EP1226142A2 - Process for the production of epothiolone b and derivatives as well as intermediate products for this process - Google Patents
Process for the production of epothiolone b and derivatives as well as intermediate products for this processInfo
- Publication number
- EP1226142A2 EP1226142A2 EP00948907A EP00948907A EP1226142A2 EP 1226142 A2 EP1226142 A2 EP 1226142A2 EP 00948907 A EP00948907 A EP 00948907A EP 00948907 A EP00948907 A EP 00948907A EP 1226142 A2 EP1226142 A2 EP 1226142A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- formula
- aldehyde
- mmol
- epothilone
- 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.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 24
- 230000008569 process Effects 0.000 title claims abstract description 23
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 12
- 239000013067 intermediate product Substances 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- 125000006239 protecting group Chemical group 0.000 claims abstract description 11
- 229930013356 epothilone Natural products 0.000 claims abstract description 9
- -1 epothilone compounds Chemical class 0.000 claims abstract description 7
- 238000007363 ring formation reaction Methods 0.000 claims abstract 3
- HESCAJZNRMSMJG-HGYUPSKWSA-N epothilone A Natural products O=C1[C@H](C)[C@H](O)[C@H](C)CCC[C@H]2O[C@H]2C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C HESCAJZNRMSMJG-HGYUPSKWSA-N 0.000 claims description 21
- 150000001299 aldehydes Chemical class 0.000 claims description 17
- QXRSDHAAWVKZLJ-OXZHEXMSSA-N Epothilone B Natural products O=C1[C@H](C)[C@H](O)[C@@H](C)CCC[C@@]2(C)O[C@H]2C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C QXRSDHAAWVKZLJ-OXZHEXMSSA-N 0.000 claims description 15
- QXRSDHAAWVKZLJ-PVYNADRNSA-N epothilone B Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 QXRSDHAAWVKZLJ-PVYNADRNSA-N 0.000 claims description 15
- 150000001336 alkenes Chemical class 0.000 claims description 6
- 230000008878 coupling Effects 0.000 claims description 4
- 238000010168 coupling process Methods 0.000 claims description 4
- 238000005859 coupling reaction Methods 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 claims description 3
- 229940126657 Compound 17 Drugs 0.000 claims description 3
- 150000007931 macrolactones Chemical class 0.000 claims description 3
- 238000007254 oxidation reaction Methods 0.000 claims description 3
- 238000005906 dihydroxylation reaction Methods 0.000 claims description 2
- 238000006841 macrolactonization reaction Methods 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims 3
- OPFJDXRVMFKJJO-ZHHKINOHSA-N N-{[3-(2-benzamido-4-methyl-1,3-thiazol-5-yl)-pyrazol-5-yl]carbonyl}-G-dR-G-dD-dD-dD-NH2 Chemical compound S1C(C=2NN=C(C=2)C(=O)NCC(=O)N[C@H](CCCN=C(N)N)C(=O)NCC(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(O)=O)C(N)=O)=C(C)N=C1NC(=O)C1=CC=CC=C1 OPFJDXRVMFKJJO-ZHHKINOHSA-N 0.000 claims 1
- 229940126086 compound 21 Drugs 0.000 claims 1
- 229960004279 formaldehyde Drugs 0.000 claims 1
- 235000019256 formaldehyde Nutrition 0.000 claims 1
- 125000004430 oxygen atom Chemical group O* 0.000 claims 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 96
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 58
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 49
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 47
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 45
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 40
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 16
- 239000003153 chemical reaction reagent Substances 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- 125000002306 tributylsilyl group Chemical group C(CCC)[Si](CCCC)(CCCC)* 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 13
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 150000002118 epoxides Chemical class 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- 238000006243 chemical reaction Methods 0.000 description 11
- 238000003786 synthesis reaction Methods 0.000 description 11
- 239000002253 acid Substances 0.000 description 10
- 230000015572 biosynthetic process Effects 0.000 description 10
- 238000004440 column chromatography Methods 0.000 description 10
- 150000003883 epothilone derivatives Chemical class 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 10
- 238000000039 preparative column chromatography Methods 0.000 description 10
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 229920006395 saturated elastomer Polymers 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000010586 diagram Methods 0.000 description 6
- HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical compound C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 HESCAJZNRMSMJG-KKQRBIROSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 6
- 238000004809 thin layer chromatography Methods 0.000 description 6
- 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 6
- 239000003921 oil Substances 0.000 description 5
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 4
- WGLLSSPDPJPLOR-UHFFFAOYSA-N 2,3-dimethylbut-2-ene Chemical compound CC(C)=C(C)C WGLLSSPDPJPLOR-UHFFFAOYSA-N 0.000 description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 3
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 3
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- NDQXKKFRNOPRDW-UHFFFAOYSA-N 1,1,1-triethoxyethane Chemical compound CCOC(C)(OCC)OCC NDQXKKFRNOPRDW-UHFFFAOYSA-N 0.000 description 2
- OZGSEIVTQLXWRO-UHFFFAOYSA-N 2,4,6-trichlorobenzoyl chloride Chemical compound ClC(=O)C1=C(Cl)C=C(Cl)C=C1Cl OZGSEIVTQLXWRO-UHFFFAOYSA-N 0.000 description 2
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 2
- HSJKGGMUJITCBW-UHFFFAOYSA-N 3-hydroxybutanal Chemical compound CC(O)CC=O HSJKGGMUJITCBW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 238000005575 aldol reaction Methods 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 238000004040 coloring Methods 0.000 description 2
- 230000002596 correlated effect Effects 0.000 description 2
- 230000000875 corresponding effect Effects 0.000 description 2
- 238000001212 derivatisation Methods 0.000 description 2
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 150000002009 diols Chemical class 0.000 description 2
- 150000003885 epothilone B derivatives Chemical class 0.000 description 2
- 125000003700 epoxy group Chemical group 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 description 2
- 150000002678 macrocyclic compounds Chemical class 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 239000005445 natural material Substances 0.000 description 2
- 239000008177 pharmaceutical agent Substances 0.000 description 2
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 2
- LEHBURLTIWGHEM-UHFFFAOYSA-N pyridinium chlorochromate Chemical compound [O-][Cr](Cl)(=O)=O.C1=CC=[NH+]C=C1 LEHBURLTIWGHEM-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000006257 total synthesis reaction Methods 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- YUCBLVFHJWOYDN-HVLQGHBFSA-N 1,4-bis[(s)-[(2r,4s,5r)-5-ethyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methoxy]phthalazine Chemical compound C1=C(OC)C=C2C([C@H](OC=3C4=CC=CC=C4C(O[C@H]([C@@H]4N5CC[C@H]([C@H](C5)CC)C4)C=4C5=CC(OC)=CC=C5N=CC=4)=NN=3)[C@H]3C[C@@H]4CCN3C[C@@H]4CC)=CC=NC2=C1 YUCBLVFHJWOYDN-HVLQGHBFSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
- HORQAOAYAYGIBM-UHFFFAOYSA-N 2,4-dinitrophenylhydrazine Chemical compound NNC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O HORQAOAYAYGIBM-UHFFFAOYSA-N 0.000 description 1
- NXFFJDQHYLNEJK-UHFFFAOYSA-N 2-[4-[(4-chlorophenyl)methyl]-7-fluoro-5-methylsulfonyl-2,3-dihydro-1h-cyclopenta[b]indol-3-yl]acetic acid Chemical compound C1=2C(S(=O)(=O)C)=CC(F)=CC=2C=2CCC(CC(O)=O)C=2N1CC1=CC=C(Cl)C=C1 NXFFJDQHYLNEJK-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
- 241000349731 Afzelia bipindensis Species 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- KCBAMQOKOLXLOX-BSZYMOERSA-N CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O Chemical compound CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O KCBAMQOKOLXLOX-BSZYMOERSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- 102100032373 Coiled-coil domain-containing protein 85B Human genes 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 101000868814 Homo sapiens Coiled-coil domain-containing protein 85B Proteins 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000005016 Intestinal Neoplasms Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 150000001204 N-oxides Chemical class 0.000 description 1
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 1
- 239000004743 Polypropylene Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- WLLIXJBWWFGEHT-UHFFFAOYSA-N [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate Chemical compound CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F WLLIXJBWWFGEHT-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 239000000956 alloy Substances 0.000 description 1
- 229910045601 alloy Inorganic materials 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- ITZXULOAYIAYNU-UHFFFAOYSA-N cerium(4+) Chemical compound [Ce+4] ITZXULOAYIAYNU-UHFFFAOYSA-N 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229940126543 compound 14 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 238000005100 correlation spectroscopy Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000004042 decolorization Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- LVTYICIALWPMFW-UHFFFAOYSA-N diisopropanolamine Chemical compound CC(O)CNCC(C)O LVTYICIALWPMFW-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000012039 electrophile Substances 0.000 description 1
- 150000003884 epothilone A derivatives Chemical class 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- CNUDBTRUORMMPA-UHFFFAOYSA-N formylthiophene Chemical compound O=CC1=CC=CS1 CNUDBTRUORMMPA-UHFFFAOYSA-N 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000000855 fungicidal effect Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Substances [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 1
- UZNGRHDUJIVHQT-UHFFFAOYSA-M magnesium;prop-1-ene;bromide Chemical compound [Mg+2].[Br-].C[C-]=C UZNGRHDUJIVHQT-UHFFFAOYSA-M 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 1
- MEFBJEMVZONFCJ-UHFFFAOYSA-N molybdate Chemical compound [O-][Mo]([O-])(=O)=O MEFBJEMVZONFCJ-UHFFFAOYSA-N 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 125000002524 organometallic group Chemical group 0.000 description 1
- 229910052762 osmium Inorganic materials 0.000 description 1
- SYQBFIAQOQZEGI-UHFFFAOYSA-N osmium atom Chemical compound [Os] SYQBFIAQOQZEGI-UHFFFAOYSA-N 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920001155 polypropylene Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Substances [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- RBWSWDPRDBEWCR-RKJRWTFHSA-N sodium;(2r)-2-[(2r)-3,4-dihydroxy-5-oxo-2h-furan-2-yl]-2-hydroxyethanolate Chemical compound [Na+].[O-]C[C@@H](O)[C@H]1OC(=O)C(O)=C1O RBWSWDPRDBEWCR-RKJRWTFHSA-N 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 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
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- AAAQKTZKLRYKHR-UHFFFAOYSA-N triphenylmethane Chemical compound C1=CC=CC=C1C(C=1C=CC=CC=1)C1=CC=CC=C1 AAAQKTZKLRYKHR-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
- C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
- C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
-
- 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
Definitions
- This invention relates to a process for the production of epothilone B and derivatives as well as intermediate products for this process.
