WO2023025138A1 - 喜树碱衍生物中间体及其合成方法和利用中间体合成喜树碱衍生物的方法 - Google Patents
喜树碱衍生物中间体及其合成方法和利用中间体合成喜树碱衍生物的方法 Download PDFInfo
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- WO2023025138A1 WO2023025138A1 PCT/CN2022/114203 CN2022114203W WO2023025138A1 WO 2023025138 A1 WO2023025138 A1 WO 2023025138A1 CN 2022114203 W CN2022114203 W CN 2022114203W WO 2023025138 A1 WO2023025138 A1 WO 2023025138A1
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- Prior art keywords
- compound
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- reaction
- catalyst
- palladium
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- 238000000034 method Methods 0.000 title claims description 9
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 title description 4
- 238000001308 synthesis method Methods 0.000 title description 3
- 230000002194 synthesizing effect Effects 0.000 title description 3
- 238000006243 chemical reaction Methods 0.000 claims abstract description 62
- 238000002360 preparation method Methods 0.000 claims abstract description 43
- 150000001875 compounds Chemical class 0.000 claims description 67
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 39
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 39
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 36
- 239000003054 catalyst Substances 0.000 claims description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 32
- 229940126062 Compound A Drugs 0.000 claims description 24
- 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 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 23
- 239000003153 chemical reaction reagent Substances 0.000 claims description 21
- 229940125898 compound 5 Drugs 0.000 claims description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 20
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 15
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 230000035484 reaction time Effects 0.000 claims description 12
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 claims description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical group [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 10
- 230000009471 action Effects 0.000 claims description 10
- 229940125782 compound 2 Drugs 0.000 claims description 10
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- 238000005859 coupling reaction Methods 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 239000003446 ligand Substances 0.000 claims description 8
- 239000012046 mixed solvent Substances 0.000 claims description 8
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 8
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethylcyclohexane Chemical compound CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- NNVCNLNYKRVMQL-UHFFFAOYSA-N 2-acetamidobut-3-enoic acid Chemical compound CC(=O)NC(C=C)C(O)=O NNVCNLNYKRVMQL-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 6
- 229940126214 compound 3 Drugs 0.000 claims description 6
- 230000008878 coupling Effects 0.000 claims description 6
- 238000010168 coupling process Methods 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 238000007363 ring formation reaction Methods 0.000 claims description 6
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical group FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 5
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical group 0.000 claims description 5
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- 239000002841 Lewis acid Substances 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 150000007517 lewis acids Chemical class 0.000 claims description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 4
- 150000002940 palladium Chemical class 0.000 claims description 4
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 4
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 claims 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 claims description 4
- 150000008065 acid anhydrides Chemical class 0.000 claims description 3
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 3
- 238000005660 chlorination reaction Methods 0.000 claims description 3
- 229940125904 compound 1 Drugs 0.000 claims description 3
- 238000006482 condensation reaction Methods 0.000 claims description 3
- 230000009615 deamination Effects 0.000 claims description 3
- 238000006481 deamination reaction Methods 0.000 claims description 3
- FXORZKOZOQWVMQ-UHFFFAOYSA-L dichloropalladium;triphenylphosphane Chemical compound Cl[Pd]Cl.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 FXORZKOZOQWVMQ-UHFFFAOYSA-L 0.000 claims description 3
- 238000006361 intramolecular Friedel-Crafts acylation reaction Methods 0.000 claims description 3
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims description 3
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 3
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 3
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 claims description 3
- 238000005727 Friedel-Crafts reaction Methods 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 claims description 2
- 238000005917 acylation reaction Methods 0.000 claims description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 2
- BTJYWUVKNAFRBF-UHFFFAOYSA-N dicyclohexyl-[2,6-di(propan-2-yl)phenyl]phosphane Chemical compound CC(C)C1=CC=CC(C(C)C)=C1P(C1CCCCC1)C1CCCCC1 BTJYWUVKNAFRBF-UHFFFAOYSA-N 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- 159000000014 iron salts Chemical class 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical group Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- GPNDARIEYHPYAY-UHFFFAOYSA-N palladium(ii) nitrate Chemical compound [Pd+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O GPNDARIEYHPYAY-UHFFFAOYSA-N 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052697 platinum Inorganic materials 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- 238000006722 reduction reaction Methods 0.000 claims description 2
- 229910052703 rhodium Inorganic materials 0.000 claims description 2
- 239000010948 rhodium Substances 0.000 claims description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 2
- 229910052707 ruthenium Inorganic materials 0.000 claims description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical group [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 2
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 claims description 2
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical compound C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 claims description 2
- IGNTWNVBGLNYDV-UHFFFAOYSA-N triisopropylphosphine Chemical compound CC(C)P(C(C)C)C(C)C IGNTWNVBGLNYDV-UHFFFAOYSA-N 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims 1
- CUQOHAYJWVTKDE-UHFFFAOYSA-N potassium;butan-1-olate Chemical group [K+].CCCC[O-] CUQOHAYJWVTKDE-UHFFFAOYSA-N 0.000 claims 1
- 239000000543 intermediate Substances 0.000 abstract description 16
- 238000004519 manufacturing process Methods 0.000 abstract description 7
- ZVYVPGLRVWUPMP-FYSMJZIKSA-N exatecan Chemical compound C1C[C@H](N)C2=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC3=CC(F)=C(C)C1=C32 ZVYVPGLRVWUPMP-FYSMJZIKSA-N 0.000 abstract description 5
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- 238000005580 one pot reaction Methods 0.000 abstract description 3
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- 238000005265 energy consumption Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 25
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 20
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- 238000001914 filtration Methods 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
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- VIMMECPCYZXUCI-MIMFYIINSA-N (4s,6r)-6-[(1e)-4,4-bis(4-fluorophenyl)-3-(1-methyltetrazol-5-yl)buta-1,3-dienyl]-4-hydroxyoxan-2-one Chemical compound CN1N=NN=C1C(\C=C\[C@@H]1OC(=O)C[C@@H](O)C1)=C(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 VIMMECPCYZXUCI-MIMFYIINSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
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- 239000001257 hydrogen Substances 0.000 description 6
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 description 6
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- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
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- 230000000052 comparative effect Effects 0.000 description 4
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- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 4
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- 238000000926 separation method Methods 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
