CN109678776A - 3-芳基琥珀酰亚胺类化合物的制备方法 - Google Patents
3-芳基琥珀酰亚胺类化合物的制备方法 Download PDFInfo
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- CN109678776A CN109678776A CN201910068552.9A CN201910068552A CN109678776A CN 109678776 A CN109678776 A CN 109678776A CN 201910068552 A CN201910068552 A CN 201910068552A CN 109678776 A CN109678776 A CN 109678776A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 55
- 238000000034 method Methods 0.000 claims abstract description 32
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 11
- 239000003960 organic solvent Substances 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 7
- 239000001257 hydrogen Substances 0.000 claims abstract description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 5
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 4
- 125000003118 aryl group Chemical group 0.000 claims abstract description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 3
- VDQQJMHXZCMNMU-UHFFFAOYSA-N 1-phenylpyrrolidine Chemical compound C1CCCN1C1=CC=CC=C1 VDQQJMHXZCMNMU-UHFFFAOYSA-N 0.000 claims description 28
- -1 N, N-disubstituted aniline compound Chemical class 0.000 claims description 14
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 11
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical class C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 11
- SEEYREPSKCQBBF-UHFFFAOYSA-N n-methylmaleimide Chemical compound CN1C(=O)C=CC1=O SEEYREPSKCQBBF-UHFFFAOYSA-N 0.000 claims description 11
- BYEAHWXPCBROCE-UHFFFAOYSA-N 1,1,1,3,3,3-hexafluoropropan-2-ol Chemical compound FC(F)(F)C(O)C(F)(F)F BYEAHWXPCBROCE-UHFFFAOYSA-N 0.000 claims description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical class C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 claims description 8
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 claims description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 5
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 5
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 5
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 5
- MKRBAPNEJMFMHU-UHFFFAOYSA-N 1-benzylpyrrole-2,5-dione Chemical compound O=C1C=CC(=O)N1CC1=CC=CC=C1 MKRBAPNEJMFMHU-UHFFFAOYSA-N 0.000 claims description 4
- HIDBROSJWZYGSZ-UHFFFAOYSA-N 1-phenylpyrrole-2,5-dione Chemical compound O=C1C=CC(=O)N1C1=CC=CC=C1 HIDBROSJWZYGSZ-UHFFFAOYSA-N 0.000 claims description 4
- RHQDFWAXVIIEBN-UHFFFAOYSA-N Trifluoroethanol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- ZQVAGPGHTQBLMM-UHFFFAOYSA-N 1-(2-methylphenyl)pyrrolidine Chemical compound CC1=CC=CC=C1N1CCCC1 ZQVAGPGHTQBLMM-UHFFFAOYSA-N 0.000 claims description 3
- OYTHXKUORVSWJZ-UHFFFAOYSA-N 1-(2-phenylphenyl)pyrrolidine Chemical compound C1CCCN1C1=CC=CC=C1C1=CC=CC=C1 OYTHXKUORVSWJZ-UHFFFAOYSA-N 0.000 claims description 3
- CZYCLVQEDDSKCW-UHFFFAOYSA-N 1-(3,5-dimethylphenyl)pyrrolidine Chemical compound CC1=CC(C)=CC(N2CCCC2)=C1 CZYCLVQEDDSKCW-UHFFFAOYSA-N 0.000 claims description 3
- SYYZESGQAICJGW-UHFFFAOYSA-N 1-(3-chlorophenyl)pyrrolidine Chemical compound ClC1=CC=CC(N2CCCC2)=C1 SYYZESGQAICJGW-UHFFFAOYSA-N 0.000 claims description 3
- SDWQEPLBCOZBFL-UHFFFAOYSA-N 1-(3-methoxyphenyl)pyrrolidine Chemical compound COC1=CC=CC(N2CCCC2)=C1 SDWQEPLBCOZBFL-UHFFFAOYSA-N 0.000 claims description 3
- LAFRMYPYBPWQKY-UHFFFAOYSA-N 1-(3-methylphenyl)pyrrolidine Chemical compound CC1=CC=CC(N2CCCC2)=C1 LAFRMYPYBPWQKY-UHFFFAOYSA-N 0.000 claims description 3
- JNPCNDJVEUEFBO-UHFFFAOYSA-N 1-butylpyrrole-2,5-dione Chemical compound CCCCN1C(=O)C=CC1=O JNPCNDJVEUEFBO-UHFFFAOYSA-N 0.000 claims description 3
