JP2017516822A - デュオカルマイシンのプロドラッグを製造するための改良された方法 - Google Patents
デュオカルマイシンのプロドラッグを製造するための改良された方法 Download PDFInfo
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- JP2017516822A JP2017516822A JP2016570985A JP2016570985A JP2017516822A JP 2017516822 A JP2017516822 A JP 2017516822A JP 2016570985 A JP2016570985 A JP 2016570985A JP 2016570985 A JP2016570985 A JP 2016570985A JP 2017516822 A JP2017516822 A JP 2017516822A
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- VQNATVDKACXKTF-XELLLNAOSA-N duocarmycin Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3C4=CC(=O)C5=C([C@@]64C[C@@H]6C3)C=C(N5)C(=O)OC)=CC2=C1 VQNATVDKACXKTF-XELLLNAOSA-N 0.000 title abstract description 14
- 229940002612 prodrug Drugs 0.000 title description 7
- 239000000651 prodrug Substances 0.000 title description 7
- 229960005501 duocarmycin Drugs 0.000 title description 5
- 229930184221 duocarmycin Natural products 0.000 title description 5
- 238000004519 manufacturing process Methods 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 94
- 238000000034 method Methods 0.000 claims abstract description 48
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 38
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- 125000001979 organolithium group Chemical group 0.000 claims abstract description 18
- 239000000611 antibody drug conjugate Substances 0.000 claims abstract description 12
- 229940049595 antibody-drug conjugate Drugs 0.000 claims abstract description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 24
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 22
- 229910052698 phosphorus Inorganic materials 0.000 claims description 20
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 19
- 239000012320 chlorinating reagent Substances 0.000 claims description 19
- 125000006239 protecting group Chemical group 0.000 claims description 18
- 230000008878 coupling Effects 0.000 claims description 16
- 238000010168 coupling process Methods 0.000 claims description 16
- 238000005859 coupling reaction Methods 0.000 claims description 16
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 238000002360 preparation method Methods 0.000 claims description 14
- PAQZWJGSJMLPMG-UHFFFAOYSA-N propylphosphonic anhydride Substances CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 claims description 13
- 239000011780 sodium chloride Substances 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 8
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 239000007821 HATU Substances 0.000 claims description 7
- DVSDBMFJEQPWNO-UHFFFAOYSA-N methyllithium Chemical compound C[Li] DVSDBMFJEQPWNO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical group 0.000 claims description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- 229910052740 iodine Inorganic materials 0.000 claims description 5
- 239000011630 iodine Substances 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 4
- 238000005580 one pot reaction Methods 0.000 claims description 3
- 238000007039 two-step reaction Methods 0.000 claims description 3
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims 2
- 239000012317 TBTU Substances 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 4
- 230000004568 DNA-binding Effects 0.000 abstract description 3
- 230000007118 DNA alkylation Effects 0.000 abstract description 2
- 101100386054 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CYS3 gene Proteins 0.000 abstract 1
- 101150035983 str1 gene Proteins 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 78
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- 239000000047 product Substances 0.000 description 28
- 239000000243 solution Substances 0.000 description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 27
- 239000000203 mixture Substances 0.000 description 25
- 239000011541 reaction mixture Substances 0.000 description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 19
- 239000012044 organic layer Substances 0.000 description 19
- 239000002904 solvent Substances 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000000725 suspension Substances 0.000 description 18
- -1 tert-butyl epoxide Chemical class 0.000 description 18
- 239000007787 solid Substances 0.000 description 16
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 14
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 14
- 229920006395 saturated elastomer Polymers 0.000 description 13
- 0 Cc(c1c2[C@](CCl)C3)cccc1c(*)cc2N3P Chemical compound Cc(c1c2[C@](CCl)C3)cccc1c(*)cc2N3P 0.000 description 12
- 239000010410 layer Substances 0.000 description 12
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 10
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 10
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 10
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 10
- 239000003054 catalyst Substances 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 8
- RROBIDXNTUAHFW-UHFFFAOYSA-N benzotriazol-1-yloxy-tris(dimethylamino)phosphanium Chemical group C1=CC=C2N(O[P+](N(C)C)(N(C)C)N(C)C)N=NC2=C1 RROBIDXNTUAHFW-UHFFFAOYSA-N 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 239000012267 brine Substances 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- RVOVHCHSWKXMQF-LJQANCHMSA-N tert-butyl (1s)-1-(chloromethyl)-9-methyl-5-phenylmethoxy-1,2-dihydrobenzo[e]indole-3-carboxylate Chemical compound C1([C@H](CCl)CN(C1=C1)C(=O)OC(C)(C)C)=C2C(C)=CC=CC2=C1OCC1=CC=CC=C1 RVOVHCHSWKXMQF-LJQANCHMSA-N 0.000 description 7
- HAMXVDIJALQDLE-UHFFFAOYSA-N 6-[[4-(methoxymethoxy)benzoyl]amino]imidazo[1,2-a]pyridine-2-carboxylic acid Chemical compound COCOC1=CC=C(C=C1)C(=O)NC1=CN2C=C(N=C2C=C1)C(O)=O HAMXVDIJALQDLE-UHFFFAOYSA-N 0.000 description 6
- JCRPWONFCIOOTF-UHFFFAOYSA-N 8-methyl-4-phenylmethoxynaphthalene-2-carboxylic acid Chemical compound CC1=C2C=C(C=C(OCC3=CC=CC=C3)C2=CC=C1)C(O)=O JCRPWONFCIOOTF-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 229910052744 lithium Inorganic materials 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- QOQUVRIVMFOCQT-HXUWFJFHSA-N n-[2-[(1s)-1-(chloromethyl)-5-hydroxy-9-methyl-1,2-dihydrobenzo[e]indole-3-carbonyl]imidazo[1,2-a]pyridin-6-yl]-4-(methoxymethoxy)benzamide Chemical compound C1=CC(OCOC)=CC=C1C(=O)NC1=CN2C=C(C(=O)N3C4=C(C5=C(C)C=CC=C5C(O)=C4)[C@H](CCl)C3)N=C2C=C1 QOQUVRIVMFOCQT-HXUWFJFHSA-N 0.000 description 6
- DKNNZNFXEAXOGR-UHFFFAOYSA-N tert-butyl N-(8-methyl-4-phenylmethoxynaphthalen-2-yl)carbamate Chemical compound C(C1=CC=CC=C1)OC1=CC(=CC2=C(C=CC=C12)C)NC(OC(C)(C)C)=O DKNNZNFXEAXOGR-UHFFFAOYSA-N 0.000 description 6
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 230000003287 optical effect Effects 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 238000001946 ultra-performance liquid chromatography-mass spectrometry Methods 0.000 description 5
- QMWVGJAFMIYQSZ-UHFFFAOYSA-N 1-(4-bromophenyl)-2,5-dimethylpyrrole-3-carbaldehyde Chemical compound CC1=CC(C=O)=C(C)N1C1=CC=C(Br)C=C1 QMWVGJAFMIYQSZ-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
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- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- BTFQKIATRPGRBS-UHFFFAOYSA-N o-tolualdehyde Chemical compound CC1=CC=CC=C1C=O BTFQKIATRPGRBS-UHFFFAOYSA-N 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- WRYQUAMTVZNYDN-FQEVSTJZSA-N tert-butyl (1S)-9-methyl-1-(methylsulfonyloxymethyl)-5-phenylmethoxy-1,2-dihydrobenzo[e]indole-3-carboxylate Chemical compound C(C1=CC=CC=C1)OC=1C2=C(C=3[C@@H](CN(C=3C=1)C(=O)OC(C)(C)C)COS(=O)(=O)C)C(=CC=C2)C WRYQUAMTVZNYDN-FQEVSTJZSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- XIFRBTZCMICRPL-UHFFFAOYSA-N 4-(methoxymethoxy)benzoic acid Chemical compound COCOC1=CC=C(C(O)=O)C=C1 XIFRBTZCMICRPL-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- PKWHXLCNUIXDIK-UHFFFAOYSA-N ethyl 6-aminoimidazo[1,2-a]pyridine-2-carboxylate Chemical compound C1=C(N)C=CC2=NC(C(=O)OCC)=CN21 PKWHXLCNUIXDIK-UHFFFAOYSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 3
- 150000003840 hydrochlorides Chemical class 0.000 description 3
- JLEZODLMOCAUOI-UHFFFAOYSA-N methyl 4-hydroxy-8-methylnaphthalene-2-carboxylate Chemical compound C1=CC=C(C)C2=CC(C(=O)OC)=CC(O)=C21 JLEZODLMOCAUOI-UHFFFAOYSA-N 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
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- 238000006798 ring closing metathesis reaction Methods 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- GTBKMUUCTQRZBD-IBGZPJMESA-N tert-butyl (1S)-1-(hydroxymethyl)-9-methyl-5-phenylmethoxy-1,2-dihydrobenzo[e]indole-3-carboxylate Chemical compound C(C1=CC=CC=C1)OC=1C2=C(C=3[C@@H](CN(C=3C=1)C(=O)OC(C)(C)C)CO)C(=CC=C2)C GTBKMUUCTQRZBD-IBGZPJMESA-N 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- 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 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
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- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
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- AIHIHVZYAAMDPM-QMMMGPOBSA-N [(2s)-oxiran-2-yl]methyl 3-nitrobenzenesulfonate Chemical compound [O-][N+](=O)C1=CC=CC(S(=O)(=O)OC[C@H]2OC2)=C1 AIHIHVZYAAMDPM-QMMMGPOBSA-N 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 125000006241 alcohol protecting group Chemical group 0.000 description 2
- 125000006242 amine protecting group Chemical group 0.000 description 2
- 235000019270 ammonium chloride Nutrition 0.000 description 2
- 239000003972 antineoplastic antibiotic Substances 0.000 description 2
- 238000004517 catalytic hydrocracking Methods 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 2
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- 239000010949 copper Substances 0.000 description 2
- 231100000433 cytotoxic Toxicity 0.000 description 2
- 230000001472 cytotoxic effect Effects 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
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- VICYTAYPKBLQFB-UHFFFAOYSA-N ethyl 3-bromo-2-oxopropanoate Chemical compound CCOC(=O)C(=O)CBr VICYTAYPKBLQFB-UHFFFAOYSA-N 0.000 description 2
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- 125000000524 functional group Chemical group 0.000 description 2
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- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 2
- PULKVUDFXWJBEG-UHFFFAOYSA-N methyl 4-(methoxymethoxy)benzoate Chemical compound COCOC1=CC=C(C(=O)OC)C=C1 PULKVUDFXWJBEG-UHFFFAOYSA-N 0.000 description 2
- AGWULHCETKXZAN-UHFFFAOYSA-N methyl 8-methyl-4-phenylmethoxynaphthalene-2-carboxylate Chemical compound C(C1=CC=CC=C1)OC1=CC(=CC2=C(C=CC=C12)C)C(=O)OC AGWULHCETKXZAN-UHFFFAOYSA-N 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
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- 239000003880 polar aprotic solvent Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000011343 solid material Substances 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- NWONKYPBYAMBJT-UHFFFAOYSA-L zinc sulfate Chemical compound [Zn+2].[O-]S([O-])(=O)=O NWONKYPBYAMBJT-UHFFFAOYSA-L 0.000 description 2
- JTRIUPVSQUCCHH-UHFFFAOYSA-N $l^{1}-oxidanylsulfinylmethane Chemical compound C[S](=O)=O JTRIUPVSQUCCHH-UHFFFAOYSA-N 0.000 description 1
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 1
- 239000001431 2-methylbenzaldehyde Substances 0.000 description 1
- SLRMQYXOBQWXCR-UHFFFAOYSA-N 2154-56-5 Chemical compound [CH2]C1=CC=CC=C1 SLRMQYXOBQWXCR-UHFFFAOYSA-N 0.000 description 1
- BGWMSAQAFGFTQK-UHFFFAOYSA-N 2h-indole-3-carboxylic acid Chemical compound C1=CC=CC2=NCC(C(=O)O)=C21 BGWMSAQAFGFTQK-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- UGSBCCAHDVCHGI-UHFFFAOYSA-N 5-nitropyridin-2-amine Chemical compound NC1=CC=C([N+]([O-])=O)C=N1 UGSBCCAHDVCHGI-UHFFFAOYSA-N 0.000 description 1
- CONKBQPVFMXDOV-QHCPKHFHSA-N 6-[(5S)-5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-2-oxo-1,3-oxazolidin-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C[C@H]1CN(C(O1)=O)C1=CC2=C(NC(O2)=O)C=C1 CONKBQPVFMXDOV-QHCPKHFHSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- FIPWRIJSWJWJAI-UHFFFAOYSA-N Butyl carbitol 6-propylpiperonyl ether Chemical compound C1=C(CCC)C(COCCOCCOCCCC)=CC2=C1OCO2 FIPWRIJSWJWJAI-UHFFFAOYSA-N 0.000 description 1
- JQEWZHAJDCSRKX-FQEVSTJZSA-N CC(C)COC(N1c2cc(OCc3ccccc3)c(cccc3C)c3c2[C@H](CO)C1)=O Chemical compound CC(C)COC(N1c2cc(OCc3ccccc3)c(cccc3C)c3c2[C@H](CO)C1)=O JQEWZHAJDCSRKX-FQEVSTJZSA-N 0.000 description 1
- JSDGDAFILYWBGU-PKNBQFBNSA-N CC/C(=C\C1=CC=CC=C1C)/C(=O)OC Chemical compound CC/C(=C\C1=CC=CC=C1C)/C(=O)OC JSDGDAFILYWBGU-PKNBQFBNSA-N 0.000 description 1
- XJUZRXYOEPSWMB-UHFFFAOYSA-N Chloromethyl methyl ether Chemical compound COCCl XJUZRXYOEPSWMB-UHFFFAOYSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 229940061627 chloromethyl methyl ether Drugs 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 125000001033 ether group Chemical group 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- NSPJNIDYTSSIIY-UHFFFAOYSA-N methoxy(methoxymethoxy)methane Chemical group COCOCOC NSPJNIDYTSSIIY-UHFFFAOYSA-N 0.000 description 1
- AZVARJHZBXHUSO-DZQVEHCYSA-N methyl (1R,4R,12S)-4-methyl-3,7-dioxo-10-(5,6,7-trimethoxy-1H-indole-2-carbonyl)-5,10-diazatetracyclo[7.4.0.01,12.02,6]trideca-2(6),8-diene-4-carboxylate Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3C[C@H]4C[C@]44C5=C(C(C=C43)=O)N[C@@](C5=O)(C)C(=O)OC)=CC2=C1 AZVARJHZBXHUSO-DZQVEHCYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- PSNIYGKWARCUAN-UHFFFAOYSA-N oxiran-2-yl carbamate Chemical compound NC(=O)OC1CO1 PSNIYGKWARCUAN-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 229960005235 piperonyl butoxide Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- UOWVMDUEMSNCAV-WYENRQIDSA-N rachelmycin Chemical compound C1([C@]23C[C@@H]2CN1C(=O)C=1NC=2C(OC)=C(O)C4=C(C=2C=1)CCN4C(=O)C1=CC=2C=4CCN(C=4C(O)=C(C=2N1)OC)C(N)=O)=CC(=O)C1=C3C(C)=CN1 UOWVMDUEMSNCAV-WYENRQIDSA-N 0.000 description 1
- 238000007142 ring opening reaction Methods 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
- 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
- 235000014347 soups Nutrition 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 1
- GTBKMUUCTQRZBD-LJQANCHMSA-N tert-butyl (1R)-1-(hydroxymethyl)-9-methyl-5-phenylmethoxy-1,2-dihydrobenzo[e]indole-3-carboxylate Chemical compound C(C1=CC=CC=C1)OC=1C2=C(C=3[C@H](CN(C=3C=1)C(=O)OC(C)(C)C)CO)C(=CC=C2)C GTBKMUUCTQRZBD-LJQANCHMSA-N 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
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/58—[b]- or [c]-condensed
- C07D209/60—Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Indole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
[式中、PおよびP’は、独立して、保護基であり、
R1は、CH3、CH2CH3、OCH3、OCH2CH3、CF3、OCF3、ClもしくはFであり、
R2、R3、R4は、独立して、HもしくはC1-6アルキルであるか、または、
R1およびR2は、一緒になって、5または6員の(ヘテロ)シクロアルキル基を形成し、
Xは、ハロゲンである]を提供する。
[式中、R1、R2、R3、R4、PおよびP’は、上記定義の意味を有する]
を提供する。
a)保護基Pの除去、および
b)カップリング試薬の存在下での、式(V)
c)保護基P’の脱離
によって、式(IV)
[式中、R1、R2、R3、R4、PおよびP’は、上記定義の意味を有し、P”は、独立して、保護基であり、X1、X2、X3は、独立して、CまたはNである]
を提供する。
他に定義しない限り、ここで使用される全ての技術的および科学的用語は、当業者によって通常理解されるものと同じ意味を有する。
例1
式(II)の化合物の調製のための一般的手順
以下の反応スキームによる、化合物(3)および(4)からの、式(II)の化合物である化合物(12)の調製:
例2aのスキームによる化合物(9)からの、式(II)の化合物である化合物(12)の調製:
tert−ブチル(4−(ベンジルオキシ)−8−メチルナフタレン−2−イル)カルバメート(9)(10.5g)を、−10℃で、THF(31.5g)中、1.01当量のN−ブロモスクシンイミド(5.20g)で処理した。反応を水酸化ナトリウム水溶液(0.75gのNaOHおよび7.5gの水)の添加によってクエンチした。抽出物を飽和NaCl水溶液(15g)で洗浄し、水層を酢酸エチル(11.25g)で抽出した。有機層を合わせ、飽和NaCl水溶液(15g)で洗浄し、真空下で濃縮して、tert−ブチル(4−(ベンジルオキシ)−1−ブロモ−8−メチルナフタレン−2−イル)カルバメート(10)を得た(14.36g、収率112.36%)。
以下のスキームによる化合物(12)からの化合物(14)の調製
例3aのスキームによる化合物(12)からの化合物(14)の調製:
化合物(12)(10g)を、Et3N(3.3g、1.37当量)の存在下、0〜5℃で90分間、THF(50g)中、塩化メタンスルホニル(3.0g、1.1当量)で処理した。反応混合物を塩酸水(1.70gの36%HClおよび10gの水)の添加によってクエンチした。有機層を、飽和NaHCO3水溶液(5g)、および飽和NaCl水溶液(5g)で洗浄した。水層を酢酸エチル(13.3g)で抽出した。有機層を合わせ、飽和NaCl水溶液(10g)で洗浄し、次いで真空下で濃縮して、(13)(13.10g)を得た。
例5に使用するための4−(メトキシメトキシ)安息香酸の調製
1g(6.6mmol)の4−ヒドロキシ安息香酸メチルを、窒素雰囲気下、25mlのDCMに溶解した。次に、溶液を0℃に冷却し、続いて、600μl(7.9mmol)のクロロメチルメチルエーテルおよび3.25ml(19.7mmol)のDIPEAを添加した。混合物を撹拌して、一晩室温まで昇温させた。翌日、水(100ml)を添加し、混合物をDCM(100ml)で2回抽出した。合わせたDCM層をブライン(100ml)で洗浄し、Na2SO4で乾燥し、真空中で濃縮して、4−(メトキシメトキシ)安息香酸メチルエステルを得た。
以下の反応スキームによる化合物(18)および(19)からの化合物(15)の調製:
以下のスキームによる(14)および(15)からの化合物(17)の調製:
例6aのスキームによる(14)および(15)からの化合物(17)の調製:
ジャケット付反応器中、化合物(14)(183g、0.418mol)をHCl/ジオキサン(4M、2.08L)溶液に懸濁させ、28〜32℃で3時間撹拌した。生成した懸濁液を18〜22℃に冷却し、次いで、懸濁液にメチル−t−ブチルエーテル(0.76L)を添加した。生成した固体をろ別し、メチル−t−ブチルエーテル(0.64L)で洗浄し、ロータリーエバポレーター中40℃で乾燥して、HCl塩[(S)−5−(ベンジルオキシ)−1−(クロロメチル)−9−メチル−2,3−ジヒドロ−1H−ベンゾ[e]インドール塩酸塩]を152.3g(収率97.4%)(HPLC純度98.08%)を得た。
以下に出願当初の請求項を実施の態様として付記する。
[1]
式(I)
式中、PおよびP’は、独立して、保護基であり、
R 1 は、CH 3 、CH 2 CH 3 、OCH 3 、OCH 2 CH 3 、CF 3 、OCF 3 、ClもしくはFであり、
R 2 、R 3 、R 4 は、独立して、HもしくはC 1-6 アルキルであるか、または、
R 1 およびR 2 は、一緒になって、5または6員の(ヘテロ)シクロアルキル基を形成し、
Xは、ハロゲンである方法。
[2]
R 1 が、CH 3 、CH 2 CH 3 、OCH 3 もしくはOCH 2 CH 3 であり、R 2 、R 3 、R 4 が、独立して、HもしくはC 1-6 アルキルであるか、または、R 1 およびR 2 が、一緒になって、5員の(ヘテロ)シクロアルキル基を形成する、[1]に記載の方法。
[3]
前記有機リチウム試薬が、モノメタル有機リチウム試薬である、[1]または[2]に記載の方法。
[4]
前記モノメタル有機リチウム試薬が、n−ブチルリチウム、tert−ブチルリチウムおよびメチルリチウムからなる群から選択される、[3]に記載の方法。
[5]
前記ハロゲンが、臭素またはヨウ素である、[1]から[5]のいずれか一に記載の方法。
[6]
強塩基を添加する、[1]から[5]のいずれか一に記載の方法。
[7]
式(II)の化合物を、塩素化試薬との一段階または二段階の反応のいずれかによって、式(III)
の化合物に変換することをさらに含む、[1]から[6]のいずれか一に記載の方法。
[8]
前記塩素化試薬が、LiCl、KCl、NaCl、NH 4 Cl、HCl、濃塩酸中のAlCl 3 、PPh 3 /CCl 4 、PPh 3 /NCS、SOCl 2 およびPCl 3 /PCl 5 からなる群から選択される、[7]に記載の方法。
[9]
前記塩素化試薬が、LiClまたはPPh 3 /CCl 4 である、[8]に記載の方法。
[10]
式(III)の化合物を、
a)保護基Pの除去、および
b)カップリング試薬の存在下での、式(V)
c)保護基P’の脱離
によって、式(IV)
[式中、R 1 、R 2 、R 3 、R 4 、PおよびP’は、[1]に定義の意味を有し、
P”は、独立して、保護基であり、
X 1 、X 2 、X 3 は、独立して、CまたはNである]。
[11]
前記カップリング試薬が、BOP、DCC、DIC、EDC、HATU、TBTUおよびT3Pからなる群から選択される、[10]に記載の方法。
[12]
前記カップリング試薬が、EDCである、[11]に記載の方法。
[13]
式(II)の前記化合物が、
[14]
式(IV)の前記化合物が、
[15]
対応する抗体薬物複合体の調製のための、式(IV)
Claims (15)
- R1が、CH3、CH2CH3、OCH3もしくはOCH2CH3であり、R2、R3、R4が、独立して、HもしくはC1-6アルキルであるか、または、R1およびR2が、一緒になって、5員の(ヘテロ)シクロアルキル基を形成する、請求項1に記載の方法。
- 前記有機リチウム試薬が、モノメタル有機リチウム試薬である、請求項1または2に記載の方法。
- 前記モノメタル有機リチウム試薬が、n−ブチルリチウム、tert−ブチルリチウムおよびメチルリチウムからなる群から選択される、請求項3に記載の方法。
- 前記ハロゲンが、臭素またはヨウ素である、請求項1から5のいずれか一項に記載の方法。
- 強塩基を添加する、請求項1から5のいずれか一項に記載の方法。
- 前記塩素化試薬が、LiCl、KCl、NaCl、NH4Cl、HCl、濃塩酸中のAlCl3、PPh3/CCl4、PPh3/NCS、SOCl2およびPCl3/PCl5からなる群から選択される、請求項7に記載の方法。
- 前記塩素化試薬が、LiClまたはPPh3/CCl4である、請求項8に記載の方法。
- 前記カップリング試薬が、BOP、DCC、DIC、EDC、HATU、TBTUおよびT3Pからなる群から選択される、請求項10に記載の方法。
- 前記カップリング試薬が、EDCである、請求項11に記載の方法。
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US9901567B2 (en) | 2007-08-01 | 2018-02-27 | Syntarga B.V. | Substituted CC-1065 analogs and their conjugates |
LT3056203T (lt) | 2010-04-21 | 2018-03-26 | Syntarga B.V. | Konjugatai cc-1065 analogų ir bifunkcinių linkerių |
JP6224268B2 (ja) | 2014-01-10 | 2017-11-01 | シントン・バイオファーマシューティカルズ・ビー.ブイ.Synthon Biopharmaceuticals B.V. | 子宮内膜癌の治療において使用するためのデュオカルマイシンadc |
KR102344354B1 (ko) | 2014-01-10 | 2021-12-28 | 비온디스 비.브이. | 향상된 생체내 항종양 활성을 나타내는 듀오카르마이신 adc |
PT3151865T (pt) | 2014-05-22 | 2021-11-17 | Byondis Bv | Conjugação específica do local de fármacos de ligação a anticorpos e adcs resultantes |
US10961311B2 (en) | 2016-04-15 | 2021-03-30 | Macrogenics, Inc. | B7-H3 binding molecules, antibody drug conjugates thereof and methods of use thereof |
JP7279042B2 (ja) | 2017-11-24 | 2023-05-22 | ビョンディス・ビー.ブイ. | リンカー薬物化合物vc-seco-DUBA製造のための改善された方法 |
HUE059919T2 (hu) * | 2018-11-09 | 2023-01-28 | Byondis Bv | Duokarmicintartalmú antitest-hatóanyag konjugátum szûrhetõ készítményei és ezekkel kapcsolatos eljárások |
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JP2012513954A (ja) * | 2008-11-03 | 2012-06-21 | シンタルガ・ビーブイ | 新規cc−1065類似体およびその複合体 |
JP2013525347A (ja) * | 2010-04-21 | 2013-06-20 | シンタルガ・ビーブイ | Cc−1065類似体の新規の複合体および二官能性リンカー |
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US9901567B2 (en) | 2007-08-01 | 2018-02-27 | Syntarga B.V. | Substituted CC-1065 analogs and their conjugates |
CA2695297C (en) | 2007-08-01 | 2017-03-21 | Syntarga B.V. | Substituted cc-1065 analogs and their conjugates |
LT3092010T (lt) | 2014-01-10 | 2018-10-25 | Synthon Biopharmaceuticals B.V. | Metodas, skirtas gryninimui cys-sujungtų antikūno-vaisto konjugatų |
PT3151865T (pt) | 2014-05-22 | 2021-11-17 | Byondis Bv | Conjugação específica do local de fármacos de ligação a anticorpos e adcs resultantes |
EP3197919A1 (en) | 2014-09-22 | 2017-08-02 | Synthon Biopharmaceuticals B.V. | Pan-reactive antibodies to duocarmycins |
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JP2013525347A (ja) * | 2010-04-21 | 2013-06-20 | シンタルガ・ビーブイ | Cc−1065類似体の新規の複合体および二官能性リンカー |
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US20170145006A1 (en) | 2017-05-25 |
CN106458892A (zh) | 2017-02-22 |
LT3152191T (lt) | 2019-08-26 |
CN106458892B (zh) | 2019-10-18 |
CY1122025T1 (el) | 2020-11-25 |
HRP20191378T1 (hr) | 2019-11-15 |
US9890159B2 (en) | 2018-02-13 |
PT3152191T (pt) | 2019-08-30 |
PL3152191T3 (pl) | 2019-10-31 |
EP3152191B1 (en) | 2019-05-15 |
WO2015185142A1 (en) | 2015-12-10 |
EP3152191A1 (en) | 2017-04-12 |
DK3152191T3 (da) | 2019-08-12 |
ES2738211T3 (es) | 2020-01-20 |
HUE045447T2 (hu) | 2019-12-30 |
JP6275881B2 (ja) | 2018-02-07 |
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