JP4861340B2 - カンプトセシンサブユニットの新規の合成法 - Google Patents
カンプトセシンサブユニットの新規の合成法 Download PDFInfo
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- JP4861340B2 JP4861340B2 JP2007555511A JP2007555511A JP4861340B2 JP 4861340 B2 JP4861340 B2 JP 4861340B2 JP 2007555511 A JP2007555511 A JP 2007555511A JP 2007555511 A JP2007555511 A JP 2007555511A JP 4861340 B2 JP4861340 B2 JP 4861340B2
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- compound
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- alkyl
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- 230000015572 biosynthetic process Effects 0.000 title description 27
- 238000003786 synthesis reaction Methods 0.000 title description 25
- 229940127093 camptothecin Drugs 0.000 title description 8
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 title description 6
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 title description 4
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 203
- 238000000034 method Methods 0.000 claims abstract description 64
- 230000008569 process Effects 0.000 claims abstract description 31
- 238000006243 chemical reaction Methods 0.000 claims description 106
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 18
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 14
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 14
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 14
- -1 (C 1 -C 6) - alkyl formamide Chemical compound 0.000 claims description 12
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 12
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 12
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 claims description 12
- 150000001340 alkali metals Chemical class 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 150000001412 amines Chemical class 0.000 claims description 8
- 239000002585 base Substances 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 8
- 150000003512 tertiary amines Chemical class 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 229910000272 alkali metal oxide Inorganic materials 0.000 claims description 6
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 claims description 6
- WUOIAOOSKMHJOV-UHFFFAOYSA-N ethyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(CC)C1=CC=CC=C1 WUOIAOOSKMHJOV-UHFFFAOYSA-N 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 6
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 claims description 6
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 6
- 235000011056 potassium acetate Nutrition 0.000 claims description 6
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 6
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 claims description 5
- 239000005695 Ammonium acetate Substances 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 235000019257 ammonium acetate Nutrition 0.000 claims description 5
- 229940043376 ammonium acetate Drugs 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 229910052761 rare earth metal Inorganic materials 0.000 claims description 5
- 150000003333 secondary alcohols Chemical class 0.000 claims description 5
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 4
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 238000007257 deesterification reaction Methods 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 3
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 3
