CN114805201A - Preparation method and application of 2-N-morpholinyl ethoxy group substituted quinoline derivatives - Google Patents
Preparation method and application of 2-N-morpholinyl ethoxy group substituted quinoline derivatives Download PDFInfo
- Publication number
- CN114805201A CN114805201A CN202110079183.0A CN202110079183A CN114805201A CN 114805201 A CN114805201 A CN 114805201A CN 202110079183 A CN202110079183 A CN 202110079183A CN 114805201 A CN114805201 A CN 114805201A
- Authority
- CN
- China
- Prior art keywords
- quinoline
- methoxy
- nitro
- chloroethoxy
- morpholinoethoxy
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title abstract description 28
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 title abstract description 8
- 125000002943 quinolinyl group Chemical class N1=C(C=CC2=CC=CC=C12)* 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 89
- 238000006243 chemical reaction Methods 0.000 claims abstract description 76
- 125000006012 2-chloroethoxy group Chemical group 0.000 claims abstract description 41
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims abstract description 38
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims abstract description 38
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims abstract description 37
- 239000003814 drug Substances 0.000 claims abstract description 21
- 238000010438 heat treatment Methods 0.000 claims abstract description 21
- 150000003248 quinolines Chemical class 0.000 claims abstract description 19
- 102100033639 Acetylcholinesterase Human genes 0.000 claims abstract description 18
- 108010022752 Acetylcholinesterase Proteins 0.000 claims abstract description 18
- 229940022698 acetylcholinesterase Drugs 0.000 claims abstract description 18
- 238000001816 cooling Methods 0.000 claims abstract description 18
- 229910000027 potassium carbonate Inorganic materials 0.000 claims abstract description 18
- 108010053652 Butyrylcholinesterase Proteins 0.000 claims abstract description 17
- 102100032404 Cholinesterase Human genes 0.000 claims abstract description 17
- 229940079593 drug Drugs 0.000 claims abstract description 15
- 230000007131 anti Alzheimer effect Effects 0.000 claims abstract description 12
- 238000001035 drying Methods 0.000 claims abstract description 9
- 230000000694 effects Effects 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 8
- NSCFHVXOVBMGAK-UHFFFAOYSA-N n-phenylquinolin-2-amine Chemical class C=1C=C2C=CC=CC2=NC=1NC1=CC=CC=C1 NSCFHVXOVBMGAK-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000000034 method Methods 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 14
- -1 p-hydroxyphenyl Chemical group 0.000 claims description 14
- 230000002401 inhibitory effect Effects 0.000 claims description 9
- 238000004321 preservation Methods 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 3
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 2
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 2
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 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
- 230000008569 process Effects 0.000 claims description 2
- 229940111121 antirheumatic drug quinolines Drugs 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 230000005764 inhibitory process Effects 0.000 abstract description 5
- 230000009977 dual effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 102
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 24
- 238000005481 NMR spectroscopy Methods 0.000 description 24
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 23
- 238000005160 1H NMR spectroscopy Methods 0.000 description 23
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- 239000002244 precipitate Substances 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- 238000001704 evaporation Methods 0.000 description 14
- 238000004090 dissolution Methods 0.000 description 13
- 238000001914 filtration Methods 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 238000001228 spectrum Methods 0.000 description 13
- 208000024827 Alzheimer disease Diseases 0.000 description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 12
- 229910052799 carbon Inorganic materials 0.000 description 12
- 229910052739 hydrogen Inorganic materials 0.000 description 12
- 239000001257 hydrogen Substances 0.000 description 12
- 239000012044 organic layer Substances 0.000 description 12
- 238000004896 high resolution mass spectrometry Methods 0.000 description 11
- 238000004611 spectroscopical analysis Methods 0.000 description 11
- 239000007864 aqueous solution Substances 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 5
- 229960004373 acetylcholine Drugs 0.000 description 5
- IBYHHJPAARCAIE-UHFFFAOYSA-N 1-bromo-2-chloroethane Chemical compound ClCCBr IBYHHJPAARCAIE-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 239000012153 distilled water Substances 0.000 description 4
- ASUTZQLVASHGKV-JDFRZJQESA-N galanthamine Chemical compound O1C(=C23)C(OC)=CC=C2CN(C)CC[C@]23[C@@H]1C[C@@H](O)C=C2 ASUTZQLVASHGKV-JDFRZJQESA-N 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- BVWTXUYLKBHMOX-UHFFFAOYSA-N methyl vanillate Chemical compound COC(=O)C1=CC=C(O)C(OC)=C1 BVWTXUYLKBHMOX-UHFFFAOYSA-N 0.000 description 4
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- YQUVCSBJEUQKSH-UHFFFAOYSA-N protochatechuic acid Natural products OC(=O)C1=CC=C(O)C(O)=C1 YQUVCSBJEUQKSH-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- WKOLLVMJNQIZCI-UHFFFAOYSA-N vanillic acid Chemical compound COC1=CC(C(O)=O)=CC=C1O WKOLLVMJNQIZCI-UHFFFAOYSA-N 0.000 description 4
- TUUBOHWZSQXCSW-UHFFFAOYSA-N vanillic acid Natural products COC1=CC(O)=CC(C(O)=O)=C1 TUUBOHWZSQXCSW-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- 102000003914 Cholinesterases Human genes 0.000 description 3
- 108090000322 Cholinesterases Proteins 0.000 description 3
- 210000004556 brain Anatomy 0.000 description 3
- 229940048961 cholinesterase Drugs 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- MFLMLNDHJULHTK-UHFFFAOYSA-N 2-amino-4-(2-chloroethoxy)-5-methoxybenzoic acid Chemical compound COC1=CC(C(O)=O)=C(N)C=C1OCCCl MFLMLNDHJULHTK-UHFFFAOYSA-N 0.000 description 2
- 206010048650 Cholinesterase inhibition Diseases 0.000 description 2
- 229940122041 Cholinesterase inhibitor Drugs 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- PVRDAVSDHWPSOF-UHFFFAOYSA-N Vanillic acid methyl ester Natural products COC(=O)C(=O)C1=CC=C(O)C(OC)=C1 PVRDAVSDHWPSOF-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000000544 cholinesterase inhibitor Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- ADEBPBSSDYVVLD-UHFFFAOYSA-N donepezil Chemical compound O=C1C=2C=C(OC)C(OC)=CC=2CC1CC(CC1)CCN1CC1=CC=CC=C1 ADEBPBSSDYVVLD-UHFFFAOYSA-N 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 229960003980 galantamine Drugs 0.000 description 2
- ASUTZQLVASHGKV-UHFFFAOYSA-N galanthamine hydrochloride Natural products O1C(=C23)C(OC)=CC=C2CN(C)CCC23C1CC(O)C=C2 ASUTZQLVASHGKV-UHFFFAOYSA-N 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 2
- OKYLJMNWFOOEKE-UHFFFAOYSA-N methyl 2-amino-4-(2-chloroethoxy)-5-methoxybenzoate Chemical compound COC(=O)C1=CC(OC)=C(OCCCl)C=C1N OKYLJMNWFOOEKE-UHFFFAOYSA-N 0.000 description 2
- AXZCWNLUZBSALR-UHFFFAOYSA-N methyl 4-(2-chloroethoxy)-5-methoxy-2-nitrobenzoate Chemical compound COC(=O)C1=CC(OC)=C(OCCCl)C=C1[N+]([O-])=O AXZCWNLUZBSALR-UHFFFAOYSA-N 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- RNVCVTLRINQCPJ-UHFFFAOYSA-N o-toluidine Chemical compound CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 description 2
- RZXMPPFPUUCRFN-UHFFFAOYSA-N p-toluidine Chemical compound CC1=CC=C(N)C=C1 RZXMPPFPUUCRFN-UHFFFAOYSA-N 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 235000011056 potassium acetate Nutrition 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- XQDQRCRASHAZBA-UHFFFAOYSA-N 2,4-dinitro-1-thiocyanatobenzene Chemical compound [O-][N+](=O)C1=CC=C(SC#N)C([N+]([O-])=O)=C1 XQDQRCRASHAZBA-UHFFFAOYSA-N 0.000 description 1
- AKCRQHGQIJBRMN-UHFFFAOYSA-N 2-chloroaniline Chemical compound NC1=CC=CC=C1Cl AKCRQHGQIJBRMN-UHFFFAOYSA-N 0.000 description 1
- PNPCRKVUWYDDST-UHFFFAOYSA-N 3-chloroaniline Chemical compound NC1=CC=CC(Cl)=C1 PNPCRKVUWYDDST-UHFFFAOYSA-N 0.000 description 1
- JJYPMNFTHPTTDI-UHFFFAOYSA-N 3-methylaniline Chemical compound CC1=CC=CC(N)=C1 JJYPMNFTHPTTDI-UHFFFAOYSA-N 0.000 description 1
- PLIKAWJENQZMHA-UHFFFAOYSA-N 4-aminophenol Chemical compound NC1=CC=C(O)C=C1 PLIKAWJENQZMHA-UHFFFAOYSA-N 0.000 description 1
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 1
- 229940124596 AChE inhibitor Drugs 0.000 description 1
- 206010007269 Carcinogenicity Diseases 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 208000010412 Glaucoma Diseases 0.000 description 1
- 206010034719 Personality change Diseases 0.000 description 1
