JP4481255B2 - ビンドリンとのカップリング反応によりビンブラスチン類を合成する中間体製造用化合物 - Google Patents
ビンドリンとのカップリング反応によりビンブラスチン類を合成する中間体製造用化合物 Download PDFInfo
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- JP4481255B2 JP4481255B2 JP2006046110A JP2006046110A JP4481255B2 JP 4481255 B2 JP4481255 B2 JP 4481255B2 JP 2006046110 A JP2006046110 A JP 2006046110A JP 2006046110 A JP2006046110 A JP 2006046110A JP 4481255 B2 JP4481255 B2 JP 4481255B2
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- 150000001875 compounds Chemical class 0.000 title claims description 43
- 238000004519 manufacturing process Methods 0.000 title claims description 12
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 title description 25
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 title description 23
- 229960003048 vinblastine Drugs 0.000 title description 18
- 238000005859 coupling reaction Methods 0.000 title description 5
- 239000000543 intermediate Substances 0.000 title 1
- -1 sulfonyloxy group Chemical group 0.000 claims description 12
- 239000002994 raw material Substances 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims 7
- 125000003118 aryl group Chemical group 0.000 claims 4
- 125000004432 carbon atom Chemical group C* 0.000 claims 3
- 241000257303 Hymenoptera Species 0.000 claims 1
- 125000002252 acyl group Chemical group 0.000 claims 1
- 125000004442 acylamino group Chemical group 0.000 claims 1
- 125000003545 alkoxy group Chemical group 0.000 claims 1
- 125000004414 alkyl thio group Chemical group 0.000 claims 1
- 125000003277 amino group Chemical group 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- 125000005010 perfluoroalkyl group Chemical group 0.000 claims 1
- 125000004665 trialkylsilyl group Chemical group 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 105
- 239000000243 solution Substances 0.000 description 76
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 48
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 46
- 238000006243 chemical reaction Methods 0.000 description 33
- 239000012044 organic layer Substances 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 27
- 238000000034 method Methods 0.000 description 27
- 238000010898 silica gel chromatography Methods 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- 239000000203 mixture Substances 0.000 description 23
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 239000010410 layer Substances 0.000 description 20
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 17
- 230000000704 physical effect Effects 0.000 description 16
- 230000015572 biosynthetic process Effects 0.000 description 15
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 15
- 229920006395 saturated elastomer Polymers 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 15
- 238000005481 NMR spectroscopy Methods 0.000 description 14
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 13
- 235000017557 sodium bicarbonate Nutrition 0.000 description 13
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- 238000001816 cooling Methods 0.000 description 12
- 239000003921 oil Substances 0.000 description 12
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 12
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 12
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 10
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 10
- 238000001308 synthesis method Methods 0.000 description 10
- 0 COC(C(CC(*OS(C)(=O)=O)CC*CC1)c2c1c(cccc1)c1[n]2)=O Chemical compound COC(C(CC(*OS(C)(=O)=O)CC*CC1)c2c1c(cccc1)c1[n]2)=O 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 150000002009 diols Chemical class 0.000 description 9
- 230000002194 synthesizing effect Effects 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
- 150000002475 indoles Chemical class 0.000 description 7
- 238000007154 radical cyclization reaction Methods 0.000 description 7
- 238000007363 ring formation reaction Methods 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
- 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 5
- 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 5
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 5
- WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical compound C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-N 0.000 description 5
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical compound ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 5
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 5
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 5
- 239000012230 colorless oil Substances 0.000 description 5
- 229940126543 compound 14 Drugs 0.000 description 5
- 150000002118 epoxides Chemical class 0.000 description 5
- 150000003949 imides Chemical class 0.000 description 5
- 239000002243 precursor Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- GNDKYAWHEKZHPJ-UHFFFAOYSA-N 2-nitrobenzenesulfonimidic acid Chemical compound NS(=O)(=O)C1=CC=CC=C1[N+]([O-])=O GNDKYAWHEKZHPJ-UHFFFAOYSA-N 0.000 description 4
- QWKKYJLAUWFPDB-UHFFFAOYSA-N 4-nitrobenzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=C([N+]([O-])=O)C=C1 QWKKYJLAUWFPDB-UHFFFAOYSA-N 0.000 description 4
- 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 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 238000005804 alkylation reaction Methods 0.000 description 4
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 4
- 229940125833 compound 23 Drugs 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 4
- 125000001041 indolyl group Chemical group 0.000 description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- WVTGEXAIVZDLCR-UHFFFAOYSA-N Vindoline Natural products CC1C2CN3CCCC14CCC5Nc6ccccc6C25C34 WVTGEXAIVZDLCR-UHFFFAOYSA-N 0.000 description 3