- JJFUPPZOYYMAFC-UHFFFAOYSA-N 1-ethyl-2,3-dihydroindole Chemical compound C1=CC=C2N(CC)CCC2=C1 JJFUPPZOYYMAFC-UHFFFAOYSA-N 0.000 claims description 3
- QYKOLWLKTJIVEX-UHFFFAOYSA-N 1-ethyl-3,4-dihydro-2h-quinoline Chemical compound C1=CC=C2N(CC)CCCC2=C1 QYKOLWLKTJIVEX-UHFFFAOYSA-N 0.000 claims description 3
- LLSKXGRDUPMXLC-UHFFFAOYSA-N 1-phenylpiperidine Chemical compound C1CCCCN1C1=CC=CC=C1 LLSKXGRDUPMXLC-UHFFFAOYSA-N 0.000 claims description 3
- NQDOCLXQTQYUDH-UHFFFAOYSA-N 1-propan-2-ylpyrrole-2,5-dione Chemical compound CC(C)N1C(=O)C=CC1=O NQDOCLXQTQYUDH-UHFFFAOYSA-N 0.000 claims description 3
- VJPATYRREZJCLJ-UHFFFAOYSA-N 4-methyl-1-phenylpiperidine Chemical compound C1CC(C)CCN1C1=CC=CC=C1 VJPATYRREZJCLJ-UHFFFAOYSA-N 0.000 claims description 3
- 150000002240 furans Chemical class 0.000 claims description 3
- 150000002475 indoles Chemical class 0.000 claims description 3
- AJUXDFHPVZQOGF-UHFFFAOYSA-N n,n-dimethyl-1-naphthylamine Chemical compound C1=CC=C2C(N(C)C)=CC=CC2=C1 AJUXDFHPVZQOGF-UHFFFAOYSA-N 0.000 claims description 3
- 150000003233 pyrroles Chemical class 0.000 claims description 3
- DZFWNZJKBJOGFQ-UHFFFAOYSA-N julolidine Chemical compound C1CCC2=CC=CC3=C2N1CCC3 DZFWNZJKBJOGFQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 230000001681 protective effect Effects 0.000 claims description 2
- 238000006798 ring closing metathesis reaction Methods 0.000 claims description 2
- 229960001701 chloroform Drugs 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000002904 solvent Substances 0.000 abstract description 10
- 239000003054 catalyst Substances 0.000 abstract description 6
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 4
- 239000007800 oxidant agent Substances 0.000 abstract description 4
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- 238000001308 synthesis method Methods 0.000 abstract description 3
- 150000002790 naphthalenes Chemical class 0.000 abstract 1
- 238000007363 ring formation reaction Methods 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 112
- 238000012360 testing method Methods 0.000 description 61
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 32
- 238000005160 1H NMR spectroscopy Methods 0.000 description 31
- 238000001819 mass spectrum Methods 0.000 description 30
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 239000012230 colorless oil Substances 0.000 description 14
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 10
- 239000007787 solid Substances 0.000 description 9
- KZNICNPSHKQLFF-UHFFFAOYSA-N dihydromaleimide Natural products O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 7
- 239000003921 oil Substances 0.000 description 7
- 229960002317 succinimide Drugs 0.000 description 7
- 238000002844 melting Methods 0.000 description 5
- 230000008018 melting Effects 0.000 description 5
- VQKFNUFAXTZWDK-UHFFFAOYSA-N 2-Methylfuran Chemical compound CC1=CC=CO1 VQKFNUFAXTZWDK-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 125000000524 functional group Chemical group 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- OXHNLMTVIGZXSG-UHFFFAOYSA-N 1-Methylpyrrole Chemical compound CN1C=CC=C1 OXHNLMTVIGZXSG-UHFFFAOYSA-N 0.000 description 2
- BLRHMMGNCXNXJL-UHFFFAOYSA-N 1-methylindole Chemical compound C1=CC=C2N(C)C=CC2=C1 BLRHMMGNCXNXJL-UHFFFAOYSA-N 0.000 description 2
- ODFFPRGJZRXNHZ-UHFFFAOYSA-N 5-fluoroindole Chemical compound FC1=CC=C2NC=CC2=C1 ODFFPRGJZRXNHZ-UHFFFAOYSA-N 0.000 description 2