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- ZDYVRSLAEXCVBX-UHFFFAOYSA-N pyridinium p-toluenesulfonate Chemical compound C1=CC=[NH+]C=C1.CC1=CC=C(S([O-])(=O)=O)C=C1 ZDYVRSLAEXCVBX-UHFFFAOYSA-N 0.000 description 3
- KYLUAQBYONVMCP-UHFFFAOYSA-N (2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P KYLUAQBYONVMCP-UHFFFAOYSA-N 0.000 description 2
- IGVKWAAPMVVTFX-BUHFOSPRSA-N (e)-octadec-5-en-7,9-diynoic acid Chemical compound CCCCCCCCC#CC#C\C=C\CCCC(O)=O IGVKWAAPMVVTFX-BUHFOSPRSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- DSVGQVZAZSZEEX-UHFFFAOYSA-N [C].[Pt] Chemical compound [C].[Pt] DSVGQVZAZSZEEX-UHFFFAOYSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
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- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
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- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical class O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
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- WIQISTBTOQNVCE-UHFFFAOYSA-N 2-fluoro-1-methyl-4-nitrobenzene Chemical compound CC1=CC=C([N+]([O-])=O)C=C1F WIQISTBTOQNVCE-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 229910021586 Nickel(II) chloride Inorganic materials 0.000 description 1
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-M chloroacetate Chemical compound [O-]C(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-M 0.000 description 1
- 229940089960 chloroacetate Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000006324 decarbonylation Effects 0.000 description 1
- 238000006606 decarbonylation reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 229940113088 dimethylacetamide Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- CCGKOQOJPYTBIH-UHFFFAOYSA-N ethenone Chemical compound C=C=O CCGKOQOJPYTBIH-UHFFFAOYSA-N 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 150000004795 grignard reagents Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- RPNNPZHFJPXFQS-UHFFFAOYSA-N methane;rhodium Chemical compound C.[Rh] RPNNPZHFJPXFQS-UHFFFAOYSA-N 0.000 description 1
- 229940125645 monoclonal antibody drug Drugs 0.000 description 1
- QMMRZOWCJAIUJA-UHFFFAOYSA-L nickel dichloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 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 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- RWWYLEGWBNMMLJ-YSOARWBDSA-N remdesivir Chemical compound NC1=NC=NN2C1=CC=C2[C@]1([C@@H]([C@@H]([C@H](O1)CO[P@](=O)(OC1=CC=CC=C1)N[C@H](C(=O)OCC(CC)CC)C)O)O)C#N RWWYLEGWBNMMLJ-YSOARWBDSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 238000007142 ring opening reaction Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- YONPGGFAJWQGJC-UHFFFAOYSA-K titanium(iii) chloride Chemical compound Cl[Ti](Cl)Cl YONPGGFAJWQGJC-UHFFFAOYSA-K 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
- C07C233/42—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
- C07C233/43—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
- C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
- C07C309/01—Sulfonic acids
- C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
- C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C309/04—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing only one sulfo group
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Definitions
- the invention belongs to the technical field of pharmaceutical intermediates and organic synthesis, and in particular relates to an intermediate for synthesizing camptothecin derivatives, a preparation method thereof, and a synthesis method for synthesizing camptothecin derivatives using the intermediate.
- ADC Antibody-drug conjugate
- ADC combines the high specificity of monoclonal antibody drugs with the high activity of small molecule cytotoxic drugs to improve the targeting of tumor drugs and reduce toxic side effects.
- the accurate recognition of the target of ADC drugs and the immunity of non-cancer cells have greatly improved the efficacy of the drug and reduced the side effects, which has attracted the attention of personnel in the field of pharmaceutical research and development.
- an antibody-drug conjugate comprising an antibody and exitecan (which is a topoisomerase I inhibitor) as its components is known (Patent Documents 3-5 and Non-Patent Documents 4 and 5). Since these antibody-drug conjugates exert particularly excellent antitumor effects and safety, they are currently under clinical investigation.
- the structure of Exatecan (Ixitecan) is as follows:
- Patent EP0495432B1 discloses a kind of Exatecan (Ixitecan) compound and preparation method thereof, and the reaction process is as follows:
- the above-mentioned two technological routes all carry out repeated reaction continuously: in the route one, the carbonyl group is oxidized after the decarbonylation, and the amino group is protected after the deamination protection acetyl group, and the yield is only 5.6%. Ring-opening, oxidation, reduction and other processes, and potassium permanganate is used in the reaction process, which causes certain dangers to the production process.
- the two routes have long reaction steps, low atom utilization, complicated reaction operations, and are not suitable for industrial scale-up production.
- ixitecan is synthesized from 2-fluoro-1-methyl-4-nitrobenzene through a total of 10 steps, and the total yield is about 5%.
- the bromination reagent used in the bromination reaction of this synthetic route is liquid bromine, which is highly toxic and corrosive, and has certain dangers in the scale-up production, and the reaction process involves the use of Grignard reagents, which are easily Degradation, and it needs to be carried out in an ultra-low temperature environment, which requires high reaction equipment.
- the selectivity of the rearrangement reaction is low, the post-treatment is complicated, and it is not suitable for industrial scale-up production.
- Both synthetic route 3 and synthetic route 4 cannot avoid the "one-pot" reaction of oximation, catalytic hydrogenolysis and protection on amino groups, involving dangerous processes such as nitration and hydrogenation, and industrial production is relatively difficult.
- the present invention provides a preparation method of Ixitecan mesylate, its intermediate and preparation method.
- the present invention relates to a kind of preparation method of Ixitecan mesylate, it comprises the following steps:
- compound 8 is hydrolyzed under the action of methanesulfonic acid to obtain ixinotecan, namely compound 9;
- the cyclization reagent is selected from a Friedel-Crafts acylating reagent, such as a mixed reagent of a protic acid and an anhydride or a mixed reagent of a chlorinated reagent and a Lewis acid or polyphosphoric acid PPA;
- a Friedel-Crafts acylating reagent such as a mixed reagent of a protic acid and an anhydride or a mixed reagent of a chlorinated reagent and a Lewis acid or polyphosphoric acid PPA;
- the protic acid is selected from trifluoroacetic acid, hydrochloric acid or sulfuric acid;
- the acid anhydride is selected from trifluoroacetic anhydride or trifluoromethanesulfonic anhydride;
- the chlorination reagent is selected from thionyl chloride, sulfuryl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride or phosphorus pentachloride;
- the Lewis acid is selected from aluminum trichloride, tin tetrachloride, and iron salts.
- the amount of the cyclization reagent added is based on at least enabling the reaction to proceed, preferably the amount of the substance of the cyclization reagent and the compound A
- the ratio is 0.5-20:1, more preferably 1-5:1.
- reaction temperature in step (f) is preferably -40 to 150°C, more preferably 0 to 100°C, even more preferably 0 to 80°C. Further, the reaction time of step (f) is preferably 0.5-24h, more preferably 2-12h.
- step (g) is preferably carried out using hydrochloric acid or a mixed solution of hydrochloric acid and alcohol, and can be more preferably carried out using 2N hydrochloric acid/ethanol.
- the reaction temperature is preferably 40-100°C, more preferably 50-80°C; the reaction time is preferably 2-8h, more preferably 3-6h.
- step (h) compound B and compound 7 undergo condensation reaction under the action of pyridinium p-toluenesulfonate, o-cresol and toluene to obtain compound 8.
- step (h) preferably, the ratio of compound B to compound 7 is 1:0.9-1.5, more preferably 1:1.0-1.1.
- step (h) preferably, the ratio of compound B to pyridinium p-toluenesulfonate is 1:0.01-0.30, more preferably 1:0.05-0.20.
