CN116655518A - Isatin derivative and preparation method and application thereof - Google Patents
Isatin derivative and preparation method and application thereof Download PDFInfo
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- CN116655518A CN116655518A CN202310598672.6A CN202310598672A CN116655518A CN 116655518 A CN116655518 A CN 116655518A CN 202310598672 A CN202310598672 A CN 202310598672A CN 116655518 A CN116655518 A CN 116655518A
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- substituted
- piperazine
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- JXDYKVIHCLTXOP-UHFFFAOYSA-N isatin Chemical class C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 title claims abstract description 96
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 70
- 239000003814 drug Substances 0.000 claims abstract description 21
- 229940079593 drug Drugs 0.000 claims abstract description 19
- 201000006474 Brain Ischemia Diseases 0.000 claims abstract description 17
- 206010008120 Cerebral ischaemia Diseases 0.000 claims abstract description 17
- 206010008118 cerebral infarction Diseases 0.000 claims abstract description 17
- 230000000324 neuroprotective effect Effects 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 156
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 91
- -1 amino substituted benzene Chemical class 0.000 claims description 79
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 62
- 239000000243 solution Substances 0.000 claims description 60
- 239000007787 solid Substances 0.000 claims description 55
- 238000003756 stirring Methods 0.000 claims description 49
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 39
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 36
- 239000000203 mixture Substances 0.000 claims description 31
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 30
- 238000010438 heat treatment Methods 0.000 claims description 30
- 238000005406 washing Methods 0.000 claims description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 238000002156 mixing Methods 0.000 claims description 22
- 238000012544 monitoring process Methods 0.000 claims description 22
- 239000002904 solvent Substances 0.000 claims description 21
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 18
- 238000001704 evaporation Methods 0.000 claims description 18
- 239000007788 liquid Substances 0.000 claims description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 18
- XXQVRYBFEWKZBM-UHFFFAOYSA-N 3,3-dichloro-2-oxo-1h-indole-5-sulfonyl chloride Chemical compound C1=C(S(Cl)(=O)=O)C=C2C(Cl)(Cl)C(=O)NC2=C1 XXQVRYBFEWKZBM-UHFFFAOYSA-N 0.000 claims description 17
- 238000001914 filtration Methods 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 14
- 238000004440 column chromatography Methods 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 14
- 239000012074 organic phase Substances 0.000 claims description 14
- 239000005457 ice water Substances 0.000 claims description 13
- 239000011259 mixed solution Substances 0.000 claims description 12
- 239000000706 filtrate Substances 0.000 claims description 11
- 125000000623 heterocyclic group Chemical group 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- JUJRKHHCIXKFQG-UHFFFAOYSA-N 2,3-dioxo-1h-indole-5-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=C2NC(=O)C(=O)C2=C1 JUJRKHHCIXKFQG-UHFFFAOYSA-N 0.000 claims description 10
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 claims description 10
- 238000001816 cooling Methods 0.000 claims description 10
- 239000012043 crude product Substances 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000000217 alkyl group Chemical group 0.000 claims description 9
- 239000003480 eluent Substances 0.000 claims description 9
- 239000003208 petroleum Substances 0.000 claims description 9
- 238000000926 separation method Methods 0.000 claims description 9
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 8
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 8
- 238000010828 elution Methods 0.000 claims description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 238000004090 dissolution Methods 0.000 claims description 7
- PTJSLCXRMMGRLY-UHFFFAOYSA-N 1-(2-phenoxyethyl)piperazine Chemical class C=1C=CC=CC=1OCCN1CCNCC1 PTJSLCXRMMGRLY-UHFFFAOYSA-N 0.000 claims description 6
- JJFOBACUIRKUPN-UHFFFAOYSA-N 2-bromoethoxybenzene Chemical class BrCCOC1=CC=CC=C1 JJFOBACUIRKUPN-UHFFFAOYSA-N 0.000 claims description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical class OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical class CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical class C1CCNCC1 NQRYJNQNLNOLGT-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
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 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
- 238000010992 reflux Methods 0.000 claims description 6
- WBYWAXJHAXSJNI-VOTSOKGWSA-N trans-cinnamic acid Chemical class OC(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000004305 biphenyl Substances 0.000 claims description 4
- 235000010290 biphenyl Nutrition 0.000 claims description 4
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 4
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical class BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 claims description 3
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 claims description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 230000006837 decompression Effects 0.000 claims description 3
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 claims description 3
- 230000008020 evaporation Effects 0.000 claims description 3
- 238000000605 extraction Methods 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 230000001376 precipitating effect Effects 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 3
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 claims description 3
- WOGITNXCNOTRLK-VOTSOKGWSA-N (e)-3-phenylprop-2-enoyl chloride Chemical class ClC(=O)\C=C\C1=CC=CC=C1 WOGITNXCNOTRLK-VOTSOKGWSA-N 0.000 claims description 2
- QAGQGVIUPYTPQF-UHFFFAOYSA-N C(C=C)(=O)Cl.C1=CC=CC=C1 Chemical class C(C=C)(=O)Cl.C1=CC=CC=C1 QAGQGVIUPYTPQF-UHFFFAOYSA-N 0.000 claims description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 2
- 150000003935 benzaldehydes Chemical class 0.000 claims description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 238000004821 distillation Methods 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 2
- 150000002989 phenols Chemical class 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
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims 1
- 239000005426 pharmaceutical component Substances 0.000 claims 1
- 241000699670 Mus sp. Species 0.000 abstract description 12
- 230000000694 effects Effects 0.000 abstract description 12
- 230000000302 ischemic effect Effects 0.000 abstract description 11
- 230000002490 cerebral effect Effects 0.000 abstract description 10
- 230000004083 survival effect Effects 0.000 abstract description 10
- 208000006011 Stroke Diseases 0.000 abstract description 9
- 230000001154 acute effect Effects 0.000 abstract description 7
- 210000005036 nerve Anatomy 0.000 abstract description 6
- 206010008190 Cerebrovascular accident Diseases 0.000 abstract description 5
- 241001465754 Metazoa Species 0.000 abstract description 4
- 239000004480 active ingredient Substances 0.000 abstract description 4
- 230000004112 neuroprotection Effects 0.000 abstract description 4
- 230000004224 protection Effects 0.000 abstract description 4
- 230000000740 bleeding effect Effects 0.000 abstract description 2
- 230000008499 blood brain barrier function Effects 0.000 abstract description 2
- 210000001218 blood-brain barrier Anatomy 0.000 abstract description 2
- 230000007547 defect Effects 0.000 abstract description 2
- 238000002474 experimental method Methods 0.000 abstract description 2
- 230000006698 induction Effects 0.000 abstract description 2
- 230000003188 neurobehavioral effect Effects 0.000 abstract description 2
- 238000012216 screening Methods 0.000 abstract description 2
- 231100000419 toxicity Toxicity 0.000 abstract description 2
- 230000001988 toxicity Effects 0.000 abstract description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 36
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 description 18
- 229960005235 piperonyl butoxide Drugs 0.000 description 11
- 238000000746 purification Methods 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 6
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- 238000012360 testing method Methods 0.000 description 5
- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 description 3
- 230000003833 cell viability Effects 0.000 description 3
- 230000003727 cerebral blood flow Effects 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- UYGHEEKXUMTKTR-UHFFFAOYSA-N 1-[2-(2-methylphenoxy)ethyl]piperazine Chemical compound CC1=CC=CC=C1OCCN1CCNCC1 UYGHEEKXUMTKTR-UHFFFAOYSA-N 0.000 description 2
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 2
- TYCJFZIWSCJVJW-UHFFFAOYSA-N 2-(4-chlorophenoxy)-1-piperazin-1-ylethanone Chemical compound C1=CC(Cl)=CC=C1OCC(=O)N1CCNCC1 TYCJFZIWSCJVJW-UHFFFAOYSA-N 0.000 description 2
- IQHSSYROJYPFDV-UHFFFAOYSA-N 2-bromo-1,3-dichloro-5-(trifluoromethyl)benzene Chemical group FC(F)(F)C1=CC(Cl)=C(Br)C(Cl)=C1 IQHSSYROJYPFDV-UHFFFAOYSA-N 0.000 description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 2
- YJPIGAIKUZMOQA-UHFFFAOYSA-N Melatonin Natural products COC1=CC=C2N(C(C)=O)C=C(CCN)C2=C1 YJPIGAIKUZMOQA-UHFFFAOYSA-N 0.000 description 2
- QFQYZMGOKIROEC-DUXPYHPUSA-N Methylenedioxycinnamic acid Chemical compound OC(=O)\C=C\C1=CC=C2OCOC2=C1 QFQYZMGOKIROEC-DUXPYHPUSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 125000005605 benzo group Chemical group 0.000 description 2
- 210000005013 brain tissue Anatomy 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
- 230000007910 cell fusion Effects 0.000 description 2
- 230000034994 death Effects 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- QNLOWBMKUIXCOW-UHFFFAOYSA-N indol-2-one Chemical compound C1=CC=CC2=NC(=O)C=C21 QNLOWBMKUIXCOW-UHFFFAOYSA-N 0.000 description 2
- 208000028867 ischemia Diseases 0.000 description 2
- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 2
- 229960003987 melatonin Drugs 0.000 description 2
- 239000004090 neuroprotective agent Substances 0.000 description 2
- 229960000715 nimodipine Drugs 0.000 description 2
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 2
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 2
- SATCULPHIDQDRE-UHFFFAOYSA-N piperonal Chemical compound O=CC1=CC=C2OCOC2=C1 SATCULPHIDQDRE-UHFFFAOYSA-N 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- WBJQTHIVYWAEDD-DUXPYHPUSA-N (e)-3-(1,3-benzodioxol-5-yl)prop-2-enoyl chloride Chemical compound ClC(=O)\C=C\C1=CC=C2OCOC2=C1 WBJQTHIVYWAEDD-DUXPYHPUSA-N 0.000 description 1
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical group N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- WXNZTHHGJRFXKQ-UHFFFAOYSA-N 4-chlorophenol Chemical compound OC1=CC=C(Cl)C=C1 WXNZTHHGJRFXKQ-UHFFFAOYSA-N 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 229940123457 Free radical scavenger Drugs 0.000 description 1
- 208000032382 Ischaemic stroke Diseases 0.000 description 1
- VOTJZEBYPPNWOP-UHFFFAOYSA-N N1(CCNCC1)S(=O)(=O)C=1C=C2C(C(NC2=CC=1)=O)=O Chemical compound N1(CCNCC1)S(=O)(=O)C=1C=C2C(C(NC2=CC=1)=O)=O VOTJZEBYPPNWOP-UHFFFAOYSA-N 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- HFBMWMNUJJDEQZ-UHFFFAOYSA-N acryloyl chloride Chemical compound ClC(=O)C=C HFBMWMNUJJDEQZ-UHFFFAOYSA-N 0.000 description 1
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004958 brain cell Anatomy 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 210000001168 carotid artery common Anatomy 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000019522 cellular metabolic process Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 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
- 125000006547 cyclononyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000003493 decenyl group Chemical group [H]C([*])=C([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- QULRDJFRGVHKLN-UHFFFAOYSA-N ethyl 2-(4-chlorophenoxy)acetate Chemical compound CCOC(=O)COC1=CC=C(Cl)C=C1 QULRDJFRGVHKLN-UHFFFAOYSA-N 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000003825 glutamate receptor antagonist Substances 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006038 hexenyl group Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 239000000236 nitric oxide synthase inhibitor Substances 0.000 description 1
- 125000005187 nonenyl group Chemical group C(=CCCCCCCC)* 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 125000004365 octenyl group Chemical group C(=CCCCCCC)* 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 229940090668 parachlorophenol Drugs 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229940081310 piperonal Drugs 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- CSYSULGPHGCBQD-UHFFFAOYSA-N s-ethylisothiouronium diethylphosphate Chemical compound CCSC(N)=N.CCOP(O)(=O)OCC CSYSULGPHGCBQD-UHFFFAOYSA-N 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000012679 serum free medium Substances 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 210000001186 vagus nerve Anatomy 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
Classifications
-
- 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
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/38—Oxygen atoms in positions 2 and 3, e.g. isatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an isatoic derivative, and also discloses a preparation method of the isatoic derivative and application of the isatoic derivative in preparation of anti-cerebral ischemia neuroprotection drugs or drug components. The isatin derivative has good anti-cerebral ischemia neuroprotective activity, can overcome the defects of easy bleeding induction, difficult blood brain barrier permeation, poor oral bioavailability, low selectivity and high neurobehavioral toxicity of the existing active ingredients, and can be used as a cerebral nerve protecting active ingredient for treating ischemic cerebral apoplexy; animal experiments of screening cerebral nerve protection activity show that the compound can obviously prolong the survival time of acute cerebral ischemia mice after being prophylactically administered, and has good cerebral ischemia nerve protection effect.
