KR100944063B1 - 항바이러스제[1s-(1알파,3알파,4베타)]-2-아미노-1,9-디히드로-9-[4-히드록시-3-(히드록시메틸)-2-메틸렌시클로펜틸]-6h-퓨린-6-온의 제조 방법 - Google Patents
항바이러스제[1s-(1알파,3알파,4베타)]-2-아미노-1,9-디히드로-9-[4-히드록시-3-(히드록시메틸)-2-메틸렌시클로펜틸]-6h-퓨린-6-온의 제조 방법 Download PDFInfo
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- KR100944063B1 KR100944063B1 KR1020057010722A KR20057010722A KR100944063B1 KR 100944063 B1 KR100944063 B1 KR 100944063B1 KR 1020057010722 A KR1020057010722 A KR 1020057010722A KR 20057010722 A KR20057010722 A KR 20057010722A KR 100944063 B1 KR100944063 B1 KR 100944063B1
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- benzyl
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- 239000003443 antiviral agent Substances 0.000 title abstract description 4
- 238000004519 manufacturing process Methods 0.000 title description 27
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 title 1
- 238000000034 method Methods 0.000 claims abstract description 196
- 238000002360 preparation method Methods 0.000 claims abstract description 86
- 229960000980 entecavir Drugs 0.000 claims abstract description 16
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 claims abstract 7
- 150000001875 compounds Chemical class 0.000 claims description 346
- -1 benzyl halide Chemical class 0.000 claims description 241
- 239000000203 mixture Substances 0.000 claims description 158
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 153
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 140
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 77
- 239000002585 base Substances 0.000 claims description 63
- 239000003153 chemical reaction reagent Substances 0.000 claims description 60
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 claims description 56
- 150000002148 esters Chemical class 0.000 claims description 51
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 47
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 47
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 46
- 239000002253 acid Substances 0.000 claims description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 40
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 39
- 125000000217 alkyl group Chemical group 0.000 claims description 38
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 38
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 35
- 230000008569 process Effects 0.000 claims description 35
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 claims description 34
- 229940126086 compound 21 Drugs 0.000 claims description 34
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 34
- 230000003647 oxidation Effects 0.000 claims description 29
- 238000007254 oxidation reaction Methods 0.000 claims description 29
- 150000002009 diols Chemical group 0.000 claims description 28
- 150000003839 salts Chemical class 0.000 claims description 28
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 27
- 238000006735 epoxidation reaction Methods 0.000 claims description 26
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 25
- 239000003054 catalyst Substances 0.000 claims description 25
- 150000004678 hydrides Chemical class 0.000 claims description 21
- 229910052801 chlorine Inorganic materials 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 20
- 125000006239 protecting group Chemical group 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 20
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical group CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims description 20
- 229910052740 iodine Inorganic materials 0.000 claims description 18
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 18
- 229910052783 alkali metal Inorganic materials 0.000 claims description 16
- 239000012442 inert solvent Substances 0.000 claims description 16
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 16
- 239000011698 potassium fluoride Substances 0.000 claims description 16
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical group [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims description 15
- 238000006460 hydrolysis reaction Methods 0.000 claims description 14
- 150000003138 primary alcohols Chemical class 0.000 claims description 14
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical group CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-N 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 235000010354 butylated hydroxytoluene Nutrition 0.000 claims description 13
- 230000007062 hydrolysis Effects 0.000 claims description 13
- 229910052751 metal Inorganic materials 0.000 claims description 13
- 239000011736 potassium bicarbonate Substances 0.000 claims description 13
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 13
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 13
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 13
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 claims description 12
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical group C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 claims description 12
- 239000002184 metal Substances 0.000 claims description 12
- 239000007800 oxidant agent Substances 0.000 claims description 12
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 12
- 230000003197 catalytic effect Effects 0.000 claims description 11
- YKGMKSIHIVVYKY-UHFFFAOYSA-N dabrafenib mesylate Chemical compound CS(O)(=O)=O.S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 YKGMKSIHIVVYKY-UHFFFAOYSA-N 0.000 claims description 11
- KRWMERLEINMZFT-UHFFFAOYSA-N O6-benzylguanine Chemical compound C=12NC=NC2=NC(N)=NC=1OCC1=CC=CC=C1 KRWMERLEINMZFT-UHFFFAOYSA-N 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 239000011975 tartaric acid Substances 0.000 claims description 10
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical group CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 claims description 10
- 230000001590 oxidative effect Effects 0.000 claims description 9
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 9
- 230000009467 reduction Effects 0.000 claims description 9
