] cyclopentane (compound shown in formula 5) by ammoniation, dess-mardin oxidation and nysted methylation, and condenses the compound shown in formula 5 with 2-amino-4-chloro-5-nitropyrimidinone (compound shown in formula 6), Then the target compound is obtained through cyclization, hydrolysis and other reactions. The invention has the advantages of easily obtained raw materials, high product yield and high yield, and the compound shown in the formula 6 is also an antiviral intermediate.
Description
Affiliated technical field
The preparation method of a kind of nucleoside compound of the present invention is specifically related to 2-amino-9-[(1S, 3S, 4S)-and 4-hydroxyl-3-methylol-2-methylene amyl group]-1, the preparation method of 9-dihydro-6-H-purine-6-one
Background technology
Formula 1 compound is the medicine of the treatment hepatitis B virus of U.S. Bristol-Myers Squibb Co. exploitation, goes on the market in China's approval in November, 2005, and be one of medicine for the treatment of at present hepatitis B virus, the 39 yuan/sheet in market price.Shi Guibao company has successively applied for method for preparing raw material in China, and number of patent application is: 91110831.9,200380105614, and aspect patent such as preparation.When using domestic raw material production the said products, therefore yield, is necessary to provide a kind of new preparation method only for to disclose 50% of described yield, reduces production costs, and improves yield.
Summary of the invention
The preparation method who the purpose of this invention is to provide the nucleoside compound of structure shown in a kind of formula 1.
It is as follows that the present invention prepares route:
The concrete steps of preparation formula 1 compound are as follows:
1, with [1s-(1 α, 2 β, 3 α, 5 α)]-and 3-(benzyloxy)-2-[(benzyloxy) methyl]-6-oxabicyclo [3.1.0] hexane (formula 2 compounds) is a kind of intermediate, and group with imine moiety (HNP) condensation production 3 compounds in the presence of highly basic reagent lithium hydride, temperature of reaction is preferably 120 ℃ between 100 ℃～150 ℃.Wherein, HNP can be succimide
Glutarimide
3,3-pentamethylene glutarimide
In a kind of.
2, formula 3 compounds are as intermediate and Dess Martin reagent generation oxidizing reaction production 4 compounds, and reaction at room temperature just can be carried out smoothly.
3, methylenation reaction generation [1s-(1 α takes place as intermediate and Nysted reagent in formula 4 compounds in the presence of titanium tetrachloride, 3 α, 4 β)]-and 5-succimide base-2-methylene radical-4-(benzyloxy)-3-[(benzyloxy) methyl] pentamethylene (formula 5 compounds), temperature of reaction is between-78 ℃～20 ℃.
4, formula 5 compounds as intermediate after hydrolysis under acidity or the alkaline condition and formula 6 compound condensations obtain formula 7 compounds.
5, become ring under intermediate 7 and orthoformic acid and acid or the acid anhydrides condition, as: triethyl orthoformate becomes ring production 8 in the presence of 2～4 equivalent concentrated hydrochloric acids, temperature of reaction 0～85 spend between, be preferably 25 and spend.
6, formula 8 compounds are as intermediate hydrolysis production 9 compounds under acidic conditions.
7, formula 9 compounds remove the protecting group benzyl as intermediate and generate target compounds of formula 1 compound in the presence of boron trichloride, and temperature of reaction is between-78 degree～20 degree.
Formula 8 compounds also can obtain target compound 1 by following approach:
1, formula 8 compounds obtain intermediate 10 as intermediate deprotection base in the presence of boron trichloride, and temperature of reaction is between-78 degree～20 degree.
2, intermediate 10 hydrolysis under acidity or alkaline condition obtains formula 1 compound.
Superiority of the present invention is: raw material is easy to get, and formula 6 compounds still are a kind of antiviral intermediate, product yield height.