- step (h) preferably, the mass ratio of compound B to o-cresol is 1:0.5-4.0, more preferably 1:1.0-3.5.
- reaction temperature is preferably 80-130°C, more preferably 100-120°C.
- the reaction time is preferably 18-72 hours, more preferably 24-36 hours.
- the reaction is carried out in a solvent, preferably, the solvent is selected from one or more of water, 2-methoxyethanol, ethylcyclohexane or toluene , preferably a mixed solution of water and toluene; the amount of the solvent added is 10-60 ml/g based on the mass of the compound 8.
- the reaction temperature is preferably 70-100°C, more preferably 80-90°C.
- reaction time is preferably 4-12 hours, more preferably 6-8 hours.
- the present invention also relates to a new intermediate compound A, which can be used to synthesize compound 6 or ixinotecan or its mesylate,
- the present invention also relates to providing a method for preparing an intermediate compound A, and the method for preparing the intermediate compound A specifically includes the following steps:
- the catalyst is selected from palladium catalyst, platinum catalyst, nickel catalyst, ruthenium catalyst or rhodium catalyst, more preferably palladium carbon catalyst, more preferably 5% palladium carbon catalyst.
- the amount of the catalyst added is at least based on the progress of the reaction, preferably the mass ratio of the catalyst to the compound 5 is 0.02-0.4:1, more preferably 0.05- 0.15.
- step (e) the reaction is performed in an organic solvent selected from the group consisting of acetonitrile, dichloromethane, chloroform, methanol, ethanol, ether, 1,2-dimethoxyethane, Tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethyl acetate, ethylcyclohexane, benzene, toluene, chlorobenzene, acetone, and water and their mixed solvents.
- an organic solvent selected from the group consisting of acetonitrile, dichloromethane, chloroform, methanol, ethanol, ether, 1,2-dimethoxyethane, Tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, ethyl acetate, ethylcyclohexane, benzene, toluene, chlorobenzene, acetone, and water and
- step (e) the amount of the organic solvent added is 10-60 ml/g based on the mass of the compound 5.
- the reaction temperature is 40-70°C, preferably 50-70°C; the reaction time is 0.5-24h, preferably 6-12h.
- the present invention also relates to providing an intermediate compound 5, which is used as an intermediate for the preparation of compound 6 or ixinotecan or its mesylate,
- the present invention also relates to providing a preparation method of compound 5, comprising the following steps:
- R is selected from halogen, sulfonate group or diazo group, such as iodine, trifluoromethanesulfonyloxy group.
- the coupling catalyst is a complex formed by a palladium salt and a phosphine ligand
- the palladium salt is selected from palladium chloride, palladium acetate, tetrakis (triphenylphosphine) palladium, palladium nitrate or triphenylphosphine palladium dichloride, preferably palladium acetate;
- the phosphine ligand is selected from triphenylphosphine, tricyclohexylphosphine, tri(o-tolyl)phosphine, tri[3,5-bis(trifluoromethyl)phenyl]phosphine, triisopropyl phosphine and dicyclohexyl-(2,6-diisopropylphenyl)phosphine, preferably tri(o-tolyl)phosphine.
- the alkaline substance is selected from triethylamine, isopropylamine, pyridine, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium tert-butoxide, preferably triethylamine.
- step (d) in step (d), the ratio of compound 4 to 2-acetylaminobut-3-enoic acid is 1:1.0-3.0, for example, 1:1.2-1.5;
- the amount of the coupling catalyst added is based on the amount of the phosphine ligand, and the ratio of the amount of compound 4 to the phosphine ligand is 1:0.05-0.75, for example, 1 : 0.15 ⁇ 0.30;
- the ratio of the compound 4 to the basic substance is 1:1.0-15.0, for example, 1:3.0-10.0.
- step (d) the reaction is carried out in an organic solvent, and the organic solvent is selected from acetonitrile, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethyl Acetamide, toluene, water and mixed solvents thereof; the amount of the organic solvent added is 10-60ml/g based on the mass of compound 4.
- the organic solvent is selected from acetonitrile, tetrahydrofuran, 1,4-dioxane, N,N-dimethylformamide, dimethyl Acetamide, toluene, water and mixed solvents thereof; the amount of the organic solvent added is 10-60ml/g based on the mass of compound 4.
- the reaction temperature is 20-110°C, such as 50-80°C; the reaction time is 2-24h, preferably 8-16h.
- the present invention also relates to providing a preparation method of compound 4, comprising the steps of:
- compound 2 is catalytically hydrogenated under the action of a catalyst to obtain compound 3;
- R is selected from halogen, sulfonate or diazo, eg iodine, trifluoromethanesulfonyloxy.
- the iodide is selected from iodine and N-iodosuccinimide, more preferably N-iodosuccinimide; the N-iodosuccinimide
- the amount of substituted succinimide is not limited as long as the reaction proceeds, and is preferably 1-1.5 equivalents.
- This step can preferably be performed in a mixed solvent of sulfuric acid and other solvents.
- the reaction solvent is selected from the group consisting of dichloromethane, chloroform, 1,2-dimethoxyethane, hexane, pentane, heptane, cyclohexane, ethylcyclohexane alkanes, benzene, toluene, chlorobenzene and their mixed solvents.
- the reaction temperature is preferably -10-30°C, more preferably 0-10°C.
- reaction time is preferably 0.5-4 hours, more preferably 1.5-2 hours.
- the catalyst is selected from one or more of rhodium carbon catalyst, platinum carbon catalyst, platinum dioxide, titanium trichloride, nickel chloride, zinc powder, iron powder , more preferably a platinum-carbon catalyst; the amount of the catalyst is not limited, as long as the reaction proceeds, preferably, the mass ratio of the catalyst to compound 2 is 0.05 to 0.4:1, more preferably 0.05 to 0.1: 1.
- the reaction solvent is selected from the group consisting of methanol, ethanol, tetrahydrofuran, 2-methyltetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, acetic acid Ethyl ester, water and their mixed solvents; the added amount of the reaction solvent is 10-60ml/g based on the mass of the compound 1.
- the reaction temperature is preferably 40-70°C, more preferably 50-70°C.
- reaction time is preferably 0.5-8 hours, more preferably 2-4 hours.
- the acylating agent is selected from one or more of acetic anhydride, acetyl chloride, ketene, chloroacetate and nitrile acetate, more preferably acetic anhydride ;
- the ratio of the amount of the acylating agent to the compound 2 is 0.5-1.5:1, more preferably 0.75-1:1.
- step (c) preferably, the reaction is carried out under the action of a base, and the base is selected from triethylamine, isopropylamine, pyridine, sodium carbonate, potassium carbonate and potassium tert-butoxide, more preferably Triethylamine; the ratio of the amount of the base to the compound 2 is 0.5-1.5:1, more preferably 0.75-1.5:1.
- the reaction solvent is selected from methanol, ethanol, tetrahydrofuran, dichloromethane, chloroform, acetone, toluene, ethyl acetate and water and mixed solvents thereof, more preferably ethyl acetate;
- the added amount of the reaction solvent is 10-60ml/g based on the mass of the compound 2.
