JP2888333B2 - Antiviral agent - Google Patents
Antiviral agentInfo
- Publication number
- JP2888333B2 JP2888333B2 JP8146548A JP14654896A JP2888333B2 JP 2888333 B2 JP2888333 B2 JP 2888333B2 JP 8146548 A JP8146548 A JP 8146548A JP 14654896 A JP14654896 A JP 14654896A JP 2888333 B2 JP2888333 B2 JP 2888333B2
- Authority
- JP
- Japan
- Prior art keywords
- group
- bis
- compound
- general formula
- mmol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 239000003443 antiviral agent Substances 0.000 title claims description 15
- 238000000034 method Methods 0.000 claims description 19
- 241000700605 Viruses Species 0.000 claims description 14
- GWFOVSGRNGAGDL-FSDSQADBSA-N 2-amino-9-[(1r,2r,3s)-2,3-bis(hydroxymethyl)cyclobutyl]-3h-purin-6-one Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1C[C@H](CO)[C@H]1CO GWFOVSGRNGAGDL-FSDSQADBSA-N 0.000 claims description 5
- 241000701022 Cytomegalovirus Species 0.000 claims description 5
- 241000700721 Hepatitis B virus Species 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 2
- 241000725303 Human immunodeficiency virus Species 0.000 claims 2
- 241000700584 Simplexvirus Species 0.000 claims 2
- 208000006454 hepatitis Diseases 0.000 claims 1
- 231100000283 hepatitis Toxicity 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 description 80
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 45
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 39
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- 239000002904 solvent Substances 0.000 description 31
- -1 dimethylcarbamoyl group Chemical group 0.000 description 29
- 239000000243 solution Substances 0.000 description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 17
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- 125000006239 protecting group Chemical group 0.000 description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 229910052739 hydrogen Inorganic materials 0.000 description 13
- 239000001257 hydrogen Substances 0.000 description 13
- 239000000203 mixture Substances 0.000 description 12
- 238000010898 silica gel chromatography Methods 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 239000003054 catalyst Substances 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 9
- 230000000840 anti-viral effect Effects 0.000 description 8
- 239000000460 chlorine Chemical group 0.000 description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
- 125000000217 alkyl group Chemical group 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
- 230000003287 optical effect Effects 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical group N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 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 6
- OMCMJVFRKZFPSO-ZCFPMLOXSA-N (1r,2s,3s)-2,3-bis[[tert-butyl(diphenyl)silyl]oxymethyl]cyclobutan-1-ol Chemical compound C([C@H]1[C@H](O)C[C@@H]1CO[Si](C(C)(C)C)(C=1C=CC=CC=1)C=1C=CC=CC=1)O[Si](C(C)(C)C)(C=1C=CC=CC=1)C1=CC=CC=C1 OMCMJVFRKZFPSO-ZCFPMLOXSA-N 0.000 description 5
- 229940126062 Compound A Drugs 0.000 description 5
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 5
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000012300 argon atmosphere Substances 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000003638 chemical reducing agent Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 229910052987 metal hydride Inorganic materials 0.000 description 5
- 150000004681 metal hydrides Chemical class 0.000 description 5
- FWRDWCSWCTWDDP-YUMQZZPRSA-N methyl (1s,2s)-3,3-bis(methylsulfanyl)-2-(2-oxo-1,3-oxazolidine-3-carbonyl)cyclobutane-1-carboxylate Chemical compound COC(=O)[C@H]1CC(SC)(SC)[C@@H]1C(=O)N1C(=O)OCC1 FWRDWCSWCTWDDP-YUMQZZPRSA-N 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 239000012046 mixed solvent Substances 0.000 description 5
- 239000002808 molecular sieve Substances 0.000 description 5
- 239000008363 phosphate buffer Substances 0.000 description 5
- LTEDQKPGOZDGRZ-UHFFFAOYSA-L propan-2-olate;titanium(4+);dichloride Chemical compound Cl[Ti+2]Cl.CC(C)[O-].CC(C)[O-] LTEDQKPGOZDGRZ-UHFFFAOYSA-L 0.000 description 5
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 5
- 230000003612 virological effect Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- OMCMJVFRKZFPSO-GDQCAIRTSA-N (1s,2s,3s)-2,3-bis[[tert-butyl(diphenyl)silyl]oxymethyl]cyclobutan-1-ol Chemical compound C([C@H]1[C@@H](O)C[C@@H]1CO[Si](C(C)(C)C)(C=1C=CC=CC=1)C=1C=CC=CC=1)O[Si](C(C)(C)C)(C=1C=CC=CC=1)C1=CC=CC=C1 OMCMJVFRKZFPSO-GDQCAIRTSA-N 0.000 description 4
- 208000030507 AIDS Diseases 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- 241000701074 Human alphaherpesvirus 2 Species 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 229960004150 aciclovir Drugs 0.000 description 4
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 229910000103 lithium hydride Inorganic materials 0.000 description 4
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- GGCGAESAURTGKY-UHFFFAOYSA-N 1,1-bis(methylsulfanyl)ethene Chemical group CSC(=C)SC GGCGAESAURTGKY-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
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 208000009746 Adult T-Cell Leukemia-Lymphoma Diseases 0.000 description 3
- 208000016683 Adult T-cell leukemia/lymphoma Diseases 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 3
- 241000700588 Human alphaherpesvirus 1 Species 0.000 description 3
- 241000701024 Human betaherpesvirus 5 Species 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 239000002841 Lewis acid Substances 0.000 description 3
- 239000012448 Lithium borohydride Substances 0.000 description 3
- 201000006966 adult T-cell leukemia Diseases 0.000 description 3
- 235000010233 benzoic acid Nutrition 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000012259 ether extract Substances 0.000 description 3
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 150000007517 lewis acids Chemical class 0.000 description 3
- 239000012280 lithium aluminium hydride Substances 0.000 description 3
- RGOXHVMJDFBAOV-NSCUHMNNSA-N methyl (e)-4-oxo-4-(2-oxo-1,3-oxazolidin-3-yl)but-2-enoate Chemical compound COC(=O)\C=C\C(=O)N1CCOC1=O RGOXHVMJDFBAOV-NSCUHMNNSA-N 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- GYAQQCQSTIRDJU-QTQRRKOQSA-N (2s,3s)-2,3-bis[[tert-butyl(diphenyl)silyl]oxymethyl]cyclobutan-1-one Chemical compound C([C@H]1C(=O)C[C@@H]1CO[Si](C(C)(C)C)(C=1C=CC=CC=1)C=1C=CC=CC=1)O[Si](C(C)(C)C)(C=1C=CC=CC=1)C1=CC=CC=C1 GYAQQCQSTIRDJU-QTQRRKOQSA-N 0.000 description 2
- FYGHSUNMUKGBRK-UHFFFAOYSA-N 1,2,3-trimethylbenzene Chemical compound CC1=CC=CC(C)=C1C FYGHSUNMUKGBRK-UHFFFAOYSA-N 0.000 description 2
- AUHZEENZYGFFBQ-UHFFFAOYSA-N 1,3,5-trimethylbenzene Chemical compound CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 2
- OMCMJVFRKZFPSO-UHFFFAOYSA-N 2,3-bis[[tert-butyl(diphenyl)silyl]oxymethyl]cyclobutan-1-ol Chemical compound C=1C=CC=CC=1[Si](C=1C=CC=CC=1)(C(C)(C)C)OCC1CC(O)C1CO[Si](C(C)(C)C)(C=1C=CC=CC=1)C1=CC=CC=C1 OMCMJVFRKZFPSO-UHFFFAOYSA-N 0.000 description 2
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 2
- PUSFOUFAFIXYCA-BPLGVMTJSA-N 9-[(1r,2r,3s)-2,3-bis[[tert-butyl(diphenyl)silyl]oxymethyl]cyclobutyl]-6-(2-methoxyethoxy)purin-2-amine Chemical compound C([C@H]1C[C@H]([C@@H]1CO[Si](C=1C=CC=CC=1)(C=1C=CC=CC=1)C(C)(C)C)N1C=2N=C(N)N=C(C=2N=C1)OCCOC)O[Si](C(C)(C)C)(C=1C=CC=CC=1)C1=CC=CC=C1 PUSFOUFAFIXYCA-BPLGVMTJSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 2
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- BJKBRBGBJCZWHS-RNFRBKRXSA-N [(1s,2s)-2-(hydroxymethyl)-3,3-bis(methylsulfanyl)cyclobutyl]methanol Chemical compound CSC1(SC)C[C@H](CO)[C@H]1CO BJKBRBGBJCZWHS-RNFRBKRXSA-N 0.000 description 2
- ITEOVPPFMFPVAO-ZPPRUVJKSA-N [(1s,2s,3s)-2,3-bis[[tert-butyl(diphenyl)silyl]oxymethyl]cyclobutyl] methanesulfonate Chemical compound C([C@H]1[C@@H](OS(C)(=O)=O)C[C@@H]1CO[Si](C(C)(C)C)(C=1C=CC=CC=1)C=1C=CC=CC=1)O[Si](C(C)(C)C)(C=1C=CC=CC=1)C1=CC=CC=C1 ITEOVPPFMFPVAO-ZPPRUVJKSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- AZWXAPCAJCYGIA-UHFFFAOYSA-N bis(2-methylpropyl)alumane Chemical compound CC(C)C[AlH]CC(C)C AZWXAPCAJCYGIA-UHFFFAOYSA-N 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 2
- SHQSVMDWKBRBGB-UHFFFAOYSA-N cyclobutanone Chemical compound O=C1CCC1 SHQSVMDWKBRBGB-UHFFFAOYSA-N 0.000 description 2
- WIGRSQDYQVWMKH-BQBZGAKWSA-N dimethyl (1s,2s)-3,3-bis(methylsulfanyl)cyclobutane-1,2-dicarboxylate Chemical compound COC(=O)[C@H]1CC(SC)(SC)[C@@H]1C(=O)OC WIGRSQDYQVWMKH-BQBZGAKWSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000004210 ether based solvent Substances 0.000 description 2
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 2
- 239000012894 fetal calf serum Substances 0.000 description 2
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
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- 210000002966 serum Anatomy 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- HHRMXBXKPDKHTG-WECIHKQLSA-N tert-butyl-[[(1s,2s)-2-[[tert-butyl(diphenyl)silyl]oxymethyl]-3,3-bis(methylsulfanyl)cyclobutyl]methoxy]-diphenylsilane Chemical compound C([C@H]1CC([C@@H]1CO[Si](C=1C=CC=CC=1)(C=1C=CC=CC=1)C(C)(C)C)(SC)SC)O[Si](C(C)(C)C)(C=1C=CC=CC=1)C1=CC=CC=C1 HHRMXBXKPDKHTG-WECIHKQLSA-N 0.000 description 1
- MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
- YTZKOQUCBOVLHL-UHFFFAOYSA-N tert-butylbenzene Chemical compound CC(C)(C)C1=CC=CC=C1 YTZKOQUCBOVLHL-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 150000003606 tin compounds Chemical class 0.000 description 1
- HIAIVILTZQDDNY-UHFFFAOYSA-J tin(4+);trifluoromethanesulfonate Chemical compound [Sn+4].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F HIAIVILTZQDDNY-UHFFFAOYSA-J 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 150000003609 titanium compounds Chemical class 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- 125000005951 trifluoromethanesulfonyloxy group Chemical group 0.000 description 1
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 210000003501 vero cell Anatomy 0.000 description 1
- 229960003636 vidarabine Drugs 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 1
- 229960002555 zidovudine Drugs 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
【０００１】[0001]
【発明の属する技術分野】本発明は、抗ウイルス剤に関
する。[0001] The present invention relates to an antiviral agent.
【０００２】[0002]
【従来の技術】核酸関連物質には抗ウイルス作用を持つ
ものが数多く知られており、そのうちいくつかのものは
有用な医薬品として臨床に供されている。例えば抗ウイ
ルス剤としてはビダラビン（M. Privat de Garilhe and
J. de Rubber, C.R. Acad.Soc. D(Paris)259, 2725(19
64) 、アシクロビル（G.B.Elion et al., Proc.Natl.Ac
ad. Sci. USA, 74,5716(1977) ）、アジドチミジン（H.
Mitsuya et al.,Proc.Natl. Acad.Sci.USA, 82,7096(1
985)）等が知られている。2. Description of the Related Art Many nucleic acid-related substances having an antiviral action are known, and some of them have been clinically used as useful pharmaceuticals. For example, antiviral agents include Vidarabine (M. Privat de Garilhe and
J. de Rubber, CR Acad. Soc. D (Paris) 259, 2725 (19
64), acyclovir (GBElion et al., Proc. Natl. Ac
ad. Sci. USA, 74, 5716 (1977)), azidothymidine (H.
Mitsuya et al., Proc. Natl. Acad. Sci. USA, 82,7096 (1
985)) and the like.
【０００３】[0003]
【発明が解決しようとする課題】しかしながら、上記抗
ウイルス剤は適用範囲が狭く、また溶解度、経口吸収
性、代謝等の影響により投与方法が限られる、また、骨
髄毒等の副作用のため長期投与が困難である等問題点を
多く残している。また、後天性免疫不全症候群（ＡＩＤ
Ｓ）、成人Ｔ細胞白血病（ＡＴＬ）等悪性なウイルス病
が増加の傾向にあることから、新たな抗ウイルス剤の開
発が望まれている。However, the above-mentioned antiviral agents have a narrow application range, and their administration methods are limited by the influence of solubility, oral absorption, metabolism, etc., and long-term administration due to side effects such as bone marrow toxin. However, many problems remain. In addition, acquired immunodeficiency syndrome (AID)
S) Since malignant viral diseases such as adult T-cell leukemia (ATL) tend to increase, development of new antiviral agents has been desired.
【０００４】[0004]
【課題を解決するための手段】本発明は、式（Ｇ）According to the present invention, there is provided a compound of formula (G)
【０００５】[0005]
【化１】 Embedded image
【０００６】で表される９−〔（１Ｒ，２Ｒ，３Ｓ）−
２，３−ビス（ヒドロキシメチル）シクロブタン−１−
イル〕−グアニン（以下、本発明化合物という）を有効
成分とする抗ウイルス剤 、に関する。式（Ｇ）で表さ
れる本発明化合物は、一般式（ＩＶ）9-[(1R, 2R, 3S)-
2,3-bis (hydroxymethyl) cyclobutane-1-
Yl] -guanine (hereinafter, referred to as the compound of the present invention) as an active ingredient. The compound of the present invention represented by the formula (G) has the general formula (IV)
【０００７】[0007]
【化２】 Embedded image
【０００８】〔式中Ｂはプリン塩基であり、Ｒ４は水素
原子又は保護基である〕で表されるシクロブタン誘導体
を合成する次の方法に従って合成することができる。Wherein B is a purine base and R 4 is a hydrogen atom or a protecting group. The cyclobutane derivative can be synthesized according to the following method.
【０００９】[0009]
【発明の実施の形態】即ち、一般式（Ｖ）DETAILED DESCRIPTION OF THE INVENTION That is, the general formula (V)
【００１０】[0010]
【化３】 Embedded image
【００１１】〔式中Ｒ４は水素原子又は保護基を示し、
Ｘは脱離基を示す〕で表わされる化合物とグアニン等の
プリン塩基とを反応することにより得られる一般式（Ｖ
Ｉ）Wherein R 4 represents a hydrogen atom or a protecting group;
X represents a leaving group] and a purine base such as guanine.
I)
【００１２】[0012]
【化４】 Embedded image
【００１３】〔式中Ｒ４は水素原子又は保護基を示し、
Ｂ１はプリン塩基を示す〕で表わされる化合物を得、こ
の化合物に保護基が存在する場合は、所望によりその保
護基を適当な脱保護試剤で除去することにより製造され
る。[Wherein R 4 represents a hydrogen atom or a protecting group,
B 1 represents a purine base], and when a protecting group is present in this compound, the compound is produced by removing the protecting group with an appropriate deprotecting reagent, if desired.
