KR101357409B1 - Process for preparing 2'-deoxy-2',2'-difluorocytidine - Google Patents
Process for preparing 2'-deoxy-2',2'-difluorocytidine Download PDFInfo
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- KR101357409B1 KR101357409B1 KR1020060108564A KR20060108564A KR101357409B1 KR 101357409 B1 KR101357409 B1 KR 101357409B1 KR 1020060108564 A KR1020060108564 A KR 1020060108564A KR 20060108564 A KR20060108564 A KR 20060108564A KR 101357409 B1 KR101357409 B1 KR 101357409B1
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- South Korea
- Prior art keywords
- formula
- deoxy
- compound
- difluoro
- reaction
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- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 title claims abstract description 18
- 238000004519 manufacturing process Methods 0.000 title claims description 14
- 150000001875 compounds Chemical class 0.000 claims abstract description 67
- 238000000034 method Methods 0.000 claims abstract description 35
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 claims abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims description 37
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 27
- -1 nucleoside compound Chemical class 0.000 claims description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 19
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical group C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 claims description 18
- 239000000203 mixture Chemical class 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 13
- 239000002777 nucleoside Substances 0.000 claims description 12
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical group O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 claims description 10
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical class C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 10
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical class C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 claims description 10
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 238000010511 deprotection reaction Methods 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
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- 239000007810 chemical reaction solvent Substances 0.000 claims description 5
- 239000012046 mixed solvent Substances 0.000 claims description 5
- 150000003833 nucleoside derivatives Chemical class 0.000 claims description 5
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- HQWDKLAIDBOLFE-UHFFFAOYSA-M 2-fluoro-1-methylpyridin-1-ium;4-methylbenzenesulfonate Chemical compound C[N+]1=CC=CC=C1F.CC1=CC=C(S([O-])(=O)=O)C=C1 HQWDKLAIDBOLFE-UHFFFAOYSA-M 0.000 claims description 3
- 125000000371 nucleobase group Chemical group 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 150000001555 benzenes Chemical class 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 238000006206 glycosylation reaction Methods 0.000 abstract description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 18
- 238000002360 preparation method Methods 0.000 description 17
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 13
- HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical group OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 239000012044 organic layer Substances 0.000 description 13
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 11
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- 238000000926 separation method Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 8
- 229940104302 cytosine Drugs 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical class C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- 230000013595 glycosylation Effects 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 235000019341 magnesium sulphate Nutrition 0.000 description 6
- 239000008213 purified water Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 5
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- 238000007796 conventional method Methods 0.000 description 5
- 238000004821 distillation Methods 0.000 description 5
- 229960005277 gemcitabine Drugs 0.000 description 5
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- ZRPAUEVGEGEPFQ-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]pyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2 ZRPAUEVGEGEPFQ-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- PQBAWAQIRZIWIV-UHFFFAOYSA-N N-methylpyridinium Chemical compound C[N+]1=CC=CC=C1 PQBAWAQIRZIWIV-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- KZEVSDGEBAJOTK-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[5-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CC=1OC(=NN=1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O KZEVSDGEBAJOTK-UHFFFAOYSA-N 0.000 description 3
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 3
- WWSJZGAPAVMETJ-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-3-ethoxypyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C(=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2)OCC WWSJZGAPAVMETJ-UHFFFAOYSA-N 0.000 description 3
- SYVNVEGIRVXRQH-UHFFFAOYSA-N 3-fluorobenzoyl chloride Chemical compound FC1=CC=CC(C(Cl)=O)=C1 SYVNVEGIRVXRQH-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
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- 125000001475 halogen functional group Chemical group 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 3
- NAWXUBYGYWOOIX-SFHVURJKSA-N (2s)-2-[[4-[2-(2,4-diaminoquinazolin-6-yl)ethyl]benzoyl]amino]-4-methylidenepentanedioic acid Chemical compound C1=CC2=NC(N)=NC(N)=C2C=C1CCC1=CC=C(C(=O)N[C@@H](CC(=C)C(O)=O)C(O)=O)C=C1 NAWXUBYGYWOOIX-SFHVURJKSA-N 0.000 description 2
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical group C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 2
- JVKRKMWZYMKVTQ-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]pyrazol-1-yl]-N-(2-oxo-3H-1,3-benzoxazol-6-yl)acetamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C=NN(C=1)CC(=O)NC1=CC2=C(NC(O2)=O)C=C1 JVKRKMWZYMKVTQ-UHFFFAOYSA-N 0.000 description 2
- YJLUBHOZZTYQIP-UHFFFAOYSA-N 2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CC2=C(CC1)NN=N2 YJLUBHOZZTYQIP-UHFFFAOYSA-N 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical group Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 229940043279 diisopropylamine Drugs 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 2
- 235000019799 monosodium phosphate Nutrition 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 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 2
- 239000000376 reactant Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000005694 sulfonylation reaction Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 1
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 1
- 125000001088 1-naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- VWVRASTUFJRTHW-UHFFFAOYSA-N 2-[3-(azetidin-3-yloxy)-4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]pyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound O=C(CN1C=C(C(OC2CNC2)=N1)C1=CN=C(NC2CC3=C(C2)C=CC=C3)N=C1)N1CCC2=C(C1)N=NN2 VWVRASTUFJRTHW-UHFFFAOYSA-N 0.000 description 1
- JWKARZDECJVQDJ-UHFFFAOYSA-N 2-fluoro-1-methylpyridin-1-ium Chemical compound C[N+]1=CC=CC=C1F JWKARZDECJVQDJ-UHFFFAOYSA-N 0.000 description 1
- MTAODLNXWYIKSO-UHFFFAOYSA-N 2-fluoropyridine Chemical compound FC1=CC=CC=N1 MTAODLNXWYIKSO-UHFFFAOYSA-N 0.000 description 1
- 125000001216 2-naphthoyl group Chemical group C1=C(C=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- JPVUWCPKMYXOKW-UHFFFAOYSA-N 4-phenylbenzoyl chloride Chemical compound C1=CC(C(=O)Cl)=CC=C1C1=CC=CC=C1 JPVUWCPKMYXOKW-UHFFFAOYSA-N 0.000 description 1
- 0 C[n+]1ccccc1OC1(C2F)OC(C*)=C(*)C12F Chemical compound C[n+]1ccccc1OC1(C2F)OC(C*)=C(*)C12F 0.000 description 1
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- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
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- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 150000008052 alkyl sulfonates Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound 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
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
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- 230000001747 exhibiting effect Effects 0.000 description 1
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- 125000000524 functional group Chemical group 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- VUQUOGPMUUJORT-UHFFFAOYSA-N methyl 4-methylbenzenesulfonate Chemical compound COS(=O)(=O)C1=CC=C(C)C=C1 VUQUOGPMUUJORT-UHFFFAOYSA-N 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- NSNPSJGHTQIXDO-UHFFFAOYSA-N naphthalene-1-carbonyl chloride Chemical compound C1=CC=C2C(C(=O)Cl)=CC=CC2=C1 NSNPSJGHTQIXDO-UHFFFAOYSA-N 0.000 description 1
- XNLBCXGRQWUJLU-UHFFFAOYSA-N naphthalene-2-carbonyl chloride Chemical compound C1=CC=CC2=CC(C(=O)Cl)=CC=C21 XNLBCXGRQWUJLU-UHFFFAOYSA-N 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000003507 refrigerant Substances 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/048—Pyridine radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
- C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical
-
- 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
Abstract
본 발명은 2-(2′-데옥시-2′,2′-디플루오로-D-리보퓨라노실)-1-메틸피리디늄 파라톨루엔설폰산염과 뉴클레오염기를 글리코실화 반응시켜 2′-데옥시-2′,2′-디플루오로시티딘을 제조하기 위한 방법 및 2′-데옥시-2′,2′-디플루오로시티딘을 제조하기 위한 중간체 화합물인 2-(2′-데옥시-2′,2′-디플루오로-D-리보퓨라노실)-1-메틸피리디늄 파라톨루엔설폰산염에 관한 것이다.The present invention provides a glycosylation reaction of 2- (2′-deoxy-2 ′, 2′-difluoro-D-ribofuranosyl) -1-methylpyridinium paratoluenesulfonate and nucleobases to 2 ′. 2- (2 'which is a method for preparing -deoxy-2', 2'-difluorocytidine and an intermediate compound for producing 2'-deoxy-2 ', 2'-difluorocytidine -Deoxy-2 ', 2'-difluoro-D-ribofuranosyl) -1-methylpyridinium paratoluenesulfonate.
본 발명에 따른 2′-데옥시-2′,2′-디플루오로시티딘의 제조방법은 2′-데옥시-2′,2′-디플루오로시티딘을 고순도로 용이하게 제조할 수 있다.Method for preparing 2'-deoxy-2 ', 2'-difluorocytidine according to the present invention can easily prepare 2'-deoxy-2', 2'-difluorocytidine with high purity have.
2-(2′-데옥시-2′,2′-디플루오로-D-리보퓨라노실)-1-메틸피리디늄 파라톨루엔설폰산염, 2′-데옥시-2′,2′-디플루오로시티딘 2- (2'-deoxy-2 ', 2'-difluoro-D-ribofuranosyl) -1-methylpyridinium paratoluenesulfonate, 2'-deoxy-2', 2'-di Fluorocytidine
Description
본 발명은 하기 화학식 1의 2′-데옥시-2′,2′-디플루오로시티딘을 제조하기 위한 중간체로서 유용하게 사용될 수 있는, 하기 화학식 3의 신규한 2-(2′-데옥시-2′,2′-디플루오로-D-리보퓨라노실)-1-메틸피리디늄 파라톨루엔설폰산염, 이의 제조방법 및 이를 이용한 2′-데옥시-2′,2′-디플루오로시티딘을 제조하는 방법에 관한 것이다.The present invention is a novel 2- (2′-deoxy) of formula (3), which can be usefully used as an intermediate for preparing 2′-deoxy-2 ′, 2′-difluorocytidine of formula (1) -2 ', 2'-difluoro-D-ribofuranosyl) -1-methylpyridinium paratoluenesulfonate, preparation method thereof and 2'-deoxy-2', 2'-difluoro using the same It relates to a process for preparing cytidine.
<화학식 1>≪ Formula 1 >
<화학식 3><Formula 3>
젬시타빈(gemcitabine)은 비소세포폐암(Non small Cell Lung Cancer : NSCLC)을 치료하는데 널리 사용되는 항암제로서, 리보퓨라노스 골격을 갖는 뉴클레오시드이며, 입체화학적으로는 리보퓨라노스의 1-위치에 시토신(cytosine)이 β-위치로 배향된 구조를 갖는다.Gemcitabine (gemcitabine) is an anticancer agent widely used to treat Non small Cell Lung Cancer (NSCLC), a nucleoside with ribofuranose skeleton, and stereochemically at the 1-position of ribofuranose. Cytosine has a structure oriented in the β-position.