Description
Technical Field
The invention relates to an isatin derivative, and also relates to a preparation method of the isatin derivative and application of the isatin derivative in preparation of anti-cerebral ischemia neuroprotection drugs or drug components.
Background
Cerebral stroke is one of the diseases with the highest mortality and disability rate nowadays, wherein nearly 80% of cerebral strokes belong to ischemic cerebral strokes. The survival of brain cells after the occurrence of a stroke depends on the extent to which neuronal cells are damaged, i.e. on the extent to which cerebral blood flow that supplies oxygen and nutrition to the cells is reduced. When ischemic cerebral apoplexy occurs, cerebral blood flow of an ischemic core part is seriously reduced, and brain tissues are irreversibly damaged after 60-90 min of ischemia; the ischemic penumbra at the periphery of the core part relatively reduces cerebral blood flow, but the cell metabolism is abnormally increased, abnormal electric activity and metabolic disturbance in the ischemic area form a chain reaction within a few hours after the ischemia occurs, which is called as an 'ischemic waterfall', and the outcome of the waterfall effect is that the ischemic core is continuously expanded and the penumbra gradually disappears, and the process is a time window for treating cerebral apoplexy.
Neuroprotective treatment of ischemic stroke was proposed abroad since the nineties of the twentieth century, and has evolved rapidly in the next decade. The goal of neuroprotection is to interfere with the pathological biochemical cascade of ischemic penumbra events, rescue the viable brain tissue, and prevent or delay cell death. At present, the neuroprotectants have various types and action mechanisms, such as voltage-dependent calcium channel blockers, glutamate receptor antagonists, antioxidants, free radical scavengers, nitric oxide synthase inhibitors and other medicaments, and become research hot spots for treating cerebral apoplexy.
Disclosure of Invention
The invention aims to: the invention aims to provide an isatoic derivative with good anti-cerebral ischemia neuroprotective activity; another object of the present invention is to provide a process for preparing the above isatin derivatives and their use in the preparation of anti-cerebral ischemia neuroprotective drugs or pharmaceutical compositions.
The technical scheme is as follows: the structural general formula of the isatin derivative is shown as follows:
wherein R is 1 Is H, halogen, hydrocarbyl, alkoxy, aralkoxy, heterocycloalkoxy, aryl, substituted heterocycle, or substituted aryl; r is R 2 Is a bridging group, in particular-O-CH 2 -CO-, -ch=ch-CO-or-O-CH 2 -CH 2 -any one of the following.
Wherein the R is 1 The aryl group in the representative aryl or aralkoxy is benzene, biphenyl or naphthalene, or F, cl, br, I, C 1~10 Alkyl, C 1~10 Alkoxy, nitro or amino substituted benzene, biphenyl or naphthalene.
Wherein the R is 1 Representative hydrocarbyl means a straight or branched alkyl group having 1 to 10 carbon atoms, or a straight or branched alkenyl group having 2 to 10 carbon atoms, or a straight or branched cycloalkyl group having 3 to 10 carbon atoms; the alkyl group in the alkoxy, aralkoxy or heterocycloalkoxy group means a straight-chain or branched alkyl group having 1 to 10 carbon atoms; the alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, neopentyl, hexyl, heptyl, octyl, nonyl or decyl; the alkenyl is ethenyl, propenyl, allyl, butenyl, isobutenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl or decenyl; the cycloalkyl is cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl.
Wherein the R is 1 Representative of the heterocyclic groups in the substituted heterocyclic ring or heterocyclic alkoxy group means a saturated heterocyclic ring or aromatic heterocyclic ring containing one or more hetero atoms selected from the group consisting of oxygen, nitrogen and sulfur atoms.
Wherein the R is 1 The representative halogen is F, cl, br or I.
Wherein the R is 1 The substituent of the substituted aryl is halogen.
Wherein when R is 2 is-O-CH 2 In the case of CO-, the structural general formula of the compound is shown in the formula (II):
the preparation method of the compound with the formula (II) comprises the following steps:
(1) Mixing the substituted aromatic phenol, ethyl chloroacetate, acetonitrile and potassium carbonate, heating to reflux temperature, filtering while the mixture is hot after reaction, and carrying out spin-drying on the filtrate, wherein if the filtrate is oily residual liquid, the distillation is carried out under reduced pressure; if the solid is obtained by concentration, the solid is recrystallized by absolute ethyl alcohol to obtain the corresponding substituted aryloxy ethyl acetate (V);
(2) Mixing substituted aryloxy ethyl acetate and anhydrous piperazine (diethylenediamine), introducing N 2 Heating to no less than 110deg.C, refluxing, standing, cooling, adding chloroform into the residue for dissolving, and dissolving with saturated NaHCO 3 Washing the solution, washing with water, and concentrating the organic phase to obtain white solid which is substituted aryloxyacetylpiperazine (VI);
(3) Slowly dropwise adding chlorosulfonic acid into isatin in ice water bath, stirring, heating for reaction, monitoring the reaction progress by TLC, and cooling to room temperature after the reaction is completed; slowly dripping the reaction solution into crushed ice, vigorously stirring until solid is separated out, adding ethyl acetate, stirring, dissolving, separating, washing an ethyl acetate layer with water and saturated sodium chloride solution in sequence, and drying anhydrous sodium sulfate overnight after washing; the next day, filtering, decompressing and evaporating the solvent to obtain brown sticky matter, and separating by column chromatography to obtain 3, 3-dichloro-2-oxoindoline-5-sulfonyl chloride (VII) and 2, 3-dioxoindoline-5-sulfonyl chloride (VIII);
(4) Mixing substituted aryloxy acetyl piperazine (VI) and N-ethyldiisopropylamine, adding tetrahydrofuran into the mixture under ice water bath, stirring and dissolving to obtain a reaction solution; dissolving 3, 3-dichloro-2-oxoindoline-5-sulfonyl chloride in tetrahydrofuran, and slowly dripping the solution into the reaction solution; after the dripping is finished, the temperature is raised to the room temperature and stirred overnight; the next day, filtering, evaporating the solvent under reduced pressure to obtain yellow sticky substance, using the mixed solution of ethyl acetate and petroleum ether as eluent, performing gradient elution, and performing column chromatography separation to obtain a compound shown in a general formula (II);
the synthetic route of the method is as follows:
wherein when R is 2 When the compound is-CH=CH-CO-, the structural general formula of the compound is shown as a formula (III):
the preparation method of the compound with the formula (III) comprises the following steps:
(1) Mixing substituted benzaldehyde, malonic acid and piperidine, adding pyridine into the mixture, stirring the mixture for dissolution, heating the mixture to not lower than 120 ℃ for stirring reaction, monitoring the reaction progress by TLC, removing the solvent by evaporation under reduced pressure after the reaction is finished, adding a concentrated hydrochloric acid/ice mixture, stirring the mixture vigorously, precipitating a large amount of white solid, carrying out suction filtration, and recrystallizing the crude product by absolute ethyl alcohol to obtain substituted benzene acrylic acid (IX);
(2) Mixing N-Boc-piperazine and triethylamine, adding dichloromethane into the mixture, and stirring and dissolving the mixture in ice bath to obtain a mixed solution; dissolving 3, 3-dichloro-2-oxoindoline-5-sulfonyl chloride (VII) or 2, 3-dioxoindoline-5-sulfonyl chloride (VIII) in methylene dichloride, slowly dripping the mixture into the mixed solution, heating to room temperature after dripping, monitoring the reaction progress by TLC, and obtaining 4- (3, 3-dichloro-2-oxoindoline-5-ylsulfonyl) piperazine-1-carboxylic acid tert-butyl ester (X) by column chromatography after the reaction is finished;
(3) Placing 4- (3, 3-dichloro-2-oxoindole-5-ylsulfonyl) piperazine-1-carboxylic acid tert-butyl ester (X) in a reaction bottle, mixing trifluoroacetic acid and dichloromethane to obtain a trifluoroacetic acid solution with the mass fraction of 25%, directly adding the trifluoroacetic acid solution into the reaction bottle, stirring at room temperature, monitoring the reaction progress by TLC, and evaporating the solvent under reduced pressure after the reaction is finished to obtain 3, 3-dichloro-5- (piperazine-1-ylsulfonyl) indol-2-one trifluoroacetate (XI);
(4) Placing 3, 3-dichloro-5- (piperazine-1-ylsulfonyl) indol-2-one trifluoroacetate (XI) into a reaction bottle, adding an aqueous acetic acid solution (acetic acid/water=50 mL/50 mL) into the reaction bottle, heating to not lower than 100 ℃ for reaction, monitoring the reaction progress by TLC, and evaporating the solvent under reduced pressure after the reaction is finished to obtain 5- (piperazine-1-ylsulfonyl) indoline-2, 3-dione trifluoroacetate (XII);
(5) Mixing 5- (piperazine-1-ylsulfonyl) indoline-2, 3-dione trifluoroacetate (XII), N-ethyldiisopropylamine (dipea) and tetrahydrofuran, stirring and dissolving under ice water bath condition to obtain a reaction solution; putting substituted benzene acrylic acid (IX), anhydrous dichloromethane and DMF into a reaction bottle, dropwise adding oxalyl chloride into the reaction bottle under ice bath condition, heating to room temperature after dropwise adding, stirring for reaction, and concentrating the reaction solution to obtain substituted benzene acrylic acid chloride; dissolving substituted benzene acryloyl chloride with tetrahydrofuran, slowly dripping into the reaction liquid, heating to room temperature after dripping, and stirring overnight; the next day, TLC monitors the reaction progress, after the reaction is finished, the yellow oily liquid is obtained by decompression concentration, the mixed liquid of ethyl acetate and petroleum ether is used as an eluent, gradient elution is carried out, and the compound of the general formula (III) is obtained by column chromatography separation;
the synthetic route of the method is as follows:
wherein when R is 2 In the case of-O-CH 2-CH2-, the structural general formula of the compound is shown in the formula (IV):
the preparation method of the compound with the formula (IV) comprises the following steps:
(1) Mixing substituted phenol, 1, 2-dibromoethane and water, stirring and heating to not lower than 95 ℃, dropwise adding sodium hydroxide aqueous solution into the mixture, continuously heating to 100 ℃ after the dropwise adding is finished, stirring and reacting, monitoring the reaction progress by TLC, cooling to room temperature after the reaction is finished, and extracting with dichloromethane; combining dichloromethane layers, washing sequentially by adopting a sodium hydroxide aqueous solution and a saturated sodium chloride solution, and drying by adopting anhydrous magnesium sulfate after washing; filtering, concentrating the filtrate under reduced pressure to obtain substituted phenoxyethyl bromide (XIII);
(2) Mixing substituted phenoxyethyl bromide, methanol and piperazine, heating to not lower than 70 ℃ for reaction, monitoring the reaction progress by TLC, and evaporating the solvent under reduced pressure after the reaction is finished; adding a mixed solution of dichloromethane and saturated sodium carbonate solution into the mixture for dissolution and liquid separation, sequentially washing a dichloromethane layer with saturated sodium bicarbonate solution and water, washing an organic phase with hydrochloric acid, adjusting the pH of a water layer with sodium hydroxide solution to be more than 10, separating out solids, extracting with dichloromethane, combining the organic phases, and drying with anhydrous sodium sulfate overnight; the next day, filtering, concentrating under reduced pressure to obtain substituted phenoxyethylpiperazine (XIV);
(3) Placing the substituted phenoxyethyl piperazine into a reaction bottle, adding tetrahydrofuran into the reaction bottle under ice water bath, stirring and dissolving, and then adding N-ethyldiisopropylamine into the reaction bottle, and continuously stirring to obtain a reaction solution; dissolving 3, 3-dichloro-2-oxoindoline-5-sulfonyl chloride or 2, 3-dioxoindoline-5-sulfonyl chloride with tetrahydrofuran, slowly dripping the solution into the reaction solution, heating to room temperature after dripping, stirring overnight, monitoring the reaction progress by TLC, and evaporating the solvent under reduced pressure after the reaction is finished to obtain substituted 3, 3-dichloro-5- (4- (2-phenoxyethyl) piperazin-1-ylsulfonyl) indol-2-one (XV);
(4) 3, 3-dichloro-5- (4- (2-phenoxyethyl) piperazine-1-ylsulfonyl) indol-2-one is placed in a reaction bottle, an aqueous solution of acetic acid (the mixing volume ratio of acetic acid to water is 1:1) is added, the temperature is raised to not lower than 96 ℃ for stirring reaction, TLC monitors the reaction progress, the reaction is cooled to room temperature after the reaction is finished, firstly, sodium hydroxide solution is added dropwise to adjust the pH to be 7, and then saturated sodium bicarbonate solution is added dropwise until no bubble is generated; extraction with ethyl acetate, combining the organic phases, washing with saturated sodium bicarbonate solution and drying over night with anhydrous sodium sulfate; the next day, filtering, concentrating the filtrate under reduced pressure to obtain yellow oily liquid, and performing gradient elution by taking a mixed solution of ethyl acetate and petroleum ether as an eluent, and performing column chromatography separation to obtain a compound shown in a general formula (IV);
the synthetic route of the method is as follows:
the isatin derivative is applied to the preparation of anti-cerebral ischemia neuroprotection drugs or drug components. In the application test, the free base of the compound and the hydrochloride salt form are used.