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 8
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical class [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 8
- 150000005690 diesters Chemical class 0.000 claims description 8
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 8
- 235000003270 potassium fluoride Nutrition 0.000 claims description 8
- 239000012312 sodium hydride Substances 0.000 claims description 8
- 235000002906 tartaric acid Nutrition 0.000 claims description 8
- STPKWKPURVSAJF-LJEWAXOPSA-N (4r,5r)-5-[4-[[4-(1-aza-4-azoniabicyclo[2.2.2]octan-4-ylmethyl)phenyl]methoxy]phenyl]-3,3-dibutyl-7-(dimethylamino)-1,1-dioxo-4,5-dihydro-2h-1$l^{6}-benzothiepin-4-ol Chemical compound O[C@H]1C(CCCC)(CCCC)CS(=O)(=O)C2=CC=C(N(C)C)C=C2[C@H]1C(C=C1)=CC=C1OCC(C=C1)=CC=C1C[N+]1(CC2)CCN2CC1 STPKWKPURVSAJF-LJEWAXOPSA-N 0.000 claims description 7
- 239000003963 antioxidant agent Substances 0.000 claims description 7
- YQHLDYVWEZKEOX-UHFFFAOYSA-N cumene hydroperoxide Chemical compound OOC(C)(C)C1=CC=CC=C1 YQHLDYVWEZKEOX-UHFFFAOYSA-N 0.000 claims description 7
- LVZGQWKTUCVPBQ-UHFFFAOYSA-N acetic acid;trifluoroborane Chemical compound CC(O)=O.FB(F)F LVZGQWKTUCVPBQ-UHFFFAOYSA-N 0.000 claims description 6
- 238000006264 debenzylation reaction Methods 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 6
- FPIVAWNGRDHRSQ-UHFFFAOYSA-N 2-[di(propan-2-yloxy)methoxy]propane Chemical compound CC(C)OC(OC(C)C)OC(C)C FPIVAWNGRDHRSQ-UHFFFAOYSA-N 0.000 claims description 5
- YOWQWFMSQCOSBA-UHFFFAOYSA-N 2-methoxypropene Chemical compound COC(C)=C YOWQWFMSQCOSBA-UHFFFAOYSA-N 0.000 claims description 5
- 239000007848 Bronsted acid Substances 0.000 claims description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 5
- JEDZLBFUGJTJGQ-UHFFFAOYSA-N [Na].COCCO[AlH]OCCOC Chemical compound [Na].COCCO[AlH]OCCOC JEDZLBFUGJTJGQ-UHFFFAOYSA-N 0.000 claims description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 5
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 5
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical group BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims description 5
- IRUNKQSGDBYUDC-UHFFFAOYSA-N diethoxymethyl acetate Chemical compound CCOC(OCC)OC(C)=O IRUNKQSGDBYUDC-UHFFFAOYSA-N 0.000 claims description 5
- 150000002432 hydroperoxides Chemical class 0.000 claims description 5
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 5
- 150000004965 peroxy acids Chemical class 0.000 claims description 5
- 239000012419 sodium bis(2-methoxyethoxy)aluminum hydride Substances 0.000 claims description 5
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 5
- 238000010511 deprotection reaction Methods 0.000 claims description 4
- DFGZNAMXGSJIKP-UHFFFAOYSA-N di(propan-2-yloxy)methyl acetate Chemical compound CC(C)OC(OC(C)C)OC(C)=O DFGZNAMXGSJIKP-UHFFFAOYSA-N 0.000 claims description 4
- XEBCWEDRGPSHQH-UHFFFAOYSA-N diisopropyl tartrate Chemical compound CC(C)OC(=O)C(O)C(O)C(=O)OC(C)C XEBCWEDRGPSHQH-UHFFFAOYSA-N 0.000 claims description 4
- 230000003301 hydrolyzing effect Effects 0.000 claims description 4
- 125000002346 iodo group Chemical group I* 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- VUEGYUOUAAVYAS-JGGQBBKZSA-N (6ar,9s,10ar)-9-(dimethylsulfamoylamino)-7-methyl-6,6a,8,9,10,10a-hexahydro-4h-indolo[4,3-fg]quinoline Chemical compound C1=CC([C@H]2C[C@@H](CN(C)[C@@H]2C2)NS(=O)(=O)N(C)C)=C3C2=CNC3=C1 VUEGYUOUAAVYAS-JGGQBBKZSA-N 0.000 claims description 3
- 125000003047 N-acetyl group Chemical group 0.000 claims description 3
- AVYVHIKSFXVDBG-UHFFFAOYSA-N N-benzyl-N-hydroxy-2,2-dimethylbutanamide Chemical compound C(C1=CC=CC=C1)N(C(C(CC)(C)C)=O)O AVYVHIKSFXVDBG-UHFFFAOYSA-N 0.000 claims description 3
- 230000003078 antioxidant effect Effects 0.000 claims description 3
- 150000002978 peroxides Chemical class 0.000 claims description 3
- FRIBMENBGGCKPD-UHFFFAOYSA-N 3-(2,3-dimethoxyphenyl)prop-2-enal Chemical compound COC1=CC=CC(C=CC=O)=C1OC FRIBMENBGGCKPD-UHFFFAOYSA-N 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims description 2
- 229940073608 benzyl chloride Drugs 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims 3
- 150000002431 hydrogen Chemical class 0.000 claims 3
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 claims 2
- 230000029936 alkylation Effects 0.000 claims 1
- 238000005804 alkylation reaction Methods 0.000 claims 1
- 150000001733 carboxylic acid esters Chemical group 0.000 claims 1
- 150000004862 dioxolanes Chemical class 0.000 claims 1
- 150000002084 enol ethers Chemical class 0.000 claims 1
- 150000002085 enols Chemical class 0.000 claims 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims 1
- 230000001012 protector Effects 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 55
- 238000000746 purification Methods 0.000 abstract description 31
- 229920005989 resin Polymers 0.000 abstract description 22
- 239000011347 resin Substances 0.000 abstract description 22
- 238000001179 sorption measurement Methods 0.000 abstract description 6
- 238000002955 isolation Methods 0.000 abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 246
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 219
- 239000000243 solution Substances 0.000 description 179
- 239000011541 reaction mixture Substances 0.000 description 175
- 238000006243 chemical reaction Methods 0.000 description 149
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 104
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 103
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 91
- 235000019439 ethyl acetate Nutrition 0.000 description 82
- 239000012044 organic layer Substances 0.000 description 77
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 66
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 62
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 62
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 56
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 56
- 239000003921 oil Substances 0.000 description 54
- 239000012267 brine Substances 0.000 description 52
