CN115806531B - Preparation method of 4, 5-dihydro-5, 5-diphenyl isoxazole-3-formic acid and derivatives thereof - Google Patents
Preparation method of 4, 5-dihydro-5, 5-diphenyl isoxazole-3-formic acid and derivatives thereof Download PDFInfo
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- CN115806531B CN115806531B CN202111076366.3A CN202111076366A CN115806531B CN 115806531 B CN115806531 B CN 115806531B CN 202111076366 A CN202111076366 A CN 202111076366A CN 115806531 B CN115806531 B CN 115806531B
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- Prior art keywords
- compound
- dihydro
- formula
- reaction
- alkali
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- ITGSCCPVERXFGN-UHFFFAOYSA-N isoxadifen Chemical compound C1C(C(=O)O)=NOC1(C=1C=CC=CC=1)C1=CC=CC=C1 ITGSCCPVERXFGN-UHFFFAOYSA-N 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- 238000006243 chemical reaction Methods 0.000 claims abstract description 37
- -1 acrylic ester Chemical class 0.000 claims abstract description 32
- 239000002253 acid Substances 0.000 claims abstract description 21
- 150000002443 hydroxylamines Chemical class 0.000 claims abstract description 15
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 13
- 239000004305 biphenyl Substances 0.000 claims abstract description 12
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000007259 addition reaction Methods 0.000 claims abstract description 10
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 9
- 230000020477 pH reduction Effects 0.000 claims abstract description 8
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical class CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 claims abstract description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 83
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 60
- 150000001875 compounds Chemical class 0.000 claims description 58
- 239000003513 alkali Substances 0.000 claims description 34
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 32
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 28
- 239000002904 solvent Substances 0.000 claims description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- 239000000706 filtrate Substances 0.000 claims description 19
- 239000003054 catalyst Substances 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 17
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 238000001914 filtration Methods 0.000 claims description 15
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical group COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 claims description 14
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 13
- 239000012074 organic phase Substances 0.000 claims description 13
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-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
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- 239000002585 base Substances 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- 239000000460 chlorine Substances 0.000 claims description 11
- 238000007363 ring formation reaction Methods 0.000 claims description 11
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 10
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical group Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000012065 filter cake Substances 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- 239000012071 phase Substances 0.000 claims description 8
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 7
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 230000001105 regulatory effect Effects 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 4
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- ULWOJODHECIZAU-UHFFFAOYSA-N n,n-diethylpropan-2-amine Chemical compound CCN(CC)C(C)C ULWOJODHECIZAU-UHFFFAOYSA-N 0.000 claims description 4
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 4
- FTTATHOUSOIFOQ-UHFFFAOYSA-N 1,2,3,4,6,7,8,8a-octahydropyrrolo[1,2-a]pyrazine Chemical compound C1NCCN2CCCC21 FTTATHOUSOIFOQ-UHFFFAOYSA-N 0.000 claims description 3
- ZNBNBTIDJSKEAM-UHFFFAOYSA-N 4-[7-hydroxy-2-[5-[5-[6-hydroxy-6-(hydroxymethyl)-3,5-dimethyloxan-2-yl]-3-methyloxolan-2-yl]-5-methyloxolan-2-yl]-2,8-dimethyl-1,10-dioxaspiro[4.5]decan-9-yl]-2-methyl-3-propanoyloxypentanoic acid Chemical compound C1C(O)C(C)C(C(C)C(OC(=O)CC)C(C)C(O)=O)OC11OC(C)(C2OC(C)(CC2)C2C(CC(O2)C2C(CC(C)C(O)(CO)O2)C)C)CC1 ZNBNBTIDJSKEAM-UHFFFAOYSA-N 0.000 claims description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 3
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000012295 chemical reaction liquid Substances 0.000 claims description 3
- 229910000378 hydroxylammonium sulfate Inorganic materials 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 3
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 claims description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 claims description 3
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 claims description 3
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 claims description 2