- 206010039966 Senile dementia Diseases 0.000 description 1
- 101001003192 Vigna unguiculata Bowman-Birk type seed trypsin and chymotrypsin inhibitor Proteins 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000007670 carcinogenicity Effects 0.000 description 1
- 231100000260 carcinogenicity Toxicity 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229940121657 clinical drug Drugs 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- 229960003530 donepezil Drugs 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- ZRJBHWIHUMBLCN-SEQYCRGISA-N huperzine a Chemical compound N1C(=O)C=CC2=C1C[C@H]1/C(=C/C)[C@]2(N)CC(C)=C1 ZRJBHWIHUMBLCN-SEQYCRGISA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- NCBZRJODKRCREW-UHFFFAOYSA-N m-anisidine Chemical compound COC1=CC=CC(N)=C1 NCBZRJODKRCREW-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 206010027175 memory impairment Diseases 0.000 description 1
- LQVPFNOFBAQSAZ-UHFFFAOYSA-N methyl 4-(2-chloroethoxy)-3-methoxybenzoate Chemical compound COC(=O)C1=CC=C(OCCCl)C(OC)=C1 LQVPFNOFBAQSAZ-UHFFFAOYSA-N 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- VMPITZXILSNTON-UHFFFAOYSA-N o-anisidine Chemical compound COC1=CC=CC=C1N VMPITZXILSNTON-UHFFFAOYSA-N 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 1
- 230000008529 pathological progression Effects 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 230000003997 social interaction Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000016978 synaptic transmission, cholinergic Effects 0.000 description 1
- 229960001685 tacrine Drugs 0.000 description 1
- YLJREFDVOIBQDA-UHFFFAOYSA-N tacrine Chemical compound C1=CC=C2C(N)=C(CCCC3)C3=NC2=C1 YLJREFDVOIBQDA-UHFFFAOYSA-N 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
-
- 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
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
- C07D215/42—Nitrogen atoms attached in position 4
- C07D215/44—Nitrogen atoms attached in position 4 with aryl radicals attached to said nitrogen atoms
Abstract
The preparation and the application of 2-N-morpholinyl ethoxy group substituted quinoline derivatives are as follows: dissolving 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-substituted anilino-quinoline in dimethyl sulfoxide serving as a solvent, adding anhydrous potassium carbonate, dropwise adding morpholine, heating to react, cooling to room temperature after the reaction is finished, drying and purifying to obtain the target compound. The 2-N-morpholinyl ethoxy group substituted quinoline derivatives comprise eleven compounds, the eleven compounds have acetylcholinesterase and butyryl cholinesterase dual inhibition activities, are suitable for lipophilicity, can be used for preparing anti-Alzheimer's disease medicines, and provide a new way for developing new anti-Alzheimer's disease medicines.
Description
Technical Field
The invention relates to the technical field of preparation of medicaments for resisting Alzheimer disease, in particular to a preparation method and application of 2-N-morpholinyl ethoxy group substituted quinoline derivatives.
Background
Alzheimer's Disease (AD), also known as primary senile dementia, is a degenerative disease of the nervous system. This disease was first described by the german physician AloisAlzheimer in 1906, and is one of the most common types of dementia. Epidemiological studies have shown that the prevalence of AD increases with age, about 5% in people over 65 years of age and about 20% in people over 85 years of age. Clinically, AD is a disease that has progressive memory impairment, cognitive dysfunction, personality change, language impairment and the like as main manifestations, and seriously affects the social interaction, work and life of the elderly, and places a heavy burden on families and society. Currently, clinically used anti-AD drugs are mainly acetylcholinesterase (AChE) inhibitors, such as donepezil, huperzine a, galantamine and the like, and these drugs improve the acetylcholine level in the brain of a patient by inhibiting the activity of acetylcholinesterase, thereby being beneficial to improving the cognitive function of the patient and improving the behavioral disturbance of the patient. Compared to AChE, butyrylcholinesterase (BChE) plays a major back-up role for cholinergic neurotransmission. In the brain of healthy adults, AChE is more active than BChE, resulting in hydrolysis of 80% of the acetylcholine in the brain. However, with increasing levels of AD, AChE can drop to 90% of normal levels, while BChE levels rise by a factor of 2, with a continuing trend to increase. In the pathological progression of AD, acetylcholine regulation is increasingly dependent on BChE. Therefore, in the treatment scheme of AD, the double inhibitors of AChE and BChE have more important development value.
Quinoline derivatives and analogues thereof have various physiological activities and are widely used in clinical applications, such as pharmacological activities of anti-tumor, anti-malaria, bacteriostasis, cholinesterase inhibition, and the like, wherein tacrine has been used as an AChE inhibitor for treating AD. In addition, the morpholine group is a pharmacophore which is commonly used in the design of cholinesterase inhibitor drugs. Therefore, a novel characteristic structure is designed by adopting a molecular splicing principle, namely a flexible alkoxy chain containing two carbon atoms is combined between a quinoline mother core and a morpholine fragment so as to increase the binding capacity of a target compound and receptor protein cholinesterase. And carrying out replacement modification on the 4-position of a quinoline ring by using different aniline groups, thereby synthesizing a series of 2-N-morpholinoethoxy group-substituted quinoline derivatives.
Disclosure of Invention
The invention aims to search novel cholinesterase inhibitor drugs, and designs a series of 2-N-morpholinylethoxy group-substituted quinoline compounds. The invention carries out deep chemical and pharmacological activity research on series of 2-N-morpholinyl ethoxy group-substituted quinoline compounds, finds that eleven compounds have better double inhibition effects on AChE and BChE, shows good lipophilicity, has the prospect of developing new anti-AD medicaments, and provides a new way for developing new anti-Alzheimer medicaments and abundant clinical medicament varieties.
The technical scheme of the invention is as follows:
2-N-morpholinyl ethoxy group substituted quinoline derivatives, which have the following chemical structural formula:
in the structural formula, R is phenyl, m-chlorophenyl, p-tolyl, p-methoxyphenyl, p-hydroxyphenyl, m-tolyl, m-methoxyphenyl, o-chlorophenyl, o-tolyl or o-methoxyphenyl.
The derivatives include 6-methoxy-7- (2-N-morpholinoethoxy) -3-nitro-4-N-anilino-quinoline, 6-methoxy-7- (2-N-morpholinoethoxy) -3-nitro-4-N-m-chloroanilino-quinoline, 6-methoxy-7- (2-N-morpholinoethoxy) -3-nitro-4-N-p-toluidino-quinoline, 6-methoxy-7- (2-N-morpholinoethoxy) -3-nitroethoxy-quinoline -4-N-p-methoxyanilino-quinoline, 6-methoxy-7- (2-N-morpholinoethoxy) -3-nitro-4-N-p-hydroxyphenylamino-quinoline, 6-methoxy-7- (2-N-morpholinoethoxy) -3-nitro-4-N-m-toluidino-quinoline, 6-methoxy-7- (2-N-morpholinoethoxy) -3-nitro-4-N-m-methoxyanilino-quinoline, 6-methoxy-7- (2-N-morpholinoethoxy) -3-nitro-4-N-o-chloroanilino-quinoline, 6-methoxy-7- (2-N-morpholinoethoxy) -3-nitro-4-N-o-toluidino-quinoline and 6-methoxy-7- (2-N-morpholinoethoxy) -3-nitro-4-N-o-methoxyanilino-quinoline.
The preparation method of the 2-N-morpholinyl ethoxy group substituted quinoline derivative comprises the following steps: dissolving 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-substituted anilino-quinoline in dimethyl sulfoxide serving as a solvent, adding anhydrous potassium carbonate, dropwise adding morpholine, heating for carrying out heat preservation reaction after dropwise adding is finished, cooling to room temperature after the reaction is finished, and drying and purifying to obtain a target compound; the method comprises the following specific steps:
step 1: putting vanillic acid into a container, adding methanol to completely dissolve the vanillic acid, adding concentrated hydrochloric acid, heating and refluxing at 60-80 ℃, and reacting for 12-14 hours. After the reaction is finished, purifying to obtain the compound a, namely the vanillic acid methyl ester.
Step 2: and (3) putting the compound a into a container, dissolving the compound a with acetone, adding anhydrous potassium carbonate and 1-bromo-2-chloroethane, and heating and reacting at 50-70 ℃ for 12-15 hours. Filtering while hot after the reaction is finished, evaporating the organic solvent to dryness and purifying to obtain a compound b, namely 4- (2-chloroethoxy) -3-methoxy-methyl benzoate.