【００１４】一般式（Ｖ）〜（ＶＩ）に於ける保護基
（Ｒ４ ）としては、一般に保護基として使用されるも
のなら特に制限なく、エステル型保護基例えば、アセチ
ル基、ベンゾイル基等のアシル基、ジメチルカルバモイ
ル基、ジフェニルカルバモイル基等のカルバモイル基ま
たは、エーテル型保護基例えば、ｔ−ブチルジメチルシ
リル基、ｔ−ブチルジフェニルシリル基等のシリル基ま
たは、メトキシメチル基等の（Ｃ１ −Ｃ４ ）アルコキ
シ−（Ｃ１ −Ｃ４ ）アルキル基、テトラヒドロピラニ
ル基、ベンジル基、４−メトキシベンジル基、トリチル
基等の１つ以上のフェニル基で置換されたメチル基があ
げられる。The protecting group (R 4 ) in the general formulas (V) to (VI) is not particularly limited as long as it is generally used as a protecting group, and ester-type protecting groups such as acetyl and benzoyl groups. A carbamoyl group such as an acyl group, a dimethylcarbamoyl group or a diphenylcarbamoyl group; or an ether-type protecting group such as a silyl group such as a t-butyldimethylsilyl group or a t-butyldiphenylsilyl group or a (C1-C4) group such as a methoxymethyl group. A) a methyl group substituted with one or more phenyl groups such as an alkoxy- (C1-C4) alkyl group, a tetrahydropyranyl group, a benzyl group, a 4-methoxybenzyl group, and a trityl group.
【００１５】一般式（Ｖ）に於ける脱離基（Ｘ）として
は、例えば、メタンスルホニルオキシ基、ｐ−トルエン
スルホニルオキシ基、トリフルオロメタンスルホニルオ
キシ基等のスルホニルオキシ基、塩素、臭素、ヨウ素等
のハロゲンが挙げられる。The leaving group (X) in the general formula (V) includes, for example, sulfonyloxy groups such as methanesulfonyloxy group, p-toluenesulfonyloxy group and trifluoromethanesulfonyloxy group, chlorine, bromine and iodine. And the like.
【００１６】プリン塩基としては、グアニンが挙げられ
る。この化合物は保護基を有していても良い。例えば、
式The purine base includes guanine. This compound may have a protecting group. For example,
formula
【００１７】[0017]
【化５】 Embedded image
【００１８】〔式中、Ｒ４ は前記と同じものを示す〕
に示されるような化合物を挙げることができる。[Wherein R 4 is the same as defined above]
And the like.
【００１９】一般式（Ｖ）で表される化合物と一般式
（ＸＩＩ）の化合物との反応に於て、一般式（Ｖ）の化
合物と一般式（ＸＩＩ）の化合物の使用割合は、前者１
当量に対し後者約０．５−１０倍当量、好ましくは約１
−５当量程度が良い。又、両者の反応は、塩基触媒存在
下にあるいは無触媒で行なわれる。In the reaction between the compound represented by the general formula (V) and the compound represented by the general formula (XII), the ratio of the compound represented by the general formula (V) to the compound represented by the general formula (XII) is 1
The latter is about 0.5-10 times equivalent, preferably about 1 equivalent.
About -5 equivalents is good. The reaction between the two is carried out in the presence or absence of a base catalyst.
【００２０】塩基触媒としては、炭酸カリウム、水素化
リチウム、水素化ナトリウム等を用い、Ｎ，Ｎ−ジメチ
ルホルムアミド（ＤＭＦ）、ジメチルスルホキシド（Ｄ
ＭＳＯ）、１，３−ジメチル−２−イミダゾリノン、ヘ
キサメチルフォスフォリックトリアミド（ＨＭＰＡ）等
の溶媒中、０℃から溶媒の還流温度、好ましくは、室温
付近から１７０℃程度で行なわれる。塩基触媒の使用量
は、一般式（ＸＩＩ）の化合物に対して０当量から２倍
当量、好ましくは、０．５から１．５倍当量程度、さら
に好ましくは，０．８から１．２倍当量程度がよい。As the base catalyst, potassium carbonate, lithium hydride, sodium hydride or the like is used, and N, N-dimethylformamide (DMF), dimethyl sulfoxide (D
(MSO), 1,3-dimethyl-2-imidazolinone, hexamethylphosphoric triamide (HMPA) or the like, at a temperature from 0 ° C. to the reflux temperature of the solvent, preferably from about room temperature to about 170 ° C. The amount of the base catalyst to be used is 0 equivalent to 2 equivalents, preferably about 0.5 to 1.5 equivalents, more preferably 0.8 to 1.2 equivalents, relative to the compound of general formula (XII). The equivalent is good.
【００２１】また、一般式（ＶＩ）で示される化合物の
保護基（アルキル基を含む）の除去は、その保護基の違
いにより適当な脱保護試剤、或いは、脱保護方法を用い
ることで達成される。例えば、水酸化ナトリウム、ナト
リウムメチラート、アンモニア等のアルカリ、塩酸、硫
酸等の酸、フッ化テトラブチルアンモニウム等のフッ素
試剤、水素化分解等が挙げられる。The removal of the protecting group (including the alkyl group) of the compound represented by the general formula (VI) can be achieved by using an appropriate deprotecting reagent or a deprotecting method depending on the difference of the protecting group. You. Examples thereof include alkalis such as sodium hydroxide, sodium methylate, and ammonia, acids such as hydrochloric acid and sulfuric acid, fluorine reagents such as tetrabutylammonium fluoride, hydrogenolysis, and the like.
【００２２】また、一般式（ＩＶ）で表される化合物
は、反応式The compound represented by the general formula (IV)
【００２３】[0023]
【化６】 Embedded image
【００２４】〔式中、Ｒ４ は水素または保護基を示
し、Ｘは脱離基を示し、Ｂはプリン塩基を示し、Ｂ２
は一工程あるいは多工程でＢに導ける置換基を示す〕に
示すように、一般式（Ｖ）で表わされる化合物をナトリ
ウムアジド等のアジドイオンと処理した後還元する等の
通常の手法で一般式（ＸＸＩＩ）で表わされるアミン誘
導体を合成し、この一般式（ＸＸＩＩ）で表わされる化
合物を既知の方法（R. Vince et al., J. Med.Chem., 2
7,1358(1984), R. Vince et al., J.Med.Chem., 30,202
6(1987). Y. F. Shealy and C.A.O'Dell, J. Heterocyc
lic Chem., 13,1015(1976),Y.F.Shealy et al., J. Het
erocyclic Chem., 18, 383(1981) 等）に従い一般式
（ＸＸＩＩＩ）で表わされる中間体を経由して、式（Ｉ
Ｖ）を得ることができる。[Wherein, R 4 represents hydrogen or a protecting group, X represents a leaving group, B represents a purine base, B 2
Represents a substituent which can be introduced into B in one step or multiple steps] as shown in the general formula (V), wherein the compound represented by the general formula (V) is treated with an azide ion such as sodium azide and then reduced, and the like. XXII), and the compound represented by the general formula (XXII) is synthesized by a known method (R. Vince et al., J. Med. Chem., 2
7,1358 (1984), R. Vince et al., J. Med.Chem., 30,202
6 (1987). YF Shealy and CAO'Dell, J. Heterocyc
lic Chem., 13,1015 (1976), YFShealy et al., J. Het
erocyclic Chem., 18, 383 (1981), etc.), via an intermediate represented by the general formula (XXIII),
V) can be obtained.
【００２５】また、一般式（Ｖ）の化合物、更には一般
式（ＩＶ）で表される本発明化合物を製造するに当り、
一般式（ＩＩＩ）で表される化合物が非常に有用であ
る。また、一般式（ＩＩＩ）で表される化合物は、光学
活性にも製造できることから一般式（ＩＶ）で表される
化合物も光学活性に製造できる。即ち、反応式In producing the compound of the general formula (V), and further the compound of the present invention represented by the general formula (IV),
The compound represented by the general formula (III) is very useful. Further, since the compound represented by the general formula (III) can be produced optically active, the compound represented by the general formula (IV) can also be produced optically active. That is, the reaction formula
【００２６】[0026]
【化７】 Embedded image
【００２７】〔式中Ｒ１ は炭素数１から５のアルキル
基、アラルキル基または二つのＲ１ が結合して炭素数
２から３の環状アルキレン基を示し、Ｒ２ は水素、炭
素数１から５のアルキル基、保護されたヒドロキシアル
キル基または保護されたカルボキシル基を示し、Ｒ３
は水素、Ｃ１ −Ｃ５ の低級アルキル基、Ｃ１ −Ｃ５
の低級アルコキシ基、またはアラキルオキシ基を示す。
Ａは炭素数２から５の直鎖状または分枝状のアルキレン
基を、Ｙは酸素またはイオウ原子を、Ｚは置換または無
置換メチレン基または酸素またはイオウ原子を示す〕に
示すように、一般式（Ｉ）で表される化合物と一般式
（ＩＩ）で表される化合物を縮合触媒を用いて反応する
と、触媒の種類によりラセミ体のあるいは光学活性な一
般式（ＩＩＩ）で表されるシクロブタン化合物が高収率
で得られる。[In the formula, R 1 represents an alkyl group having 1 to 5 carbon atoms, an aralkyl group or a cyclic alkylene group having 2 to 3 carbon atoms by bonding two R 1 , and R 2 represents hydrogen, 1 to 5 carbon atoms. R 3 represents an alkyl group, a protected hydroxyalkyl group or a protected carboxyl group;
Represents hydrogen, a C1-C5 lower alkyl group, C1-C5
A lower alkoxy group or an aralkyloxy group.
A represents a linear or branched alkylene group having 2 to 5 carbon atoms, Y represents an oxygen or sulfur atom, and Z represents a substituted or unsubstituted methylene group or an oxygen or sulfur atom. When the compound represented by the formula (I) is reacted with the compound represented by the general formula (II) using a condensation catalyst, a racemic or an optically active cyclobutane represented by the general formula (III) is obtained depending on the type of the catalyst. The compound is obtained in high yield.
【００２８】この反応に於ける縮合触媒としては、例え
ばルイス酸あるいはルイス酸と当量または過剰量のリガ
ンドを組合わせたものが挙げられる。ルイス酸として
は、例えば四塩化チタン、ジクロロジイソプロポキシチ
タンなどのチタン化合物、二塩化スズ、四塩化スズ、二
価スズトリフラート等のスズ化合物、塩化ジメチルアル
ミニウム、塩化ジエチルアルミニウム等のアルミニウム
化合物が挙げられる。リガンドとしては立体的に込み合
ったジオール類が好ましく、例えば（２Ｓ，３Ｓ）−
２，３−Ｏ−（１−フェニルエチリデン）−１，１，
４，４−テトラフェニル−１，２，３，４−ブタンテト
ラオール（化合物Ａ）、（２Ｓ，３Ｓ）−２，３−Ｏ−
ベンジリデン−１，１，４，４−テトラフェニル−１，
２，３，４−ブタンテトラオール（化合物Ｃ）、（２
Ｓ，３Ｓ）−２，３−Ｏ−（１−フェニルエチリデン）
−１，１，４，４−テトラキス（４−メトキシフェニ
ル）−１，２，３，４−ブタンテトラオール（化合物
Ｅ）、等の分子内に５員環以上の環、好ましくは５−８
員環を有し、その環をはさんで両側に水酸基の結合した
基を有するもの等が挙げられる。Examples of the condensation catalyst in this reaction include a Lewis acid or a combination of a Lewis acid and an equivalent or excess amount of a ligand. Examples of the Lewis acid include titanium compounds such as titanium tetrachloride and dichlorodiisopropoxy titanium, tin compounds such as tin dichloride, tin tetrachloride and divalent tin triflate, and aluminum compounds such as dimethyl aluminum chloride and diethyl aluminum chloride. Can be As the ligand, diols which are sterically hindered are preferable, for example, (2S, 3S)-
2,3-O- (1-phenylethylidene) -1,1,1
4,4-tetraphenyl-1,2,3,4-butanetetraol (compound A), (2S, 3S) -2,3-O-
Benzylidene-1,1,4,4-tetraphenyl-1,
2,3,4-butanetetraol (compound C), (2
(S, 3S) -2,3-O- (1-phenylethylidene)
In the molecule of -1,1,4,4-tetrakis (4-methoxyphenyl) -1,2,3,4-butanetetraol (compound E) or the like, a 5- or more-membered ring, preferably 5-8
And those having a membered ring and a group having a hydroxyl group bonded on both sides of the ring.
【００２９】一般式（Ｉ）で示される化合物と一般式
（ＩＩ）で示される化合物の使用割合は前者１当量に対
し後者０．１から５当量好ましくは、０．５から２当量
である。縮合触媒の使用量は一般式（Ｉ）の化合物１当
量に対し０．００１から２当量好ましくは０．０１当量
から１．２当量である。この反応に於て、反応系中にモ
レキュラーシーブス４Ａなどの脱水剤を加えることによ
り反応がより効率よく進行することがある。反応の溶媒
としては、例えばペンタン、ヘキサン、ヘプタン、石油
エーテル、ベンゼン、トルエン、エチルベンセン、トリ
メチルベンゼン、トリイソプロピルベンゼン等の炭化水
素系溶媒、フロン等のハロゲン化炭素系溶媒、エーテ
ル、テトラヒドロフラン等のエーテル系溶媒、アセトニ
トリル等の溶媒及びこれらの混合溶媒が挙げられ、反応
温度は、反応溶媒の凝固点から沸点程度がよく、好まし
くは、−５０℃から３０℃位がよい。The ratio of the compound represented by the general formula (I) to the compound represented by the general formula (II) is 0.1 to 5 equivalents, preferably 0.5 to 2 equivalents, per equivalent of the former. The amount of the condensation catalyst to be used is 0.001 to 2 equivalents, preferably 0.01 to 1.2 equivalents, per 1 equivalent of the compound of the formula (I). In this reaction, the reaction may proceed more efficiently by adding a dehydrating agent such as Molecular Sieves 4A to the reaction system. Examples of the solvent for the reaction include hydrocarbon solvents such as pentane, hexane, heptane, petroleum ether, benzene, toluene, ethylbenzene, trimethylbenzene, and triisopropylbenzene, halogenated carbon solvents such as chlorofluorocarbons, ethers, and tetrahydrofuran. Examples of the solvent include ether solvents and solvents such as acetonitrile and mixed solvents thereof. The reaction temperature is preferably about the boiling point to the freezing point of the reaction solvent, and more preferably about -50 ° C to about 30 ° C.
【００３０】例えば、Ｒ２ がメトキシカルボニル基、
ＡがＣＨ２ＣＨ２ 、Ｙが酸素、Ｚが酸素である一般式
（Ｉ）の化合物（１当量）及び、Ｒ１ がメチル基、Ｒ
３ が水素である一般式（ＩＩ）の化合物（１．２５当
量）を、縮合触媒としてジクロロジイソプロポキシチタ
ン（０．０５当量）及び（２Ｓ，３Ｓ）−２，３−Ｏ−
（１−フェニルエチリデン）−１，１，４，４−テトラ
フェニル−１，２，３，４−ブタンテトラオール（化合
物Ａ）（０．０５５当量）を組み合わせた物を用い、モ
レキュラーシーブス４Ａを加え、ヘキサン−トルエン混
合触媒中、０℃で反応させることにより（２Ｓ，３Ｓ）
−３−メトキシカルボニル−１，１−ビス（メチルチ
オ）−２−（オキサゾリジン−２−オン−３−イル）カ
ルボニルシクロブタンが高化学収率、高光学収率で得ら
れる。For example, when R 2 is a methoxycarbonyl group,
A compound of the general formula (I) wherein A is CH 2 CH 2 , Y is oxygen, and Z is oxygen (1 equivalent); R 1 is a methyl group;
Compound (II) of formula (II) wherein 3 is hydrogen is converted to dichlorodiisopropoxytitanium (0.05 equivalent) and (2S, 3S) -2,3-O- as a condensation catalyst.