통상적으로 젬시타빈은 하기 반응식 1에 도시한 바와 같이 보호된 옥소리보스 화합물(I)을 이용하여 제조할 수 있는데, 우선 일반적인 방법을 이용하여 옥소리보스 화합물을 환원시켜 락톨 화합물(II)을 제조할 수 있다. 이 때 락톨 화합물(II)의 1-하이드록시기는 뉴클레오염기와의 직접적인 글리코실화(glycosylation) 반응이 어려우므로 반응성이 뛰어난 이탈기(L)가 도입된 리보퓨라노스 화합물(III)로 전환시킨 다음, 활성화된 리보퓨라노스 화합물(III)을 뉴클레오염기와 글리코실화 반응시켜 뉴클레오시드를 수득한 후 탈보호하여 젬시타빈 화합물(IV)을 제조할 수 있다.Typically, gemcitabine may be prepared using a protected oxoribose compound (I), as shown in Scheme 1 below. First, the lactose compound (II) may be prepared by reducing the oxoribose compound using a general method. have. At this time, the 1-hydroxy group of the lactol compound (II) is difficult to directly glycosylation reaction with the nucleobase group, so it is converted into ribofuranose compound (III) having a highly reactive leaving group (L) introduced therein. Gemcitabine compound (IV) can be prepared by glycosylation of the activated ribofuranose compound (III) with a nucleobase to obtain a nucleoside, followed by deprotection.
<반응식 1><Reaction Scheme 1>
상기 식에서, P는 하이드록시 보호기이고, L은 이탈기를 의미한다.Wherein P is a hydroxy protecting group and L means a leaving group.
대한민국 특허등록 제312,389호에는 설포네이트 이탈기가 도입된 1-설포네이트리보퓨라노스의 활성화된 리보퓨라노스 화합물(III)이 알려져 있으며, 대한민국 특허등록 제252,452호에는 할로 이탈기가 도입된 1-할로리보퓨라노스가 공지되었으며, 특히 설포네이트 이탈기의 일종인 α-메탄설포네이트리보퓨라노스가 가장 바람직한 것으로 알려져 있다.Korean Patent Registration No. 312,389 discloses activated ribofuranose compound (III) of 1-sulfonate ribofuranose having a sulfonate leaving group, and Korean Patent Registration No. 252,452 has a 1-haloribo having a halo leaving group introduced therein. Furanos is known, in particular α-methanesulfonate ribofuranose, which is a kind of sulfonate leaving group, is known to be the most preferred.
우수한 글리코실화 반응물질로 알려진 α-메탄설포네이트리보퓨라노스의 경우 글리코실화 반응에서 뉴클레오염기와 입체 선택적으로 진행되는 장점은 있으나, 미국특허 제5,401,861호에 공지된 바와 같이 -80℃ 내외의 극저온에서 반응을 시켜야 α-아노머가 증가된 1-메탄설포네이트리보퓨라노스를 제조할 수 있다는 산업상의 제약이 있다. 예를 들어 하기 반응식 2에 도시한 바와 같이 -80 ℃ 내외의 극저온에서 설포닐화 반응을 진행할 경우 설포네이트 아노머가 생성된다. 즉, -80 ℃ 내외의 극저온에서 설포닐화 반응을 진행시킬 경우 1-메탄설포네이트의 α-아노머(Ⅶ)가 β-아노머(Ⅵ)에 비하여 4배 정도 더 많은 비율로 생성된다.Α-methanesulfonate ribofuranose, known as an excellent glycosylation reactant, has the advantage of undergoing steric selective with nucleobases in glycosylation reaction, but it is cryogenic at around -80 ° C as known in US Pat. No. 5,401,861. There is an industrial constraint that 1-methanesulfonate ribofuranose with increased α-anomer must be reacted at. For example, as shown in Scheme 2, when the sulfonylation reaction is performed at a cryogenic temperature of about -80 ° C, sulfonate anomer is produced. That is, when the sulfonylation reaction proceeds at a cryogenic temperature of about -80 ° C, α-anomer (1) of 1-methanesulfonate is produced at about 4 times more than the β-anomer (VI).
<반응식 2><Reaction Scheme 2>
상기 식에서, Bz는 벤조일이고, Ms는 메탄설포닐이다.Wherein Bz is benzoyl and Ms is methanesulfonyl.
그러나, -80 ℃ 이하의 초저온을 유지하며 대량생산 반응을 산업적 규모로 수행한다는 것은 반응기나 냉매의 관점에서 볼 때 현실적으로 용이하게 접근할 수 있는 방법이 아니며, 특히 미국특허 제5,256,797호에 기재된 바와 같이 특정의 용매에서 저온을 유지하며 원하는 α-설포네이트 아노머(VII)만을 분리하여야 되므로 별도의 분리 공정이 필요하고, 순수하게 수득하는 수율도 떨어지므로 산업적 생산 관점에서는 단점을 가지고 있다.However, maintaining the ultra low temperature below -80 ° C. and performing the mass production reaction on an industrial scale is not a realistically accessible method from the viewpoint of a reactor or a refrigerant, and in particular, as described in US Pat. No. 5,256,797. It is necessary to separate only the desired α-sulfonate anomer (VII) while maintaining a low temperature in a specific solvent, and thus a separate separation process is required.
한편, 미국특허 제5,744,597호 및 유럽특허 제577304호에는 α-할로 아노머가 풍부한 리보퓨라노스 유도체를 뉴클레오염기와 반응시켜 원하는 β-위치에 뉴클레오염기가 도입된 β-뉴클레오시드를 제조하는 방법이 공지되어 있다. 그러나, 이 와 같이 이탈기가 할로인 1-할로리보퓨라노스를 사용하여 글리코실화 반응을 시키는 경우에는 뉴클레오염기가 리보퓨라노스 1-위치의 이탈기를 공격하고 치환되는 반응에 있어서, 반응 후 떨어져 나간 이탈기가 뉴클레오염기와 경쟁적으로 리보퓨라노스 1-위치를 공격함으로써 1-위치에 아노머화(anomerization)가 유도되며 그에 따라 반응 초기와는 다른 α-아노머 대 β-아노머 비율을 보여주게 된다. 즉 α-위치로만 배향된 아노머를 사용하여 글리코실화 반응을 시키더라도 시간이 지날수록 β-아노머의 양이 증가하게 되며 그에 따라 반응이 비 입체선택적으로(nonstereoselective) 진행되어 뉴클레오염기가 β-위치로 배향된 소망하는 β-뉴클레오시드 뿐만 아니라 α-뉴클레오시드도 불순물로 상당히 생성된다.On the other hand, US Patent No. 5,744,597 and European Patent No. 57304 discloses a ribofuranose-rich ribofuranose derivative reacted with a nucleobase to prepare a β-nucleoside having a nucleobase introduced at a desired β-position. Methods are known. However, in the case where the leaving group is subjected to the glycosylation reaction using halo 1-halobofuranose, in the reaction where the nucleobase attacks the leaving group at the ribofuranose 1-position and is replaced, Leaving groups attack the ribofuranose 1-position competitively with nucleobases, leading to anomerization at the 1-position, resulting in a different α-anomer to β-anomer ratio than at the beginning of the reaction. . That is, even if the glycosylation reaction is carried out using an anomer oriented only at the α-position, the amount of β-anomer increases with time, and thus the reaction proceeds nonstereoselectively so that the nucleobase is β As well as the desired β-nucleosides oriented in the -position, α-nucleosides are also produced significantly as impurities.
그러므로 종래 공지된 방법에 있어서 1-설포네이트리보퓨라노스를 사용하는 방법은 반응이 입체선택적으로 진행되기는 하지만, 가장 중요한 중간체인 α-설포네이트리보퓨라노스를 수득하기 위하여 -80 ℃ 내외의 극저온이 필요하기 때문에 산업적인 대량생산을 위한 방법으로는 적합하지 않으며, 1-할로리보퓨라노스를 사용하는 방법의 경우 극저온을 요하지 않으나, 뉴클레오염기가 SN2 치환반응을 통해 α-할로 아노머와 글리코실화 반응을 할 때 1-위치의 아노머화가 동시에 경쟁적으로 일어나서 α-할로 아노머가 β-할로 아노머로 전환됨에 따라 반응이 비입체선택적으로 진행되며, 그 결과 원하는 β-뉴클레오시드가 낮은 비율로 얻어지며, 분리 수율도 낮아서 비효율적이며 비경제적인 제법이라는 문제점이 있다. 또한, 락톨 화 합물을 이용하여 이탈기가 도입된 1-할로리보퓨라노스 또는 1-설포네이트리보퓨라노스 화합물을 제조 후에 정제, 분리하는 단계가 필수적으로 추가됨에 따라 다단계에 따른 생산 소요기간이 길어지는 점이 비효율적인 단점으로 지적되고 있다.Therefore, the method using 1-sulfonate ribofuranose in the conventionally known method has a cryogenic temperature of around -80 ° C. in order to obtain α-sulfonate ribofuranose, which is the most important intermediate, although the reaction proceeds stereoselectively. It is not suitable for industrial mass production because it is necessary, and the method using 1-halobofuranose does not require cryogenic temperature. However, the nucleobase is reacted with α-halo-anomer through S N 2 substitution. In the glycosylation reaction, anodicization of the 1-position occurs at the same time and the reaction proceeds non-sterically as the α-halo anomer is converted to β-halo anomer, resulting in a lower ratio of the desired β-nucleoside. It is obtained as, the separation yield is also low, there is a problem of inefficient and inefficient manufacturing method. In addition, since the step of purifying and separating the 1-halo ribofuranose or 1-sulfonate ribofuranose compound having a leaving group introduced therein by using a lactol compound is essentially added, the production lead time according to the multi-step becomes longer. This is pointed out as an inefficient disadvantage.
이에, 본 발명자들은 종래의 제조방법상의 문제점을 해결하고자 예의 노력한 결과, 락톨 화합물의 이탈기 도입 물질로서 신규한 화합물인 2-(2′-데옥시-2′,2′-디플루오로-D-리보퓨라노실)-1-메틸피리디늄 파라톨루엔설폰산염 화합물을 제조하는데 성공하였고, 이 물질을 분리 과정 없이 한 반응기(one-pot 반응)에서 간단한 방법으로 글리코실화 반응을 진행함으로써 본 발명을 완성하였다.Accordingly, the present inventors have made diligent efforts to solve the problems in the conventional manufacturing method, and as a result of introducing the leaving group of the lactol compound, a novel compound, 2- (2'-deoxy-2 ', 2'-difluoro-D Ribofuranosyl) -1-methylpyridinium paratoluenesulfonate compound was successfully prepared, and the present invention was carried out by glycosylation reaction in a simple manner in one reactor (one-pot reaction) without separation process. Completed.