- diastereomer-pure fragments as starting products and intermediate products are required for a successful epothilone synthesis.
- Diastereomer purity is often decisive for the action and reliability of a pharmaceutical agent and thus a requirement for its production.
- Epothilone derivatives were already described by H ⁇ fle et al. in WO 97/19086. These derivatives were produced starting from natural epothilone A or B.
- n object of this invention is to indicate a process for the production of epothilone B and epothilone B derivatives, in which the cis-epoxide is introduced at a considerably earlier time via dihydroxylation-monosulfonation of a suitable (E)- olefin, whereby the ⁇ -configuraticn of the cis-epoxide is to come
- T ⁇ S stands for a tributylsilyl group.
- another suitable pro ective group can also be another suitable rrctective group can also be used as a starting compound, in v.-hich the epoxy group of the epothilone is already contained, and this epoxy group remains unchanged in all subsequent steps up to the end product.
- Diagram 3 shows possible derivatizations that allow for the process according to the invention if compound 11 that is to be used and/or next steps 13 or 14 are modified as indicated. This invention therefore extends not only to the process for the production of epothilone B, but also to a process for the production of correspondingly modified derivatives that are derived from modified compounds 11, 13 or 14.
- the invention also relates to the compounds of formulas 5 to 21, which are all new, as well as the correspondingly modified derivatives, which are obtained in the procedures indicated above and in diagram 3.
- IR (Film) v ma ⁇ 2956, 2930, 2887, 2857, 1737, 1472, 1462, 1454, 1370, 1300, 1255, 1155, 1098, 939, 836, 776, 737 cm "1 .
- IR (Film) v MX 3513 (br) , 2932, 2874, 2855, 1738, 1463, 1372, 1255, 1157, 1088, 836, 777 cm "1 .
- IR (Film) v ma ⁇ 2955, 2874, 2857, 1740, 1656, 1505, 1439, 1380, 1312, 1230, 1180, 1077, 835, 778 cm "1 .
- aldehyde 15 (di ⁇ olved in 1.5 ml of THF) is added in drop ⁇ within 2-3 minute ⁇ . After 15 minute ⁇ at -78°C, it is quenched with 4 ml of ⁇ aturated NH 4 C1 ⁇ olution while being ⁇ tirred vigorou ⁇ ly (initially ⁇ lowly then quickly added) , 6 ml of ether i ⁇ added, and the cooling bath i ⁇ replaced by a water bath. After thawing, ⁇ ome water i ⁇ added, and the pha ⁇ e ⁇ are ⁇ eparated after ⁇ haking out.
- reaction mixture is concentrated by evaporation to about 5 ml and filtered on a short ⁇ ilica gel column (rewa ⁇ hed with 30 ml of hexane/ethyl acetate) . Removal of the ⁇ olvent and ⁇ ubsequent column chromatography (hexane/ethyl acetate 4:1) yield 18 mg (34%) of macrolactone 22 as a colorless oil.
- NMR data are identical to the data of K. C. Nicolaou and A. Mantoulidis (Tet. Lett. 39 (1998) 8633-8636). HPLC analysi ⁇ with a comparison sample of A. Mantoulidis shows identical material.
- Methylene chloride is predried on a ba ⁇ ic aluminum oxide column of activity ⁇ tage I (Woel ) and made absolute on calcium hydride. After predrying on a ba ⁇ ic aluminum oxide column over an 8:1 sodiu /pota ⁇ ium alloy, diethyl ether i ⁇ refluxed until ⁇ table blue coloring of the benzophenone indicator i ⁇ achieved, and it is fre ⁇ hly distilled off before use.
- the tetrahydrofuran (THF) is predried over KOH, filtered on a column that i ⁇ coated with basic aluminum oxide and then distilled on potassium with triphenylmethane as an indicator.
- reaction ⁇ are monitored by thin-layer chromatography (TLC) on silica gel-60-aluminum foils with UV-indicator F 254 of the Merck Company.
- TLC thin-layer chromatography
- a ⁇ a mobile ⁇ olvent, in mo ⁇ t cases ⁇ olvent mixtures that con ⁇ i ⁇ t of hexane (Hex) and ethyl acetate (EE) are used.
- Hex hexane
- EE ethyl acetate
- ani ⁇ aldehyde/glacial acetic acid/ ⁇ ulfuric acid (1:100:1) ha ⁇ been taken a ⁇ a ⁇ tandard dip reagent.
- HPLC high-pre ⁇ sure liquid chromatographic ⁇ eparation ⁇
- Dye Reagent I (F I) : In the case of mo ⁇ t compound ⁇ that can be reduced, 1 g of cerium (IV) ⁇ ulfate in 10 ml of concentrated ⁇ ulfuric acid and 90 ml of water yield an inten ⁇ ive blue color reaction during drying.
- Dye reagent II A 10% ethanolic ⁇ olution of molbydatophosphoric acid represents another dip reagent for detecting unsaturated and reducible compounds.
- the molybdate dye reagent ⁇ e ⁇ pecially pertaining to ⁇ everal functionalitie ⁇ , ⁇ how ⁇ a broader color ⁇ pectrum in the case of virtually identical reliability.
- Dye reagent III 1 ml of ani ⁇ aldehyde in 100 ml of ethanol and 2 ml of concentrated ⁇ ulfuric acid repre ⁇ ents an extremely sensitive dye reagent that in addition al ⁇ o ⁇ how ⁇ probably the broade ⁇ t color ⁇ pectrum.
- Dye reagent IV Like the ani ⁇ aldehyde reagent, 1 g of vanillin in 100 ml ethanol and 2 ml of concentrated ⁇ ulfuric acid i ⁇ a very ⁇ en ⁇ itive dye reagent with a broad color ⁇ pectrum.
- Dye reagent V (F V) l g of 2 , 4-dinitrophenylhydrazine in 25 ml of ethanol, 8 ml of water and 5 ml of concentrated ⁇ ulfuric acid represent an excellent dip reagent that re ⁇ ponds selectively to aldehydes even without being heated and that responds somewhat more ⁇ lowly to ketone ⁇ .
- Dye reagent VI (F VI) : A 0.5% aqueou ⁇ ⁇ olution of pota ⁇ sium permanganate indicate ⁇ groups that can be oxidized by decolorization, whereby unsaturated, non-aromatic structural units react spontaneously without heating.
- the 1 H-NMR spectra are recorded a ⁇ an internal standard with a DRX 250 DRX 400 ⁇ pectrometer of the Bruker Company with the ⁇ ub ⁇ tance ⁇ a ⁇ a ⁇ olution in deuterated ⁇ olvent ⁇ and tetramethyl ⁇ ilane.
- the evaluation of the spectra is carried out according to rules of the first order. If a signal multiplicity that occurs cannot be explained in this way, the indication of the observed line set i ⁇ done.
- NOE- ⁇ pectro ⁇ copy Nuclear Overhau ⁇ er Effect
- ⁇ ( ⁇ inglet) , d (doublet) , dd (double doublet) , ddd (6-line ⁇ y ⁇ tem with two identical coupling con ⁇ tant ⁇ or an 8-line ⁇ ystem in three different coupling constants) , t (triplet) , q (quartet) , quint (quintet) , ⁇ ext ( ⁇ extet) , sept (septet) , m (multiplet) , mc
- the 13 C NMR ⁇ pectra are mea ⁇ ured a ⁇ an internal ⁇ tandard with an AC 250 of the Bruker Company with a CDC1 3 ⁇ ignal at 77.0 ppm, whereby the proton re ⁇ onances are wideband-coupled.
- the infrared ⁇ pectra are recorded with device ⁇ of the Perkin-El er Company (model 257 or 580 B) and Nicolet Company (FTIR-interfero eter ⁇ y ⁇ tem 55XC) .
- the oils are measured a ⁇ films between pota ⁇ ium bromide di ⁇ ks.
- the bands are indicated according to decreasing wave number (cm "1 ).
- de ⁇ ignation ⁇ are ⁇ elected: v ⁇ (very ⁇ trong) , ⁇ ( ⁇ trong) , m (medium) , w (weak) .
- TBDPS tert-butyldiphenyl- ⁇ ilyl chloride
- TBDPSCl tert-butyldiphenyl- ⁇ ilyl chloride
- TBS tert-butyldimethyl- ⁇ ilyl chloride
- TBSCI tert-butyldi ethyl- ⁇ ilyl chloride
- TBSTriflate tert-butyldimethyl-silyl-triflate
- TEA triethylamine, tert/t: tertiary
- TFA trifluoroethanoic acid
- TFAA trifluoroethanoic acid anhydride
- TFMS trifluoromethane ⁇ ulfonic acid
- THF tetrahydrofuran
- TMS trimethyl ⁇ ilyl-, u: g-mol '1 .
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Abstract
The present invention is directed to a process for the production of epothilone compounds, the improvement comprising preparing said compounds by cyclization of a compound produced from an intermediate of formula (II) wherein PG is a protecting group.
Description
Process for the Production of Epothiolone B and Derivatives as well as Intermediate Products for this Process
This application claims the benefit of the filing date of U.S. Provisional Application Serial No. 60/145,005, filed July 22 , - ISrS .
This invention relates to a process for the production of epothilone B and derivatives as well as intermediate products for this process.
It is known that the natural substances epothilone A (R = H) and epothilone B (R = methyl) (compound I, DE 195 42 986 Al , DE 41 38 042 C2)
have a fungicidal and cytotoxic effect. According to indications for in vitro activity against mammary and intestinal tumor cell lines, this family of compounds appears especially advantageous for the development of a pharmaceutical agent. Various working groups have successfully endeavored to synthesize these macrocyclic compounds. In this connection, the working groups start from various fragments of the macrocycle to synthesize the desired natural substances.
In any case, diastereomer-pure fragments as starting products and intermediate products are required for a successful epothilone synthesis. Diastereomer purity is often decisive for
the action and reliability of a pharmaceutical agent and thus a requirement for its production.
The total synthesis of epothilone A is described by Schinzer et al. in Chem. Eur. J. 1996, 2, No. 11, 1477-1482 and in Angew. Chem. 1997, 109, No. 5, pp. 543-544).
Epothilone derivatives were already described by Hδfle et al. in WO 97/19086. These derivatives were produced starting from natural epothilone A or B.