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 51
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 49
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 45
- 239000007787 solid Substances 0.000 description 45
- 239000011734 sodium Substances 0.000 description 38
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 37
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 34
- 229910052786 argon Inorganic materials 0.000 description 31
- 239000000725 suspension Substances 0.000 description 31
- 239000012043 crude product Substances 0.000 description 30
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 28
- 239000010410 layer Substances 0.000 description 28
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 27
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 26
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 25
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 25
- 239000000047 product Substances 0.000 description 25
- 239000000706 filtrate Substances 0.000 description 24
- 238000003756 stirring Methods 0.000 description 23
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 21
- 230000002829 reductive effect Effects 0.000 description 20
- 229960000583 acetic acid Drugs 0.000 description 19
- 229910052938 sodium sulfate Inorganic materials 0.000 description 19
- 235000011152 sodium sulphate Nutrition 0.000 description 19
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 18
- 235000019341 magnesium sulphate Nutrition 0.000 description 18
- 239000005909 Kieselgur Substances 0.000 description 17
- 238000005859 coupling reaction Methods 0.000 description 17
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 17
- 238000010992 reflux Methods 0.000 description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 150000001412 amines Chemical class 0.000 description 16
- 238000001914 filtration Methods 0.000 description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 16
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
- 239000002243 precursor Substances 0.000 description 15
- 238000010898 silica gel chromatography Methods 0.000 description 15
- 239000002002 slurry Substances 0.000 description 15
- 230000008878 coupling Effects 0.000 description 14
- 238000010168 coupling process Methods 0.000 description 14
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 14
- 239000007858 starting material Substances 0.000 description 14
- 150000003512 tertiary amines Chemical class 0.000 description 14
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 14
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- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 9
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- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 7
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- PAHNHUXFZKDRAA-OALUTQOASA-N methyl (4s,5r)-4-[tert-butyl(dimethyl)silyl]oxy-5-(phenylmethoxymethyl)cyclopentene-1-carboxylate Chemical compound COC(=O)C1=CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1COCC1=CC=CC=C1 PAHNHUXFZKDRAA-OALUTQOASA-N 0.000 description 7
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- JLXSJCOOJJFUMR-MOPGFXCFSA-N [(4s,5r)-4-phenylmethoxy-5-(phenylmethoxymethyl)cyclopenten-1-yl] trifluoromethanesulfonate Chemical compound O([C@H]1CC=C([C@@H]1COCC=1C=CC=CC=1)OS(=O)(=O)C(F)(F)F)CC1=CC=CC=C1 JLXSJCOOJJFUMR-MOPGFXCFSA-N 0.000 description 4
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- OCYJXSUPZMNXEN-YGPZHTELSA-N (1r)-2-amino-1-(4-nitrophenyl)propane-1,3-diol Chemical compound OCC(N)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 OCYJXSUPZMNXEN-YGPZHTELSA-N 0.000 description 3
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- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- UQEAIHBTYFGYIE-UHFFFAOYSA-N hexamethyldisiloxane Chemical compound C[Si](C)(C)O[Si](C)(C)C UQEAIHBTYFGYIE-UHFFFAOYSA-N 0.000 description 1
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 1
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 description 1
- MHAJPDPJQMAIIY-UHFFFAOYSA-M hydroperoxide group Chemical group [O-]O MHAJPDPJQMAIIY-UHFFFAOYSA-M 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 150000004694 iodide salts Chemical group 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- RENRQMCACQEWFC-UGKGYDQZSA-N lnp023 Chemical compound C1([C@H]2N(CC=3C=4C=CNC=4C(C)=CC=3OC)CC[C@@H](C2)OCC)=CC=C(C(O)=O)C=C1 RENRQMCACQEWFC-UGKGYDQZSA-N 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
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- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- LULAYUGMBFYYEX-UHFFFAOYSA-N metachloroperbenzoic acid Natural products OC(=O)C1=CC=CC(Cl)=C1 LULAYUGMBFYYEX-UHFFFAOYSA-N 0.000 description 1
- XKUHKOZOZQRQLW-SFTDATJTSA-N methyl (4s,5r)-4-phenylmethoxy-5-(phenylmethoxymethyl)cyclopentene-1-carboxylate Chemical compound O([C@H]1CC=C([C@@H]1COCC=1C=CC=CC=1)C(=O)OC)CC1=CC=CC=C1 XKUHKOZOZQRQLW-SFTDATJTSA-N 0.000 description 1
- FJEGEQZRLGQSGP-UHFFFAOYSA-N methyl 2-methylcyclopentene-1-carboxylate Chemical compound COC(=O)C1=C(C)CCC1 FJEGEQZRLGQSGP-UHFFFAOYSA-N 0.000 description 1
- CXHHBNMLPJOKQD-UHFFFAOYSA-M methyl carbonate Chemical compound COC([O-])=O CXHHBNMLPJOKQD-UHFFFAOYSA-M 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- CXHHBNMLPJOKQD-UHFFFAOYSA-N methyl hydrogen carbonate Chemical class COC(O)=O CXHHBNMLPJOKQD-UHFFFAOYSA-N 0.000 description 1
- OKDQKPLMQBXTNH-UHFFFAOYSA-N n,n-dimethyl-2h-pyridin-1-amine Chemical compound CN(C)N1CC=CC=C1 OKDQKPLMQBXTNH-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 238000006772 olefination reaction Methods 0.000 description 1
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
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- 235000005985 organic acids Nutrition 0.000 description 1
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- SJGALSBBFTYSBA-UHFFFAOYSA-N oxaziridine Chemical compound C1NO1 SJGALSBBFTYSBA-UHFFFAOYSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- 150000002940 palladium Chemical class 0.000 description 1
