JPH11502826A - ヌクレオシド類似体の合成方法 - Google Patents
ヌクレオシド類似体の合成方法Info
- Publication number
- JPH11502826A JPH11502826A JP8528932A JP52893296A JPH11502826A JP H11502826 A JPH11502826 A JP H11502826A JP 8528932 A JP8528932 A JP 8528932A JP 52893296 A JP52893296 A JP 52893296A JP H11502826 A JPH11502826 A JP H11502826A
- Authority
- JP
- Japan
- Prior art keywords
- ethoxy
- formula
- oxathiolan
- pyrimidin
- fluoro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims abstract description 25
- 239000002777 nucleoside Substances 0.000 title abstract description 10
- 150000003833 nucleoside derivatives Chemical class 0.000 title description 2
- 230000002194 synthesizing effect Effects 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 39
- 239000000203 mixture Substances 0.000 claims description 36
- -1 hydroxy, amino Chemical group 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 150000002367 halogens Chemical class 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 12
- 150000002431 hydrogen Chemical group 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 11
- 239000002841 Lewis acid Substances 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 150000007517 lewis acids Chemical class 0.000 claims description 9
- 230000003287 optical effect Effects 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- YUIOPHXTILULQC-UHFFFAOYSA-N 1,4-Dithiane-2,5-diol Chemical compound OC1CSC(O)CS1 YUIOPHXTILULQC-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- 239000001677 (2R,5R)-1,4-dithiane-2,5-diol Substances 0.000 claims description 5
- 239000003880 polar aprotic solvent Substances 0.000 claims description 5
- CLJNSJBNZBWLSU-BDAKNGLRSA-N 4-ethoxy-1-[(2s,5r)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]pyrimidin-2-one Chemical compound O=C1N=C(OCC)C=CN1[C@@H]1O[C@H](CO)SC1 CLJNSJBNZBWLSU-BDAKNGLRSA-N 0.000 claims description 4
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- DLNKOYKMWOXYQA-UHFFFAOYSA-N dl-pseudophenylpropanolamine Natural products CC(N)C(O)C1=CC=CC=C1 DLNKOYKMWOXYQA-UHFFFAOYSA-N 0.000 claims description 4
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 4
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims description 3
- DLNKOYKMWOXYQA-VXNVDRBHSA-N (+)-norephedrine Chemical compound C[C@@H](N)[C@@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-VXNVDRBHSA-N 0.000 claims description 2
- DLNKOYKMWOXYQA-CBAPKCEASA-N (-)-norephedrine Chemical compound C[C@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-CBAPKCEASA-N 0.000 claims description 2
- HIFHEYYHDHORTR-UHFFFAOYSA-N 2-(4-ethoxypyrimidin-2-yl)oxyacetaldehyde Chemical compound CCOC1=CC=NC(OCC=O)=N1 HIFHEYYHDHORTR-UHFFFAOYSA-N 0.000 claims description 2
- PKLFGVBOPRTJMD-GXSJLCMTSA-N [(2r,5s)-5-(4-ethoxy-5-fluoro-2-oxopyrimidin-1-yl)-1,3-oxathiolan-2-yl]methyl propanoate Chemical compound C1=C(F)C(OCC)=NC(=O)N1[C@H]1O[C@@H](COC(=O)CC)SC1 PKLFGVBOPRTJMD-GXSJLCMTSA-N 0.000 claims description 2
- HGDZDHQIQFSJIX-UHFFFAOYSA-N [2-[(4-ethoxy-5-fluoropyrimidin-2-yl)oxymethyl]-1,3-oxathiolan-5-yl] acetate Chemical compound C1=C(F)C(OCC)=NC(OCC2SCC(O2)OC(C)=O)=N1 HGDZDHQIQFSJIX-UHFFFAOYSA-N 0.000 claims description 2
