CN1090632C - 双联霉素与其衍生物的制备中间体及其制备方法 - Google Patents
双联霉素与其衍生物的制备中间体及其制备方法 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- VQNATVDKACXKTF-UHFFFAOYSA-N Duocarmycin SA Natural products COC1=C(OC)C(OC)=C2NC(C(=O)N3C4=CC(=O)C5=C(C64CC6C3)C=C(N5)C(=O)OC)=CC2=C1 VQNATVDKACXKTF-UHFFFAOYSA-N 0.000 title abstract description 15
- 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 15
- 229960005510 duocarmycin SA Drugs 0.000 title abstract description 15
- 238000000034 method Methods 0.000 title abstract description 6
- 239000000543 intermediate Substances 0.000 title abstract 2
- 238000004519 manufacturing process Methods 0.000 title description 3
- 150000005592 pyrroloindoles Chemical class 0.000 claims abstract description 11
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 9
- 229940054051 antipsychotic indole derivative Drugs 0.000 claims abstract description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 9
- 150000002475 indoles Chemical class 0.000 claims abstract description 9
- 125000006239 protecting group Chemical group 0.000 claims description 19
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 230000003647 oxidation Effects 0.000 claims description 9
- 238000007254 oxidation reaction Methods 0.000 claims description 9
- 238000007363 ring formation reaction Methods 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims 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 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 abstract 1
- 229940041181 antineoplastic drug Drugs 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
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- 238000006243 chemical reaction Methods 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 14
- -1 2,2,2-trichloro-ethoxycarbonyl Chemical group 0.000 description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- IPDOBVFESNNYEE-UHFFFAOYSA-N 1h-indole-7-carboxylic acid Chemical compound OC(=O)C1=CC=CC2=C1NC=C2 IPDOBVFESNNYEE-UHFFFAOYSA-N 0.000 description 8
- 150000004702 methyl esters Chemical class 0.000 description 8
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 8
- 229910052763 palladium Inorganic materials 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 4
- 230000003327 cancerostatic effect Effects 0.000 description 4
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- 239000012141 concentrate Substances 0.000 description 4
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 235000002639 sodium chloride Nutrition 0.000 description 4