- 239000011707 mineral Substances 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 229940126062 Compound A Drugs 0.000 claims 1
- 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 claims 1
- 150000001721 carbon Chemical group 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000002246 antineoplastic agent Substances 0.000 abstract description 2
- FBDOJYYTMIHHDH-OZBJMMHXSA-N (19S)-19-ethyl-19-hydroxy-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-2,4,6,8,10,14,20-heptaen-18-one Chemical compound CC[C@@]1(O)C(=O)OCC2=CN3Cc4cc5ccccc5nc4C3C=C12 FBDOJYYTMIHHDH-OZBJMMHXSA-N 0.000 abstract 1
- 229940041181 antineoplastic drug Drugs 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 66
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 31
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
- 239000000243 solution Substances 0.000 description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 20
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 19
- 239000012043 crude product Substances 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 0 CC1C(*(C23CCC2)C3=C)[C@@]2C1C(C1)C1CC2 Chemical compound CC1C(*(C23CCC2)C3=C)[C@@]2C1C(C1)C1CC2 0.000 description 15
- 239000000203 mixture Substances 0.000 description 15
- 239000007788 liquid Substances 0.000 description 13
- 239000012074 organic phase Substances 0.000 description 13
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 11
- 239000002904 solvent Substances 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
- 229910052938 sodium sulfate Inorganic materials 0.000 description 10
- 235000011152 sodium sulphate Nutrition 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- AIYUHDOJVYHVIT-UHFFFAOYSA-M caesium chloride Chemical compound [Cl-].[Cs+] AIYUHDOJVYHVIT-UHFFFAOYSA-M 0.000 description 8
- 238000001704 evaporation Methods 0.000 description 8
- 230000008020 evaporation Effects 0.000 description 8
- 239000012065 filter cake Substances 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- 239000012267 brine Substances 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- TYEYBOSBBBHJIV-UHFFFAOYSA-N 2-oxobutanoic acid Chemical compound CCC(=O)C(O)=O TYEYBOSBBBHJIV-UHFFFAOYSA-N 0.000 description 6
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 229910000033 sodium borohydride Inorganic materials 0.000 description 6
- 239000012279 sodium borohydride Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- ZBWSLOOYZRVFJS-VAWYXSNFSA-N ethyl 5-(diethylcarbamoyl)-4-[(e)-2-(dimethylamino)ethenyl]-5-ethyl-2-oxofuran-3-carboxylate Chemical compound CCOC(=O)C1=C(\C=C\N(C)C)C(CC)(C(=O)N(CC)CC)OC1=O ZBWSLOOYZRVFJS-VAWYXSNFSA-N 0.000 description 5
- IGAVZHVZWYCSIJ-UHFFFAOYSA-N ethyl 5-(diethylcarbamoyl)-5-ethyl-4-methyl-2-oxofuran-3-carboxylate Chemical compound CCOC(=O)C1=C(C)C(CC)(C(=O)N(CC)CC)OC1=O IGAVZHVZWYCSIJ-UHFFFAOYSA-N 0.000 description 5
- JKJMVMKRTBCHAL-UHFFFAOYSA-N n,n-diethyl-2-oxobutanamide Chemical compound CCN(CC)C(=O)C(=O)CC JKJMVMKRTBCHAL-UHFFFAOYSA-N 0.000 description 5
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 5
- 238000001665 trituration Methods 0.000 description 5
- WTQIZFCJMGWUGZ-BPLDGKMQSA-N (1r,2s,5r)-5-methyl-2-(2-phenylpropan-2-yl)cyclohexan-1-ol Chemical compound O[C@@H]1C[C@H](C)CC[C@H]1C(C)(C)C1=CC=CC=C1 WTQIZFCJMGWUGZ-BPLDGKMQSA-N 0.000 description 4
- CXEZODQMCZFRBQ-UHFFFAOYSA-N 2-ethyl-2-hydroxy-3-methylbut-3-enoic acid Chemical compound CCC(O)(C(C)=C)C(O)=O CXEZODQMCZFRBQ-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- GVFRRCOZHJYDBB-UWWQBHOKSA-N C[C@@H]1CC[C@@H]([C@@H](C1)OC(C(CC)=O)=O)C(C)(C1=CC=CC=C1)C Chemical compound C[C@@H]1CC[C@@H]([C@@H](C1)OC(C(CC)=O)=O)C(C)(C1=CC=CC=C1)C GVFRRCOZHJYDBB-UWWQBHOKSA-N 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- VABKVSWGYZESTA-UHFFFAOYSA-N ethyl 2-(diethylamino)-2-oxoacetate Chemical compound CCOC(=O)C(=O)N(CC)CC VABKVSWGYZESTA-UHFFFAOYSA-N 0.000 description 4
- VMXAJQSUXCNZCE-UHFFFAOYSA-N n,n,2-triethyl-2-hydroxy-3-methylpent-3-enamide Chemical compound CCN(CC)C(=O)C(O)(CC)C(C)=CC VMXAJQSUXCNZCE-UHFFFAOYSA-N 0.000 description 4
- MUMVIYLVHVCYGI-UHFFFAOYSA-N n,n,n',n',n",n"-hexamethylmethanetriamine Chemical compound CN(C)C(N(C)C)N(C)C MUMVIYLVHVCYGI-UHFFFAOYSA-N 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 238000010189 synthetic method Methods 0.000 description 4
- WVTNJFMVURJIGD-AWEZNQCLSA-N (1s)-n,n,1-triethyl-3,4-dioxo-5h-furo[3,4-c]pyridine-1-carboxamide Chemical compound C1=CNC(=O)C2=C1[C@](C(=O)N(CC)CC)(CC)OC2=O WVTNJFMVURJIGD-AWEZNQCLSA-N 0.000 description 3
- LSRZMXGDMKOLSM-NSHDSACASA-N (2s)-n,n,2-triethyl-2-hydroxy-3-methylbut-3-enamide Chemical compound CCN(CC)C(=O)[C@](O)(CC)C(C)=C LSRZMXGDMKOLSM-NSHDSACASA-N 0.000 description 3
- VSJKWCGYPAHWDS-HXUWFJFHSA-N (r)-camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-HXUWFJFHSA-N 0.000 description 3
- BUXBOOPDBDMDFZ-UHFFFAOYSA-N 4-ethyl-4-hydroxy-1,7-dihydropyrano[3,4-c]pyridine-3,8-dione Chemical compound C1=CNC(=O)C2=C1C(CC)(O)C(=O)OC2 BUXBOOPDBDMDFZ-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- YTAHJIFKAKIKAV-XNMGPUDCSA-N [(1R)-3-morpholin-4-yl-1-phenylpropyl] N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]carbamate Chemical compound O=C1[C@H](N=C(C2=C(N1)C=CC=C2)C1=CC=CC=C1)NC(O[C@H](CCN1CCOCC1)C1=CC=CC=C1)=O YTAHJIFKAKIKAV-XNMGPUDCSA-N 0.000 description 3
- 150000001335 aliphatic alkanes Chemical class 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 3
- ZBWSLOOYZRVFJS-DXRVJIQQSA-N ethyl (5s)-5-(diethylcarbamoyl)-4-[(e)-2-(dimethylamino)ethenyl]-5-ethyl-2-oxofuran-3-carboxylate Chemical compound CCOC(=O)C1=C(\C=C\N(C)C)[C@@](CC)(C(=O)N(CC)CC)OC1=O ZBWSLOOYZRVFJS-DXRVJIQQSA-N 0.000 description 3
- IGAVZHVZWYCSIJ-HNNXBMFYSA-N ethyl (5s)-5-(diethylcarbamoyl)-5-ethyl-4-methyl-2-oxofuran-3-carboxylate Chemical compound CCOC(=O)C1=C(C)[C@@](CC)(C(=O)N(CC)CC)OC1=O IGAVZHVZWYCSIJ-HNNXBMFYSA-N 0.000 description 3
- 125000002950 monocyclic group Chemical group 0.000 description 3
- WVTNJFMVURJIGD-UHFFFAOYSA-N n,n,1-triethyl-3,4-dioxo-5h-furo[3,4-c]pyridine-1-carboxamide Chemical compound C1=CNC(=O)C2=C1C(C(=O)N(CC)CC)(CC)OC2=O WVTNJFMVURJIGD-UHFFFAOYSA-N 0.000 description 3
- YHRIAQMZHPYZSF-UHFFFAOYSA-N n,n-diethyl-2-hydroxy-2-[3-(hydroxymethyl)-2-oxo-1h-pyridin-4-yl]butanamide Chemical compound CCN(CC)C(=O)C(O)(CC)C=1C=CNC(=O)C=1CO YHRIAQMZHPYZSF-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- YHRIAQMZHPYZSF-AWEZNQCLSA-N (2s)-n,n-diethyl-2-hydroxy-2-[3-(hydroxymethyl)-2-oxo-1h-pyridin-4-yl]butanamide Chemical compound CCN(CC)C(=O)[C@](O)(CC)C=1C=CNC(=O)C=1CO YHRIAQMZHPYZSF-AWEZNQCLSA-N 0.000 description 2
- BUXBOOPDBDMDFZ-JTQLQIEISA-N (4s)-4-ethyl-4-hydroxy-1,7-dihydropyrano[3,4-c]pyridine-3,8-dione Chemical compound C1=CNC(=O)C2=C1[C@](CC)(O)C(=O)OC2 BUXBOOPDBDMDFZ-JTQLQIEISA-N 0.000 description 2
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 2
- GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 2
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 239000007818 Grignard reagent Substances 0.000 description 2
- 238000000023 Kugelrohr distillation Methods 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 235000019502 Orange oil Nutrition 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229910000288 alkali metal carbonate Inorganic materials 0.000 description 2
- 150000008041 alkali metal carbonates Chemical class 0.000 description 2
- 229910000102 alkali metal hydride Inorganic materials 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 239000003849 aromatic solvent Substances 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
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- 230000008025 crystallization Effects 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
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- 150000004795 grignard reagents Chemical class 0.000 description 2
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- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000004678 hydrides Chemical class 0.000 description 2
- 150000002596 lactones Chemical class 0.000 description 2
- FRIJBUGBVQZNTB-UHFFFAOYSA-M magnesium;ethane;bromide Chemical compound [Mg+2].[Br-].[CH2-]C FRIJBUGBVQZNTB-UHFFFAOYSA-M 0.000 description 2
- UZNGRHDUJIVHQT-UHFFFAOYSA-M magnesium;prop-1-ene;bromide Chemical compound [Mg+2].[Br-].C[C-]=C UZNGRHDUJIVHQT-UHFFFAOYSA-M 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000010502 orange oil Substances 0.000 description 2
- 150000002902 organometallic compounds Chemical class 0.000 description 2
- 238000005949 ozonolysis reaction Methods 0.000 description 2
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- 239000003495 polar organic solvent Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
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- 150000003839 salts Chemical class 0.000 description 2
- 229930195734 saturated hydrocarbon Natural products 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- OBKXEAXTFZPCHS-UHFFFAOYSA-N 4-phenylbutyric acid Chemical compound OC(=O)CCCC1=CC=CC=C1 OBKXEAXTFZPCHS-UHFFFAOYSA-N 0.000 description 1
- 229910017073 AlLi Inorganic materials 0.000 description 1
- 244000005894 Albizia lebbeck Species 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- KEJGAYKWRDILTF-WYCDGMCDSA-N CC(C)(OC1)O[C@@H]1[C@@H]1O[C@H]2OC(C)(C)O[C@H]2[C@H]1O Chemical compound CC(C)(OC1)O[C@@H]1[C@@H]1O[C@H]2OC(C)(C)O[C@H]2[C@H]1O KEJGAYKWRDILTF-WYCDGMCDSA-N 0.000 description 1
- KEJGAYKWRDILTF-VVULQXIFSA-N CC(C)(OC1)O[C@H]1[C@H]1O[C@@H]2OC(C)(C)O[C@@H]2[C@@H]1O Chemical compound CC(C)(OC1)O[C@H]1[C@H]1O[C@@H]2OC(C)(C)O[C@@H]2[C@@H]1O KEJGAYKWRDILTF-VVULQXIFSA-N 0.000 description 1
- NOOLISFMXDJSKH-KXUCPTDWSA-N CC(C)[C@H](CC[C@@H](C)C1)[C@@H]1O Chemical compound CC(C)[C@H](CC[C@@H](C)C1)[C@@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 1
- DAJHQXANOCVDMM-LHAVAQOQSA-N CCC/C=C/N(C=N1)c2c(CN(C3=CC([C@@]4(CC)O)=C5COC4=O)C5=O)c3nc3c2c1ccc3 Chemical compound CCC/C=C/N(C=N1)c2c(CN(C3=CC([C@@]4(CC)O)=C5COC4=O)C5=O)c3nc3c2c1ccc3 DAJHQXANOCVDMM-LHAVAQOQSA-N 0.000 description 1
- NPAAFPODGAKMTC-SANMLTNESA-N CCCCCN(C=N1)c2c(CN(C3=CC([C@]4(CC)O)=C5COC4=O)C5=O)c3nc3c2c1ccc3 Chemical compound CCCCCN(C=N1)c2c(CN(C3=CC([C@]4(CC)O)=C5COC4=O)C5=O)c3nc3c2c1ccc3 NPAAFPODGAKMTC-SANMLTNESA-N 0.000 description 1