- HXYXTCJDWHHCBW-UHFFFAOYSA-N acetonitrile;toluene Chemical compound CC#N.CC1=CC=CC=C1 HXYXTCJDWHHCBW-UHFFFAOYSA-N 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 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 3
- GKWYINOZGDHWRA-UHFFFAOYSA-N catharanthine Natural products C1C(CC)(O)CC(CC2C(=O)OC)CN1CCC1=C2NC2=CC=CC=C12 GKWYINOZGDHWRA-UHFFFAOYSA-N 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 229940125961 compound 24 Drugs 0.000 description 3
- 229940126214 compound 3 Drugs 0.000 description 3
- 229940125898 compound 5 Drugs 0.000 description 3
- 230000008878 coupling Effects 0.000 description 3
- 238000010168 coupling process Methods 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 150000002540 isothiocyanates Chemical class 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000003386 piperidinyl group Chemical group 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 229940124530 sulfonamide Drugs 0.000 description 3
- 150000003456 sulfonamides Chemical class 0.000 description 3
- 238000006257 total synthesis reaction Methods 0.000 description 3
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 3
- CXBGOBGJHGGWIE-IYJDUVQVSA-N vindoline Chemical compound CN([C@H]1[C@](O)([C@@H]2OC(C)=O)C(=O)OC)C3=CC(OC)=CC=C3[C@]11CCN3CC=C[C@]2(CC)[C@@H]13 CXBGOBGJHGGWIE-IYJDUVQVSA-N 0.000 description 3
- SSUJUUNLZQVZMO-UHFFFAOYSA-N 1,2,3,4,8,9,10,10a-octahydropyrimido[1,2-a]azepine Chemical compound C1CCC=CN2CCCNC21 SSUJUUNLZQVZMO-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- WREOTYWODABZMH-DTZQCDIJSA-N [[(2r,3s,4r,5r)-3,4-dihydroxy-5-[2-oxo-4-(2-phenylethoxyamino)pyrimidin-1-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl] phosphono hydrogen phosphate Chemical compound O[C@@H]1[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)O[C@H]1N(C=C\1)C(=O)NC/1=N\OCCC1=CC=CC=C1 WREOTYWODABZMH-DTZQCDIJSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000004421 aryl sulphonamide group Chemical group 0.000 description 2
- 229940125758 compound 15 Drugs 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 230000008034 disappearance Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 150000002678 macrocyclic compounds Chemical class 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 230000000707 stereoselective effect Effects 0.000 description 2
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- IXZDIALLLMRYOU-UHFFFAOYSA-N tert-butyl hypochlorite Chemical compound CC(C)(C)OCl IXZDIALLLMRYOU-UHFFFAOYSA-N 0.000 description 2
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 2
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 2
- 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 2
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- USVVENVKYJZFMW-ONEGZZNKSA-N (e)-carboxyiminocarbamic acid Chemical class OC(=O)\N=N\C(O)=O USVVENVKYJZFMW-ONEGZZNKSA-N 0.000 description 1
- NDQXKKFRNOPRDW-UHFFFAOYSA-N 1,1,1-triethoxyethane Chemical compound CCOC(C)(OCC)OCC NDQXKKFRNOPRDW-UHFFFAOYSA-N 0.000 description 1
- 150000000180 1,2-diols Chemical class 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-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
- UUNMKKRWFDYYKW-UHFFFAOYSA-N 2,2-dimethylpentane-3,3-diamine Chemical compound CCC(N)(N)C(C)(C)C UUNMKKRWFDYYKW-UHFFFAOYSA-N 0.000 description 1
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 1
- JARXNQUBGBXALE-UHFFFAOYSA-N C(C)[SiH](CC)CC.Cl Chemical compound C(C)[SiH](CC)CC.Cl JARXNQUBGBXALE-UHFFFAOYSA-N 0.000 description 1
- FTWFDZDKTPWDJA-UHFFFAOYSA-N CC(C)(C)[SiH](C1=CC=CC=C1)C1=CC=CC=C1.Cl Chemical compound CC(C)(C)[SiH](C1=CC=CC=C1)C1=CC=CC=C1.Cl FTWFDZDKTPWDJA-UHFFFAOYSA-N 0.000 description 1
- 240000001829 Catharanthus roseus Species 0.000 description 1
- 208000006332 Choriocarcinoma Diseases 0.000 description 1
- 229940126062 Compound A Drugs 0.000 description 1
- QXKAIJAYHKCRRA-JJYYJPOSSA-N D-arabinonic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C(O)=O QXKAIJAYHKCRRA-JJYYJPOSSA-N 0.000 description 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 241001575980 Mendoza Species 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- 244000187664 Nerium oleander Species 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000005708 Sodium hypochlorite Substances 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910052792 caesium Inorganic materials 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 238000010959 commercial synthesis reaction Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940126142 compound 16 Drugs 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- JGFBRKRYDCGYKD-UHFFFAOYSA-N dibutyl(oxo)tin Chemical compound CCCC[Sn](=O)CCCC JGFBRKRYDCGYKD-UHFFFAOYSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethyl mercaptane Natural products CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 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
- 238000000926 separation method Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 238000007070 tosylation reaction Methods 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- LALRXNPLTWZJIJ-UHFFFAOYSA-N triethylborane Chemical compound CCB(CC)CC LALRXNPLTWZJIJ-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Description
A.本発明の特徴を、一般式Bを含む出発原料、中間体およびビンブラスチンの製造法を順次記載することにより説明する。
1、一般式Cのチオアニリドは、出発原料化合物である一般式Bの2つの水酸基を保護した化合物とシリルエーテルと化合物1のイソチオシアナートとを反応させて合成される。合成工程は以下のとおりである。R5の好ましい基としてエチル基を、R6の好ましい基としてメチル基を、R10の好ましい基としてt−ブチル基と2つのフェニル基の組み合わせを、R11の好ましいものとしてエチル基を、R12の好ましい基としてメチル基を、またR13の好ましいものとしてテトラヒドロピラニル基を、それぞれ挙げることができる。
実施例1
公知の出発原料1からカルボン酸2を製造する工程は以下のとおりである。
IR(film):3083,2968,1712,1649,1438,1415,1296,892cm−1;1HNMR(CDCl3,400MHz)11.63(brs,1H),4.78(d,J=0.4Hz,1H),4.73(d,J=0.4Hz,1H),2.52(t,J=7.7Hz,2H),2.36(t,J=7.7Hz,2H),2.05(q,J=7.2Hz,2H),1.04(t,J=7.2Hz,3H);13CNMR(CDCl3,100MHz)180.2,149.4,108.3,32.6,30.7,29.0,12.3;分析;計算値(Anal.Calcdfor)C7H12O:C,65.60,H,9.44;分析結果(Found)C,65.50,H,9.37.
