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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- -1 furans isoquinolines analog Chemical class 0.000 title claims abstract description 83
- 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
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 27
- 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
- 239000000203 mixture Substances 0.000 claims description 22
- 239000002994 raw material Substances 0.000 claims description 22
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 20
- 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
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 239000012043 crude product Substances 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
- 238000001704 evaporation Methods 0.000 claims description 13
- 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
- 238000001914 filtration Methods 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 12
- 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 11
- 239000002904 solvent Substances 0.000 claims description 11
- 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 10
- 238000001816 cooling Methods 0.000 claims description 10
- 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
- 238000010438 heat treatment Methods 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
- WBIZZNFQJPOKDK-UHFFFAOYSA-N 4-hydroxy-2-methoxybenzaldehyde Chemical compound COC1=CC(O)=CC=C1C=O WBIZZNFQJPOKDK-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
- HYBBIBNJHNGZAN-UHFFFAOYSA-N furfural Chemical compound O=CC1=CC=CO1 HYBBIBNJHNGZAN-UHFFFAOYSA-N 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 7
- 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 7
- 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 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
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 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
- 239000000284 extract Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-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
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- CBHOOMGKXCMKIR-UHFFFAOYSA-N azane;methanol Chemical class N.OC CBHOOMGKXCMKIR-UHFFFAOYSA-N 0.000 claims description 5
- 239000012295 chemical reaction liquid Substances 0.000 claims description 5
- 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 5
- 239000000741 silica gel Substances 0.000 claims description 5
- 229910002027 silica gel Inorganic materials 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
- 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
- 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
- 238000007789 sealing Methods 0.000 claims description 3
- 239000000463 material Substances 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 6
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 125000004093 cyano group Chemical group *C#N 0.000 abstract description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 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
- 125000000449 nitro group Chemical group [O-][N+](*)=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
- 150000002240 furans Chemical class 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- 238000005481 NMR spectroscopy Methods 0.000 description 28
- 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
- TZBHPYXJOJGKDT-UHFFFAOYSA-N 1,3-oxazin-4-one Chemical compound O=C1C=COC=N1 TZBHPYXJOJGKDT-UHFFFAOYSA-N 0.000 description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 15
- 229910052739 hydrogen Inorganic materials 0.000 description 15
- 239000001257 hydrogen Substances 0.000 description 15
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 13
- 229910052799 carbon Inorganic materials 0.000 description 13
- 238000001228 spectrum Methods 0.000 description 13
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 9
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 2
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- 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
- 230000004071 biological effect Effects 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 230000002194 synthesizing effect Effects 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
- 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
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical class N QGZKDVFQNNGYKY-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
- 229930183118 Tanshinone Natural products 0.000 description 1
- 206010047141 Vasodilatation Diseases 0.000 description 1
- 125000000217 alkyl group Chemical group 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
- 230000015572 biosynthetic process Effects 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
- 230000007547 defect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- VDBNYAPERZTOOF-UHFFFAOYSA-N isoquinolin-1(2H)-one Chemical class C1=CC=C2C(=O)NC=CC2=C1 VDBNYAPERZTOOF-UHFFFAOYSA-N 0.000 description 1
- 150000002537 isoquinolines Chemical class 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 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
- 235000017807 phytochemicals Nutrition 0.000 description 1
- 229930000223 plant secondary metabolite Natural products 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229930004725 sesquiterpene Natural products 0.000 description 1
- 150000004354 sesquiterpene derivatives Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000024883 vasodilation Effects 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
The present invention relates to medicinal chemistry arts, it is desirable to provide a kind of substituted furans isoquinolines analog derivative and preparation method thereof.The substituted furans isoquinolines analog derivative has the structure as shown in formula (I), wherein B rings are selected from phenyl or furyl；R1、R2、R3It is each independently selected from hydrogen atom, hydroxyl, methoxyl group, dimethylamino, nitro or cyano.The product, which is one kind, has the natural furans isoquinolines of new skeleton similar to object, and there is potential pharmaceutical activity, preparing for such compound can provide support for the research of the pharmaceutical activity of furans isobioquin group.Preparation methods steps are simple, are easy to get, significant for industrialized production.
Description
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a substituted furan isoquinolone derivative and a preparation method thereof.
Background
Isoquinolone compounds widely exist in the nature, and derivatives thereof have various biological activities such as vasodilatation, anti-tumor and the like.
Although many methods for synthesizing isoquinoline derivatives have been reported in recent years, the methods are unsatisfactory because the reaction conditions are often harsh, the yield is not high, a large number of byproducts are generated, the purification is difficult, and some methods also need to use expensive catalysts, so that a new method for simply and effectively synthesizing isoquinoline and derivatives thereof is urgently needed to be developed.
Methyl-substituted furan ring structures widely exist in natural products and have various biological activities, for example, tanshinone can treat cardiovascular diseases, furan Buddha alkyl has a phytochemical effect, and a sesquiterpene compound cacalol has an anti-hyperglycemic and antibacterial effect.
Therefore, the furan isoquinolone compound with the furan ring substituted by methyl and the derivative thereof have potential pharmaceutical activity, and the compound is an isoquinolone compound with a brand new framework, which is not reported so far, and the patent discloses a simple and rapid method for preparing the derivative by using 4-hydroxy-3-methylbenzofuran-5-formamide.