- XBVLMZYIQGVMKW-CIUDSAMLSA-N CC[C@@H](CC[C@H](C)C1)[C@H]1O Chemical compound CC[C@@H](CC[C@H](C)C1)[C@H]1O XBVLMZYIQGVMKW-CIUDSAMLSA-N 0.000 description 1
- BUXBOOPDBDMDFZ-SNVBAGLBSA-N CC[C@@](C(C=CN1)=C(CO2)C1=O)(C2=O)O Chemical compound CC[C@@](C(C=CN1)=C(CO2)C1=O)(C2=O)O BUXBOOPDBDMDFZ-SNVBAGLBSA-N 0.000 description 1
- 241000759909 Camptotheca Species 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- IYXGSMUGOJNHAZ-UHFFFAOYSA-N Ethyl malonate Chemical compound CCOC(=O)CC(=O)OCC IYXGSMUGOJNHAZ-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 238000006000 Knoevenagel condensation reaction Methods 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- SUAKHGWARZSWIH-UHFFFAOYSA-N N,N‐diethylformamide Chemical compound CCN(CC)C=O SUAKHGWARZSWIH-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- OZBWYRJUQQZAEG-CFKGEZKQSA-N [(1r,2s,5r)-5-methyl-2-(2-phenylpropan-2-yl)cyclohexyl] (2s)-2-ethyl-2-hydroxy-3-methylbut-3-enoate Chemical compound CC[C@](O)(C(C)=C)C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)(C)C1=CC=CC=C1 OZBWYRJUQQZAEG-CFKGEZKQSA-N 0.000 description 1
- 150000001241 acetals Chemical class 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 238000007259 addition reaction Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 238000010640 amide synthesis reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000000538 analytical sample Substances 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 1
- 229910001863 barium hydroxide Inorganic materials 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- TVFDJXOCXUVLDH-UHFFFAOYSA-N caesium atom Chemical compound [Cs] TVFDJXOCXUVLDH-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000007942 carboxylates Chemical group 0.000 description 1
- 238000011944 chemoselective reduction Methods 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 1
- HDITUCONWLWUJR-UHFFFAOYSA-N diethylazanium;chloride Chemical compound [Cl-].CC[NH2+]CC HDITUCONWLWUJR-UHFFFAOYSA-N 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 150000002081 enamines Chemical class 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000383 hazardous chemical Substances 0.000 description 1
- 231100000206 health hazard Toxicity 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000007273 lactonization reaction Methods 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- QBZXOWQOWPHHRA-UHFFFAOYSA-N lithium;ethane Chemical compound [Li+].[CH2-]C QBZXOWQOWPHHRA-UHFFFAOYSA-N 0.000 description 1
- 229910001623 magnesium bromide Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- FGYXQBPXHQHYNU-UHFFFAOYSA-M magnesium;but-2-ene;bromide Chemical compound [Mg+2].[Br-].CC=[C-]C FGYXQBPXHQHYNU-UHFFFAOYSA-M 0.000 description 1
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 1
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- AHLBNYSZXLDEJQ-FWEHEUNISA-N orlistat Chemical compound CCCCCCCCCCC[C@H](OC(=O)[C@H](CC(C)C)NC=O)C[C@@H]1OC(=O)[C@H]1CCCCCC AHLBNYSZXLDEJQ-FWEHEUNISA-N 0.000 description 1
- 229950009215 phenylbutanoic acid Drugs 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 125000002943 quinolinyl group Chemical class N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 150000002910 rare earth metals Chemical class 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000006894 reductive elimination reaction Methods 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 239000007966 viscous suspension Substances 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 150000004799 α-ketoamides Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP05101338.1 | 2005-02-22 | ||