The beneficial effects are that: compared with the prior art, the invention has the following remarkable advantages: the isatin derivative has good anti-cerebral ischemia neuroprotective activity, can overcome the defects of easy bleeding induction, difficult blood brain barrier permeation, poor oral bioavailability, low selectivity and high neurobehavioral toxicity of the existing active ingredients, and can be used as a cerebral nerve protecting active ingredient for treating ischemic cerebral apoplexy; animal experiments of screening cerebral nerve protection activity show that the compound can obviously prolong the survival time of acute cerebral ischemia mice after being prophylactically administered, and has good cerebral ischemia nerve protection effect.
Detailed Description
Example 1
A preparation method of a compound {5- ((4- (2- (4-chlorophenoxy) acetyl) piperazine-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-A1) } with a synthetic route is as follows:
the method specifically comprises the following steps:
(1) Placing parachlorophenol (31.2 mmol) into a 250mL eggplant-shaped bottle, adding ethyl chloroacetate (4.6 g,37.4 mmol), potassium carbonate (4.4 g,31.2 mmol) and acetonitrile 60mL, stirring, heating, refluxing for 5 hours, monitoring the reaction progress by TLC, filtering while the reaction is hot, and concentrating the filtrate under reduced pressure to obtain light yellow sticky liquid which is ethyl parachlorophenoxy acetate, wherein the crude product is directly used for the next reaction without purification;
(2) Ethyl p-chlorophenoxyacetate (16.1 mmol) and piperazine (5.5 g,64.4 mmol) were placed in a 100mL eggplant-shaped bottle, and N was passed through 2 Heating to 110 ℃ and refluxing for 4 hours, monitoring the reaction progress by TLC, cooling to room temperature after the reaction is finished, adding 40mL of dichloromethane and 30mL of saturated sodium carbonate solution for separating, washing an organic phase twice by 30mL of saturated sodium bicarbonate solution and once by 30mL of water, extracting the organic phase by 15mL of hydrochloric acid with the mass fraction of 10%, leading the pH value of a water layer to be less than 3, and reserving the water layer; dissolving with 10mL of 20% sodium hydroxide by mass fractionRegulating pH to more than 10, separating out solid, extracting with 30mL of dichloromethane for 3 times, mixing organic phases, and drying over night with anhydrous sodium sulfate; the next day, filtering, concentrating the filtrate under reduced pressure to obtain light yellow sticky liquid, namely 2- (4-chlorophenoxy) -1- (piperazin-1-yl) ethanone, wherein the crude product is directly used for the next reaction without purification;
(3) Putting isatin (8.22 g,55.9 mmol) into a 250mL eggplant-shaped bottle, carrying out ice-water bath, slowly dropwise adding chlorosulfonic acid (37 mL,559 mmol), heating to 70 ℃ after the dropwise addition, continuously stirring for 3 hours, monitoring the reaction progress by TLC, cooling to room temperature after the reaction is finished, slowly dripping the reaction solution into 250g of clean crushed ice, vigorously stirring until solid is separated out, adding 150mL of ethyl acetate, stirring, dissolving and separating liquid, washing an ethyl acetate layer twice with 100mL of water, washing a saturated sodium chloride solution once with 50mL, and drying anhydrous sodium sulfate overnight; the next day, filtering, concentrating the filtrate under reduced pressure to obtain brown sticky matter, and separating by column chromatography to obtain 2, 3-dioxoindoline-5-sulfonyl chloride, white powder, 9.8g and yield 58.3%;3, 3-dichloro-2-oxoindoline-5-sulfonyl chloride, yellow powder, 1.26g, yield 9.2%;
(4) 2- (4-chlorophenoxy) -1- (piperazin-1-yl) ethanone (1.1 g,4.0 mmol) and dipea (0.5 mL,4.0 mmol) were placed in a 100mL eggplant-shaped bottle, and were ice-water bathed and dissolved with stirring by adding 30mL tetrahydrofuran; 3, 3-dichloro-2-oxoindoline-5-sulfonyl chloride (0.8 g,3.3 mmol) was dissolved in 20mL of tetrahydrofuran, slowly dropped into a eggplant-shaped bottle, and after the dropping, the temperature was raised to room temperature and stirred overnight; TLC showed no purity, and gradient elution with ethyl acetate and petroleum ether as eluent, column chromatography gave 0.75g of yellow solid, yield 49.0%, m.p.271.5-274.6deg.C. HRMS (ESI-MS, m/z): calcd.for C 20 H 17 ClN 3 O 6 S[M-H] - 462.0527,found 462.0534. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.90~2.97(m,4H,SO 2 N(CH 2 ) 2 ),3.53(s,4H,CON(CH 2 ) 2 ),4.79(s,2H,COCH 2 O),6.87~7.91(m,7H,ArH),11.52(s,1H,NH). 13 C NMR(DMSO-d 6 ,75MHz)δ:43.38,43.38,45.76,45.76,65.85,112.81,116.33,116.33,118.13,123.39,124.49,128.66,128.94,128.94,137.08,153.88,156.72,159.35,165.68,182.81。
Example 2
On the basis of example 1, R 1 Replacement of 4-chloro with 4-methoxy, with otherwise unchanged reaction conditions, gives the compound {5- ((4- (2- (4-methoxyphenoxy) acetyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-A2) }
Yellow solid, yield 61.3%, m.p.259.5-261.2 ℃. HRMS (ESI-MS, m/z): calcd.for C 21 H 20 N 3 O 7 S[M-H] - 458.1022,found 458.1029. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.73~2.94(m,4H,SO 2 N(CH 2 ) 2 ),3.55(s,4H,CON(CH 2 ) 2 ),3.65(s,3H,OCH 3 ),4.67(s,2H,COCH 2 O),6.76~7.91(m,7H,ArH),11.49(s,1H,NH). 13 C NMR(DMSO-d 6 ,75MHz)δ:43.55,43.55,45.80,45.80,55.26,66.57,112.76,114.34,114.34,115.42,115.42,118.09,123.33,128.55,137.06,151.71,153.55,153.87,159.32,166.18,182.80。
Example 3
On the basis of example 1, R 1 4-methyl can be used to replace 4-chloro, other reaction conditions are unchanged, and the compound {5- ((4- (2- (4-methylphenoxy) acetyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-A3) }
Yellow solid, yield 88.2%, m.p.278.8-280.0 ℃. HRMS (ESI-MS, m/z): calcd.for C 21 H 20 N 3 O 6 S[M-H] - 442.1073,found 442.1083. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.19(s,3H,PhCH 3 ),2.88~2.97(m,4H,SO 2 N(CH 2 ) 2 ),3.54(s,4H,CON(CH 2 ) 2 ),4.70(s,2H,COCH 2 O),6.72-7.93(m,7H,ArH),11.50(s,1H,NH). 13 C NMR(DMSO-d 6 ,75MHz)δ:19.90,43.50,43.50,45.63,45.79,65.91,112.76,114.31,114.31,118.07,123.35,128.63,129.52,129.52,129.52,137.03,153.84,155.64,159.29,166.06,182.77。
Example 4
On the basis of example 1, R 1 Replacement of 4-chloro with 2-methoxy, with otherwise unchanged reaction conditions, gives the compound {5- ((4- (2- (2-methoxyphenoxy) acetyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-A4) }
Yellow solid, yield 39.0%, m.p.278.2-279.5 ℃. HRMS (ESI-MS, m/z): calcd.for C 21 H 20 N 3 O 7 S[M-H] - 458.1022,found 458.1033. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.90~2.96(m,4H,SO 2 N(CH 2 ) 2 ),3.56(s,4H,CON(CH 2 ) 2 ),3.72(s,3H,OCH 3 ),4.71(s,2H,COCH 2 O),6.78~7.92(m,7H,ArH),11.49(s,1H,NH). 13 C NMR(DMSO-d 6 ,75MHz)δ:43.71,43.71,45.69,45.84,55.49,66.88,112.32,112.80,113.84,118.14,120.41,121.44,123.31,128.63,137.03,147.19,148.95,153.88,159.32,165.98,182.79。
Example 5
On the basis of example 1, R 1 Replacement of 4-chloro with 2-methyl, with otherwise unchanged reaction conditions, gives the compound {5- ((4- (2- (2-methylphenoxy) acetyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-A5) }
Yellow solid, yield 77.6%, m.p.304.9-306.5 ℃. HRMS (ESI-MS, m/z): calcd.for C 21 H 20 N 3 O 6 S[M-H] - 442.1073,found 442.1079. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.112(s,3H,PhCH 3 ),2.89~2.95(m,4H,SO 2 N(CH 2 ) 2 ),3.56(s,4H,CON(CH 2 ) 2 ),4.76(s,2H,COCH 2 O),6.76~7.91(m,7H,ArH),11.40(s,1H,NH). 13 C NMR(DMSO-d 6 ,75MHz)δ:15.84,43.59,43.59,45.73,45.73,66.10,111.34,112.81,118.05,120.44,123.33,125.61,126.61,128.57,130.34,137.05,153.89,155.81,159.30,166.08,182.81。
Example 6
On the basis of example 1, R 1 Replacement of 4-chloro with 4-bromo, with otherwise unchanged reaction conditions, gives the compound {5- ((4- (2- (4-bromophenoxy) acetyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-A6) }
Yellow solid, yield 38.9%, m.p.276.7-278.5 ℃. HRMS (ESI-MS, m/z): calcd.for C 21 H 17 N 3 O 6 SBr[M-H] - 506.0021,found 506.0026. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.90~2.98(m,4H,SO 2 N(CH 2 ) 2 ),3.53(s,4H,CON(CH 2 ) 2 ),4.79(s,2H,COCH 2 O),6.82~7.93(m,7H,ArH),11.47(s,1H,NH). 13 C NMR(DMSO-d 6 ,75MHz)δ:43.36,43.36,45.60,45.66,65.77,112.16,112.79,116.84,116.84,118.07,123.35,128.72,131.80,131.80,137.04,153.87,157.15,159.28,165.61,182.79。
Example 7
On the basis of example 1, R 1 Replacing the 4-chlorophenyl group with 2-naphthyl, leaving the other reaction conditions unchanged, the compound {5- ((4- (2- (2-naphthoxy) acetyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-A7) }