- DWAQDRSOVMLGRQ-UHFFFAOYSA-N 5-methoxyindole Chemical compound COC1=CC=C2NC=CC2=C1 DWAQDRSOVMLGRQ-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-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 compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
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- 238000004440 column chromatography Methods 0.000 description 2
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- 230000001105 regulatory effect Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 229940126558 11β-HSD1 inhibitor Drugs 0.000 description 1
- 150000003923 2,5-pyrrolediones Chemical class 0.000 description 1
- 102000002254 Glycogen Synthase Kinase 3 Human genes 0.000 description 1
- 108010014905 Glycogen Synthase Kinase 3 Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium chloride Substances Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000001430 anti-depressive effect Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 description 1
- 239000007805 chemical reaction reactant Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 125000000664 diazo group Chemical group [N-]=[N+]=[*] 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 231100001261 hazardous Toxicity 0.000 description 1
- 150000002390 heteroarenes Chemical class 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 238000009434 installation Methods 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 150000003953 γ-lactams Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members 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
- C07D207/36—Oxygen or sulfur atoms
- C07D207/40—2,5-Pyrrolidine-diones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
- C07D405/04—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 directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/06—Peri-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyrrole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及一种3‑芳基琥珀酰亚胺类化合物的制备方法,包括以下步骤:将N,N‑二取代苯胺类化合物或富电子杂芳环化合物与式(1)所示的化合物在有机溶剂中反应,反应温度为80~140℃,得到3‑芳基琥珀酰亚胺类化合物;式(1)如下:其中,R为氢、烷基、苯基或苄基;N,N‑二取代苯胺类化合物的结构式为式(2)‑式(5)中的任一种: 其中,表示R1和R2环合形成了五元环或六元环;表示R1和Ar基环合形成了五元环或六元环;式(5)表示R1、R2和Ar基环合形成了五元环或六元环;Ar代表芳基、取代芳基或萘环;R1和R2独立地选自烷基。本发明的方法简单经济,不需要外加氧化剂和催化剂,在溶剂中直接得到产物,是一种高效、经济、环保的合成方法。
Description
技术领域
本发明涉及有机合成领域,尤其涉及一种3-芳基琥珀酰亚胺类化合物的制备方法。
背景技术
3-芳基琥珀酰亚胺是一类普遍存在于药物和材料科学中的重要结构。3-芳基琥珀酰亚胺,不仅自身具有广泛的生物活性,可作为抗惊厥药物、抗炎药物以及免疫调节药物IDO抑制剂,而且其还可转化成其它杂环(如马来酰亚胺,吡咯烷和γ-内酰胺等),具有更丰富的生物活性,可作为抗抑郁的GSK-3抑制剂、抗菌药物、代谢调节的11β-HSD1抑制剂。
传统上,3-芳基琥珀酸通常是在210℃下由3-芳基琥珀酸与氨或伯胺缩合制备的(图1a)。然而,这个方法会使用大量的剧毒氰化钾/钠、高温和多步反应,并且起始原料的多样性限制了所制备的3-芳基琥珀酸产物的多样性。随后发展了AlCl3或AlBr3介导的苯与马来酰亚胺的反应,然而这个条件需要使用大大过量的AlCl3或AlBr3,后处理也会变得复杂(图1b)。近年来,还开发了一些二步反应的合成方法,即首先安装各种官能化基团,如硼酸、硅烷、重氮等,然后在钌或铜等金属催化下进行偶联反应,如图1c-d所示。
总之,现有的3-芳基琥珀酰亚胺的制备方法都存在以下几个缺点:高的催化剂负载量、额外安装预官能团、昂贵催化剂或有害试剂的使用、为提高反应性而使用苛刻的反应条件(如高温和微波辐射)、选择性差而导致产物多使得后处理繁复。
发明内容
为解决上述技术问题,本发明的目的是提供一种简单经济的3-芳基琥珀酰亚胺类化合物的制备方法,本发明的方法具有较好的原子经济性和步骤经济性,不需要外加氧化剂和催化剂,在溶剂中直接得到产物,是一种高效、经济、环保的合成方法。
本发明提供了一种3-芳基琥珀酰亚胺类化合物的制备方法,包括以下步骤:
将N,N-二取代苯胺类化合物或富电子杂芳环化合物与式(1)所示的化合物在有机溶剂中反应,反应温度为80~140℃,得到所述3-芳基琥珀酰亚胺类化合物;所述有机溶剂中至少包括氟碳醇溶剂;
式(1)如下:
其中,R为氢、C1-C8烷基、苯基或苄基;
所述N,N-二取代苯胺类化合物的结构式为式(2)-式(5)中的任一种,式(2)-式(5)如下:
其中,
表示R1和R2环合形成了五元环或六元环;
表示R1和Ar基环合形成了五元环或六元环;
式(5)表示R1、R2和Ar基环合形成了五元环或六元环;
式(2)-式(5)中,Ar代表芳基、取代芳基或萘环;取代芳基中的取代基为C1-C8烷基、C1-C8烷氧基或卤素;R1和R2独立地选自C1-C8烷基。
反应路线如下:
其中,HArNR1R2代表N,N-二取代苯胺类化合物,(Het)ArH代表富电子杂芳环化合物。
进一步地,当N,N-二取代苯胺类化合物的结构式为式(2)、式(3)、式(4)或式(5)时,所得到的3-芳基琥珀酰亚胺类化合物的结构式分别如下:
其中,R、R1、R2和Ar基所代表的含义式(2)-(5)中的相同。
进一步地,富电子杂芳环化合物为吲哚、取代吲哚、吡咯、取代吡咯、呋喃或取代呋喃。
进一步地,取代吲哚、取代吡咯或取代呋喃中的取代基为C1-C8烷基、C1-C8烷氧基或卤素。
进一步地,氟碳醇为六氟异丙醇(HFIP)和/或三氟乙醇(TFE)。
进一步地,有机溶剂中还包括三氯甲烷或甲苯。优选地,有机溶剂为HFIP。
进一步地,保护气氛为氮气。