- 229940083251 peripheral vasodilators purine derivative Drugs 0.000 description 1
- 238000003408 phase transfer catalysis Methods 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 1
- XWIJIXWOZCRYEL-UHFFFAOYSA-M potassium;methanesulfonate Chemical compound [K+].CS([O-])(=O)=O XWIJIXWOZCRYEL-UHFFFAOYSA-M 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 150000004672 propanoic acids Chemical class 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 150000004053 quinones Chemical class 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001226 reprecipitation Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- ITDJKCJYYAQMRO-UHFFFAOYSA-L rhodium(2+);diacetate Chemical compound [Rh+2].CC([O-])=O.CC([O-])=O ITDJKCJYYAQMRO-UHFFFAOYSA-L 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 229940045872 sodium percarbonate Drugs 0.000 description 1
- 150000003440 styrenes Chemical class 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 238000006277 sulfonation reaction Methods 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 230000006103 sulfonylation Effects 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005207 tetraalkylammonium group Chemical group 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000003944 tolyl group Chemical group 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
- 125000005490 tosylate group Chemical group 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- KPZSTOVTJYRDIO-UHFFFAOYSA-K trichlorocerium;heptahydrate Chemical compound O.O.O.O.O.O.O.Cl[Ce](Cl)Cl KPZSTOVTJYRDIO-UHFFFAOYSA-K 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- JPJIEXKLJOWQQK-UHFFFAOYSA-K trifluoromethanesulfonate;yttrium(3+) Chemical compound [Y+3].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F JPJIEXKLJOWQQK-UHFFFAOYSA-K 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- FTVLMFQEYACZNP-UHFFFAOYSA-N trimethylsilyl trifluoromethanesulfonate Chemical compound C[Si](C)(C)OS(=O)(=O)C(F)(F)F FTVLMFQEYACZNP-UHFFFAOYSA-N 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
- 238000009281 ultraviolet germicidal irradiation Methods 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- OENHQHLEOONYIE-JLTXGRSLSA-N β-Carotene Chemical compound CC=1CCCC(C)(C)C=1\C=C\C(\C)=C\C=C\C(\C)=C\C=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C OENHQHLEOONYIE-JLTXGRSLSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
- C07F7/083—Syntheses without formation of a Si-C bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
- C07F7/0814—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring said ring is substituted at a C ring atom by Si
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/0825—Preparations of compounds not comprising Si-Si or Si-cyano linkages
- C07F7/0827—Syntheses with formation of a Si-C bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- 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
- Organic Chemistry (AREA)
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- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Virology (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Oncology (AREA)
- Animal Behavior & Ethology (AREA)
- Communicable Diseases (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Biotechnology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Epoxy Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Description
Claims (74)
- (a) 하기 화학식 66의 에스테르를 아세톤의 에놀 에테르 및 산으로 처리하여 히드록시기를 보호하고, 이어서 수소화물 시약으로 처리하여 카르복실산 에스테르 잔기를 환원시키고, 이어서 생성된 알코올을 벤질 할라이드로 알킬화시키고 에놀 에테르 히드록시 보호기를 제거하여 하기 화학식 76의 알릴 알코올을 수득하고,(b) 단계 (a)의 생성물을 부분입체이성질체선택성 에폭시화로 에폭시화시켜 하기 화학식 77을 갖는 시클로펜탄 에폭시드를 수득하고,(c) 단계 (b)의 시클로펜탄 에폭시드를 하기 화학식 28의 퓨린 화합물의 알칼리 금속 염으로 처리하여 하기 화학식 78의 화합물을 수득하고,(d) X가 Cl 또는 I인 경우, 화학식 78의 인접한 디올을 제거하여 하기 화학식 94의 메틸렌 화합물을 형성하고,(e) 화합물 94의 1차 알코올 상의 벤질 에테르 잔기를 가수분해시키고 화합물 94의 실란 잔기를 프로토디실릴레이션 및 산화를 통해 히드록시 잔기로 변환시켜 하기 화학식 95의 화합물을 수득하고,(f) 클로로 또는 요오도 잔기 X를 가수분해시켜 화학식 21의 화합물을 수득하거나, 또는(d') X가 벤질옥시인 경우, 화학식 78의 인접한 디올을 제거하여 하기 화학식 79의 메틸렌 화합물을 형성하고,(e') 화합물 79의 1차 알코올 상의 벤질 에테르 잔기를 가수분해시키고 실란 잔기를 프로토디실릴레이션 및 산화를 통해 히드록시 잔기로 변환시켜 화학식 21의 화합물을 수득하거나, 또는(a'') 화학식 66의 에스테르를 부분입체이성질체선택성 에폭시화로 에폭시화시킨 데 이어서 환원시켜 하기 화학식 72를 갖는 시클로펜탄 에폭시드를 수득하고,(b'') 단계 (a'')의 시클로펜탄 에폭시드를 화학식 28의 퓨린 화합물의 알칼리 금속 염으로 처리하여 하기 화학식 73의 화합물을 수득하고,(c'') X가 Cl 또는 I인 경우, 화학식 73의 인접한 디올을 제거하여 하기 화학식 92의 메틸렌 화합물을 형성하고,(d'') 화합물 92의 실란 잔기를 프로토디실릴레이션 및 산화를 통해 히드록시 잔기로 변환시키고 클로로 또는 요오도 잔기 X를 가수분해시켜 화학식 21의 화합물을 수득하거나, 또는(c''') X가 벤질옥시인 경우, 화학식 73의 인접한 디올을 제거하여 하기 화학식 71의 메틸렌 화합물을 형성하고,(d''') 화합물 71의 실란 잔기를 프로토디실릴레이션 및 산화를 통해 히드록시 잔기로 변환시켜 화학식 21의 화합물을 수득하는 것을 포함하는,하기 화학식 21을 갖는 엔테카비르의 제조 방법.<화학식 21><화학식 66>(상기 식에서, Ra는 알릴, 페닐, C1 내지 C6 알킬페닐 또는 C1 내지 C6 알콕시페닐이고; Rb는 C1 내지 C6 알킬이고; R은 C1 내지 C4 알킬 또는 벤질임)<화학식 76><화학식 77><화학식 28>(상기 식에서, X는 Cl, I 또는 벤질옥시임)<화학식 78><화학식 94><화학식 95><화학식 79><화학식 72><화학식 73><화학식 92><화학식 71>
- 제1항에 있어서, 단계 (b) 및 (a'')에서, 부분입체이성질체선택성 에폭시화를 과산 또는 타르타르산의 호모키랄 디에스테르, 히드로퍼옥시드, 및 금속 촉매로 수행하는 방법.
- (a) 하기 화학식 66의 에스테르의 히드록시 잔기를 보호하여 화학식 74'의 화합물을 수득하고,(b) 화합물 74'의 카르복실 에스테르 잔기를 1 종 이상의 환원 시약으로 환원시켜 하기 화학식 75'의 화합물을 수득하고,(c) 화합물 75'의 비보호된 히드록시 잔기를 P' 제거에 사용된 조건에 대해 내성이 있는 보호기 P''로 보호하고, 이어서 화합물 75'의 보호기 P'를 제거하여 하기 화학식 76'을 갖는 화합물을 수득하고,(d) 단계 (c)의 생성물을 부분입체이성질체선택성 에폭시화로 에폭시화하여 하기 화학식 77'을 갖는 시클로펜탄 에폭시드를 수득하고,(e) 단계 (d)의 시클로펜탄 에폭시드를 하기 화학식 28의 퓨린 화합물의 알칼리 금속 염으로 처리하여 하기 화학식 78'의 화합물을 수득하고,(f) X가 벤질옥시인 경우, 화학식 78'의 인접한 디올을 제거하여 하기 화학식 79'의 메틸렌 화합물을 수득하고,(g) 화합물 79'의 1차 알코올 상의 보호기 P''를 제거하고 실란 잔기를 프로토디실릴레이션 및 산화를 통해 히드록시 잔기로 변환시켜 화학식 21의 화합물을 수득하거나, 또는(f') X가 Cl 또는 I인 경우, 화학식 78'의 인접한 디올을 제거하여 하기 화학식 94'의 메틸렌 화합물을 수득하고,(g') 화합물 94'의 1차 알코올 상의 보호기 P''을 제거하고 실란 잔기를 프로토디실릴레이션 및 산화를 통해 히드록시기로 변환시켜 하기 화학식 95의 화합물을 수득하고,(h') 클로로 또는 요오도 잔기 X를 가수분해시켜 화학식 21의 화합물을 수득하는 것을 포함하는,하기 화학식 21을 갖는 엔테카비르의 제조 방법.<화학식 21><화학식 66>(상기 식에서, Ra는 알릴, 페닐, C1 내지 C6 알킬페닐 또는 C1 내지 C6 알콕시페닐이고; Rb는 C1 내지 C6 알킬이고; R은 C1 내지 C4 알킬 또는 벤질임)<화학식 74'>(P'는 보호기임)<화학식 75'><화학식 76'><화학식 77'><화학식 28>(상기 식에서, X는 Cl, I 또는 벤질옥시임)<화학식 78'><화학식 79'><화학식 94'><화학식 95>
- 제3항에 있어서, 단계 (g)에서, 화합물 79'의 1차 알코올 상의 보호기 P''는 벤질이고, 프로토디실릴레이션으로 상기 벤질 보호기를 제거하는 방법.
