JPH10505360A - タキソールおよびその誘導体の製造方法 - Google Patents
タキソールおよびその誘導体の製造方法Info
- Publication number
- JPH10505360A JPH10505360A JP9503543A JP50354397A JPH10505360A JP H10505360 A JPH10505360 A JP H10505360A JP 9503543 A JP9503543 A JP 9503543A JP 50354397 A JP50354397 A JP 50354397A JP H10505360 A JPH10505360 A JP H10505360A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- compound
- phenyl
- heteroaryl
- symbol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 7
- 229930012538 Paclitaxel Natural products 0.000 title description 13
- 229960001592 paclitaxel Drugs 0.000 title description 13
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 title description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 185
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 29
- 125000003118 aryl group Chemical group 0.000 claims abstract description 28
- 239000001257 hydrogen Substances 0.000 claims abstract description 27
- 238000000034 method Methods 0.000 claims abstract description 24
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 20
- 125000005129 aryl carbonyl group Chemical group 0.000 claims abstract description 19
- 125000005223 heteroarylcarbonyl group Chemical group 0.000 claims abstract description 19
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims abstract description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 11
- 125000006239 protecting group Chemical group 0.000 claims abstract description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims abstract 6
- -1 t-butoxycarbonyl Chemical group 0.000 claims description 115
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 65
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 55
- 229910052796 boron Inorganic materials 0.000 claims description 22
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 19
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 16
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- 125000004665 trialkylsilyl group Chemical group 0.000 claims description 11
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 10
- 238000010511 deprotection reaction Methods 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 7
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 6
- 229910052744 lithium Inorganic materials 0.000 claims description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 5
- 150000004820 halides Chemical class 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 150000001540 azides Chemical class 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 239000002841 Lewis acid Substances 0.000 claims description 3
- 239000012024 dehydrating agents Substances 0.000 claims description 3
- 150000007517 lewis acids Chemical class 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 2
- 239000003446 ligand Substances 0.000 claims description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 claims description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 229910052709 silver Inorganic materials 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 2