〔α〕26 D−52.0(c1.15,CHCl3);IR(film)3029,2966,2921,1783,1701,1648,1454,1388,1353,1212,1110,892,762,743,703cm−1;1HNMR(CDCl3,400MHz)7.33(t,J=7.0Hz,2H),7.27(t,J=7.0Hz,1H),7.20(d,J=7.0Hz,2H),4.79(d,J=1.1Hz,1H),4.77(d,J=1.1Hz,1H),4.67(ddt,J=9.8,8.3,3.2Hz,1H),4.19(dd,J=9.0,8.3Hz,1H),4.15(dd,J=9.0,3.2Hz,1H),3.29(dd,J=13.5,3.2Hz,1H),3.14(ddd,J=17.0,8.8,6.8Hz,1H),3.06(ddd,J=7.0,8.4,7.2Hz,1H),2.76(dd,J=13.5,9.8Hz,1H),2.42(m,2H),2.09(q,J=7.3Hz,2H),1.06(t,J=7.3Hz,3H);13CNMR(CDCl3,100MHz)172.9,153.4,149.6,135.3,129.4,128.9,127.3,108.4,66.2,55.2,37.9,34.0,30.4,29.0,12.3.
〔α〕26 D−36.4(c0.978,CHCl3);IR(film)3029,2967,2935,2247,1779,1695,1646,1453,1389,1351,1291,1211,1113,1014,902,762,742,703cm−1;1HNMR(CDCl3,400MHz)7.35(t,J=7.0Hz,2H),7.29(t,J=7.0Hz,1H),7.22(d,J=7.0Hz,2H),4.83(d,J=1.4Hz,1H),4.75(d,J=1.4Hz,1H),4.65(m,1H),4.19(m,2H),4.09(ddt,J=12.0,7.3,4.4Hz,1H),3.34(dd,J=13.4,3.4Hz,1H),2.78(dd,J=13.4,10.0Hz,1H),2.49(dd,J=14.0,7.0Hz,1H),2.38(m,2H),2.15(dd,J=14.0,7.6Hz,1H),2.08(m,1H),2.04(q,J=7.3Hz,2H),1.90(m,1H),1.03(t,J=7.3Hz,3H);13CNMR(CDCl3,100MHz)174.7,153.1,147.6,135.2,129.4,129.0,127.4,119.1,110.9,66.4,55.6,40.5,39.0,38.1,28.3,27.1,15.1,12.2;
〔α〕23 D+6.49(c1.99,CHCl3);IR(film)3071,2961,2931,2858,2246,1644,1589,1471,1428,1112,1083,894,823,741,703,614,505cm−1;1HNMR(CDCl3,400MHz)7.64(d,J=7.3Hz,4H),7.44(t,J=7.3Hz,2H),7.39(t,J=7.3Hz,4H),4.76(d,J=1.4Hz,1H),4.67(d,J=1.4Hz,1H),3.56(dd,J=9.4,3.4Hz,1H),3.53(dd,J=9.4,4.2Hz,1H),2.30(ddd,J=16.8,8.3,6.3Hz,1H),2.23(dd,J=16.8,7.3Hz,1H),2.15(dd,J=13.9,6.6Hz,1H),1.94(dd,J=13.9,7.6Hz,1H),1.93(q,J=7.3Hz,2H),1.79m,1H),1.74(m,2H),1.06(s,9H),0.99(t,J=7.3Hz,3H);13CNMR(CDCl3,100MHz)148.5,135.6,135.6,133.4,133.4,129.8,129.8,127.8,127.7,120.0,110.3,65.3,38.2,37.4,28.2,27.2,26.9,19.3,15.0,12.0;
〔α〕25 D+8.5(c2.06,CHCl3);IR(film)3070,2931,2858,1471,1428,1388,1112,1063,846,823,741,704,614cm−1;1HNMR(CDCl3,400MHz)7.63(d,J=7.4Hz,4H),7.44(t,J=7.4Hz,2H),7.38(t,J=7.4Hz,4H),4.27(d,J=8.0Hz,1H),3.77(d,J=8.0Hz,1H),3.52(dd,J=9.3,5.4Hz,1H),3.48(dd,J=9.3,5.5Hz,1H),2.67(ddd,J=13.9,4.9,2.2Hz,1H),2.15(td,J=13.9,5.4Hz,1H),2.08(dt,J=13.0,2.4Hz,1H),2.02(m,1H),1.88(m,1H),1.67(dq,J=14.1,7.5Hz,1H),1.49(dq,J=14.1,7.5Hz,1H),1.20(t,J=13.0Hz,1H),1.18(qd,J=13.9,4.9Hz,1H),1.05(s,9H),0.89(t,J=7.5Hz,3H);13CNMR(CDCl3,100MHz)162.5,135.5,135.5,133.6,133.5,129.7,129.7,127.6,127.6,79.0,68.0,55.1,39.1,35.7,29.5,26.8,26.4,22.0,19.2,8.3;