Using a combination of (1-phenylethylidene) -1,1,4,4-tetraphenyl-1,2,3,4-butanetetraol (Compound A) (0.055 equivalent), molecular sieves 4A In addition, by reacting at 0 ° C. in a hexane-toluene mixed catalyst, (2S, 3S)
-3-Methoxycarbonyl-1,1-bis (methylthio) -2- (oxazolidin-2-one-3-yl) carbonylcyclobutane can be obtained with high chemical yield and high optical yield.
【００３１】Ｒ１ ，Ｒ２ ，Ｒ３ によって示される炭
素数１から５のアルキル基としては、例えばメチル基、
エチル基、ブチル基等のアルキル基が挙げられ、アラル
キル基としては、例えばベンジル基、４−メトキシベン
ジル基等の芳香族環で置換されたアルキル基が挙げられ
る。また、保護されたヒドロキシアルキル基としては、
例えばベンジルオキシメチル基、アセチルオキシメチル
基、ｔ−ブチルジフェニルシリルオキシメチル基等が挙
げられる。保護されたカルボキシル基としては、例えば
メトキシカルボニル基、エトキシカルボニル基等のよう
なアルコキシカルボニル基や、ベンジルオキシカボニル
基のアラルキルオキシカルボニル基等が挙げられる。炭
素数１から５のアルコキシ基としては、例えばメトキシ
基、アリルオキシ基等が挙げられ、アラルキルオキシ基
としては、例えばベンジルオキシ基、４−メトキシベン
ジルオキシ基、ｔ−ブチルジフェニルシリルオキシ基等
が挙げられる。Examples of the alkyl group having 1 to 5 carbon atoms represented by R 1 , R 2 and R 3 include a methyl group,
Examples of the alkyl group include an ethyl group and a butyl group. Examples of the aralkyl group include an alkyl group substituted with an aromatic ring such as a benzyl group and a 4-methoxybenzyl group. Further, as the protected hydroxyalkyl group,
Examples include a benzyloxymethyl group, an acetyloxymethyl group, a t-butyldiphenylsilyloxymethyl group, and the like. Examples of the protected carboxyl group include an alkoxycarbonyl group such as a methoxycarbonyl group and an ethoxycarbonyl group, and an aralkyloxycarbonyl group of a benzyloxycarbonyl group. Examples of the alkoxy group having 1 to 5 carbon atoms include a methoxy group and an allyloxy group, and examples of the aralkyloxy group include a benzyloxy group, a 4-methoxybenzyloxy group and a t-butyldiphenylsilyloxy group. Can be
【００３２】一般式（ＩＩＩ）で表される化合物として
は、例えば一般式（ＩＩＩ）に於てAs the compound represented by the general formula (III), for example, the compound represented by the general formula (III)
【表１】[Table 1]
【００３３】 Ｒ１ Ｒ２ Ｒ３ Ａ Ｙ Ｚ Me COOMe Ｈ CH２ＣＨ２ ０ ０ Me COOBn Ｈ CH２ＣＨ２ ０ ０ Me COOMe Ｈ CH２ＣＨ２ Ｓ ＳR 1 R 2 R 3 AYZ Me COOMe H CH 2 CH 200 Me COOBn H CH 2 CH 200 Me COOMe H CH 2 CH 2 S S
【００３４】であるような化合物が挙げられる。但し、
一般式（ＩＩＩ）で表される化合物の二つのＲ１ は同
じであっても異なっていてもよい。And the like. However,
Two R 1 of the compound represented by the general formula (III) may be the same or different.
【００３５】一般式（Ｖ）で表される化合物は、例えば
反応式The compound represented by the general formula (V) is, for example,
【００３６】[0036]
【化８】 Embedded image
【００３７】〔式中、Ｒ１ は一般式（ＩＩＩ）と同じ
であり、Ｒ１０、Ｒ１１は水素または、炭素数１から５
のアルキル基またはアラルキル基を示し、Ｒ４ は水素
または保護基を示し、Ｘは脱離基を表す〕に示すような
工程で、一般式（ＩＩＩ）（ここではＲ２ が保護され
たカルボキシル基であり、Ｒ３ が水素である）で表さ
れる化合物より製造することができる。[In the formula, R 1 is the same as in the general formula (III), and R 10 and R 11 are hydrogen or a group having 1 to 5 carbon atoms.
Wherein R 4 represents hydrogen or a protecting group, and X represents a leaving group, and a carboxyl group wherein R 2 is protected. And R 3 is hydrogen).
【００３８】まず、例えば一般式（ＩＩＩ）（ここでは
Ｒ２ が保護されたカルボキシル基でありＲ３ が水素で
ある）で表される化合物をメタノール、エタノール等の
アルコール性溶媒中、マグネシウムメトキシド、ナトリ
ウムエトキシド等の相当する金属アルコキシドで−７８
℃から溶媒の沸点付近で好ましくは、室温以下の温度で
反応させるか、或は、メタノール、エタノール等のアル
コール性溶媒中、塩酸、ｐ−トルエンスルホン酸等の酸
または、トリエチルアミン、水酸化ナトリウム等の塩基
存在下、加溶媒分解することにより、一般式（ＶＩＩ）
に於て、Ｒ１０及びＲ１１が水素以外の基である、対応
するエステルが、また、塩酸、ｐ−トルエンスルホン酸
等の酸または、水酸化ナトリウム、炭酸カリウム等の塩
基存在下、加水分解することにより一般式（ＶＩＩ）に
於てＲ１０及びＲ１１が水素であるカルボン酸が得られ
る。First, a compound represented by the general formula (III) (where R 2 is a protected carboxyl group and R 3 is hydrogen) is treated with magnesium methoxide in an alcoholic solvent such as methanol or ethanol. , With a corresponding metal alkoxide such as sodium ethoxide.
The reaction is preferably carried out at a temperature of from room temperature to the boiling point of the solvent, preferably at room temperature or lower, or in an alcoholic solvent such as methanol or ethanol, an acid such as hydrochloric acid or p-toluenesulfonic acid, or triethylamine or sodium hydroxide. By solvolysis in the presence of a base of the formula (VII)
Wherein the corresponding ester wherein R 10 and R 11 are groups other than hydrogen is also hydrolyzed in the presence of an acid such as hydrochloric acid or p-toluenesulfonic acid or a base such as sodium hydroxide or potassium carbonate. By doing so, a carboxylic acid in which R 10 and R 11 in Formula (VII) are hydrogen is obtained.
【００３９】ここに得られる一般式（ＶＩＩ）で表わさ
れる化合物を、例えば水素化リチウムアルミニウム、水
素化ジ（イソブチル）アルミニウム、水素化ホウ素ナト
リウム、水素化ホウ素リチウム、ジボラン等の金属水素
化物を用いて還元し、一般式（ＶＩＩＩ）で表されるア
ルコールを得る。さらに、一般式（ＶＩＩＩ）で表され
る化合物の水酸基を保護して得られる一般式（ＩＸ）で
表される化合物のジチオケタール部分を、例えば含水溶
媒中、ヨウ素、Ｎ−ブロモコハク酸イミド、Ｎ−クロロ
コハク酸イミド、スルフリルクロリド等のハロゲン化剤
または、硝酸銀、酸化銀、過塩素酸銀、塩化水銀、塩化
銅、酸化銅等の重金属化合物または、これらの化合物を
組み合わせた物を用いて、加水分解し一般式（Ｘ）で表
されるケトンへ導く。The compound represented by the general formula (VII) obtained here is used by using a metal hydride such as lithium aluminum hydride, di (isobutyl) aluminum hydride, sodium borohydride, lithium borohydride, diborane or the like. To obtain an alcohol represented by the general formula (VIII). Further, the dithioketal moiety of the compound represented by the general formula (IX) obtained by protecting the hydroxyl group of the compound represented by the general formula (VIII) can be converted to, for example, iodine, N-bromosuccinimide, N- Hydrolysis using halogenating agents such as chlorosuccinimide, sulfuryl chloride, or heavy metal compounds such as silver nitrate, silver oxide, silver perchlorate, mercury chloride, copper chloride, copper oxide, or a combination of these compounds To the ketone represented by the general formula (X).
【００４０】一般式（Ｘ）であらわされる化合物を、還
元剤として例えば水素化リチウムアルミニウム、水素化
リチウムトリ（ｔ−ブトキシ）アルミニウム、、水素化
ホウ素ナトリウム、水素化リチウムトリ（ｓ−ブチル）
ホウ素、水素化ホウ素リチウム等の金属水素錯化合物ま
たは、水素化ジイソブチルアルミニウム、ジボラン等の
金属水素化物を用い、溶媒として、例えばペンタン、ヘ
キサン、ヘプタン、石油エーテル、ベンゼン、トルエ
ン、エチルベンセン等の炭化水素系溶媒、塩化メチレ
ン、クロロホルム等のハロゲン化炭素系溶媒、エーテ
ル、テトラヒドロフラン等のエーテル系溶媒、メタノー
ル、エタノール等のアルコール系溶媒、水及びこれらの
混合溶媒を用い、反応温度としては、−１００℃から５
０℃、好ましくは、−８０℃から３０℃位で還元し、一
般式（ＸＩ）で表される化合物を得る。この還元反応の
際、用いる還元剤の種類、反応条件を選ぶことにより、
立体異性体の一方を優先的に得ることができる。例え
ば、反応式The compound represented by the general formula (X) is used as a reducing agent, for example, lithium aluminum hydride, lithium tri (t-butoxy) aluminum, sodium borohydride, lithium tri (s-butyl) hydride.
Using a metal hydride complex compound such as boron or lithium borohydride or a metal hydride such as diisobutylaluminum hydride or diborane, and a solvent such as pentane, hexane, heptane, petroleum ether, benzene, toluene, ethylbenzene, etc. A hydrogen-based solvent, a carbon-based solvent such as methylene chloride and chloroform, an ether-based solvent such as ether and tetrahydrofuran, an alcohol-based solvent such as methanol and ethanol, water, and a mixed solvent thereof are used. ℃ to 5
Reduction at 0 ° C., preferably at about −80 ° C. to about 30 ° C. gives the compound represented by the general formula (XI). During this reduction reaction, by selecting the type of reducing agent used and the reaction conditions,
One of the stereoisomers can be preferentially obtained. For example, the reaction formula
【００４１】[0041]
【化９】 Embedded image
【００４２】〔式中、Ｒ４ は水素または保護基を示
す〕に示すような一般式（Ｘａ）で表わされる２，３−
トランスであるシクロブタノンを、例えば比較的立体的
に込み入っていない還元試薬で還元すると、１，２−ト
ランスである一般式（ＸＩｂ）で表わされるアルコール
が選択的に得られ、例えば立体障害の大きな還元剤で処
理することにより、１，２−シスである一般式（ＸＩ
ａ）で表わされるアルコールが優先的に得られる。[Wherein R 4 represents hydrogen or a protective group].
When cyclobutanone as trans is reduced, for example, with a reducing agent which is relatively sterically intricate, an alcohol represented by the general formula (XIb) which is 1,2-trans is selectively obtained. By treating with an agent, 1,2-cis is represented by the general formula (XI
The alcohols represented by a) are preferentially obtained.
【００４３】即ち、（２Ｓ，３Ｓ）−２，３−ビス（ｔ
−ブチルジフェニルシリルオキシメチル）−１−シクロ
ブタノンを、立体障害の少ない水素化リチウムトリ（ｔ
−ブトキシ）アルミニウムまたは、水素化ホウ素ナトリ
ウムで還元すると、（１Ｒ，２Ｓ，３Ｓ）−２，３−ビ
ス（ｔ−ブチルジフェニルシリルオキシメチル）シクロ
ブタノールが選択的に（単離収率それぞれ８８％、８０
％）得られ、立体障害の大きい水素化リチウムトリ（ｓ
−ブチル）または、ホウ素水素化ジ（イソブチル）アル
ミニウムで還元すると、（１Ｓ，２Ｓ，３Ｓ）−２，３
−ビス（ｔ−ブチルジフェニルシリルオキシメチル）シ
クロブタノールが優先的（単離収率それぞれ７５％、８
２％）に得られる。結果を次表に示す。That is, (2S, 3S) -2,3-bis (t
-Butyldiphenylsilyloxymethyl) -1-cyclobutanone was converted to lithium hydride (t
Reduction with (-butoxy) aluminum or sodium borohydride selectively gives (1R, 2S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) cyclobutanol (88% isolated yield each). , 80
%) And lithium hydride (s
-Butyl) or di (isobutyl) aluminum borohydride to give (1S, 2S, 3S) -2,3
-Bis (t-butyldiphenylsilyloxymethyl) cyclobutanol is preferential (75% isolated yield, 8% isolated yield, respectively).
2%). The results are shown in the following table.
【００４４】[0044]
【表２】 condition yield(%) reagent solvent temp. XIa XIb LiAI(OtBu)３H THF −78−RT 9 88 NaBH4 THF-H２O RT 19 80 Li(sBu)３BH THF −78 75 23 (iBu)２AIH CH２Cl２ −78 74 22 (iBu)２AIH Toluene −78 82 17 Ｒ４＝t-BuPh２Si (XIa, XIb)[Table 2] condition yield (%) reagent solvent temp. XIa XIb LiAI (OtBu) 3 H THF-78-RT 988 NaBH4 THF-H 2 O RT 1980 Li (sBu) 3 BH THF -78 75 23 (iBu ) 2 AIH CH 2 Cl 2 −78 74 22 (iBu) 2 AIH Toluene −78 82 17 R 4 = t-BuPh 2 Si (XIa, XIb)
【００４５】また、ここで得られる立体異性体即ち、一
般式（ＸＩａ）で表わされる化合物及び一般式（ＸＩ
ｂ）で表わされる化合物は単離後、相互に容易に他の異
性体へ変換することができる。例えば、一般式（ＸＩ
ａ）で表わされる化合物または一般式（ＸＩｂ）で表わ
される化合物を、クロム酸／酢酸、クロム酸／ピリジン
等の金属酸化剤、ジメチルスルホキシド（ＤＭＳＯ）−
無水酢酸／酢酸、ＤＭＳＯ−オキザリルクロリドートリ
エチルアミン／塩化メチレン等のＤＭＳＯ酸化等、通常
の酸化試薬または酸化方法で一般式（Ｘａ）で表わされ
るケトンへ再度酸化して、更に選択的還元に付す方法、
あるいは、一般式（ＸＩａ）で表わされる化合物及び一
般式（ＸＩｂ）で表わされる化合物の水酸基の存在する
１位炭素の立体配置を、例えば光延反応（Mitsumobu Re
action) を利用して反転させる方法が挙げられる。The stereoisomers obtained here, that is, the compound represented by the general formula (XIa) and the compound represented by the general formula (XI
After isolation, the compounds of the formula b) can easily be converted into other isomers of one another. For example, the general formula (XI
a) a compound represented by formula (XIb) or a metal oxidizing agent such as chromic acid / acetic acid, chromic acid / pyridine, dimethyl sulfoxide (DMSO)-
Reoxidation to the ketone represented by the general formula (Xa) by a usual oxidation reagent or oxidation method such as acetic anhydride / acetic acid, DMSO oxidation of DMSO-oxalyl chloride triethylamine / methylene chloride, etc., and further selective reduction. Method,
Alternatively, the configuration of the 1-position carbon having a hydroxyl group of the compound represented by the general formula (XIa) and the compound represented by the general formula (XIb) may be determined, for example, by the Mitsunobu reaction (Mitsumobu Re
action) to reverse it.