Disclosure of Invention
The invention aims to solve the technical problem of overcoming the defects in the prior art and provides a substituted furan isoquinolone derivative and a preparation method thereof.
In order to solve the technical problem, the solution of the invention is as follows:
provided is a substituted furan isoquinolone derivative, which has a structure shown in a formula (I):
wherein,
ring B is selected from phenyl or furyl;
R1、R2、R3each independently selected from a hydrogen atom, a hydroxyl group, a methoxy group, a dimethylamino group, a nitro group or a cyano group.
In the invention, the substituted furan isoquinolone derivative has any one of the following structures:
the invention further provides a preparation method of the substituted furan isoquinolone derivative, which comprises the following steps:
(1) uniformly dispersing 1, 3-cyclohexanedione and potassium hydroxide in water, stirring at normal temperature for 5min, and adding a methanol solution of ethyl chloroacetoacetate; then the system is stirred for 5 days at room temperature and acidified by 4N hydrochloric acid; filtering the acidified reaction solution to obtain a solid product: 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylic acid ethyl ester;
the molar ratio of the 1, 3-cyclohexanedione to the potassium hydroxide to the ethyl chloroacetoacetate is 1:1:1, the feeding amount of the 1, 3-cyclohexanedione corresponding to each milliliter of water is 0.1g, and the feeding amount of the ethyl chloroacetoacetate corresponding to each milliliter of methanol is 0.2 g;
(2) dissolving 3-methyl-4-oxo-4,5,6, 7-tetrahydrobenzofuran-2-ethyl formate and potassium hydroxide in a mixed solvent of methanol and water, and stirring the system at room temperature for reaction for 5 hours; adjusting the pH of the reaction solution to 1 by using 6N hydrochloric acid, filtering the reaction solution, and filtering to obtain a solid product: 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylic acid;
the mixed solvent is methanol and water, and the weight ratio of methanol to water is 2.5:1, the material dosage of 3-methyl-4-oxygen-4, 5,6, 7-tetrahydrobenzofuran-2-ethyl formate corresponding to each milliliter of mixed solvent is 0.2 g; the molar ratio of the 3-methyl-4-oxo-4,5,6, 7-tetrahydrobenzofuran-2-ethyl formate to the potassium hydroxide is 1: 6;
(3) uniformly dispersing 3-methyl-4-oxo-4,5,6, 7-tetrahydrobenzofuran-2-formic acid in diethylene glycol, adding copper powder and pyridine, heating the system to 175 ℃, and keeping stirring for 10 hours; cooling the system to room temperature, adding ice water, and acidifying with 4N hydrochloric acid; extracting the acidified reaction liquid with petroleum ether for three times, washing the combined extract with water once, and then drying and spin-drying the extract with anhydrous sodium sulfate to obtain a solid product: 3-methyl-6, 7-dihydrobenzofuran-4- (5H) -one;
the molar ratio of the 3-methyl-4-oxo-4,5,6, 7-tetrahydrobenzofuran-2-formic acid to copper powder to pyridine is 1:1:2, and the feeding amount of the 3-methyl-4-oxo-4,5,6, 7-tetrahydrobenzofuran-2-formic acid corresponding to diethylene glycol per milliliter is 0.1 g;
(4) under the protection of nitrogen, uniformly dispersing sodium hydride in an ethylene glycol dimethyl ether solution, and cooling a system to 0 ℃; then adding glycol dimethyl ether solution of 3-methyl-6,7-dihydrobenzofuran-4(5H) -ketone into the system, and keeping the system to stir at 0 ℃ for 30 min; adding dimethyl carbonate glycol dimethyl ether solution into the system, and heating the system to 90 ℃; after keeping for 3 hours, cooling the system to room temperature, and adding saturated ammonium chloride solution to quench the reaction; extracting with ethyl acetate for 3 times, drying the organic phase with anhydrous sodium sulfate, and concentrating to obtain the product: 3-methyl-4-oxo-4,5,6, 7-tetrahydrobenzofuran-5-carboxylic acid methyl ester;
the molar ratio of the 3-methyl-6,7-dihydrobenzofuran-4(5H) -one to sodium hydride and dimethyl carbonate is 1:5:3, and the feeding amount of the 3-methyl-6,7-dihydrobenzofuran-4(5H) -one corresponding to each milliliter of ethylene glycol dimethyl ether is 0.04 g;
(5) uniformly dispersing 3-methyl-4-oxo-4,5,6, 7-tetrahydrobenzofuran-5-methyl formate in a toluene solution, adding 2, 3-dichloro-5, 6-dicyan-p-benzoquinone into the system, heating to 130 ℃, and keeping for 6 hours; cooling the system to room temperature, filtering, concentrating the filtrate, and separating the crude product by silica gel chromatographic column to obtain pure product: 4-hydroxy-3-methylbenzofuran-5-carboxylic acid methyl ester;
the molar ratio of the methyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-5-carboxylate to the 2, 3-dichloro-5, 6-dicyan p-benzoquinone is 1:1.2, and the feeding amount of the methyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-5-carboxylate corresponding to each milliliter of toluene is 0.1 g;
(6) adding 4-hydroxy-3-methylbenzofuran-5-methyl formate into a saturated ammonia methanol solution, wherein the feeding amount of 4-hydroxy-3-methylbenzofuran-5-methyl formate in each milliliter of the saturated ammonia methanol solution is 0.06 g; sealing, heating to 65 deg.C, and maintaining for 24 hr; evaporating the reaction solution to obtain pure 4-hydroxy-3-methylbenzofuran-5-formamide;
(7) uniformly dispersing 4-hydroxy-3-methylbenzofuran-5-formamide, aldehyde and weak base in a reaction solvent a to ensure that the molar ratio of the 4-hydroxy-3-methylbenzofuran-5-formamide to the aldehyde to the weak base is 1: 1-3: 0.1-1, and the feeding amount of the 4-hydroxy-3-methylbenzofuran-5-formamide corresponding to each milliliter of the solvent a is 0.02-0.06 g to obtain a raw material mixture;
wherein the aldehyde is selected from any one of 4-methoxybenzaldehyde, 2-methoxybenzaldehyde, 3,4, 5-trimethoxybenzaldehyde, 4-dimethylaminobenzaldehyde, 4-hydroxybenzaldehyde, 4-hydroxy-2-methoxybenzaldehyde, 4-nitrobenzaldehyde, 4-cyanobenzaldehyde or 2-furaldehyde; the reaction solvent a is toluene or benzene;
(8) reacting the raw material mixture at 110-130 ℃ for 1-24 hours, distilling off the reaction solvent to obtain a crude product, and separating the crude product by using a silica gel chromatographic column to obtain a pure product of the substituted furan isoquinolone derivative.