〔α〕26 D+54.4(c1.40,CHCl3);IR(film)3489,3070,2931,2858,1699,1471,1427,1389,1191,1112,1056,997,823,741,703,614,506cm−1;1HNMR(CDCl3,400MHz)7.65(d,J=7.4Hz,4H),7.44(t,J=7.4Hz,2H),7.39(t,J=7.4Hz,4H),3.67(dd,J=11.5,7.3Hz,1H),3.55(dd,J=8.8,4.9Hz,1H),3.51(dd,J=8.8,5.2Hz,1H),3.33(dd,J=11.5,6.8Hz,1H),2.51(td,J=14.6,6.6Hz,0H),2.48(dd,J=7.3,6.8Hz,1H),2.28(ddd,J=14.6,4.6,2.4Hz,1H),2.12(m,2H),1.83(dq,J=15.4,7.6Hz,1H),1.75dq,J=15.0,3.9Hz,1H),1.52(dq,J=15.4,7.6Hz,1H),1.38t,J=15.0Hz,1H),1.32(qd,J=14.6,3.7Hz,1H),1.06(s,9H),0.84(t,J=7.6Hz,3H);13CNMR(CDCl3,100MHz)218.5,135.6,135.6,133.7,133.6,129.7,129.7,127.7,127.768.1,65.9,52.6,38.3,34.8,34.4,29.5,26.9,25.4,19.3,7.7;
〔α〕27 D+10.0(c1.50,CHCl3);IR(film)3441,3071,2932,2859,1738,1462,1428,1362,1172,1112,1071,823,741,704,614,504cm−1;1HNMR(CDCl3,400MHz)7.67(m,4H),7.43(t,J=6.7Hz,2H),7.40(t,J=6.7Hz,4H),3.64(s,3H),3.57(dd,J=10.0,4.6Hz,1H),3.51(s,1H),3.46(brs,2H),3.42(dd,J=10.0,7.7Hz,0H),2.23(t,J=7.4Hz,2H),2.09(m,1H),1.82(m,1H),1.63−1.48(m,9H),1.06(s,9H),0.88(t,J=7.6Hz,3H);13CNMR(CDCl3,100MHz)174.4,135.7,135.6,132.9,132.9,129.9,129.9,127.8,127.8,74.0,68.4,67.5,51.6,38.5,35.2,31.4,30.2,28.1,26.8,19.1,8.1;
〔α〕28 D−3.48(c1.04,CHCl3);IR(film)2955,2878,1742,1461,1430,1249,1168,1109,1011,839,741,704,612cm−1;1HNMR(CDCl3,400MHz)7.66(d,J=6.7Hz,4H),7.41(t,J=6.7Hz,2H),7.36(t,J=6.7Hz,4H),3.65(s,3H),3.63(dd,J=10.0,4.4Hz,1H),3.47(dd,J=10.0,6.1Hz,1H),3.41(d,J=9.8Hz,1H),3.37(d,J=9.8Hz,1H),2.27(dd,J=9.0,7.3Hz,1H),1.81(m,3H),1.55(m,2H),1.41(dq,J=13.9,7.4Hz,1H),1.25(dd,J=14.4,4.9Hz,1H),1.05(s,9H),0.95(t,J=7.9Hz,9H),0.77(t,J=7.4Hz,3H),0.59(q,J=7.9Hz,6H),0.01(s,9H);13CNMR(CDCl3,100MHz)174.6,135.7,133.9,129.5,127.6,79.2,68.0,67.0,51.4,36.9,35.5,31.7,31.6,29.9,27.8,26.9,8.3,6.9,4.4,2.6;
参考例1
a,前記シリルエーテル10と化合物1において、R1〜R4の全てがHである化合物に相当するイソチオシアナート11から一般式Cに含まれるチオアニリド12の合成。合成工程は以下のとおりである。
1HNMR(CDCl3,400MHz)9.78(s,(1/4)1H),9.74(s,(1/4)1H),9.63(s,(1/4)1H),9.60(s,(1/4)1H),7.83(d,J=7.8Hz,1H),7.67(m、5H),7.38(m,8H),6.50(d,J=11.5Hz,1H)6.00(ddd,J=11.5,6.4,3.9Hz,1H),4.60(t,J=3.4Hz,1H),3.43(ddd,J=12.7,5.8,1.9Hz,1H),4.16(m,(1/2)1H),4.09(ddd,J=12.7,7.1,1.6Hz,1H),4.03(m,(1/2)1H),3.81(m,2H),3.74(s,3H),3.57(m,1H),3.49−3.40(m,3H),2.24(m,2H),1.93(m,(1/2)1H),1.82(m,1H+(1/2)1H),1.68(m,2H),1.53(m,4H),1.44−1.20(m,3H),1.07(s,(1/2)9H),1.05(s,(1/2)9H),0.94(t,J=7.9Hz,9H),0.79(t,J=7.3Hz,(1/2)3H),0.77(t,J=7.3Hz,(1/2)3H),0.59(q,J=7.9Hz,(1/2)6H),0.58(q,J=7.9Hz,(1/2)6H),0.01(s,(1/2)9H),0.00(s,(1/2)9H);
1HNMR(CDCl3,400MHz)8.68(s,(1/4)1H),8.65(s,(1/4)1H),8.39(s,(1/2)1H),7.61(m,6H),7.37(m,6H),7.12(m1H)、7.06(m,1H),4.54(m,(1/2)1H),4.51(m,(1/2)1H),4.12(m,1H),3.96(m,1H),3.83(m,1H),3.66(s,(1/2)3H),3.63(s,(1/2)3H),3.50(m,3H),3.39(m,3H),3.31(m,1H),2.96(m,2H),2.85(m,1H),2.33(m,1H),2.23(m,1H),2.13(m,1H),1.79(m,2H),1.60−1.37(m,4H),1.27(m,2H),1.06(s,(1/2)9H),1.05(s,(1/2)9H),0.99−0.81(m,9H),0.74(t,J=7.2HzH(1/2)3H),0.67(t,J=7.2Hz,(1/4)3H),0.66(t,J=7.2Hz,(1/4)3H),0.56(m,6H),0.11(s,(1/4)9H),0.10(s,(1/4)9H),0.00(s,(1/4)9H),−0.01(s、(1/4)9H);