Another synthesis of epothilone and epothilone derivatives was described by Nicolaou et al. in Angew. Chem. 1997, 109, No. 1/2, pp. 170-172. Nicolaou et al. also described the synthesis of epothilone A and B and several epothilone analogs in Nature, Vol. 387, 1997, pp. 268-272, and the synthesis of epothilone A and its derivatives in J. Am. Chem. Soc, Vol. 119, No. 34, 1997, pp. 7S60-7973 as well as the synthesis of epothilone A and B and several epothilone analogs in J. Am. Chem. Soc, Vol. 119, No. 34, 1997, pp. 7974-7991.
Nicolaou et al. also describe in Angew. Chem. 1997, 109, No. 19, pp. 2181-2187 the production of epothilone A analogs using combinative solid-phase synthesis. Several epothilone B analogs are also described there.
A variable synthesis for the production of epothilone and different types of derivatives is known from WO 99/07692.
Other syntheses are described in PCT Applications WO 99/02514 and WO 99/01124.
Finally, the epothilone B-εynthesis that is described by J. Mulzer et al. in Tetrahedron Letters 39 (1998) 8633-8636 can also be mentioned.
Because of the expected lability of the epoxide, in all previous syntheses of epothilone B, the corresponding (Z) -olefin was always epoxidated in the last step, whereby the diaεtereosection is 4:1 to 20:1 of the desired β-isomer. n object of this invention is to indicate a process for the production of epothilone B and epothilone B derivatives, in which the cis-epoxide is introduced at a considerably earlier time via dihydroxylation-monosulfonation of a suitable (E)- olefin, whereby the β-configuraticn of the cis-epoxide is to come
_rcxv_at__c_ Other object are evident ro :f ordinary skill. These objects are achieved by a process using a compound cf
OTBS
ir. v.-hich TΞS stands for a tributylsilyl group. Instead of TBS, another suitable pro ective group can also be another suitable rrctective group can also be used as a starting compound, in v.-hich the epoxy group of the epothilone is already contained, and this epoxy group remains unchanged in all subsequent steps up to the end product.
Diagram 3 shows possible derivatizations that allow for the process according to the invention if compound 11 that is to be used and/or next steps 13 or 14 are modified as indicated. This invention therefore extends not only to the process for the production of epothilone B, but also to a process for the production of correspondingly modified derivatives that are derived from modified compounds 11, 13 or 14.
In addition, the invention also relates to the compounds of formulas 5 to 21, which are all new, as well as the correspondingly modified derivatives, which are obtained in the procedures indicated above and in diagram 3.
The selection of protective group (PG) in the 15-hydrcxy group car. be made with cnly routine experimentation. PG should outlast all subsequent reactions up to the macrolactcnization, but in addition should also be removable in the presence of epoxide. The original TΞS-function may not be removed without destroying the substrate; however, after converting the 15-OTBS derivative into the 15-OTΣS analog (TES = triethylεilyl) , any additional synthesis step can be performed easily. Other suitable groups can be routinely determined TBS is preferably replaced by TES at steps 13, 14 or 15; at steps 15 and 17-19, PG is preferably TES.
The epoxide applied early thus was shown as stable under the following reaction conditions:
1. Reduction (neutral (DIBAH) , ionic (selectride) , metallic (Zn)
2. Oxidation (osmium tetroxide-sodium periodate)
3. Bases (fluoride in an aprotic solvent, DMAP, LDA, enolate) . In this case, it is especially surprising
that C- and O-anions that were produced intramolecularly at a 1,5-interval to the epoxidic centers do not open the epoxide nucleophilically. 4. Electrophiles (acylation with acid chloride in the
Ya aguchi reaction) . Of all the reagents used, only aqueous acid led to epoxide opening. Apart from the mechanistically valuable finding that does away with the preconception that epoxides are in any case highly reactive synthesis intermediate compounds, the early epoxide introduction alεo has considerable advantages for the production according to the invention of epothilone B and the corresponding derivatives :
The N-oxide formation on thiazole that is observed in the 12 , 13-epoxidation with peracid developε just like the separation of the 12 , 13-epimeric epoxide. No "false" epoxide is produced. The stereoεelection of the aldol reaction iε alεo considerably higher than for the 12 , 13- (Z) -olefin analogs of 21.
The examples that are tied to diagram 3 are used for a more detailed explanation of the invention.
Diagram 1
Synthesis of the Completely Functionalized C15-C7-Fragments of
Epothilone B
1 a : R = B . d.r = 3:1 2a : R = Bn 3a : R = Bπ 1b ■ R = P.. '3 d.r = 4:1 2b : R = PMB 3b : R = PMB
a R = En b _; - ϊ" 5a : R = Bn 6a : R = Bn 5b : R = PMB 6b : R = PM3
a) 03, CH2C12, -78°C, PPh3; b) isopropenyl-MgBr , THF, -10°C; c) CH3C(OEt)3, xylene, 120°C, 12 h; d) DDQ, CH2C12-H20, rt; e) Dess-Martin periodinane, CH2C12, rt, 12 h; f) AD-mix-β, tBuOH- H20. rt, 20 h; g) Thz-CH2-PBu3Cl, KHMDS -78°C then 30°C; h) MsCl, NEt3, CH2C12, 0°C, 30 min; i) K2C03, MeOH, rt, 45 min; k) DIBAH, CK.C121 -90°C, 1 h; 1) LiOH (in-situ), (EtO) 2POCH2CO (N°) , then aldehyde, Et20-THF, rt, 30 min; ) L-selectrides, THF -78°C, 1 h, then HI-IPA, mel, -78°C to 0°C, 4 h; n) DIBAH, CH2C1∑, -80°C to -70°C, 2 h.
Bn = benzyl; PMB = p-methoxy-benzyl . All selectrides (cf. Aldrich Chemical Catalog) can be used in the process. L- selectride ( lithium- tri-sec-butylborohydride) is preferred.
Diagram 2
Total Synthesis of Epothilone B (Epoxide Path)
a) LDA, THF, -78°C; b) TrocCl, pyridine, CH2C12, rt; c) i. OsOA, NMO; ii) NalO ; d) HF-Py, pyridine rt; e) NaCl02, NaH2PO , tBuOH, 2 , 3-dimethyl-2-butene; f) 2 , 4 , 6-trichlorobenzoyl chloride, NEt3, then DMAP, toluene; g) HF-Py, pyridine rt; h) Zn, NH^Cl, EtOH, reflux, 30 min.
Ketone 16 K.C. Nicolaou et al.: J. Am. Chem. Soc. 1997, 119,
7974-7991
Diagram 3 Derivatizations
see above
lkyl
Conditions
Products Conditions Products C iiLticns
13a R
13b R
13c R
13d R
13e
13f i3g 13
131 R 13k R 13m R 13n R
vrithcut further elaboration, it is believed that one skilled n. the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific e~_boάiτnents are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius; and, unless otherwise indicated, all parts and percentages are by weight .
The entire disclosure of all applications, patents and publications, cited above, and U.S. Provisional Application Serial _.c. 60, 145, 005, filed July 22, 1S99 is hereby incorporated _v _τs_fszs^ s .
E X A M P L E S
Experimental
64
8.02 g (25 mmol) of alkene 3a iε dissolved in 200 ml of abεolute methylene chloride and mixed with 10 ml of absolute MeOH. After cooling to -78°C, a dried ozone/air mixture is introduced via a gas feed frit until the blue coloring beginε. Air iε allowed to blow through for two more minutes and then quenched by the addition of 19.67 g (75 mmol) of PPh3 in portions, and it iε allowed to thaw overnight. The solvent is removed as completely as poεεible in Rotavapor, and the remaining εolid reεidue with uεe of preparative column chromatography (hexane/ethyl acetate/ ethylene chloride = 40:1:1^ for separation of PPh3, then Hx/EE 20:1 to 10:1. 7.90 g (98%) of aldehyde 4a is obtained aε a colorless liquid.
1H NMR (400 MHz, CDCl3) δ 9.76 (dd, J = 1.5, 2.0 Hz, 1H) ; 7.34-7.24 ( , 5H) , 4.58 (d, J = 11.8 Hz, 1H) , 4.45 (d, J = 11.8 Hz, 1H) , 4.31 (dt, J = 6.3, 4.5 Hz , 1H) , 3.58-3.51 (m, 1H) , 2.69- 2.62 (m, 1H) , 2.51-2.43 ( , 1H) , 1.14 (d, J = 6.3 Hz, 3H) , 0.83 (ε, 9H) , 0.01 (s, 3H) , 0.00 (s, 3H) .
13C NMR (100.6 MHz CDC13) S 201.8, 138.4, 128.4, 127.6, 71.0, 68.9, 46.0, 25.7, 17.9, 13.5, -4.7, -4.9.
IR (Film): vMχ 2956, 2857, 2712, 1730, 1472, 1255, 1102, 837, 778 cm"1.
75 ml of isopropenylmagnesium bromide (0.5 M, THF) and 25 ml of absolute THF are cooled to -10°C under Ar atmosphere, and 9.14 g (28.3 mmol) of aldehyde 4a (disεolved in 20 ml of absolute THF) iε slowly (about 20 minutes) added in drops at -10°C. It iε allowed to thaw to 0°C within 45 minuteε (TLC monitoring, Grignard optionally muεt alεo be added) , the reaction mixture is poured into 150 ml of semi-saturated NH4C1 solution and shaken out after 120 ml of ether is added. The aqueous phase iε extracted twice more with ether (100 ml) . The combined organic phases are dried (MgSO , and the solvent iε removed in Rotavapor. Preparative column chro atography (Hx/EE = 10:1) yieldε 9.48 g (92%) of allyl alcohol 5a (diaεtereomer mixture) aε a colorless, viεcouε liquid.
Diaεtereomer 1
1H NMR (400 MHz, CDC13) <S 7.34-7.24 (m, 5H) , 4.98 (s, 1H) , 4.80 (ε, 1H) , 4.60 (d, J = 12.0 Hz, 1H) , 4.53 (d, J = 12.0 Hz, 1H) , 4.17 (dbr, J = 9.5 Hz, 1H) , 4.02 (dt, J = 7.4, 4.5 Hz , 1H) , 3.61-3.54 ( , 1H) , 2.71 (dbp, J = 3.5 Hz, 1H) , 1.84-1.75 (m, 1H) , 1.72 (ε, 3H) , 1.65-1.57 (m, 1H) , 1.14 (d, J = 6.5 Hz, 3H) , 0.86 (ε, 9H) , 0.05 (ε, 3H) , -0.02 (ε, 3H) .