Embodiment
1, methyl [1s-(1 α, 2 β, 3 α, 5 β)]-5-succimide-3-(benzyloxy)-2-[(benzyloxy)] preparation of cyclopentanol (formula 3 compounds):
In the 2L there-necked flask, add 600ml dry DMF and 65g (0.66mol) succimide, stir adding 2.3g LiH (0.33mol) down, continue to stir 30min, the solution becomes clarification.Drip 102.3g (0.33mol) formula 3 compounds again, heat temperature raising to 120 ℃, reaction 3h.TLC shows that raw material reaction finishes, and is cooled to room temperature, adds the 22ml Glacial acetic acid.Continue to stir 10 minutes, add 1000ml water and 400ml ethyl acetate, stir layering.Water with ethyl acetate extraction once merges organic phase.Anhydrous magnesium sulfate drying.Evaporated under reduced pressure, silicagel column separates, and gets pure formula 3 compounds of 90 grams.
2, methyl [2R-(2 α, 3 β, 5 α)]-5-succimide-3-(benzyloxy)-2-[(benzyloxy)] preparation of cyclopentanone (formula 4 compounds):
In the 2L there-necked flask, add 90g intermediate 3 (0.22mol) and 800ml methylene dichloride, stirring and dissolving.Gradation adds 100g (0.22mol) Dess-Martin oxidising agent, and the ice-water bath holding temperature is about 20 degree.After adding, continue to stir 20 minutes.TLC shows that raw material reaction finishes.Stir down, reaction solution joins in 500ml saturated sodium bicarbonate+500ml 10% S-WAT+500ml saturated brine, continues to stir 20 minutes.Layering, water merges organic phase, anhydrous magnesium sulfate drying, evaporated under reduced pressure with ethyl acetate extraction twice.Get crude product 90 grams.
3, methyl [1s-(1 α, 3 α, 4 β)]-5-succimide base-2-methylene radical-4-(benzyloxy)-3-[(benzyloxy)] preparation of pentamethylene (formula 5 compounds):
In the 2L there-necked flask, N
2Protection adds anhydrous THF of 200ml and 500ml (0.22mol) Nysted Reagent down.Stir, be cooled to-78 ℃, splash into 90g intermediate 4 (0.22mol) and 300ml CH
2Cl
2Mixture.Drip and finish, drip 1M TiCl again
4Solution 220ml, holding temperature is at-60 ℃～-78 ℃.Drip and finish, slowly rise to room temperature, continue to stir 3h, TLC shows that raw material reaction finishes.Stir down and pour reaction solution into 1.5L saturated NaHCO
3In, continue to stir 30 minutes.Layering, water ethyl acetate extraction 2 times merge organic phase, and anhydrous magnesium sulfate drying reclaims solvent and gets crude product 85 grams.
4, [1s-(1 α, 3 α, 4 β)]-2-amino-6-chloro-4-[[4-benzyloxy-3-(benzyloxy) methyl-2-methylene radical cyclopentyl] amino]-preparation of 5-formamido group-pyrimidine (formula 7 compounds):
In the 1L there-necked flask, add 85g intermediate 5 crude products and 600ml ethanol, stirring and dissolving.Add 25ml (0.26mol) concentrated hydrochloric acid, reflux 3 hours, TLC shows that the raw material spot disappears evaporated under reduced pressure.Add 20.7g 2-amino-4-chloro-5-nitro-pyrimidine ketone (formula 6 compounds) (0.10mo1) and 300ml ethanol, stir.Add the 50ml triethylamine, temperature rising reflux reacted 15 hours, and TLC detects raw material reaction and finishes.Evaporated under reduced pressure is with 10% ethanol/ethyl acetate crystallization.Filter, filter cake washs with ethyl acetate.Get 40.5 gram faint yellow solids.Yield: 82%.