Yellow solid, yield 48.5%, m.p.299.4-301.5 ℃. HRMS (ESI-MS, m/z)):Calcd.for C 24 H 20 N 3 O 6 S[M-H] - 478.1073,found 478.1082. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.90~3.01(m,4H,SO 2 N(CH 2 ) 2 ),3.60(s,4H,CON(CH 2 ) 2 ),4.90(s,2H,COCH 2 O),7.11-7.93(m,10H,ArH),11.50(s,1H,NH). 13 C NMR(DMSO-d 6 ,75MHz)δ:43.54,43.54,45.66,45.82,65.82,107.25,112.78,118.05,118.29,123.36,123.62,126.31,126.46,127.38,128.52,128.65,129.14,133.87,137.05,153.85,155.63,159.29,165.79,182.77。
Example 8
On the basis of example 1, R 1 Replacement of 4-chloro with 3-methyl, with otherwise unchanged reaction conditions, gives the compound {5- ((4- (2- (3-methylphenoxy) acetyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-A8) }
Yellow solid, yield 46.1%, m.p.273.0-275.1 ℃. HRMS (ESI-MS, m/z): calcd.for C 21 H 20 N 3 O 6 S[M-H] - 442.1073,found 442.1081. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.22(s,3H,PhCH 3 ),2.90~2.96(m,4H,SO 2 N(CH 2 ) 2 ),3.55(s,4H,CON(CH 2 ) 2 ),4.72(s,2H,COCH 2 O),6.63-7.92(m,7H,ArH),11.50(s,1H,NH). 13 C NMR(DMSO-d 6 ,75MHz)δ:21.01,43.55,43.55,45.72,45.88,65.74,111.53,112.83,115.13,118.15,121.60,123.40,128.62,129.02,137.09,138.79,153.90,157.82,159.37,166.05,182.82。
Example 9
On the basis of example 1, R 1 Replacement of 4-chloro with 4-tert-amyl, leaving the other reaction conditions unchanged, gives the compound {5- ((4- (2- (4-tert-pentylphenoxy) acetyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-A9) }
Yellow solid, yield 53.4%, m.p.135.7-137.6 ℃. HRMS (ESI-MS, m/z): calcd.for C 25 H 28 N 3 O 6 S[M-H] - 498.1699,found 498.1675. 1 H NMR(DMSO-d 6 ,300MHz)δ:0.56(t,3H,J=7.5Hz,C(CH 3 ) 2 CH 2 CH 3 ),1.18(s,6H,C(CH 3 ) 2 CH 2 CH 3 ),1.51(q,2H,J=7.5Hz,C(CH 3 ) 2 CH 2 CH 3 ),2.90~2.99(m,4H,SO 2 N(CH 2 ) 2 ),3.55(s,4H,CON(CH 2 ) 2 ),4.72(s,2H,COCH 2 O),6.76~7.94(m,7H,ArH),11.50(s,1H,NH). 13 CNMR(DMSO-d 6 ,75MHz)δ:8.89,28.28,28.28,36.08,36.78,43.53,43.53,45.76,45.76,65.84,112.77,113.96,113.96,118.09,123.35,126.43,126.43,128.77,137.04,141.26,153.85,155.43,159.28,166.08,182.77。
Example 10
On the basis of example 1, R 1 Replacement of 4-chloro with 2-chloro, with otherwise unchanged reaction conditions, gives the compound {5- ((4- (2- (2-chlorophenoxy) acetyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-A10) }
Yellow solid, yield 64.7%, m.p.299.9-302.7 ℃. HRMS (ESI-MS, m/z): calcd.for C 20 H 17 N 3 O 6 SCl[M-H] - 462.0527,found 462.0537. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.91~2.99(m,4H,SO 2 N(CH 2 ) 2 ),3.55(s,4H,CON(CH 2 ) 2 ),4.89(s,2H,COCH 2 O),6.88-7.92(m,7H,ArH),11.50(s,1H,NH). 13 C NMR(DMSO-d 6 ,75MHz)δ:43.52,43.52,45.67,45.81,66.30,112.80,113.85,118.08,121.01,121.62,123.37,127.90,128.61,129.79,137.06,153.15,153.88,159.30,165.37,182.78。
Example 11
On the basis of example 1, R 1 Replacing the 4-chlorophenyl group with 1-naphthyl, leaving the other reaction conditions unchanged, the compound {5- ((4- (2- (1-naphthoxy) acetyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-A11) }
Yellow solid, yield 66.0%, m.p.296.0-298.4 ℃. HRMS (ESI-MS, m/z): calcd.for C 24 H 20 N 3 O 6 S[M-H] - 478.1073,found 478.1081. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.96(s,4H,SO 2 N(CH 2 ) 2 ),3.61(s,4H,CON(CH 2 ) 2 ),4.97(s,2H,COCH 2 O),6.85-8.14(m,10H,ArH),11.50(s,1H,NH). 13 C NMR(DMSO-d 6 ,75MHz)δ:43.56,43.56,45.79,45.79,66.16,105.51,112.75,118.04,120.22,121.37,123.30,124.69,125.22,125.80,126.32,127.29,128.59,133.88,136.95,153.14,153.81,159.30,165.78,182.76。
Example 12
On the basis of example 1, R 1 Replacement of 4-chloro with 4-tert-butyl, with otherwise unchanged reaction conditions, gives the compound {5- ((4- (2- (4-tert-butylphenoxy) acetyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-A12) }
Yellow solid, yield 72.1%, m.p.229.4-230.8 ℃. HRMS (ESI-MS, m/z): calcd.for C 24 H 26 N 3 O 6 S[M-H] - 484.1542,found 484.1556. 1 H NMR(DMSO-d 6 ,300MHz)δ:1.223(s,9H,C(CH 3 ) 3 ),2.91~2.99(m,4H,SO 2 N(CH 2 ) 2 ),3.55(s,4H,CON(CH 2 ) 2 ),4.72(s,2H,COCH 2 O),6.76~7.94(m,7H,ArH),11.50(s,1H,NH). 13 C NMR(DMSO-d 6 ,75MHz)δ:31.20,31.20,31.20,33.63,43.49,43.49,45.61,45.80,65.80,112.76,113.97,113.97,118.10,123.35,125.79,125.79,128.69,137.04,143.03,153.84,155.50,159.29,166.07,182.76。
Example 13
A process for the preparation of compounds of the general formula (III) { (E) -5- ((4- (3- (benzo [ d ] [1,3] dioxol-5-yl) acryloyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-B1) } by the synthetic route:
the method specifically comprises the following steps:
(1) Piperonal (41.6 mmol), malonic acid 6.4g (62.4 mmol) and piperidine 1mL (10.4 mmol) are placed in a 250mL eggplant-shaped bottle, pyridine 40mL is added for dissolution and stirring, stirring is carried out for 5 hours at the temperature of 120 ℃, TLC monitors the reaction progress, after the reaction is finished, the solvent is distilled off under reduced pressure, 26mL/52g of concentrated hydrochloric acid/ice mixture (26 mL of concentrated hydrochloric acid is mixed with 52g of ice) is added, a large amount of white solid is stirred vigorously, a large amount of white solid is separated out, suction filtration is carried out, and the crude product is recrystallized by absolute ethyl alcohol, so that white powdery crystal (E) -3- (benzo [ d ] [1,3] dioxol-5-yl) acrylic acid is obtained, and the yield is 87.8%;
(2) 9.3g (49.9 mmol) of N-Boc-piperazine and triethylamine (7 mL,49.9 mmol) were placed in a 250mL eggplant-shaped bottle, 50mL of methylene chloride was added thereto, and the mixture was dissolved in an ice bath with stirring. In addition, 30mL of methylene chloride was dissolved in 3, 3-dichloro-2-oxoindoline-5-sulfonyl chloride or 2, 3-dioxoindoline-5-sulfonyl chloride (41.6 mmol), and the mixture was slowly dropped into a eggplant-shaped bottle. After the dripping is finished, the temperature is raised to room temperature, the stirring is carried out for 5 hours, TLC monitors the reaction progress, after the reaction is finished, decompression concentration is carried out, light yellow oily matter is obtained, and the 4- (3, 3-dichloro-2-oxo-indol-5-ylsulfonyl) piperazine-1-carboxylic acid tert-butyl ester is obtained through column chromatography, white powder is obtained, and the yield is 91.8%;
(3) Tert-butyl 4- (3, 3-dichloro-2-oxoindol-5-ylsulfonyl) piperazine-1-carboxylate (27.15 g,33.3 mmol) is placed in a 250mL eggplant-shaped bottle, 25mL of trifluoroacetic acid and 100mL of dichloromethane are mixed into a trifluoroacetic acid solution with the mass fraction of 25%, the trifluoroacetic acid solution is directly added into the eggplant-shaped bottle, the stirring is carried out at room temperature for 2 hours, TLC monitors the reaction progress, and after the reaction is finished, the solvent is removed by evaporation under reduced pressure, so that white solid 3, 3-dichloro-5- (piperazine-1-ylsulfonyl) indol-2-one trifluoroacetate is obtained, and the crude product is directly used for the next reaction without purification;
(4) 10g of 3, 3-dichloro-5- (piperazine-1-ylsulfonyl) indol-2-one trifluoroacetate is placed in a 250mL eggplant-shaped bottle, 100mL of acetic acid aqueous solution (acetic acid/water=50 mL/50 mL) is added, the temperature is raised to 100 ℃ and stirred for 24 hours, TLC monitors the reaction progress, and after the reaction is finished, the solvent is distilled off under reduced pressure, so that yellow solid 5- (piperazine-1-ylsulfonyl) indoline-2, 3-dione trifluoroacetate is obtained, and the crude product is directly used for the next reaction without purification;
(5) (E) -3- (benzo [ d ] [1,3] dioxol-5-yl) acrylic acid (0.58 g,3 mmol), anhydrous dichloromethane (25 mL) were placed in a 250mL eggplant-shaped bottle, stirred, and N, N-dimethylformamide 2 drops were added dropwise; oxalyl chloride (0.6 mL,6 mmol) and dried dichloromethane (2 mL) are mixed, slowly dripped into an eggplant-shaped bottle, stirred at room temperature for 2 hours after the dripping is finished, TLC monitors the reaction progress, and after the reaction is finished, dichloromethane is distilled off under low temperature and reduced pressure to obtain yellow oily liquid (E) -3- (benzo [ d ] [1,3] dioxol-5-yl) acryloyl chloride, and the crude product is directly used for the next reaction without purification;