Diastereomer 2
'H NMR (400 MHz, CDCl3) δ 7.34-7.24 (m, 5H) , 4.99 (ε, 1H) , 4.83 (s, 1H) , 4.60 (d, J = 12.0 Hz, 1H) , 4.47 (d, J = 12.0 Hz, 1H) , 4.20 (dd, J = 8.0, 3.5 Hz, 1H) , 3.90 (dt, J = 8.5, 4.3 Hz , 1H) , 3.47 (dq, J = 6.4, 4.3 Hz, 1H) , 2.97 (sbp, 1H) , 1.86 (dt, J = 14.2, 4.1 Hz, 1H) , 1.67 (s, 3H) , 1.57 (dt, J = 14.6, 8.5 Hz, 1H) . 1.10 (d, J = 6.4 Hz, 3H) , 0.80 (s, 9H)
8.02 g (22 mmol) of allyl alcohol 5a (diaεtereomer mixture) iε disεolved in 120 ml of absolute xylene and mixed with 32 ml (176 mmol) of triethylorthoacetate and 4 dropε of propionic acid. Kith a light Ar stream through a thin capillary, it is stirred for 16-20 hourε at 120°C, whereby the ethanol that is produced is distilled off via a εmall distillation appara us . After the reaction iε completed (TLC monitoring) , the solvent iε distilled off in Rotavapor (30 mbar, 50°C, then complete vacuum) , and the crude product iε purified by column chromatography (Hx/EE = 40:1 gradient 20:1). 8.77 g (92%) of 6a iε obtained-as a colorless liquid.
1H KM (400 MHz, CDC1-.) δ 7.35-7.22 (m, 5H) ; 5.20 (t, J = 6.4 Hz, 1H) ; 4.57 (d, J = 12 Hz, 1H) , 4.48 (d, J = 12 Hz, 1H) ,
4.11 (q, J - 7.2, 2H) , 3.68 (m, J = 4 Hz, 1H) , 3.46 (dt, J = 6.3, 4.5 Hz, 1H) , 2.40-2.34 (m, 1H) , 2.32-2.24 (m, 2H) , 2.14-2.04 ( , 1H) , 1.60 (ε, 3H) , 1.23 (t, J = 7.2 Hz, 2H) , 1.11 (d, J = 6.4 Hz, 3H) , 0.84 (ε, 9H) , -0.02 (ε, 3H) , -0.05 (s, 3H) .
13C NMR (100.6 MHZ CDC13) δ 173.5, 139.1, 134.5, 128.2, 127.5, 127.4, 124.0, 122.4, 77.3, 74.0, 71.0, 60.2, 34.8, 33.1, 30.1, 25.8, 18.0, 16.1, 14.2, 14.0, -4.60, -4.61.
IR (Film) : vmaχ 2956, 2930, 2887, 2857, 1737, 1472, 1462, 1454, 1370, 1300, 1255, 1155, 1098, 939, 836, 776, 737 cm"1.
HRKS (El) Cld. for C25H420 Si 434.2852, Fnd. 434.2845
[ ]20 D - -3.9 (c = 1.2. CHC13)
S12 g (2.10 mmol) of 6a iε dissolved in 40 ml of methylene chloride and 2 ml of water, mixed with 2.86 g (12.6 mmol) of DDQ and εtirred vigorouεly for exactly 3 hourε at room temperature. The reaction mixture iε diluted with 100 ml of ether and washed with NaHC03 (aqueouε, εaturated) (2x 40 ml) . The combined aqueouε phaεeε are diluted with 80 ml of water and extracted with ether (2x 50 ml) . The combined organic phaεeε are waεhed with brine (50 ml) , dried (MgSO , and the solvent is removed in
Rotavapor. Preparative column chromatography (Hx/EE = 10:1) yields 575 mg (80%) of alcohol 7 as a colorlesε liquid.
1H NMR (400 MHz, CDCl3) δ 5.16 (dt, J = 7.3, 1.0 Hz, IH) , 4.09 (q, J = 7.07 Hz , 2H) , 3.56 (m, IH) , 3.42 (dt, J = 7.2, 4.4 Hz, IH) , 2.40-2.26 (m, 5H) , 2.15-2.07 (m, 2H) , 1.61 (m, 3H) , 1.23 (t, J = 7.0 Hz, 3H) , 1.09 (d, J = 6.5 Hz, 3H) , 0.88 (ε, 9H) , 0.06 (ε, 6H) .
13C NMR (100.6 MHZ CDC13) <S 173.7, 136.1, 120.9, 77.0, 69.0, 60.7, 35.2, 33.5, 33.0, 26.2, 20.3, 18.5, 16.6, 14.6, -3.8, -4.3.
IR (Film) : vMX 3513 (br) , 2932, 2874, 2855, 1738, 1463, 1372, 1255, 1157, 1088, 836, 777 cm"1.
HRMS (El) Cld. for (M+ -C4H?) 287.168, Fnd . 287.168 ± 5 ppm
[α]20 D = +20.2 (C = 1.08, CHC13)
1.030 g (2.99 mmol) of alcohol 7 iε diεεolved in 50 ml of absolute methylene chloride and mixed with 2.5 ml of absolute pyridine and 2.54 g (6.0 mmol) of Desε-Martin periodinane and εtirred overnight at RT (about 18 hours) . For working-up, it is mixed with 25 ml of sodium thioεulfate εolution (20%, aqueous), and it iε εtirred vigorouεly for 15 minuteε. The phases are separated, and the aqueouε phase is extracted with methylene chloride (2 x 25 ml) . The combined organic phaseε are dried
(MgS04) , and the solvent is removed in Rotavapor. Preparative column chromatography (Hx/EE = 10:1) yieldε 945 mg (92%) of ketone 8 as a colorleεε liquid.
1H NMR (400 MHz, CDC13) δ 5.15 (t, IH, J = 6.8 Hz , IH) ; 4.10 (q, J = 7.0 Hz, 2H) , 3.97 (dd, J = 6.5, 5.5 Hz, IH) , 2.40- 2.20 ( , 6H) , 2.12 (s, 3H) , 1.59 (ε, 3H) , 1.23 (t, J = 7.0 Hz, IH) , 0.89 (ε, 9H) , 0.03 (ε, 3H) , 0.02 (ε, 3H) .
13C NMR (100.6 MHZ CDC13) δ 212.5, 173.7, 137.0, 119.7, 79.2, 60.7, 35.1, 33.9, 33.7, 33.4, 26.1, 25.9, 18.5, 16.6, 14.6, -4.5, -4.6.
IR (Film): vmaχ 2932, 2875, 2858, 1737, 1351, 1256, 1203, 1160, 1137, 1102, 959, 927, 899, 839, 779 cm"1.
HRMS (El) Cld. for (M+-CH3) 327.1992. Fnd. 327.199 ± 0.0016
[ Q ] 2° = - 19 . 4 ( c = 1 . 05 , CHCl, )
a) 830 mg (2.42 mmol) of 8 is diεsolved in 30 ml of tBuOH- H20 (1:1) and mixed with 1.5 g of NaHC03, 5.0 g of AD-Mix-β and 230 g of methaneεulfonamide. After 36-48 hourε at room temperature while being εtirred vigorouεly, it iε quenched by
adding 5 g of εodium εulfite (10 more inuteε of εtirring) . After 25 ml of H.,0 and 100 ml of methylene chloride are added, the phaεeε are εeparated, and the aqueouε phaεe iε extracted with methylene chloride (3 x 30 ml) . The combined organic phases are dried (MgSO , and the solvent is removed in Rotavapor. Preparative column chromatography (Hx/EE = 2:1, R. (3-1. = 0.09 to 0.29) yieldε 942 mg of product mixture 8a.
IR (Film): vmaχ 3432, 2933, 2858, 1736, 1377, 1256, 1229, 1095, 837, 778 cm'1.
b) 1.82 g of Wittig salt (5.2 mmol) iε diεεolved in 30 ml of absolute THF under Ar atmoεphere, cooled to -78°C, and 10.4 ml of KHKDS (0.5 M, toluene) iε added in dropε and stirred for 45 minutes at -78°C. Then, 920 mg of 8a (dissolved in 2.5 ml of THF) is added smoothly in drops. It is allowed to stir for 5 more minutes
at -78°C, the cooling bath iε then quickly exchanged for an approximately 40°C water bath and allowed to thaw. After 5 minuteε, the bath is removed, and it iε allowed to stir for another 5 minuteε before being quenched with 50 ml of NH^Cl (saturated, aqueous) and 75 ml of ether. The aqueous phase is extracted with ether (2x 30 ml) . The combined organic phases are dried (MgSO , and the solvent is removed in Rotavapor. Preparative column chromatography (Hx/EE = 2:1) yields 632 mg (61% on both εynthesiε εtepε) of alkene 9 as a colorless, viεcouε liquid.
1H NMR (400 MHz, CDCl3) δ 6.93 (ε, IH) , 6.47 (ε, IH) , 4.41 (dd, J = 8.5, 4.5 Hz, IH) , 3.67 (d, J = 10.0 Hz, IH) , 3.45 (s,
IH) , 2.71-2.61 (m, IH) , 2.68 (ε, 3H) , 2.66-2.46 (m, IH) , 2.37- 2.28 (m, IH) , 1.99 (ε, 3H) , 1.80-1.66 (m, 2H) , 1.70 (dd, J = 14.3, 4.8 Hz, IH) , 1.34 (ε, 3H) , 0.88 (ε, 9H) , 0.10 (ε, 3H) , 0.01 (ε, 3H) .
12C NMR (100.6 MHZ CDC13) <S 177.6, 165.1, 152.9, 141.4, 120.4, 116.3, 88.0, 79.9, 76.7, 37.1, 30.9, 29.9, 26.2, 23.6, 19.6, 18.4, 14.1, -4.0, -4.8.
IR (Film): vmaχ 3469, 2955, 2943, 2930, 2910, 2892, 2856, 1768, 1656, 1505, 1462, 1386, 1252, 1066, 838 cm'1.
HRMS (El) Cld. for C21H35N04SiS 425.2056 Fnd . 425,2060 ± 0.0025
[α]20 D = -27.1 (c = 1.0, CHC13)
12.7
313 mg (0.737 mmol) of alcohol 9 iε diεεolved under Ar atmoεphere in 5 ml of abεolute methylene chloride and mixed at 0°C with 0.31 ml of abεolute triethylamine and 0.09 ml of methaneεulfonic acid chloride. After 30 minutes, it is quenched with 10 ml of NaHC03 (aqueouε, εaturated) , the phaεeε are εeparated, and the aqueouε phaεe iε extracted with methylene chloride (3x 10 ml) . The combined organic phaεeε are dried
(MgS04) , and the solvent iε removed in Rotavapor. Preparative column chromatography (Hx/EE = 4:1) yields 283 mg (76%) of meεylate 10 aε a strongly viεcouε, yellowish liquid.
