JP2009256214A - ポリエチレングリコールの誘導体およびその中間体の製造方法 - Google Patents
ポリエチレングリコールの誘導体およびその中間体の製造方法 Download PDFInfo
- Publication number
- JP2009256214A JP2009256214A JP2008104089A JP2008104089A JP2009256214A JP 2009256214 A JP2009256214 A JP 2009256214A JP 2008104089 A JP2008104089 A JP 2008104089A JP 2008104089 A JP2008104089 A JP 2008104089A JP 2009256214 A JP2009256214 A JP 2009256214A
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- Prior art keywords
- mmol
- added
- room temperature
- silica gel
- thf
- Prior art date
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- Granted
Links
- 239000002202 Polyethylene glycol Substances 0.000 title claims abstract description 15
- 229920001223 polyethylene glycol Polymers 0.000 title claims abstract description 15
- 238000004519 manufacturing process Methods 0.000 title abstract description 9
- 150000002334 glycols Chemical class 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 35
- 238000000034 method Methods 0.000 claims abstract description 7
- 125000001424 substituent group Chemical group 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 3
- 150000002148 esters Chemical class 0.000 claims description 7
- 150000002430 hydrocarbons Chemical group 0.000 claims description 4
- -1 p-toluenesulfonyl group Chemical group 0.000 abstract description 6
- 239000002246 antineoplastic agent Substances 0.000 abstract description 4
- 125000001183 hydrocarbyl group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 297
- 239000000243 solution Substances 0.000 description 211
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 133
- 238000006243 chemical reaction Methods 0.000 description 126
- 238000005160 1H NMR spectroscopy Methods 0.000 description 119
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 112
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 112
- 238000001035 drying Methods 0.000 description 110
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 108
- UREBWPXBXRYXRJ-UHFFFAOYSA-N ethyl acetate;methanol Chemical compound OC.CCOC(C)=O UREBWPXBXRYXRJ-UHFFFAOYSA-N 0.000 description 108
- 239000012046 mixed solvent Substances 0.000 description 108
- 239000000741 silica gel Substances 0.000 description 108
- 229910002027 silica gel Inorganic materials 0.000 description 108
- 238000010898 silica gel chromatography Methods 0.000 description 108
- 239000002904 solvent Substances 0.000 description 108
- 238000003756 stirring Methods 0.000 description 108
- 239000000725 suspension Substances 0.000 description 104
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 103
- 239000002480 mineral oil Substances 0.000 description 103
- 235000010446 mineral oil Nutrition 0.000 description 103
- 239000012312 sodium hydride Substances 0.000 description 103
- 229910000104 sodium hydride Inorganic materials 0.000 description 103
- WGKYSFRFMQHMOF-UHFFFAOYSA-N 3-bromo-5-methylpyridine-2-carbonitrile Chemical compound CC1=CN=C(C#N)C(Br)=C1 WGKYSFRFMQHMOF-UHFFFAOYSA-N 0.000 description 85
