CN110627720A - Synthesis method of 1-amino polysubstituted isoquinoline compound - Google Patents
Synthesis method of 1-amino polysubstituted isoquinoline compound Download PDFInfo
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- CN110627720A CN110627720A CN201810664915.0A CN201810664915A CN110627720A CN 110627720 A CN110627720 A CN 110627720A CN 201810664915 A CN201810664915 A CN 201810664915A CN 110627720 A CN110627720 A CN 110627720A
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- amino
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- isoquinoline
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- 238000001308 synthesis method Methods 0.000 title claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- -1 isonitrile compounds Chemical class 0.000 claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 11
- 239000003513 alkali Substances 0.000 claims abstract description 4
- 150000008359 benzonitriles Chemical class 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims abstract 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- ZKXWKVVCCTZOLD-UHFFFAOYSA-N copper;4-hydroxypent-3-en-2-one Chemical compound [Cu].CC(O)=CC(C)=O.CC(O)=CC(C)=O ZKXWKVVCCTZOLD-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 4
- 125000004185 ester group Chemical group 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- JFDZBHWFFUWGJE-KWCOIAHCSA-N benzonitrile Chemical group N#[11C]C1=CC=CC=C1 JFDZBHWFFUWGJE-KWCOIAHCSA-N 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- CZKMPDNXOGQMFW-UHFFFAOYSA-N chloro(triethyl)germane Chemical compound CC[Ge](Cl)(CC)CC CZKMPDNXOGQMFW-UHFFFAOYSA-N 0.000 claims description 2
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 2
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical compound [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 claims description 2
- 125000004494 ethyl ester group Chemical group 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 125000004492 methyl ester group Chemical group 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- ZMLPZCGHASSGEA-UHFFFAOYSA-M zinc trifluoromethanesulfonate Chemical compound [Zn+2].[O-]S(=O)(=O)C(F)(F)F ZMLPZCGHASSGEA-UHFFFAOYSA-M 0.000 claims description 2
- CITILBVTAYEWKR-UHFFFAOYSA-L zinc trifluoromethanesulfonate Substances [Zn+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F CITILBVTAYEWKR-UHFFFAOYSA-L 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims 4
- 230000008901 benefit Effects 0.000 abstract description 5
- 238000002360 preparation method Methods 0.000 abstract description 3
- 238000007363 ring formation reaction Methods 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 14
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- FPULFENIJDPZBX-UHFFFAOYSA-N ethyl 2-isocyanoacetate Chemical compound CCOC(=O)C[N+]#[C-] FPULFENIJDPZBX-UHFFFAOYSA-N 0.000 description 10
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 238000001514 detection method Methods 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 description 4
- QVTPWONEVZJCCS-UHFFFAOYSA-N 2-formylbenzonitrile Chemical compound O=CC1=CC=CC=C1C#N QVTPWONEVZJCCS-UHFFFAOYSA-N 0.000 description 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N iso-quinoline Natural products C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 3
- MSQCQINLJMEVNJ-UHFFFAOYSA-N 1-chloroisoquinoline Chemical compound C1=CC=C2C(Cl)=NC=CC2=C1 MSQCQINLJMEVNJ-UHFFFAOYSA-N 0.000 description 2
- UZSGWJQJDLCCFN-UHFFFAOYSA-N 2-acetylbenzonitrile Chemical compound CC(=O)C1=CC=CC=C1C#N UZSGWJQJDLCCFN-UHFFFAOYSA-N 0.000 description 2
- HQENAWFYEWLGTH-UHFFFAOYSA-N 2-formyl-5-methylbenzonitrile Chemical compound CC1=CC=C(C=O)C(C#N)=C1 HQENAWFYEWLGTH-UHFFFAOYSA-N 0.000 description 2
- BYJXTELCSQYYOA-UHFFFAOYSA-N 4-chloro-2-formylbenzonitrile Chemical compound ClC1=CC=C(C#N)C(C=O)=C1 BYJXTELCSQYYOA-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- ATHLLZUXVPNPAW-UHFFFAOYSA-N lamellarin d Chemical compound C1=C(O)C(OC)=CC(C2=C3C4=CC(OC)=C(O)C=C4C=CN3C3=C2C=2C=C(OC)C(O)=CC=2OC3=O)=C1 ATHLLZUXVPNPAW-UHFFFAOYSA-N 0.000 description 2
