CN1415622A - Method for preparing 6-alkoxy-2',3'-double deoxidated guanosine - Google Patents
Method for preparing 6-alkoxy-2',3'-double deoxidated guanosine Download PDFInfo
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- CN1415622A CN1415622A CN 02138503 CN02138503A CN1415622A CN 1415622 A CN1415622 A CN 1415622A CN 02138503 CN02138503 CN 02138503 CN 02138503 A CN02138503 A CN 02138503A CN 1415622 A CN1415622 A CN 1415622A
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- guanosine
- alkoxyl group
- deoxidation
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Links
- 229940029575 guanosine Drugs 0.000 title claims abstract description 6
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical compound C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 title claims abstract 5
- 238000000034 method Methods 0.000 title claims description 6
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 title abstract 2
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 6
- OXTYJSXVUGJSGM-HTVVRFAVSA-N N-Isobutyrylguanosine Chemical compound C1=2NC(NC(=O)C(C)C)=NC(=O)C=2N=CN1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OXTYJSXVUGJSGM-HTVVRFAVSA-N 0.000 claims abstract description 5
- 230000029936 alkylation Effects 0.000 claims abstract description 3
- 238000005804 alkylation reaction Methods 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- 238000002360 preparation method Methods 0.000 claims description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- UYTPUPDQBNUYGX-UHFFFAOYSA-N Guanine Natural products O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 17
- -1 guanine nucleoside Chemical class 0.000 claims description 16
- 239000002777 nucleoside Substances 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 14
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 238000000926 separation method Methods 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 6
- 239000012065 filter cake Substances 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 5
- 238000004440 column chromatography Methods 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 230000006837 decompression Effects 0.000 claims description 4
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 239000000047 product Substances 0.000 claims description 4
- 239000000243 solution Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- 229910007565 Zn—Cu Inorganic materials 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- TVZPLCNGKSPOJA-UHFFFAOYSA-N copper zinc Chemical compound [Cu].[Zn] TVZPLCNGKSPOJA-UHFFFAOYSA-N 0.000 claims description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 2
- 235000002597 Solanum melongena Nutrition 0.000 claims description 2
- 244000061458 Solanum melongena Species 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 239000007789 gas Substances 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- LSACYLWPPQLVSM-UHFFFAOYSA-N isobutyric acid anhydride Chemical compound CC(C)C(=O)OC(=O)C(C)C LSACYLWPPQLVSM-UHFFFAOYSA-N 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 2
- 238000010992 reflux Methods 0.000 claims description 2
- 239000007787 solid Substances 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- OROIAVZITJBGSM-OBXARNEKSA-N 3'-deoxyguanosine Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](CO)C[C@H]1O OROIAVZITJBGSM-OBXARNEKSA-N 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 239000012141 concentrate Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- OCLZPNCLRLDXJC-NTSWFWBYSA-N 2-amino-9-[(2r,5s)-5-(hydroxymethyl)oxolan-2-yl]-3h-purin-6-one Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@H]1CC[C@@H](CO)O1 OCLZPNCLRLDXJC-NTSWFWBYSA-N 0.000 abstract 1
- KAXSTRNQRKPUNP-RUKNTYHSSA-N [[(2S,5R)-5-(2-amino-6-chloro-6-hydroxy-3H-purin-9-yl)oxolan-2-yl]-hydroxymethyl] acetate Chemical compound C(C)(=O)OC([C@@H]1CC[C@@H](O1)N1C=NC=2C(O)(NC(N)=NC12)Cl)O KAXSTRNQRKPUNP-RUKNTYHSSA-N 0.000 abstract 1
