CN1043528C - 用噁嗪酮制备紫杉酚的方法 - Google Patents
用噁嗪酮制备紫杉酚的方法 Download PDFInfo
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- CN1043528C CN1043528C CN90109112A CN90109112A CN1043528C CN 1043528 C CN1043528 C CN 1043528C CN 90109112 A CN90109112 A CN 90109112A CN 90109112 A CN90109112 A CN 90109112A CN 1043528 C CN1043528 C CN 1043528C
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- aryl
- hydrogen
- alkenyl
- alkynyl
- radical
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- 229930012538 Paclitaxel Natural products 0.000 title claims abstract description 53
- 229960001592 paclitaxel Drugs 0.000 title claims abstract description 53
- 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 claims abstract description 51
- FBXGQDUVJBKEAJ-UHFFFAOYSA-N 4h-oxazin-3-one Chemical compound O=C1CC=CON1 FBXGQDUVJBKEAJ-UHFFFAOYSA-N 0.000 title claims abstract description 35
- 238000000034 method Methods 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 42
- 125000003118 aryl group Chemical group 0.000 claims abstract description 38
- 239000001257 hydrogen Substances 0.000 claims abstract description 38
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 28
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 28
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 26
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 25
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 4
- -1 alkenoyloxy Chemical group 0.000 claims description 57
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 28
- 125000004423 acyloxy group Chemical group 0.000 claims description 26
- 150000002431 hydrogen Chemical group 0.000 claims description 19
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 18
- 229910052760 oxygen Inorganic materials 0.000 claims description 17
- 125000005333 aroyloxy group Chemical group 0.000 claims description 16
- 239000001301 oxygen Substances 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 238000003786 synthesis reaction Methods 0.000 claims description 15
- 230000015572 biosynthetic process Effects 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000006239 protecting group Chemical group 0.000 claims description 10
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 239000012190 activator Substances 0.000 claims description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- 125000002252 acyl group Chemical group 0.000 claims description 6
- 125000003368 amide group Chemical group 0.000 claims description 5
- 150000003512 tertiary amines Chemical class 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- AHHWIHXENZJRFG-UHFFFAOYSA-N oxetane Chemical compound C1COC1 AHHWIHXENZJRFG-UHFFFAOYSA-N 0.000 claims description 3
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 10
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 2
- 150000003254 radicals Chemical class 0.000 claims 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims 1
- 125000004043 oxo group Chemical group O=* 0.000 claims 1
- 125000000304 alkynyl group Chemical group 0.000 abstract description 24
- 125000001072 heteroaryl group Chemical group 0.000 abstract description 17
- 125000005741 alkyl alkenyl group Chemical group 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 114
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 66
- 239000000243 solution Substances 0.000 description 45
- 239000000203 mixture Substances 0.000 description 32
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 17
- 229910052938 sodium sulfate Inorganic materials 0.000 description 17
- 235000011152 sodium sulphate Nutrition 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 17
- 125000004432 carbon atom Chemical group C* 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 239000000741 silica gel Substances 0.000 description 13
- 229910002027 silica gel Inorganic materials 0.000 description 13
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- 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 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 239000003480 eluent Substances 0.000 description 8
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 7
- 238000001953 recrystallisation Methods 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000012230 colorless oil Substances 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 239000012044 organic layer Substances 0.000 description 5
- FBZSDKXFQUKDLD-SFYZADRCSA-N (3s,4r)-3-hydroxy-4-phenylazetidin-2-one Chemical compound N1C(=O)[C@@H](O)[C@H]1C1=CC=CC=C1 FBZSDKXFQUKDLD-SFYZADRCSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 239000012267 brine Substances 0.000 description 4
- 229910000365 copper sulfate Inorganic materials 0.000 description 4
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- FJKIXWOMBXYWOQ-UHFFFAOYSA-N ethenoxyethane Chemical compound CCOC=C FJKIXWOMBXYWOQ-UHFFFAOYSA-N 0.000 description 4
- 238000003818 flash chromatography Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- NNKCQQPVYUHCHF-UHFFFAOYSA-N 5-(1-ethoxyethoxy)-2-[(2-methylpropan-2-yl)oxy]-4-phenyl-4,5-dihydro-1,3-oxazin-6-one Chemical compound N1=C(OC(C)(C)C)OC(=O)C(OC(C)OCC)C1C1=CC=CC=C1 NNKCQQPVYUHCHF-UHFFFAOYSA-N 0.000 description 3
- 229940123237 Taxane Drugs 0.000 description 3