- CRXFROMHHBMNAB-UHFFFAOYSA-N methyl 2-isocyanoacetate Chemical compound COC(=O)C[N+]#[C-] CRXFROMHHBMNAB-UHFFFAOYSA-N 0.000 description 2
- XQYZDYMELSJDRZ-UHFFFAOYSA-N papaverine Chemical compound C1=C(OC)C(OC)=CC=C1CC1=NC=CC2=CC(OC)=C(OC)C=C12 XQYZDYMELSJDRZ-UHFFFAOYSA-N 0.000 description 2
- 229930008281 A03AD01 - Papaverine Natural products 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical group C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 1
- KEIZXGINFPDITQ-UHFFFAOYSA-N UNPD138008 Natural products C1=C(O)C(OC)=CC=C1C1=C(OC2C(C(O)C(O)C(COC3C(C(O)C(O)C(C)O3)O)O2)O)C(=O)C2=C(O)C=C(O)C=C2O1 KEIZXGINFPDITQ-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- OSILBMSORKFRTB-UHFFFAOYSA-N isoquinolin-1-amine Chemical compound C1=CC=C2C(N)=NC=CC2=C1 OSILBMSORKFRTB-UHFFFAOYSA-N 0.000 description 1
- 150000002537 isoquinolines Chemical class 0.000 description 1
- UIDGLYUNOUKLBM-GEBJFKNCSA-N isorhamnetin-3-O-rutinoside Chemical compound C1=C(O)C(OC)=CC(C2=C(C(=O)C3=C(O)C=C(O)C=C3O2)O[C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO[C@H]3[C@@H]([C@H](O)[C@@H](O)[C@H](C)O3)O)O2)O)=C1 UIDGLYUNOUKLBM-GEBJFKNCSA-N 0.000 description 1
- BGLPQQKZNUKSAR-UHFFFAOYSA-N isorhamnetin-3-O-rutinoside Natural products COc1ccc(cc1O)C2=C(OC3OC(COCC4OC(O)C(O)C(O)C4O)C(O)C(O)C3O)C(=O)c5c(O)cc(O)cc5O2 BGLPQQKZNUKSAR-UHFFFAOYSA-N 0.000 description 1
- IEPKWJCBNGNVDF-UHFFFAOYSA-N narcissin Natural products OC1=C(O)C(OC)=CC(C2=C(C(=O)C3=C(O)C=C(O)C=C3O2)OC2C(C(O)C(O)C(COC3C(C(O)C(O)C(C)O3)O)O2)O)=C1 IEPKWJCBNGNVDF-UHFFFAOYSA-N 0.000 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 229960001789 papaverine Drugs 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 229940081310 piperonal Drugs 0.000 description 1
- SATCULPHIDQDRE-UHFFFAOYSA-N piperonal Natural products O=CC1=CC=C2OCOC2=C1 SATCULPHIDQDRE-UHFFFAOYSA-N 0.000 description 1
- 238000011165 process development Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of a 1-amino polysubstituted isoquinoline compound, which has a reaction general formula as follows:
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a synthesis method of a 1-amino polysubstituted isoquinoline compound.
Background
Isoquinoline heterocycles are important chemical skeleton structures and have wide application in organic synthetic chemistry, pharmaceutical chemistry and pesticide chemistry, such as papaverine, lamellarin D, narcissin and the like. The 1-amino isoquinoline is an important isoquinoline heterocyclic compound, and the amino group, aromatic ring substituent and ester group in the compound can cause the multi-substituted isoquinoline compound to generate derivatization reaction, thereby further expanding the application range of the 1-amino multi-substituted isoquinoline derivative. At present, the existing synthetic literature for the compounds is obtained by firstly preparing 1-chloroisoquinoline and then reacting amine compounds serving as nucleophilic reagents with the 1-chloroisoquinoline, the reaction conditions are harsh, the steps are complicated, and strong base and expensive transition metal (J.org.chem.,2006,71, 6522-one 6529) are inevitably used. The invention creatively adds polysubstituted benzonitrile, substituted isonitrile compound, catalyst and alkali into an organic solvent in turn, and directly obtains the 1-amino polysubstituted isoquinoline through cyclization reaction under heating condition. The synthetic method has the advantages of easily available raw materials, simple operation, mild reaction conditions and low cost of the copper catalyst, has obvious advantages in the aspect of cost benefit, and overcomes many defects of the existing preparation method. Therefore, the invention has good practical value and social and economic efficiency, and has good reference significance for the process development of similar products and downstream products.
Disclosure of Invention
The invention aims to overcome the defects of the prior preparation technology and provide a synthesis method of 1-amino polysubstituted isoquinoline compounds, which has the advantages of simple and easily obtained starting materials, high yield and convenient operation.
The technical scheme of the invention is as follows: a synthesis method of 1-amino polysubstituted isoquinoline compounds is characterized in that polysubstituted benzonitrile, substituted isonitrile compounds, catalyst and alkali are sequentially added into an organic solvent, and 1-amino polysubstituted isoquinoline is obtained under the condition of heating, wherein the reaction formula is as follows:
wherein:
R1can be hydrogen, halogen, methyl, methoxy, 4, 5-dimethoxy, 4, 5-methylenedioxy, phenyl, 2-naphthyl; r2Can be hydrogen or methyl; r3Can be an ethyl ester group, a methyl ester group and a tert-butyl ester group.
The catalyst used in the above scheme is selected from: silver trifluoromethanesulfonate, copper trifluoromethanesulfonate, zinc trifluoromethanesulfonate, cuprous bromide, cuprous iodide, and copper acetylacetonate, preferably copper acetylacetonate.
The base used in the above scheme is selected from: 1, 8-diazabicycloundecen-7-ene, potassium tert-butoxide, sodium hydroxide, cesium carbonate, triethylamine, triphenylphosphine and preferably 1, 8-diazabicycloundecen-7-ene.
The solvents used in the above scheme are selected from: acetonitrile, dichloromethane, toluene, tetrahydrofuran, ethanol, 1, 4-dioxane and N, N-dimethylformamide, preferably acetonitrile.
In the above scheme, the heating temperature is 65-125 deg.C, and the maintaining time is 6-18 hr, preferably 85 deg.C, and maintaining time is 12 hr.
In the scheme, the molar weight ratio of each substance in the reaction is as follows: aryl alkene or aryl alkyne: polysubstituted benzonitrile: substituted isonitrile compounds: catalyst: base ═ 1:0.8-1.2:0.05-0.5:0.8-3, preferably polysubstituted benzazoles: substituted isonitrile compounds: catalyst: base 1:1.2:0.2: 1.2.
Detailed Description
The present invention will be further described with reference to specific examples, but it should not be construed that the scope of the above-described subject matter of the present invention is limited to the following examples, and that all the technologies implemented based on the above-described contents of the present invention belong to the scope of the present invention.
Examples
Starting from 2-cyanobenzaldehyde and ethyl isocyanoacetate (reaction formula 1)
2-Cyanobenzaldehyde (100mg, 0.76mmol), copper acetylacetonate (40mg,0.15mmol), ethyl isocyanoacetate (100. mu.L, 0.92mmol) and 1, 8-diazabicycloundec-7-ene (137. mu.L, 0.92mmol) were added in this order to stirred acetonitrile (2mL) in a 10mL thick-walled pressure tube, the reaction was completed at 85 ℃ for 12 hours, the solvent was drained on a rotary evaporator and column chromatography gave a pale yellow solid (131.8mg, 80%).
The product detection data were as follows:
1H NMR(400MHz,CDCl3)δ7.93(s,1H),7.87(d,J＝8.4Hz,1H),7.81(d,J＝8.0Hz,1H),7.68-7.64(m,1H),7.60-7.56(m,1H),5.88(s,2H),4.46(q,J＝7.2Hz,2H),1.43(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)δ166.09,156.49,140.05,136.77,130.60,128.55,128.27,122.75,119.41,115.78,61.40,14.39；HRMS(ESI)calcd for C12H12N2O2[M+H]+217.0972, found 217.0967; melting range: 203.8-206.1 ℃.