1H NMR (400 MHz, CDC13) δ 6.96 (ε, IH) , 6.56 (ε, IH) , 4.57 (dd, J = 8.0, 2.5 Hz, IH) , 4.41 (dd, J = 8.8, 4.8 Hz, IH) , 3.13 (ε, 3H) , 2.68 (ε, 3H) , 2.60-2.53 (m, 2H) , 2.02 (d, J = 1.0 Hz, 3H) , 2.07-1.81 (m, 4H) , 1.42 (ε, 3H) , 0.87 (ε, 9H) , 0.08 (ε, 3H) , 0.02 (ε, 3H) .
13C NMR (100.6 MHz CDC13) δ 175.5, 165.0, 153.2, 138.7, 122.1, 117.2, 86.5, 83.8, 75.7, 39.6, 38.0, 31.2, 28.8, 26.2, 21.7, 19.7, 18.5, 13.1, -4.3, -4.6.
256 g (0.508 mmol) of meεylate 10 iε diεεolved in 10 ml of abεolute methanol and mixed with finely pulverized potaεsium carbonate. After 45 minutes at room temperature, it is diluted with 30 ml of ether and then filtered. Saturated NH^Cl solution (15 ml) iε added to the filtrate until two clear phaεes form. The phaεeε are εeparated, and the aqueous phaεe iε extracted with ether (3x 10 ml) . The combined organic phaεeε are dried (MgSO , and the εolvent iε removed in Rotavapor. Preparative column
chromatography (Hx/EE = 5:1) yields 202 mg (90%) of epoxide 11 as a colorless, viεcouε liquid.
1H NMR (400 MHz, CDC13) <S 6.91 (s, IH) , 6.49 (s, IH) , 4.32 (dd, J = 9.0, 3.5 Hz, IH) , 3.65 (s, 3H) , 2.89 (dd, J = 7.0, 4.5 Hz, IH) , 2.68 (ε, 3H) , 2.46-2.40 (m, 2H) , 1.99 (d, J = 1.5 Hz, IH) , 1.94-1.77 (m, 3H) , 1.63-1.55 (m, IH) , 1.26 (ε, 3H) , 0.88 (s, 9H) , 0.07 (ε, 3H) , 0.01 (s, 3H) .
13C NMR (100.6 MHz CDC13) δ 173.6, 164.9, 153.4, 142.4, 119.3, 115.8, 76.7, 62.8, 60.4, 52.1, 36.3, 30.5, 28.6, 26.3, 22.5, 19.6, 18.6, 14.4, -4.2, -4.7.
IR (Film) : vmaχ 2955, 2874, 2857, 1740, 1656, 1505, 1439, 1380, 1312, 1230, 1180, 1077, 835, 778 cm"1.
HRMS (El) Cld. for C∑2H37N04SiS 439.2213 Fnd. 439.221 ± 0.0025.
[ ]20 = -12.6 (c = 1.04, CHC1,)
176 mg (0.40 mmol) of epoxide 11 iε dissolved in 6 ml of abεolute MC under argon and εlowly (about 5 minuteε) mixed with 0.29 ml (0.44 mmol) of DIBAH (1.5M toluene) ' at -95°C. It iε allowed to come to -85°C within 45 minuteε, mixed with 0.15 ml of
NH4C1 solution and 10 ml of ether while being εtirred vigorouεly, and it iε allowed to thaw quickly. After sufficient MgS04 is added, it is allowed to stir for 1-2 hours and filtered off. After the solvent is removed in Rotavapor, the crude aldehyde is purified by column chromatography (Hx/EE = 3:1), and 140 mg (85%) of aldehyde 11a is obtained as a colorless oil.
IR (Film): vMχ 2930, 2781, 1727, 1677, 1076, 919, 836.
4 ml of abεolute ether at 0°C and 0.32 ml of nBuLi (1.6M, hexane, 0.51 mmol) are introduced under Ar atmosphere and mixed with 0.36 ml of THF/H-,0 (19:1, 1 mmol of H-,0) . After 5 minutes, 193 g of phosphonate (0.49 mmol, dissolved in 1 ml of THF) is added in drops, and after another 10 minutes, 135 mg (0.33 mmol, dissolved in 1 ml of THF) of aldehyde 11a is added in dropε. The cooling bath is removed, and after 30 minutes at room temperature, it iε quenched with 4 ml of saturated NH4C1 solution, the phases are εeparated, and the aqueouε phaεe iε extracted with ether (2x 5 ml) . The combined organic phaεeε are dried (MgS04) , and the solvent is removed in Rotavapor.
Preparative column chromatography (Hx/EE = 3:1) yields 194 mg (91%) of enoylsultam 12 aε a viscous oil, which solidifies like a foam after freezing-out.
Η NMR (400 MHz, CDC13) δ 7.03 (dt, J = 14.8, 7.3 Hz, IH) , 6.91 (s, IH) , 6.55 (d, J = 14.8 Hz, IH) , 6.49 (s, IH) , 4.32 (dd, J = 8.8, 3.8 Hz, IH) , 3.90 (dd, J = 7.3, 5.3 Hz, IH) , 3.48 (d, J = 13.8 Hz, IH) ; 3.40 (d, J = 13, 8 Hz, IH) , 2.89 (dd, J = 7.5, 4.5 Hz, IH) , 2.68 (ε, 3H) , 2.42-2.33 (m, 2H) , 2.13-2.02 (m, 2H) , 1.99 (ε, 3H) , 1.95-1.81 (m, 5H) , 1.71-1.51 (m, 4H) , 1.27 (s, 3H) , 1.14 (ε, 3H) , 0.95 (ε, 3H) , 0.88 (ε, 9H) , 0.07 (ε, 3H) , 0.01 (s, 3H) . C NMR (100.6 MHz CDC13) δ 164.8, 164.3, 153.4, 149.9, 142.4, 121.6, 119.3, 115.8, 76.8, 65.5, 62.6, 60.7, 53.5, 50.7, 48.8, 48.2, 45.1, 38.9, 36.2, 33.3, 31.9, 28.8, 26.9, 26.2, 22.6, 21.2, 20.3, 19.6, 18.6, 14.4, -4.2, -4.7.
172 mg (0.265 mmol) of sultam 12 iε diεεolved in 5 ml of abεolute THF and mixed at -95°C with 0.32 ml of L-εelectrides (1.0 M, THF, 0.32 mmol) and heated within 45 minuteε to -40°C. After another 15 minuteε, it is cooled to -78°C, and after 0.12 ml of HMPA iε added, it iε mixed with 0.132 ml of Mel. Then, it iε heated within 3 hourε to 0°C, and after another 2 hourε at 0°C, it iε quenched by adding 5 ml of NHACl and 10 ml of ether. The phaεeε are εeparated, and the aqueouε phase is extracted with ether (2x 5 ml) . The combined organic phaseε are dried (MgS04) , and the solvent is removed in Rotavapor. Preparative column chromatography (Hx/EE = 3:1) yieldε 90 mg of 13 and 85 mg of 14.
Compound 13
1H NMR (400 MHz, CDC13) <S 6.88 (ε, IH) , 6.47 (ε, IH) , 4.29 (dd, J = 9.0, 3.5 Hz, IH) , 3.85 (t, J = 6.3 Hz, IH) , 3.44 (d, J = 13.5 Hz, IH) , 3.37 (d, J = 3.5 Hz, IH) , 3.07-3.97 (m, IH) , 2.83 (dd, J = 8.0, 4.0 Hz, IH) , 2.66 (s, 3H) , 2.02-1.98 (m, 2H) , 1.98 (d, J = 1.0 Hz, 3H) , 1.92-1.68 (m, 5H) , 1.57-1.26 (m, 8H) , 1.22 (ε, 3H) , 1.16 (d, J = 7.0 Hz, 3H) , 1.11 (s, 3H) , 0.92 (s, 3H) , 0.86 (s, 9H) , 0.05 (ε, 3H) , -0.01 (ε, 3H) .
Compound 14
^ NMR (400 MHz, CDC13) «5 6.91 (ε, IH) , 6.49 (ε, IH) , 4.31 (dd, J = 9.0, 3.5 Hz, IH) , 3.83, (dd, J = 7.3, 5.3 Hz, IH) , 3.45 (d, J = 13.6 Hz, IH) , 3.39 (d, J = 13.6 Hz, IH) , 2.86 (dd, J = 7.8, 4.3 Hz, IH) , 2.75-2.63 (m, 2H) , 2.68 (ε, 3H) , 2.12-2.03 (m, 2H) , 2.00 (d, J = 1.0 Hz, 3H) , 1.93-1.80 (m, 4H) , 1.72-1.30 (m,
9H) , 1.24 (ε, 3H) , 1.12 (ε, 3H) , 0.93 (s, 3H) , 0.88 (ε, 9H) , 0.07 (ε, 3H) , 0.01 (s, 3H) .
50 mg (0.075 mmol) of sultam 13 is dissolved under argon in 2.5 ml of absolute methylene chloride and mixed slowly with 0.083 ml (0.083 mmol) of DIBAH (1.0 M, toluene) at -95°C. It iε allowed to come to -75°C within 2-2.5 hours while being εtirred vigorously with 0.05 ml of MeOH and 0.1 ml of NH^Cl solution, as well aε 5 ml of ether, and it iε allowed to thaw quickly. After εufficient MgS04 is added, it iε allowed to εtir for about 1 hour (even overnight) and filtered off. After the εolvent iε removed in Rotavapor, the crude aldehyde iε purified by column chromatography (Hx/EE = 3:1), and 24 mg (71%) of aldehyde 15 iε obtained aε a waxy εolid.
1H NMR (400 MHz, CDC13) 6 9.58 (d, J = 5.0 Hz, IH) , 6.90 (ε, IH) , 6.49 (ε, IH) , 4.31 (dd, J = 9.0, 4.0 Hz, IH) , 2.87 (dd, J = 7.0, 4.5 Hz, IH) , 2.68 (ε, 3H) , 2.36-2.26 ( , IH) , 2.00 (ε, 3H) , 1.92-1.84 (m, IH) , 1.74-1.64 (m, IH) , 1.60-1.52 (m, IH) , 1.50-1.32 (m, 5H) , 1.26 (ε, 3H) , 1.08 (d, J = 7.0 Hz, 3H) , 0.88 (ε, 9H) , 0.07 (ε, 3H) , 0.01 (ε, 3H) .