- 238000001212 derivatisation Methods 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims 7
- 125000002252 acyl group Chemical group 0.000 claims 2
- FJKYFKBZMRPFGI-UHFFFAOYSA-N 2-(2,2-dimethoxyethoxy)-4-ethoxy-5-fluoropyrimidine Chemical compound CCOC1=NC(OCC(OC)OC)=NC=C1F FJKYFKBZMRPFGI-UHFFFAOYSA-N 0.000 claims 1
- NLFRDKMWZHMSFP-UHFFFAOYSA-N 2-(4-ethoxy-5-fluoropyrimidin-2-yl)oxyacetaldehyde Chemical compound CCOC1=NC(OCC=O)=NC=C1F NLFRDKMWZHMSFP-UHFFFAOYSA-N 0.000 claims 1
- RUWZHDXXQQVYBD-UHFFFAOYSA-N 2-[(4-ethoxy-5-fluoropyrimidin-2-yl)oxymethyl]-1,3-oxathiolan-5-ol Chemical compound C1=C(F)C(OCC)=NC(OCC2SCC(O)O2)=N1 RUWZHDXXQQVYBD-UHFFFAOYSA-N 0.000 claims 1
- NNSWGDKXSOGUOD-SFYZADRCSA-N 4-ethoxy-5-fluoro-1-[(2s,5r)-2-(hydroxymethyl)-1,3-oxathiolan-5-yl]pyrimidin-2-one Chemical compound C1=C(F)C(OCC)=NC(=O)N1[C@@H]1O[C@H](CO)SC1 NNSWGDKXSOGUOD-SFYZADRCSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 10
- 230000000840 anti-viral effect Effects 0.000 abstract description 4
- 238000006206 glycosylation reaction Methods 0.000 abstract description 4
- WJJSZTJGFCFNKI-UHFFFAOYSA-N 1,3-oxathiolane Chemical compound C1CSCO1 WJJSZTJGFCFNKI-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 28
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 239000002904 solvent Substances 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 15
- 239000000284 extract Substances 0.000 description 14
- 239000000460 chlorine Substances 0.000 description 12
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 12
- 239000008346 aqueous phase Substances 0.000 description 11
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 7
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000012230 colorless oil Substances 0.000 description 6
- 229940104302 cytosine Drugs 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- 229910000831 Steel Inorganic materials 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 239000003921 oil Substances 0.000 description 4
- 235000019198 oils Nutrition 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 239000010959 steel Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- 108090000371 Esterases Proteins 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- 239000004809 Teflon Substances 0.000 description 3
- 229920006362 Teflon® Polymers 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 150000001720 carbohydrates Chemical class 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 230000013595 glycosylation Effects 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- LOZWAPSEEHRYPG-UHFFFAOYSA-N 1,4-dithiane Chemical compound C1CSCCS1 LOZWAPSEEHRYPG-UHFFFAOYSA-N 0.000 description 2
- 102100027324 2-hydroxyacyl-CoA lyase 1 Human genes 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- 101001009252 Homo sapiens 2-hydroxyacyl-CoA lyase 1 Proteins 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- YHASWHZGWUONAO-UHFFFAOYSA-N butanoyl butanoate Chemical compound CCCC(=O)OC(=O)CCC YHASWHZGWUONAO-UHFFFAOYSA-N 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 1
- WJRPLNODFHBCQD-UHFFFAOYSA-N 2-(2,2-dimethoxyethoxy)-4-ethoxypyrimidine Chemical compound CCOC1=CC=NC(OCC(OC)OC)=N1 WJRPLNODFHBCQD-UHFFFAOYSA-N 0.000 description 1