And step 3: and dissolving the compound b in dichloromethane in a container, slowly dropwise adding fuming nitric acid, and reacting for 4-6 hours at normal temperature. After the reaction was completed, excess fuming nitric acid was removed with an aqueous sodium bicarbonate solution. The dichloromethane layer was separated by a separatory funnel and the solvent was evaporated to give compound c, methyl 4- (2-chloroethoxy) -5-methoxy-2-nitrobenzoate.
And 4, step 4: and dissolving the compound c in ethanol in a round-bottom flask, adding a saturated ammonium chloride aqueous solution after complete dissolution, adding iron powder, and reacting at 60-80 ℃ for 12-15 hours. After the reaction, the mixture was filtered while hot through a funnel and extracted with dichloromethane. Evaporating the organic solvent to dryness, and purifying by column chromatography to obtain compound d, i.e. 2-amino-4- (2-chloroethoxy) -5-methoxybenzoic acid methyl ester.
And 5: dissolving the compound d in a small amount of methanol in a container, adding a 5% sodium hydroxide aqueous solution, heating to 50-60 ℃, reacting for 12-16 hours, cooling to room temperature, adding hydrochloric acid to adjust the pH value to 2-3, and performing liquid separation extraction with dichloromethane. Evaporating the organic solvent to dryness to obtain a compound e, namely 2-amino-4- (2-chloroethoxy) -5-methoxybenzoic acid.
Step 6: (1) compound e was added to distilled water and concentrated hydrochloric acid solution to form an aqueous solution of compound e. (2) Weighing sodium hydroxide, adding water with the mass being two times of that of the sodium hydroxide to dissolve the sodium hydroxide, adding nitromethane with the equivalent being 1.0-2.0 times of that of the sodium hydroxide at 25-30 ℃, heating to 40 ℃, keeping the temperature at 40-45 ℃, adding the same amount of nitromethane again, heating to 50 ℃, keeping the temperature at 50-55 ℃ for 5-8 minutes, and cooling to room temperature. Hydrochloric acid solution was slowly added dropwise in ice bath and mixed well to form a reddish brown solution. Adding the reddish brown solution into an aqueous solution of a compound e, and reacting at normal temperature for 18-20 hours. And (4) performing suction filtration by using a Buchner funnel until the distilled water is washed to be neutral, and drying to obtain the compound f, namely 4- (2-chloroethoxy) -5-methoxy-2- (2-nitroethylidene amino) benzoic acid.
And 7: and (3) putting the dried compound f into a container, adding anhydrous acetic anhydride, heating at 100 ℃ for dissolving, adding anhydrous potassium acetate after the solution is clarified, carrying out oil bath reflux reaction for 15-30 min, and cooling to room temperature. And (3) carrying out suction filtration on the sand core funnel, washing with glacial acetic acid, washing with water to be neutral, and drying to obtain a compound j, namely 7- (2-chloroethoxy) -6-methoxy-3-nitro-4-hydroxyquinoline.
And 8: and (3) putting the compound j into a container, slowly dropwise adding phosphorus oxychloride, and stirring and refluxing the mixture in an oil bath at the temperature of 60-80 ℃ for 12-14 hours. After the reaction is finished, the redundant phosphorus oxychloride is evaporated, dichloromethane is added to dissolve the product, and then the cooled saturated potassium carbonate aqueous solution is added. Stirring for half an hour in ice bath, separating a dichloromethane layer by using a separating funnel, washing twice, and drying by using anhydrous magnesium sulfate to obtain a compound h, namely 7- (2-chloroethoxy) -6-methoxy-3-nitro-4-chloroquinoline.
And step 9: the compound h is put into a container, then isopropanol is added, and the mixture is heated and dissolved. Adding aniline containing different substituents, and reacting at 82-100 ℃ for 12-18 hours. After the reaction is finished, the mixture is placed at room temperature until a precipitate is separated out, filtered, washed by water and dried by anhydrous magnesium sulfate to obtain the 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-substituted anilino-quinoline compound.
Step 10: and (3) dissolving the 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-substituted anilino-quinoline compound obtained in the step (9) by using dimethyl sulfoxide, adding 1.0-6.0 times of equivalent of anhydrous potassium carbonate, and dropwise adding 1.0-6.0 times of equivalent of morpholine. After the dropwise addition, the temperature is raised to 71-90 ℃, and the reaction is carried out for 10-20 hours under the condition of heat preservation. And after the reaction is finished, cooling to room temperature, drying, and purifying by column chromatography to obtain the target compound.
The 2-N-morpholinyl ethoxy group-substituted quinoline derivative provided by the invention has the activity of inhibiting both acetylcholinesterase and butyrylcholinesterase, and can be used for preparing a medicament for resisting Alzheimer disease.
The invention has the advantages and beneficial effects that:
2-N-morpholinyl ethoxy group substituted quinoline derivatives have good AChE and BChE inhibitory activity and appropriate lipophilicity, and provide a new way for developing new anti-AD drugs and abundant clinical drug varieties; in the process of synthesizing the morpholine group-substituted compound, the literature reports that acetonitrile is used as a solvent, and considering that the acetonitrile is used as a second solvent and has carcinogenicity, the invention also achieves the aim of synthesis by using three solvents, namely dimethyl sulfoxide which can be used for medicine production as a reaction solvent, and no literature about synthesis improvement exists at home and abroad so far.
Detailed Description
In order to find an anti-Alzheimer disease drug with better curative effect, in combination with the current knowledge of the anti-Alzheimer disease drug, according to literature reports and research results of applicant subject groups for many years, a plurality of 2-N-morpholinoethoxy group substituted quinoline derivatives are synthesized, and cholinesterase inhibition screening is performed on the obtained target compounds, so that eleven compounds are found to have better double inhibition activities of acetylcholinesterase and butyrylcholinesterase, have proper lipophilicity and have the prospect of being developed into a new anti-Alzheimer disease drug. The structure of the target compound is shown by high resolution mass spectrum (HR-ESI-MS), nuclear magnetic resonance hydrogen spectrum (HR-ESI-MS) 1 H-NMR), nuclear magnetic resonance carbon spectrum (C 13 C-NMR).
Example 1:
the preparation of 6-methoxy-7- (2-N-morpholinylethoxy) -3-nitro-4-N-anilino-quinoline comprises the following steps:
step 1: 5.00g of vanillic acid (29.76mmol) is put into a 100mL round-bottom flask, 50mL of methanol is added until all the vanillic acid is dissolved, 3mL of concentrated hydrochloric acid is added, and the mixture is heated and refluxed at 70 ℃ to react for 12 hours. After the reaction was completed, it was evaporated to dryness to obtain 5.33g of a white solid compound a, i.e., vanillic acid methyl ester, with a yield of 98%. Multiple reactions accumulate the mass of this compound.
Step 2: 5.27g (29.04mmol) of Compound a was placed in a 100mL round-bottomed flask and dissolved in acetone, followed by addition of 8.0g of anhydrous potassium carbonate and 10.22g of 1-bromo-2-chloroethane and reaction by heating at 70 ℃ for 12 hours. After the reaction, the mixture was filtered while hot, and the organic solvent was evaporated to dryness to obtain 6.80g of a compound b, i.e., 4- (2-chloroethoxy) -3-methoxy-benzoic acid methyl ester, in a yield of 96%. The mass of this compound was accumulated over multiple reactions.
And step 3: 6.80g (27.87mmol) of Compound b was dissolved in methylene chloride in a 100mL round-bottomed flask, and 1.99mL (55.74mmol) of fuming nitric acid was slowly dropped, followed by reaction at ordinary temperature for 6 hours. After the reaction was completed, excess fuming nitric acid was removed with an aqueous sodium bicarbonate solution. The dichloromethane layer was separated by a separatory funnel and solvent was evaporated to dryness to give 7.10g of Compound c, methyl 4- (2-chloroethoxy) -5-methoxy-2-nitrobenzoate in 89% yield. The mass of this compound was accumulated over multiple reactions.
And 4, step 4: 7.10g (24.57mmol) of Compound c was dissolved in ethanol in a 150ml round-bottomed flask, and after complete dissolution, a saturated aqueous ammonium chloride solution was added, and 3.70g (0.0667mol) of iron powder was further added, followed by reaction at 70 ℃ for 12 hours. After the reaction, the mixture was filtered while hot through a funnel and extracted with dichloromethane. The organic solvent was evaporated to dryness and the organic layer was purified over normal phase silica gel column using dichloromethane as eluent to give 5.10g of compound d, i.e. methyl 2-amino-4- (2-chloroethoxy) -5-methoxybenzoate in 73% yield. The mass of this compound was accumulated over multiple reactions.