- 제3항에 있어서, 실란 잔기를 히드록시 잔기로 변환시킨 후 화합물 79'의 1차 알코올 상의 보호기 P''를 제거하는 방법.
- 제3항에 있어서, 단계 (a)에서, 2-메톡시프로펜 및 촉매량의 산으로 처리하여 2-메톡시-2-프로폭시-아세탈 (MOP)로서 히드록시 잔기를 보호하는 방법.
- 제3항에 있어서, 단계 (b)에서, 염기의 존재하에 하나 이상의 소듐 비스(2-메톡시에톡시)알루미늄 하이드라이드 및 리튬 알루미늄 하이드라이드로부터 선택된 수소화물 시약으로 화합물 74'의 카르복실 에스테르 잔기를 환원시키는 방법.
- 제8항에 있어서, 염기가 하나 이상의 포타슘 tert-부톡시드, 수소화나트륨, 포타슘 헥사메틸디실아지드 (KHMDS) 및 수성 NaOH로부터 선택되고, 벤질 할라이드가 벤질 브로마이드 또는 벤질 클로라이드인 방법.
- 제3항에 있어서, 단계 (d)에서, 부분입체이성질체선택성 에폭시화를 과산 처리로 수행하는 방법.
- 제3항에 있어서, 단계 (d)에서, 부분입체이성질체선택성 에폭시화를 타르타르산의 호모키랄 디에스테르, 히드로퍼옥시드, 및 금속 촉매 처리로 수행하는 방 법.
- 제11항에 있어서, 타르타르산의 호모키랄 디에스테르가 (-)-디이소프로필 타르트레이트이고, 히드로퍼옥시드가 tert-부틸히드로퍼옥시드 또는 α,α-디메틸벤질히드로퍼옥시드이고, 금속 촉매가 티타늄(IV) 이소프로폭시드인 방법.
- 제3항에 있어서, 단계 (e)에서, 디클로로메탄 중 2-아미노-6-벤질옥시퓨린으로 단계 (d)의 시클로펜탄 에폭시드를 처리하는 방법.
- 제3항에 있어서, X가 벤질옥시이고 단계 (f)에서,(f)(i) 화합물 78'를 불활성 용매 중 오르쏘포르메이트 유도체로 처리하여 하기 화학식 101' 및 103'을 갖는 디옥소란의 부분입체혼합물을 수득하는 단계,(f)(ii) 단계 (f)(i)의 생성물을 1종 이상의 항산화제의 존재하에 아세트산 무수물로 처리하여 하기 화학식 105'의 알켄 화합물을 수득하는 단계, 및(f)(iii) 단계 (f)(ii)의 생성물을 산으로 처리하여 6-벤질옥시 및 N-아세틸기를 가수분해시켜 화학식 79'의 화합물을 수득하는 단계에 의해화합물 78'의 인접한 디올을 제거하여 화학식 79'의 메틸렌 화합물을 수득하는 것을 달성시키는 방법.<화학식 101'>, <화학식 103'>(상기 식에서, R22는 Cl-4알킬 또는 -C(=O)C1-4알킬임)<화학식 105'>
- 제14항에 있어서, 단계 (f)(i)에서, 오르쏘포르메이트 유도체가 하나 이상의 디에톡시메틸 아세테이트, 디이소프로필옥시메틸 아세테이트, 트리메틸오르쏘포르메이트 (TMOF), 트리-에틸오르쏘포르메이트 (TEOF) 및 트리이소프로필오르쏘포르메이트 (TiPOF)로부터 선택된 것인 방법.
- 제14항에 있어서, 단계 (f)(ii)에서, 1종 이상의 산화제가 2,6-디-tert-부틸-4-메틸페놀 (BHT) 및 벤조산으로부터 선택된 것인 방법.
- 제3항에 있어서, 단계 (g)에서, 프로토디실릴레이션을 용매 중 KOH 또는 NaOH, 또는 트리플루오로아세트산 (TFA)로 수행하고, 실란 잔기를 히드록시기로 변환시킨 후 1차 알코올 잔기를 탈보호시켜 화학식 21의 화합물을 수득하는 방법.
- 제3항에 있어서, 단계 (g)에서, 보론 트리플루오라이드-아세트산 착체 및 브뢴스테드 산으로부터 선택된 1 종 이상의 산으로 프로토디실릴레이션을 달성시키는 방법.
- 제3항에 있어서, 단계 (g)에서, 중탄산칼륨의 존재하에 과산화수소로 산화를 달성시키는 방법.