5, [1s-(1 α, 3 α, 4 β)]-2-amino-6-chloro-9-[[4-benzyloxy-3-(benzyloxy) methyl-2-methylene radical cyclopentyl] amino]-preparation of 9-hydrogen-purine (formula 8 compounds):
In the 1L there-necked flask, add 40.5g intermediate 7 (0.082mol) and 810ml triethyl orthoformate, stir.Be cooled to 0 degree, add the 32.4ml concentrated hydrochloric acid.Stirring at room 5 hours.TLC detects raw material reaction and finishes.Filter, filter cake washs with ethyl acetate.50 degree decompression oven dry get 35.2 gram faint yellow solids.
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 (intermediate 9):
In the 1L there-necked flask, add 35.2 gram formulas 8 (0.074mol) and 0.74 liter of 1M hydrochloric acid, stir.Reflux 1 hour.TLC detects raw material reaction and finishes.Evaporated under reduced pressure is used the 500ml dissolved in distilled water, and lM hydrochloric acid is regulated PH=5.Cooling is filtered, filter cake 60 degree decompressions dry 23.0 gram off-white color solids.Yield: 68%.
7,2-amino-9-[(1S, 3S, 4S)-and 4-hydroxyl-3-methylol-2-methylene amyl group]-1, the preparation of 9-dihydro-6-H-purine-6-one:
In the 1L there-necked flask, under the nitrogen protection, add 23g intermediate 9 (0.05mol) and 300ml anhydrous methylene chloride.Stir, be cooled to-78 ℃, add the dichloromethane solution 300ml of 1M boron trichloride, be warming up to-20 ℃ after 1 hour, half an hour, postcooling was extremely-78 ℃, slowly added 1.6L methyl alcohol.Naturally rise to room temperature, add methyl alcohol 2.0L after the solvent removed in vacuo again.Twice of repetitive operation., use 700ml dissolved in distilled water residue then, solution is neutralized to neutrality with sodium hydroxide after with ethyl acetate extraction, has solid to separate out to 300ml solution concentration, obtains formula 1 crude product 10 grams (0.036mol) after the filtration, yield: 72.2%.
8,2-amino-9-[(1S, 3S, 4S)-and 4-hydroxyl-3-methylol-2-methylene amyl group]-1,9-dihydro-6-H-purine-6-one (formula 1) refining:
In the 1L there-necked flask, adding formula 1 compound crude product 10g and 200ml distilled water are heated to backflow, and dissolving adds the 0.3g gac, stirring and refluxing 20 minutes.Filter, filtrate is cooled to 0 ℃ of crystallization.Filter, collect filter cake, 50 ℃ of following vacuum-drying 8 hours, the pure product of 8.1g formula 1 compound, yield: 81.0%.
9, [1s-(1 α, 3 α, 4 β)]-2-amino-9-[4-hydroxyl-3-methylol-2-methylene radical cyclopentyl]-1, the preparation of 9-dihydro-6H-purine-6-one (formula 10 compounds):
In the 1L there-necked flask, under the nitrogen protection, add 35.2 gram intermediate 8 (0.074mol) and 444ml anhydrous methylene chlorides.Stir, be cooled to-78 ℃, add the dichloromethane solution 444ml of 1M boron trichloride, be warming up to-20 ℃ after 1 hour, half an hour, postcooling was extremely-78 ℃, slowly added 2.368L methyl alcohol.Naturally rise to room temperature, add methyl alcohol 2.96L after the solvent removed in vacuo again.Twice of repetitive operation., use 1.036L dissolved in distilled water residue then, solution is neutralized to neutrality with sodium hydroxide after with ethyl acetate extraction, has solid to separate out to 444ml solution concentration, obtains title compound 15.8 grams after the filtration, yield: 72.2%.
10,2-amino-9-[(1S, 3S, 4S)-and 4-hydroxyl-3-methylol-2-methylene amyl group]-1, the preparation of 9-dihydro-6-H-purine-6-one (formula 1):
In the 1L there-necked flask, under the nitrogen protection, add 15.8 gram intermediate 10 (0.053mol) and 0.53 liter of 1M hydrochloric acid, stir.Reflux 1 hour.TLC detects raw material reaction and finishes.Evaporated under reduced pressure is used the 360ml dissolved in distilled water, and 1M hydrochloric acid is regulated PH=5.Cooling is filtered, filter cake 60 degree decompressions dry 7.9 gram off-white color solids.Yield: 50.5%.