본 발명은 이탈기가 도입된 락톨 화합물로부터 생성물의 분리 과정 없이 한 반응기(one-pot 반응)에서 간단한 방법으로 2′-데옥시-2′,2′-디플루오로시티딘을 제조하는 방법을 제공하는 것을 목적으로 한다.The present invention provides a method for preparing 2'-deoxy-2 ', 2'-difluorocytidine in a simple method in a reactor (one-pot reaction) without separation of the product from the lactol compound having a leaving group introduced therein. It aims to do it.
또한 본 발명은 2′-데옥시-2′,2′-디플루오로시티딘을 제조하기 위한 신규한 중간체 화합물을 제공하는 것을 목적으로 한다.It is also an object of the present invention to provide a novel intermediate compound for preparing 2'-deoxy-2 ', 2'-difluorocytidine.
아울러 본 발명은 락톨 화합물을 제조하기 위한 1-옥소리보스 화합물의 결정화 방법을 제공하는 것을 목적으로 한다.In addition, an object of the present invention is to provide a method for crystallizing a 1-oxoribose compound for producing a lactol compound.
상기 목적을 달성하기 위하여, 본 발명은 2′-데옥시-2′,2′-디플루오로시티딘을 제조하기 위한 신규한 중간체 화합물로서 하기 화학식 3의 2-(2′-데옥시-2′,2′-디플루오로-D-리보퓨라노실)-1-메틸피리디늄 파라톨루엔설폰산염 화합물을 제공한다.In order to achieve the above object, the present invention provides a novel intermediate compound for preparing 2'-deoxy-2 ', 2'-difluorocytidine 2- (2'-deoxy-2) ', 2'-difluoro-D-ribofuranosyl) -1-methylpyridinium paratoluenesulfonate compound.
<화학식 3><Formula 3>
상기 식에서, R1, R2는 각각 독립된 변수로서, 
또한, 본 발명은 하기 화학식 6의 락톨 화합물을 염기 존재하에서 하기 화학 식 5의 피리디늄화합물과 반응시키는 단계를 포함하는 상기 화학식 3의 2-(2′-데옥시-2′,2′-디플루오로-D-리보퓨라노실)-1-메틸피리디늄 파라톨루엔설폰산염 화합물의 제조방법을 제공한다.In addition, the present invention is a 2- (2'-deoxy-2 ', 2'-di of the formula (3) comprising the step of reacting the lactol compound of formula 6 with a pyridinium compound of formula 5 in the presence of a base Provided is a method for preparing a fluoro-D-ribofuranosyl) -1-methylpyridinium paratoluenesulfonate compound.
<화학식 5>≪ Formula 5 >
<화학식 6>(6)
상기 식에서, R1, R2는 상기 화학식 3에서 정의한 바와 같다.Wherein R 1 and R 2 are the same as defined in Chemical Formula 3.
또한, 본 발명은 상기 화학식 3의 2-(2′-데옥시-2′,2′-디플루오로-D-리보퓨라노실)-1-메틸피리디늄 파라톨루엔설폰산염 화합물과 하기 화학식 4의 뉴클레오염기를 반응시켜 생성된 하기 화학식 2의 뉴클레오시드를 수득하고, 통상적인 방법에 따라 탈보호하는 하기 화학식 1의 2′-데옥시-2′,2′-디플루오로시티딘의 제조방법을 제공한다.In addition, the present invention is the 2- (2'-deoxy-2 ', 2'-difluoro-D-ribofuranosyl) -1-methylpyridinium paratoluenesulfonate compound of formula 3 and the formula A nucleoside of the following formula (2) produced by reacting a nucleobase of and obtained by deprotection according to a conventional method of 2'-deoxy-2 ', 2'-difluorocytidine It provides a manufacturing method.
<화학식 1>≪ Formula 1 >
<화학식 2>(2)
<화학식 4>≪ Formula 4 >
상기 식에서, R1, R2는 상기 화학식 3에서 정의한 바와 같고, Z는 메틸이며 P는 아미노 보호기이다.Wherein R 1 and R 2 are as defined in Formula 3, Z is methyl and P is an amino protecting group.
본 발명은 신규한 용매 조성을 이용하는 결정화 방법을 통해 에리트로 형태의 하기 화학식 7 화합물을 고순도로 제조하는 방법을 제공한다.The present invention provides a method for preparing a compound of formula 7 in erythro form with high purity through a crystallization method using a novel solvent composition.
<화학식 7>≪ Formula 7 >
상기 식에서, R1, R2는 상기 화학식 3에서 정의한 바와 같다.Wherein R 1 and R 2 are the same as defined in Chemical Formula 3.
이하 본 발명을 더욱 상세하게 설명한다.Hereinafter, the present invention will be described in more detail.
본 발명에서 출발물질인 화학식 7의 1-옥소리보스 화합물은 하기 화학식 10의 화합물을 이용하여 하기 반응식 3에 기재된 공정에 의해 제조할 수 있다.1-Oxoribose compound of the formula (7) which is a starting material in the present invention can be prepared by the process described in Scheme 3 using a compound of the formula (10).
<반응식 3><Reaction Scheme 3>
상기 식에서, R1, R2는 상기 화학식 3에서 정의한 바와 같고, R3, R4는 C1 내 지 C6의 저급 알킬기이며, 화학식 8의 화합물은 3R- 및 3S-에난티오머 혼합물이다.Wherein R 1 and R 2 are as defined in Formula 3, R 3 and R 4 are lower alkyl groups of C 1 to C 6 , and the compound of Formula 8 is a mixture of 3R- and 3S-enantiomers.
3- 및 5-하이드록시기를 각각 다른 보호기로 보호할 경우(R1≠R2), 화학식 10의 3-하이드록시기는 반응성을 지닌 관능기이므로 우선적으로 보호를 하고, 보호된 화학식 9의 에스터 혼합물을 약산과 반응시키면 우선적으로 디옥소란기가 탈보호되어 카르복실산이 생성되고, 고온에서 물을 제거하며 락톤화 반응을 진행시키면 에리트로와 트레오가 혼합된 상태인 화학식 8의 락톤 화합물을 제조할 수 있으며, 5-하이드록시기를 보호하고, 이소프로필에테르 또는 이소프로필에테르/n-헥산 혼합 용매 중에서 -5℃ 내지 10℃의 저온으로 냉각시킴으로써 에리트로와 트레오 혼합물로부터 소망하는 화학식 7의 에리트로 에난티오머만을 침전물로 분리, 수득할 수 있다.When the 3- and 5-hydroxy groups are each protected by a different protecting group (R 1 ≠ R 2 ), the 3-hydroxy group of the formula (10) is a reactive functional group, and thus is preferentially protected, and the protected ester mixture of the formula (9) is When reacted with a weak acid, the dioxolane group is first deprotected to form carboxylic acid, and the water is removed at a high temperature to proceed with the lactonation reaction, thereby preparing a lactone compound of Formula 8 in a state where erythro and treo are mixed. Protect the 5-hydroxy group and cool only the desired erythro-enantiomer of the formula (7) from the erythro and threo mixtures by cooling to a low temperature of -5 ° C to 10 ° C in isopropylether or isopropylether / n-hexane mixed solvent as a precipitate. Can be separated and obtained.
또한, 3- 및 5-하이드록시기를 같은 보호기로 보호할 경우(R1=R2)에는 상기 방법보다 더 효율적인 과정을 통해 제조할 수 있다. 화학식 10의 화합물을 먼저 약산과 반응시켜 디옥소란기가 탈보호된 카르복실산을 생성시키고, 고온에서 물을 제거하여 락톤화 반응을 진행함으로써 락톤 화합물을 제조한 후, 3- 및 5-하이드록시기를 동시에 보호하고, 이소프로필에테르 또는 이소프로필에테르/n-헥산 혼합 용매 중에서 저온으로 냉각시킴으로써 소망하는 화학식 7의 에리트로 에난티오머만을 침전물로 분리, 수득할 수 있다.In addition, when protecting 3- and 5-hydroxy groups with the same protecting group (R 1 = R 2 ) it can be prepared through a more efficient process than the above method. The compound of formula 10 is first reacted with a weak acid to produce a carboxylic acid in which the dioxolane group is deprotected, and water is removed at a high temperature to proceed with the lactonation reaction to prepare a lactone compound, followed by 3- and 5-hydroxy By simultaneously protecting the group and cooling to low temperature in isopropyl ether or isopropyl ether / n-hexane mixed solvent, only the desired erythro enantiomer of the formula (7) can be separated and obtained as a precipitate.
상기 제조 공정에 따른 본 발명은 화학식 7의 3- 및 5-하이드록시기의 동일/상이한 보호기에 따른 제조방법을 제공함으로써 보다 짧고 간단하게 소망하는 에리트로 에난티오머만을 고순도 및 고효율로 제조할 수 있다는 점이 특징이다.The present invention according to the above manufacturing process is to provide a manufacturing method according to the same / different protecting group of the 3- and 5-hydroxy groups of the general formula (7) can be produced in high purity and high efficiency only short and simple desired erythro enantiomer It is characteristic.
이와 같이 본 발명의 에리트로 구조를 갖는 화학식 7의 1-옥소리보스의 제조방법은 종래의 방법에 비하여 간단하게 결정화 단계에서의 용매 조성을 이용하여 소망하는 물질만을 분리하는 우수한 입체선택성을 나타내는 진일보된 제조방법이며, 특히 화학식 10의 3-하이드록시 에스터 화합물로부터 화학식 7의 2′,2′-디플루오로-2-데옥시-1-옥소리보스를 수득하는 총 반응 수율에 있어서도 종래의 방법에 비하여 우수한 45 내지 50 %의 수율(화학식 10의 화합물의 에리트로/트레오의 비율이 약 3/1인 출발물질로부터)을 나타내므로 매우 경제적인 제조방법이라 할 수 있다.As described above, the method for preparing 1-oxoris boose of Formula 7 having the erythro structure of the present invention is an advanced production method that shows superior stereoselectivity for separating only a desired substance by using a solvent composition in the crystallization step as compared with the conventional method. In particular, even in the total reaction yield for obtaining 2 ′, 2′-difluoro-2-deoxy-1-oxorisose of formula 7 from 3-hydroxy ester compound of formula 10, It can be said to be a very economical method because it shows a yield of 50% (from the starting material of the erythro / threo ratio of the compound of Formula 10 is about 3/1).