- FAXWOOXWNJNCJE-UHFFFAOYSA-N 2-[(4-ethoxypyrimidin-2-yl)oxymethyl]-1,3-oxathiolan-5-ol Chemical compound CCOC1=CC=NC(OCC2SCC(O)O2)=N1 FAXWOOXWNJNCJE-UHFFFAOYSA-N 0.000 description 1
- HRPOUYCSSTWMEQ-UHFFFAOYSA-N 2-chloro-4-ethoxy-5-fluoropyrimidine Chemical compound CCOC1=NC(Cl)=NC=C1F HRPOUYCSSTWMEQ-UHFFFAOYSA-N 0.000 description 1
- SFLGIMGLWCVAHP-UHFFFAOYSA-N 5h-oxathiole Chemical compound C1OSC=C1 SFLGIMGLWCVAHP-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 1
- ICKLXISMHNLMQT-UHFFFAOYSA-N ClC1=NC=CC(=N1)Cl.ClC1=NC=CC(=N1)OCC Chemical compound ClC1=NC=CC(=N1)Cl.ClC1=NC=CC(=N1)OCC ICKLXISMHNLMQT-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- OIKLJFVWDZOFPT-UHFFFAOYSA-N OC(CC1)CS[S+]1O Chemical compound OC(CC1)CS[S+]1O OIKLJFVWDZOFPT-UHFFFAOYSA-N 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- NOMSWCCJZPAACH-UHFFFAOYSA-N [2-[(4-ethoxypyrimidin-2-yl)oxymethyl]-1,3-oxathiolan-5-yl] acetate Chemical compound CCOC1=CC=NC(OCC2SCC(O2)OC(C)=O)=N1 NOMSWCCJZPAACH-UHFFFAOYSA-N 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001244 carboxylic acid anhydrides Chemical class 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- 150000001805 chlorine compounds Chemical group 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical class O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 150000002243 furanoses Chemical class 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 229940127073 nucleoside analogue Drugs 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- MWKJTNBSKNUMFN-UHFFFAOYSA-N trifluoromethyltrimethylsilane Chemical compound C[Si](C)(C)C(F)(F)F MWKJTNBSKNUMFN-UHFFFAOYSA-N 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D411/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms
- C07D411/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D411/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen and sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Cephalosporin Compounds (AREA)
Abstract
Description
Claims (1)
- 【特許請求の範囲】 1. 式(I) (式中、Rは水素、C1-6アルキルまたはハロゲンであり、Yはヒドロキシ、ア ミノ、C1-6アルコキシまたはOR1であり、R1はキラル補助基である) の化合物の製造方法であって、式(II) (式中、RおよびYは上記定義通りであり、R2は水素、C1-6アシル、C1-6ア ルキルまたはハロゲンである) の化合物を、基OR2を脱離基に変換するのに適した適当なルイス酸または試薬 で処理することを含む方法。 2. 式(Ia) (式中、Rは水素、C1-6アルキルまたはハロゲンであり、Yはヒドロキシ、ア ミノ、C1-6アルコキシまたはOR1であり、R1はキラル補助基である) の化合物の製造方法であって、式(IIa) (式中、R、YおよびR2は上記定義通りである) の化合物を、基OR2を脱離基に変えるのに適した適当なルイス酸または試薬で 処理することを含む方法。 3. ルイス酸が塩化第二スズまたはトリメチルシリルトリフレートである、 請求項1または2に記載の方法。 4. ルイス酸が塩化第二スズであり、処理を極性非プロトン性溶媒中、低温 で行う、請求項3に記載の方法。 5. 式(II)の化合物を、式(III) (式中、Rは水素、C1-6アルキルまたはハロゲンであり、Yはヒドロキシ、ア ミノ、C1-6アルコキシまたはOR1であり、R1はキラル補助基である) の化合物と、1,4−ジチアン−2,5−ジオールとを反応させ、そして必要ま たは望ましいならば、誘導体化することによって製造する、請求項1〜4のいず れか一項に記載の方法。 6. 1,4−ジチアン−2,5−ジオールとの反応を、非極性非プロトン性 溶媒中、高温で行う、請求項5に記載の方法。 7. 1,4−ジチアン−2,5−ジオールとの反応を、無水トルエン中、約 100℃で行う、請求項6に記載の方法。 8. RがHであり、YがOR1である式(IIa)の化合物を、少なくとも一 部が溶液中の異性体混合物を、RがHであり、YがOR1である所望の単一の光 学的対掌体(IIa)の結晶化を完全に抑制することなく異性体の相互変換を行う ことができる薬剤で処理することによって異性体混合物から得る方法。 9. 式(IV) (式中、R(同一でも異なっていてもよい)は水素、C1-6アルキルまたはハロ ゲンであり、Yはヒドロキシ、アミノ、C1-6アルコキシまたはOR1であり、R1 はキラル補助基である) の化合物であって、2−(2,2−ジメトキシエトキシ)−4−エトキシ−5− フルオロピリミジンおよび2−(2,2−ジメトキシエトキシ)−4−エトキシ −5−ピリミジンから選択される化合物。 10. 