【００４６】例えば、一般式（ＸＩａ）で表わされる化
合物または、一般式（ＸＩｂ）で表わされる化合物をト
リフェニルフォスフィン、亜リン酸トリメチル、亜リン
酸トリエチル等の３価リン化合物、酢酸、安息香酸等の
カルボン酸、及びジエチルアゾジカルボキシレート等の
アゾジカルボン酸エステルを、溶媒として、例えばペン
タン、ヘキサン、ヘプタン、石油エーテル、ベンゼン、
トルエン、エチルベンセン等の炭化水素系溶媒、塩化メ
チレン、クロロホルム等のハロゲン化炭素系溶媒、エー
テル、テトラヒドロフラン等のエーテル系溶媒及びこれ
らの混合溶媒を用い、反応温度としては、−１００℃か
ら５０℃、好ましくは、−５０℃から３０℃位で反応
し、生成するエステルを、例えば、炭酸カリウム、水酸
化ナトリウム、ナトリウムメチラート、アンモニア等の
アルカリ、塩酸、硫酸等の酸による加水分解または、水
素化リチウムアルミニウム、水素化リチウムトリ（ｓ−
ブチル）ホウ素、水素化ホウ素リチウム等の金属水素錯
化合物または、水素化ジイソブチルアルミニウム、ジボ
ラン等の金属水素化物を用い還元し、一般式（ＸＩｂ）
で表わされる化合物または、一般式（ＸＩａ）で表わさ
れる化合物を得ることができる。For example, a compound represented by the general formula (XIa) or a compound represented by the general formula (XIb) is converted to a trivalent phosphorus compound such as triphenylphosphine, trimethyl phosphite, triethyl phosphite, acetic acid, benzoic acid and the like. Carboxylic acids such as acids, and azodicarboxylic esters such as diethyl azodicarboxylate as solvents, for example, pentane, hexane, heptane, petroleum ether, benzene,
Using a hydrocarbon solvent such as toluene and ethyl benzene, a carbon halide solvent such as methylene chloride and chloroform, an ether solvent such as ether and tetrahydrofuran, and a mixed solvent thereof, the reaction temperature is from -100 ° C to 50 ° C. Preferably, the ester formed by reacting at about -50 ° C to about 30 ° C is hydrolyzed with an acid such as an alkali such as potassium carbonate, sodium hydroxide, sodium methylate and ammonia, hydrochloric acid, sulfuric acid, or hydrogen. Lithium aluminum hydride, lithium trihydride (s-
Butyl) boron or a metal hydride complex such as lithium borohydride or a metal hydride such as diisobutylaluminum hydride or diborane to obtain a compound represented by the general formula (XIb)
Or the compound represented by the general formula (XIa) can be obtained.
【００４７】例えば、（１Ｒ，２Ｓ，３Ｓ）−２，３−
ビス（ｔ−ブチルジフェニルシリルオキシメチル）シク
ロブタノールを、ベンゼン中、トリフェニルフォスフィ
ン・安息香酸・ジエチルアゾジカルボキシレートと反応
し、（１Ｓ，２Ｓ，３Ｓ）−１−ベンゾイル−２，３−
ビス（ｔ−ブチルジフェニルシリルオキシメチル）シク
ロブタンへ導いた後、トルエン中、水素化ジイソブチル
アルミニウムで還元しベンゾイル基を除去することによ
り、（１Ｓ，２Ｓ，３Ｓ）−２，３−ビス（ｔ−ブチル
ジフェニルシリルオキシメチル）シクロブタノールが得
られる。このようにして得られる一般式（ＸＩ）で表さ
れる化合物の二級水酸基を脱離基へ導くことにより一般
式（Ｖ）で表される化合物が製造される。For example, (1R, 2S, 3S) -2,3-
Bis (t-butyldiphenylsilyloxymethyl) cyclobutanol is reacted with triphenylphosphine / benzoic acid / diethylazodicarboxylate in benzene to give (1S, 2S, 3S) -1-benzoyl-2,3-
After leading to bis (t-butyldiphenylsilyloxymethyl) cyclobutane, the mixture was reduced with diisobutylaluminum hydride in toluene to remove the benzoyl group, thereby obtaining (1S, 2S, 3S) -2,3-bis (t-). (Butyldiphenylsilyloxymethyl) cyclobutanol is obtained. The compound represented by the general formula (V) is produced by introducing the secondary hydroxyl group of the compound represented by the general formula (XI) thus obtained into a leaving group.
【００４８】本発明化合物は次の実験例から、幅広く強
い抗ウイルス作用を発揮することがわかる。The following experimental examples show that the compounds of the present invention exert a broad and strong antiviral action.
【００４９】実験例１． ＤＮＡウイルスである単純ヘルペス１型ウイルス（ＨＳ
Ｖ−Ｉ）、単純ヘルペス２型ウイルス（ＨＳＶ−ＩＩ）
に対する抗ウイルス作用を下記の方法で試験した。 （方法１） Ｖｅｒｏ細胞（アフリカミドリザル腎細胞由来）の単層
を有する６穴のマルチプレートにウイルス１００−１５
０ＰＦＵ（Plaque Forming Unit)を感染させ、３７℃で
１時間吸着後、各濃度の試料（本発明化合物）を含む寒
天培地（１．５％寒天を含むイーグルＭＥＭ培地）を重
層し、３７℃、５％（ｖ／ｖ）の炭酸ガスフ卵器中で４
８時間培養した後プラーク（Plaque) の形成を測定し、
５０％抑制値（IC５０) を求めた。Experimental Example 1 Herpes simplex type 1 virus (HS), a DNA virus
VI), herpes simplex virus 2 (HSV-II)
Was tested for antiviral activity in the following manner. (Method 1) Virus 100-15 was placed on a 6-well multiplate having a monolayer of Vero cells (derived from African green monkey kidney cells).
After infecting with 0 PFU (Plaque Forming Unit) and adsorbing at 37 ° C. for 1 hour, an agar medium (Eagle MEM medium containing 1.5% agar) containing each concentration of the sample (the compound of the present invention) was overlaid. 4% in a 5% (v / v) carbon dioxide incubator
After culturing for 8 hours, the formation of plaque was measured.
The 50% inhibition value (IC 50 ) was determined.
【００５０】実験例２． ＤＮＡウイルスであるヒトサイトメガロウイルス（ＨＣ
ＭＶ）に対する作用を下記の方法で試験した。 （方法２） 抗サイトメガロウイルス活性は人胎児繊維芽細胞の単層
を有する３５ｍｍディシュ（dish) にサイトメガロウイ
ルス（Ａ０１６９株）１００ＰＦU Plaque Forming Uni
t) を感染させ、１時間吸着後、各濃度の本発明化合物
を含む培地〔０．５％アガロース（agarose)、２％牛胎
児血清（fetal calfserum)〕で重層し、３７℃、５％
（ｖ／ｖ）の炭酸ガスフ卵器中にて１０日間培養した後
プラーク（P-laque)形成を測定し、５０％抑制値（IC
５０) を求めた。Experimental Example 2 Human cytomegalovirus (HC) which is a DNA virus
MV) was tested in the following manner. (Method 2) The anti-cytomegalovirus activity was measured in a 35 mm dish having a monolayer of human fetal fibroblasts by cytomegalovirus (A0169 strain) 100 PFU Plaque Forming Uni.
t), adsorbed for 1 hour, and overlaid with a medium (0.5% agarose, 2% fetal calfserum) containing each concentration of the compound of the present invention, 37 ° C., 5%
(V / v) After culturing for 10 days in a CO2 egg container, plaque (P-laque) formation was measured, and the 50% inhibition value (IC
50 ).
【００５１】実験例３． ＤＮＡウイルスであるＢ型肝炎ウイルス（ＨＢＶ）に対
する作用を下記の方法で試験した。 （方法３） 活性Ｂ型肝炎ウイルスを産生放出する培養肝細胞株ＨＢ
６１１（Proc. Natl.Acad. Sci. USA, 84, 444 (198
7)）をDulbeccoに従いmodified Eagle培地（GIBCO)中に
て１０％子牛胎児血清、２００μｇ／ｍｌＧ４１８、ペ
ニシリンおよびストレプトマイシン（各１００ｕ／ｍ
ｌ）存在下に３７℃、５％ＣＯ２ を用いて培養する。
６穴プレートに５×１０４ ｃｅｌｌ／穴（３５mm）と
なるよう接種し、１〜２日後５０％コンフルエントとな
ったところで本発明化合物の一定量を加えて培養、以降
３日毎に同じ濃度に薬剤（本発明化合物）を含む培地と
交換しつつ１５日間培養を続けた後、培地を除去。細胞
を０．５ｍｌのリシスバッハー（Lysis buffer)(10mM T
risHCl pH7.8/5mM Na２EDTA,１％SDS/0.1mg/ml Pronas
e K) にて３７℃１hr処理して溶解し、得られたＤＮＡ
をＲＮａｓｅ処理、フェノール・クロロホルム処理エタ
ノールを沈澱法により純化した。次いで５μｇＤＮＡを
ＨｉｎｄＩＩＩ処理し、サザン法によって３２Ｐ−標式
Ｂ型肝炎ウイルスＤＮＡをプロープとしてＤＮＡのパタ
ーンを分析した。Experimental Example 3 The effect on hepatitis B virus (HBV), a DNA virus, was tested by the following method. (Method 3) Cultured hepatocyte cell line HB that produces and releases active hepatitis B virus
611 (Proc. Natl. Acad. Sci. USA, 84, 444 (198
7)) in Dulbecco's modified Eagle's medium (GIBCO) in 10% fetal calf serum, 200 μg / ml G418, penicillin and streptomycin (100 u / m each)
1) Incubate in the presence at 37 ° C. using 5% CO 2 .
A 6-well plate was inoculated to give 5 × 10 4 cells / well (35 mm), and when it reached 50% confluence 1-2 days later, a certain amount of the compound of the present invention was added and cultured. After culturing for 15 days while replacing with a medium containing (the compound of the present invention), the medium was removed. Cells are lysed in 0.5 ml of lysis buffer (10 mM T
risHCl pH7.8 / 5mM Na 2 EDTA, 1% SDS / 0.1mg / ml Pronas
e K) at 37 ° C for 1 hour to dissolve, and obtain the obtained DNA.
Was treated with RNase and ethanol treated with phenol / chloroform was purified by a precipitation method. Next, 5 μg of the DNA was treated with HindIII, and the DNA pattern was analyzed by Southern method using 32 P-labeled hepatitis B virus DNA as a probe.
【００５２】実験例４． ＲＮＡウイルスであるＨＩＶ（Human Immunodeficiency
Virus) に対する作用を下記の方法で試験した。 （方法４） ２４穴トレーにＭＴ−４細胞約５万個／ml入れ、さらに
本発明化合物の一定量を含む溶液１００μｇを加え、３
７℃、５％（ｖ／ｖ）炭酸ガスフ卵器中にて２時間培養
した後、ＨＩＶ１０３ 〜１０４ 感染単位を加え、４日
間培養後、培養液の一部をスライドグラスに塗抹し、ア
セトン固定をした後、螢光抗体法にてウイルス抗原の発
現をみた。なお、螢光抗体法の一次抗体にはエイズ患者
の血清、二次抗体にはＦＩＴＣをラベルした抗ヒト１ｇ
Ｇを用いた。以上の実験例１−４の結果を次表に示す。Experimental Example 4 HIV (Human Immunodeficiency), an RNA virus
Virus) was tested in the following manner. (Method 4) Approximately 50,000 MT-4 cells / ml were placed in a 24-well tray, and 100 μg of a solution containing a fixed amount of the compound of the present invention was added.
7 ℃, 5% (v / v) was incubated for 2 hours carbonate Gasufu egg device in, adding HIV10 3 ~10 4 infectious units, and spread after 4 days of culture, a portion of the culture liquid to a glass slide, After fixation with acetone, the expression of the virus antigen was observed by the fluorescent antibody method. The primary antibody in the fluorescent antibody method was serum of AIDS patients, and the secondary antibody was 1 g of anti-human labeled with FITC.
G was used. The results of Experimental Examples 1-4 are shown in the following table.
【００５３】[0053]
【表３】 IC５０（μg/ml） 化合物 No. HSV-1 HSV-2 HIV HCMV HBV 本発明化合物 0.047 0.08 0.3 0.4 0.86Table 3 IC 50 (μg / ml) Compound No. HSV-1 HSV-2 HIV HCMV HBV Compound of the present invention 0.047 0.08 0.3 0.4 0.86
【００５４】実験例５． 単純ヘルペス２型ウイルス（ＨＳＶ−ＩＩ）に対するin
vivo 抗ウイルス作用を下記の方法で試験した。 （方法５） ＢＡＬＢ／ｃマウス（雄、６週令）にＨＳＶ−ＩＩ（st
rain 186, 4.8 ×10５PFU/0.2ml/mouse) を腹腔内移植
し、６時間後より生理食塩水に溶解した薬剤を１日１回
１０日間連日腹腔内または経口投与した。感染後２０日
間観察し、延命したマウスの匹数と平均生存日数より化
合物の抗ウイルス効果を判定した。Experimental Example 5 In herpes simplex virus type 2 (HSV-II)
The in vivo antiviral effect was tested in the following manner. (Method 5) BALB / c mice (male, 6 weeks old) were treated with HSV-II (st
rain 186, 4.8 × 10 5 PFU / 0.2 ml / mouse) was implanted intraperitoneally, and after 6 hours, a drug dissolved in physiological saline was intraperitoneally or orally administered once a day for 10 days every day. The compound was observed for 20 days after infection, and the antiviral effect of the compound was determined from the number of surviving mice and the average number of surviving days.
【００５５】また、市販の抗ウイルス薬アシクロビル
（ＡＣＶ）を対照薬として用い、抗ウイルス効果を比較
した。The antiviral effect was compared using a commercially available antiviral drug acyclovir (ACV) as a control drug.
【００５６】（結果） 次表に示すように、本発明化合物は、非常に強くＨＳＶ
−ＩＩ感染マウスの死亡率を抑制した。コントロール群
では、平均生存日数が７．７日であるのに対し、本発明
化合物投与群では、広い用量範囲で（1.25-20mg/kg/da
y) 多数のマウスが観察した２０日間生存した。アシク
ロビル投与群でも生存は観察されたが、有効幅は狭かっ
た。(Results) As shown in the following table, the compounds of the present invention showed very strong HSV
-The mortality of the II-infected mice was suppressed. In the control group, the average survival time was 7.7 days, whereas in the group administered with the compound of the present invention, a wide dose range (1.25-20 mg / kg / da
y) A large number of mice survived the observed 20 days. Survival was observed in the acyclovir-administered group, but the effective range was narrow.
【００５７】[0057]
【表４】 in vivo 抗ＨＳＶ−ＩＩ作用 化合物 Rout Dose MST a) S/T b) (mg/kg/day) (day) control 7.7 0/10 本発明化合物 i.p. 20 20.0 10/10 10 20.0 10/10 5 20.0 10/10 2.5 18.9 9/10 1.25 19.8 7/10 p.o. 20 19.7 9/10 10 19.8 9/10 5 18.9 8/10 2.5 14.7 4/10 1.25 12.4 2/10 ACV i.p. 100 5.4 2/10 50 16.1 5/10 25 12.7 1/10 12.5 11.1 1/10 p.o. 100 14.3 2/10 50 14.8 4/10 25 11.1 0/10 12.5 9.3 0/10 ａ：平均生存日数 ｂ：生存匹数／総数Table 4 In vivo anti-HSV-II action compound Rout Dose MST a) S / T b) (mg / kg / day) (day) control 7.7 0/10 Compound of the present invention ip 20 20.0 10/10 10 20.0 10 / 10 5 20.0 10/10 2.5 18.9 9/10 1.25 19.8 7/10 po 20 19.7 9/10 10 19.8 9/10 5 18.9 8/10 2.5 14.7 4/10 1.25 12.4 2/10 ACV ip 100 5.4 2/10 50 16.1 5/10 25 12.7 1/10 12.5 11.1 1/10 po 100 14.3 2/10 50 14.8 4/10 25 11.1 0/10 12.5 9.3 0/10 a: Average number of surviving days b: Number of surviving animals / total number
【００５８】本発明の化合物は強い抗ウイルス作用を持
つことから、***、性器ヘルペス、帯状疱疹、免疫抑制
時の単純ヘルペスウイルス−１型、２型（ＨＳＶ−Ｉ，
ＩＩ）、バリセラゾスターウイルス（ＶＺＶ）、サイト
メガロウイルス（ＣＭＶ）、エプスタイン−バールウイ
ルス（ＥＢＶ）感染症、ウイルス性肝炎、ウイルス性呼
吸器疾患、ウイルス性消化器疾患、ＡＩＤＳ、ＡＴＬ等
の多くのウイルス性疾患に有効であることが期待され
る。Since the compound of the present invention has a strong antiviral effect, herpes simplex virus type 1 and type 2 (HSV-I, lip, genital herpes, shingles, immunosuppression)
II), Balicerazostar virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV) infection, viral hepatitis, viral respiratory disease, viral digestive disease, AIDS, ATL, etc. It is expected to be effective for many viral diseases.