13C NMR (100.6 MHz CDC1-.) δ 205.2, 164.9, 153.4, 142.5, 119.2, 115.8, 76.7, 62.4, 61.1, 46.7, 36.4, 33.6, 31.0, 26.2, 23.3, 22.7, 19.6, 18.6, 14.4, 13.7, -4.2, -4.7.
Aldol Reaction
Example: R2 = TES, R3 = TBS
1.75 ml (1.23 mmol) of iεopropylamine iε diεεolved in 4 ml of absolute THF and mixed at -45°C with 0.75 ml of nBuLi (1.6 M in hexane; 1.20 mmol), heated to 0°C after 5 minuteε and εtirred for 20 minuteε at 0°C. After cooling to -78°C, 345 mg (1.21 mmol) of ketone 16 (diεεolved in 1 ml of THF) iε added in dropε within 2 minuteε, and the reaction mixture iε heated to -40°C within 30 minuteε. It iε again cooled to -78°C, and 532 mg (1.18 mmol) of aldehyde 15 (diεεolved in 1.5 ml of THF) is added in dropε within 2-3 minuteε. After 15 minuteε at -78°C, it is quenched with 4 ml of εaturated NH4C1 εolution while being εtirred vigorouεly (initially εlowly then quickly added) , 6 ml of ether iε added, and the cooling bath iε replaced by a water bath. After thawing, εome water iε added, and the phaεeε are εeparated after εhaking out. Extraction with ether, drying (MgSOA) ,
removal of the εolvent and subsequent column chromatography (hexane/ethyl acetate 10:1 → 5:1) yield 668 mg (77%) of desired main iεomer 17 aε a colorleεε, viscouε liquid.
Compound 17 (R2 = TES, R3 = TBS)
1H NMR (400 MHz, CDCl3) δ = 6.93 (s, IH) , 6.51 (ε, IH) , 5.72 (ddt, J = 17.1, 10.0, 7.0 Hz, IH) , 4.99 (m, 2H) , 4.33 (dd, J = 9.0, 3.5 Hz, IH) , 3.92 (d, J = 6.3, 4.3 Hz, IH) , 3.49 (s, IH) , 3.31 (d, J = 9.0 Hz, IH) , 3.25 (q, J = 7.0 Hz, IH) , 2.88 (dd, J = 7.5, 4.0 Hz, IH) , 2.70 (ε, 3H) , 2.24-2.06 (m, 2H) , 2.01 (d, J = 1.0 Hz, 3H) , 1.95-1.87 (m, IH) , 1.82-1.72 (m, IH) , 1.63-1.45 (m, 5H) , 1.41-1.30 ( , IH) , 1.28 (ε, 3H) , 1.18 (ε, 3H) , 1.20-1.05 (m, IH) , 1.12 (ε, 3H) , 1.03 (d, J = 7.0 Hz , 3H) , 0.90 (ε, 9H) , 0.89 (ε, 9H) , 0.83 (d, J = 7.0 Hz, 3H) , 0.09 (s, 3H) , 0.07 (ε, 3H) , 0.06 (ε, 3H) , 0.03 (ε, 3H) , 13C NMR (100.6 MHz, CDCl3) : δ = 222.5, 164.4, 153.1, 142.2, 136.3, 118.8, 116.7, 115.3, 76.5,
76.4, 74.9, 62.1, 61.1, 54.3, 41.1, 39.6, 36.0, 35.6, 33.4, 33.1,
26.05, 25.9, 23.4, 22.7, 22.4, 19.4, 19.2, 18.24, 18.21, 15.3, 14.0, 9.7, -3.5, -4.90, -4.6, -5.1.
7-OH Protection
Example: R2 = TES, R3 = TBS, R4 = Troc
200 mg (0.27 mmol) of aldol 17 iε diεεolved in 10 ml of methylene chloride and 5 ml of pyridine and mixed at 20°C (water bath) with 0.5 ml (2.4 mmol) of chloroformic acid-2,2,2- trichloroethyl ester and stirred for 30-45 minutes at room temperature. For working-up, the reaction mixture iε εhaken out with 50 ml of εaturated NaHC03 εolution and 40 ml of methylene chloride. Extraction with methylene chloride, drying (MgS04) , removal of the solvent and εubεequent column chromatography (hexane/ethyl acetate 10:1) yield 231 mg (94%) of deεired product 18 aε a colorleεε oil.
Compound 18 (R2 = TES, R3 = TBS, R4 = Troc)
1H NMR (400 MHz, CDC13) δ = 6.92 (ε, IH) , 6.51 (ε, IH) , 5.79 (ddt, J = 16.6, 10.5, 7.0 Hz, IH) , 5.05-4.97 (m, 2H) , 4.85 (d, J = 12.1 Hz, IH) , 4.81 (dd, J = 7.0, 4.5 Hz, IH) , 4.69 (d, J = 12.1 Hz, IH) , 4.33 (dd, J = 9.0, 3.5 Hz, IH) , 3.75 (dd, J = 6.5, 4.0 Hz, IH) , 3.44 (m, IH) , 2.88 (dd, J = 7.5, 4.0 Hz, IH) , 2.70 (ε, 3H) , 2.28-2.19 (m, IH) , 2.06-1.95 (m, IH) , 2.02 (ε, 3H) , 1.92-1.84 (m, IH) , 1.75-1.65 ( , IH) , 1.57-1.41 (m, 5H) , 1.33- 1.11 (m, 2H) , 1.30 (ε, 3H) , 1.27 (ε, 3H) , 1.21-1.12 (m, IH) , 1.07 (d, J = 7.0 Hz, 3H) , 1.04 (ε, 3H) , 0.96 (d, J = 7.0 Hz, 3H) , 0.91 (ε, 9H) , 0.89 (ε, 9H) , 0.09 (ε, 3H) , 0.07 (ε, 3H) , 0.06 (ε, 3H) , 0.03 (s, 3H) , 13C NMR (100.6 MHz, CDC13) : <5 = 215.6, 164.4, 154.2, 153.1, 142.1, 136.4, 118.9, 116.6, 115.4, 94.8, 82.9, 78.1, 76.6, 76.4, 62.1, 60.8, 54.0, 42.3, 39.4, 36.0, 35.0, 33.3, 31.8, 26.1, 25.9, 24.0, 22.7, 22.3, 20.0, 19.2, 18.23, 18.21,
16.1, 14.0, 11.5, -3.6, -3.9, -4.6, -5.1. IR (film) ϋ^ = 2956, 2930, 2858, 1760, 1699, 1472, 1384, 1251, 1081, 992, 928, 836, 777, 732. Rotation: [α]20 D = -30 (c = 1.4, CH2Cl2) . Analysis Cld. for C43H74Cl3N07SSi2 (911,65): C 56.65, H 8.18, N 1.54, Fnd.: C 56.54 H 8.18 N 1.47.
Dihydroxylation/Glycol Cleavage
Example: R2 = TES, R3 = TBS, Rc = Troc
148 g (0.162 mmol) of alkene 18 iε dissolved in 8 ml of TKF-tBuOH (1:1) and mixed with 2 mg of Os04 (5 mol%) and 0.89 ml of KMO (0.2 M in H20, 0.178 mmol). After 16 hourε of εtirring at 25°C, it iε shaken out vigorously and for a long time with 10 ml of Na-.S-.03 (10% in H∑0) and 15 ml of methylene chloride. The phases are separated, and the aqueouε phaεe iε extracted three more times with methylene chloride. Drying (MgS04) , removal of the εolvent and filtration via a εhort silica gel column (hexane/ethyl acetate 1:1) yields 131 mg (86%) of diol aε an iεoroer mixture, which iε further uεed without additional purification.
131 mg (0.139 mmol) of diol iε diεεolved in 15 ml of ethanol and 3 ml of H-.0 and mixed with 90 mg (0.420 mmol) of NaI04.
After three hours of stirring at 25°C, it is shaken out with 30 ml of semi-saturated NaHC03 solution and 30 ml of ether, and the phases are separated. Extraction with ether, drying (MgS04) , removal of the εolvent and εubεequent column chromatography (Hexane/ethyl acetate 10:1 → 5:1) yield 115 mg (78% in terms of alkene) of aldehyde 19 aε a colorleεε oil.
Compound 19 (R2 = TES, R3' = TBS, R4 = Troc)
1H NMR (400 MHz, CDC13) : <5 = 9.73 (dd, J = 2.0, 1.0 Hz, IH) , 6.92 (ε, IH) , 6.50 (ε, IH) , 4.83 (d, J = 12.0 Hz, IH) , 4.74 (dd, J = 7.5, 4.0 HZ, IH) , 4.67 (d, J = 11.8 Hz, IH) , 4.36-4.29 ( , 2H) , 3.49-3.38 (m, IH) , 2.88 (dd, J = 7.5, 4.0 Hz, IH) , 2.70 (ε, 3H) , 2.67 (ddd, J = 17.5, 4.5, 1.0 Hz, IH) , 2.39 (ddd, J =
17.5, 5.5, 2.0 Hz, IH) , 2.39 (s, 3H) , 1.88 (ddd, J = 13.9, 9.4, 4.0 Hz, IH) , 1.76-1.66 ( , IH) , 1.60-1.40 (m, 5H) , 1.35-1.10, (m, 2H) , 1.33 (s, 3H) , 1.26 (s, 3H) , 1.20 (d, J = 6.5 Hz, IH) , 1.02 (s, 3H) , 0.97 (d, J = 6.5 Hz, 3H) , 0.90 (s, 9H) , 0.86 (ε, 9H) , 0.11 (ε, 3H) , 0.09 (ε, 3H) , 0.03 (ε, 3H) , 0.02 (ε, 3H) , 13C NMR (100.6 MHz, CDC13) : <5 = 215.4, 200.2, 164.2, 154.2, 153.0, 142.1, 118.9, 115.4, 94.7, 82.3, 76.65, 76.3, 72.3, 62.1, 60.8, 53.4, 49.3, 42.2, 35.9, 34.9, 3.33, 31.9, 25.87, 25.85, 23.0,
22.6, 22.3, 20.0, 19.2, 18.2, 18.1, 15.9, 14.0, 11.1, -4.4, -4.5, -4.6, -5.1. IR (Film) fiMj( = 2956, 2930, 2885, 2857, 1759, 1726, 1699, 1472, 1384, 1361, 1252, 1082, 992, 927, 836, 777, 734. Rotation: [c.]20 D = -42.7 (c = 1.2, CHC13)
15-O-Protection Removal
Example: R2 = TES, R3 = TBS, K1 = Troc
68 mg (0.074 mmol) of 19 iε diεεolved in a polypropylene reaction vesεel (with a cover) in 2.5 ml of abεolute THF and mixed with 2.5 ml of a standard solution of HF-pyridine (produced from: 5 ml of HF-pyridine, 15 ml of pyridine and 10 ml of THF) that is buffered with pyridine. After 30 minuteε, the reaction iε completed. For working-up, 80 ml of εaturated NaHC03 εolution iε introduced, and the reaction mixture iε carefully added (plastic syringe) while being εtirred vigorouεly. After extraction with ether (4 timeε 25 ml) and drying (MgS04) , the εolvent iε removed in Rotavapor, whereby the pyridine iε removed by repeated εpinning-in with toluene. The reεidue iε put on a column with deactivated εilica gel (hexane/ethyl acetate 2 : 1 → 1:1), and 51 mg (92%) of product 20 iε obtained aε a pale yellow, viεcouε oil.