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 claims description 2
- GJFNRSDCSTVPCJ-UHFFFAOYSA-N 1,8-bis(dimethylamino)naphthalene Chemical compound C1=CC(N(C)C)=C2C(N(C)C)=CC=CC2=C1 GJFNRSDCSTVPCJ-UHFFFAOYSA-N 0.000 claims description 2
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 claims description 2
- LMAUULKNZLEMGN-UHFFFAOYSA-N 1-ethyl-3,5-dimethylbenzene Chemical compound CCC1=CC(C)=CC(C)=C1 LMAUULKNZLEMGN-UHFFFAOYSA-N 0.000 claims description 2
- CFVWNXQPGQOHRJ-UHFFFAOYSA-N 2-methylpropyl prop-2-enoate Chemical compound CC(C)COC(=O)C=C CFVWNXQPGQOHRJ-UHFFFAOYSA-N 0.000 claims description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- GCTPMLUUWLLESL-UHFFFAOYSA-N benzyl prop-2-enoate Chemical compound C=CC(=O)OCC1=CC=CC=C1 GCTPMLUUWLLESL-UHFFFAOYSA-N 0.000 claims description 2
- 238000009835 boiling Methods 0.000 claims description 2
- CQEYYJKEWSMYFG-UHFFFAOYSA-N butyl acrylate Chemical compound CCCCOC(=O)C=C CQEYYJKEWSMYFG-UHFFFAOYSA-N 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 239000003208 petroleum Substances 0.000 claims description 2
- ZOGYOOUMDVKYLM-UHFFFAOYSA-N phosphane phosphorous acid Chemical compound P.OP(O)O ZOGYOOUMDVKYLM-UHFFFAOYSA-N 0.000 claims description 2
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- LYBIZMNPXTXVMV-UHFFFAOYSA-N propan-2-yl prop-2-enoate Chemical compound CC(C)OC(=O)C=C LYBIZMNPXTXVMV-UHFFFAOYSA-N 0.000 claims description 2
- PNXMTCDJUBJHQJ-UHFFFAOYSA-N propyl prop-2-enoate Chemical compound CCCOC(=O)C=C PNXMTCDJUBJHQJ-UHFFFAOYSA-N 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000007790 solid phase Substances 0.000 claims description 2
- XTTGYFREQJCEML-UHFFFAOYSA-N tributyl phosphite Chemical compound CCCCOP(OCCCC)OCCCC XTTGYFREQJCEML-UHFFFAOYSA-N 0.000 claims description 2
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical group COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 claims description 2
- QOPBTFMUVTXWFF-UHFFFAOYSA-N tripropyl phosphite Chemical compound CCCOP(OCCC)OCCC QOPBTFMUVTXWFF-UHFFFAOYSA-N 0.000 claims description 2
- 239000008096 xylene Substances 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 19
- CZZYITDELCSZES-UHFFFAOYSA-N diphenylmethane Chemical compound C=1C=CC=CC=1CC1=CC=CC=C1 CZZYITDELCSZES-UHFFFAOYSA-N 0.000 abstract description 9
- 239000002994 raw material Substances 0.000 abstract description 9
- 238000007086 side reaction Methods 0.000 abstract description 9
- 230000007062 hydrolysis Effects 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 4
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 239000013067 intermediate product Substances 0.000 abstract description 3
- 239000000203 mixture Substances 0.000 description 18
- 238000010992 reflux Methods 0.000 description 14
- 238000003756 stirring Methods 0.000 description 12
- 238000004821 distillation Methods 0.000 description 10
- 239000007791 liquid phase Substances 0.000 description 10
- 238000001816 cooling Methods 0.000 description 8
- 230000002363 herbicidal effect Effects 0.000 description 8
- 239000004009 herbicide Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- ZMYIIHDQURVDRB-UHFFFAOYSA-N 1-phenylethenylbenzene Chemical group C=1C=CC=CC=1C(=C)C1=CC=CC=C1 ZMYIIHDQURVDRB-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- KONORNDPKQTLGG-UHFFFAOYSA-N methyl 4,4-diphenylbutanoate Chemical compound COC(=O)CCC(C1=CC=CC=C1)C1=CC=CC=C1 KONORNDPKQTLGG-UHFFFAOYSA-N 0.000 description 4
- 230000035484 reaction time Effects 0.000 description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 4
- 241000196324 Embryophyta Species 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- GJRHDKLNYOFTLF-UHFFFAOYSA-N ethyl 4,4-diphenylbutanoate Chemical compound CCOC(=O)CCC(C1=CC=CC=C1)C1=CC=CC=C1 GJRHDKLNYOFTLF-UHFFFAOYSA-N 0.000 description 3
- 238000006200 ethylation reaction Methods 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- TXTWXQXDMWILOF-UHFFFAOYSA-N (2-ethoxy-2-oxoethyl)azanium;chloride Chemical compound [Cl-].CCOC(=O)C[NH3+] TXTWXQXDMWILOF-UHFFFAOYSA-N 0.000 description 2
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Chemical compound CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 238000003747 Grignard reaction Methods 0.000 description 2
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- FHKYMEGVIVZQAD-UHFFFAOYSA-N [N].ON Chemical group [N].ON FHKYMEGVIVZQAD-UHFFFAOYSA-N 0.000 description 2
- 239000006096 absorbing agent Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 2
- PWLNAUNEAKQYLH-UHFFFAOYSA-N butyric acid octyl ester Natural products CCCCCCCCOC(=O)CCC PWLNAUNEAKQYLH-UHFFFAOYSA-N 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 230000006203 ethylation Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000005650 intramolecular substitution reaction Methods 0.000 description 2
- UUIQMZJEGPQKFD-UHFFFAOYSA-N n-butyric acid methyl ester Natural products CCCC(=O)OC UUIQMZJEGPQKFD-UHFFFAOYSA-N 0.000 description 2
- 239000000575 pesticide Substances 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000002699 waste material Substances 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 238000006736 Huisgen cycloaddition reaction Methods 0.000 description 1