- 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 4
- DBBRZSJIOOBCOI-SFHVURJKSA-N C(C)(=O)[C@@H]1CN(C2=CC(=C(C=C12)N)OCC1=C(C=CC=C1)C)C(=O)OC(C)(C)C Chemical compound C(C)(=O)[C@@H]1CN(C2=CC(=C(C=C12)N)OCC1=C(C=CC=C1)C)C(=O)OC(C)(C)C DBBRZSJIOOBCOI-SFHVURJKSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000006181 4-methyl benzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])C([H])([H])* 0.000 description 2
- OTLNPYWUJOZPPA-UHFFFAOYSA-N 4-nitrobenzoic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1 OTLNPYWUJOZPPA-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- NIUGOOXNOVXWFB-IRKXTDDOSA-N C(C)(=O)[C@@H]1C(N(C2=CC(=C(C=C12)C(C)C(=O)OC)OCC1=C(C=CC=C1)C)C(=O)OC(C)(C)C)N Chemical compound C(C)(=O)[C@@H]1C(N(C2=CC(=C(C=C12)C(C)C(=O)OC)OCC1=C(C=CC=C1)C)C(=O)OC(C)(C)C)N NIUGOOXNOVXWFB-IRKXTDDOSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- MQRWBMAEBQOWAF-UHFFFAOYSA-N acetic acid;nickel Chemical compound [Ni].CC(O)=O.CC(O)=O MQRWBMAEBQOWAF-UHFFFAOYSA-N 0.000 description 2
- 150000003863 ammonium salts Chemical class 0.000 description 2
- 125000005002 aryl methyl group Chemical group 0.000 description 2
- 229940073608 benzyl chloride Drugs 0.000 description 2
- 244000309464 bull Species 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- JXTHNDFMNIQAHM-UHFFFAOYSA-N dichloroacetic acid Chemical compound OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 2
- 229940078494 nickel acetate Drugs 0.000 description 2
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 2
- 150000002940 palladium Chemical class 0.000 description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 229910052723 transition metal Inorganic materials 0.000 description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- MONMFXREYOKQTI-UHFFFAOYSA-N 2-bromopropanoic acid Chemical compound CC(Br)C(O)=O MONMFXREYOKQTI-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical class [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000003435 aroyl group Chemical group 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 1
- 229910000365 copper sulfate Inorganic materials 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- NWFNSTOSIVLCJA-UHFFFAOYSA-L copper;diacetate;hydrate Chemical compound O.[Cu+2].CC([O-])=O.CC([O-])=O NWFNSTOSIVLCJA-UHFFFAOYSA-L 0.000 description 1
- 229960005215 dichloroacetic acid Drugs 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 125000004993 haloalkoxycarbonyl group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- RBBOWEDMXHTEPA-UHFFFAOYSA-N hexane;toluene Chemical compound CCCCCC.CC1=CC=CC=C1 RBBOWEDMXHTEPA-UHFFFAOYSA-N 0.000 description 1