- 229920000847 nonoxynol Polymers 0.000 description 85
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 56
- 239000000203 mixture Substances 0.000 description 47
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 40
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- WRZXKWFJEFFURH-UHFFFAOYSA-N dodecaethylene glycol Chemical compound OCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO WRZXKWFJEFFURH-UHFFFAOYSA-N 0.000 description 27
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 230000010354 integration Effects 0.000 description 9
- 210000004027 cell Anatomy 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- 238000000746 purification Methods 0.000 description 7
- ARNKHYQYAZLEEP-UHFFFAOYSA-N 1-naphthalen-1-yloxynaphthalene Chemical compound C1=CC=C2C(OC=3C4=CC=CC=C4C=CC=3)=CC=CC2=C1 ARNKHYQYAZLEEP-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- YWYHGNUFMPSTTR-UHFFFAOYSA-N 1-methyl-4-(4-methylphenoxy)benzene Chemical compound C1=CC(C)=CC=C1OC1=CC=C(C)C=C1 YWYHGNUFMPSTTR-UHFFFAOYSA-N 0.000 description 5
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 5
- CGARGJZZBOHMIZ-UHFFFAOYSA-N methyl 4-(4-methoxycarbonylphenoxy)benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1OC1=CC=C(C(=O)OC)C=C1 CGARGJZZBOHMIZ-UHFFFAOYSA-N 0.000 description 5
- 238000000926 separation method Methods 0.000 description 5
- AJDONJVWDSZZQF-UHFFFAOYSA-N 1-(2,4,4-trimethylpentan-2-yl)-4-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]benzene Chemical compound C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OC1=CC=C(C(C)(C)CC(C)(C)C)C=C1 AJDONJVWDSZZQF-UHFFFAOYSA-N 0.000 description 4
- KBDBBNZIVQWKGV-UHFFFAOYSA-N 1-(trifluoromethyl)-2-[2-(trifluoromethyl)phenoxy]benzene Chemical compound FC(F)(F)C1=CC=CC=C1OC1=CC=CC=C1C(F)(F)F KBDBBNZIVQWKGV-UHFFFAOYSA-N 0.000 description 4
- CBWUXOLLRSLJNU-UHFFFAOYSA-N 1-(trifluoromethyl)-3-[3-(trifluoromethyl)phenoxy]benzene Chemical compound FC(F)(F)C1=CC=CC(OC=2C=C(C=CC=2)C(F)(F)F)=C1 CBWUXOLLRSLJNU-UHFFFAOYSA-N 0.000 description 4
- WLZFDTRREUSCGR-UHFFFAOYSA-N 1-(trifluoromethyl)-4-[4-(trifluoromethyl)phenoxy]benzene Chemical compound C1=CC(C(F)(F)F)=CC=C1OC1=CC=C(C(F)(F)F)C=C1 WLZFDTRREUSCGR-UHFFFAOYSA-N 0.000 description 4
- ZGJHWJHXKZLZFC-UHFFFAOYSA-N 1-[2,4-bis(2-methylbutan-2-yl)phenoxy]-2,4-bis(2-methylbutan-2-yl)benzene Chemical compound CC(CC)(C)C1=C(C=CC(=C1)C(CC)(C)C)OC1=C(C=C(C=C1)C(CC)(C)C)C(CC)(C)C ZGJHWJHXKZLZFC-UHFFFAOYSA-N 0.000 description 4
- PLHWNVGKMDMLGU-UHFFFAOYSA-N 1-[3,5-bis(trifluoromethyl)phenoxy]-3,5-bis(trifluoromethyl)benzene Chemical compound FC(C=1C=C(C=C(C1)C(F)(F)F)OC1=CC(=CC(=C1)C(F)(F)F)C(F)(F)F)(F)F PLHWNVGKMDMLGU-UHFFFAOYSA-N 0.000 description 4
- ALSVFJIXSNRBLE-UHFFFAOYSA-N 1-bromo-3-(3-bromophenoxy)benzene Chemical compound BrC1=CC=CC(OC=2C=C(Br)C=CC=2)=C1 ALSVFJIXSNRBLE-UHFFFAOYSA-N 0.000 description 4
- YAWIAFUBXXPJMQ-UHFFFAOYSA-N 1-bromo-4-(4-bromophenoxy)benzene Chemical compound C1=CC(Br)=CC=C1OC1=CC=C(Br)C=C1 YAWIAFUBXXPJMQ-UHFFFAOYSA-N 0.000 description 4
