NO325345B1 - Fremgangsmate for fremstilling av ecteinascidin 770 og ecteinascidin 743, mellomprodukter for anvendelse ved fremgangsmaten, samt fremgangsmate for fremstilling av mellomproduktene - Google Patents
Fremgangsmate for fremstilling av ecteinascidin 770 og ecteinascidin 743, mellomprodukter for anvendelse ved fremgangsmaten, samt fremgangsmate for fremstilling av mellomproduktene Download PDFInfo
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- NO325345B1 NO325345B1 NO19991301A NO991301A NO325345B1 NO 325345 B1 NO325345 B1 NO 325345B1 NO 19991301 A NO19991301 A NO 19991301A NO 991301 A NO991301 A NO 991301A NO 325345 B1 NO325345 B1 NO 325345B1
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- compound
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- following structure
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- 238000000034 method Methods 0.000 title claims abstract description 19
- PKVRCIRHQMSYJX-AIFWHQITSA-N trabectedin Chemical compound C([C@@]1(C(OC2)=O)NCCC3=C1C=C(C(=C3)O)OC)S[C@@H]1C3=C(OC(C)=O)C(C)=C4OCOC4=C3[C@H]2N2[C@@H](O)[C@H](CC=3C4=C(O)C(OC)=C(C)C=3)N(C)[C@H]4[C@@H]21 PKVRCIRHQMSYJX-AIFWHQITSA-N 0.000 title claims abstract description 16
- 229960000977 trabectedin Drugs 0.000 title claims abstract description 13
- XXPXYPLPSDPERN-UHFFFAOYSA-N Ecteinascidin 743 Natural products COc1cc2C(NCCc2cc1O)C(=O)OCC3N4C(O)C5Cc6cc(C)c(OC)c(O)c6C(C4C(S)c7c(OC(=O)C)c(C)c8OCOc8c37)N5C XXPXYPLPSDPERN-UHFFFAOYSA-N 0.000 title claims abstract description 12
- YMAUZYADYYYPHZ-UHFFFAOYSA-N Ecteinascidin 770 Natural products COc1cc2C(NCCc2cc1O)C(=O)OCC3N4C(C#N)C5Cc6cc(C)c(OC)c(O)c6C(C4C(S)c7c(OC(=O)C)c(C)c8OCOc8c37)N5C YMAUZYADYYYPHZ-UHFFFAOYSA-N 0.000 title claims description 8
- BGFXHQYUWCGGLL-QWIBJBKUSA-N ecteinascidin 770 Chemical compound C([C@@]1(C(OC2)=O)NCCC3=C1C=C(C(=C3)O)OC)S[C@@H]1C3=C(OC(C)=O)C(C)=C4OCOC4=C3[C@H]2N2[C@@H](C#N)[C@H](CC=3C4=C(O)C(OC)=C(C)C=3)N(C)[C@H]4[C@@H]21 BGFXHQYUWCGGLL-QWIBJBKUSA-N 0.000 title claims description 8
- 239000000543 intermediate Substances 0.000 title abstract 3
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims description 63
- 239000000203 mixture Substances 0.000 claims description 40
- -1 (3-unsaturated malonic acid ester Chemical class 0.000 claims description 28
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 15
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 13
- 150000001299 aldehydes Chemical class 0.000 claims description 11
- 239000002808 molecular sieve Substances 0.000 claims description 11
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 11
- 239000003153 chemical reaction reagent Substances 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 claims description 6
- LGRLWUINFJPLSH-UHFFFAOYSA-N methanide Chemical compound [CH3-] LGRLWUINFJPLSH-UHFFFAOYSA-N 0.000 claims description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium on carbon Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 5
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 5
- 238000005828 desilylation reaction Methods 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- NSPJNIDYTSSIIY-UHFFFAOYSA-N methoxy(methoxymethoxy)methane Chemical compound COCOCOC NSPJNIDYTSSIIY-UHFFFAOYSA-N 0.000 claims description 5
- 230000002829 reductive effect Effects 0.000 claims description 5
- PBVZQAXFSQKDKK-UHFFFAOYSA-N 3-Methoxy-3-oxopropanoic acid Chemical compound COC(=O)CC(O)=O PBVZQAXFSQKDKK-UHFFFAOYSA-N 0.000 claims description 4
- 238000006969 Curtius rearrangement reaction Methods 0.000 claims description 4