- ACKFDYCQCBEDNU-UHFFFAOYSA-J lead(2+);tetraacetate Chemical compound [Pb+2].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O ACKFDYCQCBEDNU-UHFFFAOYSA-J 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 1
- CWKLZLBVOJRSOM-UHFFFAOYSA-N methyl pyruvate Chemical compound COC(=O)C(C)=O CWKLZLBVOJRSOM-UHFFFAOYSA-N 0.000 description 1
- AJUXDFHPVZQOGF-UHFFFAOYSA-N n,n-dimethyl-1-naphthylamine Chemical compound C1=CC=C2C(N(C)C)=CC=CC2=C1 AJUXDFHPVZQOGF-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- SWMBQMGPRYJSCI-UHFFFAOYSA-N octylphosphane Chemical class CCCCCCCCP SWMBQMGPRYJSCI-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-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
- 150000003839 salts Chemical class 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 229960004249 sodium acetate Drugs 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- 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
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/12—Radicals substituted by oxygen atoms
-
- 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
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Indole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
通式(1)、通式(2a)或(2b)所示的吲哚衍生物和通式(3)所示的吡咯并吲哚衍生物以及它们的制备方法，上述化合物是可期待具有作为抗癌剂的用途的双联霉素SA与其衍生物的制备中间体。式中R1是氨基的保护基，R2是羟基的保护基，R3是羟基的保护基，R4表示C1～C6的直链至支链低级烷基、苄基。
Description
本发明涉及可期待具有作为抗癌剂的用途的如下式A的吡咯并吲哚衍生物双联霉素SA(Duocarmycin SA)与其衍生物的制备中间体及其制备方法。
可期待具有作为抗癌剂的用途的双联霉素SA与其衍生物的制备中间体及其制备方法已有公开〔例如《抗生素杂志》(J.Antibiotics)〕43卷，1037页(1990年)、同一杂志44卷，1045页(1991年)、特开平2-177890号公报、特开平5-208979号公报、特开平7-53558号公报、《美国化学会志》(J.Am.Chem.Soc.)114卷，10056页(1992年)、《四面体快报》(Tetrahedron Lett.)35卷，2573页(1994年)、《化学与药学通报》(Chem.Pharm.Bull.)43卷，1064页(1995年)。
上述已知的双联霉素SA与其衍生物的制备方法之中，通过发酵的制备方法生产效率低，通过化学合成制备光学活性体的制备方法或者需要多步骤，或者制备中间体难以光学分离，因此难以高效地制备光活的双联霉素SA与其衍生物。
本发明的目的在于提供为高效制备可期待具有作为抗癌剂的用途的双联霉素SA与其衍生物的制备中间体及其制备方法。
本发明人等提供了如下所示的双联霉素SA与其衍生物的制备中间体吲哚衍生物和吡咯并吲哚衍生物，通式(1)
(其中R1是氨基的保护基，R2是羟基的保护基，R3是羟基的保护基，R4表示C1～C6的直链或支链低级烷基、苄基)；
下述通式(2a)或(2b)
(其中R1、R2、R3和R4同上)和下述通式(3)
(其中R1、R2、R3和R4同上)。
另外本发明人等提供了如下通式(3)所示的双联霉素SA与其衍生物的制备中间体吡咯并吲哚衍生物的制备方法，其特征在于是由下述通式(1)：
(其中R1、R2、R3和R4同上)表示的吲哚衍生物氧化合环而得到的；
(其中R1、R2、R3和R4同上)；
以及下述如下通式(3)所示的双联霉素SA与其衍生物的制备中间体吡咯并吲哚衍生物的制备方法，其特征在于是由通式(2a)或(2b)
(其中R1、R2、R3和R4同上)表示的吲哚衍生物氧化合环而得到的，
(其中R1、R2、R3和R4同上)。
作为上述R1的氨基的保护基，可使用甲氧羰基、乙氧羰基、异丙氧羰基和叔丁氧羰基等C1～C6的直链或支链低级烷氧羰基，2，2，2-三氯乙氧羰基、2，2，2-三氯-1，1-二甲基乙氧羰基等卤代烷氧羰基，苄氧羰基、4-甲基苄氧羰基、3-氯苄氧羰基、4-甲氧基苄氧羰基、二苯甲基羰基、二-(4-甲氧基苯基)甲氧羰基、三苯甲氧基羰基和芴基甲氧基羰基等取代或非取代的芳烷氧基。