In the present invention, the weak base in step (7) is piperidine or tetrahydropyrrole (the weak base is preferably piperidine, and the reaction solvent a is preferably toluene).
Compared with the prior art, the invention has the following beneficial effects:
(1) the furan isoquinolone derivative provided by the invention is a natural furan isoquinolone analogue with a new skeleton, has potential pharmaceutical activity, and can provide support for research on the pharmaceutical activity of furan isoquinolones.
(2) The preparation method of the furan isoquinolone derivative provided by the invention is simple in steps and easy to obtain. Has important significance for industrial production.
Drawings
FIG. 1 is a schematic diagram of the synthesis of substituted furan isoquinolinone derivatives provided by the present invention.
Detailed Description
The present invention will be described in detail with reference to specific examples. The following examples will assist those skilled in the art in further understanding the invention, but are not intended to limit the invention in any way. It should be noted that variations and modifications can be made by persons skilled in the art without departing from the spirit of the invention. All falling within the scope of the present invention.
Example 1
Uniformly dispersing 1, 3-cyclohexanedione and potassium hydroxide in water, stirring at normal temperature for 5min, adding a methanol solution of ethyl chloroacetoacetate, stirring the system at room temperature for 5 days, acidifying the system with 4N hydrochloric acid, and filtering the acidified reaction solution to obtain a solid, namely a product: 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylic acid ethyl ester. In the step, the molar ratio of the 1, 3-cyclohexanedione to the potassium hydroxide to the ethyl chloroacetoacetate is 1:1:1, the feeding amount of the 1, 3-cyclohexanedione corresponding to each milliliter of water is 0.1g, and the feeding amount of the ethyl chloroacetoacetate corresponding to each milliliter of methanol is 0.2 g. The yield of this step was 65%. The structure of the obtained product is:
the molecular formula is as follows: c12H14O4
Chinese naming: 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylic acid ethyl ester
English naming: ethyl 3-methyl-4-oxo-4,5,6, 7-tetrahydrobenzofurane-2-carboxylate
Molecular weight: 222.09
Appearance: white solid
Hydrogen nuclear magnetic resonance spectroscopy: (400MHz, Chloroform-d) δ 4.38(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.
Example 2
Dissolving 3-methyl-4-oxo-4,5,6, 7-tetrahydrobenzofuran-2-ethyl formate and potassium hydroxide in a mixed solvent of methanol and water, and stirring the system at room temperature for reaction for 5 h. Then adjusting the pH of the reaction liquid to 1 by using 6N hydrochloric acid, filtering the reaction liquid, and obtaining a solid obtained by filtering, namely a product: 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylic acid. The mixed solvent used in the step is prepared by methanol and water in a ratio of 2.5: 1. The amount of ethyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylate charged per ml of mixed solvent was 0.2 g. In the step, the molar ratio of the ethyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylate to the potassium hydroxide is 1: 6. The yield of this step was 90%. The structure of the obtained product is:
the molecular formula is as follows: c10H10O4
Chinese naming: 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylic acid
English naming: 3-methyl-4-oxo-4,5,6, 7-tetrahydrobenzofurane-2-carboxylic acid
Molecular weight: 194.06
Appearance: white solid
Hydrogen nuclear magnetic resonance spectroscopy: (400MHz, DMSO-d)6)δ2.91(t,J＝6.2Hz,2H),2.44(m,5H),2.08
(p,J＝6.4Hz,2H)ppm。
Example 3
3-methyl-4-oxo-4,5,6, 7-tetrahydrobenzofuran-2-formic acid is uniformly dispersed in diethylene glycol, copper powder and pyridine are added, and then the system is heated to 175 ℃, and is kept stirring for 10 hours. The system was cooled to room temperature, ice water was added and acidified with 4N hydrochloric acid, the acidified reaction solution was extracted three times with petroleum ether, the combined extracts were washed once with water, and then the extracts were dried over anhydrous sodium sulfate and spin dried. The obtained solid is the product: 3-methyl-6, 7-dihydrobenzofuran-4- (5H) -one. The amount of 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylic acid charged per ml of diethylene glycol in this step was 0.1 g. In the step, the molar ratio of the 3-methyl-4-oxo-4,5,6, 7-tetrahydrobenzofuran-2-formic acid to the copper powder and the pyridine is 1:1: 2. The yield of this step was 85%. The structure of the obtained product is:
the molecular formula is as follows: c9H10O2
Chinese naming: 3-methyl-6, 7-dihydrobenzofuran-4- (5H) -one
English naming: 3-methyl-6, 7-dihydrobenzofurane-4 (5H) -one
Molecular weight: 150.07
Appearance: yellow solid
Hydrogen nuclear magnetic resonance spectroscopy: (400MHz, Chloroform-d) δ 7.11-6.98 (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.