(6) 5- (piperazine-1-ylsulfonyl) indoline-2, 3-dione (1.67 g,3.6 mmol), dipea (1.3 mL,7.5 mmol) and tetrahydrofuran (20 mL) were placed in a 100mL eggplant-shaped bottle, and stirred and dissolved under ice water bath conditions; dissolving (E) -3- (benzo [ d) with 10mL of tetrahydrofuran][1,3]Dioxol-5-yl) acryloyl chloride, slowly dripping into eggplant-shaped bottle; after the dripping is finished, the temperature is raised to the room temperature, and the mixture is stirred overnight; TLC showed no purity, and gradient elution with ethyl acetate and petroleum ether as eluent gave 0.54g of yellow solid as a yield of 38.3%, m.p.202.3-204.7 ℃. HRMS (ESI-MS, m/z): calcd.for C 22 H 18 N 3 O 7 S[M-H] - 468.0865,found 468.0873. 1 H NMR(CDCl 3 ,300MHz)δ:3.71(s,8H,SO 2 N(CH 2 ) 4 NCO),6.00(s,2H,OCH 2 O),6.63(d,1H,J=15.3Hz,COCH=),6.79~8.07(m,6H,ArH),7.59(d,1H,J=15.3Hz,PhCH=),11.05(s,1H,NH). 13 C NMR(CDCl 3 ,75MHz)δ:42.15,44.81,45.24,101.46,106.36,108.52,114.11,120.34,123.97,125.54,126.82,129.33,132.24,141.28,143.57,148.28,149.26,165.39,165.78,184.65。
Example 14
On the basis of example 13, R 1 Replacing 5-piperonyl with 4-chlorophenyl, the other reaction conditions are unchanged, resulting in the compound { (E) -5- ((4- (3- (4-chlorophenyl) acryloyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-B2)
Yellow solid, yield 29.0%, m.p.322.7-324.6 ℃. HRMS (ESI-MS, m/z): calcd.for C 21 H 17 N 3 O 5 SCl[M-H] - 458.0577,found 458.0588. 1 H NMR(CDCl 3 ,300MHz)δ:2.94(s,4H,SO 2 N(CH 2 ) 2 ),3.67(bs,4H,CON(CH 2 ) 2 ),7.09~7.72(m,7H,ArH),7.19(d,1H,J=15.3Hz,COCH=),7.40(d,1H,J=15.3Hz,PhCH=),11.45(s,1H,NH). 13 C NMR(CDCl 3 ,75MHz)δ:44.72,46.34,46.84,113.25,118.71,119.08,123.83,128.98,129.15,129.15,130.15,130.15,134.37,134.51,137.46,141.00,154.36,159.84,164.69,183.26。
Example 15
On the basis of example 13, R 1 Replacing 5-piperonyl with 4-methylphenyl, the other reaction conditions being unchanged, the compound { (E) -5- ((4- (3- (4-methylphenyl) acryloyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-B3) } was obtained
Yellow solid, yield 45.5%, m.p.308.8-310.5 ℃. HRMS (ESI-MS, m/z): calcd.for C 22 H 20 N 3 O 5 S[M-H] - 438.1124,found 438.1130. 1 H NMR(CDCl 3 ,300MHz)δ:2.31(s,3H,PhCH 3 ),2.93(s,4H,SO 2 N(CH 2 ) 2 ),3.66(bs,4H,CON(CH 2 ) 2 ),7.08~7.92(m,7H,ArH),7.15(d,1H,J=15.3Hz,COCH=),7.37(d,1H,J=15.3Hz,PhCH=),11.46(s,1H,NH). 13 C NMR(CDCl 3 ,75MHz)δ:20.85,44.13,44.33,45.89,46.34,112.75,116.49,118.24,123.29,127.93,127.93,128.33,129.24,129.24,132.14,136.94,139.36,141.97,154.03,159.44,164.48,182.85。
Example 16
On the basis of example 13, R 1 Replacing 5-piperonyl with 4-methoxyphenyl, the other reaction conditions are unchanged, yielding the compound { (E) -5- ((4- (3- (4-methoxyphenyl) propenoyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-B4) }
Yellow solid, yield 32.2%, m.p.312.1-314.8 ℃. HRMS (ESI-MS, m/z): calcd.for C 22 H 20 N 3 O 6 S[M-H] - 454.1073,found 454.1079. 1 H NMR(CDCl 3 ,300MHz)δ:2.94(s,4H,SO 2 N(CH 2 ) 2 ),3.78(s,3H,PhOCH 3 ),3.78(bs,4H,CON(CH 2 ) 2 ),6.93~7.93(m,7H,ArH),7.01(d,1H,J=15.3Hz,COCH=),7.38(d,1H,J=15.3Hz,PhCH=),11.45(s,1H,NH). 13 C NMR(CDCl 3 ,75MHz)δ:44.19,46.28,55.18,112.72,114.09,114.93,118.22,123.30,127.50,128.40,129.61,136.94,141.81,153.84,159.34,160.43,164.63,182.73。
Example 17
On the basis of example 13, R 1 Replacing 5-piperonyl with 2-methoxyphenyl, the other reaction conditions are unchanged, yielding the compound { (E) -5- ((4- (3- (2-methoxyphenyl) propenoyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-B5) }
Yellow solid, yield 30.8%, m.p.267.8-269.9 ℃. HRMS (ESI-MS, m/z): calcd.for C 22 H 20 N 3 O 6 S[M-H] - 454.1073,found 454.1081. 1 H NMR(CDCl 3 ,300MHz)δ:2.93(s,4H,SO 2 N(CH 2 ) 2 ),3.66(bs,4H,CON(CH 2 ) 2 ),3.82(s,3H,PhOCH 3 ),6.93(d,1H,J=15.3Hz,COCH=),7.03~7.93(m,7H,ArH),7.33(d,1H,J=15.3Hz,PhCH=),11.47(s,1H,NH). 13 C NMR(CDCl 3 ,75MHz)δ:44.23,45.84,46.42,55.53,111.56,112.75,117.40,118.27,120.45,123.21,123.34,127.79,128.37,131.13,136.56,136.98,153.87,157.36,159.39,164.67,182.77。
Example 18
On the basis of example 13, R 1 Replacing 5-piperonyl with 4-fluorophenyl, other reaction conditions are unchanged, resulting in the compound { (E) -5- ((4- (3- (4-fluorophenyl) acryloyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-B6) }
Yellow solid, yield 64.8%, m.p.289.8-299.1 ℃. HRMS (ESI-MS, m/z): calcd.for C 21 H 17 N 3 O 5 FS[M-H] - 442.0873,found 442.0883. 1 H NMR(CDCl 3 ,300MHz)δ:2.93(s,4H,SO 2 N(CH 2 ) 2 ),3.66(bs,4H,CON(CH 2 ) 2 ),7.03~7.93(m,7H,ArH),7.13(d,1H,J=15.6Hz,COCH=),7.41(d,1H,J=15.6Hz,PhCH=),11.47(s,1H,NH). 13 C NMR(CDCl 3 ,75MHz)δ:44.23,45.84,46.42,55.53,111.56,112.75,117.40,118.27,120.45,123.21,123.34,127.79,128.37,131.13,136.56,136.98,153.87,157.36,159.39,164.67,182.77。
Example 19
On the basis of example 13, R 1 Replacement of 5-piperonyl with 2-chlorophenyl with other reaction conditions unchanged gave the compound { (E) -5- ((4- (3- (2-chlorophenyl) acryloyl)Yl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-B7) }
Yellow solid, yield 51.4%, m.p.297.2-299.2 ℃. HRMS (ESI-MS, m/z): calcd.for C 21 H 17 N 3 O 5 SCl[M-H] - 458.0577,found 458.0588. 1 H NMR(CDCl 3 ,300MHz)δ:2.95(s,4H,SO 2 N(CH 2 ) 2 ),3.68(bs,4H,CON(CH 2 ) 2 ),7.10~7.98(m,7H,ArH),7.23(d,1H,J=15.3Hz,COCH=),7.73(d,1H,J=15.3Hz,PhCH=),11.47(s,1H,NH). 13 C NMR(CDCl 3 ,75MHz)δ:44.24,45.77,46.32,112.74,118.22,120.81,123.31,127.40,128.11,128.47,129.73,131.01,132.56,133.29,136.82,136.97,153.85,159.34,163.89,182.75。
Example 20
On the basis of example 13, R 1 Replacing 5-piperonyl with 3-chlorophenyl, the other reaction conditions are unchanged, resulting in the compound { (E) -5- ((4- (3- (3-chlorophenyl) acryloyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-B8) }
Yellow solid, yield 58.1%, m.p.302.7-304.6 ℃. HRMS (ESI-MS, m/z): calcd.for C 21 H 17 N 3 O 5 SCl[M-H] - 458.0577,found 458.0568. 1 H NMR(CDCl 3 ,300MHz)δ:2.94(s,4H,SO 2 N(CH 2 ) 2 ),3.67(bs,4H,CON(CH 2 ) 2 ),7.10~7.94(m,7H,ArH),7.26(d,1H,J=15.3Hz,COCH=),7.39(d,1H,J=15.3Hz,PhCH=),11.47(s,1H,NH). 13 C NMR(CDCl 3 ,75MHz)δ:44.21,45.77,46.33,112.73,118.19,119.48,123.29,127.00,128.49,129.11,130.40,133.55,136.93,137.15,140.24,153.84,159.30,164.06,182.73。
Example 21
On the basis of example 13, R 1 Replacing 5-piperonyl with 2, 4-dichlorophenyl, other reaction conditions remain, resulting in the compound { (E) -5- ((4- (3- (2, 4-dichlorophenyl) acryloyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-B9) }
Yellow solid, yield 40.5%, m.p.340.5-342.9 ℃. HRMS (ESI-MS, m/z): calcd.for C 21 H 16 N 3 O 5 SCl 2 [M-H] - 492.0188,found 492.0196. 1 H NMR(CDCl 3 ,300MHz)δ:2.95(s,4H,SO 2 N(CH 2 ) 2 ),3.67(bs,4H,CON(CH 2 ) 2 ),7.09~8.02(m,6H,ArH),7.27(d,1H,J=15.3Hz,COCH=),7.73(d,1H,J=15.3Hz,PhCH=),11.47(s,1H,NH). 13 C NMR(CDCl 3 ,75MHz)δ:44.25,45.70,46.28,112.77,118.17,121.47,123.32,127.63,128.54,129.16,129.34,131.64,134.06,134.59,135.61,136.97,153.88,159.30,163.72,182.77。
Example 22
On the basis of example 13, R 1 Replacing 5-piperonyl with 3-bromophenyl, the other reaction conditions being unchanged, the compound { (E) -5- ((4- (3- (3-bromophenyl) acryloyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-B10) } was obtained
Yellow solid, yield 46.5%, m.p.299.9-302.8 ℃. HRMS (ESI-MS, m/z): calcd.for C 21 H 17 N 3 O 5 SBr[M-H] - 502.0072,found 502.0065. 1 H NMR(CDCl 3 ,300MHz)δ:2.94(s,4H,SO 2 N(CH 2 ) 2 ),3.66(bs,4H,CON(CH 2 ) 2 ),7.09~8.00(m,7H,ArH),7.25(d,1H,J=15.3Hz,COCH=),7.37(d,1H,J=15.3Hz,PhCH=),11.46(s,1H,NH). 13 C NMR(CDCl 3 ,75MHz)δ:44.21,45.83,46.40,112.76,118.26,119.45,122.19,123.23,127.49,128.40,129.87,130.72,132.08,136.97,137.44,140.26,153.87,159.37,164.07,182.76。
Example 23
On the basis of example 13, R 1 Replacing 5-piperonyl with 2-furyl, the other reaction conditions being unchanged, to give the compound { (E) -5- ((4- (3- (furan-2-yl) acryloyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-B11) }
Yellow solid, yield 48.1%, m.p.278.4-279.6 ℃. HRMS (ESI-MS, m/z): calcd.for C 19 H 16 N 3 O 6 S[M-H] - 414.0760,found 414.0768. 1 H NMR(CDCl 3 ,300MHz)δ:2.93(s,4H,SO 2 N(CH 2 ) 2 ),3.68(bs,4H,CON(CH 2 ) 2 ),6.57~7.92(m,6H,ArH&funan),6.81(d,1H,J=15.0Hz,COCH=),7.25(d,1H,J=15.0Hz,PhCH=),11.45(s,1H,NH). 13 C NMR(CDCl 3 ,75MHz)δ:44.23,46.03,112.40,112.73,114.06,114.47,118.19,123.30,128.49,129.14,136.93,144.83,150.97,153.83,159.33,164.01,182.74。
Example 24
On the basis of example 13, R 1 Replacing 5-piperonyl with 3, 4-dimethoxyphenyl, other reaction conditions are unchanged, resulting in the compound { (E) -5- ((4- (3, 4-dimethoxyphenyl) acryloyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-B12) }
Yellow solid, yield 57.6%, m.p.285.2-286.8 ℃. HRMS (ESI-MS, m/z): calcd.for C 23 H 22 N 3 O 7 S[M-H] - 484.1178,found 484.1186. 1 H NMR(CDCl 3 ,300MHz)δ:2.94(s,4H,SO 2 N(CH 2 ) 2 ),3.70(bs,4H,CON(CH 2 ) 2 ),3.78(bs,6H,Ph(OCH 3 ) 2 ),6.93~7.93(m,7H,ArH),7.02(d,1H,J=15.0Hz,COCH=),7.37(d,1H,J=15.0Hz,PhCH=),11.46(s,1H,NH). 13 C NMR(CDCl 3 ,75MHz)δ:44.14,45.97,46.24,55.48,55.65,110.39,111.47,112.74,114.90,118.24,122.38,123.34,127.72,128.39,136.97,142.39,148.86,150.35,153.87,159.36,164.68,182.76。
Example 25
A preparation method of a compound {5- ((4- (2- (2-methylphenoxy) ethyl) piperazine-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-C1) } shown in the general formula (IV) comprises the following synthetic route:
the method specifically comprises the following steps:
(1) O-methylphenol (40.3 mmol), 11.3g (60.4 mmol) of 1, 2-dibromoethane and 25mL of water are placed in a 250mL eggplant-shaped bottle, stirred and heated to 95 ℃, 7.2mL of sodium hydroxide solution with the mass fraction of 25% is dropwise added, the mixture is continuously heated to 100 ℃ after the dropwise addition, the mixture is stirred for 12 hours, TLC monitors the reaction progress, after the reaction is completed, the mixture is cooled to room temperature, and 30mL of dichloromethane is used for extraction for 3 times; taking a dichloromethane layer, washing twice with 15mL of sodium hydroxide solution with the mass fraction of 5%, washing once with 15mL of saturated sodium chloride solution, drying for 5 hours with anhydrous magnesium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain colorless liquid which is 1- (2-bromooxy) -2-methylbenzene, wherein the crude product is directly used for the next reaction without purification;
(2) 1- (2-Bromoxy) -2-methylbenzene (25.3 mmol), methanol 50mL and piperazine 8.7g (101.1 mmol) were placed in a 100mL eggplant-shaped bottle, the temperature was raised to 70℃and stirred for 3 hours, TLC monitored the progress of the reaction, and after the completion of the reaction, the solvent was distilled off under reduced pressure. Adding 60mL of dichloromethane and 30mL of saturated sodium carbonate solution for dissolution and liquid separation; the dichloromethane layer is washed twice with 30mL of saturated sodium bicarbonate solution and once with 30mL of water, the organic phase is extracted with 15mL of 10% hydrochloric acid with mass fraction, the pH of the water layer is less than 3, and the water layer is reserved; adjusting pH to be more than 10 with 10mL of sodium hydroxide solution with mass fraction of 20%, precipitating solid, extracting with 30mL of dichloromethane for 3 times, mixing organic phases, and drying over night with anhydrous sodium sulfate; the next day, filtering, concentrating under reduced pressure to obtain colorless viscous liquid, namely 1- (2- (2-methylphenoxy) ethyl) piperazine, wherein the crude product is directly used for the next reaction without purification;
(3) 1- (2- (2-methylphenoxy) ethyl) piperazine (1.94 g,8.8 mmol) was placed in a 100mL eggplant-shaped bottle, ice-water bath, 30mL of tetrahydrofuran was added and stirred for dissolution, dipea (3.4 mL,11 mmol) was added and stirring continued for 5min; dissolving 3, 3-dichloro-2-oxoindole-5-sulfonyl chloride (2.2 g,7.3 mmol) in 10mL of tetrahydrofuran, slowly dripping the 3, 3-dichloro-2-oxoindole-5-sulfonyl chloride into an eggplant-shaped bottle, heating to room temperature after dripping, stirring overnight, monitoring the reaction progress by TLC, and evaporating the solvent under reduced pressure after the reaction is finished to obtain 3, 3-dichloro-5- (4- (2- (2-methylphenoxy) ethyl) piperazin-1-yl) sulfonyl) indol-2-one which is directly used for the next reaction without purification;
(4) Placing the 3, 3-dichloro-5- (4- (2- (2-methylphenoxy) ethyl) piperazin-1-yl) sulfonyl) indol-2-one in a 100mL eggplant-shaped bottle, adding 40mL (V water: V acetic acid=1:1) of a mixed solution of water and acetic acid, heating to 96 ℃ and stirring for 30 hours, TLC monitoring the reaction progress, cooling to room temperature after the reaction is finished, dropwise adding 10% sodium hydroxide solution to pH=7, and dropwise adding saturated sodium bicarbonate solution until no bubbles are generated; extracting with ethyl acetate twice (40 mL×2), mixing organic phases, evaporating solvent under reduced pressure to obtain brown viscous liquid, performing TLC to show impurity, gradient eluting with mixed solution of ethyl acetate and petroleum ether as eluent, and performing column chromatography to obtain yellow solid 1.62g with yield of 42.9%, m.p.208.5-210.4deg.C. HRMS (ESI-MS, m/z): calcd.for C 21 H 22 N 3 O 5 S[M-H] - 428.1280,found 428.1273. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.10(s,3H,PhCH 3 ),2.60(bs,4H,SO 2 N(CH 2 ) 2 ),2.71(t,2H,J=5.4Hz,NCH 2 -),2.91(bs,4H,CN(CH 2 ) 2 ),3.80(t,2H,J=5.4Hz,OCH 2 -),6.78~7.92(m,7H,ArH),11.46(s,1H,NH). 13 C NMR(DMSO-d 6 ,75MHz)δ:15.91,45.90,51.85,55.98,65.87,111.21,112.66,118.12,120.14,123.31,125.61,126.81,128.60,130.27,136.98,153.75,156.39,159.37,182.82。
Example 26
On the basis of example 25, R in o-methylphenol 1 2-methyl is replaced by 3-methyl, other reaction conditions are unchanged, and the compound {5- ((4- (2- (3-methylphenoxy) ethyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-C2) } is obtained
Yellow solid, yield 58.2%, m.p.208.1-210.0 ℃. HRMS (ESI-MS, m/z): calcd.for C 21 H 22 N 3 O 5 S[M-H] - 428.1280,found 428.1272. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.24(s,3H,PhCH 3 ),2.56(bs,4H,SO 2 N(CH 2 ) 2 ),2.66(t,2H,J=5.4Hz,NCH 2 -),2.90(bs,4H,CN(CH 2 ) 2 ),3.95(t,2H,J=5.4Hz,OCH 2 -),6.65~7.92(m,7H,ArH),11.46(s,1H,NH). 13 C NMR(DMSO-d 6 ,75MHz)δ:20.97,45.87,51.74,55.89,65.19,111.34,112.64,115.04,118.12,121.19,123.30,128.49,129.06,136.98,138.81,153.76,158.29,159.36,182.80。
Example 27
On the basis of example 25, R in o-methylphenol 1 2-methyl was replaced with 4-chloro, and the other reaction conditions were unchanged, to give the compound {5- ((4- (2- (4-chlorophenoxy) ethyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-C3) }
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Yellow solid, yield 47.5%, m.p.198.9-200.6 ℃. HRMS (ESI-MS, m/z): calcd.for C 20 H 19 N 3 O 5 SCl[M-H] - 448.0734,found 448.0742. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.56(bs,4H,SO 2 N(CH 2 ) 2 ),2.66(t,2H,J=5.4Hz,NCH 2 -),2.90(bs,4H,CN(CH 2 ) 2 ),3.98(t,2H,J=5.4Hz,OCH 2 -),6.89~7.92(m,7H,ArH),11.45(s,1H,NH). 13 CNMR(DMSO-d 6 ,75MHz)δ:45.82,51.70,55.73,65.73,112.64,116.15,118.08,123.29,124.14,128.55,129.05,136.96,153.75,157.14,159.34,182.79。
Example 28
On the basis of example 25, R in o-methylphenol 1 2-methyl is replaced by 4-methoxy, other reaction conditions are unchanged, and the compound {5- ((4- (2- (4-methoxyphenoxy) ethyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-C4) } is obtained
Yellow solid, yield 48.0%, m.p.202.1-203.6 ℃. HRMS (ESI-MS, m/z): calcd.for C 21 H 22 N 3 O 6 S[M-H] - 444.1229,found 444.1236. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.56(bs,4H,SO 2 N(CH 2 ) 2 ),2.64(t,2H,J=5.4Hz,NCH 2 -),2.90(bs,4H,CN(CH 2 ) 2 ),3.67(s,3H,PhOCH 3 ),3.91(t,2H,J=5.4Hz,OCH 2 -),6.81~7.92(m,7H,ArH),11.45(s,1H,NH). 13 C NMR(DMSO-d 6 ,75MHz)δ:45.85,51.75,55.26,55.95,65.89,112.63,114.48,115.31,118.11,123.29,128.49,136.97,152.30,153.29,153.75,159.36,182.79。
Example 29
On the basis of example 25, R in o-methylphenol 1 2-methyl is replaced by 4-methyl, other reaction conditions are unchanged, and the compound {5- ((4- (2- (4-methylphenoxy) ethyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-C5) } is obtained
Yellow solid, yield 61.4%, m.p.212.6-213.6 ℃. HRMS (ESI-MS, m/z): calcd.for C 21 H 22 N 3 O 5 S[M-H] - 428.1280,found 428.1276. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.20(s,3H,PhCH 3 ),2.56(bs,4H,SO 2 N(CH 2 ) 2 ),2.65(t,2H,J=5.4Hz,NCH 2 -),2.90(bs,4H,CN(CH 2 ) 2 ),3.93(t,2H,J=5.4Hz,OCH 2 -),6.75~7.92(m,7H,ArH),11.45(s,1H,NH). 13 C NMR(DMSO-d 6 ,75MHz)δ:19.95,45.85,51.76,55.90,65.35,112.65,114.23,118.12,123.31,128.53,129.09,129.67,136.98,153.76,156.17,159.36,182.81。
Example 30
On the basis of example 25, R in o-methylphenol 1 2-methyl was replaced with 4-bromo, and the other reaction conditions were unchanged, to give the compound {5- ((4- (2- (4-bromophenoxy) ethyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-C6) }
Yellow solid, yield 50.6%, m.p.207.5-208.7 ℃. HRMS (ESI-MS, m/z): calcd.for C 20 H 19 N 3 O 5 SBr[M-H] - 492.0229,found 492.0236. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.56(bs,4H,SO 2 N(CH 2 ) 2 ),2.67(t,2H,J=5.4Hz,NCH 2 -),2.90(bs,4H,CN(CH 2 ) 2 ),3.98(t,2H,J=5.4Hz,OCH 2 -),6.85~7.92(m,7H,ArH),11.47(s,1H,NH). 13 CNMR(DMSO-d 6 ,75MHz)δ:45.82,51.70,55.71,65.66,111.83,112.65,116.70,118.09,123.30,128.52,131.96,136.97,153.75,157.59,159.34,182.80。
Example 31
On the basis of example 25, R in o-methylphenol 1 2-methyl was replaced with 2-chloro, and the other reaction conditions were unchanged, to give the compound {5- ((4- (2- (2-chlorophenoxy) ethyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-C7) }
Yellow solid, yield 47.7%, m.p.222.2-223.9 ℃. HRMS (ESI-MS, m/z): calcd.for C 20 H 19 N 3 O 5 SCl[M-H] - 448.0734,found 448.0742. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.56(bs,4H,SO 2 N(CH 2 ) 2 ),2.74(t,2H,J=5.4Hz,NCH 2 -),2.91(bs,4H,CN(CH 2 ) 2 ),4.08(t,2H,J=5.4Hz,OCH 2 -),6.90~7.93(m,7H,ArH),11.47(s,1H,NH). 13 CNMR(DMSO-d 6 ,75MHz)δ:45.84,51.80,55.64,66.92,112.64,113.83,118.06,121.29,121.41,123.31,128.13,128.57,129.74,136.97,153.69,153.74,159.33,182.80。