作为R2的羟基的保护基，可使用甲酰基、乙酰基、甲氧基乙酰基、苯氧基乙酰基和新戊酰基等C1～C6直链或支链的取代或非取代低级烷酰基，苯甲酰基、甲苯甲酰基、3-氯苯甲酰基、和4-苯基苯甲酰基等取代或非取代的芳酰基，苄基、4-甲基苄基、3-氯苄基、4-甲氧基苄基、2，4-二甲氧基苄基、二苯甲基、二-(4-甲氧基苯基)甲基和三苯甲基等取代或非取代的芳甲基，三乙基甲硅烷基、异丙基二甲基甲硅烷基、叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基等取代甲硅烷基。
作为R3的羟基的保护基，可使用甲基和乙基等C1～C6直链或支链低级烷基，苄基、4-甲基苄基、3-氯苄基、4-甲氧基苄基、2，4-二甲氧基苄基、二苯甲基、二-(4-甲氧基苯基)甲基和三苯甲基等取代或非取代的芳甲基等。
作为R4表示的C1～C6的直链或支链低级烷基、可使用甲基、乙基、丙基、丁基、异丙基、叔丁基。
根据本发明，本发明化合物可按照以下步骤制备。步骤1
本步反应是由通式(4)表示的化合物制备通式(1)表示的化合物的步骤。本步反应可参考公知的方法(例如《四面体》(Tetrahedron)，50卷，2793页(1994年)等)进行。步骤2
本步反应是通过将通式(1)表示的化合物氧化合环，制备通式(3)表示的化合物的步骤。本步反应的氧化合环反应中可单独使用氯化钯、醋酸钯、三氟醋酸钯、乙酰乙酸钯等钯盐，氯化镍、醋酸镍等过渡金属盐，优选是并用高锰酸钾、二氧化锰、过氧化镍、硫酸铜、氧化银等氧化剂，在醋酸、丙酸、二氯乙酸、草酸、琥珀酸、戊二酸、苯甲酸、4-硝基苯甲酸、2，4-二硝基苯甲酸、甲苯磺酸等酸催化剂、氯化苄基三乙铵、碘化四丁铵等铵盐的存在或非存在下进行。作为反应所用的溶剂，只要是与反应无关的均可使用，反应在20～150℃下可顺利地进行。步骤3
本步反应是由通式(4)表示的化合物制备通式(2a)或(2b)表示的化合物的步骤。本步反应可参考公知的方法(例如《日本化学会通报》(Bull.Chem.Soc.Jpn.)，44卷，474页(1971年)等)进行。步骤4
本步反应是通过将通式(2a)或(2b)表示的化合物氧化合环，制备通式(3)表示的化合物的步骤。本步反应的氧化合环反应中可单独或复合并用使用氯化钯、醋酸钯、三氟醋酸钯、乙酰乙酸钯等钯盐，氯化镍、醋酸镍等过渡金属盐，四乙酸铅、醋酸铜等重金属盐，在三苯基膦、三辛基膦等膦类，三乙胺、N-甲基吗啉、吡啶等有机碱，碳酸氢钠、碳酸钾、醋酸钠、醋酸钾等碱金属盐、氯化苄基三乙铵、碘化四丁铵等铵盐的存在或非存在下进行。作为反应所用的溶剂，只要是与反应无关的均可使用，反应在20～150℃下可顺利地进行。
根据本发明制备的通式(3)表示的化合物可按照以下各步骤转变为通式(5)、通式(6)、通式(7)表示的化合物，步骤5～7均可参考公知的方法(《美国化学会志》(J.Am.Chem.Soc.)114卷，10056页(1992年)，特开平6-116269号公报)而进行。
(其中R1、R2、R3和R4同上，X表示卤素原子)
以下实施例表示本发明的实用性，本发明不受此限制。
实施例1
(3S)-3-乙酰氧甲基-5-氨基-6-苄氧基-1-叔丁氧羰基吲哚满4.95g(12.0mmol)、2-溴丙酸甲酯1.61ml(14.4mmol)和1，8-双(二甲氨基)萘3.09g(14.4mmol)在18ml苯中，90℃加热回流50小时。将反应液用苯稀释后，用水、饱和食盐水洗，无水硫酸钠干燥，过滤、浓缩，残渣用硅胶柱层析(己烷∶乙酸乙酯＝4∶1→2∶1)纯化，得到(3S)-3-乙酰氧甲基-5-[1-(甲氧羰基)乙基]氨基-6-苄氧基-1-叔丁氧羰基吲哚满5.82g(97％)。
HRMS：C27H34N2O7 计算值498.2366
实测值498.2387
实施例2
(3S)-3-乙酰氧甲基-5-[1-(甲氧羰基)乙基]氨基-6-苄氧基-1-叔丁氧羰基吲哚满5.82g(11.7mmol)、醋酸钯5.24g(23.4mmol)、二氧化锰1.52g(17.5mmol)和4-硝基苯甲酸1.95g(11.7mmol)在500ml二甲基乙酰胺中，90℃下加热18小时。浓缩反应液，加入乙酸乙酯，滤去不溶物，浓缩，残渣用硅胶柱层析(苯∶乙酸乙酯＝5∶1→10∶1)纯化，得到(1S)-1-乙酰氧甲基-5-苄氧基-3-叔丁氧羰基-1，2，3，6-四氢吡咯并[3，2-e]吲哚-7-羧酸甲酯1.34g(23％)。熔点128.5-129.5℃(异丙醚)。
C H N
元素分析：C27H30N2O7 计算值 65.57 6.11 5.66
实测值 65.40 6.05 5.64
NMR(CDCl3)δ：1.58(9H，s)，2.10(3H，s)，3.80-3.92(2H，m)，3.92(3H，s)，
4.06(1H，t，J＝10.3Hz)，4.15(1H，dd，J＝9.3，11.2Hz)，4.48(1H，dd，J＝5.4，10.8Hz)，5.
22(2H，s)，7.13(1H，d，J＝2.4Hz)，7.39-7.48(5H，m)，7.82(1H，brs)，9.00(1H，s)
[α]D 25＝-11.1°(c0.21，甲醇)
实施例3
(3S)-3-乙酰氧甲基-5-氨基-6-苄氧基-1-叔丁氧羰基吲哚满1.24g(3.0mmol)、丙酮酸甲酯0.46g(4.5mmol)和醋酸0.2ml在30ml苯中用Dean-Stark加热回流5小时。反应液用5％碳酸氢钠水溶液洗，无水硫酸钠干燥，过滤、浓缩，所得残渣中加入醋酸钯1.35g(6.0mmol)，在100ml二甲基乙酰胺中90℃下加热1小时。反应液倾入水中，用甲苯-己烷(5∶1)萃取3次，无水硫酸钠干燥后，过滤、浓缩，残渣用硅胶柱层析(己烷∶乙酸乙酯＝3∶1→2.5∶1)纯化，得到(1S)-1-乙酰氧甲基-5-苄氧基-3-叔丁氧羰基-1，2，3，6-四氢吡咯并[3，2-e]吲哚-7-羧酸甲酯0.15g(10％)。该物质与实施例2所得的化合物波谱数据相同。参考例1