And 5: 5.10g (19.6mmol) of Compound d was dissolved in 50mL of methanol in a 100mL round-bottomed flask, and then 23mL of a 5% aqueous solution of sodium hydroxide was added, the temperature was raised to 50 ℃ to react for 12 hours, the mixture was cooled to room temperature, and then the pH was adjusted to 3 by adding hydrochloric acid, followed by liquid-separation extraction with methylene chloride. The organic solvent was evaporated to dryness to give 4.00g of compound e, i.e., 2-amino-4- (2-chloroethoxy) -5-methoxybenzoic acid, in 83.1% yield. The mass of this compound was accumulated over multiple reactions.
Step 6: (1) 4.00g (15.74mmol) of compound e was added to 20mL of distilled water and 1.25mL of concentrated hydrochloric acid to form an aqueous solution of compound e. (2) 2.20g (55mmol) of sodium hydroxide was weighed out, dissolved in 4.35mL of water, 0.95g (17.92mmol) of nitromethane was added at 30 ℃ and the temperature was raised to 40 ℃ and 0.95g (17.92mmol) of nitromethane was added again at 40 ℃ and the temperature was raised to 50 ℃ and the temperature was maintained at 50 ℃ for 5 minutes and then cooled to room temperature. Ice was then added, followed by 5.7mL hydrochloric acid and mixed thoroughly to form a reddish brown solution. The reddish brown solution was added to an aqueous solution of compound e and reacted at room temperature for 18 hours. Suction filtration, washing with distilled water to neutrality and drying gave 4.50g of compound f, i.e. 4- (2-chloroethoxy) -5-methoxy-2- (2-nitroethylamino) benzoic acid, in 79% yield. The mass of this compound was accumulated over multiple reactions.
And 7: 2.00g (6.32mmol) of compound f is placed in a 50mL round bottom flask, then 6mL of anhydrous acetic anhydride is added, the mixture is heated and dissolved at 100 ℃, 0.59g (6.02mmol) of anhydrous potassium acetate is added after the solution is clarified, the oil bath is refluxed for reaction for 15min, and the reaction is cooled to room temperature. Filtration, washing with glacial acetic acid, then water to neutrality and drying gave 0.60g of compound j, i.e. 7- (2-chloroethoxy) -6-methoxy-3-nitro-4-hydroxyquinoline, in 31.9% yield. The mass of this compound was accumulated over multiple reactions.
And 8: 0.50g (1.68mmol) of Compound j is placed in a 100mL round-bottom flask, 2.60mL of phosphorus oxychloride is slowly added, and the mixture is stirred in an oil bath at 70 ℃ under reflux for 14 hours. After the reaction is finished, the redundant phosphorus oxychloride is evaporated, dichloromethane is added to dissolve the product, and then the cooled saturated potassium carbonate aqueous solution is added. Stirring is carried out for half an hour in ice bath, a dichloromethane layer is separated by a separating funnel, washing is carried out twice, and after anhydrous magnesium sulfate is dried, 0.35g of a compound h, namely 7- (2-chloroethoxy) -6-methoxy-3-nitro-4-chloroquinoline is obtained, wherein the yield is 65.9%. The mass of this compound was accumulated over multiple reactions.
And step 9: 0.50g (1.58mmol) of the compound h was placed in a 100mL round-bottom flask, followed by addition of 40mL of isopropanol and dissolution by heating. 1.896mmol of aniline was added and the reaction was refluxed at 85 ℃ for 12 hours. After the reaction, the reaction mixture was allowed to stand at room temperature until a precipitate was precipitated, filtered, washed with water, and dried over anhydrous magnesium sulfate to obtain 0.449g of 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-anilino-quinoline in a yield of 76%.
Step 10: 0.10g (0.26mmol) of 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-anilino-quinoline are dissolved in 30mL of dimethyl sulfoxide, 2.0 equivalents of anhydrous potassium carbonate are added, 1.5 equivalents of morpholine are added dropwise, after the addition is complete, the temperature is raised to 87 ℃ and the reaction is carried out for 17 hours. After the reaction is finished, cooling to room temperature, filtering and evaporating to dryness, extracting dichloromethane and water, purifying an organic layer by a chromatographic column, and eluting dichloromethane and methanol (20: 1) to obtain 6-methoxy-7- (2-N-morpholinoethoxy) -3-nitro-4-N-anilino-quinoline, namely the compound 1.
By high resolution mass spectrometry (HR-ESI-MS), nuclear magnetic resonance hydrogen spectroscopy ( 1 H-NMR), nuclear magnetic resonance carbon spectrum (C 13 C-NMR) confirmed the structure of compound 1: mp: 183.1-185.2 deg.C; 1 H-NMR(400MHz，CDCl 3 )δ：2.65(br.s，4H)，2.95(t，J＝5.6Hz，2H，NCH 2 )，3.33(s，3H，OCH 3 )，3.76(t-like，4H)，4.33(t，J＝5.6Hz，2H，OCH 2 )，6.89(s，1H，ArH)，7.20(d，J＝7.9Hz，2H，ArH)，7.26(t，J＝7.9Hz，1H，ArH)，7.34(s，1H，ArH)，7.41(t，J＝7.9Hz，2H，ArH)，9.37(s，1H，2-H)，10.44(s，1H，NH)； 13 C-NMR(100MHz，CDCl 3 )δ：153.3，148.2，147.9，145.3，145.0，141.2，129.7(2C)，128.6，126.1，124.0(2C)，112.9，110.0，106.5，66.9，66.8(2C)，56.9，55.2，54.1(2C)；HR-ESI-MS(positive mode)m/z：425.1845[M+H] + (calculated for C 22 H 25 N 4 O 5 ，425.1825)。
example 2:
the preparation of 6-methoxy-7- (2-N-morpholinylethoxy) -3-nitro-4-N-m-chloroanilino-quinoline comprises the following steps:
the procedure for the preparation of the eight steps from step 1 to step 8 was substantially the same as in example 1 except for the amount used.
And step 9: 0.50g (1.58mmol) of the compound h was placed in a 100mL round-bottom flask, followed by addition of 40mL of isopropanol and dissolution by heating. 1.896mmol of m-chloroaniline was added and the reaction was refluxed at 82 ℃ for 16 hours. After the reaction, the reaction mixture was left at room temperature until a precipitate was precipitated, filtered, washed with water, and dried over anhydrous magnesium sulfate to obtain 0.45g of 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-m-chloroanilino-quinoline in a yield of 70%.
Step 10: 0.10g (0.24mmol) of 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-m-chloroanilino-quinoline is dissolved in 30mL of dimethyl sulfoxide, 2.5 times the equivalent of anhydrous potassium carbonate is added, 6.0 times the equivalent of morpholine is added dropwise, after the addition is complete, the temperature is raised to 73 ℃ and the reaction is carried out for 13 hours. After the reaction is finished, cooling to room temperature, filtering and evaporating to dryness, extracting dichloromethane and water, purifying an organic layer by a chromatographic column, and eluting dichloromethane and methanol (15: 1) to obtain 6-methoxy-7- (2-N-morpholinoethoxy) -3-nitro-4-N-m-chloroanilino-quinoline, namely the compound 2.
By high resolution mass spectrometry (HR-ESI-MS), nuclear magnetic resonance hydrogen spectroscopy ( 1 H-NMR), nuclear magnetic resonance carbon spectrum (C 13 C-NMR) confirmed the structure of compound 2: mp: 161.1-163.2 ℃; 1 H-NMR(400MHz，CDCl 3 )δ：2.62(br.s，4H)，2.92(t，J＝5.4Hz，2H，NCH 2 )，3.40(s，3H，OCH 3 )，3.72(t-like，4H)，4.31(t，J＝5.4Hz，2H，OCH 2 )，6.82(s，1H，ArH)，6.97(d，J＝8.0Hz，1H，ArH)，7.12(s，1H，ArH)，7.16(d，J＝8.0Hz，1H，ArH)，7.27(t，J＝8.0Hz，1H，ArH)，7.33(s，1H，ArH)，9.32(s，1H，2-H)，10.18(s，1H，NH)； 13 C-NMR(100MHz，CDCl 3 )δ：148.7，148.1，145.1，143.9，142.4，135.3，130.5，129.3，125.6，123.2，121.3，114.6，113.1，110.1，105.9，66.9，66.7(2C)，56.9，55.5，54.1(2C)；HR-ESI-MS(positive mode)m/z：459.1422[M+H] + (calculated for C 22 H 24 ClN 4 O 5 ，459.1435)。
example 3:
the preparation of 6-methoxy-7- (2-N-morpholinylethoxy) -3-nitro-4-N-p-chloroanilino-quinoline comprises the following steps:
the procedure for the preparation of the eight steps from step 1 to step 8 was substantially the same as in example 1 except for the amount used.
And step 9: 0.50g (1.58mmol) of the compound h was placed in a 100mL round-bottom flask, followed by addition of 40mL of isopropanol and dissolution by heating. 1.896mmol of p-chloroaniline was added and the reaction was refluxed at 90 ℃ for 14 hours. After the reaction, the reaction mixture was allowed to stand at room temperature until a precipitate was precipitated, and the precipitate was filtered, washed with water, and dried over anhydrous magnesium sulfate to obtain 0.47g of 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-p-chloroanilino-quinoline in a yield of 73%.