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 125000005396 acrylic acid ester group Chemical group 0.000 description 1
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
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- 238000006193 diazotization reaction Methods 0.000 description 1
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- 229940008406 diethyl sulfate Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical compound CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 description 1
- UXOLDCOJRAMLTQ-UHFFFAOYSA-N ethyl 2-chloro-2-hydroxyiminoacetate Chemical compound CCOC(=O)C(Cl)=NO UXOLDCOJRAMLTQ-UHFFFAOYSA-N 0.000 description 1
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- ANRQGKOBLBYXFM-UHFFFAOYSA-M phenylmagnesium bromide Chemical compound Br[Mg]C1=CC=CC=C1 ANRQGKOBLBYXFM-UHFFFAOYSA-M 0.000 description 1
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- BXQYQBFZTKKPHI-UHFFFAOYSA-M sodium;nitrite;hydrochloride Chemical compound [Na+].Cl.[O-]N=O BXQYQBFZTKKPHI-UHFFFAOYSA-M 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention provides a preparation method of 4, 5-dihydro-5, 5-diphenyl isoxazole-3-formic acid and derivatives thereof; 4, 4-diphenyl butyrate is obtained by the addition reaction of diphenylmethane and acrylic ester, then 4-chloro-4, 4-diphenyl-2-oxo-butyric acid is obtained by chlorination, hydrolysis and acidification, and then the 4-chloro-4, 4-diphenyl-2-oxo-butyric acid and hydroxylamine salt are cyclized to obtain the product. The obtained 4, 5-dihydro-5, 5-diphenylisoxazole-3-carboxylic acid can be further used for preparing bisbenzoxazole acid and isopropyl amine salt of 4, 5-dihydro-5, 5-diphenylisoxazole-3-carboxylic acid. The invention has the advantages of easily available raw materials, simple preparation method, safety, environmental protection and low cost; the used raw materials and intermediate products are stable, the reaction selectivity is high, the side reaction is less, the yield and purity of the target product are high, and the green industrial production is facilitated.
Description
Technical Field
The invention relates to a preparation method of 4, 5-dihydro-5, 5-diphenyl isoxazole-3-formic acid and derivatives thereof, belonging to the technical field of pesticide chemical industry.
Background
Herbicide safeners (Safener), also known as antidotes and safeners, are useful for protecting crops from herbicide injury, thereby increasing the safety of the herbicide and improving weed control. The herbicide safener can enhance the selectivity of herbicide to remove weeds, can improve the drug resistance of crops and can protect the crops from being damaged by pesticide residues. The bisbenzoxazole acid is an important herbicide safener, the chemical name of the bisbenzoxazole acid is 4, 5-dihydro-5, 5-diphenyl-isoxazole-3-ethyl formate, the CAS number is [163520-33-0], and the bisbenzoxazole acid is the herbicide safener researched and developed by Anvant company and is used for compounding with the herbicide to prevent and remove annual and perennial weeds in corn fields, and the bisbenzoxazole acid is widely applied to related products of Bayer and DuPont companies, has wide market, so research and optimization of synthesis of the bisbenzoxazole acid have important significance.
For the preparation of the bisbenzoxazole acid, the bisbenzoxazole acid is mainly prepared by 1, 3-dipolar cycloaddition reaction of 1, 1-diphenylethylene and 2-chloro-2-oximinoacetic ether. Patent DE4331448, chinese patent CN103709113A, CN 103172582A, CN1133038A, CN108440435A and 'pesticides, 2012, 51 (11) 792-793, 810' all use ethyl 2-chloro-2-oximido acetate and 1, 1-diphenylethylene to prepare bisbenzoxazole acid under the action of different solvents and different kinds of acid binding agents (reaction route 1), the cyclic addition one-step yield difference is larger, and the reported yield is between 64-90%.
The raw materials 1, 1-diphenylethylene and 2-chloro-2-oximido ethyl acetate used in the method are not easy to obtain, and the cost is high. The 1, 1-diphenylethylene is prepared by Grignard reaction of bromobenzene to obtain phenylmagnesium bromide, then adding acetophenone, and dehydrating. The 2-chloro-2-oximinoacetic acid ethyl ester is prepared by esterifying 2-amino acetic acid to prepare 2-amino acetic acid ethyl ester hydrochloride, and then the 2-amino acetic acid ethyl ester hydrochloride reacts with sodium nitrite-hydrochloric acid to obtain the 2-amino acetic acid ethyl ester. The whole route is long, the Grignard reaction and the diazotization reaction are involved, the operation safety is poor, and the wastewater quantity is large. In addition, the 2-chloro-2-oximido ethyl acetate has poor stability, poor reaction selectivity, more impurities, high non-cyclic impurity content and difficult purification, and is not beneficial to green industrial production.