- 239000013067 intermediate product Substances 0.000 claims description 4
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 4
- 230000003647 oxidation Effects 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 3
- WJXQFVMTIGJBFX-UHFFFAOYSA-N 4-methoxytyramine Chemical compound COC1=CC=C(CCN)C=C1O WJXQFVMTIGJBFX-UHFFFAOYSA-N 0.000 claims description 3
- FTUOOHMRWMKTAD-UHFFFAOYSA-N 7-methyl-6-phenylmethoxy-1,3-benzodioxole-5-carbaldehyde Chemical compound CC1=C2OCOC2=CC(C=O)=C1OCC1=CC=CC=C1 FTUOOHMRWMKTAD-UHFFFAOYSA-N 0.000 claims description 3
- 238000005798 acetal elimination reaction Methods 0.000 claims description 3
- 238000005937 allylation reaction Methods 0.000 claims description 3
- 235000001014 amino acid Nutrition 0.000 claims description 3
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 3
- 235000018417 cysteine Nutrition 0.000 claims description 3
- 238000007275 deallylation reaction Methods 0.000 claims description 3
- 238000007257 deesterification reaction Methods 0.000 claims description 3
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 3
- 230000033444 hydroxylation Effects 0.000 claims description 3
- 238000005805 hydroxylation reaction Methods 0.000 claims description 3
- 238000011065 in-situ storage Methods 0.000 claims description 3
- 238000002955 isolation Methods 0.000 claims description 3
- 238000007069 methylation reaction Methods 0.000 claims description 3
- 238000006884 silylation reaction Methods 0.000 claims description 3
- 238000005891 transamination reaction Methods 0.000 claims description 3
- HYHGLTGCHQJAIK-UHFFFAOYSA-N 3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-4-methoxybenzaldehyde Chemical compound COC1=C(O[Si](C)(C)C(C)(C)C)C=C(C=O)C=C1O[Si](C)(C)C(C)(C)C HYHGLTGCHQJAIK-UHFFFAOYSA-N 0.000 claims description 2
- 230000006378 damage Effects 0.000 claims description 2
- 239000012948 isocyanate Substances 0.000 claims description 2
- 150000002513 isocyanates Chemical class 0.000 claims description 2
- 150000002989 phenols Chemical class 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- SPXSEZMVRJLHQG-XMMPIXPASA-N [(2R)-1-[[4-[(3-phenylmethoxyphenoxy)methyl]phenyl]methyl]pyrrolidin-2-yl]methanol Chemical compound C(C1=CC=CC=C1)OC=1C=C(OCC2=CC=C(CN3[C@H](CCC3)CO)C=C2)C=CC=1 SPXSEZMVRJLHQG-XMMPIXPASA-N 0.000 claims 3
- 229940127271 compound 49 Drugs 0.000 claims 3
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 claims 1
- OVSKIKFHRZPJSS-UHFFFAOYSA-N 2,4-D Chemical compound OC(=O)COC1=CC=C(Cl)C=C1Cl OVSKIKFHRZPJSS-UHFFFAOYSA-N 0.000 claims 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims 1
- 125000000686 lactone group Chemical group 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 239000002246 antineoplastic agent Substances 0.000 abstract description 2
- 230000003389 potentiating effect Effects 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 249
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 158
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 148
- 239000000243 solution Substances 0.000 description 107
- 235000019439 ethyl acetate Nutrition 0.000 description 83
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 53
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 34
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 34
- 238000003818 flash chromatography Methods 0.000 description 31
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- 239000011541 reaction mixture Substances 0.000 description 30
- 229920006395 saturated elastomer Polymers 0.000 description 28