본 발명에 따른 화학식 3의 화합물의 제조방법은 하기 반응식 4에 도시한 바와 같다.Method for preparing a compound of Formula 3 according to the present invention is shown in Scheme 4 below.
<반응식 4><Reaction Scheme 4>
상기 식에서 R1, R2는 상기 화학식 3에서 정의한 바와 같다.Wherein R 1 , R 2 are as defined in the formula (3).
본 발명에 따른 화학식 3 화합물의 제조공정은 상기 반응식 4에 도시한 바와 같이, 화학식 7의 1-옥소리보스 화합물을 통상적인 방법으로 환원시켜 1-위치에 α-아노머 및 β-아노머가 혼합된 화학식 6의 락톨 화합물을 제조하는 단계; 얻어진 락톨 화합물을 염기의 존재하에서 화학식 5의 1-메틸-2-플루오로피리디늄 파라톨루엔설포네이트와 반응시킴으로써 목적 화합물인 화학식 3의 2-(2′-데옥시-2′,2′-디플루오로-D-리보퓨라노실)-1-메틸피리디늄 파라톨루엔설폰산염 화합물을 정량적인 수율로 제조하는 단계로 이루어진다.In the process for preparing the compound of Formula 3 according to the present invention, as shown in Scheme 4, the 1-oxoribose compound of Formula 7 is reduced by a conventional method, and α- and β-anomers are mixed in the 1-position. Preparing a lactol compound of Formula 6; 2- (2'-deoxy-2 ', 2'-di of formula 3 as the target compound by reacting the obtained lactol compound with 1-methyl-2-fluoropyridinium paratoluenesulfonate of formula 5 in the presence of a base Fluoro-D-ribofuranosyl) -1-methylpyridinium paratoluenesulfonate compound is prepared in quantitative yield.
이렇게 제조된 화합물은 별다른 분리 공정을 거치지 않고 뉴클레오염기와 반응함으로써 목적하는 뉴클레오시드를 얻을 수 있으므로, 기존의 알킬설포네이트와 할라이드와 같이 이탈기가 도입된 물질을 분리 공정을 거친 후 글리코실화 반응에 사용하는 번거로움을 피할 수 있다는 것이 본 발명의 가장 유용한 장점이다.The compound thus prepared can obtain a desired nucleoside by reacting with a nucleobase without undergoing a separate separation process. Thus, glycosylation reaction is carried out after separation of a substance into which a leaving group is introduced, such as an alkylsulfonate and a halide. It is the most useful advantage of the present invention that the hassle of using can be avoided.
화학식 3 화합물의 제조공정에서 사용되는 화학식 5의 피리디늄 화합물은 시약으로 구입하거나, 하기 반응식 5와 같이 문헌[Tetrahedron Lett., 1999, 40, 6661] 또는 [J.Org.Chem., 1991, 56, 509]에 기재된 바와 같은 공지된 방법에 의해 합성하여 사용할 수 있다.Pyridinium compounds of formula (5) used in the preparation of compounds of formula (3) may be purchased as reagents, or described in Tetrahedron Lett., 1999, 40 , 6661 or J. Org. Chem. , 1991, 56 , 509 can be synthesized and used by known methods.
<반응식 5><Reaction Scheme 5>
상기 반응식 5와 같이 제조된 화학식 5의 2-플루오로-1-메틸피리디늄 파라톨루엔설포네이트 화합물은 상업적으로 판매하는 경우 고가이나, 직접 제조할 경우 고수율로 간단히 제조가 가능하여 경제적인 제조 및 사용이 가능하다.The 2-fluoro-1-methylpyridinium paratoluenesulfonate compound of Chemical Formula 5 prepared as in Scheme 5 is expensive when sold commercially, but can be easily manufactured in high yield when manufactured directly, and thus economical preparation and Can be used.
상기 과정을 통하여 수득한 화학식 5의 피리디늄 화합물은 바로 다음 반응에 사용하여도 무방하나, 재결정 용매로 n-헥산, 이소프로필에테르, 메틸렌클로라이드/n-헥산, 에틸 아세테이트/n-헥산을 사용하고, 재결정을 통하여 목적하는 화학식 5의 2-플루오로-1-메틸피리디늄 파라톨루엔설포네이트를 고순도로 얻어 사용할 수 있다.The pyridinium compound of Formula 5 obtained through the above process may be used for the next reaction, but n-hexane, isopropyl ether, methylene chloride / n-hexane, ethyl acetate / n-hexane are used as a recrystallization solvent. By recrystallization, the desired 2-fluoro-1-methylpyridinium paratoluenesulfonate of Chemical Formula 5 can be obtained and used in high purity.
상기에서 제조된 화학식 5의 피리디늄 화합물은 화학식 6의 락톨 화합물의 사용량에 대하여 1.0 내지 2.0 몰 당량의 양으로 사용하는 것이 바람직하다.The pyridinium compound of Chemical Formula 5 prepared above is preferably used in an amount of 1.0 to 2.0 molar equivalents relative to the amount of the lactol compound of Chemical Formula 6.
반응이 진행됨에 따라 생성되는 유리 산은 피리딘, 트리에틸아민, 트리부틸아민, 디이소프로필에틸아민, 메틸피페리딘 등의 염기, 바람직하게는 디이소프로필에틸아민을 사용하여 제거할 수 있으며, 이때 염기는 화학식 6의 락톨 화합물의 사 용량에 대하여 1.0 내지 2.0 몰 당량의 양으로 사용하는 것이 바람직하다.The free acid produced as the reaction proceeds may be removed using a base such as pyridine, triethylamine, tributylamine, diisopropylethylamine, methylpiperidine, preferably diisopropylethylamine, wherein The base is preferably used in an amount of 1.0 to 2.0 molar equivalents relative to the use amount of the lactol compound of formula (6).
반응 용매로는 벤젠, 톨루엔, 아세토니트릴, 테트라하이드로퓨란, 에틸아세테이트, 메틸렌클로라이드, 또는 클로로포름, 바람직하게는 메틸렌클로라이드를 사용하고, 반응 온도는 -78 내지 40 ℃, 반응 시간은 2내지 5시간이 바람직하다.As the reaction solvent, benzene, toluene, acetonitrile, tetrahydrofuran, ethyl acetate, methylene chloride, or chloroform, preferably methylene chloride, and the reaction temperature is -78 to 40 ℃, the reaction time is 2 to 5 hours desirable.
상기에서 얻어진 신규한 화합물인 화학식 2의 2-(2′-데옥시-2′,2′-디플루오로-D-리보퓨라노실)-1-메틸피리디늄 파라톨루엔설폰산염 화합물을 이용한 젬시타빈의 제조방법은 하기 반응식 6에 도시한 바와 같다.Gemsci using a novel compound obtained above, 2- (2'-deoxy-2 ', 2'-difluoro-D-ribofuranosyl) -1-methylpyridinium paratoluenesulfonate compound of formula (2) The method for preparing tarbin is shown in Scheme 6 below.
<반응식 6><Reaction Scheme 6>
상기 식에서 R1, R2, Z, P는 상기 화학식 3과 화학식 4에서 정의한 바와 같다.Wherein R 1 , R 2 , Z, P are as defined in Formula 3 and Formula 4.
화학식 4의 뉴클레오염기의 아미노기 보호기로는 트리메틸실릴이 일반적으로 가장 바람직하며 헥사메틸디실라잔을 이용해서 진행할 수 있다. 120 ℃ 이상의 온 도에서 시토신과 헥사메틸디실라잔을 혼합한 후 반응하면 트리메틸실릴기로 보호된 시토신이 형성된다. 이 때 반응 후 시약 및 용매로 사용된 헥사메틸디실라잔을 제거하고 글리코실화 반응 용매를 하기에서 언급한 용매 중에 선택하여 화학식 3의 리보퓨라노실피리디늄 화합물과 반응시킬 수도 있으며, 시토신의 보호에 사용된 헥사메틸디실라잔을 제거하지 않고, 보호 반응 후 화학식 3의 리보퓨라노실피리디늄 화합물을 가하여 글리코실화 반응을 진행할 수도 있다. 즉 보호 반응 용매인 헥사메틸디실라잔을 글리코실화 반응 용매로도 계속 사용할 수 있으며, 또는 보호 반응 후 용매를 바꾸어 글리코실화 반응을 진행할 수도 있다.As the amino group protecting group of the nucleobase of the general formula (4), trimethylsilyl is generally most preferred and can proceed with hexamethyldisilazane. When cytosine and hexamethyldisilazane are mixed and reacted at a temperature of 120 ° C. or higher, the cytosine protected by trimethylsilyl group is formed. At this time, hexamethyldisilazane used as a reagent and a solvent after the reaction may be removed, and a glycosylation reaction solvent may be selected from the solvents mentioned below to react with the ribofuranosylpyridinium compound represented by Chemical Formula 3, and protection of cytosine It is also possible to proceed with the glycosylation reaction by adding the ribofuranosylpyridinium compound of the formula (3) after the protection reaction without removing the hexamethyldisilazane used in. That is, hexamethyldisilazane, which is a protection reaction solvent, may be continuously used as a glycosylation reaction solvent, or the glycosylation reaction may be performed by changing the solvent after the protection reaction.
상기 반응의 용매로는 헥사메틸디실라잔, 벤젠, 톨루엔, 자일렌, 치환된 벤젠, 디페닐에테르, 치환된 디페닐에테르, 비페닐(Biphenyl), 치환된 비페닐, 6내지 14개의 탄소수를 갖는 알칸 및 치환된 알칸으로 이루어진 군에서 1종 이상 선택하여 사용할 수 있고, 특히 디페닐에테르 또는 헥사메틸디실라잔 용매가 가장 바람직하다.The solvent of the reaction is hexamethyldisilazane, benzene, toluene, xylene, substituted benzene, diphenyl ether, substituted diphenyl ether, biphenyl, substituted biphenyl, and 6 to 14 carbon atoms. It is possible to use one or more selected from the group consisting of alkanes and substituted alkanes, and particularly preferred is diphenyl ether or hexamethyldisilazane solvent.
본 발명의 글리코실화 반응은 80 내지 300 ℃의 온도에서 수행할 수 있으며, 바람직하게는 130 내지 150 ℃의 온도가 좋으며, 2내지 4시간이면 거의 완결된다.The glycosylation reaction of the present invention can be carried out at a temperature of 80 to 300 ℃, preferably a temperature of 130 to 150 ℃ is good, it is almost completed in 2 to 4 hours.
본 발명에 따른 글리코실화 반응의 진행 상태는 박층크로마토그래피(TLC)를 통하여 추적할 수 있으며, 보다 정밀하게는 고압액체크로마토그래피(HPLC) 기기를 사용하여 분석할 수 있다.The progress of the glycosylation reaction according to the present invention can be tracked through thin layer chromatography (TLC), and more precisely can be analyzed using a high pressure liquid chromatography (HPLC) instrument.