- the reaction temperature is preferably -10-40°C, more preferably 0-30°C.
- reaction time is preferably 2-24 hours, more preferably 3-12 hours.
- the E and Z forms represented by the compounds 5 and 6 described in the present invention exist in the form of geometric isomers, and both are included in the represented compounds, so they are included in the scope of the present invention.
- the compound represented by compound 5 of the present invention may be a mixture of forms E and Z, and this mixture may be directly used in the next step.
- the present invention provides a new Ixitecan mesylate intermediate 5 and A, which opens up the research field of important intermediates of Ixitecan derivatives;
- a suspension was obtained by adding tetrahydrofuran (100 mL), purified water (100 mL) and 5% palladium on carbon (2.1 g) to crude compound 5 (10.8 g) containing geometric isomers, and the atmosphere was replaced with nitrogen and then hydrogen .
- the mixture was stirred at 60° C. for 8 hours under hydrogen flow (0.5 MPa), and cooled to room temperature.
- the insoluble material was separated from the resulting suspension by filtration and washed with tetrahydrofuran (30 mL).
- the pH of the filtrate was adjusted to about 2 with 1N hydrochloric acid solution.
- a suspension was obtained by adding tetrahydrofuran (100 mL), purified water (100 mL) and 5% palladium on carbon (2.1 g) to crude compound 5 (9.0 g) containing geometric isomers, and the atmosphere was replaced with nitrogen and then hydrogen .
- the mixture was stirred at 40° C. for 16 hours under hydrogen flow (0.4 MPa), and cooled to room temperature.
- the insoluble material was separated from the resulting suspension by filtration and washed with tetrahydrofuran (20 mL).
- the pH of the filtrate was adjusted to about 2 with 1N hydrochloric acid solution.
- the reaction solution was sampled for detection by LCMS, and no target compound was obtained from the reaction.
- the reaction solution was sampled for detection by LCMS, and no target compound was obtained from the reaction.
- the reaction solution was sampled for detection by LCMS, and no target compound was obtained from the reaction.
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Abstract
本发明公开了一种新的伊喜替康甲磺酸盐中间体5和A及伊喜替康甲磺酸盐的制备方法。所述的制备方法原料便宜易得,中间体的合成路线简单,避免了肟化、催化氢解和氨基上保护的"一锅法"反应,大大减少了反应步骤,操作条件温和,降低了操作难度,能耗低,适合工业化放大生产;提高原子利用率,更符合绿色化学的工业化应用;提高了伊喜替康衍生物合成的收率,进一步降低成本。
Description
本发明属于医药中间体和有机合成技术领域,特别是涉及一种用于合成喜树碱衍生物的中间体及其制备方法和利用中间体合成喜树碱衍生物的合成方法。
抗体偶联药物(antibody-drug conjugate,ADC)是将单克隆抗体药物的高特异性和小分子细胞毒药物的高活性相结合,用以提高肿瘤药物的靶向性、减少毒副作用。ADC药物对靶点的准确识别性及非癌细胞不受影响性,极大地提高了药效并减少了毒副作用,备受医药研发领域人员的关注。(专利文献1和2和非专利文献1-3)
作为一种这样的抗体-药物缀合物,已知包含抗体和依喜替康(其为拓扑异构酶I抑制剂)作为其组分的抗体-药物缀合物(专利文献3-5和非专利文献4和5)。由于这些抗体-药物缀合物发挥了特别优异的抗肿瘤作用和安全性,因此它们目前正在临床研究中。Exatecan(伊喜替康)的结构如下所示:
专利EP0495432B1公开了一种Exatecan(伊喜替康)化合物及其制备方法,反应过程如下:
在专利WO1996026181A1中还公开了伊喜替康衍生物的另一种合成方法:
上述两条工艺路线均不断进行了重复的反应:路线一中经过了脱羰基后氧化上羰基,脱氨基保护乙酰基后上氨基保护,收率仅为5.6%;路线二重复进行了关环、开环,氧化、还原等工艺,且反应过程采用了高锰酸钾,对生产过程造成一定的危险性。两条路线反应步骤长,原子利用率低,反应操作较复杂,也不适合工业化放大生产。
专利文件WO2019044946A1对伊喜替康衍生物中间体合成进行了一系列优化并公开了以下合成路线三:
该工艺路线由2-氟-1-甲基-4-硝基苯合成制备伊喜替康共经过10步,总收率约为5%。
上海皓元公司在专利CN111470998B中还公开了伊喜替康衍生物中间体的另一种合成路线四:
该合成路线进行溴化反应时使用的溴代试剂为液溴,属于剧毒品和腐蚀品,在放大生产中有一定的危险性,且反应过程涉及使用格氏试剂,格氏试剂遇空气易降解,且需要在超低温的环境下进行,对反应设备要求较高。重排反应选择性较低,后处理复杂,不适用于工业放大生产。合成路线三和合成路线四均无法避免肟化、催化氢解和氨基上保护的“一锅法”反应,涉及硝化和氢化等危险工艺,而且工业生产难度较大。
由此可见,为了满足伊喜替康的生产需求,亟需开发一种高收率且适合工业化生产的伊喜替康中间体的合成路线。
发明内容
为解决现有技术存在的问题,本发明提供了一种伊喜替康甲磺酸盐的制备方法、其中间体及制备方法。
本发明涉及一种伊喜替康甲磺酸盐的制备方法,其包括以下步 骤:
(f)化合物A在分子内环化试剂的作用下,进行分子内傅克酰基化反应得到化合物6;
(g)将化合物6进行选择性脱氨基保护得到化合物B;
(h)将所述的化合物B与化合物7进行缩合反应得到化合物8;
(i)化合物8在甲磺酸的作用下水解得到伊喜替康,即化合物9;
其中,步骤(f)中,所述的环化试剂选自傅克酰基化试剂,例如质子酸和酸酐的混合试剂或者氯代试剂与路易斯酸的混合试剂或者多聚磷酸PPA;
优选的,所述的质子酸选自三氟乙酸、盐酸或硫酸;
和/或,所述的酸酐选自三氟乙酸酐或三氟甲磺酸酐;
优选的,所述的氯代试剂选自亚硫酰氯、硫酰氯、草酰氯、三氯氧磷、三氯化磷或五氯化磷;
和/或,所述的路易斯酸选自三氯化铝、四氯化锡、铁盐。
作为一种实施方式,步骤(f)中,所述的环化试剂的加入量为以至少能使反应能够进行为准,优选为所述的环化试剂与所述的化合物A的物质的量之比为0.5~20:1,更优选为1~5:1。
进一步,步骤(f)的反应温度优选为-40~150℃,更优选为0~100℃,进一步优选为0~80℃。进一步,步骤(f)的反应时间优选为0.5~24h,更优选为2~12h。
进一步,步骤(g)中,优选使用盐酸或盐酸与醇的混合溶液进行,并且可以更优选使用2N盐酸/乙醇进行。
进一步,步骤(g)中,所述的反应温度优选为40~100℃,更优选为50~80℃;反应时间优选为2~8h,更优选为3~6h。
作为一种实施方式,步骤(h)中,化合物B与化合物7在对甲苯磺酸吡啶盐、邻甲酚和甲苯的作用下,进行缩合反应得到化合物8。
进一步,步骤(h)中,优选的,化合物B与化合物7的物质的量之比为1:0.9~1.5,更优选为1:1.0~1.1。
进一步,步骤(h)中,优选的,所述的化合物B与对甲苯磺酸吡啶盐的物质的量之比为1:0.01~0.30,更优选为1:0.05~0.20。
进一步,步骤(h)中,优选的,所述的化合物B与邻甲酚的质量之比为1:0.5~4.0,更优选为1:1.0~3.5。
进一步,步骤(h)中,所述的反应温度优选为80~130℃,更优选为100~120℃。
进一步,步骤(h)中,所述的反应时间优选为18~72h,更优选为24~36h。作为一种实施方式,步骤(i)中,所述的反应在溶剂中进行,优选的,溶剂选自水、2-甲氧基乙醇、乙基环己烷或甲苯中的一种或多种,优选为水和甲苯的混合溶液;所述溶剂的加入量以所述的化合物8的质量计为10~60ml/g。
进一步,步骤(i)中,反应温度优选为70~100℃,更优选为80~90℃。
进一步,步骤(i)中,反应时间优选为4~12h,更优选为6~8h。
本发明还涉及一种新的中间体化合物A,其可用作合成化合物6或者伊喜替康或其甲磺酸盐,
本发明还涉及提供一种中间体化合物A的制备方法,所述的中间体化合物A的制备方法具体包括如下步骤:
(e)将化合物5在催化剂的存在下进行催化氢化反应,得到化合物A,
进一步,步骤(e)中,所述的催化剂选自钯催化剂、铂催化剂、镍催化剂、钌催化剂或铑催化剂,更优选为钯碳催化剂,更优选为5%钯碳催化剂。
进一步,步骤(e)中,所述催化剂的加入量至少为以反应能够进行为基准,优选为所述的催化剂与所述的化合物5的质量比为0.02~0.4:1,更优选为0.05~0.15。
进一步,步骤(e)中,所述的反应在有机溶剂中进行,所述的 有机溶剂选自乙腈、二氯甲烷、氯仿、甲醇、乙醇、乙醚、1,2-二甲氧基乙烷、四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、乙酸乙酯、乙基环己烷、苯、甲苯、氯苯、丙酮、和水及其混合溶剂。
进一步,步骤(e)中,所述的有机溶剂的加入量以所述的化合物5的质量计为10~60ml/g。
进一步,步骤(e)中,所述的反应温度为40~70℃,优选为50~70℃;反应时间为0.5~24h,优选为6~12h。
本发明还涉及提供一种中间体化合物5,作为中间体应用于制备化合物6或伊喜替康或其甲磺酸盐,
本发明还涉及提供一种化合物5的制备方法,包括以下步骤:
(d)化合物4与2-乙酰氨基丁-3-烯酸在偶联催化剂、碱性物质的作用下,进行偶联反应,得到化合物5,
其中,R选自卤素、磺酸酯基或重氮基,例如碘、三氟甲磺酰氧基。
进一步,步骤(d)中,步骤(d)中,所述的偶联催化剂为钯盐与膦配体形成的配合物;
和/或所述的钯盐选自氯化钯、醋酸钯、四(三苯基膦)钯、硝 酸钯或三苯基膦二氯化钯,优选为醋酸钯;
和/或所述的膦配体选自三苯基膦、三环己基膦、三(邻甲苯基)膦、三[3,5-双(三氟甲基)苯基]膦、三异丙基膦和二环己基-(2,6-二异丙基苯基)膦,优选三(邻甲苯基)膦。
进一步,步骤(d)中,所述的碱性物质选自三乙胺、异丙胺、吡啶、碳酸钠、碳酸氢钠、碳酸钾和叔丁醇钾,优选为三乙胺。
进一步,步骤(d)中,步骤(d)中,所述的化合物4与2-乙酰氨基丁-3-烯酸的物质的量之比为1:1.0~3.0,例如1:1.2~1.5;
和/或所述的偶联催化剂的加入量以所述的膦配体的物质的量来计,所述的化合物4与膦配体的物质的量之比为1:0.05~0.75,例如1:0.15~0.30;
和/或所述的化合物4与碱性物质的物质的量之比为1:1.0~15.0,例如1:3.0~10.0。
进一步,步骤(d)中,所述的反应在有机溶剂中进行,所述的有机溶剂选自乙腈、四氢呋喃、1,4-二氧六环、N,N-二甲基甲酰胺、二甲基乙酰胺、甲苯、水及其混合溶剂;所述的有机溶剂的加入量以化合物4的质量计为10~60ml/g。
进一步,步骤(d)中,所述的反应温度为20~110℃,例如50~80℃;反应时间为2~24h,优选为8~16h。
本发明还涉及提供一种化合物4的制备方法,包括如下步骤:
(a)化合物1转化得到化合物2;
(b)化合物2在催化剂的作用下催化加氢反应得到化合物3;
(c)化合物3与酰化剂在催化剂的作用下,进行酰化反应,得到化合物4;
R选自卤素、磺酸酯基或重氮基,例如碘、三氟甲磺酰氧基。
进一步,步骤(a)中,优选的,所述的碘化剂选自碘和N-碘代丁二酰亚胺,更优选为N-碘代丁二酰亚胺;所述的N-碘代丁二酰亚胺的量没有限制,只要反应进行即可,优选为1-1.5当量。该步骤可以优选在硫酸和其他溶剂的混合溶剂中进行。