进一步地,N,N-二取代苯胺类化合物或富电子杂芳环化合物和式(1)所示的化合物的摩尔比为1∶(2~6);优选1∶(3~5),进一步优选1∶4。
进一步地,N,N-二取代苯胺类化合物为1-苯基吡咯烷、1-苯基哌啶、4-甲基-1-苯基哌啶、N,N-二乙基苯胺、N,N-二甲基苯胺、1-(3-甲氧基苯基)吡咯烷、1-(3-氯苯基)吡咯烷、1-([1,1'-联苯基]-2-基)吡咯烷、1-(邻甲苯基)吡咯烷、1-(间-甲苯基)吡咯烷、1-(3,5-二甲基苯基)吡咯烷、1-乙基-1,2,3,4-四氢喹啉、1-乙基二氢吲哚、1,2,3,5,6,7-六氢吡啶并[3,2,1-ij]喹啉或N,N-二甲基萘-1-胺。其结构式依次如下:
进一步地,富电子杂芳环化合物的结构式为如下结构式中的一种:
其中,R1’为氢、C1-C8烷基、C1-C8烷氧基或卤素。
优选地,富电子杂芳环化合物为1-甲基-1H-吲哚、2-甲基呋喃、1H-吲哚、5-氟-1H-吲哚、5-甲氧基-1H-吲哚、1-甲基-1H-吡咯或1H-吡咯。其结构式依次如下:
进一步地,式(1)所示的化合物为1-甲基-1H-吡咯-2,5-二酮、1-丁基-1H-吡咯-2,5-二酮、1-异丙基-1H-吡咯-2,5-二酮、1-苯基-1H-吡咯-2,5-二酮、1-苄基-1H-吡咯-2,5-二酮或1H-吡咯-2,5-二酮。其结构式依次如下:
进一步地,氟碳醇的体积与式(1)所示的化合物的摩尔数的比例为(1-8)mL:(1-4)mmol,优选为4mL:2mmol。
进一步地,反应时间为12-24小时。
优选地,反应的温度为100℃~120℃,反应时间为15-20小时;进一步优选地,反应的温度为100℃,反应时间为18小时。
进一步地,反应完成后还包括去除溶剂并干燥以及柱层析纯化的步骤。
进一步地,本发明的反应在无氧化剂以及无催化剂的惰性环境中进行。
以溶剂为HFIP,N,N-二取代苯胺类化合物为1-苯基吡咯烷,式(1)所示的化合物为1-甲基-1H-吡咯-2,5-二酮为例,本发明的反应原理如下:
反应的最初步骤是HFIP通过氢键作用对2a进行活化。然后,1a对2a进行亲核进攻产生中间体7,其随后经历氢转移得到预期的产物。
借由上述方案,本发明至少具有以下优点:
本发明首次公开了以N,N-二取代苯胺类化合物或富电子杂芳环化合物和马来酰亚胺或其衍生物为原料,以氟碳醇作为反应溶剂和反应促进剂,制备3-芳基琥珀酰亚胺类化合物,该方法是3-芳基琥珀酰亚胺合成的简易方法,不需要氧化剂和金属催化剂的参与,且使用的是环境友好的氟碳醇作为反应溶剂,相比于常用的预先安装官能团化基团的金属催化偶联的方法,此方法更加简易,原子经济性好,安全性更高,步骤经济性好,反应收率高。
上述说明仅是本发明技术方案的概述,为了能够更清楚了解本发明的技术手段,并可依照说明书的内容予以实施,以下以本发明的较佳实施例并配合附图详细说明如后。
附图说明
图1是现有的3-芳基琥珀酰亚胺类化合物的制备方法路线图。
具体实施方式
下面结合附图和实施例,对本发明的具体实施方式作进一步详细描述。以下实施例用于说明本发明,但不用来限制本发明的范围。
本发明以下实施例中,核磁测试是以CDCl3为溶剂,以四甲基硅烷(TMS)为内标,在400或600MHz(13C NMR为100或150MHz)上记录1H NMR谱。化学位移以TMS 0.00ppm的低磁场百万分率(ppm,δ标度)报告,并参考CDCl3为7.26ppm(1H NMR)或77.16ppm(13C NMR)。HRMS记录在GCT PremierTM(CI)质谱仪上。柱色谱法在硅胶(200-300目)上进行。所有反应均采用薄层色谱法(TLC)在硅胶板上进行监测。除另有说明外,所有市售试剂均未经进一步纯化而使用。
本发明以下实施例中的反应原料1-苯基吡咯烷类化合物以四氢呋喃及其相应的苯胺为原料,参照文献Catal.Comm.2017,94,56-59中的方法制得。而非商业性的马来酰亚胺衍生物反应原料则由顺丁烯二酸酐及其相应的烷基胺按照文献J.Agric.FoodChem.2016,64,4876-4881中的方法制得,在此不在赘述。
实施例1
向装有螺旋盖并搅拌的15mL压力管中加入1-苯基吡咯烷(0.5mmol)并溶解在HFIP(4mL)中。随后加入1-甲基-1H-吡咯-2,5-二酮(2.0mmol)。将反应混合物在氮气保护下在100℃下搅拌24小时。反应完全后,将反应混合物冷却至室温。除去压力管中的溶剂后,通过硅胶柱色谱(PE:EA=5:1)纯化残余物,得到相应的产物(117mg,91%),为白色固体(熔点:174.8-175.5℃),其结构式如下:
其核磁测试结果和质谱测试结果分别如下:
1H NMR(400MHz,CDCl3)δ6.97(d,J=8.4Hz,2H),6.45(d,J=8.4Hz,2H),3.83(dd,J=9.1,4.3Hz,1H),3.20–3.15(m,4H),3.14–3.04(m,1H),2.97(s,3H),2.71(dd,J=18.4,4.2Hz,1H),1.93–1.89(m,4H)。
13C NMR(150MHz,CDCl3)δ178.68,176.80,147.50,128.00,123.15,112.02,47.57,45.20,37.27,25.44,25.07。
HRMS(CI)calcd for C15H19N2O2[M+H]+:259.1447,found 259.1440。
实施例2
将实施例1中的1-苯基吡咯烷替换为等摩尔的1-苯基哌啶,其他条件不变,按照实施例1的方法制备3-芳基琥珀酰亚胺类化合物(产量55mg,产率40%,为无色油状物),其结构式如下:
其核磁测试结果和质谱测试结果分别如下:
1H NMR(400MHz,CDCl3)δ6.99(d,J=7.7Hz,2H),6.82(d,J=7.8Hz,2H),3.85(dd,J=8.9,4.1Hz,1H),3.11–3.04(m,5H),2.97(s,3H),2.72(dd,J=18.4,3.8Hz,1H),1.62–1.59(m,4H),1.49(d,J=4.3Hz,2H)。
13C NMR(150MHz,CDCl3)δ178.35,176.58,151.72,127.92,126.85,116.73,50.32,45.15,37.12,25.67,25.12,24.22。
HRMS(CI)calcd for C16H21N2O2[M+H]+:273.1603,found 273.1605。
实施例3
将实施例1中的1-苯基吡咯烷替换为等摩尔的4-甲基-1-苯基哌啶,其他条件不变,按照实施例1的方法制备3-芳基琥珀酰亚胺类化合物(产量80mg,产率56%,为无色油状物),其结构式如下:
其核磁测试结果和质谱测试结果分别如下:
1H NMR(400MHz,CDCl3)δ7.08(d,J=8.3Hz,2H),6.92(d,J=7.7Hz,2H),3.95–3.94(m,1H),3.64(d,J=11.8Hz,2H),3.17(dd,J=18.4,9.5Hz,1H),3.06(s,3H),2.81(dd,J=18.4,4.0Hz,1H),2.69(t,J=12.0Hz,2H),1.73(d,J=12.6Hz,2H),1.52–1.51(m,1H),1.33(d,J=10.7Hz,2H),0.98(d,J=6.2Hz,3H)。
13C NMR(150MHz,CDCl3)δ178.36,176.59,151.42,127.94,126.81,116.71,49.69,45.15,37.12,33.91,30.66,25.13,21.85。
HRMS(CI)calcd for C17H23N2O2[M+H]+:287.1760,found287.1756。
实施例4
将实施例1中的1-苯基吡咯烷替换为等摩尔的N,N-二乙基苯胺,其他条件不变,按照实施例1的方法制备3-芳基琥珀酰亚胺类化合物(产量105mg,产率81%,为无色油状物),其结构式如下:
其核磁测试结果和质谱测试结果分别如下:
1H NMR(400MHz,CDCl3)δ7.05(d,J=8.5Hz,2H),6.66(d,J=8.6Hz,2H),3.92(dd,J=9.3,4.5Hz,1H),3.35(q,J=7.0Hz,4H),3.17(dd,J=18.4,9.5Hz,1H),3.06(s,3H),2.81(dd,J=18.4,4.5Hz,1H),1.16(t,J=7.0Hz,6H)。