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- 238000005160 1H NMR spectroscopy Methods 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- 101150041968 CDC13 gene Proteins 0.000 description 23
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 23
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 23
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 23
- 229910052938 sodium sulfate Inorganic materials 0.000 description 23
- 235000011152 sodium sulphate Nutrition 0.000 description 23
- 239000000725 suspension Substances 0.000 description 23
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 239000012044 organic layer Substances 0.000 description 20
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 17
- 238000010828 elution Methods 0.000 description 17
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 17
- 238000005481 NMR spectroscopy Methods 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- 235000017557 sodium bicarbonate Nutrition 0.000 description 15
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 15
- 229910001868 water Inorganic materials 0.000 description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- YMWUJEATGCHHMB-DICFDUPASA-N dichloromethane-d2 Chemical compound [2H]C([2H])(Cl)Cl YMWUJEATGCHHMB-DICFDUPASA-N 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 229960000583 acetic acid Drugs 0.000 description 11
- 239000011780 sodium chloride Substances 0.000 description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 10
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 10
- 239000010410 layer Substances 0.000 description 10
- 239000000047 product Substances 0.000 description 9
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- 101100109871 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) aro-8 gene Proteins 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 7
- AZQWKYJCGOJGHM-UHFFFAOYSA-N 1,4-benzoquinone Chemical compound O=C1C=CC(=O)C=C1 AZQWKYJCGOJGHM-UHFFFAOYSA-N 0.000 description 6
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-dimethylaminophenol Chemical compound CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 5
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 5
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 5
- 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 5
- NYPNCQTUZYWFGG-UHFFFAOYSA-N 2,2-dimethoxyethanol Chemical compound COC(CO)OC NYPNCQTUZYWFGG-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- 229910004373 HOAc Inorganic materials 0.000 description 4
- 238000003776 cleavage reaction Methods 0.000 description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 230000007017 scission Effects 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-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
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 3
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- 239000001257 hydrogen Substances 0.000 description 3
- 150000002596 lactones Chemical group 0.000 description 3
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 230000000707 stereoselective effect Effects 0.000 description 3
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
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- DIOHEXPTUTVCNX-UHFFFAOYSA-N 1,1,1-trifluoro-n-phenyl-n-(trifluoromethylsulfonyl)methanesulfonamide Chemical compound FC(F)(F)S(=O)(=O)N(S(=O)(=O)C(F)(F)F)C1=CC=CC=C1 DIOHEXPTUTVCNX-UHFFFAOYSA-N 0.000 description 2