1HNMR(CDCl3,400MHz)7.95(m,1H),7.67(m,3H),7.53(t,J=8.3Hz,2H),7.37(m,6H),7.21(m,2H),4.57(m,1H),4.51(m,1H),4.23(m,(1/2)1H),4.12(m,(1/2)1H),3.92(m,(1/2)1H),3.85(m,(1/2)1H),3.82(m,1H),3.70(m,1H),3.60(s,(1/2)3H),3.59(s,(1/4)3H),3.58(s,(1/4)3H),3.57(m,2H),3.43(m,3H),3.19(m,2H),2.92(m,2H),2.82(m,2H),2.53(m,(1/2)1H),2.12(m,(1/2)1H),1.86(m,1H),1.64(s,(1/4)9H),1.60(s,(1/4)9H),1.57(s,(1/2)9H),1.72−1.40(m,4H),1.28(m,2H),1.27(brs,(1/2)9H),1.06(s,(1/2)9H),0.93(t,J=8.0Hz,(1/4)9H),0.89(t,J=8.0Hz,(1/4)9H),0.85(t,J=8.0Hz,(1/4)9H),0.84(t,J=8.0Hz,(1/4)9H),0.74(t,J=7.2Hz,(1/2)3H),0.65(t,J=7.2Hz,(1/2)3H),0.56(q,J=8.0Hz,(1/2)6H),0.45(q,J=8.0Hz,(1/4)6H),0.44(q,J=8.0Hz,(1/4)6H),−0.03(s,(1/2)9H),−0.10(s,(1/4)9H),−0.11(s,(1/4)9H);
I、低極性異性体〔α〕26 D+78(c0.57,CHCl3);IR(film)3423,2934,2860,1731,1457,1431,1366,1325,1231,1163,1131,1113,1047,910,823,738,705,614cm−1;1HNMR(CDCl3,400MHz)7.96(d,J=7.8Hz,1H),7.65(d,J=7.8Hz,2H),7.62(d,J=7.8Hz,2H),7.44(m,3H),7.37(m,3H),7.30(td,J=7.8,1.2Hz,1H),7.23(dd,J=7.8,1.2Hz,1H),4.05(t,J=6.3Hz,1H),3.74(m,1H),3.68(m,1H),3.61(s,3H),3.60(dd,J=9.9,4.9Hz,1H),3.36(dd,J=9.9,7.9Hz,1H),3.28(s,2H),2.82(dt,J=14.4,4.3Hz,1H),2.67(ddd,J=14.4,9.0,5.6Hz,1H),2.42(dt,J=13.7,6.3Hz,1H),1.87(m,1H),1.79(ddd,J=13.7,7.3,5.6Hz,1H),1.63(s,9H),1.62(dd,J=15.0,5.9Hz,1H),1.50(dd,J=15.0,4.3Hz,1H),1.34(q,J=7.6Hz,2H),1.03(s,9H),0.75(t,J=7.6Hz,3H);13CNMR(CDCl3,100MHz)173.2,150.4,135.8,135.7,135.6,135.5,132.9,132.8,129.9,129.8,129.1,127.8,127.8,124.6,122.7,118.6,117.8,115.9,84.4,73.8,68.6,67.2,61.7,52.2,41.3,38.6,34.1,34.0,30.0,28.2,27.7,26.8,19.1,7.8;
〔α〕26.5 D−59(c0.47,CHCl3);IR(film)3430,2934,2863,1728,1458,1430,1366,1326,1230,1163,1131,1116,1048,910,738,705,614cm−1;1HNMR(CDCl3,400MHz)7.93(d,J=8.0Hz,1H),7.61(d,J=8.1Hz,2H),7.58(d,J=8.1Hz,2H),7.42(t,J=8.0Hz,1H),7.39(t,J=8.1Hz,2H),7.32(t,J=8.1Hz,4H),7.26(dd,J=8.0,1.0Hz,1H),7.23(td,J=8.0,1.0Hz,1H),3.96(brs,1H),3.66(m,2H),3.63(s,3H),3.55(dd,J=10.2,4.2Hz,1H),3.51(d,J=11.0Hz,1H),3.47(d,J=11.0Hz,1H),3.37(dd,J=10.2,8.4Hz,1H),2.74(dt,J=14.4,4.7Hz,1H),2.58(ddd,J=14.4,8.3,6.4Hz,1H),2.47(ddd,J=14.7,6.8,5.1Hz,1H),1.98(m,1H),1.68(dd,J=14.9,5.9Hz,1H),1.61(dd,J=14.9,7.1Hz,1H),1.60(m,2H),1.60(s,9H),1.45(ddd,J=14.7,7.6,4.9Hz,1H),0.98(s,9H),0.91(t,J=7.4Hz,3H);13CNMR(CDCl3,100MHz)173.5,150.3,135.8,135.6,135.6,135.6,132.9,132.8,129.8,129.8,129.2,127.8,127.7,124.5,122.7,118.6,116.9,115.9,84.4,74.2,68.9,67.6,61.8,52.3,42.0,39.2,35.6,34.9,30.2,28.1,27.7,26.7,19.0,8.2;