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims 2
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims 1
- 125000000392 cycloalkenyl group Chemical group 0.000 claims 1
- 229910052753 mercury Inorganic materials 0.000 claims 1
- 230000007704 transition Effects 0.000 claims 1
- 230000000259 anti-tumor effect Effects 0.000 abstract description 2
- 230000004044 response Effects 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 138
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 99
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 77
- 239000000203 mixture Substances 0.000 description 67
- 238000006243 chemical reaction Methods 0.000 description 54
- 239000000243 solution Substances 0.000 description 54
- 238000005160 1H NMR spectroscopy Methods 0.000 description 48
- 239000011734 sodium Substances 0.000 description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
- 238000003756 stirring Methods 0.000 description 30
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 28
- 239000000284 extract Substances 0.000 description 26
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 23
- WSDQIHATCCOMLH-UHFFFAOYSA-N phenyl n-(3,5-dichlorophenyl)carbamate Chemical compound ClC1=CC(Cl)=CC(NC(=O)OC=2C=CC=CC=2)=C1 WSDQIHATCCOMLH-UHFFFAOYSA-N 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
- 239000000460 chlorine Substances 0.000 description 22
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 22
- 239000000126 substance Substances 0.000 description 20
- 239000007864 aqueous solution Substances 0.000 description 19
- 239000012074 organic phase Substances 0.000 description 19
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 18
- 238000005481 NMR spectroscopy Methods 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 17
- 239000012043 crude product Substances 0.000 description 17
- 229920006395 saturated elastomer Polymers 0.000 description 17
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 17
- 238000004587 chromatography analysis Methods 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 238000003818 flash chromatography Methods 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 description 14
- 239000002253 acid Substances 0.000 description 14
- 239000000047 product Substances 0.000 description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 13
- 229910052786 argon Inorganic materials 0.000 description 13
- 239000003960 organic solvent Substances 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 12
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 12
- 239000008363 phosphate buffer Substances 0.000 description 12
- 239000007787 solid Substances 0.000 description 11
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 238000004458 analytical method Methods 0.000 description 10
- 239000008346 aqueous phase Substances 0.000 description 10
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 10
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 10
- NFLGAXVYCFJBMK-BDAKNGLRSA-N (-)-menthone Chemical compound CC(C)[C@@H]1CC[C@@H](C)CC1=O NFLGAXVYCFJBMK-BDAKNGLRSA-N 0.000 description 9
- 230000003197 catalytic effect Effects 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- FJKIXWOMBXYWOQ-UHFFFAOYSA-N ethenoxyethane Chemical compound CCOC=C FJKIXWOMBXYWOQ-UHFFFAOYSA-N 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- 229930007506 (+)-menthone Natural products 0.000 description 6
- NFLGAXVYCFJBMK-DTWKUNHWSA-N (+)-menthone Chemical compound CC(C)[C@H]1CC[C@H](C)CC1=O NFLGAXVYCFJBMK-DTWKUNHWSA-N 0.000 description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 6
- 125000000217 alkyl group Chemical group 0.000 description 6
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 6
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 6
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 6
- 235000019253 formic acid Nutrition 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 150000002466 imines Chemical class 0.000 description 6
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 6
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 6
- OVCRWFXFVNFFNF-UHFFFAOYSA-N 3-phenylpropanethioyl acetate Chemical compound CC(=O)OC(=S)CCC1=CC=CC=C1 OVCRWFXFVNFFNF-UHFFFAOYSA-N 0.000 description 5
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical group O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 5
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 5
- 230000010933 acylation Effects 0.000 description 5
- 238000005917 acylation reaction Methods 0.000 description 5
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- XDVXACICGRFHLJ-QMMMGPOBSA-N (2S)-2-hydroxy-3-phenylpropanethioic S-acid Chemical compound SC(=O)[C@@H](O)CC1=CC=CC=C1 XDVXACICGRFHLJ-QMMMGPOBSA-N 0.000 description 4
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 4
- TYLVGQKNNUHXIP-MHHARFCSSA-N 10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)C=4C=CC=CC=4)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 TYLVGQKNNUHXIP-MHHARFCSSA-N 0.000 description 4
- 125000004797 2,2,2-trichloroethoxy group Chemical group ClC(CO*)(Cl)Cl 0.000 description 4
- YWLXLRUDGLRYDR-ZHPRIASZSA-N 5beta,20-epoxy-1,7beta,10beta,13alpha-tetrahydroxy-9-oxotax-11-ene-2alpha,4alpha-diyl 4-acetate 2-benzoate Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](O)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 YWLXLRUDGLRYDR-ZHPRIASZSA-N 0.000 description 4
- OVMSOCFBDVBLFW-VHLOTGQHSA-N 5beta,20-epoxy-1,7beta,13alpha-trihydroxy-9-oxotax-11-ene-2alpha,4alpha,10beta-triyl 4,10-diacetate 2-benzoate Chemical compound O([C@@H]1[C@@]2(C[C@H](O)C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)O)C(=O)C1=CC=CC=C1 OVMSOCFBDVBLFW-VHLOTGQHSA-N 0.000 description 4
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Natural products OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 4
- 125000001246 bromo group Chemical group Br* 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 125000000950 dibromo group Chemical group Br* 0.000 description 4
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 4
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 4
- UKJFVOWPUXSBOM-UHFFFAOYSA-N hexane;oxolane Chemical compound C1CCOC1.CCCCCC UKJFVOWPUXSBOM-UHFFFAOYSA-N 0.000 description 4
- 230000010354 integration Effects 0.000 description 4
- 229940098779 methanesulfonic acid Drugs 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 4
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 4
- 239000011701 zinc Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 239000007795 chemical reaction product Substances 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- 238000006345 epimerization reaction Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- KTNTVTQVEAPQNT-UHFFFAOYSA-N methyl 2-[tert-butyl(dimethyl)silyl]oxyacetate Chemical compound COC(=O)CO[Si](C)(C)C(C)(C)C KTNTVTQVEAPQNT-UHFFFAOYSA-N 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- RUKZQNFDJNSZKF-UHFFFAOYSA-N o-phenyl 2-trimethylsilyloxyethanethioate Chemical compound C[Si](C)(C)OCC(=S)OC1=CC=CC=C1 RUKZQNFDJNSZKF-UHFFFAOYSA-N 0.000 description 3
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 3
- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
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- ZYKVJJOPTIWVED-WOJBJXKFSA-N o-phenyl (2r,3r)-3-benzamido-2-hydroxy-3-phenylpropanethioate Chemical compound N([C@@H]([C@@H](O)C(=S)OC=1C=CC=CC=1)C=1C=CC=CC=1)C(=O)C1=CC=CC=C1 ZYKVJJOPTIWVED-WOJBJXKFSA-N 0.000 description 1
- ZYKVJJOPTIWVED-PMACEKPBSA-N o-phenyl (2s,3s)-3-benzamido-2-hydroxy-3-phenylpropanethioate Chemical compound N([C@H]([C@H](O)C(=S)OC=1C=CC=CC=1)C=1C=CC=CC=1)C(=O)C1=CC=CC=C1 ZYKVJJOPTIWVED-PMACEKPBSA-N 0.000 description 1
- MTVYKCZLFVIYQL-VQTJNVASSA-N o-phenyl (4s,5r)-2,4-diphenyl-4,5-dihydro-1,3-oxazole-5-carbothioate Chemical compound S=C([C@H]1[C@@H](N=C(O1)C=1C=CC=CC=1)C=1C=CC=CC=1)OC1=CC=CC=C1 MTVYKCZLFVIYQL-VQTJNVASSA-N 0.000 description 1
- YOJYDGFGORKDFX-SJORKVTESA-N o-tert-butyl (2s,3r)-3-benzamido-2-hydroxy-3-phenylpropanethioate Chemical compound N([C@@H]([C@H](O)C(=S)OC(C)(C)C)C=1C=CC=CC=1)C(=O)C1=CC=CC=C1 YOJYDGFGORKDFX-SJORKVTESA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 150000002918 oxazolines Chemical class 0.000 description 1
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 1
- 125000005400 pyridylcarbonyl group Chemical group N1=C(C=CC=C1)C(=O)* 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- WMXCDAVJEZZYLT-UHFFFAOYSA-N tert-butylthiol Chemical compound CC(C)(C)S WMXCDAVJEZZYLT-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
- 235000021419 vinegar Nutrition 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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 ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
Description
Claims (1)
- 【特許請求の範囲】 1. 式(I): [式中、R1はアリールもしくはヘテロアリール基であり;R2は水素、アリール カルボニル、ヘテロアリールカルボニルもしくはC1〜C6アルコキシカルボニル であり;R3は水素もしくはアセチルである] の化合物の製造方法であって、 式(II): [式中、R1は上記の意味を有し、記号−−−は単結合もしくは二重結合を示し 、R7はC1〜C6アルコキシカルボニル、アリールカルボニルもしくはヘテロア リールカルボニルであり、R4およびR5の各々は独立して水素、C1〜C6アルキ ル、C1〜C3アルコキシ、アリールもしくはヘテロアリールであり、R6はC1〜 C6アルキル、アリールもしくはヘテロアリールであり、ただし記号−−−が二 重結合である場合R7およびR4は存在せず、R5はアリールもしくはヘテロアリ ールである] の化合物を式(III): [式中、R8およびR9の各々は独立してヒドロキシ保護基である] の化合物と縮合剤の存在下に反応させて、式(IV): [式中、R1、R4、R5、R7、R8およびR9、並びに記号−−−は上記の意味を 有し、ただし−−−が二重結合である場合R7およびR4は存在せず、R5はアリ ールもしくはヘテロアリールである] の化合物を得、 式(IV)の化合物を上記式(I)の化合物を生成させるような条件下で脱保護 し、必要に応じ式(I)の化合物を式(I)の他の化合物に変換する、 ことを包含する前記方法。 2. R1がフェニル、2−フリル、4−ピリジル、4−メトキシフェニルであ り;R2が水素、ベンゾイル、t−ブトキシカルボニル、p−クロルフェニルカ ルボニル、p−メチルフェニルカルボニルであり;R3が水素、アセチルである 式(I)の化合物を製造するに際し、請求項1に記載の式(II)[式 中、記号−−−は単結合もしくは二重結合であり、R1は前記の意味を有し; R4およびR5の各々は独立して水素、C1〜C6アルキル、C1〜C3アルコキシ、 フェニル基、または1個もしくはそれ以上のC1〜C4アルコキシ基で置換された フェニル基であり; R6はC1〜C4アルキルもしくはフェニルもしくはピリジルであり; R7はエトキシカルボニル、n−プロポキシカルボニル、n−ブトキシカルボニ ル、t−ブトキシカルボニル、ベンゾイル、p−クロルフェニルカルボニル、p −メチルフェニルカルボニルであり; ただし記号−−−が二重結合である場合R7およびR4は存在せず、R5はフェニ ル、または1個もしくはそれ以上のC1〜C4アルコキシ基で置換されたフェニル 基である]の化合物を、請求項1に記載の式(III)[式中、R8はアセチル もしくは2,2,2−トリクロルエトキシカルボニルであり;R9はフェニルジ メチルシリル、トリエチルシリル、2,2,2−トリクロルエトキシカルボニル である]の化合物と、縮合剤 の存在下で反応させて、請求項1に記載の式(IV)[式中、記号−−−並びに R1、R4、R5、R7、R8およびR9は前記の意味を有する]の化合物を得、式( IV)の化合物を上記式(I)の化合物を生成するような条件下で脱保護し、必 要に応じ式(I)の化合物を式(I)の他の化合物に変換することを特徴とする 請求項1に記載の方法。 3. 請求項1に記載の式(I)[式中、R1はフェニルであり;R2はベンゾイ ル、t−ブトキシカルボニルであり;R3は水素もしくはアセチルである]の化 合物を製造するに際し、請求項1に記載の式(II)[式中、記号−−−は単結 合もしくは二重結合であり、R1は前記の意味を有し;R4およびR5の各々は独 立して水素、メチル、エチル、メトキシ、フェニル、2,4−ジメトキシフェニ ル、3,4−ジメトキシフェニルもしくは4−メトキシフェニルであり;R6は t−ブチルもしくはフェニルであり;R7はベンゾイルもしくはt−ブトキシカ ルボニルであり;ただし記号−−−が二重結合である場合R4およびR7は存在せ ず、R5はフェニル、2,4−ジメトキシフェニル、3,4−ジメトキシフェニ ルもしくは4−メトキシフェニルである]の化合物を、請求項1に記載の式(I II) [式中、R8はアセチルもしくは2,2,2−トリクロルエトキシカルボニルで あり、R9はトリエチルシリルもしくは2,2,2−トリクロルエトキシカルボ ニルである]の化合物と、縮合剤の存在下に反応させて、式(IV)[式中、記 号−−−並びにR1、R4、R5、R7、R8およびR9は前記の意味を有する]の化 合物を得、式(IV)の化合物を脱保護して上記式(I)の化合物を生成し、必 要に応じ式(I)の化合物を式(I)の他の化合物に変換することを特徴とする 請求項2に記載の方法。 4. 縮合剤がNaH、n−BuLi、リチウムジイソプロピルアミド(LDA )、MNH2または式(V): MN[Si(R)3]2 (V) [式中、RはC1〜C4アルキルであり、MはLi、NaもしくはKである] の化合物である請求項1〜3のいずれか一項に記載の方法。 5. 縮合剤がチオフィリック金属塩である請求項1〜3のいずれか一項に記載 の方法。 6. チオフィリック金属塩を、Cu、AgもしくはHgのトリフレート、トリ フルオロアセテート、アセテートおよびメシ レートから選択する請求項5に記載の方法。 7. 式(II): [式中、記号−−−は単結合もしくは二重結合を示し; R1はアリールもしくはヘテロアリールであり; R4およびR5の各々は独立して水素、C1〜C6アルキル、C1〜C3アルコキシ、 アリールもしくはヘテロアリールであり; R6はC1〜C6アルキル、アリールもしくはヘテロアリールであり; R7はC1〜C6アルコキシカルボニル、アリールカルボニルもしくはヘテロアリ ールカルボニルであり; ただし記号−−−が二重結合である場合R7およびR4は存在せず、R5はアリー ルもしくはヘテロアリールである] の化合物。 8. 記号−−−が単結合もしくは二重結合であり; R1がフェニルであり; R4およびR5の各々が独立して水素、C1〜C6アルキル、C1〜C3アルコキシ、 フェニル、または1個もしくはそれ以上のC1〜C4アルコキシ基により置換され たフェニル基であり; R6がC1〜C4アルキル、フェニルもしくはピリジルであり; R7がベンゾイル、t−ブトキシカルボニルであり; ただし記号−−−が二重結合である場合R4およびR7が存在せず、R5がフェニ ル、または1個もしくはそれ以上のC1〜C4アルコキシ基で置換されたフェニル 基である、ことを特徴とする請求項7に記載の式(II)の化合物。 9. R1がフェニルであり; R4およびR5の各々が独立して水素、メチル、エチル、メトキシ、フェニル、2 ,4−ジメトキシフェニル、3,4−ジメトキシフェニルもしくは4−メトキシ フェニルであり; R6がt−ブチルもしくはフェニルであり; R7がt−ブトキシカルボニルもしくはベンゾイルであり; ただし記号−−−が二重結合である場合R4およびR7が存在 せず、R5がフェニル、2,4−ジトメキシフェニル、3,4−ジメトキシフェ ニルもしくは4−メトキシフェニルである、ことを特徴とする請求項8に記載の 式(II)の化合物。 10. (a)式(VI): [式中、R6は請求項7に記載の意味を有し、R10はアリールカルボニル、ヘテ ロアリールカルボニル、トリアルキルシリルもしくは1−アルコキシアルキルで ある] の化合物を式(VII): L2BX (VII) [式中、Lはキラル配位子であり、Xはハロゲン原子である] の硼素錯体と反応させ、次いで式(VIII): R1−CH=N−Z (VIII) [式中、R1は請求項7に記載の意味を有し、Zはトリアルキルシリル、C1〜C6 アルコキシカルボニル、アリールカルボニル、ヘテロアリールカルボニルであ る] の化合物と、必要に応じ追加のルイス酸の存在下に、反応させ、 および或いは、 (i)R10がアリールカルボニルもしくはヘテロアリールカルボニルであり、R6 がC1〜C6アルキルである場合、アリールカルボニルもしくはヘテロアリール カルボニルは酸素から窒素まで転移するか、または、 (ii)R7Y[式中、R7は請求項7に記載の意味を有し、Yは−OR10基を遊 離ヒドロキシ基まで脱保護した後または脱保護する前の離脱基である]と反応さ せ、式(IX): [式中、R1、R6およびR7は前記の意味を有する] の化合物を得;次いで、 (b)上記で得られた式(IX)の化合物を環化させるが、この環化を、 (b′)主としてsyn配置である式(IX)の化合物を式(X)、(XI)も しくは(XII): [式中、R4およびR5は請求項7に記載の意味を有し、R11はC1〜C3アルキル 基である] の化合物と反応させて、式(II)[式中、記号−−−は単結合であり、R1、 R4、R5、R6、R7は前記の意味を有する]の化合物を得るか、または、 (b″)主としてanti配置である式(IX)の化合物を脱水剤と反応させて 、式(II)[式中、記号−−−は二重結合であり、R7およびR4は存在せず、 R5はアリールもしくはヘテロアリールである]の化合物を得る、 ことによって行うことからなる請求項7に記載の式(II)の化合物の製造方法 。 11. Yがハライド、アジドもしくはOR7[ここでR7は請求項7に記載の意 味を有する]であることを特徴とする請求項10に記載の方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9512471.5 | 1995-06-20 | ||
GBGB9512471.5A GB9512471D0 (en) | 1995-06-20 | 1995-06-20 | Method for the preparation of taxol and its derivatives |
PCT/EP1996/002409 WO1997000870A1 (en) | 1995-06-20 | 1996-06-04 | Method for the preparation of taxol and its derivatives |
Publications (2)
Publication Number | Publication Date |
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JPH10505360A true JPH10505360A (ja) | 1998-05-26 |
JP3889047B2 JP3889047B2 (ja) | 2007-03-07 |
Family
ID=10776319
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP50354397A Expired - Fee Related JP3889047B2 (ja) | 1995-06-20 | 1996-06-04 | タキソールおよびその誘導体の製造方法 |
Country Status (17)
Country | Link |
---|---|
US (1) | US5767282A (ja) |
EP (2) | EP1116718A3 (ja) |
JP (1) | JP3889047B2 (ja) |
KR (1) | KR970705552A (ja) |
CN (1) | CN1179955C (ja) |
AT (1) | ATE208381T1 (ja) |
AU (1) | AU712898B2 (ja) |
CA (1) | CA2197467C (ja) |
DE (1) | DE69616719T2 (ja) |
ES (1) | ES2168489T3 (ja) |
GB (1) | GB9512471D0 (ja) |
HU (1) | HUP9702399A3 (ja) |
IL (1) | IL120165A (ja) |
MX (1) | MX9701274A (ja) |
NO (1) | NO970766D0 (ja) |
WO (1) | WO1997000870A1 (ja) |
ZA (1) | ZA964951B (ja) |
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US6150537A (en) * | 1997-12-12 | 2000-11-21 | Emory University | Methods for the esterification of alcohols and compounds useful therefor as potential anticancer agents |
WO2000047434A1 (en) | 1999-02-10 | 2000-08-17 | Erik Zapletal | Balanced suspension system |
IT1308636B1 (it) * | 1999-03-02 | 2002-01-09 | Indena Spa | Procedimento per la preparazione di tassani da 10-desacetilbaccatinaiii. |
AU757591B2 (en) | 1999-04-12 | 2003-02-27 | Kinetic Pty Limited | Active ride control for a vehicle suspension system |
EP2266607A3 (en) | 1999-10-01 | 2011-04-20 | Immunogen, Inc. | Immunoconjugates for treating cancer |
WO2001030770A1 (en) * | 1999-10-26 | 2001-05-03 | Dong Kook Pharmaceutical Co., Ltd. | Stereoselective synthesis of oxazoline derivative |
PL194032B1 (pl) * | 2002-12-19 | 2007-04-30 | Agropharm Sa | Sposób wytwarzania półproduktów użytecznych w syntezie paklitakselu |
CN101020672B (zh) * | 2006-12-28 | 2010-08-25 | 上海百灵医药科技有限公司 | 多烯紫杉醇的合成方法 |
CN101007795B (zh) * | 2007-01-26 | 2010-08-18 | 浙江大学 | 紫杉醇及多烯紫杉醇的合成方法 |
CN115260130A (zh) * | 2022-07-07 | 2022-11-01 | 上海卓鼎生物技术有限公司 | 一种10-脱乙酰基紫杉醇的制备方法 |
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MX9102128A (es) * | 1990-11-23 | 1992-07-08 | Rhone Poulenc Rorer Sa | Derivados de taxano,procedimiento para su preparacion y composicion farmaceutica que los contiene |
FR2687151B1 (fr) * | 1992-02-07 | 1994-03-25 | Rhone Poulenc Rorer Sa | Nouveaux derives de la baccatine iii et de la desacetyl-10 baccatine iii, leur preparation et les compositions pharmaceutiques qui les contiennent. |
FR2696458B1 (fr) * | 1992-10-05 | 1994-11-10 | Rhone Poulenc Rorer Sa | Procédé de préparation de dérivés du taxane. |
-
1995
- 1995-06-20 GB GBGB9512471.5A patent/GB9512471D0/en active Pending
-
1996
- 1996-06-04 EP EP01201499A patent/EP1116718A3/en not_active Withdrawn
- 1996-06-04 AU AU62215/96A patent/AU712898B2/en not_active Ceased
- 1996-06-04 IL IL12016596A patent/IL120165A/en not_active IP Right Cessation
- 1996-06-04 HU HU9702399A patent/HUP9702399A3/hu unknown
- 1996-06-04 CA CA002197467A patent/CA2197467C/en not_active Expired - Fee Related
- 1996-06-04 JP JP50354397A patent/JP3889047B2/ja not_active Expired - Fee Related
- 1996-06-04 WO PCT/EP1996/002409 patent/WO1997000870A1/en not_active Application Discontinuation
- 1996-06-04 US US08/776,607 patent/US5767282A/en not_active Expired - Lifetime
- 1996-06-04 KR KR1019970701092A patent/KR970705552A/ko not_active Application Discontinuation
- 1996-06-04 MX MX9701274A patent/MX9701274A/es not_active IP Right Cessation
- 1996-06-04 DE DE69616719T patent/DE69616719T2/de not_active Expired - Lifetime
- 1996-06-04 CN CNB961907630A patent/CN1179955C/zh not_active Expired - Fee Related
- 1996-06-04 EP EP96920783A patent/EP0776322B1/en not_active Expired - Lifetime
- 1996-06-04 ES ES96920783T patent/ES2168489T3/es not_active Expired - Lifetime
- 1996-06-04 AT AT96920783T patent/ATE208381T1/de not_active IP Right Cessation
- 1996-06-11 ZA ZA964951A patent/ZA964951B/xx unknown
-
1997
- 1997-02-19 NO NO970766A patent/NO970766D0/no unknown
Also Published As
Publication number | Publication date |
---|---|
NO970766L (no) | 1997-02-19 |
ATE208381T1 (de) | 2001-11-15 |
DE69616719T2 (de) | 2002-08-01 |
KR970705552A (ko) | 1997-10-09 |
CA2197467A1 (en) | 1997-01-09 |
EP0776322B1 (en) | 2001-11-07 |
HUP9702399A3 (en) | 1999-12-28 |
ES2168489T3 (es) | 2002-06-16 |
US5767282A (en) | 1998-06-16 |
MX9701274A (es) | 1997-05-31 |
WO1997000870A1 (en) | 1997-01-09 |
IL120165A0 (en) | 1997-06-10 |
CA2197467C (en) | 2008-02-12 |
CN1179955C (zh) | 2004-12-15 |
JP3889047B2 (ja) | 2007-03-07 |
IL120165A (en) | 2002-02-10 |
DE69616719D1 (de) | 2001-12-13 |
CN1158126A (zh) | 1997-08-27 |
AU712898B2 (en) | 1999-11-18 |
EP1116718A2 (en) | 2001-07-18 |
EP0776322A1 (en) | 1997-06-04 |
NO970766D0 (no) | 1997-02-19 |
EP1116718A3 (en) | 2001-08-29 |
HUP9702399A2 (hu) | 1998-07-28 |
AU6221596A (en) | 1997-01-22 |
ZA964951B (en) | 1997-01-23 |
GB9512471D0 (en) | 1995-08-23 |
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