- VHEGXFQQYZIMMF-UHFFFAOYSA-N 1-iodo-4-(4-iodophenoxy)benzene Chemical compound C1=CC(I)=CC=C1OC1=CC=C(I)C=C1 VHEGXFQQYZIMMF-UHFFFAOYSA-N 0.000 description 4
- VIOJQBMMOKZZMO-UHFFFAOYSA-N 2-(2,6-dimethylphenoxy)-1,3-dimethylbenzene Chemical compound CC1=CC=CC(C)=C1OC1=C(C)C=CC=C1C VIOJQBMMOKZZMO-UHFFFAOYSA-N 0.000 description 4
- RSAUOQFEFINEDM-UHFFFAOYSA-N 4-(4-cyanophenoxy)benzonitrile Chemical compound C1=CC(C#N)=CC=C1OC1=CC=C(C#N)C=C1 RSAUOQFEFINEDM-UHFFFAOYSA-N 0.000 description 4
- GXZZHLULZRMUQC-UHFFFAOYSA-N 4-(4-formylphenoxy)benzaldehyde Chemical compound C1=CC(C=O)=CC=C1OC1=CC=C(C=O)C=C1 GXZZHLULZRMUQC-UHFFFAOYSA-N 0.000 description 4
- YCUFSWSSTPKFHC-UHFFFAOYSA-N 4-methyl-2-(5-methyl-2-propan-2-ylphenoxy)-1-propan-2-ylbenzene Chemical compound CC(C)C1=CC=C(C)C=C1OC1=CC(C)=CC=C1C(C)C YCUFSWSSTPKFHC-UHFFFAOYSA-N 0.000 description 4
- DAVCBXCICIGLET-UHFFFAOYSA-N 6-(5,6,7,8-tetrahydronaphthalen-2-yloxy)-1,2,3,4-tetrahydronaphthalene Chemical compound C1CCCC2=CC(OC=3C=C4CCCCC4=CC=3)=CC=C21 DAVCBXCICIGLET-UHFFFAOYSA-N 0.000 description 4
- ILNMRZOJXLDNNY-UHFFFAOYSA-N 6-quinolin-6-yloxyquinoline Chemical compound N1=CC=CC2=CC(OC=3C=C4C=CC=NC4=CC=3)=CC=C21 ILNMRZOJXLDNNY-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000030833 cell death Effects 0.000 description 3
- 230000003833 cell viability Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- ZBGCFGDFVQCFOT-UHFFFAOYSA-N 1,5-ditert-butyl-2-(2,4-ditert-butyl-5-methylphenoxy)-4-methylbenzene Chemical compound C(C)(C)(C)C1=C(C=C(C(=C1)C(C)(C)C)OC1=CC(=C(C=C1C(C)(C)C)C(C)(C)C)C)C ZBGCFGDFVQCFOT-UHFFFAOYSA-N 0.000 description 2
- WTJNUOZMYRVHKU-UHFFFAOYSA-N 1-(2-phenylpropan-2-yl)-4-[4-(2-phenylpropan-2-yl)phenoxy]benzene Chemical compound C=1C=C(OC=2C=CC(=CC=2)C(C)(C)C=2C=CC=CC=2)C=CC=1C(C)(C)C1=CC=CC=C1 WTJNUOZMYRVHKU-UHFFFAOYSA-N 0.000 description 2
- GUTHFMAFQRJHLG-UHFFFAOYSA-N 1-(trifluoromethoxy)-4-[4-(trifluoromethoxy)phenoxy]benzene Chemical compound C1=CC(OC(F)(F)F)=CC=C1OC1=CC=C(OC(F)(F)F)C=C1 GUTHFMAFQRJHLG-UHFFFAOYSA-N 0.000 description 2
- OHTSCIJMYOSITC-UHFFFAOYSA-N 1-[2,4-di(propan-2-yl)phenoxy]-2,4-di(propan-2-yl)benzene Chemical compound CC(C)C1=CC(C(C)C)=CC=C1OC1=CC=C(C(C)C)C=C1C(C)C OHTSCIJMYOSITC-UHFFFAOYSA-N 0.000 description 2
- VNASEHKLANBWAG-UHFFFAOYSA-N 1-[2-[2-(1-adamantyl)-4-methylphenoxy]-5-methylphenyl]adamantane Chemical compound C12(CC3CC(CC(C1)C3)C2)C1=C(C=CC(=C1)C)OC1=C(C=C(C=C1)C)C12CC3CC(CC(C1)C3)C2 VNASEHKLANBWAG-UHFFFAOYSA-N 0.000 description 2
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- CMMGEVGTZSDNFN-UHFFFAOYSA-N CC1(OC2=C(C1)C=CC=C2OC1=CC=CC=2CC(OC=21)(C)C)C Chemical compound CC1(OC2=C(C1)C=CC=C2OC1=CC=CC=2CC(OC=21)(C)C)C CMMGEVGTZSDNFN-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- RQZMBFMQSSMQKJ-UHFFFAOYSA-N N1C(CCC2=CC(=CC=C12)OC=1C=C2CCC(NC2=CC=1)=O)=O Chemical compound N1C(CCC2=CC(=CC=C12)OC=1C=C2CCC(NC2=CC=1)=O)=O RQZMBFMQSSMQKJ-UHFFFAOYSA-N 0.000 description 2