- XLPBAIYJSIMQKM-IBHKLULDSA-N [[(2S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)oxolan-2-yl]-hydroxymethyl] acetate Chemical compound C(C)(=O)OC([C@@H]1CC[C@@H](O1)N1C=NC=2C(=O)NC(N)=NC12)O XLPBAIYJSIMQKM-IBHKLULDSA-N 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- XNKLLVCARDGLGL-JGVFFNPUSA-N Stavudine Chemical compound O=C1NC(=O)C(C)=CN1[C@H]1C=C[C@@H](CO)O1 XNKLLVCARDGLGL-JGVFFNPUSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229960000523 zalcitabine Drugs 0.000 description 2
- CYDWUXHXQWOUKH-DTBIBVQVSA-N (2r,3r,4s,5r)-2-(2-amino-6-chloro-6-hydroxy-3h-purin-9-yl)-5-(hydroxymethyl)oxolane-3,4-diol Chemical compound OC1(Cl)NC(N)=NC2=C1N=CN2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O CYDWUXHXQWOUKH-DTBIBVQVSA-N 0.000 description 1
- HBOMLICNUCNMMY-UHFFFAOYSA-N 1-[4-azido-5-(hydroxymethyl)oxolan-2-yl]-5-methylpyrimidine-2,4-dione Chemical compound O=C1NC(=O)C(C)=CN1C1OC(CO)C(N=[N+]=[N-])C1 HBOMLICNUCNMMY-UHFFFAOYSA-N 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229910052701 rubidium Inorganic materials 0.000 description 1
- IGLNJRXAVVLDKE-UHFFFAOYSA-N rubidium atom Chemical compound [Rb] IGLNJRXAVVLDKE-UHFFFAOYSA-N 0.000 description 1
- 229960001203 stavudine Drugs 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229960002555 zidovudine Drugs 0.000 description 1
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 1
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- Saccharide Compounds (AREA)
Abstract
A process for preparing 6-alkoxy-2',3'-dideoxyguanosine from guanosine as initial raw material includes such steps as synthesizing 2',3'-deoxy-2',3'-dehydro-guanosine, ordinary-pressure reducing by 10% Pd/C, alkylation, preparing N2-isobutyryl guanosine, preparing 2',3'-dideoxy-2',3'-dihydro-N2-isobutyryl guanosine, preparing 2',3'-dideoxy-guanosine, preparing 5'-acetoxy-2',3'-dideoxy-guanosine, preparing 5'-acetoxy-6-chloro-2',3'-dideoxy-guanosine, and preparing target product. Advantages include mild reaction condition, low raw material price etc.
Description
Technical field
The present invention relates to a kind of preparation method of compound, relate to a kind of 6-alkoxyl group-2 ' specifically, the preparation method of 3 '-dideoxy guanine nucleoside.
Background technology
2 ' can be incorporated in the DNA chain as substrate by the DNA polymerase with 3 ' position deoxynucleoside.Because 3 ' position hydroxyl is damaged, the continuation prolongation of DNA chain is terminated.This principle is widely applied in the design of antiviral.As zidovudine (Zidovudine, AZT), zalcitabine (Zalcitabine, DDC), Si Tanfuding (Stavudine, D4T), the red promise heart (Didannosine, ddI) [people such as Mitsuya H., Science 1990,249,1533-44; People such as Huryn D.M., Chem.Rev.1992,92,1745; People such as De Clereq E., Nucleoside Nucleotide1994,13,1271-95; People such as De Clereq E., J.Med.Chem.1995,38,2491-517; People such as Mansour T.S., Current Pharmac.Design 1997,3,227]
Structural formula is the 6-alkoxyl group-2 ' of formula (1), and the existing report of the synthetic method of 3 '-dideoxy guanine nucleoside (people such as RobinsM.J.., J.Org.Chem.1995,60 (24), 7902-7908).Adopt 6-chloro-guanosine-as starting raw material; the first step with α-acetyl oxygen isobutyl bromide to hydroxyl bromo and acidylate on the sugar; second step removed bromine with zinc powder and generates two strong in acetum; the 3rd step deprotection in the methanol solution of ammonia obtains 6-chloro-2 '; 3 '-deoxidation-2 '; 3 '-dehydrogenation-guanosine-and 2 ', the 3 '-deoxidation-2 ' of 6-bromo-, the mixture that 3 '-dehydrogenation-guanosine-is formed.The 4th step is with RhAl
2O
3Be the catalyzer hydro-reduction; In alcoholic solution, replace at last, obtain target compound with sodium alkyl alcohol.Because as starting raw material, the chlorine atom can be replaced by bromine in the first step with unsettled 6-chloro-guanosine-, adopted the expensive catalysts rubidium in the 4th step, and had 20% nucleosides to take place to decompose in the reaction approximately to make into productive rate and descend.