請求項5で定義した式(III) の化合物であって、2−[(4−エトキシ−5−フルオロ−2−ピリミジニル) オキシ]アセトアルデヒドおよび2−[(4−エトキシ−2−ピリミジニル)オ キシ]アセトアルデヒドから選択される化合物。 11. 請求項1で定義した式(II) の化合物であって、2−{[(4−エトキシ−5−フルオロ−2−ピリミジニル )オキシ]メチル}−1,3−オキサチオラン−5−オール、2−{[(4−エ トキシ−2−ピリミジニル)オキシ]メチル}−1,3−オキサチオラン−5− オール、2−{[(4−エトキシ−5−フルオロ−2−ピリミジニル)オキシ] メ チル}−1,3−オキサチオラン−5−イル アセテートおよび2−{[(4− エトキシ−2−ピリミジニル)オキシ]メチル}−1,3−オキサチオラン−5 −イル アセテートから選択される化合物。 12. 式(IIa) (式中、Rは水素、C1-6アルキルまたはハロゲンであり、R2は水素、C1-6ア シル、C1ー6アルキルまたはハロゲンであり、YはOR1であり、R1は(d)− メンチル、(1)−メンチル、(d)−8−フェニルメンチル、(1)−8−フ ェニルメンチル、(+)−ノルエフェドリンまたは(−)−ノルエフェドリンで ある) の化合物。 13. R1が(1)−メンチルである、請求項12に記載の化合物。 14. 請求項1で定義した式(I) の化合物であって、(2S*,5R*)−4−エトキシ−5−フルオロ−1− [2−(ヒドロキシメチル)−1,3−オキサチオラン−5−イル]ピリミジン −2−オンおよび(2S*,5R*)−4−エトキシ−1−[2−(ヒドロキシメ チル)−1,3−オキサチオラン−5−イル]ピリミジン−2−オンから選択さ れる化合物。 15. 式(VIII) (式中、R(同一でも異なっていてもよい)は水素、C1-6アルキルまたはハロ ゲンであり、XはSであり、Yはヒドロキシ、アミノまたはC1-6アルコキシで ある) の化合物であって、(2S*,5R*)−4−エトキシ−5−フルオロ−1−[2 −(プロピオニルオキシメチル)−1,3−オキサチオラン−5−イル]ピリミ ジン−2−オンおよび(2S*,5R*)−4−エトキシ−1−[2−(プロピオ ニルオキシメチル)−1,3−オキサチオラン−5−イル]ピリミジン−2−オ ンから選択される化合物。 16. 式(IX) (式中、Rは水素、C1-6アルキルまたはハロゲンであり、Yはヒドロキシ、ア ミノまたはC1-6アルコキシである) の化合物であって、(2S,5R)−4−エトキシ−5−フルオロ−1−[2− (ヒドロキシメチル)−1,3−オキサチオラン−5−イル]ピリミジン−2− オンおよび(2S,5R)−4−エトキシ−1−[2−(ヒドロキシメチル)− 1,3−オキサチオラン−5−イル]ピリミジン−2−オンから選択される化合 物。 17. 式(X) (式中、R(同一でも異なっていてもよい)は水素、C1-6アルキルまたはハロ ゲンであり、Yはヒドロキシ、アミノまたはC1-6アルコキシである) の化合物であって、(2R,5S)−4−エトキシ−5−フルオロ−1−[2− (プロピオニルオキシメチル)−1,3−オキサチオラン−5−イル]ピリミジ ン−2−オンおよび(2R,5S)−4−エトキシ−1−[2−(プロピオニル オキシメチル)−1,3−オキサチオラン−5−イル]ピリミジン−2−オンか ら選択される化合物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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GBGB9506644.5A GB9506644D0 (en) | 1995-03-31 | 1995-03-31 | Preparation of nucleoside analogues |
GB9506644.5 | 1995-03-31 | ||
PCT/EP1996/001353 WO1996030369A1 (en) | 1995-03-31 | 1996-03-26 | Process for the synthesis of nucleoside analogues |
Publications (2)
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JPH11502826A true JPH11502826A (ja) | 1999-03-09 |
JP4173195B2 JP4173195B2 (ja) | 2008-10-29 |
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JP52893296A Expired - Lifetime JP4173195B2 (ja) | 1995-03-31 | 1996-03-26 | ヌクレオシド類似体の合成方法 |
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US (2) | US6143748A (ja) |
EP (1) | EP0817784B1 (ja) |
JP (1) | JP4173195B2 (ja) |
CN (2) | CN1995022B (ja) |
AT (1) | ATE241619T1 (ja) |
AU (1) | AU5497396A (ja) |
BR (2) | BR9607850B1 (ja) |
DE (1) | DE69628424T2 (ja) |
DK (1) | DK0817784T3 (ja) |
ES (1) | ES2200060T3 (ja) |
GB (1) | GB9506644D0 (ja) |
HK (1) | HK1009451A1 (ja) |
HU (1) | HU223100B1 (ja) |
NO (1) | NO316174B1 (ja) |
PL (1) | PL188693B1 (ja) |
PT (1) | PT817784E (ja) |
WO (1) | WO1996030369A1 (ja) |
Families Citing this family (4)
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GB9506644D0 (en) * | 1995-03-31 | 1995-05-24 | Wellcome Found | Preparation of nucleoside analogues |
KR100856416B1 (ko) | 1998-08-12 | 2008-09-04 | 길리애드 사이언시즈, 인코포레이티드 | 1,3-옥사티올란 뉴클레오시드의 제조 방법 |
US6979561B1 (en) | 1998-10-09 | 2005-12-27 | Gilead Sciences, Inc. | Non-homogeneous systems for the resolution of enantiomeric mixtures |
CN110156699A (zh) * | 2019-05-22 | 2019-08-23 | 南京合巨药业有限公司 | 一种4-乙氧基-1h-嘧啶-2-酮的制备方法 |