(1S)-1-乙酰氧甲基-5-苄氧基-3-叔丁氧羰基-1，2，3，6-四氢吡咯并[3，2-e]吲哚-7-羧酸甲酯1.34g(2.7mmol)悬浮于30ml甲醇中，加入碳酸钾0.75g(5.4mmol)，室温搅拌1小时。用20％柠檬酸水溶液中和，用水稀释，用乙酸乙酯萃取。有机层用饱和食盐水洗，无水硫酸钠干燥，过滤、浓缩，所得残渣硅胶柱层析(二氯甲烷∶乙酸乙酯＝5∶1)纯化，得到(1S)-5-苄氧基-3-叔丁氧羰基-1-羟甲基-1，2，3，6-四氢吡咯并[3，2-e]吲哚-7-羧酸甲酯1.14g(93％)。
NMR(CDCl3)δ：1.44(1H，brs)，1.57(9H，s)，3.74(1H，m)，3.90(2H，m)，3.92(3H，s)，4.03(1H，dd，J＝3.9，11.7Hz)，4.16(1H，t，J＝10.8Hz)，5.23(2H，s)，7.12(1H，s)，7.39-7.50(5H，m)，7.84(1H，brs)，9.01(1H，s)
[α]D 25＝-17.1°(c0.20，甲醇)参考例2
(1S)-5-苄氧基-3-叔丁氧羰基-1-羟甲基-1，2，3，6-四氢吡咯并[3，2-e]吲哚-7-羧酸甲酯256.5mg(0.57mmol)、三苯基膦297.4mg(1.13mmol)溶解于6ml无水二氯甲烷中，加入0.33ml四氯化碳，在氩气气氛下暗处搅拌2小时。蒸去溶剂后，所得残渣用硅胶柱层析(己烷∶乙酸乙酯＝4∶1)纯化，用己烷结晶，得到(1S)-5-苄氧基-3-叔丁氧羰基-1-氯甲基-1，2，3，6-四氢吡咯并[3，2-e]吲哚-7-羧酸甲酯245.3mg(92％)。
NMR(CDCl3)δ：1.58(9H，s)，3.56(1H，t，J＝9.8Hz)，3.88-3.97(2H，m)，3.93(3H，s)，4.09(1H，m)，4.19(1H，m)，5.22(2H，s)，7.08(1H，d，J＝2.0Hz)，7.39-7.50(5H，m)，7.81(1H，brs)，9.03(1H，s)
[α]D 25＝-29.3°(c0.18，甲醇)参考例3
(1S)-5-苄氧基-3-叔丁氧羰基-1-氯甲基-1，2，3，6-四氢吡咯并[3，2-e]吲哚-7-羧酸甲酯150.7mg(0.32mmol)、10％钯-碳90mg悬浮于4ml四氢呋喃中，冰冷却下滴入1ml 25％甲酸铵，搅拌1小时。乙(己烷∶乙酸乙酯＝1∶1)纯化，己烷结晶。得到(1S)-3-叔丁氧羰基-1-氯甲基-5-羟基-1，2，3，6-四氢吡咯并[3，2-e]吲哚-7-羧酸甲酯115.9mg(95％)。
NMR(CDCl3)δ：1.58(9H，s)，3.54(1H，t，J＝9.8Hz)，3.87-3.94(2H，m)，3.96(3H，s)，4.06(1H，m)，4.17(1H，dd，J＝9.3，11.7Hz)，6.36(1H，brs)，7.08(1H，s)，7.
64(1H，brs)，9.23(1H，brs)
[α]D 25＝-42.6°(c0.21，甲醇)
根据本发明制备的上述通式(1)和(2a)或(2b)表示的吲哚衍生物通过氧化合环成为可以容易地制备可期待具有作为抗癌剂的用途的双联霉素SA与其衍生物的制备中间体——上述通式(3)表示的吡咯并吲哚衍生物。采用上述通式(3)表示的吡咯并吲哚衍生物，可以制备上述通式(6)表示的吡咯并吲哚衍生物，进一步，参考已知方法，可以制备双联霉素SA。根据本发明的制备方法，通过采用光活的上述通式(4)化合物，例如(3S)-3-乙酰氧甲基-5-氨基-6-苄氧基-1-叔丁氧羰基吲哚满(特开平7-89933号公报)，可以容易地制备光活的双联霉素SA。
Claims (5)
1.如下通式(1)所示的吲哚衍生物：
其中R1是叔丁氧羰基，R2是羟基的保护基，R3是羟基的保护基，R4表示C1～C6的直链或支链低级烷基、苄基。
2.下述通式(2a)或(2b)表示的吲哚衍生物：
其中R1是氨基的保护基，R2是羟基的保护基，R3是羟基的保护基，R4表示C1～C6的直链或支链低级烷基、苄基。
3.下述通式(3)表示的吡咯并吲哚衍生物：
其中R1是氨基的保护基，R2是乙酰基，R3是羟基的保护基，R4表示C1～C6的直链或支链低级烷基、苄基。
4.如下通式(3)所示的吡咯并吲哚衍生物的制备方法，其特征在于是由下述通式(1)：
表示的吲哚衍生物氧化合环而得到的；
通式(1)中，R1是氨基的保护基，R2是羟基的保护基，R3是羟基的保护基，R4表示C1～C6的直链或支链低级烷基、苄基；通式(3)中R1、R2、R3和R4同上。
5.如下通式(3)所示的吡咯并吲哚衍生物的制备方法，其特征在于是由通式(2a)或(2b)
表示的吲哚衍生物氧化合环而得到的；
通式(2a)和(2b)中R1是氨基的保护基，R2是羟基的保护基，R3是羟基的保护基，R4表示C1～C6的直链或支链低级烷基、苄基；通式(3)中R1、R2、R3和R4同上。
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| KR20130009760A (ko) | 2010-02-10 | 2013-01-23 | 이뮤노젠 아이엔씨 | Ｃｄ２０ 항체 및 이의 용도 |
| WO2014080251A1 (en) | 2012-11-24 | 2014-05-30 | Hangzhou Dac Biotech Co., Ltd. | Hydrophilic linkers and their uses for conjugation of drugs to cell binding molecules |
| DK3122757T3 (da) | 2014-02-28 | 2023-10-09 | Hangzhou Dac Biotech Co Ltd | Ladede linkere og anvendelse deraf til konjugering |