Example 32
On the basis of example 25, R in o-methylphenol 1 2-methyl is replaced by 2-methoxy, other reaction conditions are unchanged, and the compound {5- ((4- (2- (2-methoxyphenoxy) ethyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-C8) } is obtained
Yellow solid, yield 49.8%, m.p.205.6-207.7 ℃. HRMS (ESI-MS, m/z): calcd.for C 21 H 22 N 3 O 6 S[M-H] - 444.1229,found 444.1236. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.58(bs,4H,SO 2 N(CH 2 ) 2 ),2.67(t,2H,J=5.4Hz,NCH 2 -),2.90(bs,4H,CN(CH 2 ) 2 ),3.71(s,3H,PhOCH 3 ),3.96(t,2H,J=5.4Hz,OCH 2 -),6.83~7.92(m,7H,ArH),11.46(s,1H,NH). 13 C NMR(DMSO-d 6 ,75MHz)δ:45.86,51.80,55.46,55.94,66.44,112.29,112.65,113.68,118.12,120.62,121.03,123.32,128.51,136.99,147.90,149.12,153.77,159.37,182.82。
Example 33
On the basis of example 25, o-methylbenzene is reacted withR in phenol 1 2-methyl was replaced with 4-t-amyl, the other reaction conditions were unchanged, resulting in the compound {5- ((4- (2- (4-t-pentylphenoxy) ethyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-C9) }
Yellow solid, yield 73.1%, m.p.219.8-221.6 ℃. HRMS (ESI-MS, m/z): calcd.for C 25 H 30 N 3 O 5 S[M-H] - 484.1906,found 484.1916. 1 H NMR(DMSO-d 6 ,300MHz)δ:0.57(t,3H,J=7.5Hz,C(CH 3 ) 2 CH 2 CH 3 ),1.19(s,6H,C(CH 3 ) 2 CH 2 CH 3 ),1.51(q,2H,J=7.5Hz,C(CH 3 ) 2 CH 2 CH 3 ),2.57(bs,4H,SO 2 N(CH 2 ) 2 ),2.66(t,2H,J=5.4Hz,NCH 2 -),2.90(bs,4H,CN(CH 2 ) 2 ),3.95(t,2H,J=5.4Hz,OCH 2 -),6.78~7.92(m,7H,ArH),11.45(s,1H,NH). 13 C NMR(DMSO-d 6 ,75MHz)δ:8.9,28.32,36.13,36.76,45.85,51.76,55.92,65.26,112.64,113.77,118.09,123.30,126.53,128.51,136.98,140.76,153.75,155.93,159.34,182.79。
Example 34
On the basis of example 25, R in o-methylphenol 1 2-methyl is replaced by 4-tertiary butyl, other reaction conditions are unchanged, and the compound {5- ((4- (2- (4-tertiary butyl phenoxy) ethyl) piperazine-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-C10) } is obtained
Yellow solid, yield 64.6%, m.p.236.2-238.1 ℃. HRMS (ESI-MS, m/z): calcd.for C 24 H 28 N 3 O 5 S[M-H] - 471.1750,found 471.1745. 1 H NMR(DMSO-d 6 ,300MHz)δ:1.23(s,9H,C(CH 3 ) 3 ),2.56(s,4H,SO 2 N(CH 2 ) 2 ),2.66(t,2H,J=5.4Hz,NCH 2 -),2.90(s,4H,CN(CH 2 ) 2 ),3.95(t,2H,J=5.4Hz,OCH 2 -),6.78~7.92(m,7H,ArH),11.46(s,1H,NH. 13 C NMR(DMSO-d 6 ,75MHz)δ:31.25,33.63,45.87,51.77,55.92,65.34,112.67,113.85,118.12,123.32,125.91,128.55,137.00,142.64,153.78,156.04,159.36,182.82。
Example 35
On the basis of example 25, R 1 2-naphthyl is used to replace 2-methylphenyl, other reaction conditions are unchanged, and the compound {5- ((4- (2- (2-naphthoxy) ethyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-C11) }
Yellow solid, yield 61.1%, m.p.260.1-262.5 ℃. HRMS (ESI-MS, m/z): calcd.for C 24 H 22 N 3 O 5 S[M-H] - 464.1280,found 464.1270. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.60(s,4H,SO 2 N(CH 2 ) 2 ),2.75(t,2H,J=5.4Hz,NCH 2 -),2.91(s,4H,CN(CH 2 ) 2 ),4.12(t,2H,J=5.4Hz,OCH 2 -),7.09~7.92(m,10H,ArH),11.46(s,1H,NH. 13 CNMR(DMSO-d 6 ,75MHz)δ:45.86,51.77,55.84,65.44,106.73,112.64,118.08,118.55,123.31,123.43,126.24,126.52,127.36,128.37,128.51,129.13,134.14,136.97,153.75,156.19,159.34,182.80。
Example 36
On the basis of example 25, R 1 Replacing 2-methylphenyl with 1-naphthyl, leaving the other reaction conditions unchanged, to give the compound {5- ((4- (2- (1-naphthoxy) ethyl) piperazin-1-yl) sulfonyl) indoline-2, 3-dione (ZJG-C12) }
A yellow solid was used as the starting material,the yield is 64.0%, m.p.219.4-220.4 ℃. HRMS (ESI-MS, m/z): calcd.for C 24 H 22 N 3 O 5 S[M-H] - 464.1280,found 464.1286. 1 H NMR(DMSO-d 6 ,300MHz)δ:2.66(s,4H,SO 2 N(CH 2 ) 2 ),2.85(t,2H,J=5.4Hz,NCH 2 -),2.91(s,4H,CN(CH 2 ) 2 ),4.18(t,2H,J=5.4Hz,OCH 2 -),6.91~8.11(m,10H,ArH),11.46(s,1H,NH. 13 CNMR(DMSO-d 6 ,75MHz)δ:45.90,51.81,55.93,66.09,105.20,112.64,118.08,119.87,121.42,123.30,124.85,125.16,126.06,126.28,127.32,128.55,133.91,136.97,153.74,153.83,159.34,182.79。
Effect of the compounds prepared in examples 1 to 36 on survival time of acute cerebral ischemia mice.
Preparing a suspension with required concentration by using 0.5% wt of sodium carboxymethyl cellulose before using the target compound and the positive control medicine nimodipine; the test animals are ICR mice, the weight of which is 19-25 g, and the animals are male. The mice were randomly grouped, 10 mice per group; the test drug was administered by gavage at 0.2mL/10g, the blank control group was given equal volume of NS, the positive control group was given equal volume of nimodipine at 80mg/Kg, ether was anesthetized 1 hour after administration, the middle of the neck was cut after fixation, the common carotid artery and the vagus nerve on both sides were separated and ligated, and the survival time of the mice (5 times per minute of breathing was considered as death of the mice) was recorded, and the results are shown in Table 1.
Table 1 shows the effect (min) of the compounds prepared in examples 1 to 36 on the survival time of mice suffering from acute cerebral ischemia
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* P<0.05, ** P<0.01 is compared to the NS group, # P<0.05, ## P<0.01 compared to nimodipine group.
The test results show that the compounds of the invention have anti-cerebral ischemia effects, and the compounds ZJG-A1, ZJG-A2, ZJG-A4, ZJG-A5, ZJG-A8, ZJG-A11, ZJG-A12, ZJG-B1, ZJG-B2, ZJG-B3, ZJG-B4, ZJG-B6, ZJG-B11, ZJG-B12, ZJG-C4, ZJG-C7, ZJG-C8, ZJG-C10 can remarkably prolong the survival time of acute cerebral ischemia mice in each dosage group, and have good neuroprotective activity on the acute cerebral ischemia mice. The compounds ZJG-A6, ZJG-A7, ZJG-A10, ZJG-C2, ZJG-C3, ZJG-C5, ZJG-C11 can significantly prolong the death time of acute cerebral ischemic mice in the high dose group (200 mg/Kg), but have no obvious effect in the medium dose and low dose groups.
The compound can also resist oxidation, improve the survival rate of cells, and has a protective effect.
The pairs of compounds prepared in examples 1 to 36 were H 2 O 2 Effect of induced PC-12 cell viability.
PC-12 cells at 1.0X10 4 The density of each hole is inoculated in a 96-well plate, and after the cells are cultured for 24 hours in an incubator, the cell fusion degree is observed under a microscope, and the cell administration operation can be carried out when the cell fusion degree reaches about 60 percent. Blank control group, H are arranged in the 96-well plate 2 O 2 Group, drug-H 2 O 2 Groups of 5 duplicate wells. Blank control group 100. Mu.L of DMEM medium given only 2% BSA, H 2 O 2 The group was given only 450. Mu. Mol H 2 O 2 100. Mu.L of DMEM containing 2% BSA was incubated, and the drug groups were given different concentration gradients of drug (0.5. Mu. Mol, 2.5. Mu. Mol, 5.0. Mu. Mol), 100. Mu.L of DMEM medium containing 2% BSA, drug/H 2 O 2 The group was first incubated with different concentration gradient drugs (0.5. Mu. Mol, 2.5. Mu. Mol, 5.0. Mu. Mol) in 100. Mu.L of DMEM medium containing 2% BSA for 6H, after which different concentration gradient drugs, 450. Mu. Mol H were added 2 O 2 100. Mu.L of DMEM medium containing 2% BSA was incubated for 24h. Drug group and drug/H 2 O 2 The group is simultaneously given different concentration gradient drugs and placed in an incubator for 6 hours of incubation,at this time H 2 O 2 100. Mu.L of DMEM medium containing 2% BSA was administered to the group; after 6h, the drug group was incubated for 24h, H 2 O 2 The group culture solution is sucked and discarded, and the culture solution containing the corresponding concentration H is given 2 O 2 Is incubated for 24H, drug/H 2 O 2 The group culture solution is sucked and discarded, and medicines with different concentrations and corresponding H are given 2 O 2 The mixed culture solution is incubated for 24 hours. After 24h incubation, the medium was aspirated and 100. Mu.L of MTS with 1.0mg/mL serum-free medium was added to each well, incubation was stopped in an incubator for 1h, and the absorbance of each well was measured at 490nm on an microplate reader. Cell viability (%) was determined according to the following formula:
cell survival (%) = (Z-B)/(G-B) ×100%
Wherein Z, B, G each represents drug-H 2 O 2 Group, blank group, H 2 O 2 Average value of absorbance of group. The results are shown in Table 2.
Table 2 shows the pairs of compounds H obtained in examples 1 to 36 2 O 2 Effect of induced PC-12 cell viability (%).
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* P<0.05 and H 2 O 2 Group comparison.