- ATVJXMYDOSMEPO-UHFFFAOYSA-N 3-prop-2-enoxyprop-1-ene Chemical compound C=CCOCC=C ATVJXMYDOSMEPO-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 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
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 2
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 125000005219 aminonitrile group Chemical group 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 2
- JAMFGQBENKSWOF-UHFFFAOYSA-N bromo(methoxy)methane Chemical compound COCBr JAMFGQBENKSWOF-UHFFFAOYSA-N 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 229940043279 diisopropylamine Drugs 0.000 description 2
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000006138 lithiation reaction Methods 0.000 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
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- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- VXKWYPOMXBVZSJ-UHFFFAOYSA-N tetramethyltin Chemical compound C[Sn](C)(C)C VXKWYPOMXBVZSJ-UHFFFAOYSA-N 0.000 description 2
- 239000003039 volatile agent Substances 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical compound NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 description 1
- WBJWXIQDBDZMAW-UHFFFAOYSA-N 2-hydroxynaphthalene-1-carbonyl chloride Chemical compound C1=CC=CC2=C(C(Cl)=O)C(O)=CC=C21 WBJWXIQDBDZMAW-UHFFFAOYSA-N 0.000 description 1
- YQHJFPFNGVDEDT-UHFFFAOYSA-N 2-tert-butyl-1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(N(C)C)=NC(C)(C)C YQHJFPFNGVDEDT-UHFFFAOYSA-N 0.000 description 1
- PJAIMBYNTXNOCN-UHFFFAOYSA-N 3,6-dibromo-1h-indole Chemical compound BrC1=CC=C2C(Br)=CNC2=C1 PJAIMBYNTXNOCN-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- CSDQQAQKBAQLLE-UHFFFAOYSA-N 4-(4-chlorophenyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine Chemical compound C1=CC(Cl)=CC=C1C1C(C=CS2)=C2CCN1 CSDQQAQKBAQLLE-UHFFFAOYSA-N 0.000 description 1
- QJNLUNBGDFUULX-UHFFFAOYSA-N 4-n,4-n'-dimethyl-3h-pyridine-4,4-diamine Chemical compound CNC1(NC)CC=NC=C1 QJNLUNBGDFUULX-UHFFFAOYSA-N 0.000 description 1
- MXHVORUHWLKKMZ-UHFFFAOYSA-N 9h-fluoren-9-ylmethanethiol Chemical compound C1=CC=C2C(CS)C3=CC=CC=C3C2=C1 MXHVORUHWLKKMZ-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- MOGWWAFCJNJSFF-UHFFFAOYSA-N C1OC=2C=C(C=CC2O1)COCOCOCC1=CC2=C(C=C1)OCO2 Chemical compound C1OC=2C=C(C=CC2O1)COCOCOCC1=CC2=C(C=C1)OCO2 MOGWWAFCJNJSFF-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-OUBTZVSYSA-N Carbon-13 Chemical compound [13C] OKTJSMMVPCPJKN-OUBTZVSYSA-N 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 241000276498 Pollachius virens Species 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- YZCKVEUIGOORGS-IGMARMGPSA-N Protium Chemical compound [1H] YZCKVEUIGOORGS-IGMARMGPSA-N 0.000 description 1
- 241000720974 Protium Species 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 1
- OKJPEAGHQZHRQV-UHFFFAOYSA-N Triiodomethane Natural products IC(I)I OKJPEAGHQZHRQV-UHFFFAOYSA-N 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- PYHXGXCGESYPCW-UHFFFAOYSA-N alpha-phenylbenzeneacetic acid Natural products C=1C=CC=CC=1C(C(=O)O)C1=CC=CC=C1 PYHXGXCGESYPCW-UHFFFAOYSA-N 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 238000010719 annulation reaction Methods 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- XLJMAIOERFSOGZ-UHFFFAOYSA-M cyanate Chemical compound [O-]C#N XLJMAIOERFSOGZ-UHFFFAOYSA-M 0.000 description 1
- 238000005988 cycloreversion reaction Methods 0.000 description 1
- 150000005690 diesters Chemical class 0.000 description 1
- POCFBDFTJMJWLG-UHFFFAOYSA-N dihydrosinapic acid methyl ester Natural products COC(=O)CCC1=CC(OC)=C(O)C(OC)=C1 POCFBDFTJMJWLG-UHFFFAOYSA-N 0.000 description 1