进一步,步骤(a)中,优选的,反应溶剂选自包括二氯甲烷、氯仿、1,2-二甲氧基乙烷、己烷、戊烷、庚烷、环己烷、乙基环己烷、苯、甲苯、氯苯及其混合溶剂。
进一步,步骤(a)中,反应温度优选为-10~30℃,更优选为0~10℃。
进一步,步骤(a)中,反应时间优选为0.5~4h,更优选为1.5~2h。
进一步,步骤(b)中,优选的,所述的催化剂选自铑炭催化剂、铂碳催化剂、二氧化铂、三氯化钛、氯化镍、锌粉、铁粉中的一种或多种,更优选为铂碳催化剂;所述的催化剂的量没有限制,只要反应进行即可,优选的,所述的催化剂与化合物2的质量比为0.05~0.4:1,更优选为0.05~0.1:1。
进一步,步骤(b)中,优选的,反应溶剂选自包括括甲醇、乙醇、四氢呋喃、2-甲基四氢呋喃、1,2-二甲氧基乙烷、1,4-二氧六环、乙酸乙酯和水及其混合溶剂;所述的反应溶剂的加入量以所述的化合物1的质量计为10~60ml/g。
进一步,步骤(b)中,反应温度优选为40~70℃,更优选为 50~70℃。
进一步,步骤(b)中,反应时间优选为0.5~8h,更优选为2~4h。
进一步,步骤(c)中,优选的,所述的酰化剂选自乙酸酐、乙酰氯、乙烯酮、氯乙酸酯和腈乙酸酯中的一种或多种,更优选为乙酸酐;所述的酰化剂与化合物2的物质的量之比为0.5~1.5:1,更优选为0.75~1:1。
进一步,步骤(c)中,优选的,所述的反应在碱的作用进行,所述的碱选自三乙胺、异丙胺、吡啶、碳酸钠、碳酸钾和叔丁醇钾,更优选为三乙胺;所述碱与化合物2的物质的量之比为0.5~1.5:1,更优选为0.75~1.5:1。
进一步,步骤(c)中,优选的,反应溶剂选自包括甲醇、乙醇、四氢呋喃、二氯甲烷、氯仿、丙酮、甲苯、乙酸乙酯和水及其混合溶剂,更优选乙酸乙酯;所述的反应溶剂的加入量以所述的化合物2的质量计为10~60ml/g。
进一步,步骤(c)中,反应温度优选为-10~40℃,更优选为0~30℃。
进一步,步骤(c)中,反应时间优选为2~24h,更优选为3~12h。
本发明所述的化合物5、6表示的E和Z形式以几何异构体形式存在,并且两者都包括在表示的化合物内,因此包括在本发明的范围内。本发明的化合物5表示的化合物可以是E和Z形式的混合物,并且该混合物可以直接用于下一步。
与现有技术相比,本发明的有益效果为:
(1)本发明提供了一种新的伊喜替康甲磺酸盐中间体5和A, 开拓了伊喜替康衍生物重要中间体的研究领域;
(2)原料便宜易得,中间体的合成路线简单,避免了肟化、催化氢解和氨基上保护的“一锅法”反应,大减少了反应步骤,操作条件温和,降低了操作难度,能耗低,适合工业化放大生产;
(3)提高原子利用率,更符合绿色化学的工业化应用;提高了伊喜替康衍生物合成的收率,进一步降低成本。
下面将结合具体实施方式对本发明的技术方案进行清楚、完整地描述,但是本领域技术人员将会理解,下列所描述的实施例是本发明一部分实例,而不是全部的实施例,仅用于说明本发明,而不应视为限制本发明的范围。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。实施例中未注明具体条件者,按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者,均为可以通过市售购买获得的常规产品。
实施例1
化合物4a的制备
将浓硫酸(90%,50mL)加入到三口烧瓶中,冷却至约1℃后加入化合物1(10g,64.5mmol),然后将N-碘代琥珀酰亚胺(20.4g,90.2 mmol)分六份加入到反应瓶中。混合物在约2℃下搅拌2小时。将得到的反应溶液加入冷水(100mL)中。加入甲苯(50mL)进行萃取分离后,除去水层。然后,将有机层用水(50mL)、5.0wt%碳酸钠水溶液(50mL)、5wt%亚硫酸钠水溶液(25mL,3次)洗涤。然后将有机层减压浓缩,得到化合物2的粗品(200g)。
向反应釜中加入化合物2和乙酸乙酯(15mL),然后加入1%铂炭催化剂(2.1g)和乙酸乙酯(90mL)的悬浮液,用氮气置换气氛,然后用氢气置换。将反应液在氢气流(0.2MPa)中在65℃下搅拌3小时,并冷却至室温。通过过滤将不溶物与所得悬浮液分离,并用乙酸乙酯(30mL)洗涤。然后,将滤液用6.5wt%的碳酸氢钠水溶液(25mL)和5wt%的盐水(25mL)洗涤,并将得到的有机层在减压下浓缩,得到化合物3于乙酸乙酯中的溶液(50mL)。
将化合物3的乙酸乙酯溶液和三乙胺加入到三口烧瓶中,冷却至约0℃,缓慢加入乙酸酐(3.4ml,35.4mmol),并将混合物在室温下搅拌4小时。反应完全后加入饱和食盐水(50ml),进行分离后除去水层。将有机层在减压下浓缩。将乙腈(50mL)和水(50mL)加至浓缩的残留物中,并将浓缩的残留物在25℃下搅拌。通过过滤收集沉淀的晶体,并用50%乙腈水溶液(20mL)洗涤。将得到的晶体在40℃下在减压下干燥,得到化合物4a,为白色晶体(6.4g,收率38%)。
1H NMR(500MHz,CDCl
3)δ7.43(s,1H),7.38(d,J=7.8Hz,1H),7.19(m,1H),2.27(d,J=7.8Hz,,3H),2.15(s,3H).
实施例2
化合物A的制备
将化合物4a(10.0g,34.1mmol)、2-乙酰氨基丁-3-烯酸(6.1g,42.6mmol)和三乙胺(23.7mL,170.6mmol)于乙腈(200mL)的溶液在减压下脱气并用氮气置换气氛,然后加入三(邻甲苯基)膦(1.5g,5.12mmol)和醋酸钯(II)(0.4g,1.71mmol),并将混合物在减压下脱气,用氮气置换气氛,然后加热回流8小时,并冷却至室温。将2-甲基四氢呋喃(100mL)和水(100mL)加至已冷却至室温的反应溶液中,加入25w/v%的氢氧化钠水溶液(6.5mL,40.2mmol),除去有机层。用2-甲基四氢呋喃(30mL,2次)洗涤水层,除去有机层。将浓盐酸(36%,6.0g,60.1mmol)和2-甲基四氢呋喃(30mL,2次)加入到水层中。分离后,除去水层,有机层用10wt%盐水(60mL)洗涤。在减压下浓缩得到有机层,得到含有几何异构体的化合物5粗品(10.8g)。
通过将四氢呋喃(100mL)、纯化水(100mL)和5%钯炭(2.1g)加至含有几何异构体的化合物5粗品(10.8g)中得到悬浮液,用氮气置换气氛,然后用氢气置换。将混合物在氢气流(0.5MPa)中在60℃下搅拌8小时,并冷却至室温。通过过滤将不溶物与所得悬浮液分离,并用四氢呋喃(30mL)洗涤。滤液用1N盐酸溶液将pH调节至约2。将溶剂减压浓缩至干,将乙腈(40mL)和水(80mL)加至浓缩的残留物中,并将浓缩的残留物在25℃下搅拌。通过过滤收集沉淀的晶体,并用50%乙腈水溶液(10mL)洗涤。将得到的晶体在40℃下在减压下干燥,得到化合物A,为白色晶体(9.2g,收率87%)。
1H NMR(500MHz,DMSO-d6)δ12.64(s,1H),9.99(s,1H),8.29(d,J=7.8Hz,1H),7.41(dd,J=12.2,2.1Hz,1H),7.07(d,J=2.1Hz, 1H),4.21(m,1H),1.75-1.88(m,2H),2.59(m,2H),2.08(s,3H),2.02(s,3H),1.89(s,3H).
13C NMR(126MHz,DMSO-d6)δ174.02,169.93,168.88,161.73,159.83,142.40,138.36,117.15,115.18,104.20,52.05,32.07,29.34,24.45,22.84,10.07.
ESI-MS:m/z C
15H
19FN
2O
4[M+H]+计算值:311.13;实测值311.18;
实施例3
化合物A的制备
将化合物4a(10.0g,34.1mmol)、2-乙酰氨基丁-3-烯酸(6.1g,42.6mmol)和碳酸氢钠(8.6g,102mmol)加入甲苯和水(150mL/50mL)混合溶剂中,该反应液在减压下脱气并用氮气置换气氛,然后加入三苯基膦二氯化钯(1.2g,1.7mmol),并将混合物在减压下脱气,用氮气置换气氛,100℃加热回流反应24小时。将2-甲基四氢呋喃(100mL)和水(100mL)加至已冷却至室温的反应溶液中,加入25w/v%的氢氧化钠水溶液(6.5mL,40.2mmol),除去有机层。用2-甲基四氢呋喃(30mL,2次)洗涤水层,除去有机层。将浓盐酸(36%,6.0g,60.1mmol)和2-甲基四氢呋喃(30mL,2次)加入到水层中。分离后,除去水层,有机层用10wt%盐水(60mL)洗涤。在减压下浓缩得到有机层,得到化合物5粗品(9.2g)。
通过将四氢呋喃(100mL)、纯化水(100mL)和5%钯炭(2.1g)加至含有几何异构体的化合物5粗品(9.0g)中得到悬浮液,用氮气置换气 氛,然后用氢气置换。将混合物在氢气流(0.4MPa)中在40℃下搅拌16小时,并冷却至室温。通过过滤将不溶物与所得悬浮液分离,并用四氢呋喃(20mL)洗涤。滤液用1N盐酸溶液将pH调节至约2。将溶剂减压浓缩至干,将乙腈(40mL)和水(80mL)加至浓缩的残留物中,并将浓缩的残留物在25℃下搅拌。通过过滤收集沉淀的晶体,并用50%乙腈水溶液(10mL)洗涤。将得到的晶体在40℃下在减压下干燥,得到化合物A,为白色晶体(8.5g,收率80%)。
对比例1
将化合物4a(0.84g,3.4mmol)、2-丁烯酸-3-(乙酰氨基)-苯基甲酯(1.2g,4.2mmol)和三乙胺(2.3mL,17.1mmol)于N,N-二甲基甲酰胺(10mL)的溶液在减压下脱气并用氮气置换气氛,然后加入三(邻甲苯基)膦(0.3g,0.48mmol)和醋酸钯(II)(0.08g,0.16mmol),并将混合物在减压下脱气,用氮气置换气氛,然后加热回流8小时,并冷却至室温。
反应液取样检测LCMS,反应未得到目标化合物。
对比例2
将化合物4b(0.84g,3.4mmol)、2-氨基-3-丁酸(0.7g,4.2mmol)和三乙胺(2.3mL,17.1mmol)于N,N-二甲基甲酰胺(10mL)的溶液在减压下脱气并用氮气置换气氛,然后加入三(邻甲苯基)膦(0.3g,0.48mmol)和醋酸钯(II)(0.08g,0.16mmol),并将混合物在减压下脱气,用氮气置换气氛,然后加热回流8小时,并冷却至室温。
反应液取样检测LCMS,反应未得到目标化合物。
对比例3
将化合物4a(1.0g,3.4mmol)、2-氨基-3-丁酸(0.7g,4.2mmol)和三乙胺(2.3mL,17.1mmol)于N,N-二甲基甲酰胺(10mL)的溶液在减压下脱气并用氮气置换气氛,然后加入三(邻甲苯基)膦(0.3g,0.48mmol)和醋酸钯(II)(0.08g,0.16mmol),并将混合物在减压下脱气,用氮气置换气氛,然后加热回流8小时,并冷却至室温。
反应液取样检测LCMS,反应未得到目标化合物。
实施例4
化合物6的制备
将三氟乙酸酐(25mL,176.8mmol)投入到反应瓶中,冷却至0℃,加入化合物A(5.0g,16.1mmol),再加入浓硫酸(2mL),0℃条件下继续搅拌1h,然后缓慢升至35℃,继续搅拌反应12h。将得到的反应溶液逐滴加入到已冷却至5℃的50%乙腈水溶液(120mL)中。用25wt%的氢氧化钠水溶液将pH调节至约7后,加入水(20mL)。然后,使反应液温度回到室温,通过过滤收集沉淀的晶体,并用水(60mL)和75%乙腈水溶液(60mL)洗涤。在减压下干燥得到的晶体,得到化合物6,为白色晶体(4.2g,收率90%)。
1H NMR(500MHz,CDCl
3)δ11.77(s,1H),8.41(d,1H),6.58(d,1H),4.63(dt,1H),2.95-3.06(m,2H),2.71-2.76(m,1H),2.23(s,3H),2.14(d,3H),2.11(s,3H),1.79-1.88(m,1H).
ESI-MS:m/z C
15H
18FN
2O
3[M+H]+计算值:293.1301;实测值293.1310;
实施例5
化合物6的制备
将1,2-二氯乙烷(50mL)投入到反应瓶中,冷却至-40℃,加入化 合物A(3.1g,10mmol)和五氯化磷(2.1g,10mmol),-40℃条件下继续搅拌2h,然后缓慢升至室温。向反应液中加入AlCl
3(2.8g,21mmol),加热回流反应10小时。TLC监测反应结束,将反应液缓慢加入冰水(200mL)中,乙酸乙酯萃取,干燥,过滤,旋干,将所得固体在减压下干燥得到化合物6,为白色晶体(1.4g,收率48%)。结构表征数据同实施例3。
对比例4
化合物6a的制备
将多聚磷酸(2mL)和化合物A(100mg)投入到反应瓶中,100℃下反应12h。然后,使反应液温度回到室温,冰浴条件下中和至PH=7,二氯甲烷萃取,收集有机相。有机相经Na
2SO
4干燥,过滤,旋干,得到白色化合物6a(80mg,收率91%)。
1H NMR(500MHz,DMSO-d6/CDCl
3)δ10.01(s,1H),9.86(s,1H),8.27(s,1H),7.87(d,J=9.1Hz,1H),7.75(d,J=9.1Hz,1H),7.54(d,J=11.1Hz,1H),2.49(s,3H),2.26(s,3H),2.17(s,1H).
ESI-MS:m/z[M+H]+计算值:275.12;实测值275.18;
实施例6
化合物B的制备
将化合物6(5.0g,17.1mmol)于2N盐酸/乙醇(50mL)中的悬浮液在50℃下搅拌6小时。将水(45mL)加入所得反应溶液中,并将混合物冷却至1℃。在1℃下逐滴加入三乙胺(14.5mL,103.9mmol)后,加入亚硫酸钠(45mg,0.3mmol)。将混合物在1℃搅拌2小时后,通过过滤收集沉淀的晶体,并用冷的60%乙醇水溶液(50mL)和水(15mL)洗涤。将得到的晶体于丙酮(30mL)中的悬浮液在50℃下搅拌2小时,然后冷却至室温。通过过滤收集沉淀的晶体,并用丙酮(10mL)洗涤。将所得晶体在40℃在减压下干燥,得到化合物B(3.6g,收率85%)。
1H NMR(500MHz,DMSO_d6)δ8.08(d,1H),7.41(s,2H),6.39(d,1H),4.48(dt,1H),2.93(d,1H),2.78-2.85(m,1H),2.16(m,1H),2.14(s,3H),2.13(s,3H),1.81-1.98(m,1H).
ESI-MS:m/z C
13H
16FN
2O
2[M+H]+计算值:251.1196;实测值251.1194;
实施例7
化合物8的制备
将化合物B(10g,40.0mmol)、化合物7(10g,38.0mmol)、对甲苯磺酸吡啶盐(1.5g,6.0mmol)和邻甲酚(30ml,264mmol)加入到三口瓶中,加入甲苯(400mL),108℃反应32小时并冷却。通过过滤收集沉淀的晶体,并用丙酮(30mL)洗涤。将所得晶体在40℃在减压下干燥,得到化合物8(15.4g,收率85%)。
ESI-MS:m/z C
26H
25FN
3O
5[M+H]+计算值:478.1778;实测值478.1782;
实施例8
化合物9的制备
将化合物8(10g,20.9mmol)悬浮于水(300ml)和甲苯(300ml)中,缓慢加入甲磺酸(150mL),固体溶解并有放热现象。加热到90℃反应8h,冷却至室温,分液并除去有机相。水相过滤,滤液用乙醇(4L)稀释,固体析出,室温下搅拌20min,过滤,抽干,将粗品悬浮于乙醇/水=4:1中,加热回流2h,冷却到室温,过滤,固体用少量乙醇洗涤后抽干,干燥后得到化合物9即伊喜替康甲磺酸盐(4.6g,45%)。
1H NMR(500MHz,DMSO_d6)δ8.47(s,3H),7.88(d,1H),7.34(s,1H),6.59(s,1H),5.72-5.40(m,4H),5.11(s,1H),3.30(m,1H),3.10(t,1H),2.53(m,1H),2.42(s,3H),2.32(s,3H),2.19(m,1H),1.88(m,2H),0.88(t,3H).
ESI-MS:m/z C
24H
23FN
3O
4[M+H]+计算值:436.1673;实测值 436.1678。
Claims (24)
- 如权利要求1或2所述的制备方法,其特征在于,步骤(f)中,所述的环化试剂选自傅克酰基化试剂,例如质子酸和酸酐的混合试剂或者氯代试剂与路易斯酸的混合试剂或者多聚磷酸PPA;优选的,所述的质子酸选自三氟乙酸、盐酸或硫酸;和/或,所述的酸酐选自三氟乙酸酐或三氟甲磺酸酐;优选的,所述的氯代试剂选自亚硫酰氯、硫酰氯、草酰氯、三氯氧磷、三氯化磷或五氯化磷;和/或,所述的路易斯酸选自三氯化铝、四氯化锡、铁盐。
- 如权利要求1或2所述的制备方法,其特征在于,步骤(f)中,所述的环化试剂的加入量为以至少能使反应能够进行为基准,优选的,所述的环化试剂与所述的化合物A的物质的量之比为0.5~20:1,更优选为1~10:1,再优选为1~5:1。
- 如权利要求1或2所述的制备方法,其特征在于:步骤(f)中,所述的反应温度为-40~150℃,例如0~100℃;和/或反应时间为0.5~24h,例如2~12h。
- 如权利要求1或7所述的制备方法,其特征在于,步骤(e)中,所述的催化剂选自钯催化剂、铂催化剂、镍催化剂、钌催化剂 或铑催化剂,优选为钯碳催化剂,更优选为5%钯碳催化剂。
- 如权利要求1或7所述的制备方法,其特征在于:步骤(e)中,所述催化剂的加入量至少为以反应能够进行为基准,优选的,所述的催化剂与所述的化合物5的质量比为0.02~0.4:1,更优选为0.05~0.15。
- 如权利要求1或7所述的制备方法,其特征在于:步骤(e)中,所述的反应在有机溶剂中进行,所述的有机溶剂选自乙腈、二氯甲烷、氯仿、甲醇、乙醇、乙醚、1,2-二甲氧基乙烷、四氢呋喃、2-甲基四氢呋喃、1,4-二氧六环、乙酸乙酯、乙基环己烷、苯、甲苯、氯苯、丙酮、水或任意几种的混合溶剂。
- 如权利要求1或7所述的制备方法,其特征在于:步骤(e)中,所述的反应温度为25~100℃,例如40~60℃;反应时间为0.5~24h,例如6~12h。
- 如权利要求1或14所述的制备方法,其特征在于:步骤(d)中,所述的偶联催化剂为钯盐与膦配体形成的配合物;优选的,所述的钯盐选自氯化钯、醋酸钯、四(三苯基膦)钯、硝酸钯或三苯基膦二氯化钯,例如醋酸钯;和/或所述的膦配体选自三苯基膦、三环己基膦、三(邻甲苯基)膦、三[3,5-双(三氟甲基)苯基]膦、三异丙基膦和二环己基-(2,6-二异丙基苯基)膦,例如三(邻甲苯基)膦。
- 如权利要求1或14所述的制备方法,其特征在于:步骤(d)中,所述的碱性物质选自三乙胺、异丙胺、吡啶、碳酸钠、碳酸氢钠、碳酸钾或叔丁醇钾,例如三乙胺。
- 如权利要求1或14所述的制备方法,其特征在于:步骤(d)中,所述的化合物4与2-乙酰氨基丁-3-烯酸的物质的量之比为1:1.0~3.0,例如1:1.2~1.5;和/或所述的偶联催化剂的加入量以所述的膦配体的物质的量来计,所述的化合物4与膦配体的物质的量之比为1:0.05~0.75,例如1:0.15~0.30;和/或所述的化合物4与碱性物质的物质的量之比为1:1.0~15.0,例如1:3.0~10.0。
- 如权利要求1或14所述的制备方法,其特征在于:步骤(d)中,所述的反应在有机溶剂中进行,所述的有机溶剂选自乙腈、四氢呋喃、1,4-二氧六环、N,N-二甲基甲酰胺、二甲基乙酰胺、甲苯、水及其混合溶剂。
- 如权利要求1或14所述的制备方法,其特征在于:步骤(d)中,所述的反应温度为20~110℃,例如50~80℃;反应时间为2~24h,优选为8~16h。
- 如权利要求21所述的制备方法,其特征在于:所述的化合物A按权利要求7~11之一所述的方法制备由化合物5制备得到。
- 如权利要求22所述的制备方法其特征在于:所述的化合物5按权利要求14~19之一所述的方法制备由化合物4制备得到。
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