- XTQYNKFHRKIHFA-UHFFFAOYSA-N N=1N(N=C2C=1C=CC=C2)C1=C(C=CC(=C1)CC(CC(C)C)(C)C)OC1=C(C=C(C=C1)CC(CC(C)C)(C)C)N1N=C2C(=N1)C=CC=C2 Chemical compound N=1N(N=C2C=1C=CC=C2)C1=C(C=CC(=C1)CC(CC(C)C)(C)C)OC1=C(C=C(C=C1)CC(CC(C)C)(C)C)N1N=C2C(=N1)C=CC=C2 XTQYNKFHRKIHFA-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- RFESNAMUUSDBQQ-UHFFFAOYSA-N [4-(4-benzoylphenoxy)phenyl]-phenylmethanone Chemical compound C=1C=C(OC=2C=CC(=CC=2)C(=O)C=2C=CC=CC=2)C=CC=1C(=O)C1=CC=CC=C1 RFESNAMUUSDBQQ-UHFFFAOYSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 229910052728 basic metal Inorganic materials 0.000 description 2
- 238000004166 bioassay Methods 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- BOTLEXFFFSMRLQ-UHFFFAOYSA-N cyclopentyloxycyclopentane Chemical compound C1CCCC1OC1CCCC1 BOTLEXFFFSMRLQ-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- RJSQMNBJPSWPTF-UHFFFAOYSA-N ethyl 4-(4-ethoxycarbonylphenoxy)benzoate Chemical compound C1=CC(C(=O)OCC)=CC=C1OC1=CC=C(C(=O)OCC)C=C1 RJSQMNBJPSWPTF-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- SRFOAYBAHXFDEW-UHFFFAOYSA-N methyl 2-[4-[4-(2-methoxy-2-oxoethyl)phenoxy]phenyl]acetate Chemical compound C1=CC(CC(=O)OC)=CC=C1OC1=CC=C(CC(=O)OC)C=C1 SRFOAYBAHXFDEW-UHFFFAOYSA-N 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- BUGCHAIWUSBYIZ-UHFFFAOYSA-N n-[4-(4-acetamidophenoxy)phenyl]acetamide Chemical compound C1=CC(NC(=O)C)=CC=C1OC1=CC=C(NC(C)=O)C=C1 BUGCHAIWUSBYIZ-UHFFFAOYSA-N 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- RNOJOOFUHCJCSQ-UHFFFAOYSA-N 1-(2,4-dimethylphenoxy)-2,4-dimethylbenzene Chemical compound CC1=CC(C)=CC=C1OC1=CC=C(C)C=C1C RNOJOOFUHCJCSQ-UHFFFAOYSA-N 0.000 description 1
- GZRGHDIUPMPHCB-UHFFFAOYSA-N 1-[4-(4-acetylphenoxy)phenyl]ethanone Chemical compound C1=CC(C(=O)C)=CC=C1OC1=CC=C(C(C)=O)C=C1 GZRGHDIUPMPHCB-UHFFFAOYSA-N 0.000 description 1
- LPVUODKKDACXRD-UHFFFAOYSA-N 2-[4-[4-(2-aminoethyl)phenoxy]phenyl]ethanamine Chemical compound C1=CC(CCN)=CC=C1OC1=CC=C(CCN)C=C1 LPVUODKKDACXRD-UHFFFAOYSA-N 0.000 description 1
- WVDRSXGPQWNUBN-UHFFFAOYSA-N 4-(4-carboxyphenoxy)benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1OC1=CC=C(C(O)=O)C=C1 WVDRSXGPQWNUBN-UHFFFAOYSA-N 0.000 description 1
- HLBLWEWZXPIGSM-UHFFFAOYSA-N 4-Aminophenyl ether Chemical compound C1=CC(N)=CC=C1OC1=CC=C(N)C=C1 HLBLWEWZXPIGSM-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ODPHOPZAWJIMTB-UHFFFAOYSA-N CC(C)OCCC(C)(C)Oc(cc1)ccc1C(O)=O Chemical compound CC(C)OCCC(C)(C)Oc(cc1)ccc1C(O)=O ODPHOPZAWJIMTB-UHFFFAOYSA-N 0.000 description 1
- RQUIRHCEXVKHFW-UHFFFAOYSA-N CCOCCC(C)(C)Oc(cc1)ccc1C(OC)=O Chemical compound CCOCCC(C)(C)Oc(cc1)ccc1C(OC)=O RQUIRHCEXVKHFW-UHFFFAOYSA-N 0.000 description 1
- NWVVVBRKAWDGAB-UHFFFAOYSA-N COc(cc1)ccc1O Chemical compound COc(cc1)ccc1O NWVVVBRKAWDGAB-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- UMKXSOXZAXIOPJ-UHFFFAOYSA-N Oc1cc(CCCC2)c2cc1 Chemical compound Oc1cc(CCCC2)c2cc1 UMKXSOXZAXIOPJ-UHFFFAOYSA-N 0.000 description 1