- (a) 하기 화학식 66의 에스테르를 2-메톡시프로펜 및 촉매량의 산으로 처리하여 하기 화학식 74의 화합물을 수득하고,(b) 화합물 74의 카르복실 에스테르 잔기를 염기의 존재하에 하나 이상의 소듐 비스(2-메톡시에톡시)알루미늄 하이드라이드 및 리튬 알루미늄 하이드라이드로부터 선택된 수소화물 시약으로 환원시켜 하기 화학식 75의 화합물을 수득하고,(c) 화합물 75를 염기 및 벤질 할라이드로 처리하여 벤질 에테르로서 화합물 75의 비보호 히드록시 잔기를 보호하고, 이어서 화합물 75의 2-메톡시-2-프로폭시-아세탈 (MOP)기를 제거하여 하기 화학식 76을 갖는 알릴 알코올을 수득하고,(d) 단계 (c)의 생성물을 (-)-디이소프로필 타르트레이트, tert-부틸히드로퍼옥시드 또는 큐멘 히드로퍼옥시드, 및 티타늄(IV) 이소프로폭시드로 에폭시화하여 하기 화학식 77을 갖는 시클로펜탄 에폭시드를 수득하고,(e) 단계 (d)의 시클로펜탄 에폭시드를 하기 화학식 28의 퓨린 화합물의 알칼리 금속 염으로 처리하여 하기 화학식 78의 화합물을 수득하고,(f)(i) 화합물 78을 불활성 용매 중 디에톡시메틸 아세테이트 및 디이소프로필옥시메틸 아세테이트로부터 선택된 오르쏘포르메이트 유도체로 처리하여 하기 화학식 101 및 103을 갖는 디옥소란의 부분입체혼합물을 수득하고,(f)(ii) 2,6-디-tert-부틸-4-메틸페놀 (BHT)의 존재하에 단계 (f)(i)의 생성물을 아세트산 무수물로 처리하여 하기 화학식 105를 갖는 알켄 화합물을 수득하고,(f)(iii) 단계 (f)(ii)의 생성물을 산으로 처리하여 6-벤질옥시 및 N-아세틸기를 가수분해시켜서 하기 화학식 79의 화합물을 수득하고,(g) 화합물 79의 실란 잔기를 프로토디실릴레이션에 사용되는 1 종 이상의 시약으로 처리하여 프로토디실릴화하여 실란 잔기를 히드록시 잔기로 변환시키고, 이어서 퍼옥시드로 산화시키고, 화합물 79를 탈벤질화 (탈벤질화는 프로토디실릴레이션 시 달성될 수 있음)시켜 화학식 21의 화합물을 수득하는 것을 포함하는,하기 화학식 21을 갖는 엔테카비르의 제조 방법.<화학식 21><화학식 66>(상기 식에서, Ra는 알릴, 페닐, C1 내지 C6 알킬페닐 또는 C1 내지 C6 알콕시페닐이고; Rb는 C1 내지 C6 알킬이고; R은 C1 내지 C4 알킬 또는 벤질임)<화학식 74><화학식 75><화학식 76><화학식 77><화학식 28>(상기 식에서, X는 벤질옥시임)<화학식 78><화학식 101>, <화학식 103>(상기 식에서, R22는 에틸, -C(=O)에틸, 이소프로필 또는 -C(=O)이소프로필임)<화학식 105><화학식 79>
- 제23항에 있어서,Ra가 페닐이고,Rb가 메틸이고,R20이 벤질인 화합물.
- 하기 화학식의 화합물 또는 그의 염.상기 식에서,Ra는 페닐, C1 내지 C6 알킬페닐 또는 C1 내지 C6 알콕시페닐이고,Rb는 C1 내지 C6 알킬이고,R20은 수소 또는 벤질이고,X는 Cl, I 또는 벤질옥시이고,Ry 및 Rz는 함께 메틸렌 (=CH2)을 형성하거나, 또는 Ry는 OR23이고, RZ는 -CH2OR24이고, 여기서 R23 및 R24는 각각 수소이거나 또는 함께 고리를 형성하여 -O(C1-4알킬) 또는 -O(C=O)(C1-4알킬)로 치환될 수 있는 디옥소란을 형성하고,R25 및 R26은 모두 수소이거나, 또는 R25 및 R26 중 하나는 수소이고 다른 하나는 아세틸이거나, 또는 R25 및 R26은 함께 =CH(OCl-4알킬) 또는 =CH(OC(=O)(C1-4알킬)을 형성한다.
- 제25항에 있어서,Ra가 페닐이고,Rb가 메틸이고,X가 벤질옥시인 화합물.
- 제26항에 있어서,R20이 벤질이고,Ry가 OH이고, Rz가 -CH2OH이고,R25 및 R26이 모두 수소인 화합물.
- 제25항에 있어서,Ra가 페닐이고,Rb가 메틸이고,X가 벤질옥시이고,Ry가 OR23이고, Rz가 -CH2OR24이고, 여기서 R23 및 R24는 조합되어 -O(C1-4 알킬) 또는 O(C=O)(C1-4 알킬)로 치환될 수 있는 디옥소란을 형성하고,R25 및 R26은 모두 수소이거나, 또는 R25 및 R26은 함께 =CH(OC1-4알킬) 또는 =CH(O(C=O)C1-4알킬)을 형성한다.
- 제25항에 있어서,Ra가 페닐이고,Rb가 메틸이고,X가 벤질옥시이고,Ry 및 Rz가 함께 메틸렌을 형성하고,R25가 수소이고 R26이 아세틸인 화합물.
- 하기 화학식의 화합물 또는 그의 염.상기 식에서,Ra는 페닐, C1 내지 C6 알킬페닐 또는 C1 내지 C6 알콕시페닐이고,Rb는 C1 내지 C6 알킬이고,R20은 수소 또는 벤질이다.
- 제31항에 있어서,Ra가 페닐이고,Rb가 메틸이고,R20이 수소인 화합물.
- 제31항에 있어서,Ra가 페닐이고,Rb가 메틸이고,R20이 벤질인 화합물
- 제33항의 화합물의 메탄술포네이트 염.
- 제36항에 있어서, Rb가 메틸인 화합물.
- 제38항에 있어서, A가 결합이고, R27이 수소인 화합물.