Compound 20 (R3 = TBS, R = Troc)
Η NMR (400 MHz, CDC13) <S = 9.74 (ε, IH) , 6.95 (ε, IH) , 6.60 (ε, IH) , 4.84 (d, J = 12.0 Hz, IH) , 4.75 (dd, J = 7.8, 4.3 Hz, IH) , 4.68 (d, J = 12.0 Hz , IH) , 4.41-4.35 (m, IH) , 4.34 (t, J
= 4.8 Hz, IH) ; 3.49-3.41 (m, IH) , 2.96 (dd, J = 8.0, 4.0 Hz, IH) , 2.96 (ε, 3H) , 2.67 (dd, J = 17.5 Hz, 4.0 Hz , IH) , 2.40 (ddd, J =
17.5, 5.5, 2.0 Hz, IH) , 2.09 (d, J = 3.5 Hz, IH) , 2.06 (ε, 3H) , 1.94 (ddd, J = 14.6, 8.5, 4.0 Hz, IH) , 1.78-1.68 (m, IH) , 1.67 (ddd, J = 14.0, 8.0, 4.0 Hz, IH) , 1.58-1.41 (m, 4H) , 1.35-1.25 (m, IH) , 1.34 (ε, 3H) , 1.28 (ε, 3H) , 1.07 (d, J = 6.5 Hz, 3H) , 1.04 (ε, 3H) , 0.98 (d, J = 7.0 Hz , 3H) , 0.87 (ε, 9H) , 0.11 (ε, 3H) , 0.03 (ε, 3H) , 13C NMR (100.6 MHz, CDCl3) : δ = 215.4, 200.5, 164.6, 154.2, 152.7, 141.7, 118.9, 94.7, 82.3, 76.7, 75.4, 72.2, 61.8, 60.7, 53.4, 49.3, 42.2, 34.9, 34.1, 33.2, 32.0, 25.9, 23.0,
22.6, 22.1, 20.0, 19.2, 18.1, 15.9, 14.5, 11.2, -4.4, -4.5.
Pinnick-Oxidation/Macrolactonization
Example: R3 = TBS, R = Troc
54 mg (0.068 mmol) of aldehyde 20 iε diεεolved in 2.5 ml of tBuOH and 2.5 ml of 2 , 3-dimethyl-2-butene and mixed with a εolution of 30 mg of NaCl02 and 30 mg of NaH2P04 in 0.5 ml of H20 and εtirred for 45 minuteε at room temperature. For working-up, the reaction mixture iε mixed with 20 ml of εemi-εaturated NH4Cl εolution and extracted with methylene chloride (4 x 10 ml) .
After drying, the solvent is removed, and crude acid 21 (51 mg) that iε thuε obtained iε uεed directly in the next reaction.
51 g (0.062 mmol) of crude acid 21 iε diεεolved in 1.5 ml of absolute THF and mixed at 0°C with 57 μl (0.36 mmol) of triethylamine and 43 μl (0.24 mmol) of 2 , 4 , 6-trichlorobenzoyl chloride and εtirred for 20 minuteε at room temperature. The active eεter that is thus produced is εlowly added in dropε (15 minuteε) to a solution of 80 mg (0.60 mmol) of DMAP in 35 ml of absolute toluene and εtirred for 2 hourε at room temperature (25°C) . The reaction mixture is concentrated by evaporation to about 5 ml and filtered on a short εilica gel column (rewaεhed with 30 ml of hexane/ethyl acetate) . Removal of the εolvent and εubsequent column chromatography (hexane/ethyl acetate 4:1) yield 18 mg (34%) of macrolactone 22 as a colorless oil.
Compound 22 (R3 = TBS, R4 = Troc)
'H NMR (600 MHZ, CDC13) <5 = 6.99 (s, IH) , 6.56 (s, IH) , 5.21-5.14 (m, 2H) , 4.87 (d, J = 12.0 Hz, IH) , 4.75 (d, J = 12 Hz, IH) , 4.05 (d, J = 9.8 Hz, IH) , 3.30 (dq, J = 10.2, 6.3 Hz, IH) , 2.82 (dd, J = 10.3, 4.0 Hz , IH) , 2.79 (dd, J = 16.5, 1.5 Hz , IH) ,
2.71 (s, 3H) , 2.64 (dd, J = 16.5, 10.0 Hz, IH) , 2.25-2.21 (m,
IH) , 2.11 (s, 3H) , 1.93-1.64 (m, 4H) , 1.55-1.42 (m, 2H) , 1.32-
1.24 (m, IH) , 1.28 (ε, 3H) , 1.21 (ε, 3H) , 1.19 (s, 3H) , 1.16-1.08
(m, IH) , 1.12 (d, J = 6.7 Hz, 3H) , 1.03 (d, J = 6.7 Hz, 3H) , 0.88
(S, 9H) , 0.16 (s, 3H) , -0.03 (ε, 3H) .
Protection Removal at 3-0
Example: R3 = TBS, R4 = Troc
IS mg (23 μmol) of macrolactone 22 iε diεεolved in 0.5 ml of THF and mixed with 2.5 ml of buffered HF-Py (εee above) and εtirred for 72 hourε at room temperature, and then it iε added carefully to 35 ml of a εaturated NAHC0-. εolution and extracted with ether. Removal of the εolvent (repeated εpinning-in with toluene) and εubεequent column chromatography (hexane/ethyl acetate 2:1 — 1:1) yield 5 mg (32%) of deεired product 23 aε a colorless oil. At the same time, 6 mg of starting material iε recovered.
Compound 23 (R4 = Troc)
1H NMR (250 MHz, CDCl3) : δ = 6.99 (ε, IH) , 6.63 (ε, IH) , 5.52 (t, J = 4.5 Hz, IH) , 5.18 (dd, J = 9.0, 2.0 Hz, IH) , 4.84 (d, J = 12 Hz, IH) , 4.78 (d, J = 12 Hz, IH) , 4.15-4.05 (m, IH) , 3.79-3.70 (m, 2H) , 3.64-3.52 (m, IH) , 2.87 (t, J = 6.0 Hz, IH) , 2.72 (ε, 3H) , 2.59 (dd, J = 14.0, 10.0 Hz, IH) , 2.48 (dd, J = 14.0, 4.0 Hz, IH) , 2.35 (t, J = 7.5 Hz, 2H) , 2.12 (ε, 3H) , 2.00 (t, J = 5.5 H∑, 2H) , 1.89-1.81 (m, 2H) , 1.75-1.25 ( , 3H) , 1.39 (ε, 3H) , 1.28 (ε, 3H) , 1.15 (d, J = 7.0 Hz, 3H) , 1.09 (ε, 3H) , 0.9S (d, J = 7.0 Hz, 3H) .
7-O-Protection Removal -* Epothilone B
Example: R4 = Troc
2.7 mg (4.4 μmol) of 23 iε diεεolved in 1.5 ml of ethanol, mixed with 25 mg of NH4C1 and 25 mg of zinc (powder) and refluxed for 30 minuteε. After cooling to room temperature, it iε filtered on Celite, waεhed with ethyl acetate, and the εolvent iε removed in Rotavapor. Subεequent column chromatography (hexane/ethyl acetate 1:1) yieldε 1.4 mg (about 90%) of 24 (epothilone B) .
Compound 24 (Epothilone B)
1H NMR (600 MHz, CDC13) δ = 6.97 (ε, IH) , 6.60 (ε, IH) , 5.41 (d, J = 7.8, 2.4 Hz, IH) , 4.27-4.18 (m, 2H) , 3.77 (ε, IH) , 3.30 ( , IH) , 2.81 (dd, J = 7.5, 4.5 Hz, IH) , 2.70 (ε, 3H) , 2.65 (sbr, IH) , 2.54 (dd, J = 14.0, 10.2 Hz, IH) , 2.37 (dd, J = 14.0, 3.0 Hz, IH) , 2.13-2.05 (m, IH) , 2.09 (ε, 3H) , 1.92 (ddd, J = 15.3, 7.7, 7.7 Hz, IH) , 1.78-1.68 (m, 2H) , 1.55-1.46 (m, 2H) , 1.45-1.33 (m, 2H) , 1.37 (ε, 3H) , 1.30-1.22 (m, IH) , 1.28 (s, 3H) , 1.25 (ε, 3H) , 1.17 (d, J = 6.7 Hz, 3H) , 1.08 (s, 3H) , 1.01 (d, J = 7.0 Hz, 3H) .
NMR data are identical to the data of K. C. Nicolaou and A. Mantoulidis (Tet. Lett. 39 (1998) 8633-8636). HPLC analysiε with a comparison sample of A. Mantoulidis shows identical material.
Preparative Methods:
All reactions of organometallic reagentε and all reactionε in abεolute solvents are performed in an air-free and moisture- free environment. The glass equipment that is used iε heated εeveral times in a vacuum (about 0.01 mbar) before the beginning of the test and aerated with dry argon of the Linde Company. Unless otherwise indicated, all reaction batches are εtirred magnetically.
Methylene chloride is predried on a baεic aluminum oxide column of activity εtage I (Woel ) and made absolute on calcium hydride. After predrying on a baεic aluminum oxide column over an 8:1 sodiu /potaεεium alloy, diethyl ether iε refluxed until εtable blue coloring of the benzophenone indicator iε achieved, and it is freεhly distilled off before use. The tetrahydrofuran (THF) is predried over KOH, filtered on a column that iε coated with basic aluminum oxide and then distilled on potassium with triphenylmethane as an indicator.
After predrying over calcium chloride just like hexane (Hex) before use for column chromatography in a rotary evaporator, the ethyl acetate (EE) iε distilled off.