4, 5-Dihydro-5, 5-diphenylisoxazole-3-carboxylic acid (I) is a key intermediate for the preparation of bisbenzoxazole acid, having the structure shown below:
The optimized research of the green industrialized preparation method of 4, 5-dihydro-5, 5-diphenyl isoxazole-3-carboxylic acid is simple, safe, environment-friendly, low in cost, high in reaction selectivity, less in side reaction and high in yield and purity, and has important significance for the research of preparing the bisbenzoxazole acid and the derivatives thereof.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a preparation method of 4, 5-dihydro-5, 5-diphenyl isoxazole-3-carboxylic acid and derivatives thereof, and the prepared 4, 5-dihydro-5, 5-diphenyl isoxazole-3-carboxylic acid can be used for further preparing bisbenzoxazole acid and isopropyl amine salt of 4, 5-dihydro-5, 5-diphenyl isoxazole-3-carboxylic acid. The invention has the advantages of easily available raw materials, simple preparation method, safety, environmental protection and low cost; the used raw materials and intermediate products are stable, the reaction selectivity is high, the side reaction is less, the yield and purity of the target product are high, and the green industrial production is facilitated.
Description of the terminology:
a compound of formula ii: diphenyl methane;
A compound of formula III 4, 4-diphenyl butyrate;
a compound of formula iv: 2, 4-trichloro-4, 4-diphenyl butyrate;
A compound of formula V4-chloro-4, 4-diphenyl-2-oxobutanoic acid;
A compound of formula i: 4, 5-dihydro-5, 5-diphenylisoxazole-3-carboxylic acid;
In the specification, the compound numbers are completely consistent with the structural formula numbers, and have the same reference relationship, and the structural formula is taken as a basis.
The technical scheme of the invention is as follows:
a preparation method of 4, 5-dihydro-5, 5-diphenyl isoxazole-3-formic acid comprises the following steps:
(1) In a solvent A, under the action of a catalyst 1, carrying out addition reaction on a compound of a formula II and acrylic ester to obtain a compound of a formula III;
wherein, the substituent R in the compound of the formula III is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or benzyl;
(2) In a solvent B, under the action of a catalyst 2, preparing a compound of a formula IV by chlorination reaction of the compound of the formula III and chlorine; then, carrying out hydrolysis reaction and acidification under the action of alkali 1 to obtain a compound of a formula V;
Wherein the substituent R in the compound of formula IV is the same as the substituent R in the compound of formula III;
(3) In a solvent C, under the action of alkali 2, cyclizing the compound shown in the formula V and hydroxylamine salt to obtain 4, 5-dihydro-5, 5-diphenyl isoxazole-3-formic acid I;
According to the invention, the solvent A in the step (1) is one or more than two of N, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, acetonitrile, 1, 2-dichloroethane, alkane with 6 to 8 carbon atoms, benzene, toluene, ethanol or xylene; the mass ratio of the solvent A to the compound of the formula II is 2-7:1.
According to a preferred embodiment of the present invention, in the step (1), the catalyst 1 is one or more than two of piperidine, 4-dimethylaminopyridine, tri-n-butylamine, 1, 8-diazabicyclo undec-7-ene (DBU), 1, 4-diazabicyclo [2, 2] octane (DABCO), 1, 8-bis-dimethylaminonaphthalene, tetramethylguanidine, sodium methoxide, sodium ethoxide or potassium tert-butoxide; the mass of the catalyst 1 is 0.5% -5.0% of the mass of the compound of the formula II.
According to a preferred embodiment of the present invention, in the step (1), the acrylic acid ester is methyl acrylate, ethyl acrylate, n-propyl acrylate, isopropyl acrylate, n-butyl acrylate, isobutyl acrylate, sec-butyl acrylate, t-butyl acrylate or benzyl acrylate; the molar ratio of the acrylic ester to the compound of formula II is (1.0-1.5): 1.
According to a preferred embodiment of the invention, in step (1), the addition reaction temperature is 50 to 100 ℃, preferably 60 to 80 ℃. The addition reaction time is 2-8 hours.
According to a preferred embodiment of the invention, in step (1), the compound of formula III is methyl 4, 4-diphenylbutyrate, ethyl 4, 4-diphenylbutyrate or tert-butyl 4, 4-diphenylbutyrate.
According to a preferred embodiment of the invention, in step (1), the acrylate is added dropwise to the system comprising solvent A, catalyst 1 and the compound of formula II.
According to the invention, in the step (1), the reaction mixture obtained by the addition reaction of the compound of formula II and the acrylic ester is worked up as follows: adding water and dichloromethane into the reaction solution, regulating the pH value of the system to 1-3, layering, extracting the water layer with dichloromethane, merging the organic phases, drying the organic phases through anhydrous sodium sulfate, filtering, distilling the filtrate to recover the organic solvent, and distilling under reduced pressure to obtain the compound shown in the formula III.
According to the invention, preferably, the solvent B in the step (2) is one or more than two of dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, trichloroethane, cyclohexane, petroleum ether with the boiling range of 60-90 ℃, normal hexane or chlorobenzene; the mass ratio of the solvent B to the compound of the formula III is 2-10:1.
According to the invention, the catalyst 2 in the step (2) is one or more than two of phosphorus trichloride, organic phosphorus phosphite or organic amine; preferably, the organophosphorus phosphite is trimethyl phosphite, triethyl phosphite, tripropyl phosphite or tributyl phosphite; the organic amine is tri-N-butylamine, 4-dimethylaminopyridine, N-methylpiperidine or pyridine; the catalyst 2 is 0.1-5.0% of the mass of the compound of the formula III.