Summary of the invention
The technical problem to be solved in the present invention is exactly rare, the synthetic high problem of cost of prior art raw material.
The invention provides a kind of preparation formula (I) 6-alkoxyl group-2 ', the novel method of 3 '-dideoxy guanine nucleoside.The following Fig. 1 of reflection route.By guanosine-cheap and easy to get is starting raw material, at first Synthetic 2 ', 3 '-deoxidation-2 ', 3 '-dehydrogenation-guanosine-, with the reduction of 10%Pd/C normal pressure, yield reaches 80%.Then chloro carries out alkylation without separation, makes product through six-step process.This route reaction mild condition, cost of material is lower, is fit to mass production.
A.[(CH
3)
2CH]
2CO/HMDSA b.CH3COOC (CH3) 2COB/ anhydrous acetonitrile/ethyl acetate/anhydrous methanol c.Zn-Cu is neat/methanol/ethyl acetate/sodium/chloroform methanol column chromatography for separation pyridine/aceticanhydride/acetone f.TEBA/N d.10%Pd/ce., and N-Diethyl Aniline/anhydrous acetonitrile/POCI3 g. absolute alcohol/sodium Metal 99.5
Embodiment
Specifically describe detailed process process of the present invention below.
1, preparation N
2-isobutyryl guanosine
Guanine (20.0g, 70.67mmol), exsiccant DMF (75ml), add hmds (110ml), stirred 12.5 hours, be cooled to 10 ℃, add pyridine (100ml), isobutyric anhydride (180ml) reacted 24 hours, cool to 0 ℃, add methyl alcohol (200ml), reacted 4 hours, be concentrated into 100ml, add the mixed solution (500ml) of normal hexane and ether (1: 1), placement is spent the night, filter faint yellow solid 24g, yield 96%.
2, preparation 2 ', 3 '-two deoxidations-2 ', 3 '-two dehydrogenation-N
2-isobutyryl guanosine
N
2-isobutyryl guanosine (6.74g, 20mmol), dry acetonitrile (80ml), add water 0.4ml, add acetyl oxygen isobutyl bromide again, stirring at room 1 hour, filter, filtrate adds ethyl acetate (200ml), washes with water to neutrality, with being concentrated into 50ml behind the anhydrous magnesium sulfate drying, add the Zn-Cu agent of new system, vigorous stirring 5 minutes, filter, the filter cake methanol wash, merging filtrate also is spin-dried for, add ethyl acetate 250ml, wash neutrality with water, be spin-dried for after the drying, add methyl alcohol 100ml, the sodium methoxide solution that adds 20mmol again, stirring at room 10 minutes adds the acetate neutrality that neutralizes, column chromatography for separation (chloroform: methyl alcohol=9: 1) then, get object 2.4g, yield 45%.
3, preparation 2 ', 3 '-two deoxidation-guanosines
2 ', 3 '-two deoxidations-2 ', 3 '-two dehydrogenation-N
2-isobutyryl guanosine (6.38g 20mmol), adds methyl alcohol (150ml), 10% palladium carbon 0.03g, normal pressure hydrogenation till do not inhale hydrogen, filtration, the filter cake methanol wash, concentrated filtrate gets object 5.10g, yield 88%.
4, preparation 5 '-acetyl oxygen-2 ', 3 '-two deoxidation-guanosines
2 ', 3 '-two deoxidation-guanosines (3.94g, 0.0157mol), pyridine (4ml) and diacetyl oxide (60ml) add reaction flask, and stirring at room to TLC demonstration reacts completely.Filter, with the washing with acetone filter cake, after the drying almost with quantitative product.
5, preparation 5 '-acetyl oxygen-6-chloro-2 ', 3 '-two deoxidation-guanosines
Add 5 '-acetyl oxygen-2 ' in the 150ml reaction flask, 3 '-two deoxidation-guanosine (4.4g, 0.015mol), EDTA (6g, 0.026mol) exsiccant N, N-Diethyl Aniline (2.8ml, 0.0176mol) and anhydrous acetonitrile 100ml, stirring at room 10 minutes, and the new POCI3 that steams of adding (8ml, 0.086mol), reflux, the decompression of cooling back steams solvent.To remain oily matter and add frozen water, with methylene dichloride (4 * 100ml) extractions, spissated oily matter behind the dry extraction liquid, through the post level separate object 4.1g, yield 73%.