Step 10: 0.10g (0.24mmol) of 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-p-chloroanilino-quinoline is dissolved in 40mL of dimethyl sulfoxide, 6.0 equivalents of anhydrous potassium carbonate are added, 5.5 equivalents of morpholine are added dropwise, after the addition, the temperature is raised to 90 ℃ and the reaction is carried out for 20 hours. After the reaction is finished, cooling to room temperature, filtering and evaporating to dryness, extracting dichloromethane and water, purifying an organic layer by a chromatographic column, and eluting dichloromethane and methanol (15: 1) to obtain 6-methoxy-7- (2-N-morpholinoethoxy) -3-nitro-4-N-p-chloroanilino-quinoline, namely the compound 3.
By high resolution mass spectrometry (HR-ESI-MS), nuclear magnetic resonance hydrogen spectroscopy ( 1 H-NMR), nuclear magnetic resonance carbon spectrum (C 13 C-NMR) confirmed the structure of compound 3: mp: 171.3-174.3 ℃; 1 H-NMR(400MHz，CDCl 3 )δ：2.67(br.s，4H)，2.97(br.s，2H，NCH 2 )，3.43(s，3H，OCH 3 )，3.78(br.s，4H)，4.35(br.s，2H，OCH 2 )，6.83(s，1H，ArH)，7.10(d，J＝8.4Hz，2H，ArH)，7.35(s，1H，ArH)，7.36(d，J＝8.4Hz，2H，ArH)，9.37(s，1H，2-H)，10.26(s，1H，NH)； 13 C-NMR(100MHz，CDCl 3 )δ：153.8，148.6，148.1，145.2，144.4，139.8，131.1，129.7(2C)，129.1，124.7(2C)，112.9，110.1，106.0，67.1，66.8(2C)，56.9，55.4，54.1(2C)；HR-ESI-MS(positive mode)m/z：459.1443[M+H] + (calculated for C 22 H 24 ClN 4 O 5 ，459.1435)。
example 4:
the preparation of 6-methoxy-7- (2-N-morpholinylethoxy) -3-nitro-4-N-p-toluidino-quinoline comprises the following steps:
the procedure for the preparation of the eight steps from step 1 to step 8 was substantially the same as in example 1 except for the amount used.
And step 9: 0.50g (1.58mmol) of the compound h was placed in a 100mL round-bottom flask, followed by addition of 40mL of isopropanol and dissolution by heating. 1.896mmol of p-methylaniline was added and the reaction was refluxed at 95 ℃ for 18 hours. After the reaction, the reaction mixture was allowed to stand at room temperature until a precipitate was precipitated, and the precipitate was filtered, washed with water, and dried over anhydrous magnesium sulfate to obtain 0.42g of 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-p-toluidino-quinoline in a yield of 69%.
Step 10: 0.10g (0.26mmol) of 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-p-toluidino-quinoline is dissolved in 40mL of dimethyl sulfoxide, 4.0 equivalents of anhydrous potassium carbonate are added, 4.5 equivalents of morpholine are added dropwise, after the addition, the temperature is raised to 77 ℃ and the reaction is carried out for 15 hours. After the reaction is finished, cooling to room temperature, filtering and evaporating to dryness, extracting dichloromethane and water, purifying an organic layer by a chromatographic column, and eluting dichloro and methanol (20: 1) to obtain 6-methoxy-7- (2-N-morpholinylethoxy) -3-nitro-4-N-p-toluidino-quinoline, namely the compound 4.
By high resolution mass spectrometry (HR-ESI-MS), nuclear magnetic resonance hydrogen spectroscopy (H-ESI-MS) ((R)) 1 H-NMR), nuclear magnetic resonance carbon spectrum (C 13 C-NMR) confirmed the structure of compound 4: mp: 175.1-179.2 ℃; 1 H-NMR(400MHz，DMSO-d 6 )δ：2.28(s，3H，CH 3 )，2.69(br.s，4H)，2.95(br.s，2H，NCH 2 )，3.65(br.s，4H)，3.72(s，3H，OCH 3 )，4.35(br.s，2H，OCH 2 )，7.01(d，J＝6.2Hz，2H，ArH)，7.14(d，J＝6.2Hz，2H，ArH)，7.42(s，1H，ArH)，7.57(s，1H，ArH)，8.94(s，1H，2-H)，9.83(s，1H，NH)； 13 C-NMR(100MHz，DMSO-d 6 )δ：153.0，149.3，146.9，145.1，142.2，139.2，134.2，130.1(2C)，129.4，121.4(2C)，114.9，110.3，104.5，66.3，66.1(2C)，56.8，56.2，53.8(2C)，20.9；HR-ESI-MS(positive mode)m/z：439.2001[M+H] + (calculated for C 23 H 26 N 4 O 5 ，439.1981)。
example 5:
the preparation of 6-methoxy-7- (2-N-morpholinylethoxy) -3-nitro-4-N-p-methoxyanilino-quinoline comprises the following steps:
the procedure for the preparation of the eight steps from step 1 to step 8 was substantially the same as in example 1 except for the amount used.
And step 9: 0.50g (1.58mmol) of the compound h was placed in a 100mL round-bottom flask, followed by addition of 40mL of isopropanol and dissolution by heating. 1.896mmol of p-anisidine were added and the reaction was refluxed at 84 ℃ for 14 hours. After the reaction, the mixture was left at room temperature until a precipitate was precipitated, filtered, washed with water, and dried over anhydrous magnesium sulfate to obtain 0.46g of 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-p-methoxyanilino-quinoline in a yield of 72%.
Step 10: 0.10g (0.25mmol) of 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-p-methoxyanilino-quinoline is dissolved in 50mL of dimethyl sulfoxide, 1.0 equivalent of anhydrous potassium carbonate is added, 4.0 equivalents of morpholine are added dropwise, after the addition, the temperature is raised to 88 ℃ and the reaction is carried out for 10 hours. After the reaction is finished, cooling to room temperature, filtering and evaporating to dryness, extracting dichloromethane and water, purifying an organic layer by a chromatographic column, and eluting dichloromethane and methanol (15: 1) to obtain 6-methoxy-7- (2-N-morpholinylethoxy) -3-nitro-4-N-p-methoxyanilino-quinoline, namely the compound 5.
By high resolution mass spectrometry (HR-ESI-MS), nuclear magnetic resonance hydrogen spectroscopy (H-ESI-MS) ((R)) 1 H-NMR), nuclear magnetic resonance carbon spectrum (C 13 C-NMR) confirmed the structure of compound 5: mp: 152.1-156.2 ℃; 1 H-NMR(400MHz，CDCl 3 )δ：2.70(br.s，4H)，2.98(br.s，2H，NCH 2 )，3.36(s，3H，OCH 3 )，3.79(br.s，4H)，3.84(s，3H，OCH 3 )，4.35(br.s，2H，OCH 2 )，6.94(s，1H，ArH)，6.95(d，J＝8.8Hz，2H，ArH)，7.17(d，J＝8.8Hz，2H，ArH)，7.32(s，1H，ArH)，9.34(s，1H，2-H)，10.53(s，1H，NH)； 13 C-NMR(100MHz，CDCl 3 )δ：158.1，152.9，147.9，147.8，145.9，145.6，133.9，127.7，126.1(2C)，115.0(2C)，112.7，110.1，106.6，66.6，66.5(2C)，56.9，55.7，55.2，54.0(2C)；HR-ESI-MS(positive mode)m/z：455.1944[M+H] + (calculated for C 23 H 27 N 4 O 6 ，455.1931)。
example 6:
the preparation of 6-methoxy-7- (2-N-morpholinylethoxy) -3-nitro-4-N-p-hydroxyphenylamino-quinoline comprises the following steps:
the procedure for the preparation of the eight steps from step 1 to step 8 was substantially the same as in example 1 except for the amount used.
And step 9: 0.50g (1.58mmol) of the compound h was placed in a 100mL round-bottom flask, followed by addition of 50mL of isopropanol and dissolution by heating. 1.896mmol of p-hydroxyaniline was added and the reaction was refluxed at 97 ℃ for 18 hours. After the reaction, the mixture was left at room temperature until a precipitate was precipitated, filtered, washed with water, and dried over anhydrous magnesium sulfate to obtain 0.48g of 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-p-hydroxyanilino-quinoline in a yield of 78%.
Step 10: 0.10g (0.26mmol) of 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-p-hydroxyphenylamino-quinoline is dissolved in 50mL of dimethyl sulfoxide, 5.0 times equivalent of anhydrous potassium carbonate is added, 5.0 times equivalent of morpholine is added dropwise, after the dropwise addition is completed, the temperature is raised to 71 ℃ and reaction is carried out for 12 hours. After the reaction is finished, cooling to room temperature, filtering and evaporating to dryness, extracting dichloromethane and water, purifying an organic layer by a chromatographic column, and eluting dichloromethane and methanol (15: 1) to obtain 6-methoxy-7- (2-N-morpholinylethoxy) -3-nitro-4-N-p-hydroxyphenylamino-quinoline, namely the compound 6.