- AASUFOVSZUIILF-UHFFFAOYSA-N diphenylmethanone;sodium Chemical compound [Na].C=1C=CC=CC=1C(=O)C1=CC=CC=C1 AASUFOVSZUIILF-UHFFFAOYSA-N 0.000 description 1
- 229920001971 elastomer Polymers 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 239000003269 fluorescent indicator Substances 0.000 description 1
- 230000022244 formylation Effects 0.000 description 1
- 238000006170 formylation reaction Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 238000006317 isomerization reaction Methods 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-M malonate(1-) Chemical compound OC(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-M 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- BDGDWWGTAFXEEW-UHFFFAOYSA-N methylsulfinylmethane;oxalyl dichloride Chemical compound CS(C)=O.ClC(=O)C(Cl)=O BDGDWWGTAFXEEW-UHFFFAOYSA-N 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000005935 nucleophilic addition reaction Methods 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- HVAMZGADVCBITI-UHFFFAOYSA-M pent-4-enoate Chemical compound [O-]C(=O)CCC=C HVAMZGADVCBITI-UHFFFAOYSA-M 0.000 description 1
- 229940117803 phenethylamine Drugs 0.000 description 1
- FHPZOWOEILXXBD-UHFFFAOYSA-N phenylseleninyl benzeneseleninate Chemical compound C=1C=CC=CC=1[Se](=O)O[Se](=O)C1=CC=CC=C1 FHPZOWOEILXXBD-UHFFFAOYSA-N 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- CAEWJEXPFKNBQL-UHFFFAOYSA-N prop-2-enyl carbonochloridate Chemical compound ClC(=O)OCC=C CAEWJEXPFKNBQL-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- BGUWFUQJCDRPTL-UHFFFAOYSA-N pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1 BGUWFUQJCDRPTL-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 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
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 238000006177 thiolation reaction Methods 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- PTMFUWGXPRYYMC-UHFFFAOYSA-N triethylazanium;formate Chemical compound OC=O.CCN(CC)CC PTMFUWGXPRYYMC-UHFFFAOYSA-N 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 238000005406 washing Methods 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
- C07D491/12—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 three hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
- C07D317/64—Oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
- Saccharide Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Peptides Or Proteins (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/715,541 US5721362A (en) | 1996-09-18 | 1996-09-18 | Process for producing ecteinascidin compounds |
| PCT/US1997/016470 WO1998012198A1 (en) | 1996-09-18 | 1997-09-17 | Process for producing ecteinascidin compounds |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO991301D0 NO991301D0 (no) | 1999-03-17 |
| NO991301L NO991301L (no) | 1999-05-14 |
| NO325345B1 true NO325345B1 (no) | 2008-04-07 |
Family
ID=24874473
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO19991301A NO325345B1 (no) | 1996-09-18 | 1999-03-17 | Fremgangsmate for fremstilling av ecteinascidin 770 og ecteinascidin 743, mellomprodukter for anvendelse ved fremgangsmaten, samt fremgangsmate for fremstilling av mellomproduktene |
Country Status (21)
| Country | Link |
|---|---|
| US (1) | US5721362A (es) |
| EP (1) | EP0931083B1 (es) |
| JP (1) | JP4425995B2 (es) |
| KR (1) | KR100358832B1 (es) |
| CN (1) | CN1096463C (es) |
| AT (1) | ATE232868T1 (es) |
| AU (1) | AU738282B2 (es) |
| BR (1) | BR9712073B1 (es) |