- YWTCDTFWPNSBIU-SJORKVTESA-N [(3s,4r)-1-(4-methoxyphenyl)-2-oxo-4-phenylazetidin-3-yl] acetate Chemical compound C1=CC(OC)=CC=C1N1C(=O)[C@@H](OC(C)=O)[C@H]1C1=CC=CC=C1 YWTCDTFWPNSBIU-SJORKVTESA-N 0.000 description 3
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- BFAKENXZKHGIGE-UHFFFAOYSA-N bis(2,3,5,6-tetrafluoro-4-iodophenyl)diazene Chemical compound FC1=C(C(=C(C(=C1F)I)F)F)N=NC1=C(C(=C(C(=C1F)F)I)F)F BFAKENXZKHGIGE-UHFFFAOYSA-N 0.000 description 3
- 238000004587 chromatography analysis Methods 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- HZDNNJABYXNPPV-UHFFFAOYSA-N (2-chloro-2-oxoethyl) acetate Chemical compound CC(=O)OCC(Cl)=O HZDNNJABYXNPPV-UHFFFAOYSA-N 0.000 description 2
- QMIZAASILSBRMQ-UHFFFAOYSA-N 5-(1-ethoxyethoxy)-2-[(2-methylpropan-2-yl)oxy]-4,4-diphenyl-5h-1,3-oxazin-6-one Chemical compound CCOC(C)OC1C(=O)OC(OC(C)(C)C)=NC1(C=1C=CC=CC=1)C1=CC=CC=C1 QMIZAASILSBRMQ-UHFFFAOYSA-N 0.000 description 2
- FEYQACXBKHREMV-UHFFFAOYSA-N 5-(1-ethoxyethoxy)-5-methyl-2,4-diphenyl-4h-1,3-oxazin-6-one Chemical compound O1C(=O)C(OC(C)OCC)(C)C(C=2C=CC=CC=2)N=C1C1=CC=CC=C1 FEYQACXBKHREMV-UHFFFAOYSA-N 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 241001116498 Taxus baccata Species 0.000 description 2
- YTBSMLRVFPHDOB-ZJUUUORDSA-N [(3s,4r)-2-oxo-4-phenylazetidin-3-yl] acetate Chemical compound N1C(=O)[C@@H](OC(=O)C)[C@H]1C1=CC=CC=C1 YTBSMLRVFPHDOB-ZJUUUORDSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- 229940034982 antineoplastic agent Drugs 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 239000012300 argon atmosphere Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 2
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 125000006038 hexenyl group Chemical group 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000005980 hexynyl group Chemical group 0.000 description 2
- 150000002466 imines Chemical class 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000003107 substituted aryl group Chemical group 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
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 150000003952 β-lactams Chemical class 0.000 description 2
- WSKFEANLIDSKSN-CXRLMVSZSA-N (4s,5r)-5-(1-ethoxyethoxy)-2,4-diphenyl-4,5-dihydro-1,3-oxazin-6-one Chemical compound N([C@H]([C@H](C(O1)=O)OC(C)OCC)C=2C=CC=CC=2)=C1C1=CC=CC=C1 WSKFEANLIDSKSN-CXRLMVSZSA-N 0.000 description 1
- FVXIPVHDRCDSRW-UHFFFAOYSA-N 2-[6-methoxy-6-(trifluoromethyl)cyclohexa-2,4-dien-1-yl]acetic acid Chemical compound COC1(C(F)(F)F)C=CC=CC1CC(O)=O FVXIPVHDRCDSRW-UHFFFAOYSA-N 0.000 description 1
- LUYQINUDJUXWNB-UHFFFAOYSA-N 3-(1-ethoxyethoxy)-4-phenylazetidin-2-one Chemical compound N1C(=O)C(OC(C)OCC)C1C1=CC=CC=C1 LUYQINUDJUXWNB-UHFFFAOYSA-N 0.000 description 1
- FQOAQSKCRBQNAS-UHFFFAOYSA-N 3-[1-ethoxyethyl-[(2-methylpropan-2-yl)oxycarbonyloxy]amino]-2-hydroxy-3,3-diphenylpropanoic acid Chemical compound C(C)(C)(C)OC(=O)ON(C(C(O)C(=O)O)(C1=CC=CC=C1)C1=CC=CC=C1)C(C)OCC FQOAQSKCRBQNAS-UHFFFAOYSA-N 0.000 description 1
- XHSOADPDMLUHPW-UHFFFAOYSA-N 3-[1-ethoxyethyl-[(2-methylpropan-2-yl)oxycarbonyloxy]amino]-2-hydroxy-3-phenylpropanoic acid Chemical compound C(C)(C)(C)OC(=O)ON(C(C(O)C(=O)O)C1=CC=CC=C1)C(C)OCC XHSOADPDMLUHPW-UHFFFAOYSA-N 0.000 description 1
- HOPLWKIYJSEHOL-UHFFFAOYSA-N 3-[benzoyloxy(1-ethoxyethyl)amino]-2-hydroxy-2-methyl-3-phenylpropanoic acid Chemical compound C(C1=CC=CC=C1)(=O)ON(C(C(O)(C(=O)O)C)C1=CC=CC=C1)C(C)OCC HOPLWKIYJSEHOL-UHFFFAOYSA-N 0.000 description 1
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- WSKFEANLIDSKSN-UHFFFAOYSA-N 5-(1-ethoxyethoxy)-2,4-diphenyl-4,5-dihydro-1,3-oxazin-6-one Chemical compound O1C(=O)C(OC(C)OCC)C(C=2C=CC=CC=2)N=C1C1=CC=CC=C1 WSKFEANLIDSKSN-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical class [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 235000009065 Taxus cuspidata Nutrition 0.000 description 1
- 239000004098 Tetracycline Substances 0.000 description 1
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- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
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- 230000000719 anti-leukaemic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 150000005840 aryl radicals Chemical group 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
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- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- 239000000039 congener Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002170 ethers Chemical group 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
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- 235000007586 terpenes Nutrition 0.000 description 1
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Abstract
一种制备紫杉酚中间体的方法,它包括将一种醇和一种如下式所示的嗪酮相接触。式中R1是芳基,杂芳基,烷基,烯基,炔基,或OR7,其中R7是烷基,烯基,炔基,芳基或杂环基;R2和R5分别选自氢,烷基,烯基,炔基,芳基,杂芳基和OR8,其中R8是烷基,烯基,炔基,芳基,杂芳基或羟基保护基;R3和R6分别选自氢,烷基,烯基,炔基,芳基和杂芳基。
Description
本发明涉及一种新的噁嗪酮,其制备方法,和一种使用这样的噁嗪酮制备紫杉酚的方法。
萜中的紫杉烷族(紫杉酚是其中一员)已经吸引了生物和化学工艺方面的相当多的兴趣。紫杉酚是一个具有广谱抗白血病和抑制肿瘤活性的有前途的癌症化疗剂,具有如下结构:由于其大有希望的活性,紫杉酚目前正在法国和美国进行临床试验。
目前用于这些临床试验的紫杉酚的供应是由几种紫杉属树木的树皮来提供的。然而,人们发现紫杉酚仅以微小的量存在于这些生长缓慢的长青植物的树皮中,紫杉酚的有限的供应将难以满足需要,这一点已引起了相当的关注。随后,在最近一些年里,化学家们把精力花费在试图寻找一条可行的用于制备紫杉酚的合成路线上。到目前为止,结果还不能完全令人满意。