By high resolution mass spectrometry (HR-ESI-MS), nuclear magnetic resonance hydrogen spectroscopy ( 1 H-NMR), nuclear magnetic resonance carbon spectrum (C 13 C-NMR) confirmed the structure of compound 6: mp: 144.1-146.2 ℃; 1 H-NMR(400MHz，DMSO-d 6 )δ：3.53(br.s，4H)，3.55(br.s，2H，NCH 2 )，3.67(s，3H，OCH 3 )，3.84(br.s，4H)，4.59(br.s，2H，OCH 2 )，6.76(d，J＝8.4Hz，2H，ArH)，7.00(d，J＝8.4Hz，2H，ArH)，7.44(s，1H，ArH)，7.55(s，1H，ArH)，8.95(s，1H，2-H)，9.59(s，1H，NH)，9.95(s，1H，OH)； 13 C-NMR(100MHz，DMSO-d 6 )δ：155.6，152.1，148.7，145.4，143.7，133.0，128.5，124.4(2C)，116.3(2C)，115.6，114.6，110.7，105.2，64.2(2C)，63.7，56.1，55.4，52.7(2C)；HR-ESI-MS(positive mode)m/z：441.1769[M+H] + (calculated for C 22 H 25 N 4 O 6 ，441.1774)。
example 7:
the preparation of 6-methoxy-7- (2-N-morpholinylethoxy) -3-nitro-4-N-m-toluidino-quinoline comprises the following steps:
the procedure for the preparation of the eight steps from step 1 to step 8 was substantially the same as in example 1 except for the amount used.
And step 9: 0.50g (1.58mmol) of the compound h was placed in a 100mL round-bottom flask, followed by addition of 35mL of isopropanol and dissolution by heating. 1.896mmol of m-methylaniline was added and the reaction was refluxed at 89 ℃ for 15 hours. After the reaction, the reaction mixture was allowed to stand at room temperature until a precipitate was precipitated, and the precipitate was filtered, washed with water, and dried over anhydrous magnesium sulfate to obtain 0.47g of 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-m-toluidino-quinoline in a yield of 77%.
Step 10: 0.10g (0.26mmol) of 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-m-toluidino-quinoline is dissolved in 45mL of dimethyl sulfoxide, 3.0 equivalents of anhydrous potassium carbonate are added, 4.5 equivalents of morpholine are added dropwise, after the addition, the temperature is raised to 83 ℃ and the reaction is carried out for 18 hours. After the reaction is finished, cooling to room temperature, filtering and evaporating to dryness, extracting dichloromethane and water, purifying an organic layer by a chromatographic column, and eluting dichloromethane and methanol (20: 1) to obtain 6-methoxy-7- (2-N-morpholinylethoxy) -3-nitro-4-N-m-toluidino-quinoline, namely the compound 7.
By high resolution mass spectrometry (HR-ESI-MS), nuclear magnetic resonance hydrogen spectroscopy ( 1 H-NMR), nuclear magnetic resonance carbon spectrum (C 13 C-NMR) confirmed the structure of compound 7: mp: 170.1-174.2 ℃. 1 H-NMR(400MHz，CDCl 3 )δ：2.36(s，3H，CH 3 )，2.63(br.s，4H)，2.93(t，J＝5.8Hz，2H，NCH 2 )，3.35(s，3H，OCH 3 )，3.75(t-like，4H)，4.32(t，J＝5.8Hz，2H，OCH 2 )，6.93(s，1H，ArH)，7.00(d，J＝7.7Hz，1H，ArH)，7.03(s，1H，ArH)，7.08(d，J＝7.7Hz，1H，ArH)，7.29(t，J＝7.7Hz，1H，ArH)，7.34(s，1H，ArH)，9.36(s，1H，2-H)，10.45(s，1H，NH)； 13 C-NMR(100MHz，CDCl 3 )δ：154.1，149.7，147.3，141.6，140.5，140.1，138.8，129.9，128.8，126.8，124.7，121.2，113.8，106.4，104.0，64.7，63.9(2C)，55.9，55.7，53.0(2C)，21.3；HR-ESI-MS(positive mode)m/z：439.1988[M+H] + (calculated for C 23 H 27 N 4 O 5 ，439.1981)。
Example 8:
the preparation of 6-methoxy-7- (2-N-morpholinylethoxy) -3-nitro-4-N-m-methoxyanilino-quinoline comprises the following steps:
the procedure for the preparation of the eight steps from step 1 to step 8 was substantially the same as in example 1 except for the amount used.
And step 9: 0.50g (1.58mmol) of the compound h was placed in a 100mL round-bottom flask, followed by addition of 45mL of isopropanol and dissolution by heating. 1.896mmol of m-methoxyaniline were added and the reaction was refluxed at 93 ℃ for 17 hours. After the reaction, the reaction mixture was allowed to stand at room temperature until a precipitate was precipitated, and then the precipitate was filtered, washed with water, and dried over anhydrous magnesium sulfate to obtain 0.49g of 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-m-methoxyanilino-quinoline in a yield of 77%.
Step 10: 0.10g (0.22mmol) of 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-m-methoxyanilino-quinoline are dissolved in 40mL of dimethyl sulfoxide, 5.0 equivalents of anhydrous potassium carbonate are added, 4.0 equivalents of morpholine are added dropwise, after the addition, the temperature is raised to 75 ℃ and the reaction is carried out for 20 hours. After the reaction is finished, cooling to room temperature, filtering and evaporating to dryness, extracting dichloromethane and water, purifying an organic layer by a chromatographic column, and eluting dichloromethane and methanol (20: 1) to obtain 6-methoxy-7- (2-N-morpholinoethoxy) -3-nitro-4-N-m-methoxyanilino-quinoline, namely the compound 8.
By high resolution mass spectrometry (HR-ESI-MS), nuclear magnetic resonance hydrogen spectroscopy ( 1 H-NMR), nuclear magnetic resonance carbon spectrum (C 13 C-NMR) confirmed the structure of compound 8: mp: 159.1 to 161.2 ℃. 1 H-NMR(400MHz，CDCl 3 )δ：2.64(br.s，4H)，2.94(t，J＝5.2Hz，2H，NCH 2 )，3.39(s，3H，OCH 3 )，3.76(br.s，4H)，3.78(s，3H，OCH 3 )，4.33(t，J＝5.2Hz，2H，OCH 2 )，6.71(s，1H，ArH)，6.75(d，J＝8.0Hz，1H，ArH)，6.79(d，J＝8.0Hz，1H，ArH)，6.95(s，1H，ArH)，7.29(t，J＝8.0Hz，1H，ArH)，7.33(s，1H，ArH)，9.35(s，1H，2-H)，10.37(s，1H，NH)； 13 C-NMR(100MHz，CDCl 3 )δ：160.8，153.4，148.3，147.9，145.2，144.8，142.3，130.4，128.7，116.2，113.1，111.6，110.0，109.7，106.5，67.0，66.8(2C)，57.0，55.5，55.3，54.1(2C)；HR-ESI-MS(positive mode)m/z：455.1931[M+H] + (calculated for C 23 H 27 N 4 O 6 ，455.1931)。
Example 9:
the preparation of 6-methoxy-7- (2-N-morpholinylethoxy) -3-nitro-4-N-o-chloroanilino-quinoline comprises the following steps:
the procedure for the preparation of the eight steps from step 1 to step 8 was substantially the same as in example 1 except for the amount used.
And step 9: 0.50g (1.58mmol) of the compound h was placed in a 100mL round-bottom flask, followed by addition of 35mL of isopropanol and dissolution by heating. 1.896mmol of o-chloroaniline was added and the reaction was refluxed at 93 ℃ for 14 hours. After the reaction, the reaction mixture was left at room temperature until a precipitate was precipitated, filtered, washed with water, and dried over anhydrous magnesium sulfate to obtain 0.49g of 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-chloroanilino-quinoline in a yield of 76%.
Step 10: 0.10g (0.24mmol) of 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-o-chloroanilino-quinoline are dissolved in 25mL of dimethyl sulfoxide, 1.5 times the equivalent of anhydrous potassium carbonate is added, 2.5 times the equivalent of morpholine are added dropwise, after the addition is complete, the temperature is raised to 76 ℃ and the reaction is carried out for 14 hours. After the reaction is finished, cooling to room temperature, filtering and evaporating to dryness, extracting dichloromethane and water, purifying an organic layer by a chromatographic column, and eluting dichloromethane and methanol (13: 1) to obtain 6-methoxy-7- (2-N-morpholinylethoxy) -3-nitro-4-N-o-chloroanilino-quinoline, namely the compound 9.