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US5204466A (en) * | 1990-02-01 | 1993-04-20 | Emory University | Method and compositions for the synthesis of bch-189 and related compounds |
ZA923640B (en) * | 1991-05-21 | 1993-02-24 | Iaf Biochem Int | Processes for the diastereoselective synthesis of nucleosides |
GB9116601D0 (en) * | 1991-08-01 | 1991-09-18 | Iaf Biochem Int | 1,3-oxathiolane nucleoside analogues |
JP3499896B2 (ja) * | 1993-03-12 | 2004-02-23 | 財団法人野口研究所 | 2’−デオキシヌクレオシド類の製造方法 |
IL113432A (en) * | 1994-04-23 | 2000-11-21 | Glaxo Group Ltd | Process for the diastereoselective synthesis of nucleoside analogues |
GB9506644D0 (en) * | 1995-03-31 | 1995-05-24 | Wellcome Found | Preparation of nucleoside analogues |
-
1995
- 1995-03-31 GB GBGB9506644.5A patent/GB9506644D0/en active Pending
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1996
- 1996-03-26 CN CN200710001872XA patent/CN1995022B/zh not_active Expired - Lifetime
- 1996-03-26 AT AT96911954T patent/ATE241619T1/de active
- 1996-03-26 DE DE69628424T patent/DE69628424T2/de not_active Expired - Lifetime
- 1996-03-26 ES ES96911954T patent/ES2200060T3/es not_active Expired - Lifetime
- 1996-03-26 DK DK96911954T patent/DK0817784T3/da active
- 1996-03-26 WO PCT/EP1996/001353 patent/WO1996030369A1/en active IP Right Grant
- 1996-03-26 CN CNB961930160A patent/CN1290845C/zh not_active Expired - Lifetime
- 1996-03-26 BR BRPI9607850-2A patent/BR9607850B1/pt not_active IP Right Cessation
- 1996-03-26 PT PT96911954T patent/PT817784E/pt unknown
- 1996-03-26 AU AU54973/96A patent/AU5497396A/en not_active Abandoned
- 1996-03-26 PL PL96322503A patent/PL188693B1/pl unknown
- 1996-03-26 BR BRPI9607850A patent/BRPI9607850B8/pt unknown
- 1996-03-26 HU HU9801576A patent/HU223100B1/hu active IP Right Grant
- 1996-03-26 US US08/930,224 patent/US6143748A/en not_active Expired - Lifetime
- 1996-03-26 JP JP52893296A patent/JP4173195B2/ja not_active Expired - Lifetime
- 1996-03-26 EP EP96911954A patent/EP0817784B1/en not_active Expired - Lifetime
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Also Published As
Publication number | Publication date |
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US6066733A (en) | 2000-05-23 |
HUP9801576A3 (en) | 2000-07-28 |
BR9607850B1 (pt) | 2010-11-30 |
EP0817784B1 (en) | 2003-05-28 |
ES2200060T3 (es) | 2004-03-01 |
HK1009451A1 (en) | 1999-09-10 |
DK0817784T3 (da) | 2003-09-08 |
DE69628424D1 (de) | 2003-07-03 |
BRPI9607850B8 (pt) | 2019-11-05 |
DE69628424T2 (de) | 2004-03-18 |
ATE241619T1 (de) | 2003-06-15 |
NO974512D0 (no) | 1997-09-29 |
EP0817784A1 (en) | 1998-01-14 |
AU5497396A (en) | 1996-10-16 |
JP4173195B2 (ja) | 2008-10-29 |
CN1180356A (zh) | 1998-04-29 |
PL188693B1 (pl) | 2005-03-31 |
HUP9801576A2 (hu) | 1999-05-28 |
NO316174B1 (no) | 2003-12-22 |
CN1995022A (zh) | 2007-07-11 |
GB9506644D0 (en) | 1995-05-24 |
BR9607850A (pt) | 1998-07-14 |
PL322503A1 (en) | 1998-02-02 |
CN1290845C (zh) | 2006-12-20 |
NO974512L (no) | 1997-09-29 |
HU223100B1 (hu) | 2004-03-29 |
CN1995022B (zh) | 2013-01-02 |
WO1996030369A1 (en) | 1996-10-03 |
US6143748A (en) | 2000-11-07 |
PT817784E (pt) | 2003-10-31 |
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