I、低極性異性体〔α〕24 D+73(c0.41,CHCl3);IR(film)3543,3397,2934,1731,1597,1457,1431,1364,1325,1253,1232,1175,1130,1113,1044,973,911,842,821,740,705,667,615,555cm-1;1HNMR(CDCl3,400MHz)7.96(d,J=8.3Hz,1H),7.68(d,J=8.1Hz,2H),7.50(m,5H),7.39(m,2H),7.32(td,J=7.3,1.2Hz,1H),7.29(t,J=7.3Hz,4H),7.26(dd,J=7.3,1.2Hz,1H),7.23(d,J=8.1Hz,2H),3.96(brs,1H),3.93(d,J=9.2Hz,1H),3.79(d,J=9.2Hz,1H),3.69(m,2H),3.63(s,3H),3.47(dd,J=10.3,3.8Hz,1H),3.33(dd,J=10.3,8.3Hz,1H),2.90(dt,J=14.4,4.5Hz,1H),2.65(ddd,J=14.4,9.0,6.1Hz,1H),2.41(ddd,J=15.9,6.1,4.6Hz,1H),2.37(s,2H),1.83(m,1H),1.69(dd,J=14.9,4.4Hz,1H),1.61(m,1H),1.58(s,9H),1.51(m,1H),1.00(m,2H),0.91(s,9H),0.79(t,J=7.6Hz,3H);13CNMR(CDCl3,100MHz)173.2,150.3,144.7,135.7,135.5,135.5,135.4,132.6,132.5,132.5,129.9,129.8,129.8,129.3,128.0,127.8,127.8,124.5,122.7,118.8,117.5,116.0,84.4,73.1,72.4,68.9,61.8,52.3,41.8,40.2,35.3,34.7,30.5,28.1,27.8,26.7,21.6,19.0,7.5;
〔α〕25 D−20(c0.57,CHCl3);IR(film)3416,2934,1729,1597,1457,1431,1364,1325,1254,1231,1175,1131,1112,1045,974,912,841,821,739,705,667,614,556,508cm−1;1HNMR(CDCl3,400MHz)7.96(d,J=7.6Hz,1H),7.68(d,J=8.3Hz,2H),7.61(m,4H),7.47(t,J=7.6Hz,1H),7.43(m,2H),7.37(m,4H),7.29(td,J=7.6,1.2Hz,1H),7.26(d,J=8.3Hz,2H),7.23(dd,J=7.6,1.2Hz,1H),3.98(t,J=5.5Hz,1H),3.82(d,J=9.3Hz,1H),3.74(m,2H),3.64(d,J=9.3Hz,1H),3.63(dd,J=10.0,2.3Hz,1H),3.61(s,3H),3.33(dd,J=10.0,8.3Hz,1H),2.92(dt,J=14.2,5.2Hz,1H),2.72(dt,J=14.2,8.0Hz,1H),2.41(s,2H),2.40(m,1H),1.98(m,1H),1.65(m,1H),1.61(s,9H),1.58(m,2H),1.37(dq,J=14.4,7.4Hz,1H),1.31(dq,J=14.4,7.4Hz,1H),1.00(s,9H),0.68(t,J=7.4Hz,3H);13CNMR(CDCl3,100MHz)172.9,150.3,144.9,135.8,135.7,135.6,135.6,132.5,132.5,132.5,132.4,130.0,129.9,129.3,128.0,127.9,127.8,124.4,122.6,118.6,117.4,116.0,84.3,72.9,72.0,68.8,61.8,52.1,41.2,39.4,34.5,34.2,30.5,28.1,28.0,26.8,21.6,19.1,7.3;
低極性異性体
〔α〕23 D+93(c0.31,CHCl3);IR(film)3456,2934,2859,1731,1588,1458,1431,1364,1324,1254,1229,1164,1130,1113,1049,1004,910,822,741,705,616cm−1;1HNMR(CDCl3,400MHz)7.98(d,J=7.7Hz,1H),7.64(m,4H),7.43(m,3H),7.36(m,4H),7.29(td,J=7.7,1.2Hz,1H),7.23(td,J=7.7,1.2Hz,1H),4.01(dd,J=9.9,4.3Hz,1H),3.68(m,2H),3.66(s,3H),3.55(dd,J=10.2,4.1Hz,1H),3.47(dd,J=10.2,4.7Hz,1H),2.82(dt,J=14.7,3.9Hz,1H),2.55(m,2H),2.34(d,J=4.7Hz,1H),2.27(d,J=4.7Hz,1H),2.11(dd,J=9.6,3.8Hz,1H),2.05(ddd,J=14.7,9.8,3.4Hz,1H),1.66(m,1H),1.65(s,9H),1.44(brs,1H),1.21(qd,J=7.4,3.6Hz,2H),1.05(s,9H),0.64(t,J=7.4Hz,3H);13CNMR(CDCl3,100MHz)173.0,150.3,136.0,135.8,135.6,135.1,133.5,133.5,129.8,129.7,129.7,127.7,127.7,124.5,122.7,118.5,118.3,116.0,84.4,65.9,61.7,58.7,52.1,51.6,41.8,36.2,35.0,31.8,28.2,27.8,26.9,26.5,19.3,8.5;