| CA (1) | CA2266081C (es) |
| CZ (1) | CZ299596B6 (es) |
| DE (1) | DE69719201T2 (es) |
| DK (1) | DK0931083T3 (es) |
| ES (1) | ES2192273T3 (es) |
| HU (1) | HU229407B1 (es) |
| IL (2) | IL128993A0 (es) |
| NO (1) | NO325345B1 (es) |
| NZ (1) | NZ334704A (es) |
| PL (1) | PL188572B1 (es) |
| PT (1) | PT931083E (es) |
| RU (1) | RU2194709C2 (es) |
| WO (1) | WO1998012198A1 (es) |
Families Citing this family (47)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL138856A0 (en) * | 1998-04-06 | 2001-10-31 | Univ Illinois | Semi-synthetic ecteinascidins |
| US6316214B1 (en) * | 1998-05-11 | 2001-11-13 | The Board Of Trustees Of The University Of Illinois | ETM-775 metabolite of ecteinascidin 743 |
| US6124292A (en) * | 1998-09-30 | 2000-09-26 | President And Fellows Of Harvard College | Synthetic analogs of ecteinascidin-743 |
| MY164077A (en) * | 1999-05-13 | 2017-11-30 | Pharma Mar Sa | Compositions and uses of et743 for treating cancer |
| GB9918178D0 (en) * | 2000-05-15 | 1999-10-06 | Pharma Mar Sa | Synthetic methods |
| BG65893B1 (bg) * | 1999-05-14 | 2010-04-30 | Pharma Mar S.A. | Полусинтетичен метод и нови съединения |
| MY130271A (en) * | 1999-05-14 | 2007-06-29 | Pharma Mar Sa | Hemisynthetic method and new compounds |
| AU783562B2 (en) * | 2000-01-19 | 2005-11-10 | Trustees Of Columbia University In The City Of New York, The | Compounds of the saframycin-ecteinascidin series, uses, and synthesis thereof |
| US6815544B2 (en) | 2000-02-11 | 2004-11-09 | President And Fellows Of Harvard College | Synthetic process for an intermediate for ecteinascidin and phthalascidin compounds |
| CZ300326B6 (cs) * | 2000-02-11 | 2009-04-22 | President And Fellows Of Harvard College | Zpusob syntézy meziproduktu pro ekteinascidin a ftalascidin |
| US6569859B1 (en) | 2000-02-22 | 2003-05-27 | President And Fellows Of Harvard College | Synthetic analogs of ecteinascidin-743 |
| PT1280809E (pt) * | 2000-04-12 | 2005-11-30 | Pharma Mar Sa | Derivados antitumorais de ecteinascidina |
| US7919493B2 (en) * | 2000-04-12 | 2011-04-05 | Pharma Mar, S.A. | Anititumoral ecteinascidin derivatives |
| MXPA02011319A (es) * | 2000-05-15 | 2003-06-06 | Pharma Mar Sa | Analogos antitumorales de ecteinascidina 743. |
| US7420051B2 (en) * | 2000-05-15 | 2008-09-02 | Pharma Mar, S.A. | Synthetic process for the manufacture of an ecteinaschidin compound |
| JP4942900B2 (ja) * | 2000-05-15 | 2012-05-30 | ファルマ・マール・ソシエダード・アノニマ | エクチナサイジン化合物の製造のための合成方法 |
| CA2447553A1 (en) | 2000-11-03 | 2002-05-23 | President And Fellows Of Harvard College | Saframycins, analogues and uses thereof |
| CN100374162C (zh) * | 2000-11-06 | 2008-03-12 | 法马马有限公司 | 海鞘素－743在制备用于治疗肿瘤的药剂中的应用 |
| GB0117402D0 (en) * | 2001-07-17 | 2001-09-05 | Pharma Mar Sa | New antitumoral derivatives of et-743 |
| GB0119243D0 (en) * | 2001-08-07 | 2001-10-03 | Pharma Mar Sa | Antitumoral analogs of ET-743 |
| JP4208469B2 (ja) * | 2002-01-29 | 2009-01-14 | 独立行政法人科学技術振興機構 | エクテナサイジン類の全合成方法、エクテナサイジン類に類縁構造を持つ前記全合成用中間体化合物類、及び該中間体化合物類の合成方法 |
| GB0202544D0 (en) * | 2002-02-04 | 2002-03-20 | Pharma Mar Sa | The synthesis of naturally occuring ecteinascidins and related compounds |
| GB0312407D0 (en) * | 2003-05-29 | 2003-07-02 | Pharma Mar Sau | Treatment |
| US7183054B2 (en) | 2003-06-03 | 2007-02-27 | President And Fellows Of Harvard College | Assay for identifying biological targets of polynucleotide-binding compounds |
| GB0324201D0 (en) * | 2003-10-15 | 2003-11-19 | Pharma Mar Sau | Improved antitumoral combinations |