6, preparation 6-alkoxyl group-2 ', 3 '-dideoxy guanine nucleoside
Add the anhydrous 5 '-acetyl oxygen of 250ml-6-chloro-2 ' in the 50ml eggplant type bottle, 3 '-two deoxidations-guanosine alcohol, and the adding sodium Metal 99.5 (100mg, 4.35mmol), stirring at room does not produce to there being gas, adding 5 '-acetyl oxygen-6-chloro-2 ', 3 '-two deoxidation-guanosines (262Mg, 0.84mmol), stirring at room to TLC demonstration reacts completely, decompression steams solvent, and column chromatography for separation makes object 231mg, yield 91%
Claims (8)
1, a kind of 6-alkoxyl group-2 ', the preparation method of 3 '-dideoxy guanine nucleoside is characterized in that it is is starting raw material, at first Synthetic 2 with the guanosine-', 3 '-deoxidation-2 ', 3 '-dehydrogenation-guanosine-is with the reduction of 10%Pd/C normal pressure; Then chloro carries out alkylation without separation, makes product through six-step process.
2,6-alkoxyl group-2 ' as claimed in claim 1, the preparation method of 3 '-dideoxy guanine nucleoside is characterized in that comprising the steps:
(1) preparation N
2-isobutyryl guanosine;
(2) preparation 2 ', 3 '-two deoxidations-2 ', 3 '-two dehydrogenation-N
2-isobutyryl guanosine;
(3) preparation 2 ', 3 '-two deoxidation-guanosines;
(4) preparation 5 '-acetyl oxygen-2 ', 3 '-two deoxidation-guanosines;
(5) preparation 5 '-acetyl oxygen-6-chloro-2 ', 3 '-two deoxidation-guanosines;
(6) preparation 6-alkoxyl group-2 ', 3 '-dideoxy guanine nucleoside;
3,6-alkoxyl group-2 ' as claimed in claim 2, the preparation method of 3 '-dideoxy guanine nucleoside is characterized in that described step (1) comprises the steps:
A. get guanine, exsiccant DMF, add hmds, stirred 12.5 hours, be cooled to 10 ℃;
B. add pyridine, isobutyric anhydride, reacted 24 hours, cool to 0 ℃;
C. add methyl alcohol, reacted 4 hours, concentrate;
D. add the mixed solution of normal hexane and ether (1: 1), placement is spent the night, filter faint yellow solid.
4,6-alkoxyl group-2 ' as claimed in claim 2, the preparation method of 3 '-deoxyguanosine is characterized in that described step (2) comprises the steps:
A. get N
2-isobutyryl guanosine, dry acetonitrile add water, add acetyl oxygen isobutyl bromide again, stirring at room 1 hour;
B. filter, filtrate adds ethyl acetate, washes with water to neutrality, with concentrating behind the anhydrous magnesium sulfate drying;
C. the Zn-Cu agent that adds new system, vigorous stirring 5 minutes is filtered the filter cake methanol wash;
D. merging filtrate and being spin-dried for adds ethyl acetate, washes neutrality with water, is spin-dried for after the drying;
F. add methyl alcohol, add sodium methoxide solution again, stirring at room 10 minutes adds the acetate neutrality that neutralizes then, column chromatography for separation (chloroform: methyl alcohol=9: 1), object.
5,6-alkoxyl group-2 ' as claimed in claim 2, the preparation method of 3 '-dideoxy guanine nucleoside is characterized in that described step (3) comprises the steps:
A. get 2 ', 3 '-two deoxidations-2 ', 3 '-two dehydrogenation-N
2-isobutyryl guanosine adds methyl alcohol, 10% palladium carbon 0.03g, and normal pressure hydrogenation is not till inhale hydrogen;
B. filter, the filter cake methanol wash, concentrated filtrate gets object.
6,6-alkoxyl group-2 ' as claimed in claim 2, the preparation method of 3 '-dideoxy guanine nucleoside is characterized in that described step (4) comprises the steps:
A. get 2 ', 3 '-two deoxidation-guanosines, pyridine (4m1) and diacetyl oxide and add reaction flask, stirring at room to TLC demonstration reacts completely;
B. filter, with the washing with acetone filter cake, after the drying almost with quantitative product.
7,6-alkoxyl group-2 ' as claimed in claim 2, the preparation method of 3 '-dideoxy guanine nucleoside is characterized in that described step (5) comprises the steps:
A. in reaction flask, add 5 '-acetyl oxygen-2 ', 3 '-two deoxidation-guanosines, EDTA, exsiccant N, N-Diethyl Aniline and anhydrous acetonitrile, stirring at room 10 minutes;
B. add the new POCI3 that steams, reflux, the decompression of cooling back steams solvent;
C. will remain oily matter and add frozen water, with dichloromethane extraction, spissated oily matter behind the dry extraction liquid, through the post level separate object.
8,6-alkoxyl group-2 ' as claimed in claim 2,3, the preparation method of-dideoxy guanine nucleoside is characterized in that described step (6) comprises the steps:
A. add anhydrous 5 '-acetyl oxygen-6-chloro-2 ', 3 '-two deoxidations-guanosine alcohol in eggplant type bottle, and add sodium Metal 99.5, stirring at room does not produce to there being gas;
B. add 5 '-acetyl oxygen-6-chloro-2 ', 3 '-two deoxidation-guanosines, stirring at room to TLC demonstration reacts completely;
C. decompression steams solvent, and column chromatography for separation makes object.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021385033A CN1309732C (en) | 2002-10-28 | 2002-10-28 | Method for preparing 6-alkoxy-2',3'-double deoxidated guanosine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB021385033A CN1309732C (en) | 2002-10-28 | 2002-10-28 | Method for preparing 6-alkoxy-2',3'-double deoxidated guanosine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1415622A true CN1415622A (en) | 2003-05-07 |
| CN1309732C CN1309732C (en) | 2007-04-11 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB021385033A Expired - Lifetime CN1309732C (en) | 2002-10-28 | 2002-10-28 | Method for preparing 6-alkoxy-2',3'-double deoxidated guanosine |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009089702A1 (en) | 2008-01-17 | 2009-07-23 | Nanjing Changao Pharmaceutical Science & Technology Co., Limited | Stable 6-methoxy-2',3'-dideoxyguanosine, method for preparing the same and pharmaceutical composition containing the same |
| CN117586307A (en) * | 2024-01-19 | 2024-02-23 | 凯莱英生命科学技术(天津)有限公司 | PMO guanosine monomer synthesis method |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AP160A (en) * | 1987-08-15 | 1991-11-18 | The Wellcome Foundation Ltd | Therapeutic acyclic nucleosides. |
| CN1091445C (en) * | 1999-12-29 | 2002-09-25 | 湖北省医药工业研究院 | Internmediate of anti viral medicine, their preparation and use |
-
2002
- 2002-10-28 CN CNB021385033A patent/CN1309732C/en not_active Expired - Lifetime
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009089702A1 (en) | 2008-01-17 | 2009-07-23 | Nanjing Changao Pharmaceutical Science & Technology Co., Limited | Stable 6-methoxy-2',3'-dideoxyguanosine, method for preparing the same and pharmaceutical composition containing the same |
| US8349811B2 (en) | 2008-01-17 | 2013-01-08 | Nanjing Changao Pharmaceutical Science & Technology Co., Limited | Stable 6-methoxy-2′,3′-dideoxyguanosine, method for preparing the same and pharmaceutical composition containing the same |
| CN117586307A (en) * | 2024-01-19 | 2024-02-23 | 凯莱英生命科学技术(天津)有限公司 | PMO guanosine monomer synthesis method |
| CN117586307B (en) * | 2024-01-19 | 2024-04-16 | 凯莱英生命科学技术(天津)有限公司 | PMO guanosine monomer synthesis method |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1309732C (en) | 2007-04-11 |
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