- (a) 하기 화학식 66의 에스테르를 2-메톡시프로펜 및 촉매량의 산으로 처리하여 하기 화학식 74의 화합물을 수득하고,(b) 화합물 74의 카르복실 에스테르 잔기를 하나 이상의 수소화물 시약으로 환원시켜 하기 화학식 75의 화합물을 수득하고,(c) 염기 및 벤질 할라이드로 화합물 75의 처리로 벤질 에테르로서 화합물 75의 비보호 히드록시 잔기를 보호하고, 이어서 화합물 75의 2-메톡시-2-프로폭시-아세탈 (MOP)기를 제거하여, 하기 화학식 76을 갖는 알릴 알코올을 수득하고,(d) 단계 (c)의 생성물을 부분입체이성질체선택성 에폭시화로 에폭시화시켜 하기 화학식 77을 갖는 시클로펜탄 에폭시드를 수득하고,(e) 단계 (d)의 시클로펜탄 에폭시드를 하기 화학식 28의 퓨린 화합물의 알칼리 금속 염으로 처리하여 화학식 78의 화합물을 수득하는 것을 포함하는,제30항에 따른 화학식 78의 화합물의 제조 방법.<화학식 66>(상기 식에서, Ra는 알릴, 페닐, C1 내지 C6 알킬페닐 또는 C1 내지 C6 알콕시페닐이고; Rb는 C1 내지 C6 알킬이고; R은 C1 내지 C4 알킬 또는 벤질임)<화학식 74><화학식 75><화학식 76><화학식 77><화학식 28>(상기 식에서, X는 벤질옥시, I 또는 Cl임)
- 제19항에 있어서, 단계 (g)에서, 중탄산칼륨 및 불화칼륨의 존재 하에 과산화수소로 산화를 달성시키는 방법.
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101269491B1 (ko) * | 2010-12-23 | 2013-05-31 | 주식회사 한서켐 | 엔테카비어 제조방법 |
Families Citing this family (60)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2283788T3 (es) * | 2002-06-27 | 2007-11-01 | F. Hoffmann-La Roche Ag | Sintesis de derivados de purina. |
BRPI0317255B8 (pt) * | 2002-12-11 | 2021-05-25 | Bristol Myers Squibb Co | processo para preparar o agente antiviral [1s-(1alfa, 3alfa, 4beta)]-2-amino-1,9-diidro-9-[4-hidróxi-3-(hidroximetil)-2-metilenociclopentil]-6h-purin-6-ona método de seu isolamento, preparação do éster e respectivos compostos |
US7511139B2 (en) * | 2004-06-04 | 2009-03-31 | Bristol-Myers Squibb Company | Process for the preparation of entecavir and novel intermediates thereof via carbon-silicon oxidation |
TW200540175A (en) * | 2004-06-04 | 2005-12-16 | Bristol Myers Squibb Co | Process for the preparation of entecavir and novel intermediates thereof via carbon-silicon oxidation |
CN100379736C (zh) * | 2005-05-13 | 2008-04-09 | 上海仲夏化学有限公司 | 恩替卡韦的制备方法 |
CN1699366A (zh) * | 2005-06-03 | 2005-11-23 | 北京市典范科技有限责任公司 | 嘌呤衍生物 |
US20070060599A1 (en) * | 2005-09-09 | 2007-03-15 | Dimarco John D | Crystalline forms of [1S-(1alpha, 3alpha, 4beta)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one |
CN101863842B (zh) * | 2006-08-24 | 2012-02-01 | 江苏正大天晴药业股份有限公司 | 恩替卡韦中间体及合成方法 |
CN101130542B (zh) * | 2006-08-24 | 2010-08-04 | 江苏正大天晴药业股份有限公司 | 抗病毒核苷类似物的合成方法 |
CN101838207B (zh) * | 2006-08-24 | 2012-04-25 | 江苏正大天晴药业股份有限公司 | 恩替卡韦的中间体及合成方法 |
CN101838270B (zh) * | 2006-08-24 | 2012-04-18 | 江苏正大天晴药业股份有限公司 | 恩替卡韦的中间体及制备 |
US8299152B2 (en) * | 2006-10-30 | 2012-10-30 | Pirelli Tyre S.P.A. | Tire for vehicle wheels comprising crosslinked elastomeric composition |
CN101371841A (zh) * | 2007-08-23 | 2009-02-25 | 浙江医药股份有限公司新昌制药厂 | 结晶型恩替卡韦制剂及其制备方法和应用 |
CN101245068A (zh) * | 2007-02-14 | 2008-08-20 | 浙江医药股份有限公司新昌制药厂 | 结晶型态的恩替卡韦及其制备方法和其药物组合物及用途 |
CN101284799B (zh) | 2007-03-23 | 2013-04-03 | 浙江医药股份有限公司新昌制药厂 | 咖啡酰奎宁酸含氮衍生物及其制备方法和其药物组合物及用途 |
CN101074217B (zh) * | 2007-04-04 | 2010-11-24 | 北京精华耀邦医药科技有限公司 | 通过制备色谱分离得到高纯度恩替卡韦关键中间体的方法 |
CN101397333A (zh) | 2007-09-27 | 2009-04-01 | 浙江医药股份有限公司新昌制药厂 | 去羟基万古霉素及其制备方法、和其药物组合物及其用途 |
CN101723945B (zh) * | 2008-10-17 | 2011-11-02 | 上海清松制药有限公司 | 一种制备抗病毒药物恩替卡韦中间体的方法 |
KR101150254B1 (ko) * | 2008-12-26 | 2012-06-12 | 한미사이언스 주식회사 | 신규 중간체 및 이를 활용한 엔테카비르 제조방법 |
CN101828693B (zh) | 2009-03-09 | 2013-01-02 | 浙江医药股份有限公司新昌制药厂 | 制备低粘度高流动性类胡萝卜素油悬浮液的方法及其应用 |
CN101531660B (zh) * | 2009-04-14 | 2012-07-04 | 安徽贝克联合制药有限公司 | 一种恩替卡韦一水合物的工业化生产工艺 |
JP5788398B2 (ja) * | 2009-10-12 | 2015-09-30 | ハンミ・サイエンス・カンパニー・リミテッド | エンテカビルの新規な製造方法及びこれに使用される中間体 |
CN101693713B (zh) * | 2009-10-28 | 2011-11-09 | 福建广生堂药业有限公司 | 一种恩替卡韦的晶型及其制备方法和药物应用 |
CN101781301B (zh) * | 2010-01-15 | 2013-04-10 | 复旦大学 | 一种制备恩替卡韦的方法 |
US8481728B2 (en) | 2010-02-16 | 2013-07-09 | Scinopharm Taiwan, Ltd. | Process for preparing entecavir and its intermediates |
CN101805339B (zh) * | 2010-04-12 | 2012-01-11 | 王明 | 一种制备恩替卡韦化合物的方法 |
CA2705953C (en) * | 2010-05-31 | 2018-05-01 | Alphora Research Inc. | Carbanucleoside synthesis and intermediate compounds useful therein |
CN101891741B (zh) * | 2010-07-06 | 2013-01-23 | 苏州汉德森医药科技有限公司 | 抗病毒药恩替卡韦的新合成工艺 |
CN102336754B (zh) * | 2010-07-15 | 2017-04-12 | 浙江奥翔药业股份有限公司 | 恩替卡韦的合成方法及其中间体化合物 |
TWI668220B (zh) * | 2010-08-30 | 2019-08-11 | 浙江奧翔藥業股份有限公司 | 恩替卡韋的合成方法及其中間體化合物 |
EP2474548A1 (en) | 2010-12-23 | 2012-07-11 | Esteve Química, S.A. | Preparation process of an antiviral drug and intermediates thereof |