Nuclear magnetic resonance carbon spectrum (101MHz, Chloroform-d) delta 195.70,167.40,138.90,120.41,119.07,38.29,23.63,22.75,9.07 ppm.
Example 4
Under the protection of nitrogen, sodium hydride is uniformly dispersed in ethylene glycol dimethyl ether solution, the system is cooled to 0 ℃, then the ethylene glycol dimethyl ether solution of 3-methyl-6,7-dihydrobenzofuran-4(5H) -ketone is added into the system, and the system is kept to be stirred for 30min at 0 ℃. Dimethyl carbonate in ethylene glycol dimethyl ether solution was then added to the system, and the system was then heated to 90 ℃. Keeping for 3h, cooling the system to room temperature, adding saturated ammonium chloride solution to quench reaction, extracting for 3 times by using ethyl acetate, drying an organic phase by using anhydrous sodium sulfate, and concentrating to obtain a product of the step: 3-methyl-4-oxo-4,5,6, 7-tetrahydrobenzofuran-5-carboxylic acid methyl ester. In the step, the molar ratio of the 3-methyl-6,7-dihydrobenzofuran-4(5H) -one to the sodium hydride to the dimethyl carbonate is 1:5:3, and the feeding amount of the 3-methyl-6,7-dihydrobenzofuran-4(5H) -one corresponding to each milliliter of ethylene glycol dimethyl ether is 0.04 g. The yield from this step was 87%. The structure of the obtained product is:
the molecular formula is as follows: c11H12O4
Chinese naming: 3-methyl-4-oxo-4,5,6, 7-tetrahydrobenzofuran-5-carboxylic acid methyl ester
English naming: methyl 3-methyl-4-oxo-4,5,6, 7-tetrahydrobenzofurane-5-carboxylate
Molecular weight: 208.07
Appearance: white solid
Hydrogen nuclear magnetic resonance spectroscopy: (400MHz, Chloroform-d) δ 7.09(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).
Nuclear magnetic resonance carbon spectrum (101MHz, Chloroform-d) delta 189.80,170.49,166.90,139.42,119.74,119.33,53.68,52.36,25.83,22.10,8.90.
Example 5
3-methyl-4-oxo-4,5,6, 7-tetrahydrobenzofuran-5-methyl formate is uniformly dispersed in a toluene solution, 2, 3-dichloro-5, 6-dicyan-p-benzoquinone is added into the system, and the system is heated to 130 ℃ and kept for 6 hours. Cooling the system to room temperature, filtering, concentrating the filtrate, and separating the crude product by using a silica gel chromatographic column to obtain a pure product: 4-hydroxy-3-methylbenzofuran-5-carboxylic acid methyl ester. In the step, the molar ratio of the methyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-5-carboxylate to the 2, 3-dichloro-5, 6-dicyan-p-benzoquinone is 1:1.2, and the feeding amount of the methyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-5-carboxylate corresponding to each milliliter of toluene is 0.1 g. The yield from this step was 87%. The structure of the obtained product is:
the molecular formula is as follows: c11H10O4
Chinese naming: 4-hydroxy-3-methylbenzofuran-5-carboxylic acid methyl ester
English naming: methyl 4-hydroxy-3-methylbenzofuran-5-carboxylate
Molecular weight: 206.06
Appearance: pale yellow solid
Hydrogen nuclear magnetic resonance spectroscopy: (400MHz, Chloroform-d) δ 11.43(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).
Nuclear magnetic resonance carbon spectrum (101MHz, Chloroform-d) delta 171.28,160.21,159.02,140.65,125.86,117.59,116.87,105.68,103.85,52.10,9.59.
Example 6
Adding 4-hydroxy-3-methylbenzofuran-5-methyl formate into saturated ammonia methanol solution, sealing, heating to 65 ℃, keeping for 24h, and evaporating reaction liquid to obtain pure 4-hydroxy-3-methylbenzofuran-5-formamide. The amount charged in this step was 0.06g per ml of saturated ammonia in methanol. The yield of this step was 100%. The structure of the obtained product is:
the molecular formula is as follows: c10H9NO3
Chinese naming: 4-hydroxy-3-methylbenzofuran-5-carboxamides
English naming: 4-hydroxy-3-methylbenzofuron-5-carboxamide
Molecular weight: 191.06
Appearance: white solid
Hydrogen nuclear magnetic resonance spectroscopy: (400MHz, Chloroform-d) δ 14.32(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).
Nuclear magnetic resonance carbon 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.