The test results show that the compounds of the invention have antioxidant activity, and the compounds ZJG-A1, ZJG-A2, ZJG-A7, ZJG-A9, ZJG-B3, ZJG-B4, ZJG-B5, ZJG-B9, ZJG-B11, ZJG-B12, ZJG-C3, ZJG-C4, ZJG-C6, ZJG-C7, ZJG-C8 and ZJG-C10 can obviously improve H in each dosage group 2 O 2 The induced PC-12 cell survival rate is excellentThe positive control Melatonin (MLT) at the same concentration showed good antioxidant activity.
Claims (10)
1. An isatin derivative is characterized by having the following structural general formula:
wherein R is 1 Is H, halogen, hydrocarbyl, alkoxy, aralkoxy, heterocycloalkoxy, aryl, substituted heterocycle, or substituted aryl; r is R 2 Is a bridging group, in particular-O-CH 2 -CO-, -ch=ch-CO-or-O-CH 2 -CH 2 -any one of the following.
2. Isatin derivative according to claim 1, characterized in that: the R is 1 The aryl group in the representative aryl or aralkoxy is benzene, biphenyl or naphthalene, or F, cl, br, I, C 1~10 Alkyl, C 1~10 Alkoxy, nitro or amino substituted benzene, biphenyl or naphthalene.
3. Isatin derivative according to claim 1, characterized in that: the R is 1 Representative hydrocarbyl means a straight or branched alkyl group having 1 to 10 carbon atoms, or a straight or branched alkenyl group having 2 to 10 carbon atoms, or a straight or branched cycloalkyl group having 3 to 10 carbon atoms; the alkyl group in the alkoxy group, aralkoxy group or heterocyclic alkoxy group means a straight chain or branched alkyl group having 1 to 10 carbon atoms.
4. Isatin derivative according to claim 1, characterized in that: the R is 1 Representative of the heterocyclic groups in the substituted heterocyclic ring or heterocyclic alkoxy group means a saturated heterocyclic ring or aromatic heterocyclic ring containing one or more hetero atoms selected from the group consisting of oxygen, nitrogen and sulfur atoms.
5. According to claim 1The isatin derivative is characterized in that: the R is 1 The representative halogen is F, cl, br or I.
6. Isatin derivative according to claim 1, characterized in that: the R is 1 The substituent of the substituted aryl is halogen.
7. The process for preparing isatin derivatives according to claim 1, wherein when R 2 is-O-CH 2 In the case of CO-, the structural general formula of the compound is shown in the formula (II):
the preparation method of the compound with the formula (II) comprises the following steps:
(1) Mixing the substituted aromatic phenol, ethyl chloroacetate, acetonitrile and potassium carbonate, heating to reflux temperature, filtering while the mixture is hot after reaction, and carrying out spin-drying on the filtrate, wherein if the filtrate is oily residual liquid, the distillation is carried out under reduced pressure; if the solid is obtained by concentration, the solid is recrystallized by absolute ethyl alcohol to obtain the corresponding substituted aryloxy ethyl acetate (V);
(2) Mixing substituted aryloxy ethyl acetate with anhydrous piperazine, introducing N 2 Heating to no less than 110deg.C, refluxing, standing, cooling, adding chloroform into the residue for dissolving, and dissolving with saturated NaHCO 3 Washing the solution, washing with water, and concentrating the organic phase to obtain white solid which is substituted aryloxyacetylpiperazine (VI);
(3) Slowly dropwise adding chlorosulfonic acid into isatin in ice water bath, stirring, heating for reaction, monitoring the reaction progress by TLC, and cooling to room temperature after the reaction is completed; slowly dripping the reaction solution into crushed ice, vigorously stirring until solid is separated out, adding ethyl acetate, stirring, dissolving, separating, washing an ethyl acetate layer with water and saturated sodium chloride solution in sequence, and drying anhydrous sodium sulfate overnight after washing; the next day, filtering, decompressing and evaporating the solvent to obtain brown sticky matter, and separating by column chromatography to obtain 3, 3-dichloro-2-oxoindoline-5-sulfonyl chloride (VII) and 2, 3-dioxoindoline-5-sulfonyl chloride (VIII);
(4) Mixing substituted aryloxy acetyl piperazine (VI) and N-ethyldiisopropylamine, adding tetrahydrofuran into the mixture under ice water bath, stirring and dissolving to obtain a reaction solution; dissolving 3, 3-dichloro-2-oxoindoline-5-sulfonyl chloride in tetrahydrofuran, and slowly dripping the solution into the reaction solution; after the dripping is finished, the temperature is raised to the room temperature and stirred overnight; the next day, filtering, evaporating the solvent under reduced pressure to obtain yellow sticky substance, using the mixed solution of ethyl acetate and petroleum ether as eluent, performing gradient elution, and performing column chromatography separation to obtain a compound shown in a general formula (II);
the synthetic route of the method is as follows:
8. the process for preparing isatin derivatives according to claim 1, wherein when R 2 When the compound is-CH=CH-CO-, the structural general formula of the compound is shown as a formula (III):
the preparation method of the compound with the formula (III) comprises the following steps:
(1) Mixing substituted benzaldehyde, malonic acid and piperidine, adding pyridine into the mixture, stirring the mixture for dissolution, heating the mixture to not lower than 120 ℃ for stirring reaction, monitoring the reaction progress by TLC, removing the solvent by evaporation under reduced pressure after the reaction is finished, adding a concentrated hydrochloric acid/ice mixture, stirring the mixture vigorously, precipitating a large amount of white solid, carrying out suction filtration, and recrystallizing the crude product by absolute ethyl alcohol to obtain substituted benzene acrylic acid (IX);
(2) Mixing N-Boc-piperazine and triethylamine, adding dichloromethane into the mixture, and stirring and dissolving the mixture in ice water bath to obtain a mixed solution; dissolving 3, 3-dichloro-2-oxoindoline-5-sulfonyl chloride (VII) or 2, 3-dioxoindoline-5-sulfonyl chloride (VIII) in methylene dichloride, slowly dripping the mixture into the mixed solution, heating to room temperature after dripping, monitoring the reaction progress by TLC, and obtaining 4- (3, 3-dichloro-2-oxoindoline-5-ylsulfonyl) piperazine-1-carboxylic acid tert-butyl ester (X) by column chromatography after the reaction is finished;
(3) Placing 4- (3, 3-dichloro-2-oxoindole-5-ylsulfonyl) piperazine-1-carboxylic acid tert-butyl ester (X) in a reaction bottle, mixing trifluoroacetic acid and dichloromethane to obtain a trifluoroacetic acid solution with the mass fraction of 25%, directly adding the trifluoroacetic acid solution into the reaction bottle, stirring at room temperature, monitoring the reaction progress by TLC, and evaporating the solvent under reduced pressure after the reaction is finished to obtain 3, 3-dichloro-5- (piperazine-1-ylsulfonyl) indol-2-one trifluoroacetate (XI);
(4) Placing 3, 3-dichloro-5- (piperazine-1-ylsulfonyl) indol-2-one trifluoroacetate (XI) into a reaction bottle, adding an aqueous acetic acid solution into the reaction bottle, heating to not lower than 100 ℃ for reaction, monitoring the reaction progress by TLC, and evaporating the solvent under reduced pressure after the reaction is finished to obtain 5- (piperazine-1-ylsulfonyl) indoline-2, 3-dione trifluoroacetate (XII);
(5) Mixing 5- (piperazine-1-ylsulfonyl) indoline-2, 3-diketone trifluoroacetate (XII), N-ethyldiisopropylamine and tetrahydrofuran, stirring and dissolving under ice water bath condition to obtain a reaction solution; putting substituted benzene acrylic acid (IX), anhydrous dichloromethane and DMF into a reaction bottle, dropwise adding oxalyl chloride into the reaction bottle under ice bath condition, heating to room temperature after dropwise adding, stirring for reaction, and concentrating the reaction solution to obtain substituted benzene acrylic acid chloride; dissolving substituted benzene acryloyl chloride with tetrahydrofuran, slowly dripping into the reaction liquid, heating to room temperature after dripping, and stirring overnight; the next day, TLC monitors the reaction progress, after the reaction is finished, the yellow oily liquid is obtained by decompression concentration, the mixed liquid of ethyl acetate and petroleum ether is used as an eluent, gradient elution is carried out, and the compound of the general formula (III) is obtained by column chromatography separation;
the synthetic route of the method is as follows:
9. the process for preparing isatin derivatives according to claim 1, wherein when R 2 In the case of-O-CH 2-CH2-, the structural general formula of the compound is shown in the formula (IV):
the preparation method of the compound with the formula (IV) comprises the following steps:
(1) Mixing substituted phenol, 1, 2-dibromoethane and water, stirring and heating to not lower than 95 ℃, dropwise adding sodium hydroxide aqueous solution into the mixture, continuously heating to 100 ℃ after the dropwise adding is finished, stirring and reacting, monitoring the reaction progress by TLC, cooling to room temperature after the reaction is finished, and extracting with dichloromethane; combining dichloromethane layers, washing sequentially by adopting a sodium hydroxide aqueous solution and a saturated sodium chloride solution, and drying by adopting anhydrous magnesium sulfate after washing; filtering, concentrating the filtrate under reduced pressure to obtain substituted phenoxyethyl bromide (XIII);
(2) Mixing substituted phenoxyethyl bromide, methanol and piperazine, heating to not lower than 70 ℃ for reaction, monitoring the reaction progress by TLC, and evaporating the solvent under reduced pressure after the reaction is finished; adding a mixed solution of dichloromethane and saturated sodium carbonate solution into the mixture for dissolution and liquid separation, sequentially washing a dichloromethane layer with saturated sodium bicarbonate solution and water, washing an organic phase with hydrochloric acid, adjusting the pH of a water layer with sodium hydroxide solution to be more than 10, separating out solids, extracting with dichloromethane, combining the organic phases, and drying with anhydrous sodium sulfate overnight; the next day, filtering, concentrating under reduced pressure to obtain substituted phenoxyethylpiperazine (XIV);
(3) Placing the substituted phenoxyethyl piperazine into a reaction bottle, adding tetrahydrofuran into the reaction bottle under ice water bath, stirring and dissolving, and then adding N-ethyldiisopropylamine into the reaction bottle, and continuously stirring to obtain a reaction solution; dissolving 3, 3-dichloro-2-oxoindoline-5-sulfonyl chloride or 2, 3-dioxoindoline-5-sulfonyl chloride with tetrahydrofuran, slowly dripping the solution into the reaction solution, heating to room temperature after dripping, stirring overnight, monitoring the reaction progress by TLC, and evaporating the solvent under reduced pressure after the reaction is finished to obtain substituted 3, 3-dichloro-5- (4- (2-phenoxyethyl) piperazin-1-ylsulfonyl) indol-2-one (XV);
(4) Placing 3, 3-dichloro-5- (4- (2-phenoxyethyl) piperazine-1-ylsulfonyl) indol-2-one in a reaction bottle, adding an aqueous solution of acetic acid, heating to not lower than 96 ℃, stirring for reaction, monitoring the reaction progress by TLC, cooling to room temperature after the reaction is finished, firstly dropwise adding a sodium hydroxide solution to adjust the pH to be 7, and then dropwise adding a saturated sodium bicarbonate solution until no bubbles are generated; extraction with ethyl acetate, combining the organic phases, washing with saturated sodium bicarbonate solution and drying over night with anhydrous sodium sulfate; the next day, filtering, concentrating the filtrate under reduced pressure to obtain yellow oily liquid, and performing gradient elution by taking a mixed solution of ethyl acetate and petroleum ether as an eluent, and performing column chromatography separation to obtain a compound shown in a general formula (IV);
the synthetic route of the method is as follows:
10. use of an isatin derivative according to claim 1 for the preparation of an anti-cerebral ischemia neuroprotective drug or pharmaceutical component.
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