Chromatographic Process:
All reactionε are monitored by thin-layer chromatography (TLC) on silica gel-60-aluminum foils with UV-indicator F254 of the Merck Company. Aε a mobile εolvent, in moεt cases εolvent mixtures that conεiεt of hexane (Hex) and ethyl acetate (EE) are used. For viεualization of non-UV-active εubεtanceε, in moεt
cases aniεaldehyde/glacial acetic acid/εulfuric acid (1:100:1) haε been taken aε a εtandard dip reagent.
The preparative column chromatography iε performed on εilica gel-60 of the Merck Company (0.04-0.063 mm, 230-400 meεh) , whereby εolvent mixtureε that conεiεt of hexane (Hex) and ethyl acetate (EE) or diiεopropyl ether are uεed aε eluantε.
On an analytical εcale aε well aε on a preparative εcale, the high-preεsure liquid chromatographic εeparationε (HPLC) are performed on modular εyεtemε of the Knauer Company (pump 64 , UV and RI detectorε, columns and recorderε) , Waterε/Millipore Company (injection εyεtem U6K9) and Milton-Roy (integrator CI- 10) . For the analytical HPLC, in moεt caεes a Knauer column (4-250 mm) with 5 μm of nucleoεil iε uεed, and for the preparative HPLC, a column (16*250 mm, 32*250 mm or 64-300 mm) with 7 μm or 5 μm nuceloεil 50 iε used.
Dye Reagents
Dye Reagent I (F I) : In the case of moεt compoundε that can be reduced, 1 g of cerium (IV) εulfate in 10 ml of concentrated εulfuric acid and 90 ml of water yield an intenεive blue color reaction during drying.
Dye reagent II (F II) : A 10% ethanolic εolution of molbydatophosphoric acid represents another dip reagent for detecting unsaturated and reducible compounds. In contrast to dye reagent I, the molybdate dye reagentε, eεpecially pertaining to εeveral functionalitieε, εhowε a broader color εpectrum in the case of virtually identical reliability.
Dye reagent III (F III) : 1 ml of aniεaldehyde in 100 ml of ethanol and 2 ml of concentrated εulfuric acid repreεents an extremely sensitive dye reagent that in addition alεo εhowε probably the broadeεt color εpectrum.
Dye reagent IV (F IV) : Like the aniεaldehyde reagent, 1 g of vanillin in 100 ml ethanol and 2 ml of concentrated εulfuric acid iε a very εenεitive dye reagent with a broad color εpectrum.
Dye reagent V (F V) : l g of 2 , 4-dinitrophenylhydrazine in 25 ml of ethanol, 8 ml of water and 5 ml of concentrated εulfuric acid represent an excellent dip reagent that reεponds selectively to aldehydes even without being heated and that responds somewhat more εlowly to ketoneε.
Dye reagent VI (F VI) : A 0.5% aqueouε εolution of potaεsium permanganate indicateε groups that can be oxidized by decolorization, whereby unsaturated, non-aromatic structural units react spontaneously without heating.
Spectroscopic Process and General Analysis: NMR-Spectroscopy
The 1H-NMR spectra are recorded aε an internal standard with a DRX 250 DRX 400 εpectrometer of the Bruker Company with the εubεtanceε aε a εolution in deuterated εolventε and tetramethylεilane. The evaluation of the spectra is carried out according to rules of the first order. If a signal multiplicity that occurs cannot be explained in this way, the indication of the observed line set iε done. To determine the εtereochemiεtry, the NOE-εpectroεcopy (Nuclear Overhauεer Effect) iε uεed.
To characterize the signalε, the following abbreviations are used: ε (εinglet) , d (doublet) , dd (double doublet) , ddd (6-line εyεtem with two identical coupling conεtantε or an 8-line εystem in three different coupling constants) , t (triplet) , q (quartet) , quint (quintet) , εext (εextet) , sept (septet) , m (multiplet) , mc
(centered multiplet) , br (broad) , hv (semi-maεked εignal) and v
( aεked εignal) .
The 13C NMR εpectra are meaεured aε an internal εtandard with an AC 250 of the Bruker Company with a CDC13 εignal at 77.0 ppm, whereby the proton reεonances are wideband-coupled.
IR-spectroscopy
The infrared εpectra are recorded with deviceε of the Perkin-El er Company (model 257 or 580 B) and Nicolet Company (FTIR-interfero eter εyεtem 55XC) . The oils are measured aε films between potaεεium bromide diεks. The bands are indicated according to decreasing wave number (cm"1). For characterization, the following deεignationε are εelected: vε (very εtrong) , ε (εtrong) , m (medium) , w (weak) .
Abbreviations: abs.: absolute, Ar: aryl/aromatic compound, Cld.: calculated, Brine: cold, saturated common εalt εolution, nBuLi: nbutyllithium, c: concentration, COSY: correlated εpectroscopy (correlated εpectroεcopy) , CSA: ca pherεulfonic acid, TLC: thin- layer chromatography, DCM: dichloromethane, DDQ: dichloro- dicyano-quinone, d.e.: diaεtereomeric excess , DIBAH: diiεobutyl-
aluminum hydride, DIPA: diiεopropylamine, DMAP: dimethylaminopyridine, DMF: N,N' -dimethylformamide, DMS : dimethyl sulfide, DMSO: dimethyl εulfoxide, ds: diaεtereoselection, EA: elementary analyεiε, e.e.: enantiomeric exceεε, EE: ethyl acetate, El: electron impact ionization, eq: equivalent (ε) , eV: electron volt, FG: functional group, FI: field ionization, gef.: found, ges.: saturated, h: hour(ε), Hex: n-hexane, HMDS: hexamethyldiεilazide, HPLC: high-preεεure liquid chromatography, Hunig Base: N-ethyl-diisopropylamine, HRMS : high resolution mass εpectrometry, HV: high vacuum, iPrOH: 2-propanol, IR: infrared εpectrometry/infrared εpectrum, J: coupling constant, LDA: lithium diiεopropylamine, Lsg. : εolution, Lsm. : solvent, MC: methylene chloride, Me: methyl, MeLi: methyllithium, min.: minute(s), MS: maεε εpectrometry/maεε εpectra, NMR: nuclear magnetic resonance, NOE: Nuclear Overhauεer Effect, PCC: pyridinium chlorochromate, PG: protective group, Ph: phenyl, ppm: partε per million, Rkt. : reaction, rt. : retention time, RT: room temperature (20-30°C) , Std. : hour(ε), TBAF: tetra-n-butylammonium fluoride, TBDPS: tert-butyldiphenyl- εilyl chloride, TBDPSCl: tert-butyldiphenyl-εilyl chloride, TBS: tert-butyldimethyl-εilyl chloride, TBSCI: tert-butyldi ethyl- εilyl chloride, TBSTriflate: tert-butyldimethyl-silyl-triflate , TEA: triethylamine, tert/t: tertiary, TFA: trifluoroethanoic acid, TFAA: trifluoroethanoic acid anhydride, TFMS: trifluoromethaneεulfonic acid, THF: tetrahydrofuran, TMS: trimethylεilyl-, u: g-mol'1.
Claims
1. In a process for the production of epothilone compounds, the improvement comprising preparing εaid compounds by cyclization of a compound produced from an intermediate of formula II
OPG wherein PG iε a protecting group.
2. The process according to claim 1, wherein PG is a TBS or TES group.
3. The process according to claim 1, wherein the compound of formula II contains a TBS group as PG, which group iε changed to a TES group during the process.
4. The process according to claim 1, wherein said cyclization reaction is of a compound of the formula 21
5. The process according to claim 4, wherein the compound of formula 21 is produced by a process comprising reducing a compound of formula 11
OPG to form an aldehyde, coupling the aldehyde with a compound -N?
to produce an enoylεultam of formula 12,
reacting enolysultam 12 with L-selectrides to produce compounds of formulae 13 and 14,
reducing sultan. 13 to form aldehyde 15,
reacting 15 with ketone 16
to form compound 17,
protecting the 17 -OH group of compound 17 so aε to produce alkene 18,
subjecting alkene 18 to dehydroxylation and glycocleavage to produce aldehyde 19,
deprot.ecr.ir_g the 15-position of aldehyde 19 to produce aldehyde 20,
and subjecting aldehyde 20 to oxidation and macrolactonization to produce compound 21
wherein each PG independently is a protecting group,
6. A process according to claim 4, comprising cyclizing a compound of formula 21 to produce a macrolactone of formula
deprotecting the oxygen atom at the 3 -position to form a compound of formula 23
and removing the protecting group at the 7-position to form epothilone B.
7. A compound of the formula 5 to 21
7
OPG OPG
10
11
17
18 19
20 21
wherein PG is a protecting group,
■na R is Bn or PMB,
Applications Claiming Priority (3)
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US14500599P | 1999-07-22 | 1999-07-22 | |
US145005P | 1999-07-22 | ||
PCT/US2000/020064 WO2001007439A2 (en) | 1999-07-22 | 2000-07-24 | Process for the production of epothiolone b and derivatives as well as intermediate products for this process |
Publications (1)
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EP1226142A2 true EP1226142A2 (en) | 2002-07-31 |
Family
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EP00948907A Withdrawn EP1226142A2 (en) | 1999-07-22 | 2000-07-24 | Process for the production of epothiolone b and derivatives as well as intermediate products for this process |
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EP (1) | EP1226142A2 (en) |
JP (1) | JP2003505459A (en) |
AU (1) | AU6233600A (en) |
NO (1) | NO20020308L (en) |
WO (1) | WO2001007439A2 (en) |
Families Citing this family (5)
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CA2273083C (en) | 1996-12-03 | 2012-09-18 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto, analogues and uses thereof |
DK1483251T3 (en) | 2002-03-12 | 2010-04-12 | Bristol Myers Squibb Co | C3-cyano-epothilone derivatives |
GB0221312D0 (en) * | 2002-09-13 | 2002-10-23 | Novartis Ag | Organic compounds |
KR20100031716A (en) * | 2007-07-04 | 2010-03-24 | 사노피-아벤티스 | Macrolactone derivatives |
CA2799202C (en) | 2010-05-18 | 2016-07-05 | Cerulean Pharma Inc. | Compositions and methods for treatment of autoimmune and other diseases |
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EP0903348B2 (en) * | 1995-11-17 | 2008-08-27 | Gesellschaft für Biotechnologische Forschung mbH (GBF) | Epothilone derivatives and preparation thereof |
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2000
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- 2000-07-24 AU AU62336/00A patent/AU6233600A/en not_active Abandoned
- 2000-07-24 WO PCT/US2000/020064 patent/WO2001007439A2/en not_active Application Discontinuation
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AU6233600A (en) | 2001-02-13 |
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WO2001007439A2 (en) | 2001-02-01 |
JP2003505459A (en) | 2003-02-12 |
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