Example 7-1:
uniformly dispersing 4-hydroxy-3-methylbenzofuran-5-formamide, p-methoxybenzaldehyde and piperidine in a reaction solvent toluene to ensure that the molar ratio of the 4-hydroxy-3-methylbenzofuran-5-formamide to the p-methoxybenzaldehyde to the piperidine is 1:1:0.5, and the corresponding feeding amount per milliliter of the reaction solvent is 0.045g, thereby obtaining a raw material mixture. Reacting the raw material mixture at 120 ℃ for 12 hours, evaporating the solvent, and separating the crude product by using a chromatographic column to obtain a pure product. The obtained furan isoquinolone derivative is as follows: 2- (4-methoxyphenyl) -9-methyl-2, 3-dihydro-4H-benzofuran [5,4-e ] [1,3] oxazine-4-one, with the yield of 78%, the structure of the derivative is as follows:
the molecular formula is as follows: c18H15NO4
Chinese naming: 2- (4-methoxyphenyl) -9-methyl-2, 3-dihydro-4H-benzofuran [5,4-e ] [1,3] oxazin-4-one
English naming: 2- (4-methoxyphenyl) -9-methyl-2,3-dihydro-4H-benzofuro [5,4-e ] [1,3] oxazin-4-one
Molecular weight: 309.1
Appearance: pale yellow solid
Hydrogen nuclear magnetic resonance spectroscopy: (400MHz, Chloroform-d) δ 7.88(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).
Nuclear magnetic resonance carbon spectrum: (101MHz, Chloroform-d) delta 164.39,161.02,159.96,153.55,141.65,128.31,128.14,124.28,117.51,115.98,114.35,111.65,106.78,85.66,55.42,9.48.
Example 7-2:
uniformly dispersing 4-hydroxy-3-methylbenzofuran-5-formamide, o-methoxybenzaldehyde and piperidine in a reaction solvent toluene to ensure that the molar ratio of the 4-hydroxy-3-methylbenzofuran-5-formamide, the o-methoxybenzaldehyde and the piperidine is 1:3:0.5, and the corresponding feeding amount per milliliter of the reaction solvent is 0.02g, thereby obtaining a raw material mixture. Reacting the raw material mixture for 1 hour at 130 ℃, evaporating the solvent, and separating the crude product by using a chromatographic column to obtain a pure product. The obtained furan isoquinolone derivative is as follows: 2- (2-methoxyphenyl) -9-methyl-2, 3-dihydro-4H-benzofuran [5,4-e ] [1,3] oxazine-4-one, with the yield of 78%, the structure of the derivative is as follows:
the molecular formula is as follows: c18H15NO4
Chinese naming: 2- (2-methoxyphenyl) -9-methyl-2, 3-dihydro-4H-benzofuran [5,4-e ] [1,3] oxazin-4-one
English naming: 2- (2-methoxyphenyl) -9-methyl-2,3-dihydro-4H-benzofuro [5,4-e ] [1,3] oxazin-4-one
Molecular weight: 309.1
Appearance: white solid
Hydrogen nuclear magnetic resonance spectroscopy: (400MHz, Chloroform-d) δ 7.89(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).
Nuclear magnetic resonance carbon spectrum: (101MHz, Chloroform-d) delta 164.53,159.86,156.34,153.59,141.63,130.88,126.85,124.28,124.22,121.01,117.56,115.94,111.71,110.71,106.68,81.11,55.51,9.54.
Examples 7 to 3:
4-hydroxy-3-methylbenzofuran-5-carboxamide, 3,4, 5-trimethoxybenzaldehyde and piperidine are uniformly dispersed in a reaction solvent toluene so that the molar ratio of 4-hydroxy-3-methylbenzofuran-5-carboxamide, 3,4, 5-trimethoxybenzaldehyde and piperidine is 1:2:0.1, and the corresponding charge amount per ml of the reaction solvent is 0.06g, thereby obtaining a raw material mixture. Reacting the raw material mixture at 110 ℃ for 12 hours, evaporating the solvent, and separating the crude product by using a chromatographic column to obtain a pure product. The obtained furan isoquinolone derivative is as follows: 9-methyl-2- (3,4,5-trimethoxyphenyl) -2, 3-dihydro-4H-benzofuran [5,4-e ] [1,3] oxazine-4-one with a yield of 75%, the structure of the derivative is:
the molecular formula is as follows: c20H19NO6
Chinese naming: 9-methyl-2- (3,4,5-trimethoxyphenyl) -2, 3-dihydro-4H-benzofuran [5,4-e ] [1,3] oxazin-4-one
English naming: 9-methyl-2- (3,4,5-trimethoxyphenyl) -2,3-dihydro-4H-benzofuro [5,4-e ] [1,3] oxazin-4-one
Molecular weight: 369.1
Appearance: white solid
Hydrogen nuclear magnetic resonance spectroscopy: (400MHz, Chloroform-d) δ 7.89(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).
Nuclear magnetic resonance carbon spectrum: (101MHz, Chloroform-d) delta 164.37,159.97,153.62,153.31,141.80,139.13,131.43,124.22,117.52,115.83,111.69,106.92,103.70,85.71,60.90,56.22,9.54.
Examples 7 to 4:
uniformly dispersing 4-hydroxy-3-methylbenzofuran-5-formamide, p-dimethylaminobenzaldehyde and piperidine in a reaction solvent toluene to ensure that the molar ratio of the 4-hydroxy-3-methylbenzofuran-5-formamide to the p-dimethylaminobenzaldehyde and the piperidine is 1:2:1, and the corresponding feeding amount per milliliter of the reaction solvent is 0.045g, thereby obtaining a raw material mixture. Reacting the raw material mixture at 120 ℃ for 24 hours, evaporating the solvent, and separating the crude product by using a chromatographic column to obtain a pure product. The obtained furan isoquinolone derivative is as follows: 2- (4- (dimethylamino) phenyl) -9-methyl-2, 3-dihydro-4H-benzofuran [5,4-e ] [1,3] oxazine-4-one, with a yield of 70%, the structure of the derivative is:
the molecular formula is as follows: c19H18N2O3
Chinese naming: 2- (4- (dimethylamino) phenyl) -9-methyl-2, 3-dihydro-4H-benzofuran [5,4-e ] [1,3] oxazin-4-one
English naming: 2- (4- (dimethylamino) phenyl) -9-methyl-2,3-dihydro-4H-benzofuro [5,4-e ] [1,3] oxazin-4-one
Molecular weight: 322.1
Appearance: white solid
Hydrogen nuclear magnetic resonance spectroscopy: (400MHz, Chloroform-d) δ 7.89(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).
Nuclear magnetic resonance carbon spectrum: (101MHz, DMSO-d)6)δ164.05,159.43,153.35,147.88,141.04,127.54,123.80,117.76,117.01,115.59,111.65,111.17,106.12,85.68,39.98,9.00.
Examples 7 to 5:
uniformly dispersing 4-hydroxy-3-methylbenzofuran-5-formamide, p-hydroxybenzaldehyde and piperidine in a reaction solvent benzene to ensure that the molar ratio of the 4-hydroxy-3-methylbenzofuran-5-formamide to the p-hydroxybenzaldehyde to the piperidine is 1:2:0.5, and the corresponding feeding amount of each milliliter of the reaction solvent is 0.06g, thereby obtaining a raw material mixture. Reacting the raw material mixture for 10 hours at 120 ℃, evaporating the solvent, and separating the crude product by using a chromatographic column to obtain a pure product. The obtained furan isoquinolone derivative is as follows: 2- (4-hydroxyphenyl) -9-methyl-2, 3-dihydro-4H-benzofuran [5,4-e ] [1,3] oxazine-4-one, yield 70%, the structure of the derivative is:
the molecular formula is as follows: c17H13NO4
Chinese naming: 2- (4-hydroxyphenyl) -9-methyl-2, 3-dihydro-4H-benzofuran [5,4-e ] [1,3] oxazin-4-one
English naming: 2- (4-hydroxypentyl) -9-methyl-2,3-dihydro-4H-benzofuro [5,4-e ] [1,3] oxazin-4-one
Molecular weight: 295.1
Appearance: white solid
Hydrogen nuclear magnetic resonance spectroscopy: (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).
Nuclear magnetic resonance carbon 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.
Examples 7 to 6:
4-hydroxy-3-methylbenzofuran-5-carboxamide, 4-hydroxy-2-methoxybenzaldehyde and piperidine were uniformly dispersed in a reaction solvent benzene so that the molar ratio of 4-hydroxy-3-methylbenzofuran-5-carboxamide, 4-hydroxy-2-methoxybenzaldehyde and piperidine was 1:2:0.5, and the charge amount per ml of the reaction solvent was 0.02g, to obtain a raw material mixture. Reacting the raw material mixture for 18 hours at 120 ℃, evaporating the solvent, and separating the crude product by using a chromatographic column to obtain a pure product. The obtained furan isoquinolone derivative is as follows: 2- (4-hydroxy-2-methoxyphenyl) -9-methyl-2, 3-dihydro-4H-benzofuran [5,4-e ] [1,3] oxazine-4-one, with a yield of 70%, the structure of the derivative is:
the molecular formula is as follows: c18H15NO5
Chinese naming: 2- (4-hydroxy-2-methoxyphenyl) -9-methyl-2, 3-dihydro-4H-benzofuran [5,4-e ] [1,3] oxazin-4-one
English naming: 2- (4-hydroxy-2-methoxyphenyl) -9-methyl-2,3-dihydro-4H-benzofuro [5,4-e ] [1,3] oxazin-4-one
Molecular weight: 325.1
Appearance: white solid
Hydrogen nuclear magnetic resonance spectroscopy: (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).
Nuclear magnetic resonance carbon spectrum: (101MHz, DMSO-d)6)δ163.11,158.71,152.55,147.62,147.41,142.55,127.56,123.65,119.97,116.93,115.05,112.35,110.89,106.04,99.49,85.18,55.52,9.14.