According to a preferred embodiment of the invention, the molar ratio of chlorine to the compound of formula III in step (2) is from (3.0 to 5.0): 1.
According to a preferred embodiment of the present invention, the chlorination reaction temperature in step (2) is 50 to 100 ℃. The chlorination reaction time is 1-12 hours.
Preferably according to the invention, the base 1 of step (2) is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or lithium hydroxide; the molar ratio of base 1 to compound of formula III is (2.0-8.0): 1, preferably (4.0-6.0): 1.
According to the invention, preferably, in step (2), the hydrolysis is carried out in the presence of water, the mass of water being 1-10:1 of the mass of the compound of formula III.
According to a preferred embodiment of the invention, the hydrolysis reaction temperature in step (2) is 20-60 ℃. The reaction time is 1-6 hours.
According to a preferred embodiment of the invention, in step (2), the acidification is an acidification with hydrochloric acid to a pH of the system of 2-3.
According to the present invention, preferably, in the step (2), the post-treatment of the reaction liquid obtained by the hydrolysis reaction includes the steps of: the reaction solution is layered, the solid phase and the organic phase in the system are washed by water, the water phase is combined, the pH value of the obtained water phase is acidified to 2-3 by hydrochloric acid, and then the compound of the formula V is obtained through filtration, water washing and drying.
According to the invention, in the step (3), the solvent C is one or more of methanol, ethanol, saturated monohydric alcohol with 3 to 5 carbon atoms, methylene chloride, 1, 2-dichloroethane, acetonitrile or water; the mass ratio of the solvent C to the compound of the formula V is 3-10:1.
According to a preferred embodiment of the present invention, in the step (3), the base 2 is one or a combination of two or more of sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, triethylamine, isopropyl diethylamine, diisopropyl ethylamine, and pyridine.
According to a preferred embodiment of the present invention, in the step (3), the hydroxylamine salt is hydroxylamine hydrochloride or hydroxylamine sulfate.
According to a preferred embodiment of the invention, in step (3), the molar ratio of hydroxylamine salt, base 2 to compound of formula V is (0.5-1.5): 1.5-4.0): 1.
According to a preferred embodiment of the present invention, in step (3), the cyclisation reaction temperature is 20 to 80 ℃, preferably 30 to 60 ℃. The cyclization reaction time is 2-8 hours.
According to the preferred embodiment of the present invention, in the step (3), the base 2 is added to the reaction system in portions; preferably, the base 2 is added to the reaction system in two portions.
According to the present invention, preferably, in the step (3), the preparation method of 4, 5-dihydro-5, 5-diphenylisoxazole-3-carboxylic acid I comprises the steps of: dissolving a compound of a formula V, hydroxylamine salt and alkali 2a in a solvent C, and carrying out cyclization reaction at 20-80 ℃; then adding alkali 2b, and continuing cyclization reaction at 20-80 ℃ to obtain 4, 5-dihydro-5, 5-diphenyl isoxazole-3-formic acid I; the alkali 2a and the alkali 2b are selected from one or more of sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, triethylamine, isopropyl diethylamine, diisopropyl ethylamine or pyridine, the types of the alkali 2a and the alkali 2b are the same or different, the molar ratio of the alkali 2a to the alkali 2b is 1:0.5-2, and the sum of the dosage of the alkali 2a and the dosage of the alkali 2b is the same as the dosage of the alkali 2.
According to a preferred embodiment of the present invention, in the step (3), the post-treatment method of the reaction solution obtained by the cyclization reaction of the compound of formula V and hydroxylamine salt comprises the steps of: filtering the reaction solution, washing a filter cake by using a solvent C, merging filtrate, distilling the filtrate to recover the solvent C, recrystallizing residues, and drying to obtain the 4, 5-dihydro-5, 5-diphenyl isoxazole-3-carboxylic acid I.
The 4, 5-dihydro-5, 5-diphenyl isoxazole-3-carboxylic acid I obtained by the invention can be further subjected to ethylation reaction with an ethylation reagent or salified with isopropylamine according to the prior method to obtain the bisbenzoxazole acid or the isopropyl amine salt of 4, 5-dihydro-5, 5-diphenyl isoxazole-3-carboxylic acid.
The process of the invention is described as the following scheme (scheme 2):
Wherein, the substituent R in the compound of the formula III is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or benzyl; the substituent R in the compound of formula IV is the same as the substituent R in the compound of formula III.
The invention has the technical characteristics and beneficial effects that:
1. The invention utilizes diphenylmethane and acrylic ester to obtain 4, 4-diphenyl butyrate through addition reaction under the action of a catalyst, then 4-chloro-4, 4-diphenyl-2-oxo-butyric acid is obtained through chlorination, hydrolysis and acidification, and then 4, 5-dihydro-5, 5-diphenyl isoxazole-3-formic acid is obtained through cyclization reaction with hydroxylamine salt under the action of alkali. The raw materials used in the invention are cheap and easy to obtain, the reaction operability is strong and safe, and the preparation route is relatively simple; the method has the advantages of stable raw materials and intermediate products, high reaction selectivity, less side reactions and byproducts, high product yield and purity, low cost, less three wastes and environmental protection.