【００５９】以上のようにして得られた本発明化合物を
抗ウイルス剤として使用する場合、経口投与、静脈内投
与、経皮投与することができる。投与量は投与する患者
の症状、年齢、投与方法によっても異なるが、通常０．
１−５００ｍｇ／ｋｇ／日である。本発明化合物は、適
当な製剤用担体と混合して調整した製剤の形で投与され
る。製剤の形としては、錠剤・顆粒剤・細粒剤・散剤・
カプセル剤・注射剤・クリーム・坐剤等が用いられる。When the compound of the present invention thus obtained is used as an antiviral agent, it can be administered orally, intravenously, or transdermally. The dosage varies depending on the condition, age, and administration method of the patient to be administered, but is usually 0,1.
1-500 mg / kg / day. The compound of the present invention is administered in the form of a preparation prepared by mixing with an appropriate preparation carrier. Formulations include tablets, granules, fine granules, powders,
Capsules, injections, creams, suppositories and the like are used.
【００６０】[0060]
【実施例】次に、実施例を挙げて本発明化合物の製造に
ついて具体的に説明する。The production of the compound of the present invention will be specifically described below with reference to examples.
【００６１】実施例１． （−）−（２Ｓ，３Ｓ）−３−メトキシカルボニル−
１，１−ビス（メチルチオ）−２−（オキサゾリジン−
２−オン−３−イル）カルボニルシクロブタンの製造Embodiment 1 (-)-(2S, 3S) -3-methoxycarbonyl-
1,1-bis (methylthio) -2- (oxazolidine-
Production of 2-one-3-yl) carbonylcyclobutane
【００６２】実施例１−１． アルゴン雰囲気中、ジクロロジイソプロポキシチタン
（９０５ｍｇ，３．８ｍｍｏｌ）及び（２Ｓ，３Ｓ）−
２，３−Ｏ−（１−フェニルエチリデン）−１，１，
４，４−テトラフェニル−１，２，３，４−ブタンテト
ラオール（化合物Ａ）（２．２２ｇ，４．２ｍｍｏｌ）
に１，３，５−トリメチルベンゼン（ＴＭＢ）（８０ｍ
ｌ）を加え、室温で３０分間攪拌する。この溶液に、粉
末モレキュラーシーブス４Ａ（３．２ｇ）を加えしばら
く攪拌した後に、３−〔（Ｅ）−３−（メトキシカルボ
ニル）プロペノイル〕−オキサゾリジン−２−オン
（３．９８ｇ，２０ｍｍｏｌ）を加え−１５℃に冷却す
る。この懸濁液に１，１−ビス（メチルチオ）エチレン
（３．６１ｇ，３０ｍｍｏｌ）のＴＭＢ溶液（２０ｍ
ｌ）を徐々に加えた後、攪拌下同温から３時間かけて０
℃に昇温する。反応液に飽和炭酸水素ナトリウム水溶液
を加え、無機物をセライトを用いて濾去した後、有機物
を酢酸エチルで抽出する。抽出液は飽和食塩水で洗浄
後、無水硫酸ナトリウムで乾燥した後、減圧下溶媒を溜
去する。残渣は、シリカゲルカラムクロマトグラフィー
（酢酸エチル：ヘキサン＝１：２，ｖ／ｖ）で精製し
（−）−（２Ｓ，３Ｓ）−３−メトキシカルボニル−
１，１−ビス（メチルチオ）−２−（オキサゾリジン−
２−オン−３−イル）カルボニルシクロブタン（３．９
４ｇ，６２％）を得る。本化合物の光学純度は８６％ｅ
ｅ（実施例３参照）。Embodiment 1-1. In an argon atmosphere, dichlorodiisopropoxytitanium (905 mg, 3.8 mmol) and (2S, 3S)-
2,3-O- (1-phenylethylidene) -1,1,1
4,4-tetraphenyl-1,2,3,4-butanetetraol (compound A) (2.22 g, 4.2 mmol)
1,3,5-trimethylbenzene (TMB) (80m
1) and stir at room temperature for 30 minutes. To this solution, powdered molecular sieves 4A (3.2 g) was added, and after stirring for a while, 3-[(E) -3- (methoxycarbonyl) propenoyl] -oxazolidin-2-one (3.98 g, 20 mmol) was added. Cool to -15 ° C. To this suspension was added a 1,1-bis (methylthio) ethylene (3.61 g, 30 mmol) TMB solution (20 m
l) was gradually added, and then stirred at the same temperature for 3 hours.
Heat to ° C. A saturated aqueous solution of sodium hydrogen carbonate is added to the reaction solution, the inorganic substances are filtered off using Celite, and the organic substances are extracted with ethyl acetate. The extract is washed with saturated saline, dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2, v / v) to give (-)-(2S, 3S) -3-methoxycarbonyl-.
1,1-bis (methylthio) -2- (oxazolidine-
2-on-3-yl) carbonylcyclobutane (3.9
4 g, 62%). The optical purity of this compound is 86% e
e (see Example 3).
【００６３】 ＮＭＲ（５００ＭＨｚＦＴ，ＣＤＣｌ３）δ： ２．０１（３Ｈ，ｓ）， ２．１０（３Ｈ，ｓ） ２．５４（１Ｈ，ｄｄ，Ｊ＝９．９，１２．３Ｈｚ）， ２．７０（１Ｈ，ｄｄ，Ｊ＝７．９，１２．３Ｈｚ）， ３．８６（１Ｈ，ｄｔ，Ｊd ＝９．９Ｈｚ，Ｊt ＝７．９Ｈｚ）， ３．７１（３Ｈ，ｓ）， ４．０２（１Ｈ，ｄｄｄ，Ｊ＝６．４，８．９，１１．０Ｈｚ）， ４．１２（１Ｈ，ｄｄｄ，Ｊ＝７．６，９．３，１１．０Ｈｚ）， ４．３９−４．４７（２Ｈ，ｍ） ５．０１（１Ｈ，ｄ，Ｊ＝７．９Ｈｚ）． ＩＲ（ｎｅａｔ）ｃｍ−１：１７８０，１７３０，１６９０．NMR (500 MHz FT, CDCl 3 ) δ: 2.01 (3H, s), 2.10 (3H, s) 2.54 (1H, dd, J = 9.9, 12.3 Hz), 2. 70 (1H, dd, J = 7.9, 12.3 Hz), 3.86 (1H, dt, Jd = 9.9 Hz, Jt = 7.9 Hz), 3.71 (3H, s), 4.02 (1H, ddd, J = 6.4, 8.9, 11.0 Hz), 4.12 (1H, ddd, J = 7.6, 9.3, 11.0 Hz), 4.39-4.47 (2H, m) 5.01 (1H, d, J = 7.9 Hz). IR (neat) cm -1 : 1780, 1730, 1690.
【００６４】実施例１−２． 実施例１−１とほぼ同様に、３−〔（Ｅ）−３−（メト
キシカルボニル）プロペノイル〕−オキサゾリジン−２
−オン（３．９８ｇ，２０ｍｍｏｌ）、１，１−ビス
（メチルチオ）エチレン（３．６１ｇ，３０ｍｍｏ
ｌ）、ジクロロジイソプロポキシチタン（４７４ｍｇ，
２．０ｍｍｏｌ）、（２Ｓ，３Ｓ）−２，３−Ｏ−（１
−フェニルエチリデン）−１，１，４，４−テトラフェ
ニル−１，２，３，４−ブタンテトラオール（化合物
Ａ）（１．１６ｇ，２．２ｍｍｏｌ）、粉末モレキュラ
ーシーブス４Ａ（４ｇ）を用いてトルエン（１６０ｍ
ｌ）及びヘキサン（１２０ｍｌ）混合溶媒中０℃で４０
分間反応させることにより、（−）−（２Ｓ，３Ｓ）−
３−メトキシカルボニル−１，１−ビス（メチルチオ）
−２−（オキサゾリジン−２−オン−３−イル）カルボ
ニルシクロブタン（６．１３ｇ，９６％）（〔α〕Ｄ＝
−１０．４°（ｃ １．３４，ＣＨ２Ｃｌ２）を得る。
このものを、塩化メチレン−イソプロピルエーテルで再
結晶すると、５．３０ｇ（８３％）（〔α〕Ｄ＝−１
１．１°（ｃ １．１５，ＣＨ２Ｃｌ２ ））の化合物
が得られる。本化合物の光学純度は９８％ｅｅ以上（実
施例３に示した方法により決定）。Embodiment 1-2. Almost in the same manner as in Example 1-1, 3-[(E) -3- (methoxycarbonyl) propenoyl] -oxazolidine-2
-One (3.98 g, 20 mmol), 1,1-bis (methylthio) ethylene (3.61 g, 30 mmol)
l), dichlorodiisopropoxytitanium (474 mg,
2.0 mmol), (2S, 3S) -2,3-O- (1
-Phenylethylidene) -1,1,4,4-tetraphenyl-1,2,3,4-butanetetraol (compound A) (1.16 g, 2.2 mmol) and powdered molecular sieves 4A (4 g) And toluene (160m
l) and hexane (120 ml) in a mixed solvent at 0 ° C.
After reacting for 2 minutes, (-)-(2S, 3S)-
3-methoxycarbonyl-1,1-bis (methylthio)
-2- (Oxazolidin-2-one-3-yl) carbonylcyclobutane (6.13 g, 96%) ([α] D =
-10.4 ° (c 1.34, CH 2 Cl 2 ) is obtained.
This was recrystallized from methylene chloride-isopropyl ether to give 5.30 g (83%) ([α] D = -1).
1.1 ° (c 1.15, CH 2 Cl 2 )) are obtained. The optical purity of this compound is 98% ee or more (determined by the method described in Example 3).
【００６５】実施例１−３． 実施例１−１とほぼ同様に、３−〔（Ｅ）−３−（メト
キシカルボニル）プロペノイル〕−オキサゾリジン−２
−オン（１９．９ｇ，１００ｍｍｏｌ）、１，１−ビス
（メチルチオ）エチレン（１５．０３ｇ，１２５ｍｍｏ
ｌ）、ジクロロジイソプロポキシチタン（１．１８ｇ，
５．０ｍｍｏｌ）、（２Ｓ，３Ｓ）−２，３−Ｏ−（１
−フェニルエチリデン）−１，１，４，４−テトラフェ
ニル−１，２，３，４−ブタンテトラオール（化合物
Ａ）（２．９１ｇ，５．５ｍｍｏｌ）、粉末モレキュラ
ーシーブス４Ａ（２０ｇ）を用いて、トルエン（８００
ｍｌ）及びヘキサン（６００ｍｌ）混合溶媒中０℃で５
時間反応させることにより、（−）−（２Ｓ，３Ｓ）−
３−メトキシカルボニル−１，１−ビス（メチルチオ）
−２−（オキサゾリジン−２−オン−３−イル）カルボ
ニルシクロブタン（２６．６９ｇ，８４％）（〔α〕Ｄ
＝−１０．５°（ｃ １．００，ＣＨ２Ｃｌ２）を得
る。Embodiment 1-3. Almost in the same manner as in Example 1-1, 3-[(E) -3- (methoxycarbonyl) propenoyl] -oxazolidine-2
-One (19.9 g, 100 mmol), 1,1-bis (methylthio) ethylene (15.03 g, 125 mmol)
l), dichlorodiisopropoxy titanium (1.18 g,
5.0 mmol), (2S, 3S) -2,3-O- (1
-Phenylethylidene) -1,1,4,4-tetraphenyl-1,2,3,4-butanetetraol (compound A) (2.91 g, 5.5 mmol) and powdered molecular sieves 4A (20 g) And toluene (800
5) at 0 ° C in a mixed solvent of 5 ml) and hexane (600 ml).
By reacting for a time, (-)-(2S, 3S)-
3-methoxycarbonyl-1,1-bis (methylthio)
-2- (Oxazolidin-2-one-3-yl) carbonylcyclobutane (26.69 g, 84%) ([α] D
= -10.5 ° (c 1.00, CH 2 Cl 2 ).
【００６６】実施例２． （−）−（２Ｓ，３Ｓ）−２，３−ビス（メトキシカル
ボニル）−１，１−ビス（メチルチオ）シクロブタンの
製造Embodiment 2 FIG. Production of (−)-(2S, 3S) -2,3-bis (methoxycarbonyl) -1,1-bis (methylthio) cyclobutane
【００６７】実施例２−１． アルゴン雰囲気中、実施例１−１で製造した（−）−
（２Ｓ，３Ｓ）−３−メトキシカルボニル−１，１−ビ
ス（メチルチオ）−２−（オキサゾリジン−２−オン−
３−イル）カルボニルシクロブタン（３．９４ｇ，１
２．３ｍｍｏｌ）のメタノール溶液（２５ｍｌ）に１Ｍ
−ジメトキシマグネシウム／メタノール（２５ｍｌ，２
５ｍｍｏｌ）を加え室温で１時間攪拌する。反応液は減
圧下濃縮した後、飽和塩化アンモニウム水溶液を加え、
エーテルで抽出する。エーテル抽出液は飽和食塩水で洗
浄した後、減圧下溶媒を溜去する。残渣はシリカゲルカ
ラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：
９，ｖ／ｖ）で精製し（−）−（２Ｓ，３Ｓ）−２，３
−ビス（メトキシカルボニル）−１，１−ビス（メチル
チオ）シクロブタン（２．１７ｇ，６７％）を得る。本
化合物の光学純度は８６％ｅｅ（実施例３参照）。Embodiment 2-1. (-)-Produced in Example 1-1 in an argon atmosphere
(2S, 3S) -3-methoxycarbonyl-1,1-bis (methylthio) -2- (oxazolidine-2-one-
3-yl) carbonylcyclobutane (3.94 g, 1
2.3 mmol) in methanol (25 ml)
-Dimethoxymagnesium / methanol (25 ml, 2
5 mmol) and stir at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and a saturated aqueous solution of ammonium chloride was added.
Extract with ether. After the ether extract is washed with a saturated saline solution, the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1).
9, v / v) and (-)-(2S, 3S) -2,3
-Bis (methoxycarbonyl) -1,1-bis (methylthio) cyclobutane (2.17 g, 67%) is obtained. The optical purity of this compound is 86% ee (see Example 3).
【００６８】 ＮＭＲ（５００ＭＨｚＦＴ，ＣＤＣｌ３ ）δ： ２．０１（３Ｈ，ｓ）， ２．１２（３Ｈ，ｓ）， ２．４７（１Ｈ，ｄｄ，Ｊ＝９．０，１２．２Ｈｚ）， ２．５０（１Ｈ，ｄｄ，Ｊ＝９．４，１２．２Ｈｚ）， ３．６３−３．７５（２Ｈ，ｍ）， ３．６９（３Ｈ，ｓ）， ３．７２（３Ｈ，ｓ）， ＩＲ（ｎｅａｔ）ｃｍ−１：１７３０．NMR (500 MHz FT, CDCl 3 ) δ: 2.01 (3H, s), 2.12 (3H, s), 2.47 (1H, dd, J = 9.0, 12.2 Hz), 2 .50 (1H, dd, J = 9.4, 12.2 Hz), 3.63-3.75 (2H, m), 3.69 (3H, s), 3.72 (3H, s), IR (Neat) cm- 1 : 1730.