13C NMR(150MHz,CDCl3)δ178.70,176.79,147.30,128.17,123.01,112.01,45.07,44.31,37.20,25.07,12.49。
HRMS(CI)calcd for C15H21N2O2[M+H]+:261.1603,found 261.1594。
实施例5
将实施例1中的1-苯基吡咯烷替换为等摩尔的N,N-二甲基苯胺,其他条件不变,按照实施例1的方法制备3-芳基琥珀酰亚胺类化合物(产量46mg,产率40%,为无色油状物),其结构式如下:
其核磁测试结果和质谱测试结果分别如下:
1H NMR(400MHz,CDCl3)δ7.07(d,J=8.4Hz,2H),6.71(d,J=8.5Hz,2H),3.93(dd,J=9.3,4.5Hz,1H),3.16(dd,J=18.4,9.5Hz,1H),3.05(s,3H),2.94(s,6H),2.85–2.76(m,1H)。
13C NMR(150MHz,CDCl3)δ178.55,176.70,150.10,127.97,124.41,112.97,45.11,40.53,37.17,25.10。
HRMS(CI)calcd for C13H17N2O2[M+H]+:233.1290,found 233.1292。
实施例6
将实施例1中的1-苯基吡咯烷替换为等摩尔的1-(3-甲氧基苯基)吡咯烷,其他条件不变,按照实施例1的方法制备3-芳基琥珀酰亚胺类化合物(产量125mg,产率87%,为无色油状物),其结构式如下:
其核磁测试结果和质谱测试结果分别如下:
1H NMR(400MHz,CDCl3)δ6.97(d,J=7.9Hz,1H),6.10(d,J=7.8Hz,1H),6.04(s,1H),3.86–3.76(m,1H),3.72(s,3H),3.28–3.26(m,4H),3.05(s,3H),3.09–2.98(m,1H),2.71(d,J=18.0,Hz,1H),2.01-1.99(m,4H)。
13C NMR(150MHz,CDCl3)δ179.62,177.41,157.78,149.20,131.06,112.45,103.78,95.36,55.23,47.70,43.36,36.77,25.43,24.85。
HRMS(CI)calcd for C16H21N2O3[M+H]+289.1552,found 289.1549。
实施例7
将实施例1中的1-苯基吡咯烷替换为等摩尔的1-(3-氯苯基)吡咯烷,其他条件不变,按照实施例1的方法制备3-芳基琥珀酰亚胺类化合物(产量108mg,产率74%,为黄色油状物),其结构式如下:
其核磁测试结果和质谱测试结果分别如下:
1H NMR(400MHz,CDCl3)δ6.97(d,J=8.4Hz,1H),6.55(s,1H),6.41–6.39(d,J=6.4Hz,1H),4.17(dd,J=9.4,5.5Hz,1H),3.26–3.23(m,4H),3.17(dd,J=18.4,9.6Hz,1H),3.08(s,3H),2.75(dd,J=18.4,5.4Hz,1H),2.02–1.99(m,4H)。
13C NMR(150MHz,CDCl3)δ178.14,176.37,148.33,134.12,130.35,120.56,112.60,110.53,47.57,44.22,36.88,25.41,25.08。
HRMS(CI)calcd for C15H18ClN2O2[M+H]+:293.1057,found 293.1056。
实施例8
将实施例1中的1-苯基吡咯烷替换为等摩尔的1-([1,1'-联苯基]-2-基)吡咯烷,其他条件不变,按照实施例1的方法制备3-芳基琥珀酰亚胺类化合物(产量134mg,产率80%,为无色油状物),其结构式如下:
其核磁测试结果和质谱测试结果分别如下:
1H NMR(400MHz,CDCl3)δ7.39(d,J=7.4Hz,2H),7.34(t,J=7.4Hz,2H),7.29–7.23(m,1H),7.05(d,J=8.4Hz,1H),6.95(s,1H),6.82(d,J=8.4Hz,1H),3.94(dd,J=9.2,4.5Hz,1H),3.16(dd,J=18.5,9.5Hz,1H),3.03(s,3H),2.87–2.79(m,5H),1.74–1.71(m,4H)。
13C NMR(150MHz,CDCl3)δ178.43,176.58,147.49,142.63,131.15,130.29,129.04,127.94,126.68,126.40,125.86,114.90,50.93,45.19,37.23,25.40,25.12。
HRMS(CI)calcd for C21H23N2O2[M+H]+:335.1760,found 335.1750。
实施例9
将实施例1中的1-苯基吡咯烷替换为等摩尔的1-(邻甲苯基)吡咯烷,其他条件不变,按照实施例1的方法制备3-芳基琥珀酰亚胺类化合物(产量102mg,产率75%,为无色油状物),其结构式如下:
其核磁测试结果和质谱测试结果分别如下:
1H NMR(400MHz,CDCl3)δ6.96–6.92(m,2H),6.84(d,J=8.7Hz,1H),3.93(dd,J=9.2,4.4Hz,1H),3.21–3.14(m,5H),3.07(s,3H),2.82(dd,J=18.5,4.3Hz,1H),2.32(s,3H),1.95–1.92(m,4H)。
13C NMR(150MHz,CDCl3)δ178.46,176.67,149.18,130.53,129.09,128.00,125.07,116.07,50.96,45.25,37.24,25.11,24.99,20.74。
HRMS(CI)calcd for C16H21N2O2[M+H]+:273.1603,found273.1605。
实施例10
将实施例1中的1-苯基吡咯烷替换为等摩尔的1-(间-甲苯基)吡咯烷,其他条件不变,按照实施例1的方法制备3-芳基琥珀酰亚胺类化合物(产量96mg,产率70%,为无色油状物),其结构式如下:
其核磁测试结果和质谱测试结果分别如下:
1H NMR(400MHz,CDCl3)δ6.83(d,J=8.2Hz,1H),6.39–6.36(m,2H),4.14(dd,J=9.0,4.5Hz,1H),3.26–3.24(m,4H),3.16(dd,J=18.5,9.6Hz,1H),3.07(s,3H),2.67(dd,J=18.4,4.3Hz,1H),2.31(s,3H),2.00–1.96(m,4H)。
13C NMR(150MHz,CDCl3)δ179.06,176.82,147.41,136.95,127.26,122.42,113.90,109.85,47.53,42.53,37.33,25.42,25.04,20.25。
HRMS(CI)calcd for C16H21N2O2[M+H]+:273.1603,found 273.1604。
实施例11
将实施例1中的1-苯基吡咯烷替换为等摩尔的1-(3,5-二甲基苯基)吡咯烷,其他条件不变,按照实施例1的方法制备3-芳基琥珀酰亚胺类化合物(产量116mg,产率82%,为白色固体),其结构式如下:
其核磁测试结果和质谱测试结果分别如下:
1H NMR(400MHz,CDCl3)δ6.24(d,J=13.6Hz,2H),4.27(dd,J=9.2,6.4Hz,1H),3.24–3.21(m,4H),3.17–3.03(m,1H),3.6(s,3H),2.64(dd,J=18.5,6.1Hz,1H),2.32(s,3H),2.00(s,3H),1.97–1.94(m,4H)。
13C NMR(150MHz,CDCl3)δ179.42,176.52,147.16,138.08,136.46,120.29,113.05,111.75,47.44,41.16,36.02,25.40,24.97,21.50,20.25。
HRMS(CI)calcd for C17H23N2O2[M+H]+:287.1760,found 287.1749。
实施例12