2. The 4, 5-dihydro-5, 5-diphenyl isoxazole-3-formic acid obtained by the method can be further ethylated with an ethylation reagent to prepare bisbenzoxazole acid, or further salified with an organic base to obtain 4, 5-dihydro-5, 5-diphenyl isoxazole-3-formate; the 4, 5-dihydro-5, 5-diphenyl isoxazole-3-formic acid has low cost, and is beneficial to the green industrial production and research of downstream products of the bisbenzoxazole acid and related compounds.
3. According to the invention, by utilizing the characteristic that diphenylmethane is easy to form carbanion under the action of an alkaline catalyst, the formed carbanion and acrylic ester are subjected to addition reaction to obtain 4, 4-diphenyl butyrate. The raw materials are cheap and easy to obtain, the process is simple and safe, the three wastes are less, the environment is protected, the reaction yield and purity are high, and the cost of the intermediate is low.
4. By utilizing the characteristic that the carbonyl ortho-position and benzyl position of the designed intermediate 4, 4-diphenyl butyrate are easy to carry out chlorination, the complete chlorination is carried out at the corresponding position, the reaction is easy to carry out, the reaction selectivity is specific, and then the 4-chloro-4, 4-diphenyl-2-oxo-butyric acid is obtained through hydrolysis and acidification, so that the high purity and the high yield of the 4-chloro-4, 4-diphenyl-2-oxo-butyric acid are essentially ensured by the reaction.
5. The invention utilizes the high activity of the 2-carbonyl of 4-chloro-4, 4-diphenyl-2-oxo-butyric acid and hydroxylamine obtained by alkali free hydroxylamine salt to react, and then the hydroxylamine is subjected to intramolecular substitution under the action of alkali to complete cyclization reaction. The alkali is preferably added in batches, and the added alkali sequentially neutralizes hydroxylamine salt and neutralizes hydrogen chloride generated by intramolecular substitution, thereby providing enough alkalinity, avoiding hydrolysis side reaction of 4-chlorine and hydroxylamine nitrogen substitution side reaction caused by excessive alkali, having high selectivity and ensuring high purity and high yield of key intermediate 4, 5-dihydro-5, 5-diphenyl isoxazole-3-formic acid.
Detailed Description
The present invention is described in detail below with reference to examples, but the present invention is not limited thereto.
The raw materials and reagents used in the examples were all commercially available products.
In the examples, "%" is mass percent unless otherwise specified. The yields described in the examples all refer to molar yields.
Example 1: preparation of methyl 4, 4-diphenylbutyrate (III 1)
To a 2000 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a constant pressure dropping funnel, 400 g of tetrahydrofuran, 168.2 g (1 mol) of diphenylmethane and 5.0 g of DBU were added, and a mixed solution of 112.0 g (1.3 mol) of methyl acrylate and 200 g of tetrahydrofuran was added dropwise from the constant pressure dropping funnel at 60 to 65℃under heating, and the addition was completed for 3 hours. Thereafter, the reaction was stirred at 60-65℃for 3 hours. Cooling to 20-25 ℃, adding 300 g of water and 400 g of dichloromethane, regulating the pH value of the system to 2 by using 30% hydrochloric acid, layering, extracting the aqueous layer by using dichloromethane twice, 200 g each time, combining organic phases, drying by using 20 g of anhydrous sodium sulfate for 4 hours, filtering, distilling filtrate to recover dichloromethane and tetrahydrofuran, and carrying out reduced pressure distillation (115-125 ℃/1-2 mmHg) to obtain 243.1 g of 4, 4-diphenyl methyl butyrate (III 1), wherein the gas phase purity is 99.5 percent and the yield is 95.6 percent.
1 HNMR data (400 MHz, DMSO-d 6) of the resulting product were as follows:
1.67(m,2H),2.23(t,2H),3.39(s,3H),3.91(t,1H),7.11-7.23(m,10H).
Example 2: preparation of ethyl 4, 4-diphenylbutyrate (III 2)
To a 2000 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a constant pressure dropping funnel, 400 g of ethanol, 168.2 g (1 mol) of diphenylmethane and 5.0 g of 1, 4-diazabicyclo [2, 2] octane were added, and the mixture was heated, and a mixed solution of 120.0 g (1.2 mol) of ethyl acrylate and 200 g of ethanol was dropped from the constant pressure dropping funnel at 70 to 75℃for 3 hours. Thereafter, the reaction was stirred at 70-75℃for 3 hours. Cooling to 20-25 ℃, adding 300 g of water and 400 g of dichloromethane, regulating the pH value of the system to 2 by using 30% hydrochloric acid, layering, extracting the aqueous layer by using dichloromethane twice, 200 g each time, combining organic phases, drying by using 20 g of anhydrous sodium sulfate for 4 hours, filtering, distilling filtrate to recover dichloromethane and ethanol, and carrying out reduced pressure distillation (120-135 ℃/1-2 mmHg) to obtain 249.3 g of ethyl 4, 4-diphenyl butyrate (III 2), wherein the gas phase purity is 99.3%, and the yield is 92.9%.