CN102225938A (zh) * | 2011-04-25 | 2011-10-26 | 海南卫康制药(潜山)有限公司 | 恩替卡韦一水合物新合成工艺 |
CN102267875B (zh) * | 2011-06-17 | 2013-04-24 | 常州寅盛药业有限公司 | 一种恩替卡韦中间体的制备方法 |
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EP2597096A1 (en) | 2011-11-24 | 2013-05-29 | Esteve Química, S.A. | Process for preparing entecavir and intermediates thereof |
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US9908840B2 (en) | 2012-10-02 | 2018-03-06 | California Institute Of Technology | Reactions of aromatic substrates with base-activated hydrosilanes-silylations and reductive cleavage |
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GB201313238D0 (en) | 2013-07-24 | 2013-09-04 | Avexxin As | Process for the preparation of a polyunsaturated ketone compound |
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KR101640503B1 (ko) | 2015-04-15 | 2016-07-18 | 동방에프티엘(주) | 엔테카비르 일수화물의 개선된 제조방법 |
KR101640504B1 (ko) | 2015-04-15 | 2016-07-18 | 동방에프티엘(주) | 엔테카비르 일수화물의 제조방법 |
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MY192374A (en) * | 2016-04-07 | 2022-08-17 | Univ Georgia | Synthesis of 2?-fluoro-6?-methylene-carbocyclic adenosine (fmca) and 2?-fluoro-6?-methylene-carbocyclic guanosine (fmcg) |
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CN109593090A (zh) * | 2019-01-25 | 2019-04-09 | 连云港贵科药业有限公司 | 一种恩替卡韦的合成方法 |
CN112625041A (zh) * | 2020-12-25 | 2021-04-09 | 常州博海威医药科技股份有限公司 | 恩替卡韦的新制备方法以及中间体 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5206244A (en) * | 1990-10-18 | 1993-04-27 | E. R. Squibb & Sons, Inc. | Hydroxymethyl (methylenecyclopentyl) purines and pyrimidines |
Family Cites Families (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4594439A (en) | 1980-08-06 | 1986-06-10 | The Board Of Trustees Of The Leland Stanford Jr. University | Method for asymmetric epoxidation |
US4471130A (en) | 1980-08-06 | 1984-09-11 | The Board Of Trustees Of The Leland Stanford Junior University | Method for asymmetric epoxidation |
US4900847A (en) | 1985-04-04 | 1990-02-13 | Massachusetts Institute Of Technology | Catalytic asymmetric epoxidation |
JPH01207257A (ja) * | 1988-02-15 | 1989-08-21 | Nippon Oil & Fats Co Ltd | α−リノレン酸の分離法 |
EP0630897A3 (en) * | 1993-06-25 | 1995-03-01 | Bristol Myers Squibb Co | 3-hydroxy-4-hydroxymethyl-2-methylene-cyclopentyl purines and pyrimidines. |
US5665890A (en) * | 1995-03-14 | 1997-09-09 | President And Fellows Of Harvard College | Stereoselective ring opening reactions |
WO1998009964A1 (en) * | 1996-09-03 | 1998-03-12 | Bristol-Myers Squibb Company | IMPROVED PROCESS FOR PREPARING THE ANTIVIRAL AGENT [1S-(1α, 3α, 4β)]-2-AMINO-1,9-DIHYDRO-9-[4-HYDROXY-3-(HYDROXYMETHYL)-2-METHYLENECYCLOPENTYL]-6H-PURIN-6-ONE |
US6127159A (en) * | 1997-06-06 | 2000-10-03 | The Board Of Trustees Of The Leland Stanford Junior University | Mitofusin genes and their uses |
NZ520024A (en) | 2000-02-29 | 2005-03-24 | Bristol Myers Squibb Co | Low dose entecavir formulation and usein treating hepatitis B virus infection |
CA2311734C (en) * | 2000-04-12 | 2011-03-08 | Bristol-Myers Squibb Company | Flash-melt oral dosage formulation |
CN100457118C (zh) * | 2000-04-13 | 2009-02-04 | 法玛塞特有限公司 | 用于治疗肝炎病毒感染的3′-或2′-羟甲基取代的核苷衍生物 |
BRPI0317255B8 (pt) * | 2002-12-11 | 2021-05-25 | Bristol Myers Squibb Co | processo para preparar o agente antiviral [1s-(1alfa, 3alfa, 4beta)]-2-amino-1,9-diidro-9-[4-hidróxi-3-(hidroximetil)-2-metilenociclopentil]-6h-purin-6-ona método de seu isolamento, preparação do éster e respectivos compostos |
US7511139B2 (en) * | 2004-06-04 | 2009-03-31 | Bristol-Myers Squibb Company | Process for the preparation of entecavir and novel intermediates thereof via carbon-silicon oxidation |
US20070060599A1 (en) * | 2005-09-09 | 2007-03-15 | Dimarco John D | Crystalline forms of [1S-(1alpha, 3alpha, 4beta)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one |
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5206244A (en) * | 1990-10-18 | 1993-04-27 | E. R. Squibb & Sons, Inc. | Hydroxymethyl (methylenecyclopentyl) purines and pyrimidines |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101269491B1 (ko) * | 2010-12-23 | 2013-05-31 | 주식회사 한서켐 | 엔테카비어 제조방법 |
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