〔α〕24 D62(c0.36,CHCl3);IR(film)3455,2934,2859,1730,1458,1431,1365,1325,1253,1229,1164,1130,1112,1079,1008,910,823,742,705,615cm−1;1HNMR(CDCl3,400MHz)7.99(d,J=7.8Hz,1H),7.56(d,J=8.0Hz,4H),7.50-7.20(m,9H),4.14(t,J=6.8Hz,1H),3.76(m,2H),3.65(s,3H),3.47(d,J=4.6Hz,2H),2.93(dt,J=14.4,4.3Hz,1H),2.80(ddd,J=14.4,9.0,5.9Hz,1H),2.45(ddd,J=14.2,6.8,4.6Hz,1H),2.42(d,J=4.6Hz,1H),2.40(d,J=4.6Hz,1H),2.27(dd,J=9.5,4.4Hz,1H),2.09(ddd,J=14.2,7.3,4.9Hz,1H),1.63(s,9H),1.62(m,1H),1.39(m,2H),1.06(m,1H),0.90(s,9H),0.76(t,J=7.6Hz,3H);13CNMR(CDCl3,100MHz)173.2,150.4,135.9,135.8,135.6,135.6,133.6,133.4,129.6,129.6,129.3,127.6,127.5,124.5,122.7,118.5,117.6,116.1,84.4,66.7,61.9,59.1,52.3,52.2,41.7,36.3,36.0,33.6,28.1,28.1,26.8,26.7,19.1,8.7;
IR(film)3397,3071,2934,2859,1731,1546,1459,1432,1367,1327,1235,1165,1115,910,735,705,581cm−1;1HNMR(CDCl3,400MHz)8.04(d,J=8.3Hz,1H),7.93(m,(1/2)1H),7.89(d,J=7.1Hz,(1/2)1H),7.78-7.16(m,13H+(1/2)1H),7.13(d,J=7.3Hz,(1/2)1H),7.11(d,J=7.3Hz,(1/2)1H),6.77(brs,(1/2)3H),4.83(s,(1/2)1H),4.31(brs,(1/2)1H),4.23(m,(1/2)2H),3.82-3.19(m,4H+(1/2)1H),3.60(s,(1/2)3H),3.56(s,(1/2)3H),3.12(m,(1/2)1H),2.98(m,1H),2.88(d,J=14.9Hz,(1/2)1H),2.75(m,(1/2)1H),2.51−1.71(m,3H),1.64(s,(1/2)9H),1.61(s,(1/2)9H),1.42−1.15(m,4H),1.06(s,(1/2)9H),0.98(s,(1/2)9H),0.89(t,J=7.6Hz,(1/2)3H),0.68(t,J=7.6Hz,(1/2)3H);
I、低極性異性体
〔α〕22 D−89(c0.37,CHCl3);IR(film)3389,2947,1728,1545,1460,1439,1370,1341,1167,910,734,580cm−1;1HNMR(CDCl3,400MHz)8.76(s,1H),7.93(dd,J=7.6,1.2Hz,1H),7.72(td,J=7.6,1.2Hz,1H),7.67(td,J=7.6,1.2Hz,1H),7.62(dd,J=7.6,1.2Hz,1H),7.42(d,J=8.0Hz,1H),7.31(d,J=8.0Hz,1H),7.15(td,J=8.0,1.0Hz,1H),7.05(td,J=8.0,1.0Hz,1H),4.17(dd,J=12.8,3.3Hz,1H),4.07(ddd,J=15.1,8.5,6.6Hz,1H),3.74(s,3H),3.58(d,J=14.4Hz,1H),3.51(dd,J=10.9,4.0Hz,1H),3.46(dd,J=10.9,6.3Hz,1H),3.40(dt,J=15.1,7.9Hz,1H),3.11(m,2H),3.10(d,J=14.4Hz,1H),2.97(ddd,J=15.4,6.6,3.3Hz,1H),2.19(d,J=15.4Hz,1H),2.10(t,J=12.1Hz,1H),1.77-1.63(m,4H),0.98(t,J=7.4Hz,3H);13CNMR(CDCl3,100MHz)174.3,148.9,136.0,133.9,131.5,131.3,130.5,129.8,127.2,124.2,122.5,119.8,118.6,112.6,111.2,74.3,68.3,60.4,53.6,52.6,39.4,37.9,37.2,33.7,33.6,26.4,7.4;
〔α〕23 D+21(c0.24,CHCl3);IR(film)3385,2930,1726,1546,1461,1440,1372,1347,1166,909,735,581cm−1;1HNMR(CDCl3,400MHz)8.56(s,1H),7.98(dd,J=7.7,1.5Hz,1H),7.76(td,J=7.7,1.5Hz,1H),7.72(td,J=7.7,1.5Hz,1H),7.64(dd,J=7.7,1.5Hz,1H),7.50(d,J=7.9Hz,1H),7.33(d,J=7.9Hz,1H),7.16(t,J=7.9Hz,1H),7.08(t,J=7.9Hz,1H),4.15(dd,J=10.0,2.4Hz,1H),4.02(m,1H),3.70(s,3H),3.58(dd,J=10.8,6.1Hz,1H),3.54(dd,J=10.8,5.7Hz,1H),3.40(d,J=15.4Hz,1H),3.31(m,3H),2.77(d,J=15.4Hz,1H),2.44(m,1H),2.17(dt,J=13.9,2.4Hz,1H),1.80(dt,J=13.9,10.8Hz,1H),1.05(m,4H),0.40(t,J=7.4Hz,3H);13CNMR(CDCl3,100MHz)174.3,149.0,136.0,134.1,132.4,131.5,131.0,130.3,127.6,124.2,122.5,119.8,118.6,111.1,110.8,73.0,68.6,61.8,53.9,52.5,42.2,37.5,37.5,36.0,34.6,25.6,7.1;