1 HNMR data (400 MHz, DMSO-d 6) of the resulting product were as follows:
1.23(t,3H),1.68(m,2H),2.26(t,2H),3.86(q,2H),3.92(t,1H),7.09-7.21(m,10H).
Example 3: preparation of tert-butyl 4, 4-diphenylbutyrate (III 3)
To a 2000 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a constant pressure dropping funnel, 400 g of tetrahydrofuran, 168.2 g (1 mol) of diphenylmethane and 5.0 g of DBU were charged, and a mixed solution of 153.7 g (1.2 mol) of t-butyl acrylate and 200 g of tetrahydrofuran was added dropwise from the constant pressure dropping funnel at 60 to 65℃under heating, and the addition was completed for 3 hours. Thereafter, the reaction was stirred at 60-65℃for 3 hours. Cooling to 20-25 ℃, adding 300 g of water and 400 g of dichloromethane, regulating the pH value of the system to 2 by using 30% hydrochloric acid, layering, extracting the aqueous layer by using dichloromethane twice, 200 g each time, combining organic phases, drying by using 20 g of anhydrous sodium sulfate for 4 hours, filtering, distilling filtrate to recover dichloromethane and tetrahydrofuran, and carrying out reduced pressure distillation (145-155 ℃/1-2 mmHg) to obtain 279.5 g of tert-butyl 4, 4-diphenyl butyrate (III 3), wherein the gas phase purity is 99.7 percent and the yield is 94.3 percent.
1 HNMR data (400 MHz, DMSO-d 6) of the resulting product were as follows:
1.47(s,9H),1.66(m,2H),2.25(t,2H),3.89(t,1H),7.03-7.21(m,10H).
Example 4: preparation of 4-chloro-4, 4-diphenyl-2-oxobutanoic acid (V)
550 G of 1, 2-dichloroethane, 127.2 g (0.5 mol) of methyl 4, 4-diphenylbutyrate (III 1) obtained in example 1, 3.0 g of phosphorus trichloride, 2.0g of 4-dimethylaminopyridine were added to a 2000 ml four-necked flask connected with a stirrer, a thermometer, a reflux condenser, an air duct and a 30wt% aqueous sodium hydroxide solution absorber, the mixture was heated, kept at 60 to 75℃and 120.0 g (1.7 mol) of chlorine was slowly introduced under stirring for about 4 to 5 hours, after which the mixture was stirred and reacted at 75 to 80℃for 2 hours, and cooled to 20 to 25℃and nitrogen was blown off to leave chlorine and hydrogen chloride for 1 hour; 300 g of water and 300.0 g (3.0 mol) of 40wt% sodium hydroxide aqueous solution are added, and the mixture is stirred and reacted for 3 hours at 40-45 ℃; cooling to 20-25 ℃, layering, washing sodium chloride salt and organic phase with 100 g of water, combining water layers, acidifying system pH value with 30wt% hydrochloric acid to 2.0-2.5, filtering, washing filter cake twice with water, each time 100 g, drying to obtain 131.6 g of 4-chloro-4, 4-diphenyl-2-oxo-butyric acid (V), yield 91.2% and liquid phase purity 99.7%.
The nuclear magnetic data of the obtained product are as follows:
1H NMR(DMSO-D6,δ,ppm)：
4.11(s,2H),7.28-7.39(m,10H),10.13(s,1H).
example 5: preparation of 4-chloro-4, 4-diphenyl-2-oxobutanoic acid (V)
550 G of cyclohexane, 134.2 g (0.5 mol) of ethyl 4, 4-diphenylbutyrate (III 2) obtained in example 2, 3.0 g of triethyl phosphite, 2.0 g of 4-dimethylaminopyridine were added to a 2000 ml four-necked flask connected with a stirrer, a thermometer, a reflux condenser, an air duct and a 30wt% aqueous sodium hydroxide solution absorber, the mixture was heated to 65 to 75℃and 120.0 g (1.7 mol) of chlorine was slowly introduced under stirring for about 4 to 5 hours, after which the mixture was stirred and reacted at 75 to 80℃for 2 hours, the mixture was cooled to 20 to 25℃and nitrogen was blown off with residual chlorine and hydrogen chloride for 1 hour; 300 g of water, 250.0 g (2.5 mol) of 40wt% aqueous potassium hydroxide solution are added, the mixture is stirred at 30-35 ℃ for reaction for 3 hours, cooled to 20-25 ℃, the mixture is layered, the potassium chloride salt and the organic phase are washed with 100 g of water, the aqueous layer is combined, the pH value of the acidification system is 2.0-2.5 with 30wt% hydrochloric acid, the filtration is carried out, the filter cake is washed twice with water, 100 g each time, and the mixture is dried, thus 132.6 g of 4-chloro-4, 4-diphenyl-2-oxobutanoic acid (V) is obtained, the yield is 91.9%, and the liquid phase purity is 99.8%.