| DE602004016376D1 (de) * | 2003-11-13 | 2008-10-16 | Pharma Mar Sau | Kombination von et-743 mit 5-fluorouracil pro-drugs zur behandlung von krebs |
| WO2005049030A1 (en) * | 2003-11-14 | 2005-06-02 | Pharma Mar, S.A. | Combination therapy comprising the use of et-743 and paclitaxel for treating cancer |
| GB0326486D0 (en) * | 2003-11-14 | 2003-12-17 | Pharma Mar Sau | Combination treatment |
| EP1768671A2 (en) * | 2004-07-09 | 2007-04-04 | Pharma Mar, S.A. | Use of ecteinascidin in the treatment of cancer in patients with low level of brca1 |
| CN100396178C (zh) * | 2004-08-06 | 2008-06-25 | 中国科学院海洋研究所 | 一种玻璃海鞘的全人工养殖方法及简易型连续投饵装置 |
| WO2006035244A2 (en) * | 2004-09-29 | 2006-04-06 | Pharma Mar S.A., Sociedad Unipersonal | Ecteinascidin compounds as anti -inflammatory agents |
| SI1827500T1 (sl) * | 2004-10-26 | 2009-10-31 | Pharma Mar Sa | Pegiliran liposomski doksorubicin v kombinaciji s ekteinescidinom 743 |
| DK1658848T3 (da) | 2004-10-29 | 2007-11-26 | Pharma Mar Sa | Formuleringer omfattende ecteinascidin og et disaccharid |
| GB0522082D0 (en) * | 2005-10-31 | 2005-12-07 | Pharma Mar Sa | Formulations |
| CN101157929B (zh) * | 2007-02-02 | 2012-05-23 | 中国科学院上海有机化学研究所 | 番红霉素的生物合成基因簇 |
| JP2011500046A (ja) * | 2007-10-19 | 2011-01-06 | ファルマ・マール・ソシエダード・アノニマ | Ｅｔ−７４３治療のための予後分子マーカー |
| WO2011147828A1 (en) | 2010-05-25 | 2011-12-01 | Pharma Mar, S.A. | Synthetic process for the manufacture of ecteinascidin compounds |
| KR20170096065A (ko) | 2010-11-12 | 2017-08-23 | 파르마 마르 에스.에이. | 항종양 알칼로이드를 이용한 병용요법 |
| CN103304478B (zh) * | 2013-06-28 | 2016-04-20 | 四川大学 | 一类合成renieramycins型生物碱的中间体及其制备方法 |
| CN104557850B (zh) * | 2013-10-29 | 2019-07-30 | 江苏盛迪医药有限公司 | 一种海鞘碱-743中间体的制备方法 |
| CN103709101B (zh) * | 2013-12-19 | 2016-06-29 | 四川大学 | 一类renieramycin G的合成中间体及其制备方法 |
| JOP20190254A1 (ar) | 2017-04-27 | 2019-10-27 | Pharma Mar Sa | مركبات مضادة للأورام |
| CN111518110B (zh) * | 2019-02-01 | 2023-11-03 | 博瑞生物医药（苏州）股份有限公司 | 一种海鞘素化合物及其中间体的制备方法 |
| CN110092802B (zh) * | 2019-06-21 | 2022-01-07 | 爱斯特（成都）生物制药股份有限公司 | 一种制备曲贝替定中间体的方法 |
| WO2020261301A1 (en) * | 2019-06-27 | 2020-12-30 | Msn Laboratories Private Limited, R&D Center | IMPROVED PROCESS FOR THE PREPARATON OF PURE (1'R,6R,6aR,7R,13S,14S,16R)-5-(ACETYLOXY)-3',4',6,6a,7,13,14,16-OCTAHYDRO-6',8,14-TRIHYDROXY-7',9-DIMETHOXY-4,10,23-TRIMETHYLSPIRO[6,16-(EPITHIOPROPANOXYMETH ANO)-7,13-IMINO-12H-1,3-DIOXOLO[7,8]ISOQUINO[3,2-b][3]BENZAZOCINE-20,1'(2'H)-ISOQUINOLIN]-19-ONE POLYMORPH THERE OF |
| CN114621245A (zh) * | 2020-12-11 | 2022-06-14 | 江苏恒瑞医药股份有限公司 | 一种曲贝替定中间体的晶型及其制备方法 |
| US20230226051A1 (en) | 2022-01-20 | 2023-07-20 | Extrovis Ag | Trabectedin composition |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5149804A (en) * | 1990-11-30 | 1992-09-22 | The Board Of Trustees Of The University Of Illinois | Ecteinascidins 736 and 722 |
| US5256663A (en) * | 1986-06-09 | 1993-10-26 | The Board Of Trustees Of The University Of Illinois | Compositions comprising ecteinascidins and a method of treating herpes simplex virus infections therewith |
| US5089273A (en) * | 1986-06-09 | 1992-02-18 | Board Of Trustees Of The University Of Illinois | Ecteinascidins 729, 743, 745, 759A, 759B and 770 |
| DE3923985C1 (es) * | 1989-07-20 | 1990-06-28 | Daimler-Benz Aktiengesellschaft, 7000 Stuttgart, De | |
| GB2252781B (en) * | 1991-02-14 | 1994-08-17 | Sanwa Shutter Corp | Architectural shutter curtain device |
| US5478932A (en) * | 1993-12-02 | 1995-12-26 | The Board Of Trustees Of The University Of Illinois | Ecteinascidins |
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