| EP05101338 | 2005-02-22 | ||
| PCT/EP2006/001306 WO2006089657A1 (en) | 2005-02-22 | 2006-02-14 | New synthesis of a camptothecin subunit |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2008531487A JP2008531487A (ja) | 2008-08-14 |
| JP2008531487A5 JP2008531487A5 (enExample) | 2011-03-17 |
| JP4861340B2 true JP4861340B2 (ja) | 2012-01-25 |
Family
ID=36177738
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2007555511A Expired - Fee Related JP4861340B2 (ja) | 2005-02-22 | 2006-02-14 | カンプトセシンサブユニットの新規の合成法 |
Country Status (11)
| Country | Link |
|---|---|
| US (1) | US7423152B2 (enExample) |
| EP (1) | EP1856124B1 (enExample) |
| JP (1) | JP4861340B2 (enExample) |
| KR (1) | KR100916175B1 (enExample) |
| CN (1) | CN101128467B (enExample) |
| AT (1) | ATE531719T1 (enExample) |
| CA (1) | CA2597388A1 (enExample) |
| IL (1) | IL185015A (enExample) |
| MX (1) | MX2007010033A (enExample) |
| TW (1) | TWI314932B (enExample) |
| WO (1) | WO2006089657A1 (enExample) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7632540B2 (en) * | 2003-07-01 | 2009-12-15 | Transitions Optical, Inc. | Alignment facilities for optical dyes |
| CN104277144A (zh) * | 2008-07-31 | 2015-01-14 | 卢布里佐尔公司 | 共聚物及其润滑组合物 |
| CN101544651B (zh) * | 2009-04-24 | 2011-11-02 | 华东师范大学 | 多取代吡啶酮化合物的合成方法 |
| CN101591342B (zh) * | 2009-07-03 | 2011-07-27 | 华东师范大学 | 用于喜树碱类化合物制备的关键中间体合成方法 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5162532A (en) * | 1990-12-20 | 1992-11-10 | North Carolina State University | Intermediates and method of making camptothecin and camptothecin analogs |
| US5491237A (en) * | 1994-05-03 | 1996-02-13 | Glaxo Wellcome Inc. | Intermediates in pharmaceutical camptothecin preparation |
-
2006
- 2006-02-14 MX MX2007010033A patent/MX2007010033A/es active IP Right Grant
- 2006-02-14 KR KR1020077019083A patent/KR100916175B1/ko not_active Expired - Fee Related
- 2006-02-14 JP JP2007555511A patent/JP4861340B2/ja not_active Expired - Fee Related
- 2006-02-14 WO PCT/EP2006/001306 patent/WO2006089657A1/en not_active Ceased
- 2006-02-14 EP EP06706913A patent/EP1856124B1/en not_active Not-in-force
- 2006-02-14 AT AT06706913T patent/ATE531719T1/de active
- 2006-02-14 CN CN2006800056195A patent/CN101128467B/zh not_active Expired - Fee Related
- 2006-02-14 CA CA002597388A patent/CA2597388A1/en not_active Abandoned
- 2006-02-17 US US11/357,273 patent/US7423152B2/en not_active Expired - Fee Related
- 2006-02-20 TW TW095105638A patent/TWI314932B/zh not_active IP Right Cessation
-
2007
- 2007-08-02 IL IL185015A patent/IL185015A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| CN101128467A (zh) | 2008-02-20 |
| EP1856124B1 (en) | 2011-11-02 |
| US20060189807A1 (en) | 2006-08-24 |
| WO2006089657A1 (en) | 2006-08-31 |
| JP2008531487A (ja) | 2008-08-14 |
| TW200640935A (en) | 2006-12-01 |
| IL185015A (en) | 2012-07-31 |
| KR20070104424A (ko) | 2007-10-25 |
| ATE531719T1 (de) | 2011-11-15 |
| MX2007010033A (es) | 2007-10-04 |
| TWI314932B (en) | 2009-09-21 |
| KR100916175B1 (ko) | 2009-09-08 |
| CA2597388A1 (en) | 2006-08-31 |
| EP1856124A1 (en) | 2007-11-21 |
| IL185015A0 (en) | 2007-12-03 |
| US7423152B2 (en) | 2008-09-09 |
| CN101128467B (zh) | 2010-12-22 |
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