Taking 4-chloro-2-formyl benzonitrile and ethyl isocyanoacetate as raw materials (reaction formula 2)
4-chloro-2-formylbenzonitrile (100mg, 0.61mmol), copper acetylacetonate (32mg,0.12mmol), ethyl isocyanoacetate (80. mu.L, 0.72mmol) and 1, 8-diazabicycloundecen-7-ene (108. mu.L, 0.72mmol) were added in this order to stirred acetonitrile (2mL) in a 10mL thick-walled pressure-resistant tube, reacted at 85 ℃ for 12 hours to complete the reaction, the solvent was evaporated on a rotary evaporator and column chromatography gave a pale yellow solid (116.5mg, 77%).
The product detection data were as follows:
1H NMR(400MHz,CDCl3)δ7.81(d,J＝8.8Hz,1H),7.74-7.72(m,2H),7.47-7.44(m,1H),6.38(s,2H),4.42(q,J＝7.2Hz,2H),1.42(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)δ165.69,156.74,141.08,137.81,136.75,128.72,127.15,124.60,117.44,114.19,61.47,14.32；HRMS(ESI)calcd for C12H11ClN2O2[M+H]+251.0582, found 251.0578; melting range: 164.3-167.3 ℃.
Taking 2-formyl-5-methylbenzonitrile and ethyl isocyanoacetate as raw materials (reaction formula 3)
2-formyl-5-methylbenzonitrile (100mg, 0.69mmol), copper acetylacetonate (36mg,0.14mmol), ethyl isocyanoacetate (91. mu.L, 0.83mmol) and 1, 8-diazabicycloundecen-7-ene (124. mu.L, 0.83mmol) were added in this order to stirred acetonitrile (2mL) in a 10mL thick-walled pressure-resistant tube, reacted at 85 ℃ for 12 hours to complete the reaction, the solvent was evaporated on a rotary evaporator and column chromatography gave a pale yellow solid (120.4mg, 76%).
The product detection data were as follows:
1H NMR(400MHz,DMSO-d6)δ8.09(s,1H),7.79(d,J＝8.4Hz,1H),7.72(s,1H),7.52(d,J＝8.0Hz,1H),7.04(s,2H),4.30(q,J＝7.2Hz,2H),2.47(s,3H),1.31(t,J＝7.2Hz,3H)；13C NMR(100MHz,DMSO-d6)δ165.89,156.90,139.59,137.75,134.37,132.31,127.98,123.28,119.07,113.30,60.46,21.61,14.41；HRMS(ESI)calcd for C13H14N2O2[M+H]+231.1128, found 231.1121; melting range: 197.9-200.6 ℃.
Taking 6-cyano piperonal and ethyl isocyanoacetate as raw materials (reaction formula 4)
6-Cyanopiperonal (100mg, 0.57mmol), copper acetylacetonate (30mg,0.11mmol), ethyl isocyanoacetate (75. mu.L, 0.68mmol) and 1, 8-diazabicycloundec-7-ene (103. mu.L, 0.68mmol) were added in this order to stirred acetonitrile (2mL) in a 10mL thick-walled pressure tube, the reaction was completed at 85 ℃ for 12 hours, the solvent was evaporated on a rotary evaporator and column chromatography gave a pale yellow solid (110.6mg, 74%).
The product detection data were as follows:
1H NMR(400MHz,DMSO-d6)δ7.69(s,1H),7.65(s,1H),7.35(s,1H),6.82(s,2H),6.18(s,2H),4.28(q,J＝7.2Hz,2H),1.30(t,J＝7.2Hz,3H)；13C NMR(100MHz,DMSO-d6)δ165.94,156.46,150.37,148.84,139.29,134.23,115.01,113.51,104.47,102.10,100.99,60.47,14.47；HRMS(ESI)calcd for C13H12N2O4[M+H]+261.0870, found 261.0860; melting range: 207.9-211.2 ℃.
Taking 2-acetylbenzonitrile and ethyl isocyanoacetate as raw materials (reaction formula 5)
2-Acetylbenzonitrile (100mg, 0.69mmol), copper acetylacetonate (36mg,0.14mmol), ethyl isocyanoacetate (91. mu.L, 0.83mmol) and 1, 8-diazabicycloundec-7-ene (124. mu.L, 0.83mmol) were added in succession to stirred acetonitrile (2mL) in a 10mL thick-walled pressure-resistant tube, the reaction was completed at 85 ℃ for 12 hours, the solvent was drained on a rotary evaporator and column chromatography gave a pale yellow solid (31.6mg, 20%).
The product detection data were as follows:
1H NMR(400MHz,CDCl3)δ8.03(d,J＝8.4Hz,1H),7.85(d,J＝8.0Hz,1H),7.76-7.72(m,1H),7.62-7.58(m,1H),5.12(s,2H),4.47(q,J＝7.2Hz,2H),2.67(s,3H),1.45(t,J＝7.2Hz,3H)；13C NMR(100MHz,DMSO-d6)δ167.87,155.57,141.30,136.47,130.49,126.59,124.36,124.19,118.00,114.11,60.57,14.27,13.24；HRMS(ESI)calcd for C13H14N2O2[M+H]+231.1128, found 231.1120; melting range: 144.6-145.9 ℃.
Using 2-cyanobenzaldehyde and methyl isocyanoacetate as raw materials (reaction formula 6)
2-Cyanobenzaldehyde (100mg, 0.76mmol), copper acetylacetonate (40mg,0.15mmol), methyl isocyanoacetate (81. mu.L, 0.83mmol) and 1, 8-diazabicycloundec-7-ene (137. mu.L, 0.83mmol) were added in this order to stirred acetonitrile (2mL) in a 10mL thick-walled pressure vessel, the reaction was completed at 85 ℃ for 12 hours, the solvent was drained on a rotary evaporator and column chromatography gave a pale yellow solid (107.2mg, 69%).
The product detection data were as follows:
1H NMR(400MHz,DMSO-d6)δ8.27(d,J＝8.0Hz,1H),7.90(d,J＝8.0Hz,1H),7.76(s,1H),7.69(t,J＝8.0Hz,1H),7.63-7.59(m,1H),7.20(s,2H),3.84(s,3H)；13C NMR(100MHz,DMSO-d6)δ166.37,157.47,140.19,136.47,130.65,128.22,128.05,124.12,118.98,113.32,51.97；HRMS(ESI)calcd for C11H10N2O2[M+H]+203.0815, found 203.0810; melting range: 209.1-210.1 deg.c.
Claims (6)
1. A synthesis method of 1-amino polysubstituted isoquinoline compounds is characterized in that polysubstituted benzonitrile, substituted isonitrile compounds, catalyst and alkali are sequentially added into an organic solvent, and 1-amino polysubstituted isoquinoline is obtained under the condition of heating, wherein the reaction formula is as follows:
wherein: r1Can be hydrogen, halogen, methyl, methoxy, 4, 5-dimethoxy, 4, 5-methylenedioxy, phenyl, 2-naphthyl; r2Can be hydrogen or methyl; r3Can be an ethyl ester group, a methyl ester group and a tert-butyl ester group.
2. The method for synthesizing a 1-amino polysubstituted isoquinoline compound according to claim 1, characterized in that the catalyst used is selected from the group consisting of: silver trifluoromethanesulfonate, copper trifluoromethanesulfonate, zinc trifluoromethanesulfonate, cuprous bromide, cuprous iodide and copper acetylacetonate.
3. The method of claim 1, wherein the base is selected from the group consisting of: 1, 8-diazabicycloundecen-7-ene, potassium tert-butoxide, sodium hydroxide, cesium carbonate, triethylamine, triphenylphosphine.
4. The method for synthesizing a 1-amino polysubstituted isoquinoline compound according to claim 1, characterized in that the solvent used is selected from: one or more of acetonitrile, dichloromethane, toluene, tetrahydrofuran, ethanol, 1, 4-dioxane and N, N-dimethylformamide.
5. The method for synthesizing a 1-amino polysubstituted isoquinoline compound according to claim 1, characterized in that the heating temperature is 65 ℃ to 125 ℃ and the holding time is 6 to 18 hours.
6. The method for synthesizing a 1-amino polysubstituted isoquinoline compound according to claim 1, characterized in that the molar weight ratio of each substance in the reaction is: polysubstituted benzonitrile: substituted isonitrile compounds: catalyst: base 1:0.8-1.2:0.05-0.5: 0.8-3.
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