| AU2015242213A1 (en) | 2015-07-12 | 2018-03-08 | Hangzhou Dac Biotech Co., Ltd | Bridge linkers for conjugation of cell-binding molecules |
| US9839687B2 (en) | 2015-07-15 | 2017-12-12 | Suzhou M-Conj Biotech Co., Ltd. | Acetylenedicarboxyl linkers and their uses in specific conjugation of a cell-binding molecule |
| KR102345175B1 (ko) | 2016-11-14 | 2021-12-31 | 항저우 디에이씨 바이오테크 씨오, 엘티디 | 결합 링커, 그러한 결합 링커를 함유하는 세포 결합 분자-약물 결합체, 링커를 갖는 그러한 결합체의 제조 및 사용 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994000453A1 (en) * | 1992-06-26 | 1994-01-06 | Pfizer Limited | Purinone antianginal agents |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU648313B2 (en) * | 1990-04-25 | 1994-04-21 | Pharmacia & Upjohn Company | Novel CC-1065 analogs |
| JP3037965B2 (ja) * | 1990-06-20 | 2000-05-08 | 財団法人相模中央化学研究所 | ２―アルコキシカルボニル―２―メチル―１―オキソ―１，２，３，６，７，８―ヘキサヒドロ―ベンゾ〔１，２―ｂ；４，３―ｂ´〕ジピロール誘導体 |
| JPH06116270A (ja) * | 1992-08-21 | 1994-04-26 | Kyorin Pharmaceut Co Ltd | テトラヒドロピロロインドール誘導体及びその製法並びにその中間体 |
-
1996
- 1996-09-18 JP JP8246097A patent/JPH1087666A/ja active Pending
-
1997
- 1997-06-26 AU AU32749/97A patent/AU3274997A/en not_active Abandoned
- 1997-06-26 US US09/254,515 patent/US6066742A/en not_active Expired - Fee Related
- 1997-06-26 CA CA002266505A patent/CA2266505A1/en not_active Abandoned
- 1997-06-26 KR KR1019997002272A patent/KR20000036211A/ko not_active Application Discontinuation
- 1997-06-26 AT AT97928473T patent/ATE234304T1/de not_active IP Right Cessation
- 1997-06-26 WO PCT/JP1997/002207 patent/WO1998012197A1/ja not_active Application Discontinuation
- 1997-06-26 CN CN97198004A patent/CN1090632C/zh not_active Expired - Fee Related
- 1997-06-26 EP EP97928473A patent/EP0937726B1/en not_active Expired - Lifetime
- 1997-06-26 DE DE69719781T patent/DE69719781D1/de not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1994000453A1 (en) * | 1992-06-26 | 1994-01-06 | Pfizer Limited | Purinone antianginal agents |
Also Published As
| Publication number | Publication date |
|---|---|
| EP0937726B1 (en) | 2003-03-12 |
| DE69719781D1 (de) | 2003-04-17 |
| EP0937726A4 (en) | 2001-04-11 |
| ATE234304T1 (de) | 2003-03-15 |
| US6066742A (en) | 2000-05-23 |
| AU3274997A (en) | 1998-04-14 |
| WO1998012197A1 (fr) | 1998-03-26 |
| CN1230960A (zh) | 1999-10-06 |
| KR20000036211A (ko) | 2000-06-26 |
| EP0937726A1 (en) | 1999-08-25 |
| JPH1087666A (ja) | 1998-04-07 |
| CA2266505A1 (en) | 1998-03-26 |
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