已经提出的一条合成路线旨在由商品化学制品来合成四环的紫杉烷母核。Holton等在JACS 110,6558(1988)中报导了紫杉酚同族物紫杉素的合成。尽管在这种探索中已取得进展,然而,紫杉酚的最终全合成看起来还是一个多步、冗长而又成本高的工艺。
制备紫杉酚的另一种方法已由Greene等在JACS110,5917(1988)中进行了描述,它涉及使用一个紫杉酚的同族物10-去乙酰基浆果赤霉素Ⅲ,它具有如下结构:10-去乙酰基浆果赤霉素Ⅲ比紫杉酚更容易得到,因为它可以得自浆果紫杉的叶子。根据Greene等人的方法,通过连缜上C位乙酰基和经C-13醇与-β-酰胺基羧酸单元之间的酯化反应连结上C-13β-酰胺酯侧链而将10-去乙酰基浆果赤霉素Ⅲ转化为紫杉酚。尽管这一方法上需要很少的步骤,但β-酰胺基羧酸单元的合成却是一个收率低的多步工艺,而且缩合反应繁冗,收率又低,然而,这一缩合反应在每一个所考虑的紫杉酚或其有生物活性的衍生物的合成中都是必须的一个关键步骤,因为Wani等人已在JACS 93,2325(1971)中指明在C-13位β-酰胺酯侧链的存在对于抗肿瘤活性来说是必要的。
在紫杉酚和其它有潜力的抗肿瘤剂的合成中仍然存在的主要困难是缺少一个相当容易得到的、能够很容易地接到C-13氧上以提供β-酰胺酯侧链的单元。这样一个单元和用于其以高收率连结上去的工艺的开发将有助于紫杉酚和有关的、具有改性的一系列母核取代基或一个改性的C13侧链的抗肿瘤剂的合成。这一需要,通过一个很容易得到的新的侧链前体化学单元及一种用于将它连结到C13氧上的有效的工艺的发现而得到了满足。
因此,本发明的目的之一是提供一种用于紫杉酚合成的侧链前体并提供一种将该侧链前体以相当高的收率连上去以提供一个紫杉酚中间体的方法。
其中,R1是芳基、杂芳基、烷基、烯基、炔基或-OR7,其中R7是烷基,烯基,炔基,芳基或杂芳基;R2和R5分别选自氢,烷基,烯基,炔基,芳基,杂芳基和-OR8,其中R8是烷基,烯基,炔基,芳基,杂芳基或羟基保护基;R3和R6分别选自氢,烷基,烯基,炔基,芳基和杂芳基。
本发明还涉及一种制备紫杉酚中间体的方法,该方法包括在足够量的活化剂的存在下将一种醇与一个噁嗪酮1相接触以引发噁嗪酮与醇起反应形成β-酰胺酯,后者被用作紫杉酚合成中的中间体。
本发明还涉及制备紫杉酚的方法,该方法包括在足够量的活化剂的存在下将一种醇与噁嗪酮1相接触以引发噁嗪酮与醇起反应形成一个β-酰胺酯紫杉酚中间体,然后该中间体用于紫杉酚的合成。
本发明的其它目的和特征,部分是显而易见的,部分将在下文中指出。
本发明涉及一种噁嗪酮1及其衍生物,其结构描述如下:如上面所表明的,R1是芳基,杂芳基,烷基,烯基,炔基或OR7,其中的R7是烷基,烯基,炔基,芳基或杂芳基;R2和R5别选自氢,烷基,烯基,炔基,芳基,杂芳基或OR8,其中的R8是烷基,烯基,炔基,芳基或杂芳基,或羟基保护基; R3和R6分别选自氢,烷基,烯基,炔基,芳基或杂芳基。
更理想些,噁嗪酮1具有如下结构:其中,R1,R3和R8如前所定义,最理想的R8是乙氧乙基或2,2,2-三氯乙氧甲基。这样,最理想的噁嗪酮结构表示如下,其中R1和R3是苯基,R5是氢,R2是OR8,其中R8是乙氧乙基,依据IUPAC规则,噁嗪酮2的名称是2,4-二苯基-5-(1-乙氧乙氧基)-4,5-二氢-1,3-噁嗪-6-酮。
A和B分别是氢或低级烷酰氧基,烯酰氧基,炔酰氧基或芳酰氧基或
A和B一起形成一氧桥;
L和D分别是氢或羟基或低级烷酰氧基,烯酰氧基,炔酰氧基或芳酰氧基;
E和F分别是氢或低级烷酰氧基,烯酰氧基,炔酰氧基或芳酰氧基或是
E和F一起形成一氧桥;
G是氢或羟基或低级烷酰氧基,烯酰氧基,炔酰氧基或芳酰氧基,或者
G和M一起形成一氧桥或甲撑,或者
G和M一起形成一个环氧乙烷环或者
M和F一起形成一个氧杂环丁烷环;
J是氢,羟基,或低级烷酰氧基,烯酰氧基,炔酰氧基或芳酰氧基,或者
I是氢,羟基,或低级烷酰氧基,烯酰氧基,炔酰氧基或芳酰氧基;或者
I和J一起形成一氧桥;
K是氢,羟基,或低级烷氧基,烷酰氧基,烯酰氧基,炔酰氧基或芳酰氧基;
P和Q分别是氢或低级烷酰氧基,烯酰氧基,炔酰氧基或芳酰氧基,或者
P和Q一起形成一氧桥;
S和T分别是氢或低级烷酰氧基,烯酰氧基,炔酰氧基或芳酰氧基,或者
S和T一起形成一氧桥,
U和V分别是氢或低级烷基,烯基,炔基,芳基或取代芳基;
W是芳基,取代芳基,低级烷基,烯基,炔基,烷氧基,或苯氧基。
紫杉酚的烷基,单独的或是带有如上文所定义的各种取代基,最好是在主链上含有1至6个碳原子并含有可高达10个碳原子的低级烷基,它们可以是直链的或支链的,包括甲基,乙基,丙基,异丙基,丁基,异丁基,特丁基,芳基,己基,等等。
紫杉酚的烯基,无论是单独的还是带有上文所定义的各种取代基的,最好是在主链上含有2至6个碳原子并含有可高达10个碳原子的低级烯基。它们可以是直链的或是支链的,包括乙烯基,丙烯基,异丙烯基,丁烯基,异丁烯基,芳基,己烯基,等等。
紫杉酚的炔基,无论是单独的还是带有上文所定义的各种取代基的,最好是在主链上含有2至6个碳原子并含有可高达10个碳原子的低级炔基。它们可以是直链的或支链的,包括乙炔基,丙炔基,丁炔基,异丁炔基,芳基,己炔基等等。
典型的烷酰氧基包括乙酸基,丙酸基,丁酸基,戊酸基,异丁酸基等。最理想的烷酰氧基是乙酸基。
紫杉酚的芳基部分,无论是单独的还是带有各种取代基的,都含有6至10个碳原子,包括苯基,α-萘基或β-萘基,等等。取代基包括烷氧基,羟基,氢,烷基,芳基,烯基,酰基,酰氧基,硝基,氨基,酰胺基等等。苯基是最理想的芳基。
如这里所定义的,“芳酰氧基”一词包括芳香杂环部分,“芳基”一词包括任何具有一个芳香环的化合物,在这一芳环中无杂原子,而“杂芳基”一词包括任何具有一个芳香环的化合物,在这一芳环包含有一个杂原子。
取代基A,B,D,L,E,F,G,M,I,J,K,P,Q,S,T,U,V,和W的比较理想的函义在表1中列举如下:
表1A和B-起形成氧桥 A=H A=OCOR A=B=H;
B=OAC, B=H,L=H L=OH L=D=H;D=OH, D=H,E=H, E-OAc, E和F一起形成 E=HF=OAc F=H 氧桥 F=O(氧杂环丁烷)G和M=CH2 G=CH2 G=O G和M一起形成氧桥G=OAc G=H
M=O M=CH2 M=CH2O M=CH2O
(环氧化物) (环氧化物) (氧杂环丁烷)(氧杂环丁烷)I=J=O, I=J=H I=COPh I=COAr
J=H; J=H;K=H, K=OH, K=OR, K=OCOR, K=OCOAr,P和Q-起形成氧桥 P=H P=OCOR P=Q=H;
Q=OAc, Q=H,S和T一起形成 S=H S=H S=OCOR S=OR S=OH S=H
氧桥 T=OCOR, T=OR, T=H, T=H, T=H, T=CH;U=H U=H U=N U=Ph U=Ar U=R U=V=H;V=R, V=Ph, V=Ar, V=H, V=H, V=H,W=R, W=Ar; W=Ar
依据本发明的方法,在一个醇和一种活化剂,最好是象三乙胺,二异丙基乙基胺,吡啶,N-甲基咪唑和4-二甲胺基吡啶(DMAP)这样的叔胺的存在下,噁嗪酮1被转化成β-酰胺酯。例如,在4-二甲胺基吡啶(DMAP)的存在下,噁嗪酮1与具有紫杉烷四环母核和一个C13羟基的化合物起反应,提供出在C13位上具有一个酰胺酯基的物质。
更理想些,这个醇是7-O-三乙基硅基浆果赤霉素Ⅲ,它可以象Greene等人在JACS 110,5917(1988)中所描述的那样而得到或通过其它路线得到。如Greene等人所报道的那样,10-去乙酰基浆果赤霉素Ⅲ可依据下述反应式而转变成7-O-三乙基硅基浆果赤霉素Ⅲ:在据说是已被仔细优化的条件下,10-去乙酰基浆果赤霉素Ⅲ在50ml吡啶(/mmol 10-去乙酰基浆果赤霉素)的存在下,在氩气气氛下与20个当量的(C2H5)3Sicl在23℃反应20小时,得到作为反应产物的7-三乙基甲硅烷基-10-去乙酰浆果赤霉素Ⅲ(31a),纯化后收率为84-86%。然后将反应产物在氩气气氛下与5个当量的CH3COCl和25ml/31a的吡啶在0℃反应48小时,得到收率为86%的7-O-三乙基甲硅烷基浆果赤霉素Ⅲ(31b)。见Greene等人JACA1105917(1988)在5918页上。
如下面反应式中所示,7-O-三乙基甲硅烷基浆果赤霉素Ⅲ可以在室温下与本发明的噁嗪酮反应生成一个紫杉酚中间体,在该中间体中C-7和C-2羟基分别用三乙基硅基和乙氧乙基保护基进行保护。然后将这些基团在温和的条件下水解以不致干扰紫杉酚取代基的酯键。按下式由噁嗪酮2合成紫杉酚:
尽管本反应式涉及天然产物紫杉酚的合成,它也可以在经过在噁嗪酮或自天然或非天然的来源衍生而来的四环醇上进行改性以后用于制备其它的考虑在本发明范围内的合成的紫杉酚。
可供选择的是,噁嗪酮1可以在活化剂和除了7-O-三乙基甲硅烷基浆果赤霉素Ⅲ以外的一种醇的存在下被转化成一个β-酰胺酯以形成一个紫杉酚中间体。然后,紫杉酚的合成可以用这个紫杉酚中间体在一适当的反应系统下进行。
噁嗪酮的烷基,无论是单独的还是带有各种如上所定义的取代基的,都最好是在主链上有1至6个碳原子并含有可高达10个碳原子的低级烷基。它们可以是直链的或支链的,包括甲基,乙基,丙基,异丙基,丁基,异丁基,特丁基,芳基,己基等等。
噁嗪酮的烯基,无论是单独的还是带有各种上文所定义的取代基的,都最好是在主链上有2至6个碳原子并含有可高达15个碳原子的低级烯基。它们可以是直链的或是支链的,包括乙烯基,丙烯基,异丙烯基,丁烯基,异丁烯基,芳基,己烯基等等。
噁嗪酮的炔基,无论是单独的还是带有上文所定义的各种取代基的,都最好是在主链上有2至6个碳原子并含有可达15个碳原子的低级炔基。它们可以是直链的或是支链的,包括乙炔基,丙炔基,丁炔基,异丁炔基,芳基,己炔基等等。
典型的噁嗪酮烷酰氧基包括乙酸基,丙酸基,丁酸基,戊酸基,异丁酸基等。最理想的烷酰氧基是乙酸基。
上述的噁嗪酮芳基部分,无论是单独的还是带有各种取代基的,都含有6至15个碳原子,包括苯基,α-萘基或β-萘基等。取代基包括烷氧基、羟基、卤素、烷基、芳基、烯基、酰基、酰氧基、硝基、氨基,酰胺基等等。苯基是最理想的芳基。
如同上面所表明的,噁嗪酮1的R2和R5可以是-OR8,R8是烷基,酰基,缩酮,乙氧乙基(“EE”),2,2,2-三氯乙氧甲基,或其它象乙缩醛和醚这样的羟基保护基,即甲氧甲基(“MOM”),苄氧甲基;也可以是象乙酸酯这样的酯;象碳酸甲酯这样的碳酸酯;等等。在T.W.Greene所著的“有机合成中的保护基团”,John Wiley and Sons1981,一书中可以发现大量的用于羟基的保护基团及其合成。所选择的羟基保护基应该能在足够温和、不足以干扰紫杉酚的酯键或其它取代基的条件下很容易地离去。然而,较理想些,R是乙氧乙基或2,2,2-三氯乙氧甲基,最理想的是乙氧乙基。
噁嗪酮取代基R1,R2,R3,R5,R6,R7和R8的较理想的函义在这里列举如下:R1=OR7 R1=Ar R1=p-MeOPh R1=烷基 R1=烯基 R1=炔基 R1=HR2=OR8R3=ph R3=Ar R3=p-MeOPh R3=烷基 R3=烯基 R3=炔基 R3=HR5=HR6=HR7=烷基 R7=烯基 R7=炔基 R7=芳基 R7=杂芳基R8=EE R8=烷基 R8=OCOR R8=MOM R8=Cl3CCH2OCH2
由于噁嗪酮1有几个不对称碳,本领域的技术人员都知道具有不对称碳原子的本发明的化合物可以以非对映异构体、外消旋体或光学活性体的形式存在。所有这些形式都被考虑在本发明的范围之内。尤其是,本发明包括对映体,非对映异构体,消旋体混合物和它们的其它混合物。
另一种作法是,羧酸33可以按照Greene等人在JACS110,5917(1988)中所描述的方法而制得。β-内酰胺32可以由容易得到的原料制得,如下述反应式所示,其中R1和R3是苯基,R5和R6是氢而R2是-OR8,其中R8是乙氧乙基:试剂:(a)三乙胺,CH2Cl2,25℃,18h;(b)4当量硝酸铈铵,CH3CN,-10℃,10min,(c)KOH,THF,H2O,0℃,30min;(d)乙基乙烯基醚,THF,对甲苯磺酸,(催化剂),0℃,1.5h;(e)CHLi;乙醚,-78℃,10min;苯甲酰氯,-78℃,1h。