본 발명에 있어서, 실릴화된 시토신을 화학식 4의 뉴클레오염기로 사용하여 글리코실화 반응을 시키는 경우, 반응 후 물 또는 알코올을 이용하여 실릴기를 분해시키면 반응에 참여하지 않고 남은 과량의 시토신이 함께 얻어진다. 이 물질을 제거하기 위해서 pH 조절을 통해 염산염 또는 브롬화수소염 형태로 변환시키면 물에 대한 용해도가 좋아지므로 물을 이용한 세척 과정에 의해 제거할 수 있다.In the present invention, when the silylated cytosine is subjected to the glycosylation reaction using the nucleobase represented by the formula (4), if the silyl group is decomposed using water or alcohol after the reaction, excess cytosine remaining without participation in the reaction is obtained together. Lose. In order to remove this substance, converting it into hydrochloride or hydrobromide form by adjusting the pH improves solubility in water and can be removed by washing with water.
또한, 상기 반응식 6에서 글리코실화 반응 후 얻어진 화학식 2의 뉴클레오시드 화합물의 탈보호 과정은 강염기를 사용하여 통상의 방법에 따라 가수분해시켜 제거할 수 있다. 이러한 강염기로는 수산화나트륨, 수산화칼륨과 같은 알칼리금속 수산화물; 소듐메톡시드, 소듐에톡시드 또는 칼륨 t-부톡시드와 같은 알칼리금속 알콕시드, 디에틸아민, 하이드록실아민, 암모니아, 하이드라진 등이 있으며 그 중 암모니아를 사용하여 탈보호하는 방법이 가장 바람직하다.In addition, the deprotection process of the nucleoside compound of Formula 2 obtained after the glycosylation reaction in Scheme 6 may be removed by hydrolysis according to a conventional method using a strong base. Such strong bases include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; Alkali metal alkoxides such as sodium methoxide, sodium ethoxide or potassium t-butoxide, diethylamine, hydroxylamine, ammonia, hydrazine and the like are the most preferred methods of deprotection using ammonia.
그러므로 본 발명은 에리트로 구조를 갖는 1-옥소리보스의 제조방법에 의해서 종래의 방법에 비하여 간단하게 결정화 단계에서의 용매 조성을 이용하여 우수한 입체선택성을 나타내는 소망하는 물질만을 분리할 수 있으며, 락톨 화합물에 도입하는 이탈기로서 신규한 2-플루오로-1-메틸피리디늄 파라톨루엔설폰산염을 이용한 화학식 3의 리보퓨라노실피리디늄 화합물을 제조함으로써, 이탈기를 도입한 물질을 분리하는 기존 공정과는 달리, 별도의 분리 공정 없이 글리코실화 반응에 사용하여 간편하게 원하는 화합물을 수득할 수 있다.Therefore, the present invention can separate only the desired material exhibiting excellent stereoselectivity by using the solvent composition in the crystallization step simply by the method of preparing 1-oxorisose having an erythro structure, compared to the conventional method, and introduced into the lactol compound Unlike the existing process of separating the substance introducing the leaving group by preparing a ribofuranosilpyridinium compound of formula (3) using a novel 2-fluoro-1-methylpyridinium paratoluene sulfonate as a leaving group to The desired compound can be obtained simply by use in the glycosylation reaction without a separate separation process.
이하 하기 실시예에 의하여 본 발명을 더욱 상세하게 설명하고자 한다. 단, 하기 실시예는 본 발명을 예시하기 위한 것일 뿐 본 발명의 범위가 이들만으로 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are intended to illustrate the present invention, but the scope of the present invention is not limited thereto.
하기 실시예에서, HPLC의 조작 조건은 화학식 1의 화합물의 경우 OP C18-51002546(4.6 X 250 ㎜, 5㎛) 컬럼을 사용하였으며, 용출액으로서 인산이수소나트륨(NaH2PO4˙ H2O) 13.8 g과 인산 2.5 ㎖을 물 1 ℓ에 녹인 액(pH 2.4 - 2.6)을 사용하였다. 또한, 화학식 2 및 3의 화합물의 경우 Inertsil ODS-2(4.6 X 150 ㎜, 5㎛) 컬럼을 사용하였으며, 용출액으로 인산이수소나트륨(NaH2PO4˙ H2O) 13.8 g과 인산 2.5 ㎖을 물 1 ℓ에 녹인 액(pH 2.4 - 2.6) 240 ㎖와 메탄올 760 ㎖를 혼합한 액을 사용하였다.In the following examples, the operating conditions of HPLC were used OP C18-51002546 (4.6 X 250 mm, 5㎛) column for the compound of formula 1, sodium dihydrogen phosphate (NaH 2 PO 4˙ H 2 O) as eluent A solution (pH 2.4-2.6) in which 13.8 g and 2.5 ml of phosphoric acid was dissolved in 1 L of water was used. In addition, Inertsil ODS-2 (4.6 X 150 mm, 5 μm) column was used for the compounds of Formulas 2 and 3, and 13.8 g of sodium dihydrogen phosphate (NaH 2 PO 4˙ H 2 O) and 2.5 mL of phosphoric acid were used as the eluent. Was mixed with 240 ml of a solution (pH 2.4-2.6) dissolved in 1 liter of water and 760 ml of methanol.
<실시예 1> D-에리트로-2,2-디플루오로-2-데옥시-1-옥소리보스 화합물의 제조(화학식 7의 화합물; R 1 = R 2 ) Example 1 Preparation of D-erythro-2,2-difluoro-2-deoxy-1-oxorisose compound (compound of Formula 7; R 1 = R 2 )
실시예 1-1 : D-에리트로-2-데옥시-2,2-디플루오로-펜토푸라노스-1-울로즈-3,5-디-(3′-플루오로)벤조에이트의 제조(R1 = R2 = 3'-플루오로벤조일)Example 1-1 Preparation of D-erythro-2-deoxy-2,2-difluoro-pentofuranos-1-ulose-3,5-di- (3'-fluoro) benzoate R 1 = R 2 = 3'-fluorobenzoyl)
에틸 2,2-디플루오로-3-하이드록시-3-(2,2-디메틸-[1,3]디옥소란-4-일)프로피오네이트(화학식 10의 화합물) 30 g을 아세토니트릴 165 ㎖에 용해시킨 후, 정제 수 11.7 ㎖와 아세트산 67.6 ㎖를 가한 뒤 2시간 동안 환류 반응시켰다. 감압 농축하여 아세토니트릴을 제거한 후 톨루엔 165 ㎖를 가하고 공비 농축하였다. 잔사에 아세토니트릴 165 ㎖를 가한 뒤, 자연 증류시키면서 제거되는 용매량과 같은 양의 톨루엔을 가하였다. 잔사에 에틸아세테이트 160 ㎖를 가하여 용해시킨 뒤, 마그네슘설페이트로 건조하고 여과하였다. 여액의 내부온도를 0 ℃ 이하로 냉각시킨 후, 3-플루오로벤조일 클로라이드 46.8 g과 디메틸아미노피리딘 2.88 g을 가한 뒤 10 ℃ 이하를 유지하며 피리딘 23.4 g을 적가하였다. 60 ℃에서 8시간 반응시킨 후, 2N-염산 수용액 180 ㎖를 가하여 유기층을 분리시켰다. 유기층에 중조 수용액 180 ㎖와 포화 소금물 180 ㎖로 각각 세척한 뒤, 마그네슘설페이트로 유기층을 건조하고 여과하였다. 감압 증류한 뒤, 농축액을 이소프로필에테르/n-헥산 혼합용매(2:0.4, v/v)로 결정화하여 고체상으로 표제화합물 24.4 g(수율 : 50.1 %)을 수득하였다.30 g of ethyl 2,2-difluoro-3-hydroxy-3- (2,2-dimethyl- [1,3] dioxoran-4-yl) propionate (compound of formula 10) was acetonitrile After dissolving in 165 mL, 11.7 mL of purified water and 67.6 mL of acetic acid were added, and the mixture was refluxed for 2 hours. After concentration under reduced pressure to remove acetonitrile, 165 ml of toluene was added and concentrated azeotropically. 165 ml of acetonitrile was added to the residue, followed by the addition of toluene in the same amount as the amount of solvent removed by natural distillation. 160 ml of ethyl acetate was added to the residue to dissolve it, which was then dried over magnesium sulfate and filtered. After the internal temperature of the filtrate was cooled to 0 ° C. or lower, 46.8 g of 3-fluorobenzoyl chloride and 2.88 g of dimethylaminopyridine were added thereto, and then 23.4 g of pyridine was added dropwise while keeping the temperature below 10 ° C. After reacting at 60 ° C. for 8 hours, 180 ml of a 2N aqueous hydrochloric acid solution was added to separate the organic layer. The organic layer was washed with 180 ml of sodium bicarbonate aqueous solution and 180 ml of saturated brine, and the organic layer was dried over magnesium sulfate and filtered. After distillation under reduced pressure, the concentrate was crystallized with an isopropyl ether / n-hexane mixed solvent (2: 0.4, v / v) to give 24.4 g (yield: 50.1%) of the title compound as a solid.
1H-NMR(300 MHz, CDCl3) : 4.65~4.82(m,2H), 4.99(dd,1H), 5.67~5.78(m,1H), 7.30~7.59(m.4H), 7.67~7.98(m,4H) 1 H-NMR (300 MHz, CDCl 3 ): 4.65 ~ 4.82 (m, 2H), 4.99 (dd, 1H), 5.67 ~ 5.78 (m, 1H), 7.30 ~ 7.59 (m.4H), 7.67 ~ 7.98 ( m, 4H)
융점(mp) : 108 ~ 109 ℃Melting Point (mp): 108 ~ 109 ℃
실시예 1-2 : D-에리트로-2-데옥시-2,2-디플루오로-펜토푸라노스-1-울로즈-3,5-디(1′-나프토에이트)의 제조(R1 = R2 = 1-나프토일)Example 1-2 Preparation of D-erythro-2-deoxy-2,2-difluoro-pentofuranos-1-ulose-3,5-di (1′-naphthoate) (R 1 = R 2 = 1-naphthoyl)
3-플루오로벤조일 클로라이드 대신 1-나프토일 클로라이드를 사용하여 상기 실시예 1-1의 방법에 기재된 방법과 동일하게 진행하여 표제 화합물을 수득하였다(수율:46.5 %).The title compound was obtained in the same manner as described in the method of Example 1-1 using 1-naphthoyl chloride instead of 3-fluorobenzoyl chloride (yield: 46.5%).