Claims (10)
1. the preparation method of a nucleoside compound, this nucleoside compound structural formula is a formula 1,
Formula 1
The preparation method comprises the steps:
(1), condensation in the presence of lithium hydride obtains formula 3 compounds to formula 2 compounds as initial compounds and a kind of group with imine moiety (HNP),
Wherein, P is an amido protecting functional group;
(2), formula 3 compounds and Dess Martin reagent generation oxidizing reaction obtain formula 4 compounds,
(3), the methylenation reaction takes place and obtains formula 5 compounds in formula 4 compounds and Nysted reagent in the presence of titanium tetrachloride,
Formula 6
(4), formula 5 compounds after hydrolysis under acidity or the alkaline condition and formula 6 compound condensations obtain formula 7 compounds,
Formula 7
(5), formula 7 compounds become ring to obtain formula 8 compounds in the presence of ortho-formiate and acid or acid anhydrides,
(6), the hydrolysis under acidity or alkaline condition of formula 8 compounds obtains formula 9 compounds, formula 9 compounds deprotection base in the presence of boron trichloride obtains formula 1 compound:
Formula 1;
(7) or formula 8 deprotection base in the presence of boron trichloride get formula 10, formula 10 hydrolysis under acidity or alkaline condition, formula 1 compound:
2. according to the preparation method of claim 1 nucleoside compound, it is characterized in that: the hydrolysis of formula 5 compounds is to carry out in the presence of hydrochloric acid or sodium hydroxide.
3. according to the preparation method of claim 1 nucleoside compound, it is characterized in that: the hydrolysis of described formula 5 compounds is carried out under ethanol and water mixed solvent condition.
4. according to the preparation method of claim 3 nucleoside compound, it is characterized in that: the condensation reaction of the hydrolysate of described formula 5 compounds and formula 6 compounds is carried out under base catalysis.
5. according to the preparation method of claim 1 nucleoside compound, it is characterized in that: the reaction solvent of the condensation of the hydrolysate of described formula 5 compounds and formula 6 compounds is selected a kind of or its combination in ethanol, Virahol, the propyl carbinol alcoholic solvent for use.
6. according to the preparation method of claim 1 nucleoside compound, it is characterized in that: in the annulation of described formula 7 compounds, one-tenth cyclization reagent and reaction solvent are a kind of or its combination in triethyl orthoformate or the trimethyl orthoformate.
7. according to the preparation method of claim 1 nucleoside compound, it is characterized in that: employed acid is the concentrated hydrochloric acid or the vitriol oil in the annulation of described formula 7 compounds, preferred concentrated hydrochloric acid; Described acid anhydrides is formic anhydride or diacetyl oxide, preferred diacetyl oxide.
8. according to the preparation method of claim 1 nucleoside compound, it is characterized in that: the hydrolysis of described formula 8 compounds is carried out under the acidic aqueous solution condition, and used acid is hydrochloric acid; Perhaps, hydrolysis is carried out under the alkaline aqueous solution condition, and used alkali is sodium hydroxide.
9. according to the preparation method of claim 1 nucleoside compound, it is characterized in that: the hydrolysis of described formula 10 compounds is carried out under the acidic aqueous solution condition, and used acid is hydrochloric acid; Perhaps, the hydrolysis of formula 10 compounds is carried out under the alkaline aqueous solution condition, and used alkali is sodium hydroxide.
10. according to the preparation method of claim 9 nucleoside compound, it is characterized in that: described group with imine moiety is a succimide
Glutarimide
, 3,3-pentamethylene glutarimide
In a kind of.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA200710047774XA CN101148450A (en) | 2007-11-02 | 2007-11-02 | Preparation method of nucleoside compound |
Applications Claiming Priority (1)
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