【００６９】実施例２−２． アルゴン雰囲気中、１Ｍ−ジメトキシマグネシウム／メ
タノール（４００ｍｌ，４００ｍｍｏｌ）に０℃で、
（−）−（２Ｓ，３Ｓ）−３−メトキシカルボニル−
１，１−ビス（メチルチオ）−２−（オキサゾリジン−
２−オン−３−イル）カルボニルシクロブタン（２６．
０ｇ，８１．４ｍｍｏｌ）を加え、同温で１５分間攪拌
する。反応液に、飽和塩化アンモニウム水溶液を加え、
エーテルで抽出する。エーテル抽出液は飽和食塩水で洗
浄した後、減圧下溶媒を溜去する。残渣はシリカゲルカ
ラムクロマトグラフィー（酢酸エチル：ヘキサン＝１：
９，ｖ／ｖ）で精製し（−）−（２Ｓ，３Ｓ）−２，３
−ビス（メトキシカルボニル）−１，１−ビス（メチル
チオ）シクロブタン（２０．７３ｇ，９６％）を得る。Embodiment 2-2. In an argon atmosphere, 1M-dimethoxymagnesium / methanol (400 ml, 400 mmol) was added at 0 ° C.
(-)-(2S, 3S) -3-methoxycarbonyl-
1,1-bis (methylthio) -2- (oxazolidine-
2-on-3-yl) carbonylcyclobutane (26.
0 g, 81.4 mmol) and stirred at the same temperature for 15 minutes. To the reaction solution was added a saturated aqueous ammonium chloride solution,
Extract with ether. After the ether extract is washed with a saturated saline solution, the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 1).
9, v / v) and (-)-(2S, 3S) -2,3
This gives -bis (methoxycarbonyl) -1,1-bis (methylthio) cyclobutane (20.73 g, 96%).
【００７０】実施例３． （−）−（２Ｓ，３Ｓ）−２，３−ビス（ヒドロキシメ
チル）−１，１−ビス（メチルチオ）シクロブタンの製
造 アルゴン雰囲気中、水素化アルミニウムリチウム（５６
２ｍｇ，１４．８ｍｍｏｌ）のエーテル懸濁液に、０℃
で実施例２−１で製造した（−）−（２Ｓ，３Ｓ）−
２，３−ビス（メトキシカルボニル）−１，１−ビス
（メチルチオ）シクロブタン（１．９６ｇ，７．４ｍｍ
ｏｌ）のエーテル溶液（１０ｍｌ）を徐々に加え０℃で
２時間攪拌する。反応液に飽和硫酸ナトリウム水溶液を
加え過剰の還元剤を分解した後、無水硫酸ナトリウムを
加えしばらく攪拌する。無機物を濾去し、更に熱イソプ
ロピルアルコールで洗浄した後、濾液及び洗液を合わせ
て減圧下溶媒を溜去する。残渣は、シリカゲルカラムク
ロマトグラフィー（酢酸エチル；ヘキサン：メタノール
＝１５：２０：１，ｖ／ｖ／ｖ）で精製し（−）−（２
Ｓ，３Ｓ）−２，３−ビス（ヒドロキシメチル）−１，
１−ビス（メチルチオ）シクロブタン（１．４８ｇ，９
６％）を得る。Embodiment 3 FIG. Production of (−)-(2S, 3S) -2,3-bis (hydroxymethyl) -1,1-bis (methylthio) cyclobutane Lithium aluminum hydride (56
2 mg, 14.8 mmol) in an ether suspension at 0 ° C.
(-)-(2S, 3S)-manufactured in Example 2-1
2,3-bis (methoxycarbonyl) -1,1-bis (methylthio) cyclobutane (1.96 g, 7.4 mm
ol) (10 ml) was slowly added thereto, followed by stirring at 0 ° C. for 2 hours. After adding an aqueous saturated sodium sulfate solution to the reaction solution to decompose excess reducing agent, anhydrous sodium sulfate is added and the mixture is stirred for a while. After the inorganic substance is removed by filtration and further washed with hot isopropyl alcohol, the filtrate and the washing solution are combined and the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate; hexane: methanol = 15: 20: 1, v / v / v) to give (-)-(2
S, 3S) -2,3-bis (hydroxymethyl) -1,
1-bis (methylthio) cyclobutane (1.48 g, 9
6%).
【００７１】 ＮＭＲ（２７０ＭＨｚＦＴ，ＣＤＣｌ３ ）δ： ２．０２（１Ｈ，ｄｄ，Ｊ＝９．１，１２．１Ｈｚ）， ２．０５（３Ｈ，ｓ）， ２．０６（３Ｈ，ｓ）， ２．２８（１Ｈ，ｄｄ，Ｊ＝８．１，１２．１Ｈｚ）， ２．４７−２．６８（２Ｈ，ｍ）， ３．２６（２Ｈ，ｂｒｓ）， ３．５４（１Ｈ，ｄｄ，Ｊ＝８．８，１０．３Ｈｚ）， ３．６７−３．７７（２Ｈ，ｍ）， ３．８３（１Ｈ，ｄｄ，Ｊ＝５．０，１０．４Ｈｚ）． ＩＲ（ｎｅａｔ）ｃｍ−１：３３５０．NMR (270 MHz FT, CDCl 3 ) δ: 2.02 (1H, dd, J = 9.1, 12.1 Hz), 2.05 (3H, s), 2.06 (3H, s), 2 .28 (1H, dd, J = 8.1, 12.1 Hz), 2.47-2.68 (2H, m), 3.26 (2H, brs), 3.54 (1H, dd, J = 8.8, 10.3 Hz), 3.67-3.77 (2H, m), 3.83 (1H, dd, J = 5.0, 10.4 Hz). IR (neat) cm -1 : 3350.
【００７２】本化合物の一部を取り常法（（Ｒ）−α−
メトキシ−α−トリフルオロメチル−フェニルアセチル
クロリド（（Ｒ）−ＭＴＰＡＣｌ），ジメチルアミノピ
リジン（ＤＭＡＰ）／ピリジン（ｐｙｒ）に従いビス
（Ｒ）−ＭＴＰＡエステルに導いた。５００ＭＨｚＮＭ
Ｒにおいて、ラセミ体由来のこの化合物のメチル基のシ
グナルは１．８５２，１．８５６，１．９１２，１．９
７０ｐｐｍの計４本観察されるが、本物質のメチル基の
シグナルは１．８５２及び１．９１２ｐｐｍのシグナル
が他のものより大きく、光学純度を求めたところ８６％
ｅｅであった。A part of the compound was obtained by a conventional method ((R) -α-
Methoxy-α-trifluoromethyl-phenylacetyl chloride ((R) -MTPACl), dimethylaminopyridine (DMAP) / pyridine (pyr) led to bis (R) -MTPA ester. 500MHzNM
In R, the signal of the methyl group of this compound derived from the racemate is 1.852, 1.856, 1.912, 1.9.
A total of four signals at 70 ppm were observed. The signals of the methyl group of the substance were 1.852 and 1.912 ppm, which were larger than those of the others.
ee.
【００７３】また、表題化合物（−）−（２Ｓ，３Ｓ）
−２，３−ビス（ヒドロキシメチル）−１，１−ビス
（メチルチオ）シクロブタンは、酢酸エチル−ヘキサン
より再結晶することにより、光学純度１００％の結晶を
得ることができる。（〔α〕Ｄ＝−３２．０°（ｃ
１．０３，ＣＨ２Ｃｌ２ ）。The title compound (-)-(2S, 3S)
-2,3-Bis (hydroxymethyl) -1,1-bis (methylthio) cyclobutane can be recrystallized from ethyl acetate-hexane to obtain a crystal having an optical purity of 100%. ([Α] D = -32.0 ° (c
1.03, CH 2 Cl 2).
【００７４】実施例４． （＋）−（２Ｓ，３Ｓ）−２，３−ビス（ｔ−ブチルジ
フェニルシリルオキシメチル）−１，１−ビス（メチル
チオ）シクロブタンの製造 （−）−（２Ｓ，３Ｓ）−２，３−ビス（ヒドロキシメ
チル）−１，１−ビス（メチルチオ）シクロブタン
（１．３７ｇ，６．５８ｍｍｏｌ）、トリエチルアミン
（２．８ｍｌ，２０ｍｍｏｌ）、４−ジメチルアミノメ
チルピリジン（触媒量）及びＤＭＦ（１ｍｌ）を塩化メ
チレン（２５ｍｌ）に溶解した溶液に、ｔ−ブチルジフ
ェニルシリルクロリド（４．５２ｇ，２５ｍｍｏｌ）を
加え室温で一晩攪拌する。反応液は、減圧化濃縮した後
エーテルに溶解し、水洗後、飽和食塩水で洗浄し無水硫
酸ナトリウムで乾燥する。エーテル溶液は、減圧下溶媒
を溜去した後シリカゲルカラムクロマトグラフィー（エ
ーテル：ヘキサン＝１：２０，ｖ／ｖ）で精製し（＋）
−（２Ｓ，３Ｓ）−２，３−ビス（ｔ−ブチルジフェニ
ルシリルオキシメチル）−１，１−ビス（メチルチオ）
シクロブタン（４．５０ｇ，１００％）を得る。Embodiment 4 FIG. Production of (+)-(2S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) -1,1-bis (methylthio) cyclobutane (-)-(2S, 3S) -2,3- Bis (hydroxymethyl) -1,1-bis (methylthio) cyclobutane (1.37 g, 6.58 mmol), triethylamine (2.8 ml, 20 mmol), 4-dimethylaminomethylpyridine (catalytic amount) and DMF (1 ml) To a solution dissolved in methylene chloride (25 ml) is added t-butyldiphenylsilyl chloride (4.52 g, 25 mmol), and the mixture is stirred at room temperature overnight. The reaction solution is concentrated under reduced pressure, dissolved in ether, washed with water, washed with saturated saline, and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the ether solution is purified by silica gel column chromatography (ether: hexane = 1: 20, v / v) (+).
-(2S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) -1,1-bis (methylthio)
Cyclobutane (4.50 g, 100%) is obtained.
【００７５】 ＮＭＲ（２００ＭＨｚＦＴ，ＣＤＣｌ３ ）δ： ０．９９（９Ｈ，ｓ）， １．０２（９Ｈ，ｓ）， ２．０６（６Ｈ，ｓ）， ２．０９−２．２５（２Ｈ，ｍ）， ２．８５（１Ｈ，ｍ）， ３．５２−３．７３（３Ｈ，ｍ）， ３．９０（１Ｈ，ｄｄ，Ｊ＝９．０，１０．８Ｈｚ）， ７．２６−７．４７（１２Ｈ，ｍ）， ７．５５−７．７４（８Ｈ，ｍ）．NMR (200 MHz FT, CDCl 3 ) δ: 0.99 (9H, s), 1.02 (9H, s), 2.06 (6H, s), 2.09-2.25 (2H, m ), 2.85 (1H, m), 3.52-3.73 (3H, m), 3.90 (1H, dd, J = 9.0, 10.8 Hz), 7.26-7.47. (12H, m), 7.55-7.74 (8H, m).
【００７６】実施例５ （＋）−（２Ｓ，３Ｓ）−２，３−ビス（ｔ−ブチルジ
フェニルシリルオキシメチル）−１−シクロブタノンの
製造 Ｎ−クロルコハク酸イミド（１．６０ｇ，１２ｍｍｏ
ｌ）及び硝酸銀（２．２９ｇ，１３．５ｍｍｏｌ）を８
０％アセトニトリル水溶液（４５ｍｌ）に溶解し、２５
℃（＋）−（２Ｓ，３Ｓ）−２，３−ビス（ｔ−ブチル
ジフェニルシリルオキシメチル）−１，１−ビス（メチ
ルチオ）シクロブタン（２．０６ｇ，３ｍｍｏｌ）をア
セトニトリル（６ｍｌ）及び塩化メチレン（１ｍｌ）に
溶解した溶液を素早く加え、１０分間攪拌する。反応液
に飽和亜硫酸ナトリウム水溶液（３ｍｌ）を加え１分間
攪拌した後、飽和炭酸水素ナトリウム水溶液（３ｍｌ）
を加え１分間攪拌し、更に飽和食塩水（３ｍｌ）を加え
１分間攪拌する。この溶液に塩化メチレン−ヘキサン混
合液（１：１，ｖ／ｖ）（６０ｍｌ）を加えた後、不溶
物をハイフロを用いて濾去する。濾液は無水硫酸ナトリ
ウムで乾燥した後減圧下溶媒を溜去し、残渣をシリカゲ
ルカラムクロマトグラフィー（エーテル：ヘキサン＝
１：１０，ｖ／ｖ）で精製し（＋）−（２Ｓ，３Ｓ）−
２，３−ビス（ｔ−ブチルジフェニルシリルオキシメチ
ル）−１−シクロブタノン（１．４９ｇ，８２％）を得
る。Example 5 Preparation of (+)-(2S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) -1-cyclobutanone N-chlorosuccinimide (1.60 g, 12 mmol)
l) and silver nitrate (2.29 g, 13.5 mmol) in 8
Dissolve in 0% acetonitrile aqueous solution (45 ml) and add 25%
C. (+)-(2S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) -1,1-bis (methylthio) cyclobutane (2.06 g, 3 mmol) in acetonitrile (6 ml) and methylene chloride (1 ml) is added quickly and stirred for 10 minutes. A saturated aqueous solution of sodium sulfite (3 ml) was added to the reaction solution, and the mixture was stirred for 1 minute.
, And the mixture is stirred for 1 minute. Saturated saline (3 ml) is further added, and the mixture is stirred for 1 minute. After adding a methylene chloride-hexane mixed solution (1: 1, v / v) (60 ml) to this solution, the insoluble matter is removed by filtration using Hyflo. After the filtrate was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ether: hexane =
1:10, v / v) (+)-(2S, 3S)-
This gives 2,3-bis (t-butyldiphenylsilyloxymethyl) -1-cyclobutanone (1.49 g, 82%).
【００７７】 ＮＭＲ（２７０ＭＨｚＦＴ，ＣＤＣｌ３ ）δ： １．０２（９Ｈ，ｓ）， １．０４（９Ｈ，ｓ）， ２．７４−３．０５（２Ｈ，ｍ）， ３．２９（１Ｈ，ｍ）， ３．６９（１Ｈ，ｄｄ，Ｊ＝３．７，１０．６Ｈｚ）， ３．８２（１Ｈ，ｄｄ，Ｊ＝４．８，１０．３Ｈｚ）， ３．８８（１Ｈ，ｄｄ，Ｊ＝４．８，１０．３Ｈｚ）， ３．９７（１Ｈ，ｄｄ，Ｊ＝４．０，１０．６Ｈｚ）， ７．３２−７．４４（１２Ｈ，ｍ）， ７．６２−７．６８（８Ｈ，ｍ）， ＩＲ（ｎｅａｔ）ｃｍ−１：１７８５．NMR (270 MHz FT, CDCl 3 ) δ: 1.02 (9H, s), 1.04 (9H, s), 2.74-3.05 (2H, m), 3.29 (1H, m) ), 3.69 (1H, dd, J = 3.7, 10.6 Hz), 3.82 (1H, dd, J = 4.8, 10.3 Hz), 3.88 (1H, dd, J = 4.8, 10.3 Hz), 3.97 (1H, dd, J = 4.0, 10.6 Hz), 7.32-7.44 (12H, m), 7.62-7.68 (8H , M), IR (neat) cm -1 : 1785.