By high resolution mass spectrometry (HR-ESI-MS), nuclear magnetic resonance hydrogen spectroscopy (H-ESI-MS) ((R)) 1 H-NMR), nuclear magnetic resonance carbon spectrum (C 13 C-NMR) confirmed the structure of compound 9: mp: 163.1-166.2 ℃. 1 H-NMR(400MHz，CDCl 3 )δ：2.63(br.s，4H)，2.94(t，J＝5.8Hz，2H，NCH 2 )，3.41(s，3H，OCH 3 )，3.75(t-like，4H)，4.33(t，J＝5.8Hz，2H，OCH 2 )，6.77(s，1H，ArH)，6.99(dd，J＝7.6，1.7Hz，1H，ArH)，7.18～7.22(m，2H，ArH)，7.37(s，1H，ArH)，7.55(dd，J＝7.5，1.6Hz，1H，ArH)，9.38(s，1H，2-H)，10.17(s，1H，NH)； 13 C-NMR(100MHz，CDCl 3 )δ：153.6，148.8，147.9，145.1，143.9，138.4，130.5，129.5，128.1，127.4，126.5，124.5，113.3，110.0，105.3，67.1，66.9(2C)，57.0，55.4，54.1(2C)；HR-ESI-MS(positive mode)m/z：459.1445[M+H] + (calculated for C 22 H 24 ClN 4 O 5 ，459.1435)。
Example 10:
the preparation of 6-methoxy-7- (2-N-morpholinylethoxy) -3-nitro-4-N-o-toluidino-quinoline comprises the following steps:
the procedure for the preparation of the eight steps from step 1 to step 8 was substantially the same as in example 1 except for the amount used.
And step 9: 0.50g (1.58mmol) of the compound h was placed in a 100mL round-bottom flask, followed by addition of 40mL of isopropanol and dissolution by heating. 1.896mmol of o-toluidine were added, and the reaction was refluxed at 88 ℃ for 17 hours. After the reaction, the reaction mixture was allowed to stand at room temperature until a precipitate was precipitated, filtered, washed with water, and dried over anhydrous magnesium sulfate to obtain 0.46g of 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-o-toluidino-quinoline in a yield of 75%.
Step 10: 0.10g (0.26mmol) of 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-o-toluidino-quinoline are dissolved in 40mL of dimethyl sulfoxide, 5.0 equivalents of anhydrous potassium carbonate are added, 5.5 equivalents of morpholine are added dropwise, after the addition is complete, the temperature is raised to 87 ℃ and the reaction is carried out for 12 hours. After the reaction is finished, cooling to room temperature, filtering and evaporating to dryness, extracting dichloromethane and water, purifying an organic layer by a chromatographic column, and eluting dichloromethane and methanol (18: 1) to obtain 6-methoxy-7- (2-N-morpholinoethoxy) -3-nitro-4-N-o-toluidino-quinoline, namely the compound 10.
By high resolution mass spectrometry (HR-ESI-MS), nuclear magnetic resonance hydrogen spectroscopy ( 1 H-NMR), nuclear magnetic resonance carbon spectrum (C 13 C-NMR) confirmed the structure of compound 10: mp: 70.1-73.2 ℃. 1 H-NMR(400MHz，CDCl 3 )δ：2.36(s，3H，CH 3 )，2.62(br.s，4H)，2.92(t，J＝5.8Hz，2H，NCH 2 )，3.27(s，3H，OCH 3 )，3.75(t-like，4H)，4.31(t，J＝5.8Hz，2H，OCH 2 )，6.79(s，1H，ArH)，7.10(m，1H，ArH)，7.23～7.26(m，2H，ArH)，7.25(d，J＝4.28Hz，1H，ArH)，7.32(s，1H，ArH)，7.38(m，1H，ArH)，9.37(s，1H，2-H)，10.54(s，1H，NH)； 13 C-NMR(100MHz，CDCl 3 )δ：153.2，148.2，147.7，146.1，145.7，139.5，133.5，131.5，127.4，127.24，127.18，125.8，112.7，110.1，105.6，66.94，66.91(2C)，57.0，55.1，54.1(2C)，18.3；HR-ESI-MS(positive mode)m/z：439.1995[M+H] + (calculated for C 23 H 27 N 4 O 5 ，439.1981)。
Example 11:
the preparation of 6-methoxy-7- (2-N-morpholinylethoxy) -3-nitro-4-N-o-methoxyanilino-quinoline comprises the following steps:
the procedure for the preparation of the eight steps from step 1 to step 8 was substantially the same as in example 1 except for the amount used.
And step 9: 0.50g (1.58mmol) of the compound h was placed in a 100mL round-bottom flask, followed by addition of 50mL of isopropanol and dissolution by heating. 1.896mmol of o-anisidine were added and the reaction refluxed at 98 ℃ for 18 hours. After the reaction, the reaction mixture was allowed to stand at room temperature until a precipitate was precipitated, and the precipitate was filtered, washed with water, and dried over anhydrous magnesium sulfate to obtain 0.51g of 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-o-methoxyanilino-quinoline in a yield of 80%.
Step 10: 0.10g (0.22mmol) of 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-o-methoxyanilino-quinoline are dissolved in 35mL of dimethyl sulfoxide, 3.5 times the equivalent of anhydrous potassium carbonate is added, 3.5 times the equivalent of morpholine are added dropwise, after the dropwise addition is complete, the temperature is raised to 78 ℃ and the reaction is carried out for 19 hours. After the reaction is finished, cooling to room temperature, filtering and evaporating to dryness, extracting dichloromethane and water, purifying an organic layer by a chromatographic column, and eluting dichloromethane and methanol (16: 1) to obtain 6-methoxy-7- (2-N-morpholinoethoxy) -3-nitro-4-N-o-methoxyanilino-quinoline, namely the compound 11.
By high resolution mass spectrometry (HR-ESI-MS), nuclear magnetic resonance hydrogen spectroscopy ( 1 H-NMR), nuclear magnetic resonance carbon spectrum (C 13 C-NMR) confirmed the structure of compound 11: mp: 163.2-165.2 ℃. 1 H-NMR(400MHz，CDCl 3 )δ：2.64(br.s，4H)，2.94(t，J＝5.6Hz，2H，NH 2 )，3.38(s，3H，OCH 3 )，3.76(br.s，4H)，3.84(s，3H，OCH 3 )，4.33(t，J＝5.6Hz，2H，OCH 2 )，6.94(td，J＝7.6，1.1Hz，1H，ArH)，7.00(s，1H，ArH)，7.01(dd，J＝8.2，1.1Hz，1H，ArH)，7.06(dd，J＝7.6，1.1Hz，1H，ArH)，7.22(td，J＝8.2，1.1Hz，1H，ArH)，7.34(s，1H，ArH)，9.36(s，1H，2-H)，10.29(s，1H，NH)； 13 C-NMR(100MHz，CDCl 3 )δ：153.2，152.4，148.2，147.5，145.4，145.2，129.6，128.5，126.8，124.0，120.6，113.4，111.6，110.0，105.7，67.0，66.9(2C)，57.0，55.8，55.3，54.1(2C)；HR-ESI-MS(positive mode)m/z：455.1944[M+H] + (calculated for C 23 H 27 N 4 O 6 ，455.1931)。
Cholinesterase inhibitory Activity assay
Screening of the inhibitory activity of the compounds prepared in the above examples on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE):
AChE and BChE inhibitory activity assays were performed using a modified Ellman method. To a 96-well plate, 140. mu.L of 100mM phosphate buffer, 20. mu.L of 0.05U/mL AChE (or 20. mu.L of 0.05U/mL BChE), and 20. mu.L of the test compound were sequentially added, mixed well, and incubated in a 25 ℃ incubator for 15 minutes. Then, 10. mu.L of 10.0mM DNTB and 10. mu.L of 7.5mM ATCI (or 10. mu.L of 7.5mM BTCI) were added, and the resulting mixture was placed in a thermostat, and after incubation at 37 ℃ for 30 minutes, the absorbance at 412nm of the solution in a 96-well plate was measured. 20 μ L of 0.01mol/L DMSO was used as a negative control, 20 μ L of galantamine was used instead of the test compound as a positive control, and the blank was prepared by adding 20 μ L of 100mM phosphate buffer instead of the test compound. Each group of data was done in parallel 3 times and the average was taken. The results were recorded and the inhibition [ inhibition (%) ═ OD blank-OD sample)/OD blank × 100% was calculated according to the formula]While calculating the median inhibitory concentration IC 50 The value is obtained. The results of the activity measurement are shown in table 1:
TABLE 1 results of the inhibitory Activity of Compounds 1-11 on cholinesterase
Evaluation of quasi-drug Properties
The lipophilicity of the compounds prepared in the above examples was calculated by ChemDraw software as follows:
TABLE 2 LogP values for the respective compounds
The detection results in table 1 show that eleven compounds prepared by the invention can effectively inhibit the activities of acetylcholinesterase and butyrylcholinesterase, so that eleven compounds of the invention are expected to be prepared into medicines for treating diseases related to insufficient acetylcholine. Diseases associated with acetylcholine deficiency include alzheimer's disease, myasthenia gravis, glaucoma, and the like. The results in table 2 show that the lipophilicity of the eleven compounds meets the drug-like property LogP index of the anti-alzheimer disease drug, and the eleven compounds have a prospect of being applied to preparation of the anti-alzheimer disease drug.