起始原料是容易得到的。α-乙酰氧基乙酰氯由乙醇酸制得,然后,在叔胺的存在下,它与由醛和对甲氧基苯胺制得的亚胺进行环缩合而给出1-对甲氧苯基-3-乙酰氧基-4-芳基氮杂环丁烷-2-酮。
对甲氧苯基可以通过用硝酸铈铵进行氧化而很容易地除去,而乙酰氧基可以在本领域技术人员所熟悉的标准条件下水解掉而给出3-羟基-4-芳基氮杂环丁烷-2-酮。
3-羟基可以用大量的象1-乙氧乙基这样的标准的保护基来进行保护。理想些,将外消旋的3-羟基-4-芳基氮杂环丁烷-2-酮在保护前先通过重结晶其相应的2-甲氧基-2-(三氟甲基)苯基乙酸酯而使之先分拆成纯的对映体,而只将右施的对映体用于紫杉酚的制备。无论怎样,3-(1-乙氧乙氧基)-4-苯基氮杂环丁烷-2-酮可以通过用一种碱,最好是正丁基锂,和一种芳酰氯在-78℃或更低的温度下进行处理而转变成β-内酰胺32。
实施例1 顺-2,4-二苯基-5-(1-乙氧基乙氧基)-4,5-二氢-1,3-二噁嗪-6-酮(2)的制备
顺-1-对甲氧苯基-3-乙酰氧基-4-苯基氮杂环丁烷-2-酮。
向962mg(4.56mmol)由苯甲醛和对甲氧基苯胺衍生生成的亚胺和0.85ml(6.07mmol)三乙胺在15ml CH2Cl2的溶液中,在-20℃滴加413mg(3.04mmol)α-乙酰氧基乙酰氯在15ml CH2Cl2中的溶液。反应混合物经18小时升温至25℃,然后用100mlCH2Cl2稀释,用30ml Hcl水溶液萃取,有机层用30ml水和30ml饱和碳酸氢的溶液洗,经硫酸钠干燥后浓缩得到一固体物。该固体用50ml己烷研制,将混合物过滤。所剩固体从乙酸乙酯/己烷中重结晶得到645mg(68%)白色晶体顺-1-对甲氧苯基-3-乙酰氧基-4-苯基氮杂环丁烷-2-酮。m.p.163℃
顺-3-羟基-4-苯基氮杂环丁烷-2-酮。
向20.0g顺-1-对甲氧苯基-3-乙酰氧基-4-苯基氮杂环丁烷-2-酮在700ml乙腈的溶液中在-10℃、1小时内慢慢滴加硝酸铈铵在450ml水的溶液。反应混合物在-10℃搅拌30分钟,用500ml乙醚稀释。水层用两份100ml的乙醚萃取,合并有机层并用两份100ml水,两份100ml饱和的亚硫酸氢钠溶液和两份100ml饱和的碳酸氢钠溶液洗,浓缩有机层得到18.5g固体。从丙酮/己烷中重结晶得到12.3g(92%)白色结晶顺-3-乙酰氧基-4-苯基氮环丁烷-2-酮。m.p.152-154℃。
顺-3-羟基-4-苯基氮杂环丁烷-2-酮。
向200ml THF和280ml 1M氢氧化钾水溶液的混合液中,在0℃、40分钟内经一滴液漏斗加入4.59g(22.4mmol)顺-3-乙酰氧基-4-苯基氮杂环丁烷-2-酮在265ml THF中的溶液。溶液在0℃搅拌1小时,加入100ml饱和的碳酸氢钠溶液。混合物用4份200ml的乙酸乙酯萃取,合并有机层,经硫酸钠干燥后浓缩得到3.54g(97%)外消旋的顺-3-羟基-4-苯基氮杂环丁烷-2-酮白色晶体,m.p.147-149℃。通过在己烷/丙酮中重结晶它的2-甲氧基-2-三氟甲基苯乙酸酯和水解可以将该物质拆分为它的对映体〔α〕25Hg177°。
顺-3-(1-乙氧基乙氧基)-4-苯基氮杂环丁烷-2-酮。
向3.4g(20.9mmol)顺-3-羟基-4-苯基氮杂环丁烷-2-酮在15ml THT的溶液中,在0℃加入5ml乙基乙烯醚和20mg(0.2mmol)甲基磺酸。混合物在0℃搅拌20分钟后用20ml饱和碳酸氢钠溶液稀释,并用3份40ml乙酸乙酯萃取。合并乙酸乙酯层,经硫酸钠干燥后浓缩得到4.87g(99%)无色油状物顺-3-(1-乙氧基乙氧基)-4-苯基氮杂环丁烷-2-酮。
顺-1-苄氧基-3-(1-乙氧基乙氧基)-4-苯基氮杂环丁烷-2-酮。
往2.35g(10mmol)顺-3-(1-乙氧基乙氧基)-4-苯基氮杂环丁烷-2-酮在40ml THF的溶液中在-78℃加入6.1ml(10.07mmol)1.65M的正丁基锂的己烷溶液。混合物在-78℃搅拌10分钟后加入1.42g(10.1mmol)氯化苄在10ml THF的溶液。混合物在-78℃搅拌1小时,用70ml饱和碳酸氢钠溶液稀释,再用3份50ml乙酸乙酯萃取。合并乙酸乙酯萃取液,经硫酸钠干燥后浓缩得到3.45g油状物。将油状物在硅胶色谱柱上用乙酸乙酯/己烷洗脱得3.22g(95%)无色油状物顺-1-苄氧基-3-(1-乙氧基乙氧基)-4-苯基氮杂环丁烷-2-酮。
2R,3S-N-苄氧基-O-(1-乙氧基乙基)-3-苯基异丝氨酸。
往460mg(1.36mmol)顺-1-苄氧基-3-(1-乙氧基乙氧基)-4-苯基氮杂环丁烷-2-酮在20mlTHF的溶液中,在0℃加入13.5ml(13.5mmol)1M的氢氧化钾溶液。混合物在0℃搅拌10分钟,蒸出THF。混合物在12ml 1N的Hcl水溶液和30ml氯仿间分开。水层再用30ml氯仿萃取。合并氯仿萃取液,经硫酸钠干燥后浓缩得到416mg(86%)2R,3S-N-苄氧基-O-(1-乙氧乙基)-3-苯基异丝氨酸(式33,式中R1和R3是苯基,R2是乙氧基乙基)。
顺-2,4-二苯基-5-(1-乙氧基乙氧基)-4,5-二氢-1,3-噁嗪-6-酮(2)。
往416mg(1.16mmol)2R,3S-N-苄氧基-O-(1-乙氧乙基)-3-苯基异丝氨酸在20ml THF的溶液中加入261mg(2.33mmol)固体叔丁醇钾,混合物在25℃搅拌30分钟,加入134mg(1.16mmol)甲基磺酰氯在3.2ml THF的溶液,混合物在25℃搅拌1.5小时后用80ml己烷和乙酸乙酯稀释,用20ml饱和碳酸氢钠溶液和10ml盐水萃取。有机层经硫酸钠干燥后浓缩得到256mg(65%)无色油状物顺-2,4-二苯基-5-(1-乙氧基乙氧基)-4,5-二氢-1,3-噁嗪-6-酮,〔α〕25 Hg-20℃(CHcl3,C1.55)。
实施例2 紫杉酚的制备
在一小反应瓶中加入77mg(0.218mmol)(-)-顺-2,4-二苯基-5-(1-乙氧基乙氧基)-4,5-二氢-1,3-噁嗪-6-酮(2)、40mg(0.057mmol)7-O-三乙基甲硅烷基浆果赤霉素Ⅲ、6.9mg(0.057mmol)4-二甲胺基吡啶(DMAP)和0.029ml吡啶。混合物在25℃搅拌12小时,用100ml乙酸乙酯稀释。乙酸乙酯溶液用20ml 10%硫酸铜溶液萃取,经硫酸钠干燥后浓缩。残余物以乙酸乙酯为洗脱剂经硅胶短柱滤过。用乙酸乙酯/己烷为洗脱剂经快速硅胶色谱分离后再以乙酸乙酯/己烷中重结晶得到46mg(77%)2′-O-(1-乙氧基乙基)-7-O-三乙基甲硅烷基紫杉酚(约2∶1非对映体的混合物)和9.3mg(23%)7-O-三乙基甲硅烷基浆果赤霉素Ⅲ。收率以消耗的7-O-三乙基甲硅烷基浆果赤霉素为基准,是定量的。
将5mg 2′-(1-乙氧基乙基)-7-O-三乙基甲硅烷基紫杉酚样品溶于2ml乙醇中,加入0.5ml 0.5%HCl水溶液。混合物在0℃搅拌30小时后用50ml乙酸乙酯稀释。溶液用20ml饱和碳酸氢钠溶液萃取,经硫酸钠干燥后浓缩。残余物在硅胶柱上用乙酸乙酯/己烷洗脱精制得到3.8mg(约90%)紫杉酚,它在所有方面都和真实样品相同。
实施例3 N-脱苯甲酰基-N-叔丁氧羰基紫杉酚的制备2-叔丁氧基-4-苯基-5-(1-乙氧基乙氧基)-4,5-二氢-1,3-噁嗪-6-酮。
往409mg(1.16mmol)N-叔丁氧羰基-O-(1-乙氧基乙基)-3-苯基异丝氨酸(3)在20ml THF的溶液中加入261mg(2.33mmol)固体叔丁醇钾,混合物在25℃搅拌30分钟。加入134mg(1.16mmol)甲基磺酰氯在3.2ml THF的溶液,混合物在25℃搅拌1.5小时。反应混合物用80ml己烷和乙酸乙酯稀释后用20ml饱和碳酸氢钠和10ml盐水萃取,有机相用硫酸钠干燥,浓缩得到2.35mg(70%)无色油状物2-叔丁氧基-4-苯基-5-(1-乙氧基乙氧基)-4,5-二氢-1,3-噁嗪-6-酮。N-脱苯甲酰基-N-叔丁氧羰基紫杉酚。
在一个小反应瓶中加入72mg(0.218mmol)2-叔丁氧-4-苯基-5-(1-乙氧基乙氧基)-4,5-二氢-1,3-噁嗪-6-酮、40mg(0.057mmol)7-O-三乙基甲硅烷基浆果赤霉素Ⅲ、6.9mg(0.057mmol)4-二甲胺基吡啶(DMAP)和0.029ml吡啶。混合物在25℃搅拌12小时,用100ml乙酸乙酯稀释。乙酸乙酯溶液用20ml 10%硫酸铜溶液萃取,用硫酸钠干燥,浓缩。残余物以乙酸乙酯为洗脱剂经一硅胶短柱滤过。以乙酸乙酯/己烷为洗脱剂经快速硅胶色谱分离后再从乙酸乙酯/己烷中重结晶得到44mg(73%)N-脱苯基-N-叔丁氧羰基-2′-(1-乙氧基乙氧基)-7-O-三乙基甲硅烷基紫杉酚(约1∶1非对映体-混合物)和9.3mg(23%)7-O-三乙基甲硅烷基浆果赤霉素Ⅲ。
将5mg N-脱苯甲酰基-N-叔丁氧羰基-2′-(1-乙氧基乙氧基)-7-O-三乙基甲硅烷基紫杉酚样品溶于2ml乙醇中,加入0.5ml 0.5%的Hcl水溶液。混合物在0℃搅拌30小时,用50乙酸乙酯稀释。溶液用20ml饱和碳酸氢钠溶液萃取,经硫酸钠干燥后浓缩。残余物在硅胶色谱在上同乙酸乙酯/己烷洗脱精制得到3.8mg(约90%)N-脱苯甲基-N-叔丁氧羰基紫杉酚。
往497mg(1.16mmol)N-叔丁氧羰基-O-(1-乙氧基乙基)-3,3-二苯基异丝氨酸(3)在20mlTHF的溶液中加入261mg(2.33mmol)固体叔丁醇钾,混合物在25℃搅拌30分钟。加入134mg(1.16mmol)甲基磺酰氯在3.2ml THF的溶液,混合物在25℃搅拌1.5小时。反应混合物用80ml己烷和乙酸乙酯稀释,用20ml饱和碳酸氢钠和10ml盐水萃取。有机相经硫酸钠干燥后浓缩得到243mg(59%)无色油状物2-叔丁氧基-4,4-二苯基-5-(1-乙氧基乙氧基)-4,5-二氢-1,3-恶嗪-6-酮。N-脱苯甲酰基-N-叔丁氧羰基-3′-苯基紫杉酚。
在一个小反应瓶中加入90mg(0.218mmol)2-叔丁氧基-4,4-二苯基-5-(1-乙氧基乙氧基)-4,5-二氢-1,3-二噁嗪-6-酮、40mg(0.057mmol)7-O-三乙基甲硅烷基浆果赤霉素、6.9mg(0.057mmol)4-二甲胺基吡啶(DMAP)和0.029ml吡啶。混合物在25℃搅拌12小时,用100ml乙酸乙酯稀释。乙酸乙酯溶液用20ml 10%的硫酸铜溶液萃取,经硫酸钠干燥后浓缩。残余物以乙酸乙酯为洗脱剂经一个硅胶短柱滤过。以乙酸乙酯/己烷为洗脱剂经快速硅胶色谱分离后再以乙酸乙酯/己烷中重结晶得到44mg(66%)N-脱苯甲酰基-N-叔丁氧羰基-2′-(1-乙氧基乙基)-3′-苯基-7-O-三乙基甲硅烷基紫杉酚(约3∶1非对映体混合物)。
将将mg N-脱苯甲酰基-N-叔丁氧羰基-2′-(1-乙氧基乙基)-3′-苯基-7-O-三乙基甲硅烷基紫杉酚溶于2ml乙醇,加入0.5ml 0.5%的HCl水溶液,混合物在0℃搅拌30小时,用50ml乙酸乙酯稀释。溶液用20ml饱和的碳酸氢钠溶液萃取,经硫酸钠干燥后浓缩。残余物在硅胶色谱柱上用乙酸乙酯/己烷洗脱精制得4.0mg(90%)N-脱苯甲酰基-N-叔丁氧羰基-3′-苯基紫杉酚。
实施例5 2,4-二苯基-5-(1-乙氧基乙氧基)-5-甲基-4,5-二氢-1,3-噁嗪-6-酮的制备
向430mg(1.16mmol)N-苯甲酰基-O-(1-乙氧基乙基)-2-甲基-3-苯基异丝氨酸在20ml THF的溶液中加入261mg(2.33mmol)固体叔丁醇钾,混合物在25℃搅拌30分钟。加入134mg(1.16mmol)甲磺酰氯在3.2ml THF的溶液,混合物在25℃搅拌1.5小时。反应液用80ml己烷和乙酸乙酯稀释,用20ml饱和碳酸氢钠溶液和10ml盐水萃取。有机相经硫酸钠干燥后浓缩得到270mg(76%)无色油状物2,4-二苯基-5-(1-乙氧基乙氧基)-5-甲基-4,5-二氢-1,3-噁嗪-6-酮。
实施例6 3′-甲基紫杉酚
在一个小反应瓶中加入77mg(0.218mmol)2,4-二苯基-5-(1-乙氧基乙氧基)-5-甲基-4,5-二氢-1,3-噁嗪-6-酮、40mg(0.057mmol)7-O-三乙基甲硅烷基浆果赤霉素Ⅲ、6.9mg(0.057mmol)4-二甲胺基吡啶(DMAP)和0.029ml吡啶。混合物在25℃搅拌12小时,用100ml乙酸乙酯稀释。乙酸乙酯溶液用20ml 10%的硫酸铜溶液萃取,经硫酸钠干燥后浓缩,残余物以乙酸乙酯为洗脱剂经一硅胶短柱滤过。以乙酸乙酯/己烷为洗脱剂经快速硅胶色谱分离后再从乙酸乙酯/己烷中重结晶得32mg(53%)2′-(1-乙氧基乙基)-3′-甲基-7-O-三乙基甲硅烷基紫杉酚(约1∶1非对映体混合物)。
将5mg 2′-(1-乙氧基乙基)-3′-甲基-7-O-三乙基甲硅烷基紫杉酚溶于2ml乙醇中,加入0.5ml 0.5%的Hcl水溶液。混合物在0℃搅拌30小时,用50ml乙酸乙酯稀释。混合液用20ml饱和碳酸氢钠溶液萃取,经硫酸钠干燥后浓缩。残余物在硅胶色谱柱上用乙酸乙酯/己烷洗脱精制得3.9mg(约90%)3′-甲基紫杉酚。
综上所述,可以看出本发明的几个目的是可以达到的。
因为在不背离本发明的范围内在上述组成和方法上可做各种改变,因此上述描述的所有内容都是说明性的而非限制本发明。
Claims (9)
1.下式紫杉酚的制备方法:其中
A和B独立地是氢或低级烷酰氧基,链烯酰氧基,炔酰氧基,或芳酰氧基,或
A和B一起成一氧桥;
L和D独立地是氢或羟基或低级烷酰氧基,链烯酰氧基,炔酰氧基,或芳酰氧基;
E和F独立地是氢或低级烷酰氧基,链烯酰氧基,炔酰氧基,或芳酰氧基,或
E和F一起形成一氧桥;
G是氢或羟基或低级烷酰氧基,链烯酰氧基,炔酰氧基,或芳酰氧基或
G和M一起形成一氧桥或亚甲基或
G和M一起形成环氧乙烷或
M和F一起形成氧杂环丁烷;
J是氢,羟基,或低级烷酰氧基,链烯酰氧基,炔酰氧基或芳酰氧基或
I是氢,羟基,或低级烷酰氧基,链烯酰氧基,炔酰氧基,或芳酰氧基;或
I和J一起成一氧桥;
K是氢,羟基或低级烷氧基,烷酰氧基,链烯酰氧基,炔酰氧基,或芳酰氧基;
P和Q独立地是氢或低级烷酰氧基,链烯酰氧基,烷酰氧基,或芳酰氧基或
P和Q一起成一氧桥;
S是羟基;
T是氢;
U和V独立地是氢,或C1-6烷基,C2-6链烯基,C2-6炔基,C6-15芳基,或取代的C6-15芳基;以及
W是C6-15芳基,取代的C6-15芳基,C1-6烷基,C2-6链烯基或C2-6炔基,该方法包括:
使下式的噁嗪酮:
其中R1是C6-10芳基,取代的C6-10芳基,杂C6-10芳基,C1-6烷基,C2-6链烯基,C2-6炔基或-OR7,其中R7是C1 -6烷基,C2-6链烯基,C2-6炔基,C6-10芳基或杂C6-10芳基;R5是氢;R2是-OR8,其中R8是羟基保护基;以及R3和R6独立地是选自氢、C1-6烷基、C2-6链烯基、C2-6炔基、C6-10芳基、取代的C6-10芳基和杂C6-10芳基,在上述基团中,所述取代基选自烷氧基,氢,卤素,烷基,芳基,链烯基,酰基,酰氧基,硝基,氨基,酰氨基;与下式醇接触:
其中所述A,B,E,F,G,I,J,K和M定义如上,且X1和X2独立地是羟基保护基,所述噁嗪酮和所述醇的接触是在足够量的叔胺活化剂存在下进行的,使噁嗪酮与醇反应,生成适用作合成紫杉酚中间体的β-酰氨酯,以及将所述中间体转化为紫杉酚。
2.权利要求1的方法,其中所说的活化剂是三乙胺,二异丙基乙基胺,吡啶,N-甲基咪唑,或是4-二甲胺基吡啶。
3.权利要求1的方法,其中醇具有如下结构式:其中R4是羟基保护基,Ph是苯基且Ac是乙酰基。
4.权利要求3的方法,其中R1和R3是苯基,R6是氢。
5.权利要求4的方法,其中所说的活化剂是三乙胺,二异丙基乙基胺,吡啶,N-甲基咪唑,或是4-二甲胺基吡啶。
与一种具有下式的噁嗪酮相接触:其中R1是C6-10芳基,取代的C6-10芳基,杂C6-10芳基,C1 -6烷基,C2-6烯基,C2-6炔基或-OR7,R7是C1-6烷基,C2-6烯基,C2-6炔基,C6-10芳基或杂C6-10芳基;R5是氢;R2是-OR8,其中R8是羟基保护基;且R3和R6独立地选自氢,C1-6烷基,C2-6烯基,C2-6炔基,C6-10芳基,取代C6-10芳基和杂C6-10芳基,在上述基团中,所述取代基选自烷氧基,氢,卤素,烷基,芳基,链烯基,酰基,酰氧基,硝基,氨基,酰氨基;
所说的醇与噁嗪酮的接触在足够量的叔胺存在下进行以引发噁嗪酮与醇反应形成β-酰胺酯,后者适合于在一种紫杉酚合成中用作中间体,并将所说的中间体转化成一种紫杉酚。
7.权利要求6的方法,其中作为羟基保护基的R4选自三乙基甲硅烷基、乙氧基乙氧基和2,2,2-三氯乙氧基甲基。
8.权利要求7的方法,其中活化剂是一种叔胺。
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US07/436,235 US5015744A (en) | 1989-11-14 | 1989-11-14 | Method for preparation of taxol using an oxazinone |
US07/436,235 | 1989-11-14 | ||
US07/603,041 US5136060A (en) | 1989-11-14 | 1990-10-30 | Method for preparation of taxol using an oxazinone |
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Families Citing this family (101)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5175315A (en) * | 1989-05-31 | 1992-12-29 | Florida State University | Method for preparation of taxol using β-lactam |
MY110249A (en) * | 1989-05-31 | 1998-03-31 | Univ Florida State | Method for preparation of taxol using beta lactam |
US5136060A (en) * | 1989-11-14 | 1992-08-04 | Florida State University | Method for preparation of taxol using an oxazinone |
US5475120A (en) * | 1990-11-02 | 1995-12-12 | University Of Florida | Method for the isolation and purification of taxol and its natural analogues |
US5380916A (en) * | 1990-11-02 | 1995-01-10 | University Of Florida | Method for the isolation and purification of taxane derivatives |
CA2071160A1 (en) * | 1991-07-31 | 1993-02-01 | Vittorio Farina | Asymmetric synthesis of taxol side chain |
US5654447A (en) * | 1991-09-23 | 1997-08-05 | Florida State University | Process for the preparation of 10-desacetoxybaccatin III |
US6495704B1 (en) | 1991-09-23 | 2002-12-17 | Florida State University | 9-desoxotaxanes and process for the preparation of 9-desoxotaxanes |
US5739362A (en) * | 1991-09-23 | 1998-04-14 | Florida State University | Taxanes having an alkoxy, alkenoxy or aryloxy substituted side-chain and pharmaceutical compositions containing them |
US5350866A (en) * | 1991-09-23 | 1994-09-27 | Bristol-Myers Squibb Company | 10-desacetoxytaxol derivatives |
US6011056A (en) | 1991-09-23 | 2000-01-04 | Florida State University | C9 taxane derivatives and pharmaceutical compositions containing them |
US5728850A (en) * | 1991-09-23 | 1998-03-17 | Florida State University | Taxanes having a butenyl substituted side-chain and pharmaceutical compositions containing them |
US5710287A (en) * | 1991-09-23 | 1998-01-20 | Florida State University | Taxanes having an amino substituted side-chain and pharmaceutical compositions containing them |
US6018073A (en) * | 1991-09-23 | 2000-01-25 | Florida State University | Tricyclic taxanes having an alkoxy, alkenoxy or aryloxy substituted side-chain and pharmaceutical compositions containing them |
US5998656A (en) | 1991-09-23 | 1999-12-07 | Florida State University | C10 tricyclic taxanes |
US6005138A (en) | 1991-09-23 | 1999-12-21 | Florida State University | Tricyclic taxanes having a butenyl substituted side-chain and pharmaceutical compositions containing them |
US6335362B1 (en) | 1991-09-23 | 2002-01-01 | Florida State University | Taxanes having an alkyl substituted side-chain and pharmaceutical compositions containing them |
US5274124A (en) * | 1991-09-23 | 1993-12-28 | Florida State University | Metal alkoxides |
US5284864A (en) | 1991-09-23 | 1994-02-08 | Florida State University | Butenyl substituted taxanes and pharmaceutical compositions containing them |
KR100252493B1 (ko) * | 1991-09-23 | 2000-05-01 | 플로리다 | 금속알콕시드 및 베타-락탐을 사용한 치환된 이소세린 에스테르의 제조방법 |
US5714513A (en) * | 1991-09-23 | 1998-02-03 | Florida State University | C10 taxane derivatives and pharmaceutical compositions |
US5721268A (en) * | 1991-09-23 | 1998-02-24 | Florida State University | C7 taxane derivatives and pharmaceutical compositions containing them |
US7074945B2 (en) * | 1991-09-23 | 2006-07-11 | Florida State University | Metal alkoxide taxane derivatives |
US6521660B2 (en) | 1991-09-23 | 2003-02-18 | Florida State University | 3′-alkyl substituted taxanes and pharmaceutical compositions containing them |
US6794523B2 (en) | 1991-09-23 | 2004-09-21 | Florida State University | Taxanes having t-butoxycarbonyl substituted side-chains and pharmaceutical compositions containing them |
US5283253A (en) * | 1991-09-23 | 1994-02-01 | Florida State University | Furyl or thienyl carbonyl substituted taxanes and pharmaceutical compositions containing them |
US5728725A (en) * | 1991-09-23 | 1998-03-17 | Florida State University | C2 taxane derivaties and pharmaceutical compositions containing them |
US5430160A (en) * | 1991-09-23 | 1995-07-04 | Florida State University | Preparation of substituted isoserine esters using β-lactams and metal or ammonium alkoxides |
US6028205A (en) * | 1991-09-23 | 2000-02-22 | Florida State University | C2 tricyclic taxanes |
US5489601A (en) * | 1991-09-23 | 1996-02-06 | Florida State University | Taxanes having a pyridyl substituted side-chain and pharmaceutical compositions containing them |
DE69329304T2 (de) * | 1992-01-15 | 2001-01-04 | E.R. Squibb & Sons, Inc. | Enzymatische Verfahren zur Resolution von Enantiomeren-Mischungen nützlich wie Zwischenprodukte zur Herstellung von Taxanen |
US5272171A (en) * | 1992-02-13 | 1993-12-21 | Bristol-Myers Squibb Company | Phosphonooxy and carbonate derivatives of taxol |
US5254703A (en) * | 1992-04-06 | 1993-10-19 | Florida State University | Semi-synthesis of taxane derivatives using metal alkoxides and oxazinones |
US5254580A (en) * | 1993-01-19 | 1993-10-19 | Bristol-Myers Squibb Company | 7,8-cyclopropataxanes |
US5294637A (en) * | 1992-07-01 | 1994-03-15 | Bristol-Myers Squibb Company | Fluoro taxols |
US5614549A (en) * | 1992-08-21 | 1997-03-25 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
FR2696463B1 (fr) | 1992-10-05 | 1994-11-25 | Rhone Poulenc Rorer Sa | Procédé d'obtention de la désacétyl-10 baccatine III. |
FR2696458B1 (fr) * | 1992-10-05 | 1994-11-10 | Rhone Poulenc Rorer Sa | Procédé de préparation de dérivés du taxane. |
FR2696462B1 (fr) | 1992-10-05 | 1994-11-25 | Rhone Poulenc Rorer Sa | Procédé d'obtention de la désacétyl-10 baccatine III. |
FR2697752B1 (fr) * | 1992-11-10 | 1995-04-14 | Rhone Poulenc Rorer Sa | Compositions antitumorales contenant des dérivés du taxane. |
DE69333605T2 (de) * | 1992-11-27 | 2005-02-03 | Mayne Pharma (Usa) Inc. | Stabile injizierbare Paclitaxel Lösung |
NZ258044A (en) * | 1992-11-27 | 1995-12-21 | Faulding F H & Co Ltd | Pharmaceutical composition comprising taxol, solubilising agent, an acid and an organic solvent |
US5380751A (en) * | 1992-12-04 | 1995-01-10 | Bristol-Myers Squibb Company | 6,7-modified paclitaxels |
FR2698871B1 (fr) | 1992-12-09 | 1995-02-24 | Rhone Poulenc Rorer Sa | Nouveau taxoïdes, leur préparation et les compositions pharmaceutiques qui les contiennent. |
IL107950A (en) | 1992-12-15 | 2001-04-30 | Upjohn Co | b 7, b 8 - Matano - Taxols, their preparation and pharmaceutical preparations against malignant tumors containing them |
US5973160A (en) * | 1992-12-23 | 1999-10-26 | Poss; Michael A. | Methods for the preparation of novel sidechain-bearing taxanes |
US5646176A (en) | 1992-12-24 | 1997-07-08 | Bristol-Myers Squibb Company | Phosphonooxymethyl ethers of taxane derivatives |
US6339164B1 (en) | 1993-01-29 | 2002-01-15 | Florida State University | C2 substituted phenyl taxane derivatives and pharmaceutical compositions containing them |
US6187916B1 (en) * | 1993-02-01 | 2001-02-13 | Research Foundation Of State University Of New York | Process for the preparation of taxane derivatives and β-lactam intermediates therefor |
US6593482B2 (en) | 1993-02-01 | 2003-07-15 | Aventis Pharma S.A. | Methods for preparing new taxoids and pharmaceutical compositions containing them |
BR9405687C1 (pt) * | 1993-02-05 | 2001-08-07 | Bryn Mawr College | Processo quìmico utilizável na produção de análogos de taxol e, composto quìmico |
US5684175A (en) * | 1993-02-05 | 1997-11-04 | Napro Biotherapeutics, Inc. | C-2' hydroxyl-benzyl protected, N-carbamate protected (2R, 3S)- 3-phenylisoserine and production process therefor |
US6710191B2 (en) * | 1993-03-05 | 2004-03-23 | Florida State University | 9β-hydroxytetracyclic taxanes |
ES2193154T3 (es) * | 1993-03-05 | 2003-11-01 | Univ Florida State | Procedimiento para la preparacion de 9-desoxotaxanos. |
TW467896B (en) * | 1993-03-19 | 2001-12-11 | Bristol Myers Squibb Co | Novel β-lactams, methods for the preparation of taxanes and sidechain-bearing taxanes |
DK1260223T3 (da) * | 1993-03-22 | 2005-09-05 | Univ Florida State | Taxaner med furyl- eller thienylsubstituerede sidekæde |
ES2219968T3 (es) * | 1993-06-11 | 2004-12-01 | PHARMACIA & UPJOHN COMPANY | Uso antineoplasico de delta 6,7-taxoles y composiciones farmaceuticas que los contienen. |
TW397866B (en) | 1993-07-14 | 2000-07-11 | Bristol Myers Squibb Co | Enzymatic processes for the resolution of enantiomeric mixtures of compounds useful as intermediates in the preparation of taxanes |
US6005120A (en) | 1993-07-20 | 1999-12-21 | Florida State University | Tricyclic and tetracyclic taxanes |
US5442065A (en) * | 1993-09-09 | 1995-08-15 | Board Of Regents, The University Of Texas System | Synthesis of tetrahydroquinoline enediyne core analogs of dynemicin |
US5965566A (en) * | 1993-10-20 | 1999-10-12 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
CA2174350A1 (en) * | 1993-10-20 | 1995-04-27 | Richard B. Greenwald | 2'- and/or 7- substituted taxoids |
US5880131A (en) * | 1993-10-20 | 1999-03-09 | Enzon, Inc. | High molecular weight polymer-based prodrugs |
US6441026B1 (en) | 1993-11-08 | 2002-08-27 | Aventis Pharma S.A. | Antitumor compositions containing taxane derivatives |
IL127597A (en) * | 1994-01-28 | 2003-07-31 | Upjohn Co | Iso-taxol analogs |
US5508447A (en) * | 1994-05-24 | 1996-04-16 | Board Of Regents, The University Of Texas System | Short synthetic route to taxol and taxol derivatives |
CA2170661A1 (en) | 1995-03-22 | 1996-09-23 | John K. Thottathil | Novel methods for the preparation of taxanes using oaxzolidine intermediates |
US5560872A (en) * | 1995-05-18 | 1996-10-01 | Lever Brothers Company | Compositions comprising oxazolidine and tetrahydrooxazine amide surfactants |
US5675025A (en) * | 1995-06-07 | 1997-10-07 | Napro Biotherapeutics, Inc. | Paclitaxel synthesis from precursor compounds and methods of producing the same |
US5654448A (en) * | 1995-10-02 | 1997-08-05 | Xechem International, Inc. | Isolation and purification of paclitaxel from organic matter containing paclitaxel, cephalomannine and other related taxanes |
US6177456B1 (en) | 1995-10-02 | 2001-01-23 | Xechem International, Inc. | Monohalocephalomannines having anticancer and antileukemic activity and method of preparation therefor |
US5840748A (en) * | 1995-10-02 | 1998-11-24 | Xechem International, Inc. | Dihalocephalomannine and methods of use therefor |
US5854278A (en) * | 1995-12-13 | 1998-12-29 | Xechem International, Inc. | Preparation of chlorinated paclitaxel analogues and use thereof as antitumor agents |
US5807888A (en) * | 1995-12-13 | 1998-09-15 | Xechem International, Inc. | Preparation of brominated paclitaxel analogues and their use as effective antitumor agents |
US5688977A (en) * | 1996-02-29 | 1997-11-18 | Napro Biotherapeutics, Inc. | Method for docetaxel synthesis |
US6107497A (en) * | 1996-02-29 | 2000-08-22 | Napro Biotherapeutics, Inc. | Intermediate for use in docetaxel synthesis and production method therefor |
FR2745814B1 (fr) * | 1996-03-06 | 1998-04-03 | Rhone Poulenc Rorer Sa | Nouveaux taxoides, leur preparation et les compositions pharmaceutiques qui les contiennent |
CA2253513A1 (en) | 1996-05-06 | 1997-11-13 | Florida State University | 1-deoxy baccatin iii, 1-deoxy taxol and 1-deoxy taxol analogs and method for the preparation thereof |
US5750737A (en) * | 1996-09-25 | 1998-05-12 | Sisti; Nicholas J. | Method for paclitaxel synthesis |
DE19726146A1 (de) * | 1997-06-19 | 1998-12-24 | Basf Ag | Neue ß-Amino und ß-Azidopcarbonsäurederivate, ihre Herstellung und Verwendung als Endothelinrezeptorantagonisten |
US7288665B1 (en) | 1997-08-18 | 2007-10-30 | Florida State University | Process for selective derivatization of taxanes |
EP1019347B1 (en) | 1997-08-21 | 2003-03-19 | Florida State University | Method for the synthesis of taxanes |
US6150537A (en) * | 1997-12-12 | 2000-11-21 | Emory University | Methods for the esterification of alcohols and compounds useful therefor as potential anticancer agents |
US6156789A (en) * | 1998-03-17 | 2000-12-05 | Rhone-Poulenc Rorer S.A. | Method for treating abnormal cell proliferation in the brain |
US6025516A (en) * | 1998-10-14 | 2000-02-15 | Chiragene, Inc. | Resolution of 2-hydroxy-3-amino-3-phenylpropionamide and its conversion to C-13 sidechain of taxanes |
CA2385528C (en) | 1999-10-01 | 2013-12-10 | Immunogen, Inc. | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
US6452024B1 (en) | 2000-02-22 | 2002-09-17 | Chaichem Pharmaceuticals International | Process for extraction and purification of paclitaxel from natural sources |
HUP0302599A3 (en) | 2000-09-22 | 2005-05-30 | Bristol Myers Squibb Co | Method for reducing toxicity of combined chemotherapic compositions |
US6919370B2 (en) | 2000-11-28 | 2005-07-19 | Transform Pharmaceuticals, Inc. | Pharmaceutical formulations comprising paclitaxel, derivatives, and pharmaceutically acceptable salts thereof |
US6452025B1 (en) | 2001-04-25 | 2002-09-17 | Napro Biotherapeutics, Inc. | Three-step conversion of protected taxane ester to paclitaxel |
US6479679B1 (en) | 2001-04-25 | 2002-11-12 | Napro Biotherapeutics, Inc. | Two-step conversion of protected taxane ester to paclitaxel |
AU2002365883A1 (en) * | 2001-11-30 | 2003-06-17 | Bristol-Myers Squibb Company | Paclitaxel solvates |
US20040132991A1 (en) * | 2002-10-09 | 2004-07-08 | Phytogen Life Sciences Inc. | Novel taxanes and methods related to use and preparation thereof |
US6759539B1 (en) | 2003-02-27 | 2004-07-06 | Chaichem Pharmaceuticals International | Process for isolation and purification of paclitaxel from natural sources |
US7202370B2 (en) * | 2003-10-27 | 2007-04-10 | Conor Medsystems, Inc. | Semi-synthesis of taxane intermediates from 9-dihydro-13-acetylbaccatin III |
WO2006116532A2 (en) * | 2005-04-28 | 2006-11-02 | University Of Massachusetts Lowell | Synthesis of oligo/poly(catechins) and methods of use |
US7847111B2 (en) | 2006-06-19 | 2010-12-07 | Canada Inc. | Semi-synthetic route for the preparation of paclitaxel, docetaxel, and 10-deacetylbaccatin III from 9-dihydro-13-acetylbaccatin III |
WO2007143839A1 (en) * | 2006-06-12 | 2007-12-21 | 6570763 Canada Inc. | Semi-synthetic route for the preparation of paclitaxel, docetaxel and 10-deacetylbaccatin iii from 9-dihydro-13-acetylbaccatin iii |
US20090292131A1 (en) * | 2008-05-07 | 2009-11-26 | Ladislav Cvak | Processes for preparation of taxanes and intermediates thereof |
KR101014438B1 (ko) * | 2008-09-26 | 2011-02-14 | 동아제약주식회사 | 탁산 유도체의 제조방법 |
RU2013103763A (ru) | 2010-07-02 | 2014-08-10 | Ангиохем Инк. | Короткие и содержащие d-аминокислоты полипептиды для терапевтических конъюгатов и их применения |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4521599A (en) * | 1983-07-11 | 1985-06-04 | The Upjohn Company | Process for the preparation of 1,3-oxazine-4-ones |
US4631340A (en) * | 1984-09-06 | 1986-12-23 | Pennwalt Corporation | 1,4-oxazinone derivatives |
US4549014A (en) * | 1984-09-06 | 1985-10-22 | Pennwalt Corporation | Adamantyl containing 1,4-oxazinone derivatives |
US4552585A (en) * | 1984-10-04 | 1985-11-12 | Fmc Corporation | Herbicidal 2-(aminophenyl)methyl derivatives of 3-isoxazolidinones or 3-oxazinones |
FR2601675B1 (fr) * | 1986-07-17 | 1988-09-23 | Rhone Poulenc Sante | Derives du taxol, leur preparation et les compositions pharmaceutiques qui les contiennent |
FR2601676B1 (fr) * | 1986-07-17 | 1988-09-23 | Rhone Poulenc Sante | Procede de preparation du taxol et du desacetyl-10 taxol |
US4876399A (en) * | 1987-11-02 | 1989-10-24 | Research Corporation Technologies, Inc. | Taxols, their preparation and intermediates thereof |
GB8803114D0 (en) * | 1988-02-11 | 1988-03-09 | Bp Chem Int Ltd | Bleach activators in detergent compositions |
FR2629819B1 (fr) * | 1988-04-06 | 1990-11-16 | Rhone Poulenc Sante | Procede de preparation de derives de la baccatine iii et de la desacetyl-10 baccatine iii |
FR2629818B1 (fr) * | 1988-04-06 | 1990-11-16 | Centre Nat Rech Scient | Procede de preparation du taxol |
US4960790A (en) * | 1989-03-09 | 1990-10-02 | University Of Kansas | Derivatives of taxol, pharmaceutical compositions thereof and methods for the preparation thereof |
US5136060A (en) * | 1989-11-14 | 1992-08-04 | Florida State University | Method for preparation of taxol using an oxazinone |
-
1990
- 1990-10-30 US US07/603,041 patent/US5136060A/en not_active Expired - Lifetime
- 1990-11-07 NZ NZ235993A patent/NZ235993A/en unknown
- 1990-11-08 AU AU65904/90A patent/AU633375B2/en not_active Ceased
- 1990-11-11 IL IL10924690A patent/IL109246A/en not_active IP Right Cessation
- 1990-11-11 IL IL9630490A patent/IL96304A/en not_active IP Right Cessation
- 1990-11-12 MY MYPI90001993A patent/MY106071A/en unknown
- 1990-11-12 IE IE960720A patent/IE76279B1/en not_active IP Right Cessation
- 1990-11-12 IE IE406190A patent/IE74154B1/en not_active IP Right Cessation
- 1990-11-13 PT PT95870A patent/PT95870B/pt not_active IP Right Cessation
- 1990-11-13 NO NO904923A patent/NO177902C/no unknown
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- 1990-11-13 CA CA002347588A patent/CA2347588C/en not_active Expired - Fee Related
- 1990-11-13 ES ES90312366T patent/ES2083438T3/es not_active Expired - Lifetime
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- 1990-11-13 FI FI905609A patent/FI104487B/fi not_active IP Right Cessation
- 1990-11-13 DK DK90312366.9T patent/DK0428376T3/da active
- 1990-11-13 AT AT90312366T patent/ATE132860T1/de not_active IP Right Cessation
- 1990-11-13 CA CA002029787A patent/CA2029787C/en not_active Expired - Fee Related
- 1990-11-14 PL PL90287757A patent/PL167898B1/pl not_active IP Right Cessation
- 1990-11-14 CZ CZ953136A patent/CZ283539B6/cs not_active IP Right Cessation
- 1990-11-14 RO RO146329A patent/RO110491B1/ro unknown
- 1990-11-14 JP JP2308463A patent/JP2507830B2/ja not_active Expired - Fee Related
- 1990-11-14 HU HU907131A patent/HU209299B/hu not_active IP Right Cessation
- 1990-11-14 CZ CS905634A patent/CZ283581B6/cs not_active IP Right Cessation
- 1990-11-14 CN CN90109112A patent/CN1043528C/zh not_active Expired - Fee Related
- 1990-11-14 YU YU216090A patent/YU48232B/sh unknown
- 1990-11-14 EG EG68490A patent/EG19641A/xx active
- 1990-11-14 KR KR1019900018425A patent/KR0161499B1/ko not_active IP Right Cessation
- 1990-11-14 RU SU904831946A patent/RU2033994C1/ru not_active IP Right Cessation
- 1990-11-14 BG BG93228A patent/BG60478B1/bg unknown
- 1990-11-14 OA OA59891A patent/OA09327A/xx unknown
-
1992
- 1992-06-15 US US07/898,438 patent/US5384399A/en not_active Expired - Lifetime
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1994
- 1994-04-07 IL IL10924694A patent/IL109246A0/xx unknown
- 1994-11-07 US US08/335,495 patent/US5532363A/en not_active Expired - Lifetime
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1996
- 1996-03-05 GR GR960400595T patent/GR3019192T3/el unknown
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