【００７８】実施例６． ２，３−ビス（ｔ−ブチルジフェニルシリルオキシメチ
ル）シクロブタノールの製造Embodiment 6 FIG. Production of 2,3-bis (t-butyldiphenylsilyloxymethyl) cyclobutanol
【００７９】実施例６−１． アルゴン雰囲気下、水素化リチウムトリ（ｔ−ブトキ
シ）アルミニウム（１．２７ｇ，５．０ｍｍｏｌ）をテ
トラヒドロフラン（ＴＨＦ）（１０ｍｌ）に加え、−７
８℃に冷却する。この懸濁液に、（＋）−（２Ｓ，３
Ｓ）−２，３−ビス（ｔ−ブチルジフェニルシリルオキ
シメチル）−１−シクロブタノン（１．２１ｇ，２．０
ｍｍｏｌ）のＴＨＦ溶液を加え、攪拌下数時間かけてゆ
っくり室温まで昇温する。反応液に０．２Ｍ−リン酸緩
衝液を加え過剰の還元剤を分解した後、塩化メチレンを
加え無機物を濾去する。濾液は、塩化メチレンで抽出
後、無水硫酸ナトリウムで乾燥した後、溶媒を溜去す
る。残渣はシリカゲルカラムクロマトグラフィー（酢酸
エチル：ヘキサン＝１：９−１：４，ｖ／ｖ）で分離精
製し、（＋）−（１Ｓ，２Ｓ，３Ｓ）−２，３−ビス
（ｔ−ブチルジフェニルシリルオキシメチル）シクロブ
タノール（０．１０４ｇ，９％）Embodiment 6-1. Under an argon atmosphere, lithium tri (t-butoxy) aluminum (1.27 g, 5.0 mmol) was added to tetrahydrofuran (THF) (10 ml).
Cool to 8 ° C. Add (+)-(2S, 3
S) -2,3-Bis (t-butyldiphenylsilyloxymethyl) -1-cyclobutanone (1.21 g, 2.0
mmol) in THF and slowly warm to room temperature over several hours with stirring. After adding 0.2M-phosphate buffer to the reaction solution to decompose excess reducing agent, methylene chloride is added and inorganic substances are removed by filtration. The filtrate is extracted with methylene chloride, dried over anhydrous sodium sulfate, and the solvent is distilled off. The residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9-1: 4, v / v), and (+)-(1S, 2S, 3S) -2,3-bis (t-butyl) Diphenylsilyloxymethyl) cyclobutanol (0.104 g, 9%)
【００８０】 ＮＭＲ（２００ＭＨｚＦＴ，ＣＤＣｌ３ ）δ： １．００（９Ｈ，ｓ）， １．０７（９Ｈ，ｓ）， １．９７−２．２５（２Ｈ，ｍ）， ２．３２（１Ｈ，ｍ）， ２．４８（１Ｈ，ｍ）， ３．１７（１Ｈ，ｄ，Ｊ＝７．３Ｈｚ）， ３．５６（２Ｈ，ｄ，Ｊ＝５．８Ｈｚ）， ３．８８（１Ｈ，ｄｄ，Ｊ＝５．６，１１．４Ｈｚ）， ３．９８（１Ｈ，ｄｄ，Ｊ＝４．０，１１．４Ｈｚ）， ４．４６（１Ｈ，ｍ）， ７．２６−７．４８（１２Ｈ，ｍ）， ７．５４−７．７２（８Ｈ，ｍ）， 及び（＋）−（１Ｒ，２Ｓ，３Ｓ）−２，３−ビス（ｔ
−ブチルジフェニルシリルオキシメチル）シクロブタノ
ール（１．０６８ｇ，８８％）を得る。NMR (200 MHz FT, CDCl 3 ) δ: 1.00 (9H, s), 1.07 (9H, s), 1.97-2.25 (2H, m), 2.32 (1H, m) ), 2.48 (1H, m), 3.17 (1H, d, J = 7.3 Hz), 3.56 (2H, d, J = 5.8 Hz), 3.88 (1H, dd, J) = 5.6, 11.4 Hz), 3.98 (1H, dd, J = 4.0, 11.4 Hz), 4.46 (1H, m), 7.26-7.48 (12H, m) , 7.54-7.72 (8H, m), and (+)-(1R, 2S, 3S) -2,3-bis (t
-Butyldiphenylsilyloxymethyl) cyclobutanol (1.068 g, 88%) is obtained.
【００８１】 ＮＭＲ（２００ＭＨｚＦＴ，ＣＤＣｌ３ ）δ： １．０３（９Ｈ，ｓ）， １．０４（９Ｈ，ｓ）， １．６０−１．７３（２Ｈ，ｍ）， １．９２（１Ｈ，ｍ）， ２．１０−２．３７（２Ｈ，ｍ）， ３．５２−３．７０（３Ｈ，ｍ）， ３．７７（１Ｈ，ｄｄ，Ｊ＝４．５，１０．４Ｈｚ）， ４．０３（１Ｈ，ｍ）， ７．２７−７．４６（１２Ｈ，ｍ）， ７．５６−７．６９（８Ｈ，ｍ）．NMR (200 MHz FT, CDCl 3 ) δ: 1.03 (9H, s), 1.04 (9H, s), 1.60-1.73 (2H, m), 1.92 (1H, m) ), 2.10-2.37 (2H, m), 3.52-3.70 (3H, m), 3.77 (1H, dd, J = 4.5, 10.4 Hz), 4.03 (1H, m), 7.27-7.46 (12H, m), 7.56-7.69 (8H, m).
【００８２】実施例６−２． アルゴン雰囲気下、（＋）−（２Ｓ，３Ｓ）−２，３−
ビス（ｔ−ブチルジフェニルシリルオキシメチル）−１
−シクロブタノン（４．１２ｇ，６．８ｍｍｏｌ）のト
ルエン（７０ｍｌ）溶液に、−７８℃で１Ｍ−水素化ジ
イソブチルアルミニウム／トルエン（８．２ｍｌ，８．
２ｍｍｏｌ）を徐々に加え、同温で１０分間攪拌する。
反応液に０．２Ｍ−リン酸緩衝液（ｐＨ７）を加え、し
ばらく攪拌した後、過剰の塩化メチレンを加え無機物を
濾去する。濾液は、塩化メチレンで抽出後、無水硫酸ナ
トリウムで乾燥した後、溶媒を溜去する。残渣はシリカ
ゲルカラムクロマトグラフィー（酢酸エチル：ヘキサン
＝１：９−１：４，ｖ／ｖ）で分離精製し、（＋）−
（１Ｓ，２Ｓ，３Ｓ）−２，３−ビス（ｔ−ブチルジフ
ェニルシリルオキシメチル）シクロブタノール（３．３
８ｇ，８２％）及び（＋）−（１Ｒ，２Ｓ，３Ｓ）−
２，３−ビス（ｔ−ブチルジフェニルシリルオキシメチ
ル）シクロブタノール（０．６９ｇ，１７％）を得る。Embodiment 6-2. Under an argon atmosphere, (+)-(2S, 3S) -2,3-
Bis (t-butyldiphenylsilyloxymethyl) -1
-To a solution of cyclobutanone (4.12 g, 6.8 mmol) in toluene (70 ml) at -78 ° C was added 1 M diisobutylaluminum hydride / toluene (8.2 ml, 8.8 mmol).
2 mmol) is slowly added and stirred at the same temperature for 10 minutes.
A 0.2 M phosphate buffer (pH 7) is added to the reaction solution, and after stirring for a while, an excess of methylene chloride is added and inorganic substances are removed by filtration. The filtrate is extracted with methylene chloride, dried over anhydrous sodium sulfate, and the solvent is distilled off. The residue was separated and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9-1: 4, v / v) to give (+)-
(1S, 2S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) cyclobutanol (3.3
8g, 82%) and (+)-(1R, 2S, 3S)-
There is obtained 2,3-bis (t-butyldiphenylsilyloxymethyl) cyclobutanol (0.69 g, 17%).
【００８３】実施例６−３． （＋）−（１Ｒ，２Ｓ，３Ｓ）−２，３−ビス（ｔ−ブ
チルジフェニルシリルオキシメチル）シクロブタノール
から（＋）−（１Ｓ，２Ｓ，３Ｓ）−２，３−ビス（ｔ
−ブチルジフェニルシリルオキシメチル）シクロブタノ
ールへの変換Embodiment 6-3. From (+)-(1R, 2S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) cyclobutanol, (+)-(1S, 2S, 3S) -2,3-bis (t
-Butyldiphenylsilyloxymethyl) cyclobutanol
【００８４】工程１． アルゴン気流中、（＋）−（１Ｒ，２Ｓ，３Ｓ）−２，
３−ビス（ｔ−ブチルジフェニルシリルオキシメチル）
シクロブタノール（７００ｍｇ，１．１５ｍｍｏｌ）、
安息香酸（１６７ｍｇ，１．３７ｍｍｏｌ）及びトリフ
ェニルフォスフィン（３６２ｍｇ，１．３８ｍｍｏｌ）
のベンゼン（１０ｍｌ）溶液に、ジエチルアゾジカルボ
キシレート（２１７μｌ，１．３８ｍｍｏｌ）を加え、
室温で終夜攪拌する。反応液は、減圧下揮発物質を溜去
した後、シリカゲルカラムクロマトグラフィー（エーテ
ル：ヘキサン＝１：１０，ｖ／ｖ）で精製し、（＋）−
（１Ｓ，２Ｓ，３Ｓ）−１−ベンゾイル−２，３−ビス
（ｔ−ブチルジフェニルシリルオキシメチル）シクロブ
タン（７９１ｍｇ，９７％）を得る。Step 1. (+)-(1R, 2S, 3S) -2,
3-bis (t-butyldiphenylsilyloxymethyl)
Cyclobutanol (700 mg, 1.15 mmol),
Benzoic acid (167 mg, 1.37 mmol) and triphenylphosphine (362 mg, 1.38 mmol)
To a benzene (10 ml) solution of was added diethyl azodicarboxylate (217 μl, 1.38 mmol),
Stir at room temperature overnight. After evaporating the volatile substances under reduced pressure, the reaction solution was purified by silica gel column chromatography (ether: hexane = 1: 10, v / v) to obtain (+)-
(1S, 2S, 3S) -1-benzoyl-2,3-bis (t-butyldiphenylsilyloxymethyl) cyclobutane (791 mg, 97%) is obtained.
【００８５】 ＮＭＲ（２００ＭＨｚＦＴ，ＣＤＣｌ３ ）δ： ０．９７（９Ｈ，ｓ）， １．０６（９Ｈ，ｓ）， ２．２３−２．４０（２Ｈ，ｍ）， ２．４５（１Ｈ，ｍ）， ２．８５（１Ｈ，ｍ）， ３．７１（２Ｈ，ｄ，Ｊ＝５．４Ｈｚ）， ３．８３（１Ｈ，ｄｄ，Ｊ＝６．１，１０．５Ｈｚ）， ３．９９（１Ｈ，ｄｄ，Ｊ＝７．３，１０．５Ｈｚ）， ５．４８（１Ｈ，ａｐｐａｒｅｎｔ ｑ．Ｊ＝６．５Ｈｚ）， ７．２１−７．４５（１４Ｈ ，ｍ）， ７．４９−７．７２（９Ｈｚ）， ７．９８（２Ｈ，ｄ，Ｊ＝７．１Ｈｚ）．NMR (200 MHz FT, CDCl 3 ) δ: 0.97 (9H, s), 1.06 (9H, s), 2.23-2.40 (2H, m), 2.45 (1H, m) ), 2.85 (1H, m), 3.71 (2H, d, J = 5.4 Hz), 3.83 (1H, dd, J = 6.1, 10.5 Hz), 3.99 (1H) , Dd, J = 7.3, 10.5 Hz), 5.48 (1H, applicable q.J = 6.5 Hz), 7.21-7.45 (14H, m), 7.49-7.72. (9 Hz), 7.98 (2H, d, J = 7.1 Hz).
【００８６】工程２． アルゴン気流中、工程１で得られた（＋）−（１Ｓ，２
Ｓ，３Ｓ）−１−ベンゾイル−２，３−ビス（ｔ−ブチ
ルジフェニルシリルオキシメチル）シクロブタン（７９
０ｍｇ，１．１ｍｍｏｌ）のトルエン（１０ｍｌ）溶液
に、−７８℃で１Ｍ−水素化ジイソブチルアルミニウム
／トルエン（２．６ｍｌ，２．６ｍｍｏｌ）を徐々に加
え、同温で３０分間攪拌する。反応液に０．２Ｍ−リン
酸緩衝液（ｐＨ７）を加え、しばらく攪拌した後、過剰
の塩化メチレンを加え無機物を濾去する。濾液は塩化メ
チレンで抽出後、無水硫酸ナトリウムで乾燥した後、溶
媒を溜去する。残渣はシリカゲルカラムクロマトグラフ
ィー（エーテル：ヘキサン＝１：５、ｖ／ｖ）で分離精
製し、（＋）−（１Ｓ，２Ｓ，３Ｓ）−２，３−ビス
（ｔ−ブチルジフェニルシリルオキシメチル）シクロブ
タノール（６４４ｍｇ，９５％）を得る。Step 2. (+)-(1S, 2) obtained in step 1 in an argon stream.
(S, 3S) -1-benzoyl-2,3-bis (t-butyldiphenylsilyloxymethyl) cyclobutane (79
(0 mg, 1.1 mmol) in toluene (10 ml) was slowly added with 1M diisobutylaluminum hydride / toluene (2.6 ml, 2.6 mmol) at -78 ° C, and the mixture was stirred at the same temperature for 30 minutes. A 0.2 M phosphate buffer (pH 7) is added to the reaction solution, and after stirring for a while, an excess of methylene chloride is added and inorganic substances are removed by filtration. The filtrate is extracted with methylene chloride, dried over anhydrous sodium sulfate, and the solvent is distilled off. The residue was separated and purified by silica gel column chromatography (ether: hexane = 1: 5, v / v), and (+)-(1S, 2S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) Cyclobutanol (644 mg, 95%) is obtained.
【００８７】実施例７． （＋）−（１Ｓ，２Ｓ，３Ｓ）−２，３−ビス（ｔ−ブ
チルジフェニルシリルオキシメチル）−１−メタンスル
ホニルオキシシクロブタンの製造 （＋）−（１Ｓ，２Ｓ，３Ｓ）−２，３−ビス（ｔ−ブ
チルジフェニルシリルオキシメチル）シクロブタノール
（９１１ｍｇ，１．５ｍｍｏｌ）及びトリエチルアミン
（０．６ｍｌ，４．３ｍｍｏｌ）の塩化メチレン溶液
に、０℃でメタンスルホニルクロリド（０．１７ｍｌ，
２．２ｍｍｏｌ）を加え、０℃で１５分間攪拌する。反
応液に０．２Ｍ−リン酸緩衝液を加え、エーテルで抽出
する。エーテル抽出液は、無水硫酸ナトリウムで乾燥し
た後、溶媒を溜去する。残渣はシリカゲルカラムクロマ
トグラフィー（酢酸エステル：ヘキサン＝１：６，ｖ／
ｖ）で精製し（＋）−（１Ｓ，２Ｓ，３Ｓ）−２，３−
ビス（ｔ−ブチルジフェニルシリルオキシメチル）−１
−メタンスルホニルオキシシクロブタン（定量的）を得
る。Embodiment 7 FIG. Production of (+)-(1S, 2S, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) -1-methanesulfonyloxycyclobutane (+)-(1S, 2S, 3S) -2,3 To a solution of -bis (t-butyldiphenylsilyloxymethyl) cyclobutanol (911 mg, 1.5 mmol) and triethylamine (0.6 ml, 4.3 mmol) in methylene chloride at 0 ° C was added methanesulfonyl chloride (0.17 ml,
2.2 mmol) and stir at 0 ° C. for 15 minutes. A 0.2 M phosphate buffer is added to the reaction solution, and the mixture is extracted with ether. After the ether extract is dried over anhydrous sodium sulfate, the solvent is distilled off. The residue was subjected to silica gel column chromatography (acetate: hexane = 1: 6, v /
v) and purified by (+)-(1S, 2S, 3S) -2,3-
Bis (t-butyldiphenylsilyloxymethyl) -1
Obtaining methanesulfonyloxycyclobutane (quantitative).