- 208000002495 Uterine Neoplasms Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 238000011481 absorbance measurement Methods 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000005018 aryl alkenyl group Chemical group 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 125000006269 biphenyl-2-yl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C1=C(*)C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical compound [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 description 1
- 229910000103 lithium hydride Inorganic materials 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 230000002438 mitochondrial effect Effects 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- YZUUTMGDONTGTN-UHFFFAOYSA-N nonaethylene glycol Chemical compound OCCOCCOCCOCCOCCOCCOCCOCCOCCO YZUUTMGDONTGTN-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 229910021642 ultra pure water Inorganic materials 0.000 description 1
- 239000012498 ultrapure water Substances 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 206010046766 uterine cancer Diseases 0.000 description 1
Landscapes
- Other In-Based Heterocyclic Compounds (AREA)
- Steroid Compounds (AREA)
- Polyethers (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
- Quinoline Compounds (AREA)
- Furan Compounds (AREA)
- Pyridine Compounds (AREA)
- Pyrane Compounds (AREA)
- Indole Compounds (AREA)
Abstract
Description
上記(1)の化合物の製造は、以下の式(2)の化合物を中間体として効率良く製造することができる。
この中間体化合物は、下記式(3):
で表されるポリエチレングリコール化合物の、一方の水酸基のみをパラトルエンスルホニルエステル化することにより得ることができる。
Nonaethylene glycol mono(p-toluenesulfonyl) ester (5)
<7aq からの合成>
<9m' からの合成>
1H-NMR(CDCl3)δ: 2.60 (2H, m), 2.92 (3H, m), 3.58-3.73 (33H, br), 3.83 (2H, t, J=4.9 Hz), 4.09 (2H, t, J=4.9 Hz), 6.65 (1H, d, J=8.5 Hz), 6.74 (2H, m)。
細胞レべルでのバイオアッセイ
MTT法を用いて腫瘍細胞に対する細胞毒性の計測を行った。MTT法は比触法の一種である。MTT試薬[3-(4,5-Dimethylthioazol-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide]は生細胞中のミトコンドリア内脱水素酵素により、不溶性のMTT formazan (暗青色)に変換される。このMTT formaznの生成量を測定し、相対的な細胞の生存率として表す。
1.細胞の前培養:初発細胞密度が2×104 cells/cm2となるように調整したHela細胞(子宮ガン由来)懸濁液を、50μ1ずつ96 well培養ブレートの各wellに分注した。CO2インキュベーター(37℃で、CO2濃度5 %)を用いて24時問培養した。
2.検定化合物の溶解:超純水に333μg/mlとなるよう溶解した。難溶で白濁するものに関しては、マグネチックスターラーによる撹拌を2時間以上継続することをもって溶解作業が終了したものとみなした。等量の2倍濃度細胞培養液と混合した後、クリーンべンチ内で濾過滅菌と同時に48 well培養ブレートに分注した。
3.検定化合物の希釈系列の作製:クリーンべンチ内で、48well培養プレートを用いて無菌的に、5倍希釈による濃度系列を作製した。細胞毒性活性の強さに応じて以下の2種類の濃度範囲のものを準備した。
1) 100、20、4、0.8およびO(ppm)(本培養時の最終濃度)
2) 4、0.8、0.16、0.032およびO(ppm)(本培養時の最終濃度)
4.本培養:所定濃度の検定化合物を含む培養液75μlを各wellに添加して本培養を開始した(培養液の全俄は125μlとなるため、検定化合物の濃度は60%に希釈される。すなわち、333μg/ml(検定化合物溶解時)→166.5 μg/ml(2倍濃度培養液との混合時)→ 99.9μg/ml(本培養開始時))。培養期間は3日間とした。
5.MTT反応:本培養終了後の培養プレートの各wellに0.5%MTT試薬を12.5μl添加し、C02インキュべーター内に4時間放置した。イソプロパノールに溶解した0.04N HClを各wellに137.5μ1加えて反応を停止させた後、青い粒子が溶けるまで十分にピペッティングを行った。
6.吸光度の測定:プレートリーダーにより570nm(peak)と630nm(bottom)における吸収光度差を測定した。
7.細胞生存率の算出:0ppm 作用区(生存率100%)における値に対する相対値を算出し、当該濃度作用区における細胞生存率(%)とした。なお、この値がマイナスになる場合は一律細胞生存率0%とみなした。
細胞レベルでのバイオアッセイにより得られた結果を以下に示す。表上に試験された化合物番号を記載している。また、PEG9は化合物2である。
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