1H-NMR(300 MHz, CDCl3) : 4.46~4.65(m,2H), 5.12(dd,1H), 6.10~6.22(m,1H), 7.49~7.67(m.6H), 7.98~8.01(m,2H), 8.12~8.20(m,2H), 8.25~8.30(m,2H), 8.73~8.84(m,2H) 1 H-NMR (300 MHz, CDCl 3 ): 4.46 ~ 4.65 (m, 2H), 5.12 (dd, 1H), 6.10 ~ 6.22 (m, 1H), 7.49 ~ 7.67 (m.6H), 7.98 ~ 8.01 ( m, 2H), 8.12 to 8.20 (m, 2H), 8.25 to 8.30 (m, 2H), 8.73 to 8.84 (m, 2H)
실시예 1-3 : D-에리트로-2-데옥시-2,2-디플루오로-펜토푸라노스-1-울로즈-3,5-디(2′-나프토에이트)의 제조(R1 = R2 = 2-나프토일)Example 1-3 Preparation of D-erythro-2-deoxy-2,2-difluoro-pentofuranos-1-ulose-3,5-di (2′-naphthoate) (R 1 = R 2 = 2-naphthoyl)
3-플루오로벤조일 클로라이드 대신 2-나프토일 클로라이드를 사용하여 상기 실시예 1-1의 방법에 기재된 방법과 동일하게 진행하여 표제 화합물을 수득하였다(수율:46.3 %).The title compound was obtained in the same manner as described in the method of Example 1-1 using 2-naphthoyl chloride instead of 3-fluorobenzoyl chloride (yield: 46.3%).
1H-NMR(300 MHz, CDCl3) : 4.43~4.64(m,2H), 5.10(dd,1H), 6.08~6.19(m,1H), 7.50~7.64(m.4H), 7.90~8.10(m,8H), 8.54~8.79(m,2H) 1 H-NMR (300 MHz, CDCl 3 ): 4.43 ~ 4.64 (m, 2H), 5.10 (dd, 1H), 6.08 ~ 6.19 (m, 1H), 7.50 ~ 7.64 (m.4H), 7.90 ~ 8.10 ( m, 8H), 8.54-8.79 (m, 2H)
<실시예 2> D-에리트로-2-데옥시-2,2-디플루오로-펜토푸라노스-1-울로즈-5-벤조일-3-(4-페닐)벤조에이트의 제조(화학식 7의 화합물; R 1 = 비페닐 , R 2 = 벤조일) Example 2 Preparation of D-erythro- 2 -deoxy-2,2-difluoro-pentofuranos-1-ulose-5-benzoyl-3- (4-phenyl) benzoate Compound; R 1 = biphenyl, R 2 = benzoyl)
에틸 2,2-디플루오로-3-하이드록시-3-(2,2-디메틸-[1,3]디옥소란-4-일)프로 피오네이트(화학식 10의 화합물) 100.0 g을 메틸렌클로라이드 1,000 ㎖ 및 트리에틸아민 84 ㎖와 섞고 4-비페닐카보닐 클로라이드 102 g을 첨가하고 상온에서 5시간 반응시킨 다음, 1N-염산 수용액 700 ㎖를 가하고 유기층을 분리하였다. 분리한 유기층을 정제수, 중조 수용액 및 소금물 각 300 ㎖로 세척하고, 마그네슘설페이트로 건조하였다. 여과, 감압 증류 후 얻어진 물질을 아세토니트릴 550 ㎖에 용해시킨 후, 정제수 39 ㎖와 아세트산 227 ㎖를 가한 뒤 2시간 동안 환류 반응시켰다. 감압 농축하여 아세토니트릴을 제거한 후 톨루엔 550 ㎖를 가하고 공비 농축하였다. 잔사에 아세토니트릴 550 ㎖를 가한 뒤, 자연 증류시키면서 제거되는 용매량과 같은 양의 톨루엔을 가하였다. 잔사에 에틸아세테이트 500 ㎖를 가하여 용해시킨 뒤, 마그네슘설페이트로 건조하고 여과하였다. 여액을 0 ℃ 이하로 냉각시킨 후, 벤조일 클로라이드 66.4 g를 가하고 10 ℃ 이하를 유지하며 피리딘 62.2 g을 적가하였다. 60 ℃에서 8시간 반응시킨 후, 2N-염산 수용액 500 ㎖를 가하여 유기층을 분리시켰다. 유기층에 중조 수용액 500 ㎖와 포화 소금물 500 ㎖로 각각 세척한 뒤, 마그네슘설페이트로 유기층을 건조하고 여과하였다. 감압 증류한 뒤, 농축액을 이소프로필에테르/n-헥산 혼합용매(2:0.4, v/v)로 결정화하여 고체상으로 표제화합물 80.4 g(수율 : 45.2 %)을 수득하였다.Methylene chloride 100.0 g of ethyl 2,2-difluoro-3-hydroxy-3- (2,2-dimethyl- [1,3] dioxolan-4-yl) propionate (compound of formula 10) 1,000 ml and 84 ml of triethylamine were mixed, 102 g of 4-biphenylcarbonyl chloride was added and reacted at room temperature for 5 hours. Then, 700 ml of 1N hydrochloric acid aqueous solution was added thereto, and the organic layer was separated. The separated organic layer was washed with purified water, aqueous sodium bicarbonate solution and brine each 300 ml, and dried over magnesium sulfate. The material obtained after filtration and distillation under reduced pressure was dissolved in 550 ml of acetonitrile, and then 39 ml of purified water and 227 ml of acetic acid were added, and the mixture was refluxed for 2 hours. After concentration under reduced pressure to remove acetonitrile, 550 ml of toluene was added and concentrated azeotropically. 550 ml of acetonitrile was added to the residue, and then toluene was added in the same amount as the amount of solvent removed by natural distillation. 500 ml of ethyl acetate was added to the residue to dissolve it, which was then dried over magnesium sulfate and filtered. After the filtrate was cooled to 0 ° C. or lower, 66.4 g of benzoyl chloride was added and 62.2 g of pyridine was added dropwise while maintaining the temperature below 10 ° C. After reacting at 60 ° C. for 8 hours, 500 ml of 2N aqueous hydrochloric acid solution was added to separate the organic layer. The organic layer was washed with 500 ml of sodium bicarbonate aqueous solution and 500 ml of saturated brine, respectively, and the organic layer was dried over magnesium sulfate and filtered. After distillation under reduced pressure, the concentrate was crystallized with an isopropyl ether / n-hexane mixed solvent (2: 0.4, v / v) to give 80.4 g (yield: 45.2%) of the title compound as a solid.
1H-NMR(300 MHz, CDCl3) : 4.88~4.72(ddd,2H), 5.09(dd,1H), 5.87(ddd,1H), 7.65~7.50(m.5H), 7.78~7.67(m,3H), 7.81(d,2H), 8.13(d,2H), 8.23(d,2H) 1 H-NMR (300 MHz, CDCl 3 ): 4.88 ~ 4.72 (ddd, 2H), 5.09 (dd, 1H), 5.87 (ddd, 1H), 7.65 ~ 7.50 (m.5H), 7.78 ~ 7.67 (m, 3H), 7.81 (d, 2H), 8.13 (d, 2H), 8.23 (d, 2H)
융점(mp) : 130 ~ 131 ℃Melting Point (mp): 130 ~ 131 ℃
<실시예 3> 2-데옥시-2,2-디플루오로-D-리보퓨라노실-3,5-디-(3′-플루오로)벤조에이트의 제조(화학식 6의 화합물; R 1 = R 2 = 3'-플루오로벤조일) Example 3 Preparation of 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-di- (3′-fluoro) benzoate (Compound 6); R 1 = R 2 = 3'-fluorobenzoyl)
실시예 1에서 수득한 D-에리트로-2-데옥시-2,2-디플루오로-펜토푸라노스-1-울로즈-3,5-디-(3′-플루오로)벤조에이트 10.1 g을 테트라하이드로퓨란 100 ㎖에 용해시킨 후, -5 ℃ ~ 0 ℃로 냉각하였다. 리튬 트리-tert-부톡시알루미노하이드라이드 7.4 g을 -5 ℃ 이하에서 적가한 후, -5 ℃ ~ 0 ℃를 유지하며 1시간 동안 반응시켰다. 내부온도 10 ℃ 이하에서 2N-염산 수용액 150 ㎖를 가한 후, 에틸아세테이트 100 ㎖를 가하여 유기층을 분리하였다. 분리한 유기층을 물 200 ㎖와 포화 소금물 100 ㎖로 순차적으로 세척한 뒤, 소듐 설페이트로 유기층을 건조하고 여과하였다. 여액을 감압하여 용매를 제거하여 황색 시럽상의 표제화합물 10.05 g(수율 : 100.0%)을 수득하였다.10.1 g of D-erythro-2-deoxy-2,2-difluoro-pentofuranos-1-ulose-3,5-di- (3'-fluoro) benzoate obtained in Example 1 After dissolving in 100 ml of tetrahydrofuran, the mixture was cooled to -5 deg. C to 0 deg. 7.4 g of lithium tri-tert-butoxyaluminohydride was added dropwise at -5 ° C or lower, and then reacted for 1 hour while maintaining at -5 ° C to 0 ° C. 150 mL of 2N aqueous hydrochloric acid solution was added at an internal temperature of 10 ° C. or lower, and then 100 mL of ethyl acetate was added to separate an organic layer. The separated organic layer was washed sequentially with 200 ml of water and 100 ml of saturated brine, and then dried over sodium sulfate and filtered. The filtrate was removed under reduced pressure to give 10.05 g (yield: 100.0%) of the title compound as a yellow syrup.
1H-NMR(300 MHz, CDCl3) : 4.09~4.11(d,1H), 4.66~4.73(m,2H), 5.35~5.74(m,2H), 7.24~7.45(m,4H), 7.71~7.89(m,4H) 1 H-NMR (300 MHz, CDCl 3 ): 4.09 ~ 4.11 (d, 1H), 4.66 ~ 4.73 (m, 2H), 5.35 ~ 5.74 (m, 2H), 7.24 ~ 7.45 (m, 4H), 7.71 ~ 7.89 (m, 4H)
<실시예 4> 2-데옥시-2,2-디플루오로-D-리보퓨라노실-3-벤조일-5-(4-페닐)벤조에이트의 제조(화학식 6의 화합물; R 1 = 4-비페닐, R 2 = 벤조일) Example 4 Preparation of 2-deoxy-2,2-difluoro-D-ribofuranosyl-3-benzoyl-5- (4-phenyl) benzoate (Compound 6); R 1 = 4 Biphenyl, R 2 = benzoyl)
실시예 2에서 수득한 D-에리트로-2-데옥시-2,2-디플루오로-펜토푸라노스-1- 울로즈-5-벤조일-3-(4-페닐)벤조에이트를 이용하여 상기 실시예 3의 방법에 기재된 방법과 동일하게 진행하여 표제 화합물을 수득하였다(수율:100 %).The above operation was carried out using the D-erythro-2-deoxy-2,2-difluoro-pentofuranos-1-ulose-5-benzoyl-3- (4-phenyl) benzoate obtained in Example 2. In the same manner as described in the method of Example 3, the title compound was obtained (yield: 100%).