Examples 7 to 7:
uniformly dispersing 4-hydroxy-3-methylbenzofuran-5-formamide, 4-nitrobenzaldehyde and tetrahydropyrrole in a reaction solvent toluene to ensure that the molar ratio of the 4-hydroxy-3-methylbenzofuran-5-formamide, the 4-nitrobenzaldehyde and the tetrahydropyrrole is 1:3:1, and the corresponding feeding amount per milliliter of the reaction solvent is 0.045g, thus obtaining a raw material mixture. Reacting the raw material mixture at 120 ℃ for 12 hours, evaporating the solvent, and separating the crude product by using a chromatographic column to obtain a pure product. The obtained furan isoquinolone derivative is as follows: 9-methyl-2- (4-nitrophenyl) -2, 3-dihydro-4H-benzofuran [5,4-e ] [1,3] oxazin-4-one, in a yield of 70%, the structure of the derivative being:
the molecular formula is as follows: c17H12N2O5
Chinese naming: 9-methyl-2- (4-nitrophenyl) -2, 3-dihydro-4H-benzofuran [5,4-e ] [1,3] oxazin-4-one
English naming: 9-methyl-2- (4-nitrophenyl) -2,3-dihydro-4H-benzofuro [5,4-e ] [1,3] oxazin-4-one
Molecular weight: 324.1
Appearance: pale yellow solid
Hydrogen nuclear magnetic resonance spectroscopy: (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＝1.4Hz,3H).
Nuclear magnetic resonance carbon 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.
Examples 7 to 8:
4-hydroxy-3-methylbenzofuran-5-carboxamide, 4-cyanobenzaldehyde and tetrahydropyrrole are uniformly dispersed in a reaction solvent toluene so that the molar ratio of 4-hydroxy-3-methylbenzofuran-5-carboxamide, 4-cyanobenzaldehyde and tetrahydropyrrole is 1:1:0.1, and the corresponding charge amount per ml of the reaction solvent is 0.045g, thereby obtaining a raw material mixture. Reacting the raw material mixture at 120 ℃ for 12 hours, evaporating the solvent, and separating the crude product by using a chromatographic column to obtain a pure product. The obtained furan isoquinolone derivative is as follows: 4- (9-methyl-4-oxo-3, 4-dihydro-2H-benzofuran [5,4-e ] [1,3] oxazin-2-yl) benzonitrile in 62% yield, the structure of the derivative is:
the molecular formula is as follows: c18H12N2O3
Chinese naming: 4- (9-methyl-4-oxo-3, 4-dihydro-2H-benzofuran [5,4-e ] [1,3] oxazin-2-yl) benzonitrile
English naming: 4- (9-methyl-4-oxo-3,4-dihydro-2H-benzofuro [5,4-e ] [1,3] oxazin-2-yl) benzonitrile
Molecular weight: 304.1
Appearance: white solid
Hydrogen nuclear magnetic resonance spectroscopy: (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).
Nuclear magnetic resonance carbon spectrum: (101MHz, DMSO-d)6)δ162.48,158.79,151.90,142.79,142.23,132.62,127.88,123.63,118.36,117.01,115.01,112.27,112.15,106.49,83.77,9.15.
Examples 7 to 9:
uniformly dispersing 4-hydroxy-3-methylbenzofuran-5-formamide, 2-furaldehyde and tetrahydropyrrole in a reaction solvent toluene to ensure that the molar ratio of the 4-hydroxy-3-methylbenzofuran-5-formamide, the 2-furaldehyde and the tetrahydropyrrole is 1:2:0.5, and the corresponding feeding amount per milliliter of the reaction solvent is 0.045g, thereby obtaining a raw material mixture. Reacting the raw material mixture at 130 ℃ for 12 hours, evaporating the solvent, and separating the crude product by using a chromatographic column to obtain a pure product. The obtained furan isoquinolone derivative is as follows: 4- (9-methyl-4-oxo-3, 4-dihydro-2H-benzofuran [5,4-e ] [1,3] oxazin-2-yl) benzonitrile in 60% yield, the structure of the derivative being:
the molecular formula is as follows: c15H11NO4
Chinese naming: 2- (furan-2-yl) -9-methyl-2, 3-dihydro-4H-benzofuran [5,4-e ] [1,3] oxazin-4-one
English naming: 2- (furan-2-yl) -9-methyl-2,3-dihydro-4H-benzofuro [5,4-e ] [1,3] oxazin-4-one
Molecular weight: 269.1
Appearance: yellow solid
Hydrogen nuclear magnetic resonance spectroscopy: (500MHz, Chloroform-d) δ 7.87(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).
Nuclear magnetic resonance carbon spectrum: (101MHz, Chloroform-d) delta 163.76,159.98,152.58,148.87,143.93,141.75,140.75,124.14,115.98,111.63,110.76,110.40,106.99,79.17, 9.42.