IR(film)3514,3393,2956,1728,1595,1546,1461,1440,1354,1173,962,754,667,580cm−1;1HNMR(CDCl3,400MHz)8.67(s,(1/2)1H),8.51(s,(1/2)1H),7.89(d,J=8.0Hz,(1/2)1H),7.81(d,J=8.0Hz,(1/2)1H),7.77(d,J=8.0Hz,(1/2)2H),7.73-7.57(m,4H),7.43(d,J=7.1Hz,1H),7.36(d,J=7.1Hz,1H),7.32(d,J=8.0Hz,(1/2)2H),7.18(t,J=7.1Hz,(1/2)1H),7.16(t,J=7.1Hz,(1/2)1H),7.11(d,J=8.0Hz,(1/2)2H),7.06(t,J=7.1Hz,(1/2)1H),7.04(t,J=7.1Hz,(1/2)1H),4.23-4.07(m,2H),3.92(dd,J=9.5,6.6Hz,(1/2)1H),3.86(dd,J=9.8,7.1Hz,(1/2)1H),3.80(m,(1/2)1H),3.70(s,(1/2)3H),3.69(s,(1/2)3H),3.38(d,J=15.0Hz,1H),3.25(m,1H),3.17(m,(1/2)1H),3.10(m,(1/2)1H),2.97(d,J=15.0Hz,(1/2)1H),2.63(d,J=15.0Hz,(1/2)1H),2.50(m,(1/2)1H),2.42(s,(1/2)3H),2.32(s,(1/2)3H),2.21(dt,J=13.9,1.5Hz,(1/2)1H),1.94(d,J=15.9Hz,(1/2)1H),1.83(m,1H),1.49(m,2H),1.28(m,2H),1.02(m,2H),0.77(t,J=7.4Hz,(1/2)3H),0.37(t,J=7.4Hz,(1/2)3H);
〔α〕28 D+27(c0.32,CHCl3);IR(film)3414,2952,2879,1778,1740,1614,1548,1498,1461,1434,1396,1226,1175,1043,913,817,734,668,580,554cm−1;1HNMR(CDCl3,400MHz)10.56(brs,1H),9.42(brs,1H),7.86(dd,J=7.8,1.2Hz,1H),7.78(td,J=7.8,1.2Hz,1H),7.76(d,J=8.3Hz,1H),7.70(td,J=7.8,1.2Hz,1H),7.64(dd,J=7.8,1.2Hz,1H),7.41(s,1H),7.34(d,J=7.3Hz,1H),7.32(d,J=8.3Hz,2H),7.14(d,J=7.3Hz,1H),7.11(t,J=7.3Hz,1H),6.94(t,J=7.3Hz,1H),5.91(dd,J=10.2,3.7Hz,1H),5.81(dd,J=10.2,3.7Hz,1H),5.57(s,1H),5.27(d,J=10.2Hz,1H),4.12(d,J=9.7Hz,1H),3.90(d,J=16.0Hz,1H),3.80(s,3H),3.79(m,1H),3.71(s,3H),3.64(d,J=9.7Hz,1H),3.44(s,3H),3.44(m,1H),3.36(t,J=7.3Hz,1H),3.29(m,1H),3.16(dd,J=16.0,6.1Hz,1H),3.04(d,J=16.6Hz,1H),2.94(t,J=12.2Hz,1H),2.82(m,2H),2.81(s,1H),2.70(m,1H),2.63(s,3H),2.54(m,2H),2.41(s,3H),2.09(s,3H),1.89(m,3H),1.71(m,2H),1.58(brs,2H),1.30(m,3H),0.59(t,J=7.4Hz,3H),0.43(t,J=7.3Hz,3H);13CNMR(CDCl3,100MHz)177.1,177.0,172.3,170.9,158.5,155.8,155.4,155.0,153.2,148.8,145.0,135.1,134.5,134.0,132.4,131.6,131.3,130.2,129.9,128.0,127.7,127.7,125.4,124.6,124.0,122.5,121.6,120.1,119.0,117.5,115.1,112.2,111.1,108.4,94.4,94.1,77.2,72.9,68.0,55.7,54.1,53.0,52.8,52.6,52.4,51.0,50.7,43.4,39.5,37.8,37.7,31.6,30.7,29.3,25.2,21.6,21.1,8.8,7.0;
AIBN = アゾビスイソブチロニトリル
Bn = ベンジル
Boc = t−ブトキシカルボニル基
DBU = 1、8−ジアザビシクロウンデセン
DEAD = ジエチルアゾジカルボン酸
DIBAL = 水素化ジイソブチルアルミニウム
DMAP = 4−ジメチルアミノピリジン
DMF = ジメチルホルムアミド
Et = エチル基
LDA = リチウムジイソプロピルアミド
Me = メチル基
Ns = 2−ニトロベンゼンスルホニル基
Ph = フェニル基
Py = ピリジン
TBDPS = t−ブチルジフェニルシリル基
TES = トリエチルシリル基
TFA = トリフルオロアセチル基またはトリフルオロ酢酸
TFAA = トリフルオロ酢酸無水物
THF = テトラヒドロフラン
THP = テトラヒドロピラニル基
TMS = トリメチルシリル基
Ts = p−トルエンスルホニル基
Claims (1)
- 一般式Bからなる一般式Aの製造用原料化合物。
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