The foregoing is merely a representative example of the present invention and is not intended to limit the invention in any manner. Any modification, equivalent change and modification of the above embodiments according to the technical spirit of the present invention still fall within the scope of the technical solution of the present invention.
Claims (6)
- 2-N-morpholinylethoxy group-substituted quinoline derivatives, characterized by the following chemical structural formula:
in the structural formula, R is phenyl, m-chlorophenyl, p-tolyl, p-methoxyphenyl, p-hydroxyphenyl, m-tolyl, m-methoxyphenyl, o-chlorophenyl, o-tolyl or o-methoxyphenyl. - 2. 2-N-morpholinoethoxy group substituted quinoline derivatives as claimed in claim 1 wherein: the derivatives specifically include 6-methoxy-7- (2-N-morpholinoethoxy) -3-nitro-4-N-anilino-quinoline, 6-methoxy-7- (2-N-morpholinoethoxy) -3-nitro-4-N-m-chloroanilino-quinoline, 6-methoxy-7- (2-N-morpholinoethoxy) -3-nitro-4-N-p-toluidino-quinoline, 6-methoxy-7- (2-N-morpholinoethoxy) -3-nitroethoxy-quinoline 4-N-p-methoxyanilino-quinoline, 6-methoxy-7- (2-N-morpholinoethoxy) -3-nitro-4-N-p-hydroxyphenylamino-quinoline, 6-methoxy-7- (2-N-morpholinoethoxy) -3-nitro-4-N-m-toluidino-quinoline, 6-methoxy-7- (2-N-morpholinoethoxy) -3-nitro-4-N-m-methoxyanilino-quinoline, 6-methoxy-7- (2-N-morpholinoethoxy) -3-nitro-4-N-o-chloroanilino-quinoline, and mixtures thereof, 6-methoxy-7- (2-N-morpholinoethoxy) -3-nitro-4-N-o-toluidino-quinoline and 6-methoxy-7- (2-N-morpholinoethoxy) -3-nitro-4-N-o-methoxyanilino-quinoline.
- 3. A method for preparing 2-N-morpholinoethoxy group-substituted quinoline derivatives according to claim 1, comprising: the compound is prepared by taking dimethyl sulfoxide as a solvent and reacting 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-substituted anilino-quinoline with morpholine. The method comprises the following specific steps:dissolving 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-substituted anilino-quinoline in dimethyl sulfoxide, adding anhydrous potassium carbonate, dropwise adding morpholine, heating after dropwise adding for heat preservation reaction, cooling to room temperature after reaction, drying and purifying to obtain the target compound.
- 4. A method for preparing 2-N-morpholinoethoxy group-substituted quinoline derivatives according to claim 3, wherein: the 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-substituted anilino-quinoline is 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-anilino-quinoline, 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-m-chloroanilino-quinoline, 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-p-toluidino-quinoline, or a salt thereof, 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-p-methoxyanilino-quinoline, 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-p-hydroxyphenylamino-quinoline, 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-m-toluidino-quinoline, 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-m-methoxyanilino-quinoline, 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-o-chloroanilino-quinoline, 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-o-methylanilino-quinoline or 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-o-methoxyanilino-quinoline.
- 5. The process for producing a 2-N-morpholinoethoxy group-substituted quinoline derivative according to claim 3 or 4, wherein: the mol ratio of the 6-methoxy-7- (2-chloroethoxy) -3-nitro-4-N-substituted anilino-quinoline to the anhydrous potassium carbonate and the morpholine is 1: 1.0-6.0 in sequence; after the dropwise addition, the heat preservation temperature is 71-90 ℃.
- 6. The use of 2-N-morpholinoethoxy group-substituted quinolines as claimed in claim 1 or 2, wherein: the derivative has the activity of inhibiting both acetylcholinesterase and butyrylcholinesterase, has proper lipophilicity, and can be used for preparing anti-Alzheimer disease drugs.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110079183.0A CN114805201A (en) | 2021-01-21 | 2021-01-21 | Preparation method and application of 2-N-morpholinyl ethoxy group substituted quinoline derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110079183.0A CN114805201A (en) | 2021-01-21 | 2021-01-21 | Preparation method and application of 2-N-morpholinyl ethoxy group substituted quinoline derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114805201A true CN114805201A (en) | 2022-07-29 |
Family
ID=82524225
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110079183.0A Pending CN114805201A (en) | 2021-01-21 | 2021-01-21 | Preparation method and application of 2-N-morpholinyl ethoxy group substituted quinoline derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN114805201A (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1830964A (en) * | 2005-03-11 | 2006-09-13 | 中国科学院上海药物研究所 | 4-Substituting anilino-3-nitroquinoline compounds, prepn. method and use thereof |
| CN107721923A (en) * | 2017-10-09 | 2018-02-23 | 天津理工大学 | 4 N anilino quinolines class compound synthesis and the application for preparing anti-Alzheimer disease medicine |
-
2021
- 2021-01-21 CN CN202110079183.0A patent/CN114805201A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1830964A (en) * | 2005-03-11 | 2006-09-13 | 中国科学院上海药物研究所 | 4-Substituting anilino-3-nitroquinoline compounds, prepn. method and use thereof |
| CN107721923A (en) * | 2017-10-09 | 2018-02-23 | 天津理工大学 | 4 N anilino quinolines class compound synthesis and the application for preparing anti-Alzheimer disease medicine |
Non-Patent Citations (1)
| Title |
|---|
| 胡栋: "吗啉或N-乙基哌嗪基团取代的喹啉类衍生物合成及生物活性研究", 中国优秀硕士学位论文全文数据库工程科技Ⅰ辑, no. 11, 15 November 2018 (2018-11-15), pages 014 - 56 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP3299369A1 (en) | Pyrido-azaheterecydic compound and preparation method and use thereof | |
| JP6966423B2 (en) | Condensed ring pyrimidine amino derivative, its production method, intermediate, pharmaceutical composition and application | |
| EP3070089A1 (en) | N-benzyl tryptanthrin derivative, and preparation method and application thereof | |
| CZ2003354A3 (en) | Benzimidazole derivatives, process of their preparation and their use for treatment | |
| MX2007013226A (en) | Acetylene derivatives. | |
| WO2017186140A1 (en) | Method for preparing tyrosine kinase inhibitor and derivative thereof | |
| JP2021522236A (en) | Racemic splitting with diastereomer tartrate (4S) -4- (4-cyano-2-methoxyphenyl) -5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthylidine-3 -How to prepare carboxamide | |
| WO2017016410A1 (en) | Preparation method for antitumor drug ap26113 | |
| EP2878595A1 (en) | Method of producing 4-[5-(pyridin-4-yl)-1h-1,2,4-triazole-3-yl]pyridin-2-carbonitrile, and intermediary thereof | |
| CN113024508A (en) | Nitrogen heterocyclic ring derivative and preparation method and application thereof | |
| JP4199668B2 (en) | Piperazine derivatives having SST1 antagonist activity | |
| CA2989265A1 (en) | Bicyclic heterocycle derivatives as bromodomain inhibitors | |
| AU2013276165B2 (en) | Tricyclic compounds as KAT II inhibitors | |
| CN110240539B (en) | Fluorine substituted diphenylethane compound, preparation method and application | |
| JP2022543924A (en) | Benzopyrazole Compounds as RHO Kinase Inhibitors, Salt Forms, Crystal Forms and Methods of Making Same | |
| EP3741746A1 (en) | Crystal form of oxopicolinamide derivative and preparation method therefor | |
| CN114805201A (en) | Preparation method and application of 2-N-morpholinyl ethoxy group substituted quinoline derivatives | |
| CN112174958B (en) | Pyrido [2,3-d ] pyrimidine compound and preparation method and application thereof | |
| EP1541149A1 (en) | Phosphodiesterase inhibitor | |
| WO2008019572A1 (en) | Meptazinol biligand derivatives and/or their salts, preparation method and uses thereof | |
| JP7355834B2 (en) | FGFR inhibitor compounds in solid form and methods for producing the same | |
| EP2258676B1 (en) | Stable vinamidinium salt and nitrogen-containing heterocyclic ring synthesis using the same | |
| CN112441970A (en) | 2, 5-disubstituted-3-aminopyridine compound and preparation method and application thereof | |
| JP7333420B2 (en) | Triazolopyrimidine compounds and salts thereof, compositions and uses | |
| RU2809821C2 (en) | Compounds based on triazolopyrimidine and their salts, compositions based on them and ways of their use |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |