CN106243126B - Substituted furans isoquinolines analog derivative and preparation method thereof - Google Patents
Substituted furans isoquinolines analog derivative and preparation method thereof Download PDFInfo
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- CN106243126B CN106243126B CN201610634416.8A CN201610634416A CN106243126B CN 106243126 B CN106243126 B CN 106243126B CN 201610634416 A CN201610634416 A CN 201610634416A CN 106243126 B CN106243126 B CN 106243126B
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- tetrahydrobenzofuran
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- methylbenzofuran
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- -1 furans isoquinolines analog Chemical class 0.000 title claims abstract description 69
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 45
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 36
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 30
- 239000000047 product Substances 0.000 claims description 26
- 239000007810 chemical reaction solvent Substances 0.000 claims description 25
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 24
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 22
- 239000000203 mixture Substances 0.000 claims description 22
- 239000002994 raw material Substances 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims description 18
- 239000012043 crude product Substances 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- ZPTMWVDSVJOEEB-UHFFFAOYSA-N 3-methyl-4-oxo-6,7-dihydro-5h-1-benzofuran-2-carboxylic acid Chemical compound C1CCC(=O)C2=C1OC(C(O)=O)=C2C ZPTMWVDSVJOEEB-UHFFFAOYSA-N 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- FUFIYZTYLVNRFU-UHFFFAOYSA-N ethyl 3-methyl-4-oxo-6,7-dihydro-5h-1-benzofuran-2-carboxylate Chemical compound C1CCC(=O)C2=C1OC(C(=O)OCC)=C2C FUFIYZTYLVNRFU-UHFFFAOYSA-N 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 claims description 10
- BEIHJKADTXXQOE-UHFFFAOYSA-N methyl 3-methyl-4-oxo-6,7-dihydro-5H-1-benzofuran-5-carboxylate Chemical compound CC1=COC2=C1C(C(CC2)C(=O)OC)=O BEIHJKADTXXQOE-UHFFFAOYSA-N 0.000 claims description 10
- HVXIXLZOMVQEPY-UHFFFAOYSA-N 3-methyl-6,7-dihydro-5h-1-benzofuran-4-one Chemical compound C1CCC(=O)C2=C1OC=C2C HVXIXLZOMVQEPY-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- HJSLFCCWAKVHIW-UHFFFAOYSA-N cyclohexane-1,3-dione Chemical compound O=C1CCCC(=O)C1 HJSLFCCWAKVHIW-UHFFFAOYSA-N 0.000 claims description 9
- OHLRLMWUFVDREV-UHFFFAOYSA-N ethyl 4-chloro-3-oxobutanoate Chemical compound CCOC(=O)CC(=O)CCl OHLRLMWUFVDREV-UHFFFAOYSA-N 0.000 claims description 9
- 239000012046 mixed solvent Substances 0.000 claims description 9
- PKZJLOCLABXVMC-UHFFFAOYSA-N 2-Methoxybenzaldehyde Chemical compound COC1=CC=CC=C1C=O PKZJLOCLABXVMC-UHFFFAOYSA-N 0.000 claims description 8
- OPHQOIGEOHXOGX-UHFFFAOYSA-N 3,4,5-trimethoxybenzaldehyde Chemical compound COC1=CC(C=O)=CC(OC)=C1OC OPHQOIGEOHXOGX-UHFFFAOYSA-N 0.000 claims description 8
- RGHHSNMVTDWUBI-UHFFFAOYSA-N 4-hydroxybenzaldehyde Chemical compound OC1=CC=C(C=O)C=C1 RGHHSNMVTDWUBI-UHFFFAOYSA-N 0.000 claims description 8
- WBIZZNFQJPOKDK-UHFFFAOYSA-N 4-hydroxy-2-methoxybenzaldehyde Chemical compound COC1=CC(O)=CC=C1C=O WBIZZNFQJPOKDK-UHFFFAOYSA-N 0.000 claims description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 6
- 150000001299 aldehydes Chemical class 0.000 claims description 6
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- FLTWNBFOWBHJEK-UHFFFAOYSA-N methyl 4-hydroxy-3-methyl-1-benzofuran-5-carboxylate Chemical compound OC1=C(C=CC2=C1C(=CO2)C)C(=O)OC FLTWNBFOWBHJEK-UHFFFAOYSA-N 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 239000012312 sodium hydride Substances 0.000 claims description 6
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 6
- 239000012265 solid product Substances 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 5
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 claims description 5
- BGNGWHSBYQYVRX-UHFFFAOYSA-N 4-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=C(C=O)C=C1 BGNGWHSBYQYVRX-UHFFFAOYSA-N 0.000 claims description 4
- WZWIQYMTQZCSKI-UHFFFAOYSA-N 4-cyanobenzaldehyde Chemical compound O=CC1=CC=C(C#N)C=C1 WZWIQYMTQZCSKI-UHFFFAOYSA-N 0.000 claims description 4
- BXRFQSNOROATLV-UHFFFAOYSA-N 4-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=C(C=O)C=C1 BXRFQSNOROATLV-UHFFFAOYSA-N 0.000 claims description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000000741 silica gel Substances 0.000 claims description 4
- 229910002027 silica gel Inorganic materials 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 3
- 239000000706 filtrate Substances 0.000 claims description 3
- HYBBIBNJHNGZAN-UHFFFAOYSA-N furfural Chemical compound O=CC1=CC=CO1 HYBBIBNJHNGZAN-UHFFFAOYSA-N 0.000 claims description 3
- 239000005457 ice water Substances 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 239000012074 organic phase Substances 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 3
- 239000012295 chemical reaction liquid Substances 0.000 claims description 2
- 238000007789 sealing Methods 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims 4
- 238000001914 filtration Methods 0.000 claims 4
- 238000010438 heat treatment Methods 0.000 claims 4
- 238000001035 drying Methods 0.000 claims 3
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical class N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 claims 2
- 238000001704 evaporation Methods 0.000 claims 2
- 239000000463 material Substances 0.000 claims 1
- 238000005406 washing Methods 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 5
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 125000004093 cyano group Chemical group *C#N 0.000 abstract description 2
- 239000003814 drug Substances 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- 125000002541 furyl group Chemical group 0.000 abstract description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 abstract description 2
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical class O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 18
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 17
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 15
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 12
- 238000001228 spectrum Methods 0.000 description 12
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 10
- IVKNUIVDQMARCO-UHFFFAOYSA-N oxazin-4-one Chemical compound O=C1C=CON=C1 IVKNUIVDQMARCO-UHFFFAOYSA-N 0.000 description 10
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- AIGAZQPHXLWMOJ-UHFFFAOYSA-N Tanshinone I Chemical compound C1=CC2=C(C)C=CC=C2C(C(=O)C2=O)=C1C1=C2C(C)=CO1 AIGAZQPHXLWMOJ-UHFFFAOYSA-N 0.000 description 2
- TVFIYRKPCACCNL-UHFFFAOYSA-N furan-2-carboxamide Chemical compound NC(=O)C1=CC=CO1 TVFIYRKPCACCNL-UHFFFAOYSA-N 0.000 description 2
- VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical class C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- QWVGKYWNOKOFNN-UHFFFAOYSA-N o-cresol Chemical compound CC1=CC=CC=C1O QWVGKYWNOKOFNN-UHFFFAOYSA-N 0.000 description 2
- OUFUBABGIIEJNV-QMMMGPOBSA-N (5s)-3,4,5-trimethyl-5,6,7,8-tetrahydrobenzo[f][1]benzofuran-9-ol Chemical compound CC1=C2[C@@H](C)CCCC2=C(O)C2=C1C(C)=CO2 OUFUBABGIIEJNV-QMMMGPOBSA-N 0.000 description 1
- TZBHPYXJOJGKDT-UHFFFAOYSA-N 1,3-oxazin-4-one Chemical compound O=C1C=COC=N1 TZBHPYXJOJGKDT-UHFFFAOYSA-N 0.000 description 1
- SXAMGRAIZSSWIH-UHFFFAOYSA-N 2-[3-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,2,4-oxadiazol-5-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NOC(=N1)CC(=O)N1CC2=C(CC1)NN=N2 SXAMGRAIZSSWIH-UHFFFAOYSA-N 0.000 description 1
- GRIWJVSWLJHHEM-UHFFFAOYSA-N 3-hydroxy-2-methoxybenzaldehyde Chemical compound COC1=C(O)C=CC=C1C=O GRIWJVSWLJHHEM-UHFFFAOYSA-N 0.000 description 1
- ZRSNZINYAWTAHE-PTQBSOBMSA-N 4-methoxybenzaldehyde Chemical group COC1=CC=C([13CH]=O)C=C1 ZRSNZINYAWTAHE-PTQBSOBMSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical class [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- GVNXBKLYRMAHMR-UHFFFAOYSA-N Cc(c1c2OC(c(cc3)ccc3C#N)N3)c[nH]c1ccc2C3=O Chemical compound Cc(c1c2OC(c(cc3)ccc3C#N)N3)c[nH]c1ccc2C3=O GVNXBKLYRMAHMR-UHFFFAOYSA-N 0.000 description 1
- BCLVPDYDULTKNM-UHFFFAOYSA-N Cc(c1c2OC(c(cc3)ccc3N(C)C)N3)c[o]c1ccc2C3=O Chemical compound Cc(c1c2OC(c(cc3)ccc3N(C)C)N3)c[o]c1ccc2C3=O BCLVPDYDULTKNM-UHFFFAOYSA-N 0.000 description 1
- UYYRFEHSWSEJAZ-UHFFFAOYSA-N Cc(c1c2OC(c(cc3)ccc3OC)N3)c[o]c1ccc2C3=O Chemical compound Cc(c1c2OC(c(cc3)ccc3OC)N3)c[o]c1ccc2C3=O UYYRFEHSWSEJAZ-UHFFFAOYSA-N 0.000 description 1
- SIOWRVQNYOLMFB-UHFFFAOYSA-N Cc(c1c2OC(c(cc3)ccc3[N+]([O-])=O)N3)c[o]c1ccc2C3=O Chemical compound Cc(c1c2OC(c(cc3)ccc3[N+]([O-])=O)N3)c[o]c1ccc2C3=O SIOWRVQNYOLMFB-UHFFFAOYSA-N 0.000 description 1
- NZMDVBDZJKUYKY-UHFFFAOYSA-N Cc(c1c2OC(c(cc3OC)cc(OC)c3OC)N3)c[o]c1ccc2C3=O Chemical compound Cc(c1c2OC(c(cc3OC)cc(OC)c3OC)N3)c[o]c1ccc2C3=O NZMDVBDZJKUYKY-UHFFFAOYSA-N 0.000 description 1
- LKVNKNSWJLRJBL-UHFFFAOYSA-N Cc(c1c2OC(c(ccc(O)c3)c3OC)N3)c[o]c1ccc2C3=O Chemical compound Cc(c1c2OC(c(ccc(O)c3)c3OC)N3)c[o]c1ccc2C3=O LKVNKNSWJLRJBL-UHFFFAOYSA-N 0.000 description 1
- JYYRGUYJVDKYKU-UHFFFAOYSA-N Cc(c1c2OC(c(cccc3)c3OC)N3)c[o]c1ccc2C3=O Chemical compound Cc(c1c2OC(c(cccc3)c3OC)N3)c[o]c1ccc2C3=O JYYRGUYJVDKYKU-UHFFFAOYSA-N 0.000 description 1
- BZUNJZCIIXUQQM-UHFFFAOYSA-N Cc(c1c2OC(c3ccc[o]3)N3)c[o]c1ccc2C3=O Chemical compound Cc(c1c2OC(c3ccc[o]3)N3)c[o]c1ccc2C3=O BZUNJZCIIXUQQM-UHFFFAOYSA-N 0.000 description 1
- BYOFFXLMXZLQMZ-UHFFFAOYSA-N Cc1c[o]c(cc2)c1c(OC(c(cc1)ccc1O)N1)c2C1=O Chemical compound Cc1c[o]c(cc2)c1c(OC(c(cc1)ccc1O)N1)c2C1=O BYOFFXLMXZLQMZ-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 229930183118 Tanshinone Natural products 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000002058 anti-hyperglycaemic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- UDXHBCLNVLIJCT-UHFFFAOYSA-N cacalol Natural products CC1CCc2c(C)c3c(C)coc3c(O)c2C1 UDXHBCLNVLIJCT-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 230000000916 dilatatory effect Effects 0.000 description 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 150000002537 isoquinolines Chemical class 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及医药化学领域，旨在提供一种取代的呋喃异喹啉酮类衍生物及其制备方法。该取代的呋喃异喹啉酮类衍生物具有如式(Ⅰ)所示的结构，其中，B环选自苯基或呋喃基；R1、R2、R3各自独立地选自氢原子、羟基、甲氧基、二甲胺基、硝基或氰基。该产品是一类具有新骨架的天然呋喃异喹啉酮类似物，具有潜在的药物活性，该类化合物的制备可以为呋喃异喹啉酮类的药物活性研究提供支撑。其制备方法步骤简单、易得，对于工业化生产有重要意义。
The invention relates to the field of medicinal chemistry and aims to provide a substituted furan isoquinolinone derivative and a preparation method thereof. The substituted furan isoquinolinone derivatives have the structure shown in formula (I), wherein, ring B is selected from phenyl or furyl; R 1 , R 2 , and R 3 are each independently selected from hydrogen atom, Hydroxyl, Methoxy, Dimethylamino, Nitro or Cyano. This product is a class of natural furan isoquinolinone analogues with a new skeleton and has potential pharmaceutical activity. The preparation of this type of compound can provide support for the research on the drug activity of furan isoquinolinones. The preparation method has simple steps and is easy to obtain, and is of great significance for industrialized production.
Description
技术领域technical field
本发明涉及医药化学领域，更具体地，涉及一种取代的呋喃异喹啉酮类衍生物及其制备方法。The invention relates to the field of medicinal chemistry, more specifically, to a substituted furan isoquinolinone derivative and a preparation method thereof.
背景技术Background technique
异喹啉酮类化合物广泛存在于自然界,其衍生物具有舒张血管、抗肿瘤等多种生物活性.异喹啉酮类化合物的分子多样性、合成方法及生物活性研究近年来受到重视。Isoquinolinone compounds widely exist in nature, and their derivatives have various biological activities such as dilating blood vessels and antitumor. The molecular diversity, synthesis methods and biological activities of isoquinolinone compounds have been paid more attention in recent years.
异喹啉环的合成一直受到有机合成化学家和药物合成化学家的特别重视.虽然近年来已有很多合成异喹啉衍生物方法的报道,但并不能令人满意,因为它们的反应条件往往比较苛刻,而产率并不高,且副产物多,提纯困难,有些方法还必须使用昂贵的催化剂,所以亟待开发简单有效的合成异喹啉及其衍生物的新方法。The synthesis of isoquinoline rings has always been paid special attention by organic synthetic chemists and pharmaceutical synthetic chemists. Although there have been many reports on the synthesis of isoquinoline derivatives in recent years, they are not satisfactory because their reaction conditions are often It is relatively harsh, but the yield is not high, and there are many by-products, the purification is difficult, and some methods must use expensive catalysts, so it is urgent to develop new methods for the synthesis of isoquinoline and its derivatives that are simple and effective.
甲基取代的呋喃环结构在天然产物中广泛存在，并具有多样的生物活性，例如丹参酮可以治疗心血管疾病，呋喃佛术烷具有植物化感作用，倍半萜类化合物cacalol具有抗高血糖和抗菌的作用。Methyl-substituted furan ring structures widely exist in natural products and have diverse biological activities, such as tanshinone can treat cardiovascular diseases, furofromane has phytoallelopathy, sesquiterpenoid cacalol has anti-hyperglycemic and Antibacterial effect.
因此呋喃环被甲基取代的呋喃异喹啉酮类化合物及其衍生物具有潜在的药物活性，并且该类化合物是一种具有全新骨架的异喹啉酮类化合物，迄今未被报道过，本专利发明了一种简单，快速的由4-羟基-3-甲基苯并呋喃-5-甲酰胺制备该类衍生物的方法。Therefore, the furan isoquinolinone compounds and derivatives thereof with the furan ring substituted by methyl groups have potential pharmaceutical activity, and this type of compound is an isoquinolinone compound with a new skeleton, which has not been reported so far. The patent has invented a simple and fast method for preparing such derivatives from 4-hydroxy-3-methylbenzofuran-5-carboxamide.
发明内容Contents of the invention
本发明要解决的技术问题是，克服现有技术中的不足，提供一种取代的呋喃异喹啉酮类衍生物及其制备方法。The technical problem to be solved by the present invention is to overcome the deficiencies in the prior art and provide a substituted furan isoquinolinone derivative and a preparation method thereof.
为解决技术问题，本发明的解决方案是：For solving technical problem, solution of the present invention is:
提供一种取代的呋喃异喹啉酮类衍生物，具有如式(Ⅰ)所示的结构：A substituted furan isoquinolinone derivative is provided, having a structure as shown in formula (I):
其中，in,
B环选自苯基或呋喃基；Ring B is selected from phenyl or furyl;
R1、R2、R3各自独立地选自氢原子、羟基、甲氧基、二甲胺基、硝基或氰基。R 1 , R 2 , and R 3 are each independently selected from a hydrogen atom, a hydroxyl group, a methoxy group, a dimethylamino group, a nitro group or a cyano group.
本发明中，该取代的呋喃异喹啉酮类衍生物具有下述任意一种结构：In the present invention, the substituted furan isoquinolinone derivatives have any of the following structures:
本发明进一步提供了所述取代的呋喃异喹啉酮类衍生物的制备方法，包括以下步骤：The present invention further provides a method for preparing the substituted furan isoquinolinone derivatives, comprising the following steps:
(1)将1,3-环己二酮和氢氧化钾均匀的分散于水中，常温搅拌5min后，加入氯乙酰乙酸乙酯的甲醇溶液；然后将体系在室温下搅拌5天，用4N的盐酸酸化；过滤酸化后的反应液，得到的固体产物：3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸乙酯；(1) Disperse 1,3-cyclohexanedione and potassium hydroxide evenly in water, stir at room temperature for 5 minutes, then add methanol solution of ethyl chloroacetoacetate; then stir the system at room temperature for 5 days, and use 4N Acidification with hydrochloric acid; filter the acidified reaction solution to obtain a solid product: ethyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylate;
所述1,3-环己二酮与氢氧化钾、氯乙酰乙酸乙酯的摩尔比为1:1:1，每毫升水对应的1,3-环己二酮的投料量为0.1g，每毫升甲醇对应的氯乙酰乙酸乙酯的投料量为0.2g；The molar ratio of described 1,3-cyclohexanedione to potassium hydroxide and ethyl chloroacetoacetate is 1:1:1, and the feeding amount of 1,3-cyclohexanedione corresponding to every milliliter of water is 0.1g, The charging capacity of ethyl chloroacetoacetate corresponding to every milliliter of methanol is 0.2g;
(2)将3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸乙酯和氢氧化钾用甲醇和水的混合溶剂溶解，溶解后将体系在室温下搅拌反应5h；将反应液用6N的盐酸调pH至1，过滤反应液，过滤得固体产物：3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸；(2) Dissolve 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylic acid ethyl ester and potassium hydroxide in a mixed solvent of methanol and water, and after dissolving, the system is Stir the reaction at room temperature for 5 hours; adjust the pH of the reaction solution to 1 with 6N hydrochloric acid, filter the reaction solution, and obtain a solid product: 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran- 2-Formic acid;
所述混合溶剂是甲醇与水以2.5：1配制而成，每毫升混合溶剂对应的3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸乙酯的投料量为0.2g；所述3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸乙酯与氢氧化钾的摩尔比为1:6；The mixed solvent is prepared by methanol and water at a ratio of 2.5:1, and the corresponding ethyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylate per milliliter of the mixed solvent The feeding amount is 0.2g; the molar ratio of the ethyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylate to potassium hydroxide is 1:6;
(3)将3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸均匀分散于二甘醇中，加入铜粉和吡啶，然后将体系加热至175℃，保持搅拌10h；将体系冷却到室温，加入冰水，并用4N的盐酸酸化；用石油醚萃取酸化后的反应液三次，将合并的萃取液用水洗涤一次， 然后将萃取液用无水硫酸钠干燥、旋干，得固体产物：3-甲基-6,7-二氢苯并呋喃-4-(5H)-酮；(3) Evenly disperse 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylic acid in diethylene glycol, add copper powder and pyridine, and then heat the system to 175 ℃, keep stirring for 10h; cool the system to room temperature, add ice water, and acidify with 4N hydrochloric acid; extract the acidified reaction solution with petroleum ether three times, wash the combined extract with water once, and then wash the extract with anhydrous sulfuric acid Sodium-dried and spin-dried to obtain a solid product: 3-methyl-6,7-dihydrobenzofuran-4-(5H)-one;
所述3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸与铜粉、吡啶的摩尔比为1:1:2，每毫升二甘醇对应的3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸的投料量为0.1g；The molar ratio of the 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylic acid to copper powder and pyridine is 1:1:2, and the corresponding amount of diethylene glycol per milliliter The feeding amount of 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylic acid is 0.1g;
(4)在氮气保护下，将氢化钠均匀分散于乙二醇二甲醚溶液中，将体系冷却到0℃；然后向体系中加入3-甲基-6,7-二氢苯并呋喃-4(5H)-酮的乙二醇二甲醚溶液，保持体系在0℃搅拌30min；向体系中加入碳酸二甲酯的乙二醇二甲醚溶液，将体系加热到90℃；保持3h后，将体系冷却到室温，加入饱和的氯化铵溶液淬灭反应；用乙酸乙酯萃取3次，有机相用无水硫酸钠干燥、浓缩，得到产品：3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-5-甲酸甲酯；(4) Under nitrogen protection, uniformly disperse sodium hydride in ethylene glycol dimethyl ether solution, cool the system to 0°C; then add 3-methyl-6,7-dihydrobenzofuran- The ethylene glycol dimethyl ether solution of 4(5H)-ketone, keep the system at 0°C and stir for 30 minutes; add the ethylene glycol dimethyl ether solution of dimethyl carbonate to the system, and heat the system to 90°C; keep it for 3 hours , the system was cooled to room temperature, and saturated ammonium chloride solution was added to quench the reaction; extracted three times with ethyl acetate, the organic phase was dried with anhydrous sodium sulfate and concentrated to obtain the product: 3-methyl-4-oxo-4 , Methyl 5,6,7-tetrahydrobenzofuran-5-carboxylate;
所述3-甲基-6,7-二氢苯并呋喃-4(5H)-酮与氢化钠、碳酸二甲酯的摩尔比为1:5:3，每毫升乙二醇二甲醚对应的3-甲基-6,7-二氢苯并呋喃-4(5H)-酮投料量为0.04g；The molar ratio of the 3-methyl-6,7-dihydrobenzofuran-4(5H)-ketone to sodium hydride and dimethyl carbonate is 1:5:3, and each milliliter of ethylene glycol dimethyl ether corresponds to The dosage of 3-methyl-6,7-dihydrobenzofuran-4(5H)-one is 0.04g;
(5)将3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-5-甲酸甲酯均匀分散于甲苯溶液中，向体系中加入2,3-二氯-5,6-二氰对苯醌，加热至130℃保持6h；将体系冷却到室温，过滤，浓缩滤液，将粗产品用硅胶色谱柱分离，得到纯净产物：4-羟基-3-甲基苯并呋喃-5-甲酸甲酯；(5) Disperse methyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-5-carboxylate evenly in toluene solution, add 2,3-dichloro- 5,6-dicyano-p-benzoquinone, heated to 130°C for 6 hours; cooled the system to room temperature, filtered, concentrated the filtrate, and separated the crude product with a silica gel column to obtain a pure product: 4-hydroxy-3-methylbenzene Methyl furan-5-carboxylate;
所述3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-5-甲酸甲酯与2,3-二氯-5,6-二氰对苯醌的摩尔比为1:1.2，每毫升甲苯对应的3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-5-甲酸甲酯的投料量为0.1g；The molar ratio of the 3-methyl-4-oxygen-4,5,6,7-tetrahydrobenzofuran-5-formic acid methyl ester to 2,3-dichloro-5,6-dicyano-p-benzoquinone The ratio is 1:1.2, and the feeding amount of 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-5-carboxylic acid methyl ester corresponding to each milliliter of toluene is 0.1g;
(6)将4-羟基-3-甲基苯并呋喃-5-甲酸甲酯加入饱和的氨的甲醇溶液，每毫升饱和的氨的甲醇溶液对应4-羟基-3-甲基苯并呋喃-5-甲酸甲酯的投料量为0.06g；封口后加热到65℃，保持24h；蒸除反应液，得到纯净的4-羟基-3-甲基苯并呋喃-5-甲酰胺；(6) Add methyl 4-hydroxy-3-methylbenzofuran-5-carboxylate to saturated methanol solution of ammonia, and every milliliter of saturated methanol solution of ammonia corresponds to 4-hydroxyl-3-methylbenzofuran- The dosage of methyl 5-formate is 0.06g; after sealing, heat to 65°C and keep for 24h; evaporate the reaction solution to obtain pure 4-hydroxy-3-methylbenzofuran-5-carboxamide;
(7)将4-羟基-3-甲基苯并呋喃-5-甲酰胺、醛和弱碱均匀分散于反应溶剂a中，使得4-羟基-3-甲基苯并呋喃-5-甲酰胺、醛和弱碱的摩尔比在1:1～3:0.1～1之间，每毫升溶剂a对应的4-羟基-3-甲基苯并呋喃-5-甲酰胺的投料量为0.02至0.06g，获得原料混合物；(7) Evenly disperse 4-hydroxy-3-methylbenzofuran-5-carboxamide, aldehyde and weak base in the reaction solvent a, so that 4-hydroxy-3-methylbenzofuran-5-carboxamide , The molar ratio of aldehyde and weak base is between 1:1～3:0.1～1, and the feeding amount of 4-hydroxy-3-methylbenzofuran-5-carboxamide corresponding to every milliliter of solvent a is 0.02 to 0.06 g, obtain raw material mixture;
其中，醛选自4-甲氧基苯甲醛、2-甲氧基苯甲醛、3，4，5-三甲氧基苯甲醛、4-二甲胺基苯甲醛、4-羟基苯甲醛、4-羟基-2-甲氧基苯甲醛、4-硝基苯甲醛、4-氰基苯甲醛或2-呋喃甲醛中的任意一种；所述反应溶剂a为甲苯或苯；Wherein, aldehyde is selected from 4-methoxybenzaldehyde, 2-methoxybenzaldehyde, 3,4,5-trimethoxybenzaldehyde, 4-dimethylaminobenzaldehyde, 4-hydroxybenzaldehyde, 4- Any one in hydroxy-2-methoxybenzaldehyde, 4-nitrobenzaldehyde, 4-cyanobenzaldehyde or 2-furylcarbaldehyde; the reaction solvent a is toluene or benzene;
(8)将原料混合物在110℃～130℃下反应1小时～24小时，蒸除反应溶剂，得粗产品，将粗产品用硅胶色谱柱分离，得到取代的呋喃异喹啉酮类衍生物的纯净产物。(8) React the raw material mixture at 110°C to 130°C for 1 hour to 24 hours, evaporate the reaction solvent to obtain a crude product, and separate the crude product with a silica gel chromatographic column to obtain a substituted furan isoquinolinone derivative Pure product.
本发明中，步骤(7)中所述的弱碱为哌啶或四氢吡咯(弱碱优选为哌啶，反应溶剂a优选为甲苯)。In the present invention, the weak base described in step (7) is piperidine or tetrahydropyrrole (the weak base is preferably piperidine, and the reaction solvent a is preferably toluene).
与现有技术相比，本发明能够取得的有益效果：Compared with prior art, the beneficial effect that the present invention can obtain:
(1)本发明提供的呋喃异喹啉酮类衍生物是一类具有新骨架的天然呋喃异喹啉酮类似物，具有潜在的药物活性，该类化合物的制备可以为呋喃异喹啉酮类的药物活性研究提供支撑。(1) The furan isoquinolinone derivatives provided by the present invention are a class of natural furan isoquinolinone analogs with new skeletons, which have potential pharmaceutical activity. The preparation of such compounds can be furan isoquinolinones The study of drug activity provides support.
(2)本发明提供的呋喃异喹啉酮类衍生物的制备方法，步骤简单，易得。对于工业化生产有重要意义。(2) The preparation method of the furan isoquinolinone derivatives provided by the present invention has simple steps and is easy to obtain. It is of great significance for industrial production.
附图说明Description of drawings
图1是本发明提供的取代的呋喃异喹啉酮类衍生物的合成示意图。Figure 1 is a schematic diagram of the synthesis of substituted furan isoquinolinone derivatives provided by the present invention.
具体实施方式Detailed ways
下面结合具体实施例对本发明进行详细说明。以下实施例将有助于本领域的技术人员进一步理解本发明，但不以任何形式限制本发明。应当指出的是，对本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进。这些都属于本发明的保护范围。The present invention will be described in detail below in conjunction with specific embodiments. The following examples will help those skilled in the art to further understand the present invention, but do not limit the present invention in any form. It should be noted that those skilled in the art can make several modifications and improvements without departing from the concept of the present invention. These all belong to the protection scope of the present invention.
实施例1Example 1
将1,3-环己二酮和氢氧化钾均匀的分散于水中，常温搅拌5min后，加入氯乙酰乙酸乙酯的甲醇溶液，然后将体系在室温下搅拌5天，然后将体系用4N的盐酸酸化，过滤酸化后的反应液，得到的固体即为产物：3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸乙酯。该步骤中1,3-环己二酮与氢氧化钾及氯乙酰乙酸乙酯的摩尔比为1:1:1，每毫升水对应的1,3-环己二酮的投料量为0.1g，每毫升甲醇对应的氯乙酰乙酸乙酯的投料量为0.2g。该步的产率为65％。所得产物的结构为：Disperse 1,3-cyclohexanedione and potassium hydroxide uniformly in water, stir at room temperature for 5 minutes, add methanol solution of ethyl chloroacetoacetate, then stir the system at room temperature for 5 days, and then use 4N Acidify with hydrochloric acid, filter the acidified reaction solution, and the obtained solid is the product: ethyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylate. In this step, the molar ratio of 1,3-cyclohexanedione to potassium hydroxide and ethyl chloroacetoacetate is 1:1:1, and the feeding amount of 1,3-cyclohexanedione corresponding to every milliliter of water is 0.1g , the feeding amount of ethyl chloroacetoacetate corresponding to every milliliter of methanol is 0.2g. The yield for this step was 65%. The structure of the resulting product is:
分子式：C12H14O4 Molecular formula: C 12 H 14 O 4
中文命名：3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸乙酯Chinese name: ethyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylate
英文命名：ethyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylateEnglish name: ethyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylate
分子量：222.09Molecular weight: 222.09
外观：白色固体Appearance: white solid
核磁共振氢谱：(400MHz,Chloroform-d)δ4.38(q,J＝7.1Hz,2H),2.94(t,J＝6.3Hz,2H),2.60–2.46(m,5H),2.20(p,J＝6.4Hz,2H),1.40(t,J＝7.1Hz,3H)ppm。Proton NMR spectrum: (400MHz, Chloroform-d) δ4.38(q, J=7.1Hz, 2H), 2.94(t, J=6.3Hz, 2H), 2.60–2.46(m, 5H), 2.20(p , J=6.4Hz, 2H), 1.40(t, J=7.1Hz, 3H) ppm.
实施例2Example 2
将3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸乙酯和氢氧化钾用甲醇与水的混合溶剂溶解，溶解后将体系在室温下搅拌反应5h。然后将反应液用6N的盐酸调pH至1，过滤反应液，过滤所得的固体即为产物：3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸。该步骤中所用的混合溶剂是甲醇与水以2.5:1配制而成。每毫升混合溶剂对应的3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸乙酯的投料量为0.2g。该步骤中3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸乙酯与氢氧化钾的摩尔比为1:6。该步的产率为90％。所得产物的结构为：Dissolve ethyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylate and potassium hydroxide in a mixed solvent of methanol and water, and stir the system at room temperature after dissolution Reaction 5h. Then adjust the pH of the reaction solution to 1 with 6N hydrochloric acid, filter the reaction solution, and filter the obtained solid as the product: 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2- formic acid. The mixed solvent used in this step is methanol and water at a ratio of 2.5:1. The feeding amount of ethyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylate per milliliter of mixed solvent is 0.2 g. In this step, the molar ratio of ethyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylate to potassium hydroxide was 1:6. The yield for this step was 90%. The structure of the resulting product is:
分子式：C10H10O4 Molecular formula: C 10 H 10 O 4
中文命名：3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸Chinese name: 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylic acid
英文命名：3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylicacidEnglish name: 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylic acid
分子量：194.06Molecular weight: 194.06
外观：白色固体Appearance: white solid
核磁共振氢谱：(400MHz,DMSO-d6)δ2.91(t,J＝6.2Hz,2H),2.44(m,5H),2.08Proton NMR spectrum: (400MHz, DMSO-d 6 ) δ2.91(t, J=6.2Hz, 2H), 2.44(m, 5H), 2.08
(p,J＝6.4Hz,2H)ppm。(p, J = 6.4 Hz, 2H) ppm.
实施例3Example 3
将3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸均匀的分散于二甘醇中，加入铜粉和吡啶，然后将体系加热至175℃，保持搅拌10h。将体系冷却到室温，加入冰水，并用4N的盐酸酸化，用石油醚萃取酸化后的反应液三次，将合并的萃取液用水洗涤一次，然后将萃取液用无水硫酸钠干燥，旋干。所得的固体即为产物：3-甲基-6,7-二氢苯并呋喃-4-(5H)-酮。该步骤中每毫升二甘醇对应的3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸的投料量为0.1g。该步骤中3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-2-甲酸与铜粉及吡啶的摩尔比为1:1:2。该步的产率为85％。所得产物的结构为：Disperse 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylic acid evenly in diethylene glycol, add copper powder and pyridine, then heat the system to 175°C, Keep stirring for 10h. Cool the system to room temperature, add ice water, and acidify with 4N hydrochloric acid, extract the acidified reaction solution with petroleum ether three times, wash the combined extract with water once, then dry the extract with anhydrous sodium sulfate, and spin dry. The obtained solid is the product: 3-methyl-6,7-dihydrobenzofuran-4-(5H)-one. In this step, the feeding amount of 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylic acid per milliliter of diethylene glycol is 0.1 g. In this step, the molar ratio of 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylic acid to copper powder and pyridine is 1:1:2. The yield for this step was 85%. The structure of the resulting product is:
分子式：C9H10O2 Molecular formula: C 9 H 10 O 2
中文命名：3-甲基-6,7-二氢苯并呋喃-4-(5H)-酮Chinese name: 3-methyl-6,7-dihydrobenzofuran-4-(5H)-one
英文命名：3-methyl-6,7-dihydrobenzofuran-4(5H)-oneEnglish name: 3-methyl-6,7-dihydrobenzofuran-4(5H)-one
分子量：150.07Molecular weight: 150.07
外观：黄色固体Appearance: yellow solid
核磁共振氢谱：(400MHz,Chloroform-d)δ7.11–6.98(m,1H),2.83(t,J＝6.3Hz,2H),2.47(dd,J＝7.2,5.8Hz,2H),2.26–2.06(m,5H)ppm。Proton NMR spectrum: (400MHz, Chloroform-d) δ7.11–6.98 (m, 1H), 2.83 (t, J = 6.3Hz, 2H), 2.47 (dd, J = 7.2, 5.8Hz, 2H), 2.26 –2.06(m,5H)ppm.
核磁共振碳谱(101MHz,Chloroform-d)δ195.70,167.40,138.90,120.41,119.07,38.29,23.63,22.75,9.07ppm。C NMR spectrum (101MHz, Chloroform-d) δ195.70, 167.40, 138.90, 120.41, 119.07, 38.29, 23.63, 22.75, 9.07ppm.
实施例4Example 4
在氮气保护下，将氢化钠均匀的分散于乙二醇二甲醚溶液中，将体系冷却到0℃，然后向体系中加入3-甲基-6,7-二氢苯并呋喃-4(5H)-酮的乙二醇二甲醚溶液，保持体系在0℃搅拌30min。然后向体系中加入碳酸二甲酯的乙二醇二甲醚溶液，然后将体系加热到90℃。保持3h后，将体系冷却到室温，加入饱和的氯化铵溶液淬灭反应，用乙酸乙酯萃取3次，有机相用无水硫酸钠干燥，浓缩，即可得到该步的产品：3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-5-甲酸甲酯。该步骤中3-甲基-6,7-二氢苯并呋喃-4(5H)-酮与氢化钠及碳酸二甲酯的摩尔比为1:5:3，每毫升乙二醇二甲醚对应的3-甲基-6,7-二氢苯并呋喃-4(5H)-酮投料量为0.04g。该步的产率为87％。所得产物的结构为：Under nitrogen protection, sodium hydride was uniformly dispersed in ethylene glycol dimethyl ether solution, the system was cooled to 0°C, and then 3-methyl-6,7-dihydrobenzofuran-4 ( 5H)-ketone solution in ethylene glycol dimethyl ether, keep the system at 0°C and stir for 30min. A solution of dimethyl carbonate in ethylene glycol dimethyl ether was then added to the system, and the system was then heated to 90°C. After keeping for 3h, the system was cooled to room temperature, and saturated ammonium chloride solution was added to quench the reaction, extracted 3 times with ethyl acetate, and the organic phase was dried with anhydrous sodium sulfate and concentrated to obtain the product of this step: 3- Methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-5-carboxylate. In this step, the molar ratio of 3-methyl-6,7-dihydrobenzofuran-4(5H)-one to sodium hydride and dimethyl carbonate is 1:5:3, and every milliliter of ethylene glycol dimethyl ether The corresponding dosage of 3-methyl-6,7-dihydrobenzofuran-4(5H)-one is 0.04g. The yield for this step was 87%. The structure of the resulting product is:
分子式：C11H12O4 Molecular formula: C 11 H 12 O 4
中文命名：3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-5-甲酸甲酯Chinese name: methyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-5-carboxylate
英文命名：methyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-5-carboxylateEnglish name: methyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-5-carboxylate
分子量：208.07Molecular weight: 208.07
外观：白色固体Appearance: white solid
核磁共振氢谱：(400MHz,Chloroform-d)δ7.09(d,J＝1.6Hz,1H),3.77(s,3H),3.50(dd,J＝9.1,4.7Hz,1H),3.02(dt,J＝17.6,5.8Hz,1H),2.85(ddd,J＝17.6,8.2,5.5Hz,1H), 2.54(dddd,J＝13.6,9.2,8.2,5.4Hz,1H),2.34(dtd,J＝13.6,5.8,4.7Hz,1H),2.19(d,J＝1.4Hz,3H).Proton NMR spectrum: (400MHz, Chloroform-d) δ7.09(d, J=1.6Hz, 1H), 3.77(s, 3H), 3.50(dd, J=9.1, 4.7Hz, 1H), 3.02(dt ,J＝17.6,5.8Hz,1H), 2.85(ddd,J＝17.6,8.2,5.5Hz,1H), 2.54(dddd,J＝13.6,9.2,8.2,5.4Hz,1H),2.34(dtd,J =13.6,5.8,4.7Hz,1H),2.19(d,J=1.4Hz,3H).
核磁共振碳谱(101MHz,Chloroform-d)δ189.80,170.49,166.90,139.42,119.74,119.33,53.68,52.36,25.83,22.10,8.90.Carbon NMR spectrum (101MHz, Chloroform-d) δ189.80, 170.49, 166.90, 139.42, 119.74, 119.33, 53.68, 52.36, 25.83, 22.10, 8.90.
实施例5Example 5
将3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-5-甲酸甲酯均匀分散于甲苯溶液中，向体系中加入2,3-二氯-5,6-二氰对苯醌，加热至130℃保持6h。将体系冷却到室温，过滤，浓缩滤液，将粗产品用硅胶色谱柱分离即可得到纯净的产物：4-羟基-3-甲基苯并呋喃-5-甲酸甲酯。该步骤中3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-5-甲酸甲酯与2,3-二氯-5,6-二氰对苯醌的摩尔比为1:1.2，每毫升甲苯对应的3-甲基-4-氧-4,5,6,7-四氢苯并呋喃-5-甲酸甲酯的投料量为0.1g。该步的产率为87％。所得产物的结构为：Disperse methyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-5-carboxylate evenly in toluene solution, add 2,3-dichloro-5,6 -Dicyano-p-benzoquinone, heated to 130°C for 6h. The system was cooled to room temperature, filtered, and the filtrate was concentrated, and the crude product was separated by silica gel chromatography to obtain a pure product: methyl 4-hydroxy-3-methylbenzofuran-5-carboxylate. The moles of 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-5-carboxylic acid methyl ester and 2,3-dichloro-5,6-dicyano-p-benzoquinone in this step The ratio is 1:1.2, and the feeding amount of methyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-5-carboxylate per milliliter of toluene is 0.1 g. The yield for this step was 87%. The structure of the resulting product is:
分子式：C11H10O4 Molecular formula: C 11 H 10 O 4
中文命名：4-羟基-3-甲基苯并呋喃-5-甲酸甲酯Chinese name: methyl 4-hydroxy-3-methylbenzofuran-5-carboxylate
英文命名：methyl 4-hydroxy-3-methylbenzofuran-5-carboxylateEnglish name: methyl 4-hydroxy-3-methylbenzofuran-5-carboxylate
分子量：206.06Molecular weight: 206.06
外观：淡黄色固体Appearance: pale yellow solid
核磁共振氢谱：(400MHz,Chloroform-d)δ11.43(s,1H),7.71(d,J＝8.8Hz,1H),7.28(q,J＝1.4Hz,1H),6.93(d,J＝8.8Hz,1H),3.95(s,3H),2.41(d,J＝1.4Hz,3H).Proton NMR spectrum: (400MHz, Chloroform-d) δ11.43(s, 1H), 7.71(d, J=8.8Hz, 1H), 7.28(q, J=1.4Hz, 1H), 6.93(d, J ＝8.8Hz, 1H), 3.95(s, 3H), 2.41(d, J＝1.4Hz, 3H).
核磁共振碳谱(101MHz,Chloroform-d)δ171.28,160.21,159.02,140.65,125.86,117.59,116.87,105.68,103.85,52.10,9.59.Carbon NMR spectrum (101MHz, Chloroform-d) δ171.28, 160.21, 159.02, 140.65, 125.86, 117.59, 116.87, 105.68, 103.85, 52.10, 9.59.
实施例6Example 6
将4-羟基-3-甲基苯并呋喃-5-甲酸甲酯加入饱和的氨的甲醇溶液，封口，加热到65℃，保持24h，蒸除反应液，得到纯净的4-羟基-3-甲基苯并呋喃-5-甲酰胺。该步骤中每毫升饱和的氨的甲醇溶液对应的投料量为0.06g。该步的产率为100％。所得产物的结构为：Add methyl 4-hydroxy-3-methylbenzofuran-5-carboxylate into saturated methanol solution of ammonia, seal, heat to 65°C, keep for 24h, distill off the reaction liquid to obtain pure 4-hydroxy-3- Methylbenzofuran-5-carboxamide. In this step, the corresponding feeding amount per milliliter of saturated ammonia solution in methanol is 0.06 g. The yield for this step was 100%. The structure of the resulting product is:
分子式：C10H9NO3 Molecular formula: C 10 H 9 NO 3
中文命名：4-羟基-3-甲基苯并呋喃-5-甲酰胺Chinese name: 4-hydroxy-3-methylbenzofuran-5-carboxamide
英文命名：4-hydroxy-3-methylbenzofuran-5-carboxamideEnglish name: 4-hydroxy-3-methylbenzofuran-5-carboxamide
分子量：191.06Molecular weight: 191.06
外观：白色固体Appearance: white solid
核磁共振氢谱：(400MHz,Chloroform-d)δ14.32(s,1H),8.40(s,1H),7.87(s,1H),7.75(d,J＝8.8Hz,1H),7.65(q,J＝1.3Hz,1H),7.02(d,J＝8.8Hz,1H),2.33(d,J＝1.4Hz,3H).Proton NMR spectrum: (400MHz,Chloroform-d)δ14.32(s,1H),8.40(s,1H),7.87(s,1H),7.75(d,J＝8.8Hz,1H),7.65(q ,J=1.3Hz,1H),7.02(d,J=8.8Hz,1H),2.33(d,J=1.4Hz,3H).
核磁共振碳谱(101MHz,DMSO-d6)δ173.38,158.90,158.44,141.19,124.09,117.13,115.87,106.98,102.54,9.35.Carbon NMR spectrum (101MHz, DMSO-d 6 ) δ173.38, 158.90, 158.44, 141.19, 124.09, 117.13, 115.87, 106.98, 102.54, 9.35.
实施例7-1：Example 7-1:
将4-羟基-3-甲基苯并呋喃-5-甲酰胺、对甲氧基苯甲醛和哌啶均匀分散于反应溶剂甲苯中，使得4-羟基-3-甲基苯并呋喃-5-甲酰胺、对甲氧基苯甲醛和哌啶的摩尔比为1:1:0.5之间，每毫升反应溶剂对应的投料量为0.045g，获得原料混合物。将原料混合物，在120℃下，反应12小时，蒸除溶剂，将粗产品用色谱柱分离，即可得到纯净产品。所得呋喃异喹啉酮类衍生物为：2-(4-甲氧基苯基)-9-甲基-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮，得率78％，该衍生物的结构为：4-Hydroxy-3-methylbenzofuran-5-carboxamide, p-methoxybenzaldehyde and piperidine were uniformly dispersed in the reaction solvent toluene, so that 4-hydroxyl-3-methylbenzofuran-5- The molar ratio of formamide, p-methoxybenzaldehyde and piperidine is between 1:1:0.5, and the corresponding feeding amount per milliliter of reaction solvent is 0.045g to obtain a raw material mixture. The raw material mixture was reacted at 120°C for 12 hours, the solvent was evaporated, and the crude product was separated by a chromatographic column to obtain a pure product. The obtained furan isoquinolinone derivatives are: 2-(4-methoxyphenyl)-9-methyl-2,3-dihydro-4H-benzofuran[5,4-e][1, 3] Oxazin-4-one, yield 78%, the structure of the derivative is:
分子式：C18H15NO4 Molecular formula: C 18 H 15 NO 4
中文命名：2-(4-甲氧基苯基)-9-甲基-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮Chinese name: 2-(4-methoxyphenyl)-9-methyl-2,3-dihydro-4H-benzofur[5,4-e][1,3]oxazin-4-one
英文命名：2-(4-methoxyphenyl)-9-methyl-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-oneEnglish name: 2-(4-methoxyphenyl)-9-methyl-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-one
分子量：309.1Molecular weight: 309.1
外观：浅黄色固体Appearance: light yellow solid
核磁共振氢谱：(400MHz,Chloroform-d)δ7.88(d,J＝8.7Hz,1H),7.62–7.52(m,2H),7.33(q,J＝1.3Hz,1H),7.19(d,J＝8.6Hz,1H),7.05–6.95(m,2H),6.31(s,1H),6.22(s,1H),3.86(s,3H),2.27(d,J＝1.4Hz,3H).Proton NMR spectrum: (400MHz, Chloroform-d) δ7.88(d, J=8.7Hz, 1H), 7.62–7.52(m, 2H), 7.33(q, J=1.3Hz, 1H), 7.19(d ,J=8.6Hz,1H),7.05–6.95(m,2H),6.31(s,1H),6.22(s,1H),3.86(s,3H),2.27(d,J=1.4Hz,3H) .
核磁共振碳谱：(101MHz,Chloroform-d)δ164.39,161.02,159.96,153.55,141.65,128.31,128.14,124.28,117.51,115.98,114.35,111.65,106.78,85.66,55.42,9.48.Carbon NMR spectrum: (101MHz, Chloroform-d) δ164.39, 161.02, 159.96, 153.55, 141.65, 128.31, 128.14, 124.28, 117.51, 115.98, 114.35, 111.65, 106.78, 85.66, 55.42, 9.
实施例7-2：Embodiment 7-2:
将4-羟基-3-甲基苯并呋喃-5-甲酰胺、邻甲氧基苯甲醛和哌啶均匀分散于反应溶剂甲苯中，使得4-羟基-3-甲基苯并呋喃-5-甲酰胺、邻甲氧基苯甲醛和哌啶的摩尔比为1:3:0.5，每毫升反应溶剂对应的投料量为0.02g，获得原料混合物。将原料混合物，在130℃下，反应1小时，蒸除溶剂，将粗产品用色谱柱分离，即可得到纯净产品。所得呋喃异喹啉酮类衍生物为：2-(2-甲氧基苯基)-9-甲基-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮，得率78％，该衍生物的结构为：4-Hydroxy-3-methylbenzofuran-5-carboxamide, o-methoxybenzaldehyde and piperidine were uniformly dispersed in the reaction solvent toluene, so that 4-hydroxyl-3-methylbenzofuran-5- The molar ratio of formamide, o-methoxybenzaldehyde and piperidine is 1:3:0.5, and the corresponding feeding amount per milliliter of reaction solvent is 0.02g to obtain a raw material mixture. The raw material mixture was reacted at 130°C for 1 hour, the solvent was evaporated, and the crude product was separated by a chromatographic column to obtain a pure product. The obtained furan isoquinolinone derivatives are: 2-(2-methoxyphenyl)-9-methyl-2,3-dihydro-4H-benzofuran[5,4-e][1, 3] Oxazin-4-one, yield 78%, the structure of the derivative is:
分子式：C18H15NO4 Molecular formula: C 18 H 15 NO 4
中文命名：2-(2-甲氧基苯基)-9-甲基-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮Chinese name: 2-(2-methoxyphenyl)-9-methyl-2,3-dihydro-4H-benzofur[5,4-e][1,3]oxazin-4-one
英文命名：2-(2-methoxyphenyl)-9-methyl-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-oneEnglish name: 2-(2-methoxyphenyl)-9-methyl-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-one
分子量：309.1Molecular weight: 309.1
外观：白色固体Appearance: white solid
核磁共振氢谱：(400MHz,Chloroform-d)δ7.89(d,J＝8.6Hz,1H),7.74(dd,J＝7.6,1.7Hz,1H),7.43(ddd,J＝8.3,7.5,1.7Hz,1H),7.35(q,J＝1.3Hz,1H),7.18(d,J＝8.7Hz,1H),7.09(td,J＝7.6,1.0Hz,1H),6.98(dd,J＝8.3,1.0Hz,1H),6.69(s,1H),6.33(s,1H),3.88(s,3H),2.35(d,J＝1.4Hz,3H).Proton NMR spectrum: (400MHz, Chloroform-d) δ7.89 (d, J = 8.6Hz, 1H), 7.74 (dd, J = 7.6, 1.7Hz, 1H), 7.43 (ddd, J = 8.3, 7.5, 1.7Hz, 1H), 7.35(q, J=1.3Hz, 1H), 7.18(d, J=8.7Hz, 1H), 7.09(td, J=7.6, 1.0Hz, 1H), 6.98(dd, J= 8.3,1.0Hz,1H),6.69(s,1H),6.33(s,1H),3.88(s,3H),2.35(d,J=1.4Hz,3H).
核磁共振碳谱：(101MHz,Chloroform-d)δ164.53,159.86,156.34,153.59,141.63,130.88,126.85,124.28,124.22,121.01,117.56,115.94,111.71,110.71,106.68,81.11,55.51,9.54.Carbon NMR spectrum: (101MHz,Chloroform-d)δ164.53,159.86,156.34,153.59,141.63,130.88,126.85,124.28,124.22,121.01,117.56,115.94,111.71,150.71,106.15,1
实施例7-3：Embodiment 7-3:
将4-羟基-3-甲基苯并呋喃-5-甲酰胺、3,4,5-三甲氧基苯甲醛和哌啶均匀分散于反应溶剂甲苯中，使得4-羟基-3-甲基苯并呋喃-5-甲酰胺、3,4,5-三甲氧基苯甲醛和哌啶的摩 尔比为1:2:0.1，每毫升反应溶剂对应的投料量为0.06g，获得原料混合物。将原料混合物，在110℃下，反应12小时，蒸除溶剂，将粗产品用色谱柱分离，即可得到纯净产品。所得呋喃异喹啉酮类衍生物为：9-甲基-2-(3,4,5-三甲氧基苯基)-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮，得率75％，该衍生物的结构为：4-Hydroxy-3-methylbenzofuran-5-carboxamide, 3,4,5-trimethoxybenzaldehyde and piperidine were evenly dispersed in the reaction solvent toluene, so that 4-Hydroxy-3-methylbenzene The molar ratio of furan-5-carboxamide, 3,4,5-trimethoxybenzaldehyde and piperidine is 1:2:0.1, and the corresponding feeding amount per milliliter of reaction solvent is 0.06g to obtain a raw material mixture. The raw material mixture was reacted at 110°C for 12 hours, the solvent was evaporated, and the crude product was separated by a chromatographic column to obtain a pure product. The obtained furan isoquinolinone derivatives are: 9-methyl-2-(3,4,5-trimethoxyphenyl)-2,3-dihydro-4H-benzofuran[5,4-e ][1,3]oxazin-4-one, yield 75%, the structure of the derivative is:
分子式：C20H19NO6 Molecular formula: C 20 H 19 NO 6
中文命名：9-甲基-2-(3,4,5-三甲氧基苯基)-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮Chinese name: 9-methyl-2-(3,4,5-trimethoxyphenyl)-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazine -4-one
英文命名：9-methyl-2-(3,4,5-trimethoxyphenyl)-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-oneEnglish name: 9-methyl-2-(3,4,5-trimethoxyphenyl)-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-one
分子量：369.1Molecular weight: 369.1
外观：白色固体Appearance: white solid
核磁共振氢谱：(400MHz,Chloroform-d)δ7.89(d,J＝8.7Hz,1H),7.36(q,J＝1.3Hz,1H),7.21(d,J＝8.7Hz,1H),6.86(s,2H),6.30(s,2H),3.91(d,J＝3.4Hz,9H),2.32(d,J＝1.4Hz,3H).Proton NMR spectrum: (400MHz, Chloroform-d) δ7.89(d, J=8.7Hz, 1H), 7.36(q, J=1.3Hz, 1H), 7.21(d, J=8.7Hz, 1H), 6.86(s,2H),6.30(s,2H),3.91(d,J=3.4Hz,9H),2.32(d,J=1.4Hz,3H).
核磁共振碳谱：(101MHz,Chloroform-d)δ164.37,159.97,153.62,153.31,141.80,139.13,131.43,124.22,117.52,115.83,111.69,106.92,103.70,85.71,60.90,56.22,9.54.Carbon NMR spectrum: (101MHz,Chloroform-d)δ164.37,159.97,153.62,153.31,141.80,139.13,131.43,124.22,117.52,115.83,111.69,106.92,103.70,55.71,60.920,96
实施例7-4：Embodiment 7-4:
将4-羟基-3-甲基苯并呋喃-5-甲酰胺、对二甲胺基苯甲醛和哌啶均匀分散于反应溶剂甲苯中，使得4-羟基-3-甲基苯并呋喃-5-甲酰胺、对二甲胺基苯甲醛和哌啶的摩尔比为1:2:1，每毫升反应溶剂对应的投料量为0.045g，获得原料混合物。将原料混合物，在120℃下，反应24小时，蒸除溶剂，将粗产品用色谱柱分离，即可得到纯净产品。所得呋喃异喹啉酮类衍生物为：2-(4-(二甲胺基)苯基)-9-甲基-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮，得率70％，该衍生物的结构为：4-Hydroxy-3-methylbenzofuran-5-carboxamide, p-dimethylaminobenzaldehyde and piperidine were evenly dispersed in the reaction solvent toluene, so that 4-hydroxyl-3-methylbenzofuran-5 - The molar ratio of formamide, p-dimethylaminobenzaldehyde and piperidine is 1:2:1, and the corresponding feeding amount per milliliter of reaction solvent is 0.045g to obtain a raw material mixture. The raw material mixture was reacted at 120°C for 24 hours, the solvent was evaporated, and the crude product was separated by a chromatographic column to obtain a pure product. The obtained furan isoquinolinone derivatives are: 2-(4-(dimethylamino)phenyl)-9-methyl-2,3-dihydro-4H-benzofuran[5,4-e] [1,3]oxazin-4-one, yield 70%, the structure of the derivative is:
分子式：C19H18N2O3 Molecular formula: C 19 H 18 N 2 O 3
中文命名：2-(4-(二甲胺基)苯基)-9-甲基-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮Chinese name: 2-(4-(dimethylamino)phenyl)-9-methyl-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazine- 4-keto
英文命名：2-(4-(dimethylamino)phenyl)-9-methyl-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-oneEnglish name: 2-(4-(dimethylamino)phenyl)-9-methyl-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-one
分子量：322.1Molecular weight: 322.1
外观：白色固体Appearance: white solid
核磁共振氢谱：(400MHz,Chloroform-d)δ7.89(d,J＝8.6Hz,1H),7.53–7.44(m,2H),7.32(d,J＝1.5Hz,1H),7.18(d,J＝8.7Hz,1H),6.80(d,J＝8.2Hz,2H),6.26(d,J＝1.1Hz,1H),5.97(s,1H),3.03(s,6H),2.27(d,J＝1.4Hz,3H).Proton NMR spectrum: (400MHz, Chloroform-d) δ7.89(d, J=8.6Hz, 1H), 7.53–7.44(m, 2H), 7.32(d, J=1.5Hz, 1H), 7.18(d ,J=8.7Hz,1H),6.80(d,J=8.2Hz,2H),6.26(d,J=1.1Hz,1H),5.97(s,1H),3.03(s,6H),2.27(d ,J=1.4Hz,3H).
核磁共振碳谱：(101MHz,DMSO-d6)δ164.05,159.43,153.35,147.88,141.04,127.54,123.80,117.76,117.01,115.59,111.65,111.17,106.12,85.68,39.98,9.00.Carbon NMR spectrum: (101MHz, DMSO-d 6 ) δ164.05, 159.43, 153.35, 147.88, 141.04, 127.54, 123.80, 117.76, 117.01, 115.59, 111.65, 111.17, 106.12, 85.68, 39.0.98, 9
实施例7-5：Embodiment 7-5:
将4-羟基-3-甲基苯并呋喃-5-甲酰胺、对羟基苯甲醛和哌啶均匀分散于反应溶剂苯中，使得4-羟基-3-甲基苯并呋喃-5-甲酰胺、对羟基苯甲醛和哌啶的摩尔比为1:2:0.5，每毫升反应溶剂对应的投料量为0.06g，获得原料混合物。将原料混合物，在120℃下，反应10小时，蒸除溶剂，将粗产品用色谱柱分离，即可得到纯净产品。所得呋喃异喹啉酮类衍生物为：2-(4-羟基苯基)-9-甲基-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮，得率70％，该衍生物的结构为：4-Hydroxy-3-methylbenzofuran-5-carboxamide, p-hydroxybenzaldehyde and piperidine are uniformly dispersed in the reaction solvent benzene, so that 4-hydroxyl-3-methylbenzofuran-5-carboxamide The molar ratio of p-hydroxybenzaldehyde and piperidine is 1:2:0.5, and the corresponding feeding amount per milliliter of reaction solvent is 0.06g to obtain a raw material mixture. The raw material mixture was reacted at 120°C for 10 hours, the solvent was evaporated, and the crude product was separated by a chromatographic column to obtain a pure product. The obtained furan isoquinolinone derivatives are: 2-(4-hydroxyphenyl)-9-methyl-2,3-dihydro-4H-benzofuran[5,4-e][1,3] Oxazin-4-one, yield 70%, the structure of this derivative is:
分子式：C17H13NO4 Molecular formula: C 17 H 13 NO 4
中文命名：2-(4-羟基苯基)-9-甲基-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮Chinese name: 2-(4-hydroxyphenyl)-9-methyl-2,3-dihydro-4H-benzofur[5,4-e][1,3]oxazin-4-one
英文命名：2-(4-hydroxyphenyl)-9-methyl-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-oneEnglish name: 2-(4-hydroxyphenyl)-9-methyl-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-one
分子量：295.1Molecular weight: 295.1
外观：白色固体Appearance: white solid
核磁共振氢谱：(400MHz,DMSO-d6)δ9.72(s,1H),8.80(d,J＝2.1Hz,1H),7.75(d,J＝1.7Hz,1H),7.70(d,J＝8.6Hz,1H),7.47–7.37(m,2H),7.26(d,J＝8.6Hz,1H),6.86–6.78(m,2H),6.39(d,J＝1.8Hz,1H),2.23(d,J＝1.4Hz,3H).Proton NMR spectrum: (400MHz, DMSO-d 6 ) δ9.72(s, 1H), 8.80(d, J=2.1Hz, 1H), 7.75(d, J=1.7Hz, 1H), 7.70(d, J＝8.6Hz, 1H), 7.47–7.37(m, 2H), 7.26(d, J＝8.6Hz, 1H), 6.86–6.78(m, 2H), 6.39(d, J＝1.8Hz, 1H), 2.23(d,J=1.4Hz,3H).
核磁共振碳谱：(101MHz,DMSO-d6)δ163.13,158.71,158.41,152.57,142.49,128.57,127.22,123.64,116.92,115.12,115.07,112.31,105.99,85.13,9.11.Carbon NMR spectrum: (101MHz, DMSO-d 6 ) δ163.13, 158.71, 158.41, 152.57, 142.49, 128.57, 127.22, 123.64, 116.92, 115.12, 115.07, 112.31, 105.99, 85.13, 9.11.
实施例7-6：Embodiment 7-6:
将4-羟基-3-甲基苯并呋喃-5-甲酰胺、4-羟基-2-甲氧基苯甲醛和哌啶均匀分散于反应溶剂苯中，使得4-羟基-3-甲基苯并呋喃-5-甲酰胺、4-羟基-2-甲氧基苯甲醛和哌啶的摩尔比为1:2:0.5，每毫升反应溶剂对应的投料量为0.02g，获得原料混合物。将原料混合物，在120℃下，反应18小时，蒸除溶剂，将粗产品用色谱柱分离，即可得到纯净产品。所得呋喃异喹啉酮类衍生物为：2-(4-羟基-2-甲氧基苯基)-9-甲基-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮，得率70％，该衍生物的结构为：4-Hydroxy-3-methylbenzofuran-5-carboxamide, 4-Hydroxy-2-methoxybenzaldehyde and piperidine are uniformly dispersed in the reaction solvent benzene, so that 4-Hydroxy-3-methylbenzene The molar ratio of furan-5-carboxamide, 4-hydroxy-2-methoxybenzaldehyde and piperidine is 1:2:0.5, and the corresponding feeding amount per milliliter of reaction solvent is 0.02g to obtain a raw material mixture. The raw material mixture was reacted at 120°C for 18 hours, the solvent was evaporated, and the crude product was separated by a chromatographic column to obtain a pure product. The resulting furan isoquinolinone derivatives are: 2-(4-hydroxyl-2-methoxyphenyl)-9-methyl-2,3-dihydro-4H-benzofuran[5,4-e ][1,3]oxazin-4-one, yield 70%, the structure of the derivative is:
分子式：C18H15NO5 Molecular formula: C 18 H 15 NO 5
中文命名：2-(4-羟基-2-甲氧基苯基)-9-甲基-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮Chinese name: 2-(4-hydroxy-2-methoxyphenyl)-9-methyl-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazine -4-one
英文命名：2-(4-hydroxy-2-methoxyphenyl)-9-methyl-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-oneEnglish name: 2-(4-hydroxy-2-methoxyphenyl)-9-methyl-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-one
分子量：325.1Molecular weight: 325.1
外观：白色固体Appearance: white solid
核磁共振氢谱：(400MHz,DMSO-d6)δ9.30(s,1H),8.82(d,J＝2.0Hz,1H),7.77(d,J＝1.6Hz,1H),7.70(d,J＝8.6Hz,1H),7.27(d,J＝8.6Hz,1H),7.17(d,J＝2.0Hz,1H),7.01(dd,J＝8.2,2.0Hz,1H),6.82(d,J＝8.1Hz,1H),6.39(d,J＝1.8Hz,1H),3.79(s,3H),2.26(d,J＝1.5Hz,3H).Proton NMR spectrum: (400MHz, DMSO-d 6 ) δ9.30(s, 1H), 8.82(d, J=2.0Hz, 1H), 7.77(d, J=1.6Hz, 1H), 7.70(d, J＝8.6Hz, 1H), 7.27(d, J＝8.6Hz, 1H), 7.17(d, J＝2.0Hz, 1H), 7.01(dd, J＝8.2, 2.0Hz, 1H), 6.82(d, J＝8.1Hz, 1H), 6.39(d, J＝1.8Hz, 1H), 3.79(s, 3H), 2.26(d, J＝1.5Hz, 3H).
核磁共振碳谱：(101MHz,DMSO-d6)δ163.11,158.71,152.55,147.62,147.41,142.55,127.56,123.65,119.97,116.93,115.05,112.35,110.89,106.04,99.49,85.18,55.52,9.14.Carbon NMR spectrum: (101MHz, DMSO-d 6 ) δ163.11,158.71,152.55,147.62,147.41,142.55,127.56,123.65,119.97,116.93,115.05,112.35,110.89,106.04,99.48,99.49,
实施例7-7：Embodiment 7-7:
将4-羟基-3-甲基苯并呋喃-5-甲酰胺、4-硝基苯甲醛和四氢吡咯均匀分散于反应溶剂甲苯中，使得4-羟基-3-甲基苯并呋喃-5-甲酰胺、4-硝基苯甲醛和四氢吡咯的摩尔比为1:3:1，每毫升反应溶剂对应的投料量为0.045g，获得原料混合物。将原料混合物，在120℃下，反应12小时，蒸除溶剂，将粗产品用色谱柱分离，即可得到纯净产品。所得呋喃异喹啉酮类衍生物为：9-甲基-2-(4-硝基苯基)-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮，得率70％，该衍生物的结构为：4-Hydroxy-3-methylbenzofuran-5-carboxamide, 4-nitrobenzaldehyde and tetrahydropyrrole were uniformly dispersed in the reaction solvent toluene, so that 4-hydroxy-3-methylbenzofuran-5 - The molar ratio of formamide, 4-nitrobenzaldehyde and tetrahydropyrrole is 1:3:1, and the corresponding feeding amount per milliliter of reaction solvent is 0.045g to obtain a raw material mixture. The raw material mixture was reacted at 120°C for 12 hours, the solvent was evaporated, and the crude product was separated by a chromatographic column to obtain a pure product. The obtained furan isoquinolinone derivatives are: 9-methyl-2-(4-nitrophenyl)-2,3-dihydro-4H-benzofuran[5,4-e][1,3 ] oxazin-4-ketone, yield 70%, the structure of this derivative is:
分子式：C17H12N2O5 Molecular formula: C 17 H 12 N 2 O 5
中文命名：9-甲基-2-(4-硝基苯基)-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮Chinese name: 9-methyl-2-(4-nitrophenyl)-2,3-dihydro-4H-benzofur[5,4-e][1,3]oxazin-4-one
英文命名：9-methyl-2-(4-nitrophenyl)-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-oneEnglish name: 9-methyl-2-(4-nitrophenyl)-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-one
分子量：324.1Molecular weight: 324.1
外观：浅黄色固体Appearance: light yellow solid
核磁共振氢谱：(400MHz,DMSO-d6)δ9.14(d,J＝2.6Hz,1H),8.40–8.24(m,2H),7.95–7.83(m,2H),7.79(q,J＝1.2Hz,1H),7.70(d,J＝8.6Hz,1H),7.28(d,J＝8.6Hz,1H),6.74(d,J＝2.4Hz,1H),2.30(d,J＝1.4Hz,3H).Proton NMR spectrum: (400MHz,DMSO-d 6 )δ9.14(d,J=2.6Hz,1H),8.40–8.24(m,2H),7.95–7.83(m,2H),7.79(q,J =1.2Hz,1H),7.70(d,J=8.6Hz,1H),7.28(d,J=8.6Hz,1H),6.74(d,J=2.4Hz,1H),2.30(d,J=1.4 Hz,3H).
核磁共振碳谱：(101MHz,DMSO-d6)δ162.39,158.81,151.82,148.04,144.11,142.80,128.36,123.75,123.63,117.04,115.02,112.29,106.52,83.53,9.15.Carbon NMR spectrum: (101MHz, DMSO-d 6 ) δ162.39, 158.81, 151.82, 148.04, 144.11, 142.80, 128.36, 123.75, 123.63, 117.04, 115.02, 112.29, 106.52, 83.53, 9.15.
实施例7-8：Embodiment 7-8:
将4-羟基-3-甲基苯并呋喃-5-甲酰胺、4-氰基苯甲醛和四氢吡咯均匀分散于反应溶剂甲苯中，使得4-羟基-3-甲基苯并呋喃-5-甲酰胺、4-氰基苯甲醛和四氢吡咯的摩尔比为1:1:0.1，每毫升反应溶剂对应的投料量为0.045g，获得原料混合物。将原料混合物，在120℃下，反应12小时，蒸除溶剂，将粗产品用色谱柱分离，即可得到纯净产品。所得呋喃异喹啉酮类衍生物为：4-(9-甲基-4-氧-3,4-二氢-2H-苯并呋喃[5,4-e][1,3]恶嗪-2-基)苯甲腈，得率62％，该衍生物的结构为：4-Hydroxy-3-methylbenzofuran-5-carboxamide, 4-cyanobenzaldehyde and tetrahydropyrrole were uniformly dispersed in the reaction solvent toluene, so that 4-hydroxy-3-methylbenzofuran-5 - The molar ratio of formamide, 4-cyanobenzaldehyde and tetrahydropyrrole is 1:1:0.1, and the corresponding feeding amount per milliliter of reaction solvent is 0.045g to obtain a raw material mixture. The raw material mixture was reacted at 120°C for 12 hours, the solvent was evaporated, and the crude product was separated by a chromatographic column to obtain a pure product. The obtained furan isoquinolinone derivatives are: 4-(9-methyl-4-oxo-3,4-dihydro-2H-benzofuro[5,4-e][1,3]oxazine- 2-base) benzonitrile, yield 62%, the structure of this derivative is:
分子式：C18H12N2O3 Molecular formula: C 18 H 12 N 2 O 3
中文命名：4-(9-甲基-4-氧-3,4-二氢-2H-苯并呋喃[5,4-e][1,3]恶嗪-2-基)苯甲腈Chinese name: 4-(9-methyl-4-oxo-3,4-dihydro-2H-benzofuro[5,4-e][1,3]oxazin-2-yl)benzonitrile
英文命名：4-(9-methyl-4-oxo-3,4-dihydro-2H-benzofuro[5,4-e][1,3]oxazin-2-yl)benzonitrileEnglish name: 4-(9-methyl-4-oxo-3,4-dihydro-2H-benzofuro[5,4-e][1,3]oxazin-2-yl)benzonitrole
分子量：304.1Molecular weight: 304.1
外观：白色固体Appearance: white solid
核磁共振氢谱：(400MHz,DMSO-d6)δ9.13–9.05(m,1H),7.96(d,J＝8.0Hz,2H),7.79(d,J＝7.0Hz,3H),7.69(d,J＝8.6Hz,1H),7.28(d,J＝8.6Hz,1H),6.68(d,J＝2.3Hz,1H),2.29(s,3H).Proton NMR spectrum: (400MHz, DMSO-d 6 ) δ9.13–9.05(m, 1H), 7.96(d, J=8.0Hz, 2H), 7.79(d, J=7.0Hz, 3H), 7.69( d,J=8.6Hz,1H),7.28(d,J=8.6Hz,1H),6.68(d,J=2.3Hz,1H),2.29(s,3H).
核磁共振碳谱：(101MHz,DMSO-d6)δ162.48,158.79,151.90,142.79,142.23,132.62,127.88,123.63,118.36,117.01,115.01,112.27,112.15,106.49,83.77,9.15.Carbon NMR spectrum: (101MHz, DMSO-d 6 ) δ162.48, 158.79, 151.90, 142.79, 142.23, 132.62, 127.88, 123.63, 118.36, 117.01, 115.01, 112.27, 112.15, 106.49, 81.77,
实施例7-9：Embodiment 7-9:
将4-羟基-3-甲基苯并呋喃-5-甲酰胺、2-呋喃甲醛和四氢吡咯均匀分散于反应溶剂甲苯中，使得4-羟基-3-甲基苯并呋喃-5-甲酰胺、2-呋喃甲醛和四氢吡咯的摩尔比为1:2:0.5，每毫升反应溶剂对应的投料量为0.045g，获得原料混合物。将原料混合物，在130℃下，反应12小时，蒸除溶剂，将粗产品用色谱柱分离，即可得到纯净产品。所得呋喃异喹啉酮类衍生物为：4-(9-甲基-4-氧-3,4-二氢-2H-苯并呋喃[5,4-e][1,3]恶嗪-2-基)苯甲腈，得率60％，该衍生物的结构为：4-Hydroxy-3-methylbenzofuran-5-carboxamide, 2-furylcarbaldehyde and tetrahydropyrrole were uniformly dispersed in the reaction solvent toluene, so that 4-hydroxyl-3-methylbenzofuran-5-methane The molar ratio of amide, 2-furfuraldehyde and tetrahydropyrrole is 1:2:0.5, and the corresponding feeding amount per milliliter of reaction solvent is 0.045g to obtain a raw material mixture. The raw material mixture was reacted at 130°C for 12 hours, the solvent was evaporated, and the crude product was separated by a chromatographic column to obtain a pure product. The obtained furan isoquinolinone derivatives are: 4-(9-methyl-4-oxo-3,4-dihydro-2H-benzofuro[5,4-e][1,3]oxazine- 2-base) benzonitrile, yield 60%, the structure of this derivative is:
分子式：C15H11NO4 Molecular formula: C 15 H 11 NO 4
中文命名：2-(呋喃-2-基)-9-甲基-2,3-二氢-4H-苯并呋喃[5,4-e][1,3]恶嗪-4-酮Chinese name: 2-(furan-2-yl)-9-methyl-2,3-dihydro-4H-benzofuran[5,4-e][1,3]oxazin-4-one
英文命名：2-(furan-2-yl)-9-methyl-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-oneEnglish name: 2-(furan-2-yl)-9-methyl-2,3-dihydro-4H-benzofuro[5,4-e][1,3]oxazin-4-one
分子量：269.1Molecular weight: 269.1
外观：黄色固体Appearance: yellow solid
核磁共振氢谱：(500MHz,Chloroform-d)δ7.87(d,J＝8.6Hz,1H),7.50(d,J＝1.7Hz,1H),7.33(d,J＝1.6Hz,1H),7.18(d,J＝8.7Hz,1H),6.64(d,J＝3.4Hz,1H),6.54(s,1H),6.48–6.41(m,2H),2.33(d,J＝1.3Hz,3H).Proton NMR spectrum: (500MHz, Chloroform-d) δ7.87 (d, J = 8.6Hz, 1H), 7.50 (d, J = 1.7Hz, 1H), 7.33 (d, J = 1.6Hz, 1H), 7.18(d, J=8.7Hz, 1H), 6.64(d, J=3.4Hz, 1H), 6.54(s, 1H), 6.48–6.41(m, 2H), 2.33(d, J=1.3Hz, 3H ).
核磁共振碳谱：(101MHz,Chloroform-d)δ163.76,159.98,152.58,148.87,143.93,141.75,140.75,124.14,115.98,111.63,110.76,110.40,106.99,79.17,9.42。Carbon NMR spectrum: (101MHz, Chloroform-d) δ163.76, 159.98, 152.58, 148.87, 143.93, 141.75, 140.75, 124.14, 115.98, 111.63, 110.76, 110.40, 106.99, 79.17, 9.42.
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