将实施例1中的1-苯基吡咯烷替换为等摩尔的1-乙基-1,2,3,4-四氢喹啉,其他条件不变,按照实施例1的方法制备3-芳基琥珀酰亚胺类化合物(产量120mg,产率88%,为黄色油状物),其结构式如下:
其核磁测试结果和质谱测试结果分别如下:
1H NMR(400MHz,CDCl3)δ6.86(d,J=8.3Hz,1H),6.75(s,1H),6.54(d,J=8.4Hz,1H),3.85(dd,J=9.3,4.4Hz,1H),3.32(q,J=7.0Hz,2H),3.25(t,J=6.1Hz,2H),3.14(dd,J=18.5,9.4Hz,1H),3.05(s,3H),2.79(dd,J=18.5,4.4Hz,1H),2.71(t,J=6.1Hz,2H),2.00–1.87(m,2H),1.11(t,J=7.0Hz,3H)。
13C NMR(150MHz,CDCl3)δ178.77,176.85,144.66,127.86,125.94,123.10,122.97,110.75,48.27,45.26,45.17,37.30,28.14,25.07,22.04,10.74。
HRMS(CI)calcd for C16H21N2O2[M+H]+273.1603,found 273.1602。
实施例13
将实施例1中的1-苯基吡咯烷替换为等摩尔的1-乙基二氢吲哚,其他条件不变,按照实施例1的方法制备3-芳基琥珀酰亚胺类化合物(产量121mg,产率94%,为无色油状物),其结构式如下:
其核磁测试结果和质谱测试结果分别如下:
1H NMR(400MHz,CDCl3)δ6.89–6.87(m,2H),6.41(d,J=8.3Hz,1H),3.90(dd,J=9.1,4.2Hz,1H),3.34(t,J=8.2Hz,2H),3.19–3.09(m,3H),3.05(s,3H),2.93(t,J=8.2Hz,2H),2.78(dd,J=18.4,4.0Hz,1H),1.17(t,J=7.1Hz,3H)。
13C NMR(150MHz,CDCl3)δ178.74,176.77,152.12,131.42,126.51,125.50,123.17,107.03,52.22,45.55,42.88,37.46,28.34,25.09,11.81。
HRMS(CI)calcd for C15H19N2O2[M+H]+:259.1447,found 259.1443。
实施例14
将实施例1中的1-苯基吡咯烷替换为等摩尔的1,2,3,5,6,7-六氢吡啶并[3,2,1-ij]喹啉,其他条件不变,按照实施例1的方法制备3-芳基琥珀酰亚胺类化合物(产量84mg,产率59%,为黄色油状物),其结构式如下:
其核磁测试结果和质谱测试结果分别如下:
1H NMR(400MHz,CDCl3)δ6.59(s,2H),3.80(dd,J=9.3,4.4Hz,1H),3.16–3.08(m,5H),3.05(s,3H),2.80–2.70(m,5H),2.00–1.90(m,4H)。
13C NMR(150MHz,CDCl3)δ178.80,176.89,142.60,125.68,123.50,122.03,49.84,45.28,37.38,27.62,25.08,21.85。
HRMS(CI)calcd for C17H21N2O2[M+H]+:285.1603,found 285.1607。
实施例15
将实施例1中的1-苯基吡咯烷替换为等摩尔的N,N-二甲基萘-1-胺,其他条件不变,按照实施例1的方法制备3-芳基琥珀酰亚胺类化合物(产量130mg,产率92%,为黄色油状物),其结构式如下:
其核磁测试结果和质谱测试结果分别如下:
1H NMR(400MHz,CDCl3)δ8.38–8.27(m,1H),7.74(d,J=5.1Hz,1H),7.58–7.48(m,2H),7.19(d,J=7.8Hz,1H),7.01(d,J=7.8Hz,1H),4.67(dd,J=9.3,4.7Hz,1H),3.34(dd,J=18.3,9.6Hz,1H),3.16(s,3H),2.88(s,6H),2.80(dd,J=18.4,4.7Hz,1H)。
13C NMR(150MHz,CDCl3)δ178.47,176.25,151.17,132.36,129.43,127.92,126.63,125.35,125.28,124.78,123.03,113.53,45.16,42.97,37.71,25.21。
HRMS(CI)calcd for C17H19N2O2[M+H]+:283.1447,found 283.1446。
实施例16
将实施例1中的1-苯基吡咯烷替换为等摩尔的1-甲基-1H-吲哚,其他条件不变,按照实施例1的方法制备3-芳基琥珀酰亚胺类化合物(产量112mg,产率92%,为白色固体,mp:123.2-125.2℃),其结构式如下:
其核磁测试结果和质谱测试结果分别如下:
1H NMR(400MHz,CDCl3)δ7.42(d,J=7.2Hz,1H),7.33(d,J=7.0Hz,1H),7.28–7.25(m,1H),7.15–7.13(m,1H),7.04(s,1H),4.31–4.28(m,1H),3.76(s,3H),3.27(dd,J=18.1,9.3Hz,1H),3.12(s,3H),2.92(d,J=18.2Hz,1H)。
13C NMR(150MHz,CDCl3)δ178.33,176.55,137.35,126.73,126.12,122.25,119.61,118.59,109.85,109.74,38.13,36.67,32.77,25.10。
HRMS(CI)calcd for C14H15N2O2[M+H]+:243.1134,found 243.1134。
实施例17
将实施例1中的1-苯基吡咯烷替换为等摩尔的2-甲基呋喃,其他条件不变,按照实施例1的方法制备3-芳基琥珀酰亚胺类化合物(产量56mg,产率58%,为无色油状物),其结构式如下:
其核磁测试结果和质谱测试结果分别如下:
1H NMR(400MHz,CDCl3)δ6.50(d,J=4.1Hz,1H),6.31(d,J=5.2Hz,1H),5.18(s,1H),2.98–2.97(m,1H),2.96(s,3H),2.72(d,J=6.0Hz,1H),1.73(s,3H)。
13C NMR(150MHz,CDCl3)δ176.22,175.01,140.47,136.87,88.08,80.55,50.65,49.44,24.85,15.61。
HRMS(CI)calcd for C10H12NO3[M+H]+:194.0817,found 194.0816。
实施例18
将实施例1中的1-甲基-1H-吡咯-2,5-二酮替换为等摩尔的1-丁基-1H-吡咯-2,5-二酮,其他条件不变,按照实施例1的方法制备3-芳基琥珀酰亚胺类化合物(产量116mg,产率77%,为无色油状物),其结构式如下:
其核磁测试结果和质谱测试结果分别如下:
1H NMR(400MHz,CDCl3)δ6.95(d,J=8.4Hz,2H),6.45(d,J=8.5Hz,2H),3.80(dd,J=9.4,4.4Hz,1H),3.47(t,J=7.3Hz,2H),3.18(t,J=6.0Hz,4H),3.05(dd,J=18.4,9.5Hz,1H),2.67(dd,J=18.4,4.4Hz,1H),1.91(t,J=6.1Hz,4H),1.56–1.44(m,2H),1.28–1.22(m,2H),0.85(t,J=7.3Hz,3H)。
13C NMR(150MHz,CDCl3)δ178.55,176.76,147.45,127.94,123.57,112.04,47.57,45.06,38.72,37.32,29.79,25.45,20.06,13.64。
HRMS(CI)calcd for C18H25N2O2[M+H]+:301.1916,found 301.1911。
实施例19
将实施例1中的1-甲基-1H-吡咯-2,5-二酮替换为等摩尔的1-异丙基-1H-吡咯-2,5-二酮,其他条件不变,按照实施例1的方法制备3-芳基琥珀酰亚胺类化合物(产量116mg,产率81%,为无色油状物),其结构式如下:
其核磁测试结果和质谱测试结果分别如下:
1H NMR(400MHz,CDCl3)δ7.03(d,J=8.1Hz,2H),6.53(d,J=8.1Hz,2H),4.46–4.39(m,1H),3.82(dd,J=9.3,4.1Hz,1H),3.28–3.25(m,4H),3.09(dd,J=18.3,9.6Hz,1H),2.71(dd,J=18.3,4.2Hz,1H),2.01-1.97(m,4H),1.41(t,J=6.5Hz,6H)。
13C NMR(150MHz,CDCl3)δ178.53,176.75,147.45,127.85,123.78,112.06,47.57,44.83,43.86,37.26,25.43,19.32,19.17。
HRMS(ESI)calcd for C17H23N2O2[M+H]+:287.1754,found 287.1756。
实施例20
将实施例1中的1-甲基-1H-吡咯-2,5-二酮替换为等摩尔的1-苯基-1H-吡咯-2,5-二酮,其他条件不变,按照实施例1的方法制备3-芳基琥珀酰亚胺类化合物(产量128mg,产率80%,为白色固体,熔点:180.6-181.8℃),其结构式如下:
其核磁测试结果和质谱测试结果分别如下:
1H NMR(400MHz,CDCl3)δ7.48–7.44(m,2H),7.31–7.29(m,1H),7.30(d,J=7.7Hz,2H),7.13(d,J=8.1Hz,2H),6.55(d,J=8.1Hz,2H),4.07(dd,J=9.4,4.3Hz,1H),3.43–3.19(m,5H),2.96(dd,J=18.5,4.2Hz,1H),2.01-1.97(m,4H)。
13C NMR(150MHz,CDCl3)δ177.42,175.70,147.58,132.06,129.12,128.54,128.00,126.49,123.21,112.11,47.59,45.25,37.45,25.45。
HRMS(CI)calcd for C20H21N2O2 321.1603[M+H]+,found 321.1602。
实施例21
将实施例1中的1-苯基吡咯烷替换为等摩尔的N,N-二乙基苯胺,1-甲基-1H-吡咯-2,5-二酮替换为等摩尔的1-苯基-1H-吡咯-2,5-二酮,其他条件不变,按照实施例1的方法制备3-芳基琥珀酰亚胺类化合物(产量126mg,产率78%,为无色油状物),其结构式如下:
其核磁测试结果和质谱测试结果分别如下:
1H NMR(400MHz,CDCl3)δ7.49–7.45(m,2H),7.41–7.37(m,1H),7.32(d,J=7.6Hz,2H),7.13(d,J=8.2Hz,2H),6.67(d,J=8.3Hz,2H),4.08(dd,J=9.3,4.3Hz,1H),3.36–3.29(m,5H),2.97(dd,J=18.5,4.3Hz,1H),1.15(t,J=6.9Hz,6H)。
13C NMR(150MHz,CDCl3)δ177.42,175.69,147.40,132.05,129.12,128.54,128.17,126.49,123.06,112.08,45.11,44.33,37.38,12.50。
HRMS(ESI)calcd for C20H23N2O2[M+H]+:323.1754,found 323.1753。
实施例22
将实施例1中的1-甲基-1H-吡咯-2,5-二酮替换为等摩尔的1-苄基-1H-吡咯-2,5-二酮,其他条件不变,按照实施例1的方法制备3-芳基琥珀酰亚胺类化合物(产量135mg,产率81%,为白色固体,熔点:161.0-161.8℃),其结构式如下:
其核磁测试结果和质谱测试结果分别如下:
1H NMR(400MHz,CDCl3)δ7.38(d,J=6.5Hz,2H),7.33–7.22(m,3H),6.98(d,J=8.6Hz,2H),6.49(d,J=8.6Hz,2H),4.69(q,J=14.0Hz,2H),3.89(dd,J=9.5,4.6Hz,1H),3.24(t,J=6.5Hz,4H),3.13(dd,J=18.5,9.5Hz,1H),2.76(dd,J=18.5,4.6Hz,1H),2.01–1.94(m,4H)。
13C NMR(150MHz,CDCl3)δ178.20,176.27,147.49,135.92,128.73,128.61,127.98,127.86,123.27,112.03,47.57,45.14,42.55,37.32,25.43。
HRMS(CI)calcd for C21H23N2O2[M+H]+:335.1760,found 335.1758。
实施例23
将实施例1中的1-苯基吡咯烷替换为等摩尔的N,N-二乙基苯胺,1-甲基-1H-吡咯-2,5-二酮替换为等摩尔的1-苄基-1H-吡咯-2,5-二酮,其他条件不变,按照实施例1的方法制备3-芳基琥珀酰亚胺类化合物(产量126mg,产率78%,为白色固体,熔点:99.2-100.2℃),其结构式如下:
其核磁测试结果和质谱测试结果分别如下:
1H NMR(400MHz,CDCl3)δ7.43(d,J=6.9Hz,2H),7.36–7.31(m,3H),7.01(d,J=8.4Hz,2H),6.64(d,J=8.4Hz,2H),4.74(q,J=14.0Hz,2H),3.93(dd,J=9.3,4.5Hz,1H),3.36(q,J=7.0Hz,4H),3.17(dd,J=18.5,9.5Hz,1H),2.81(dd,J=18.5,4.5Hz,1H),1.17(t,J=7.0Hz,6H)。
13C NMR(150MHz,CDCl3)δ178.21,176.26,147.31,135.92,128.74,128.62,128.15,127.87,123.14,112.04,45.02,44.30,42.57,37.27,12.50。
HRMS(ESI)calcd for C21H25N2O2[M+H]+:337.1911,found 337.1909。
实施例24
将实施例1中的1-甲基-1H-吡咯-2,5-二酮替换为等摩尔的1H-吡咯-2,5-二酮,其他条件不变,按照实施例1的方法制备3-芳基琥珀酰亚胺类化合物(产量101mg,产率82%,为白色固体,熔点:165.8-167.3℃),其结构式如下:
其核磁测试结果和质谱测试结果分别如下:
1H NMR(400MHz,CDCl3)δ8.28(s,1H),7.09(d,J=8.1Hz,2H),6.55(d,J=8.1Hz,2H),3.98(dd,J=9.3,4.9Hz,1H),3.38–3.16(m,5H),2.85(dd,J=18.6,4.7Hz,1H),2.02–1.98(m,4H)。
13C NMR(150MHz,CDCl3)δ178.73,176.54,147.58,128.03,122.66,112.07,47.58,46.63,38.40,25.44。
HRMS(CI)calcd for C14H17N2O2[M+H]+:245.1290,found 245.1301。
实施例25
将实施例1中的1-苯基吡咯烷替换为等摩尔的N,N-二乙基苯胺,1-甲基-1H-吡咯-2,5-二酮替换为等摩尔的1H-吡咯-2,5-二酮,其他条件不变,按照实施例1的方法制备3-芳基琥珀酰亚胺类化合物(产量75mg,产率61%,为无色油状物),其结构式如下:
其核磁测试结果和质谱测试结果分别如下:
1H NMR(400MHz,CDCl3)δ8.52(s,1H),7.09(d,J=8.3Hz,2H),6.68(d,J=8.1Hz,2H),3.99(dd,J=9.3,4.9Hz,1H),3.36(q,J=6.9Hz,4H),3.22(dd,J=18.6,9.6Hz,1H),2.87(dd,J=18.6,4.9Hz,1H),1.17(t,J=7.0Hz,6H)。
13C NMR(150MHz,CDCl3)δ178.96,176.72,147.39,128.22,122.55,112.03,46.51,44.32,38.36,12.49.HRMS(ESI)calcd for C14H19N2O2[M+H]+:247.1441,found 247.1446。
实施例26
将实施例1中的1-苯基吡咯烷替换为等摩尔的1H-吲哚,其他条件不变,按照实施例1的方法制备3-芳基琥珀酰亚胺类化合物(产量86mg,产率75%,为白色固体,熔点181.1–182.8℃)其结构式如下:
其核磁测试结果和质谱测试结果分别如下:
1H NMR(400MHz,DMSO)δ11.05(s,1H),7.41–7.35(m,2H),7.34(s,1H),7.10(t,J=7.5Hz,1H),6.99(t,J=7.4Hz,1H),4.36(dd,J=9.1,4.9Hz,1H),3.23(dd,J=18.0,9.4Hz,1H),2.92(s,3H),2.79(dd,J=18.0,4.8Hz,1H)。
13C NMR(151MHz,DMSO)δ178.86,177.08,136.88,126.35,123.87,121.76,119.20,118.82,112.11,111.16,38.03,36.57,25.03。
MS(ESI)[M+H]+:229。
实施例27
将实施例1中的1-苯基吡咯烷替换为等摩尔的5-氟-1H-吲哚,其他条件不变,按照实施例1的方法制备3-芳基琥珀酰亚胺类化合物(产量39mg,产率32%,为黄色油状)其结构式如下:
其核磁测试结果和质谱测试结果分别如下:
1H NMR(400MHz,CDCl3)δ11.16(s,1H),7.42(s,1H),7.37(dd,J=8.4,4.4Hz,1H),7.20(d,J=9.8Hz,1H),6.95(t,J=8.7Hz,1H),4.35(dd,J=8.6,5.3Hz,1H),3.22(dd,J=17.9,9.3Hz,1H),2.91(s,3H),2.82(dd,J=18.0,4.9Hz,1H)。
13C NMR(151MHz,DMSO)δ178.68,176.96,157.94,156.41,133.50,126.82,126.76,125.77,113.09,113.02,111.41,111.38,110.04,109.87,103.85,103.70,37.82,36.25,25.03。
MS(ESI)[M+H]+:247。
实施例28
将实施例1中的1-苯基吡咯烷替换为等摩尔的5-甲氧基-1H-吲哚,其他条件不变,按照实施例1的方法制备3-芳基琥珀酰亚胺类化合物(产量89mg,产率69%,为白色固体,熔点155.3–156.1℃)其结构式如下:
其核磁测试结果和质谱测试结果分别如下:
1H NMR(400MHz,DMSO)δ10.89(s,1H),7.27(s,2H),6.87(s,1H),6.75(d,J=8.7Hz,1H),4.33(dd,J=8.7,4.8Hz,1H),3.73(s,3H),3.23(dd,J=17.9,9.3Hz,1H),2.92(s,3H),2.79(dd,J=17.9,4.5Hz,1H)。
13C NMR(151MHz,DMSO)δ178.68,176.96,157.94,156.41,133.50,126.82,126.76,125.77,113.09,113.02,111.41,111.38,110.04,109.87,103.85,103.70,37.82,36.25,25.03。
MS(ESI)[M+H]+:259。
实施例29
将实施例1中的1-苯基吡咯烷替换为等摩尔的1-甲基-1H-吡咯,其他条件不变,按照实施例1的方法制备3-芳基琥珀酰亚胺类化合物(产量54mg,产率56%,为黄色油状)其结构式如下:
其核磁测试结果和质谱测试结果分别如下:
1H NMR(400MHz,CDCl3)δ6.66–6.61(m),6.11–6.04(m),5.96(dd,J=3.5,1.2Hz),4.10(dd,J=9.4,4.8Hz),3.74(s),3.16(dd,J=18.3,9.4Hz),3.01(s),2.91(dd,J=18.3,4.8Hz)。
13C NMR(151MHz,CDCl3)δ178.68,176.96,157.94,156.41,133.50,126.82,126.76,125.77,113.09,113.02,111.41,111.38,110.04,109.87,103.85,103.70,37.82,36.25,25.03。
MS(ESI)[M+H]+:193。
实施例30
将实施例1中的1-苯基吡咯烷替换为等摩尔的1H-吡咯,其他条件不变,按照实施例1的方法制备3-芳基琥珀酰亚胺类化合物(产量38mg,产率43%,为黄色油状)其结构式如下:
其核磁测试结果和质谱测试结果分别如下:
1H NMR(400MHz,CDCl3)δ9.52(s,1H),6.80(s,1H),6.16(d,J=2.2Hz,1H),6.02(s,1H),4.09(dd,J=8.8,5.0Hz,1H),3.19(dd,J=18.3,9.2Hz,1H),2.99(d,J=10.7Hz,4H)。
13C NMR(151MHz,CDCl3)δ177.84,176.34,125.31,118.82,108.15,105.45,38.66,34.34,24.92。
MS(ESI)[M+H]+:179。
将实施例1中溶剂HFIP替换成三氟乙醇(4mL),则反应产率为64%;将实施例1中溶剂替换成HFIP(2mL)和三氯甲烷(2mL)的混合溶剂,产率为30%;将实施例1中溶剂替换成HFIP(2mL)和甲醇(2mL)的混合溶剂,产率为32%。
以上所述仅是本发明的优选实施方式,并不用于限制本发明,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明技术原理的前提下,还可以做出若干改进和变型,这些改进和变型也应视为本发明的保护范围。
Claims (10)
1.一种3-芳基琥珀酰亚胺类化合物的制备方法,其特征在于,包括以下步骤:
将N,N-二取代苯胺类化合物或富电子杂芳环化合物与式(1)所示的化合物在有机溶剂中反应,反应在保护气氛下进行,反应温度为80~140℃,得到所述3-芳基琥珀酰亚胺类化合物;所述有机溶剂中至少包括氟碳醇;
式(1)如下:
其中,R为氢、C1-C8烷基、苯基或苄基;
所述N,N-二取代苯胺类化合物的结构式为式(2)-式(5)中的任一种,式(2)-式(5)如下:
其中,
表示R1和R2环合形成了五元环或六元环;
表示R1和Ar基环合形成了五元环或六元环;
式(5)表示R1、R2和Ar基环合形成了五元环或六元环;
式(2)-式(5)中,Ar代表芳基、取代芳基或萘环;R1和R2独立地选自C1-C8烷基。
2.根据权利要求1所述的制备方法,其特征在于:所述富电子杂芳环化合物为吲哚、取代吲哚、吡咯、取代吡咯、呋喃或取代呋喃。
3.根据权利要求1所述的制备方法,其特征在于:所述氟碳醇为六氟异丙醇和/或三氟乙醇。
4.根据权利要求1或3所述的制备方法,其特征在于:所述有机溶剂中还包括三氯甲烷或甲苯。
5.根据权利要求1所述的制备方法,其特征在于:所述N,N-二取代苯胺类化合物或富电子杂芳环化合物和式(1)所示的化合物的摩尔比为1∶(2~6)。
6.根据权利要求1所述的制备方法,其特征在于:所述N,N-二取代苯胺类化合物为1-苯基吡咯烷、1-苯基哌啶、4-甲基-1-苯基哌啶、N,N-二乙基苯胺、N,N-二甲基苯胺、1-(3-甲氧基苯基)吡咯烷、1-(3-氯苯基)吡咯烷、1-([1,1'-联苯基]-2-基)吡咯烷、1-(邻甲苯基)吡咯烷、1-(间-甲苯基)吡咯烷、1-(3,5-二甲基苯基)吡咯烷、1-乙基-1,2,3,4-四氢喹啉、1-乙基二氢吲哚、1,2,3,5,6,7-六氢吡啶并[3,2,1-ij]喹啉或N,N-二甲基萘-1-胺。
7.根据权利要求1所述的制备方法,其特征在于:所述富电子杂芳环化合物的结构式为如下结构式中的一种:
其中,R1’为氢、C1-C8烷基、C1-C8烷氧基或卤素。
8.根据权利要求1所述的制备方法,其特征在于:式(1)所示的化合物为1-甲基-1H-吡咯-2,5-二酮、1-丁基-1H-吡咯-2,5-二酮、1-异丙基-1H-吡咯-2,5-二酮、1-苯基-1H-吡咯-2,5-二酮、1-苄基-1H-吡咯-2,5-二酮或1H-吡咯-2,5-二酮。
9.根据权利要求1所述的制备方法,其特征在于:氟碳醇的体积与式(1)所示的化合物的摩尔数的比例为(1-8)mL:(1-4)mmol。
10.根据权利要求1所述的制备方法,其特征在于:反应时间为12-24小时。
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