1H-NMR(300 MHz, CDCl3) : 3.89~3.91(d,1H), 4.61~4.81(m,2H), 5.31~5.92(m,2H), 7.26~7.70(m,10H), 8.05~8.16(m,4H) 1 H-NMR (300 MHz, CDCl 3 ): 3.89 ~ 3.91 (d, 1H), 4.61 ~ 4.81 (m, 2H), 5.31 ~ 5.92 (m, 2H), 7.26 ~ 7.70 (m, 10H), 8.05 ~ 8.16 (m, 4H)
<실시예 5> 1-메틸피리디늄 파라톨루엔설폰산염의 제조(화학식 5의 화합물) Example 5 Preparation of 1-methylpyridinium Paratoluenesulfonate (Compound 5)
2-플루오로피리딘 60.0 ㎖와 메틸 파라톨루엔설포네이트 105.0 ㎖를 톨루엔 160 ㎖에 용해시킨 후, 2시간 동안 환류 교반시켰다. 반응액을 실온으로 냉각시켜 윗층의 톨루엔을 따라내고 아래층에 헥산 300 ㎖를 넣고 현탁시킨 후, 여과하여 미백색의 표제화합물 177.7 g(수율 : 90.0 %)을 수득하였다.60.0 mL of 2-fluoropyridine and 105.0 mL of methyl paratoluenesulfonate were dissolved in 160 mL of toluene, followed by stirring under reflux for 2 hours. The reaction solution was cooled to room temperature, decanted in toluene in the upper layer, suspended in 300 ml of hexane in the lower layer, and then filtered to give 177.7 g (yield: 90.0%) of the white compound.
1H-NMR(300 MHz, CD3CN) : 2.32(s,3H), 4.18(d,3H), 7.14(d,2H), 7.56(d,2H), 7.78(m,2H), 8.58(m,1H), 8.73(m,1H) 1 H-NMR (300 MHz, CD 3 CN): 2.32 (s, 3H), 4.18 (d, 3H), 7.14 (d, 2H), 7.56 (d, 2H), 7.78 (m, 2H), 8.58 ( m, 1H), 8.73 (m, 1H)
융점(mp) : 129 ~ 132 ℃Melting Point (mp): 129 ~ 132 ℃
<실시예 6> 2-[2′-데옥시-2′,2′-디플루오로-D-리보퓨라노실-3,5-디-(3′-플루오로)벤조일]-1-메틸피리디늄 파라톨루엔설폰산염의 제조(화학식 3의 화합물) Example 6 2- [2′-deoxy-2 ′, 2′-difluoro-D-ribofuranosyl-3,5-di- (3′-fluoro) benzoyl] -1-methyl Preparation of pyridinium paratoluene sulfonate (compound of formula 3)
실시예 6-1 : 화학식 3의 화합물을 분리하는 제조방법Example 6-1: A method for separating the compound of Formula 3
실시예 3에서 수득한 2-데옥시-2,2-디플루오로-D-리보퓨라노실-3,5-디-(3′- 플루오로)벤조에이트 50.0 g을 메틸렌클로라이드 500 ㎖에 용해시킨 후, 디이소프로필아민 31.5 ㎖를 가한 뒤 -30 ℃로 냉각시켰다. 실시예 5에서 수득한 1-메틸피리디늄 파라톨루엔설폰산염 51.3 g을 -30 ℃를 유지하며 첨가한 뒤, 실온에서 3시간 반응시켰다. 반응 완료 후 1N-염산 수용액 150 ㎖를 첨가하고 유기층을 분리하여 정제수 100 ㎖, 소금물 100 ㎖로 세척하였다. 유기층을 마그네슘설페이트로 건조시킨 후 여과, 감압 농축하여 오일상의 표제화합물 81.8 g(수율 : 100 %)을 수득하였다.50.0 g of 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-di- (3'-fluoro) benzoate obtained in Example 3 was dissolved in 500 ml of methylene chloride. After the addition, 31.5 ml of diisopropylamine was added, followed by cooling to -30 deg. 51.3 g of 1-methylpyridinium paratoluenesulfonate obtained in Example 5 was added at −30 ° C., followed by reaction at room temperature for 3 hours. After completion of the reaction, 150 ml of 1N hydrochloric acid aqueous solution was added, and the organic layer was separated and washed with 100 ml of purified water and 100 ml of brine. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 81.8 g (yield: 100%) of the title compound as an oil.
1H-NMR(300 MHz, CDCl3) : 3.08(dd,3H), 3.63(dt,3H), 4.44(m,1H), 4.68(m,1H), 5.79(m,2H), 7.27~7.42(m.8H), 7.88~7.58(m,8H) 1 H-NMR (300 MHz, CDCl 3 ): 3.08 (dd, 3H), 3.63 (dt, 3H), 4.44 (m, 1H), 4.68 (m, 1H), 5.79 (m, 2H), 7.27 ~ 7.42 (m.8H), 7.88-7.58 (m, 8H)
실시예 6-2 : 화학식 3의 화합물을 분리하지 않고 in situ 글리코실화 반응에 사용하는 제조방법Example 6-2: Preparation method for use in in situ glycosylation without separating the compound of Formula 3
실시예 3에서 수득한 2-데옥시-2,2-디플루오로-D-리보퓨라노실-3,5-디-(3′-플루오로)벤조에이트 50.0 g을 메틸렌클로라이드 500 ㎖에 용해시킨 후, 디이소프로필아민 31.5 ㎖를 가한 뒤 -30 ℃로 냉각시켰다. 실시예 5에서 수득한 1-메틸피리디늄 파라톨루엔설폰산염 51.3 g을 -30 ℃를 유지하며 첨가한 뒤, 실온에서 3시간 반응시켰다. 반응 완료 후 별도의 분리 공정 없이 글리코실화 반응에 바로 사용하였다.50.0 g of 2-deoxy-2,2-difluoro-D-ribofuranosyl-3,5-di- (3'-fluoro) benzoate obtained in Example 3 was dissolved in 500 ml of methylene chloride. After the addition, 31.5 ml of diisopropylamine was added, followed by cooling to -30 deg. 51.3 g of 1-methylpyridinium paratoluenesulfonate obtained in Example 5 was added at −30 ° C., followed by reaction at room temperature for 3 hours. After completion of the reaction, it was used directly for glycosylation without a separate separation process.
<실시예 7> 2-[2′-데옥시-2′,2′-디플루오로-D-리보퓨라노실-3-벤조일-5-(4-페닐)벤조일]-1-메틸피리디늄 파라톨루엔설폰산염의 제조 Example 7 2- [2′-deoxy-2 ′, 2′-difluoro-D-ribofuranosyl-3-benzoyl-5- (4-phenyl) benzoyl] -1-methylpyridinium Preparation of Paratoluene Sulfonate
실시예 4에서 수득한 2-데옥시-2,2-디플루오로-D-리보퓨라노실-3-벤조일-5-(4-페닐)벤조에이트를 이용하여 상기 실시예 6-2의 방법에 기재된 방법과 동일하게 반응을 진행한 후 글리코실화 반응에 바로 사용했다.The method of Example 6-2, using 2-deoxy-2,2-difluoro-D-ribofuranosyl-3-benzoyl-5- (4-phenyl) benzoate obtained in Example 4 The reaction proceeded in the same manner as described in and immediately used for glycosylation reaction.
<실시예 8> 1-(2′-데옥시-2′,2′-디플루오로-3,5-디-(3′-플루오로벤조일)-D-리보퓨라노실-4-아미노피리미딘-2-온의 제조 Example 8 1- (2′-deoxy-2 ′, 2′-difluoro-3,5-di- (3′-fluorobenzoyl) -D-ribofuranosyl-4-aminopyri Preparation of Midin-2-one
실시예 8-1. 화학식 3의 화합물을 분리하여 사용하는 방법Example 8-1. How to use the compound of formula 3 separately
시토신 67.1 g에 헥사메틸디실라잔 335 ㎖를 가한 후, 암모늄 설페이트 16.0 g을 넣고 130 ℃에서 환류 반응시켰다. 반응물(화학식 4의 화합물)이 완전히 용해된 후, 1시간 추가 환류 교반하고 실시예 6-1에서 수득된 2-[2′-데옥시-2′,2′-디플루오로-D-리보퓨라노실-3,5-디-(3′-플루오로)벤조일]-1-메틸피리디늄 파라톨루엔설폰산염 81.8 g을 3등분하여 50분 간격으로 분할 투입하고, 최종 투입 후 1시간 더 교반했다. 감압 농축하고 상온에서 이소프로필 알코올 135 ㎖와 4.4N HBr 570 ㎖를 적가한 후 70 ℃에서 1시간 교반하고 10 ℃로 냉각했다. 생성된 결정을 여과하고 정제수와 이소프로필 알코올 135 ㎖로 세척한 뒤, 여과된 고체를 메탄올 473 ㎖에 현탁시키고 40 ℃ 이상으로 가온하여 완전히 용해시켰다. 반응액을 25 ℃로 냉각한 후, 30 % 암모니아수 5.0 g을 가하고 10분간 교반한 후, 외부온도 60 ℃에서 감압 농축했다. 농축물에 에틸아세테이트 687 ㎖를 가하고 외부온도 40 ℃로 가온하여 현탁시킨 후 40 ℃의 온수 687 ㎖로 2회 세척했다. 유기층 용액을 약 100 ㎖까지 감압 농축한 후, 5 ℃로 냉각하여 결정을 여과하고 생성된 결정을 에틸아세테이트 100 ㎖로 세척하여 미백색의 고체상으로 표제화합물 13.1 g(수율 : 21.4 %)을 수득하였다.After 335 ml of hexamethyldisilazane was added to 67.1 g of cytosine, 16.0 g of ammonium sulfate was added thereto, and the mixture was refluxed at 130 ° C. After the reactants (compound of formula 4) were completely dissolved, stirring was carried out for an additional 1 hour at reflux and 2- [2'-deoxy-2 ', 2'-difluoro-D-ribofu obtained in Example 6-1. 81.8 g of lanosyl-3,5-di- (3'-fluoro) benzoyl] -1-methylpyridinium paratoluenesulfonic acid salts were divided into 3 portions, and the mixture was added at 50 minute intervals, followed by further stirring for 1 hour after the final addition. . After concentrating under reduced pressure, 135 ml of isopropyl alcohol and 570 ml of 4.4N HBr were added dropwise at room temperature, followed by stirring at 70 ° C for 1 hour and cooling to 10 ° C. The resulting crystals were filtered and washed with 135 ml of purified water and isopropyl alcohol, and then the filtered solid was suspended in 473 ml of methanol and warmed up to 40 ° C. or more to completely dissolve. After cooling the reaction liquid to 25 degreeC, 5.0 g of 30% ammonia water was added, it stirred for 10 minutes, and it concentrated under reduced pressure at the external temperature of 60 degreeC. 687 mL of ethyl acetate was added to the concentrate, which was then suspended by heating to an external temperature of 40 ° C. and washed twice with 687 mL of 40 ° C. warm water. The organic layer solution was concentrated under reduced pressure to about 100 mL, cooled to 5 ° C, the crystals were filtered off, and the resulting crystals were washed with 100 mL of ethyl acetate to obtain 13.1 g (yield: 21.4%) of the title compound as an off-white solid.
1H-NMR(300 MHz, DMSO-d6) : 4.67~4.78(m,3H), 5.78(d,1H), 5.83(m,1H), 6.34(t,1H), 7.45~7.67(m,6H), 7.78(d,2H), 7.87(d,2H) 1 H-NMR (300 MHz, DMSO-d 6 ): 4.67 ~ 4.78 (m, 3H), 5.78 (d, 1H), 5.83 (m, 1H), 6.34 (t, 1H), 7.45 ~ 7.67 (m, 6H), 7.78 (d, 2H), 7.87 (d, 2H)
융점(mp) : 248 ~ 249 ℃Melting Point (mp): 248 ~ 249 ℃
실시예 8-2 : 화학식 3의 화합물 제조 후 in situ 글리코실화 진행Example 8-2 In situ glycosylation after preparing the compound of Formula 3
실시예 6-2에서 수득된 2-[2′-데옥시-2′,2′-디플루오로-D-리보퓨라노실-3,5-디-(3′-플루오로)벤조일]-1-메틸피리디늄 파라톨루엔설폰산염을 별다른 분리 공정 없이 사용하여 실시예 8-1과 같은 방법을 이용하여 글리코실화 반응을 진행함으로써 미백색의 고체상으로 표제화합물 13.0 g(화학식 6의 락톨 화합물로부터의 총수율 : 21.2 %)을 수득하였다.2- [2'-deoxy-2 ', 2'-difluoro-D-ribofuranosyl-3,5-di- (3'-fluoro) benzoyl]-obtained in Example 6-2 Using 1-methylpyridinium paratoluenesulfonate without any separation process, proceed with glycosylation using the same method as in Example 8-1 to give 13.0 g of the title compound as a white solid (total from the lactol compound of formula 6). Yield: 21.2%) was obtained.
1H-NMR 데이터는 상기 실시예 8-1과 동일하였다. 1 H-NMR data was the same as in Example 8-1.
<실시예 9> 1-(2′-데옥시-2′,2′-디플루오로-5-벤조일-3-(4-페닐)벤조일-D-리보퓨라노실-4-아미노피리미딘-2-온의 제조 Example 9 1- (2′-deoxy-2 ′, 2′-difluoro-5-benzoyl-3- (4-phenyl) benzoyl-D-ribofuranosyl-4-aminopyrimidine- Preparation of 2-one
실시예 7에서 수득한 2-[2′-데옥시-2′,2′'-디플루오로-D-리보퓨라노실-3- 벤조일-5-(4-페닐)벤조일]-1-메틸피리디늄 파라톨루엔 설폰산염을 사용하는 것을 제외하고는 상기 실시예 8-2의 방법과 동일하게 반응을 수행하였다.2- [2'-deoxy-2 ', 2' '-difluoro-D-ribofuranosyl-3-benzoyl-5- (4-phenyl) benzoyl] -1-methyl obtained in Example 7 The reaction was carried out in the same manner as in Example 8-2, except that pyridinium paratoluene sulfonate was used.
1H-NMR(300 MHz, DMSO-d6) : 4.6~4.7(m,3H), 5.7(d,1H), 5.8(m,1H), 6.2(t,1H), 7.4~7.5(m,7H), 7.6(d,2H), 7.7(d,2H), 7.8(d,2H), 7.9(d,2H), 8.1(d,2H) 1 H-NMR (300 MHz, DMSO-d 6 ): 4.6 ~ 4.7 (m, 3H), 5.7 (d, 1H), 5.8 (m, 1H), 6.2 (t, 1H), 7.4 ~ 7.5 (m, 7H), 7.6 (d, 2H), 7.7 (d, 2H), 7.8 (d, 2H), 7.9 (d, 2H), 8.1 (d, 2H)
<실시예 10> 2′-데옥시-2′,2′-디플루오로시티딘(화학식 1의 화합물)의 제조 Example 10 Preparation of 2′-deoxy-2 ′, 2′-difluorocytidine (Compound 1)
실시예 10-1 : 실시예 8에서 수득한 화합물의 탈보호 반응Example 10-1 Deprotection of the Compound Obtained in Example 8
상기 실시예 8-1에서 수득한 1-(2′-데옥시-2′,2′-디플루오로-3,5-디-(3′-플루오로벤조일)-D-리보퓨라노실-4-아미노피리미딘-2-온(화학식 2의 화합물) 6.0 g을 메탄올 60 ㎖에 현탁시킨 후 30 % 암모니아수 10 ㎖를 가하고 25 ℃에서 3시간 반응시켰다. 반응액을 감압 농축한 뒤, 생성된 결정에 정제수 7.6 ㎖를 가하여 용해시킨 다음 에틸아세테이트 7.6 ㎖를 2회 가하여 세척한 후 물층을 분리하였다. 분리한 물층을 셀라이트 여과한 후 감압하에서 물을 제거한 뒤, 톨루엔 25 ㎖를 가하여 공비하였다. 생성된 결정에 에탄올 21 ㎖를 가하고 12N 염산 1 ㎖를 가하고 외부온도 75 ℃에서 30분간 교반시킨 후, 반응액을 40 ℃로 냉각시켜 생성된 결정을 여과하고 냉각된 무수 에탄올 (5 ㎖)로 세척한 후 훈풍 건조하여 고체상의 표제화합물 3.23 g(수율 91.2 %)을 수득하였다.1- (2′-deoxy-2 ′, 2′-difluoro-3,5-di- (3′-fluorobenzoyl) -D-ribofuranosyl- obtained in Example 8-1 above 6.0 g of 4-aminopyrimidin-2-one (compound of formula 2) was suspended in 60 ml of methanol, and then 10 ml of 30% aqueous ammonia was added and reacted at 25 ° C. for 3 hours. 7.6 ml of purified water was added to the crystals to dissolve it, and 7.6 ml of ethyl acetate was added twice to wash, and then the water layer was separated. 21 ml of ethanol was added to the resulting crystals, 1 ml of 12N hydrochloric acid was added and stirred at an external temperature of 75 ° C. for 30 minutes, the reaction solution was cooled to 40 ° C., the resulting crystals were filtered and washed with cooled anhydrous ethanol (5 ml). After drying, it was dried with hot air to obtain 3.23 g (yield 91.2%) of the title compound as a solid.
1H-NMR(300 MHz, CDCl3) : 3.7(m,1H), 3.9(m,2H), 4.2(m,1H), 5.8(t,1H), 6.1(t,1H), 6.2(d,1H), 7.4(d,1H) 7.7(d,1H) 1 H-NMR (300 MHz, CDCl 3 ): 3.7 (m, 1H), 3.9 (m, 2H), 4.2 (m, 1H), 5.8 (t, 1H), 6.1 (t, 1H), 6.2 (d , 1H), 7.4 (d, 1H) 7.7 (d, 1H)
융점(mp) : 198 ~ 202 ℃Melting Point (mp): 198 ~ 202 ℃
HPLC 순도(면적 %) : β-아노머 99.98%, α-아노머 0.01% 이하, 시토신 0.01% 이하HPLC purity (area%): β-anomer 99.98%, α-anomer 0.01% or less, cytosine 0.01% or less
실시예 10-2 : 실시예 9에서 수득한 화합물의 탈보호 반응Example 10-2 Deprotection of Compounds Obtained in Example 9
실시예 9에서 수득한 1-(2′-데옥시-2′,2′-디플루오로-5-벤조일-3-(4-페닐)벤조일-D-리보퓨라노실-4-아미노피리미딘-2-온을 사용하는 것을 제외하고는 상기 실시예 10-1의 방법과 동일하게 반응을 수행하였다.1- (2'-deoxy-2 ', 2'-difluoro-5-benzoyl-3- (4-phenyl) benzoyl-D-ribofuranosyl-4-aminopyrimidine obtained in Example 9 The reaction was carried out in the same manner as in Example 10-1, except for using 2-one.
1H-NMR 데이터는 상기 실시예 10-1과 동일하였다. 1 H-NMR data was the same as in Example 10-1.
본 발명은 락톨 화합물과 피리디늄 화합물로부터 얻어지는 2-(2′-데옥시-2′,2′-디플루오로-D-리보퓨라노실)-1-메틸피리디늄 파라톨루엔설폰산염 화합물을 별도의 분리 공정 없이 뉴클레오염기와 반응함으로써, 목적하는 뉴클레오시드 화합물을 수득할 수 있으며, 또한 2-(2′-데옥시-2′,2′-디플루오로-D-리보퓨라노실)-1-메틸피리디늄 파라톨루엔설폰산염 화합물은 젬시타빈을 제조하기 위한 중간체로서 유용하게 사용될 수 있다.The present invention separately separates 2- (2′-deoxy-2 ′, 2′-difluoro-D-ribofuranosyl) -1-methylpyridinium paratoluenesulfonate compound obtained from a lactol compound and a pyridinium compound. By reacting with a nucleobase without the separation process, a desired nucleoside compound can be obtained, and also 2- (2'-deoxy-2 ', 2'-difluoro-D-ribofuranosyl) The 1-methylpyridinium paratoluenesulfonate compound can be usefully used as an intermediate for preparing gemcitabine.
또한, 본 발명은 용매 조성을 통한 효율적인 결정화 방법을 이용함으로써 총 반응 수율이 45 내지 50 %로 크게 향상된 매우 경제적인 방법으로 D-에리트로-2,2-디플루오로-2-데옥시-옥소리보스를 대량생산할 수 있다.In addition, the present invention provides a very economical method of improving the total reaction yield to 45 to 50% by using an efficient crystallization method through the solvent composition, so that D-erythro-2,2-difluoro-2-deoxy-oxorisose is used. Mass production
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