【００８８】 ＮＭＲ（２００ＭＨｚＦＴ，ＣＤＣｌ３ ）δ： １．０４（９Ｈ，ｓ）， １．０６（９Ｈ，ｓ）， ２．２５−２．５３（３Ｈ，ｍ）， ２．７８（１Ｈ，ｍ）， ２．８７（３Ｈ，ｓ）， ３．６５（２Ｈ，ｄ，Ｊ＝４．０Ｈｚ）， ３．８５（１Ｈ，ｄｄ，Ｊ＝６．３，１０．５Ｈｚ）， ３．９３（１Ｈ，ｄｄ，Ｊ＝６．５，１０．５Ｈｚ）， ５．２５（１Ｈ，ｍ）， ７．３２−７．５０（１２Ｈ，ｍ）， ７．６０−７．７５（８Ｈ，ｍ）． 本化合物を、エーテル−ヘキサンより再結晶することに
より、結晶（〔α〕Ｄ＝＋１２．０°（ｃ １．０１，
ＣＨ２Ｃｌ２）（光学純度１００％）を得ることができ
る。NMR (200 MHz FT, CDCl 3 ) δ: 1.04 (9H, s), 1.06 (9H, s), 2.25-2.53 (3H, m), 2.78 (1H, m) ), 2.87 (3H, s), 3.65 (2H, d, J = 4.0 Hz), 3.85 (1H, dd, J = 6.3, 10.5 Hz), 3.93 (1H) , Dd, J = 6.5, 10.5 Hz), 5.25 (1H, m), 7.32-7.50 (12H, m), 7.60-7.75 (8H, m). This compound was recrystallized from ether-hexane to give a crystal ([α] D = + 12.0 ° (c 1.01,
CH 2 Cl 2 ) (optical purity 100%).
【００８９】実施例８． （＋）−９−〔（１Ｒ，２Ｒ，３Ｓ）−２，３−ビス
（ヒドロキシメチル）シクロブタン−１−イル〕−グア
ニンの製造Embodiment 8 FIG. Production of (+)-9-[(1R, 2R, 3S) -2,3-bis (hydroxymethyl) cyclobutan-1-yl] -guanine
【００９０】工程１． （＋）−２−アミノ−９−〔（１Ｒ，２Ｒ，３Ｓ）−
２，３−ビス（ｔ−ブチルジフェニルシリルオキシメチ
ル）シクロブタン−１−イル〕−６−（２−メトキシエ
トキシ）プリンの製造 ２−アミノ−６−（２−メトキシエトキシ）プリン（１
５５ｍｇ，０．７４ｍｍｏｌ）のＤＭＦ（４ｍｌ）懸濁
液に水素化リチウム（６ｍｇ，０．７５ｍｍｏｌ）を加
え、１時間攪拌する。反応液に（＋）−（１Ｓ，２Ｓ，
３Ｓ）−２，３−ビス（ｔ−ブチルジフェニルシリルオ
キシメチル）−１−メタンスルホニルオキシシクロブタ
ン（４５０ｍｇ，０．６５ｍｍｏｌ）のＤＭＦ（１．５
ｍｌ）溶液を加え、１４５℃で６時間攪拌する。冷却後
０．２Ｍ−リン酸緩衝液及び酢酸エチルを加え不溶物を
濾去した後、酢酸エチルで抽出する。抽出液は、無水硫
酸ナトリウムで乾燥した後、溶媒を溜去する。残渣は、
シリカゲルカラムクロマトグラフィー（塩化メチレン：
酢酸エチル＝１０：１，ｖ／ｖ）で精製し、（＋）−２
−アミノ−９−〔（１Ｒ，２Ｒ，３Ｓ）−２，３−ビス
（ｔ−ブチルジフェニルシリルオキシメチル）シクロブ
タン−１−イル〕−６−（２−メトキシエトキシ）−プ
リン（８８ｍｇ，３０％）を得る。Step 1. (+)-2-Amino-9-[(1R, 2R, 3S)-
Preparation of 2,3-bis (t-butyldiphenylsilyloxymethyl) cyclobutan-1-yl] -6- (2-methoxyethoxy) purine 2-amino-6- (2-methoxyethoxy) purine (1
Lithium hydride (6 mg, 0.75 mmol) is added to a suspension of 55 mg (0.74 mmol) in DMF (4 ml) and stirred for 1 hour. (+)-(1S, 2S,
3S) -2,3-Bis (t-butyldiphenylsilyloxymethyl) -1-methanesulfonyloxycyclobutane (450 mg, 0.65 mmol) in DMF (1.5
ml) and add the solution and stir at 145 ° C. for 6 hours. After cooling, a 0.2 M phosphate buffer and ethyl acetate are added, the insolubles are filtered off, and the mixture is extracted with ethyl acetate. After the extract is dried over anhydrous sodium sulfate, the solvent is distilled off. The residue is
Silica gel column chromatography (methylene chloride:
(Ethyl acetate = 10: 1, v / v) to give (+)-2
-Amino-9-[(1R, 2R, 3S) -2,3-bis (t-butyldiphenylsilyloxymethyl) cyclobutan-1-yl] -6- (2-methoxyethoxy) -purine (88 mg, 30% Get)
【００９１】 ＮＭＲ（２００ＭＨｚＦＴ，ＣＤＣｌ３ ）δ： １．０１（９Ｈ，ｓ）， １．０５（９Ｈ，ｓ）， ２．２５−２．６０（３Ｈ，ｍ）， ２．９２（１Ｈ，ｍ）， ３．４４（３Ｈ，ｓ）， ３．６０−３．９４（６Ｈ，ｍ）， ４．５０−４．９０（５Ｈ，ｍ）， ７．１５−７．５５（１２Ｈ，ｍ）， ７．５５−７．８０（８Ｈ，ｍ）， ７．６７（１Ｈ，ｓ）． 本反応の溶媒として、ＤＭＳＯ及びＨＭＰＡを用いる
と、反応はそれぞれ７５℃及び１００℃で進行し、ＤＭ
Ｆを用いた場合と同様の結果が得られる。NMR (200 MHz FT, CDCl 3 ) δ: 1.01 (9H, s), 1.05 (9H, s), 2.25-2.60 (3H, m), 2.92 (1H, m) ), 3.44 (3H, s), 3.60-3.94 (6H, m), 4.50-4.90 (5H, m), 7.15-7.55 (12H, m), 7.55-7.80 (8H, m), 7.67 (1H, s). When DMSO and HMPA were used as the solvent for this reaction, the reaction proceeded at 75 ° C. and 100 ° C., respectively.
The same result as in the case of using F is obtained.
【００９２】工程２． （＋）−９−〔（１Ｒ，２Ｒ，３Ｓ）−２，３−ビス
（ヒドロキシメチル）シクロブタン−１−イル〕−グア
ニン（本発明化合物）の製造 工程１で製造した（＋）−２−アミノ−９−〔（１Ｒ，
２Ｒ，３Ｓ）−２，３−ビス（ｔ−ブチルジフェニルシ
リルオキシメチル）シクロブタン−１−イル〕−６−
（２−メトキシエトキシ）−プリン（７９ｍｇ，０．１
０ｍｍｏｌ）のメタノール溶液（２ｍｌ）に４Ｎ−塩酸
／ジオキサン（０．１ｍｌ，０．４ｍｍｏｌ）を加え室
温で一晩攪拌する。反応液は減圧下溶媒を溜去した後、
水を加えエーテル可溶部を除き、溶媒を溜去し、２Ｎ−
塩酸水溶液（２ｍｌ）を加え、１時間加熱還流する。反
応液は１Ｍ−水酸化ナトリウム溶液で中和した後、セフ
ァデックスＨＰ−２０カラムクロマトグラフィー（水：
メタノール＝１：０−１：４，ｖ／ｖ）で精製し、
（＋）−９−〔（１Ｒ，２Ｒ，３Ｓ）−２，３−ビス
（ヒドロキシメチル）シクロブタン−１−イル〕−グア
ニン（本発明化合物）（２３ｍｇ，８８％）を得る。Step 2. Production of (+)-9-[(1R, 2R, 3S) -2,3-bis (hydroxymethyl) cyclobutan-1-yl] -guanine (compound of the present invention) (+)-2- produced in Step 1 Amino-9-[(1R,
2R, 3S) -2,3-Bis (t-butyldiphenylsilyloxymethyl) cyclobutan-1-yl] -6
(2-Methoxyethoxy) -purine (79 mg, 0.1
4N-hydrochloric acid / dioxane (0.1 ml, 0.4 mmol) was added to a methanol solution (2 ml) of 0 mmol), and the mixture was stirred at room temperature overnight. After distilling off the solvent under reduced pressure,
Water was added to remove the ether-soluble portion, the solvent was distilled off, and 2N-
An aqueous hydrochloric acid solution (2 ml) is added, and the mixture is heated under reflux for 1 hour. After the reaction solution was neutralized with a 1 M sodium hydroxide solution, Sephadex HP-20 column chromatography (water:
Methanol = 1: 0-1: 4, v / v),
(+)-9-[(1R, 2R, 3S) -2,3-bis (hydroxymethyl) cyclobutan-1-yl] -guanine (the compound of the present invention) (23 mg, 88%) is obtained.
【００９３】 ＮＭＲ（２００ＭＨｚＦＴ，ＣＤ３ＯＤ）δ： ２．１８（１Ｈ，ｍ）， ２．３２（１Ｈ，ａｐｐａｒｅｎｔ ｑ，Ｊ＝１０．０Ｈｚ）， ２．５０（１Ｈ，ｍ）， ２．７９（１Ｈ，ｍ）， ３．６２−３．７４（４Ｈ，ｍ）， ４．５４（１Ｈ，ａｐｐａｒｅｎｔ ｑ，Ｊ＝８．８Ｈｚ）， ７．８９（１Ｈ，ｓ）． ＵＶ λｍａｘ（Ｈ２Ｏ）ｎｍ： ｐＨ１，２５３，２７７（ｓｈ）；ｐＨ７，２５３，２６８（ｓｈ）；ｐＨ１３ ，２５６（ｓｈ），２６７ ＨＲＭＳ（ＦＡＢ） Ｃａｌｃｄ ｆｏｒ 〔Ｃ１１Ｈ１５Ｎ５ Ｏ３＋Ｈ〕＋：２６６．１２５３ Ｆｏｕｎｄ；２６６．１２５１． 本化合物を、水より再結晶することにより、結晶
（〔α〕Ｄ ＝＋２６．５°（ｃ ０．９９，０．１ Ｎ
−ＮａＯＨ））（光学純度＞９８％）を得ることができ
る。NMR (200 MHz FT, CD 3 OD) δ: 2.18 (1H, m), 2.32 (1H, applicable q, J = 10.0 Hz), 2.50 (1H, m), 2.79 (1H, m), 3.62-3.74 (4H, m), 4.54 (1H, applicable q, J = 8.8 Hz), 7.89 (1H, s). UV λmax (H 2 O) nm: pH 1,253,277 (sh); pH 7,253,268 (sh); pH 13,256 (sh), 267 HRMS (FAB) Calcd for [C 11 H 15 N 5 O 3 + H] + : 266.1253 Found; 266.1251. This compound was recrystallized from water to give a crystal ([α] D = + 26.5 ° (c 0.99, 0.1 N
-NaOH)) (optical purity> 98%).
【００９４】[0094]
【発明の効果】本発明の抗ウイルス剤は、強い抗ウイル
ス作用を有し、多くのウイルス性疾患に対して有効であ
る。The antiviral agent of the present invention has a strong antiviral effect and is effective against many viral diseases.
───────────────────────────────────────────────────── フロントページの続き (31)優先権主張番号 特願平1−158223 (32)優先日 平１(1989)６月22日 (33)優先権主張国 日本（ＪＰ） (72)発明者 松原 謙一 大阪府吹田市山田東３−18−１−804 (72)発明者 長幡 武光 大阪府豊中市上新田２−６−25 千里坂 ノ木ハイツ208 (72)発明者 星野 洪郎 群馬県前橋市平和町１−14−５ (72)発明者 関 淳一 群馬県高崎市岩鼻町239 (72)発明者 奈良坂 紘一 東京都江東区越中島１−３−17−310 (72)発明者 林 雄二郎 東京都大田区南雪谷２−６−２ 審査官 塚中 直子 (56)参考文献 特開 平２−6478（ＪＰ，Ａ) (58)調査した分野(Int.Cl.6，ＤＢ名) A61K 31/52 ADY C07D 473/18 ＣＡ（ＳＴＮ)──────────────────────────────────────────────────続 き Continued on the front page (31) Priority claim number Japanese Patent Application No. 1-158223 (32) Priority date Hei 1 (1989) June 22, (33) Priority claim country Japan (JP) (72) Inventor Kenichi Matsubara 3-18-1-804 Yamadahigashi, Suita-shi, Osaka (72) Inventor Takemitsu Nagahata 2-6-25 Kamishita, Toyonaka-shi, Osaka Senri-zaka Noki Heights 208 (72) Inventor Hiroo Hoshino Gunma 1-14-5 Heiwacho, Maebashi-shi, Japan (72) Inventor Junichi Seki 239, Iwanacho, Takasaki-shi, Gunma (72) Inventor Koichi Narasaka 1-3-17-310, Ecchujima, Koto-ku, Tokyo (72) Inventor Yujiro Hayashi 2-6-2 Minamiyukiya, Ota-ku, Tokyo Examiner Naoko Tsukanaka (56) References JP-A-2-6478 (JP, A) (58) Fields investigated (Int. Cl. 6 , DB name) A61K 31 / 52 ADY C07D 473/18 CA (STN)
Claims (7)
ス（ヒドロキシメチル）シクロブタン−１−イル〕−グ
アニンを有効成分とする抗ウイルス剤 。An antiviral agent comprising 9-[(1R, 2R, 3S) -2,3-bis (hydroxymethyl) cyclobutan-1-yl] -guanine as an active ingredient.
メガロウイルス、肝炎ウイルス又はエイズウイルスであ
る請求項１記載の抗ウイルス剤。2. The antiviral agent according to claim 1, wherein the virus is herpes simplex virus, cytomegalovirus, hepatitis virus or AIDS virus.
１記載の抗ウイルス剤。3. The antiviral agent according to claim 1, wherein the virus is hepatitis B virus.
記載の抗ウイルス剤。4. The method according to claim 1, wherein the virus is an AIDS virus.
The antiviral agent according to the above.
求項１記載の抗ウイルス剤。5. The antiviral agent according to claim 1, wherein the virus is a herpes simplex virus.
求項１記載の抗ウイルス剤。6. The antiviral agent according to claim 1, wherein the virus is cytomegalovirus.
る請求項１記載の抗ウイルス剤。7. The antiviral agent according to claim 1, wherein the virus is a varicella star virus.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP8146548A JP2888333B2 (en) | 1988-09-09 | 1996-05-17 | Antiviral agent |
Applications Claiming Priority (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63-224476 | 1988-09-09 | ||
| JP22447688 | 1988-09-09 | ||
| JP63-295135 | 1988-11-22 | ||
| JP29513588 | 1988-11-22 | ||
| JP1-43036 | 1989-02-27 | ||
| JP4303689 | 1989-02-27 | ||
| JP15822389 | 1989-06-22 | ||
| JP1-158223 | 1989-06-22 | ||
| JP8146548A JP2888333B2 (en) | 1988-09-09 | 1996-05-17 | Antiviral agent |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1220354A Division JP2577640B2 (en) | 1988-09-09 | 1989-08-29 | New cyclobutane derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH08301766A JPH08301766A (en) | 1996-11-19 |
| JP2888333B2 true JP2888333B2 (en) | 1999-05-10 |
Family
ID=27522293
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP8146548A Expired - Lifetime JP2888333B2 (en) | 1988-09-09 | 1996-05-17 | Antiviral agent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2888333B2 (en) |
-
1996
- 1996-05-17 JP JP8146548A patent/JP2888333B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH08301766A (en) | 1996-11-19 |
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