Claims (2)
1. A preparation method of substituted furan isoquinolone derivatives is characterized by comprising the following steps:
(1) uniformly dispersing 1, 3-cyclohexanedione and potassium hydroxide in water, stirring at normal temperature for 5min, and adding a methanol solution of ethyl chloroacetoacetate; then the system is stirred for 5 days at room temperature and acidified by 4N hydrochloric acid; filtering the acidified reaction solution to obtain a solid product: 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylic acid ethyl ester;
the molar ratio of the 1, 3-cyclohexanedione to the potassium hydroxide to the ethyl chloroacetoacetate is 1:1:1, the feeding amount of the 1, 3-cyclohexanedione corresponding to each milliliter of water is 0.1g, and the feeding amount of the ethyl chloroacetoacetate corresponding to each milliliter of methanol is 0.2 g;
(2) dissolving 3-methyl-4-oxo-4,5,6, 7-tetrahydrobenzofuran-2-ethyl formate and potassium hydroxide in a mixed solvent of methanol and water, and stirring the system at room temperature for 5 h; adjusting the pH of the reaction solution to 1 by using 6N hydrochloric acid, filtering the reaction solution, and filtering to obtain a solid product: 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-2-carboxylic acid;
the mixed solvent is methanol and water, and the weight ratio of methanol to water is 2.5:1, the material dosage of 3-methyl-4-oxygen-4, 5,6, 7-tetrahydrobenzofuran-2-ethyl formate corresponding to each milliliter of mixed solvent is 0.2 g; the molar ratio of the 3-methyl-4-oxo-4,5,6, 7-tetrahydrobenzofuran-2-ethyl formate to the potassium hydroxide is 1: 6;
(3) uniformly dispersing 3-methyl-4-oxo-4,5,6, 7-tetrahydrobenzofuran-2-formic acid in diethylene glycol, adding copper powder and pyridine, heating the system to 175 ℃, and keeping stirring for 10 hours; cooling the system to room temperature, adding ice water, and acidifying with 4N hydrochloric acid; extracting the acidified reaction liquid with petroleum ether for three times, washing the combined extract with water once, and then drying and spin-drying the extract with anhydrous sodium sulfate to obtain a solid product: 3-methyl-6, 7-dihydrobenzofuran-4- (5H) -one;
the molar ratio of the 3-methyl-4-oxo-4,5,6, 7-tetrahydrobenzofuran-2-formic acid to copper powder to pyridine is 1:1:2, and the feeding amount of the 3-methyl-4-oxo-4,5,6, 7-tetrahydrobenzofuran-2-formic acid corresponding to diethylene glycol per milliliter is 0.1 g;
(4) under the protection of nitrogen, uniformly dispersing sodium hydride in an ethylene glycol dimethyl ether solution, and cooling a system to 0 ℃; then adding glycol dimethyl ether solution of 3-methyl-6,7-dihydrobenzofuran-4(5H) -ketone into the system, and keeping the system to stir at 0 ℃ for 30 min; adding dimethyl carbonate glycol dimethyl ether solution into the system, and heating the system to 90 ℃; after keeping for 3 hours, cooling the system to room temperature, and adding saturated ammonium chloride solution to quench the reaction; extracting with ethyl acetate for 3 times, drying the organic phase with anhydrous sodium sulfate, and concentrating to obtain the product: 3-methyl-4-oxo-4,5,6, 7-tetrahydrobenzofuran-5-carboxylic acid methyl ester;
the molar ratio of the 3-methyl-6,7-dihydrobenzofuran-4(5H) -one to sodium hydride and dimethyl carbonate is 1:5:3, and the feeding amount of the 3-methyl-6,7-dihydrobenzofuran-4(5H) -one corresponding to each milliliter of ethylene glycol dimethyl ether is 0.04 g;
(5) uniformly dispersing 3-methyl-4-oxo-4,5,6, 7-tetrahydrobenzofuran-5-methyl formate in a toluene solution, adding 2, 3-dichloro-5, 6-dicyan-p-benzoquinone into the system, heating to 130 ℃, and keeping for 6 hours; cooling the system to room temperature, filtering, concentrating the filtrate, and separating the crude product by silica gel chromatographic column to obtain pure product: 4-hydroxy-3-methylbenzofuran-5-carboxylic acid methyl ester;
the molar ratio of the methyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-5-carboxylate to the 2, 3-dichloro-5, 6-dicyan p-benzoquinone is 1:1.2, and the feeding amount of the methyl 3-methyl-4-oxo-4,5,6,7-tetrahydrobenzofuran-5-carboxylate corresponding to each milliliter of toluene is 0.1 g;
(6) adding 4-hydroxy-3-methylbenzofuran-5-methyl formate into a saturated ammonia methanol solution, wherein the feeding amount of 4-hydroxy-3-methylbenzofuran-5-methyl formate in each milliliter of the saturated ammonia methanol solution is 0.06 g; sealing, heating to 65 deg.C, and maintaining for 24 hr; evaporating the reaction solution to obtain pure 4-hydroxy-3-methylbenzofuran-5-formamide;
(7) uniformly dispersing 4-hydroxy-3-methylbenzofuran-5-formamide, aldehyde and weak base in a reaction solvent a to ensure that the molar ratio of the 4-hydroxy-3-methylbenzofuran-5-formamide to the aldehyde to the weak base is 1: 1-3: 0.1-1, and the feeding amount of the 4-hydroxy-3-methylbenzofuran-5-formamide corresponding to each milliliter of the solvent a is 0.02-0.06 g to obtain a raw material mixture;
wherein the aldehyde is selected from any one of 4-methoxybenzaldehyde, 2-methoxybenzaldehyde, 3,4, 5-trimethoxybenzaldehyde, 4-dimethylaminobenzaldehyde, 4-hydroxybenzaldehyde, 4-hydroxy-2-methoxybenzaldehyde, 4-nitrobenzaldehyde, 4-cyanobenzaldehyde or 2-furaldehyde; the reaction solvent a is toluene or benzene;
(8) reacting the raw material mixture at 110-130 ℃ for 1-24 hours, evaporating the reaction solvent to obtain a crude product, and separating the crude product by using a silica gel chromatographic column to obtain a pure product of the substituted furan isoquinolone derivative;
the substituted furan isoquinolone derivative in the step (8) has any one of the following structures:
2. the process according to claim 1, wherein the weak base in the step (7) is piperidine or tetrahydropyrrole.
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