Example 6: preparation of 4-chloro-4, 4-diphenyl-2-oxobutanoic acid (V)
550 G of chlorobenzene, 148.2 g (0.5 mol) of tert-butyl 4, 4-diphenylbutyrate (III 3) obtained in example 3, 3.0 g of phosphorus trichloride and 2.0 g of N-methylpiperidine are added into a 2000 ml four-neck flask connected with a stirring device, a thermometer, a reflux condenser, an air duct and a 30wt% sodium hydroxide aqueous solution absorption device, the mixture is heated, the temperature is kept between 90 and 95 ℃, 120.0 g (1.7 mol) of chlorine is slowly introduced under stirring, the introduction is completed for about 4 to 5 hours, and after that, the mixture is stirred and reacted for 2 hours at 90 to 95 ℃, the mixture is cooled to 20 to 25 ℃, and residual chlorine and hydrogen chloride are blown by blowing nitrogen for 1 hour; 300 g of water, 250.0 g (2.5 mol) of 40wt% aqueous sodium hydroxide solution and stirring at 50-55 ℃ for reaction for 2 hours, cooling to 20-25 ℃, layering, washing sodium chloride salt and organic phase with 100 g of water, combining the aqueous layer, acidifying the system with 30wt% hydrochloric acid to pH 2.0-2.5, filtering, washing the filter cake twice with water, 100 g each time, and drying to obtain 131.2 g of 4-chloro-4, 4-diphenyl-2-oxobutanoic acid (V), yield of 90.9%, liquid phase purity of 99.3%.
Example 7: preparation of 4, 5-dihydro-5, 5-diphenylisoxazole-3-carboxylic acid (I)
To a 500 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a constant pressure dropping funnel, 200 g of ethanol, 28.9 g (0.1 mol) of 4-chloro-4, 4-diphenyl-2-oxobutanoic acid (V) obtained in example 4, 10.5 g (0.15 mol) of hydroxylamine hydrochloride, 15.2 g (0.11 mol) of potassium carbonate were charged, heated, and reacted at 40 to 45℃with stirring for 3 hours. 20.7 g (0.15 mol) of potassium carbonate are added, the mixture is stirred and reacted for 2 hours at 50-55 ℃, cooled to 20-25 ℃, filtered, and the filter cake is washed twice with 30 g of ethanol each time. The filtrates were combined, the ethanol was recovered by distillation, and the residue was recrystallized from 120 g of 75% ethanol and dried to give 24.6 g of 4, 5-dihydro-5, 5-diphenylisoxazole-3-carboxylic acid (I) having a purity of 99.7% in the liquid phase and a yield of 92.0%.
1 HNMR data (400 MHz, DMSO-d 6) of the resulting product were as follows:
3.37(s,2H),7.22-7.37(m,10H),10.03(s,1H).
example 8: preparation of 4, 5-dihydro-5, 5-diphenylisoxazole-3-carboxylic acid (I)
To a 500 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a constant pressure dropping funnel, 200 g of ethanol, 28.9 g (0.1 mol) of 4-chloro-4, 4-diphenyl-2-oxobutanoic acid (V) obtained in example 5, 12.3 g (0.075 mol) of hydroxylamine sulfate, 15.2 g (0.11 mol) of potassium carbonate were charged, heated, and reacted at 40 to 45℃under stirring for 3 hours. 20.7 g (0.15 mol) of potassium carbonate are added, the mixture is stirred and reacted for 2 hours at 50-55 ℃, cooled to 20-25 ℃, filtered, and the filter cake is washed twice with 30 g of ethanol each time. The filtrates were combined, the ethanol was recovered by distillation, and the residue was recrystallized from 120 g of 75% ethanol and dried to give 24.3 g of 4, 5-dihydro-5, 5-diphenylisoxazole-3-carboxylic acid (I) having a purity of 99.3% in the liquid phase and a yield of 90.9%.
Example 9: preparation of 4, 5-dihydro-5, 5-diphenylisoxazole-3-carboxylic acid (I)
To a 500 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a constant pressure dropping funnel, 200 g of acetonitrile, 28.9 g (0.1 mol) of 4-chloro-4, 4-diphenyl-2-oxobutanoic acid (V) obtained in example 6, 10.5 g (0.15 mol) of hydroxylamine hydrochloride, 15.2 g (0.11 mol) of potassium carbonate, heating and stirring were charged, and the reaction was carried out for 3 hours at 40-45 ℃. 20.2 g (0.2 mol) of triethylamine are added, the mixture is stirred and reacted for 2 hours at 50-55 ℃, cooled to 20-25 ℃, filtered, and the filter cake is washed twice with 30 g of acetonitrile each time. The filtrates were combined, acetonitrile was recovered by distillation of the filtrate, and the residue was recrystallized from 120 g of 75% ethanol and dried to give 24.5 g of 4, 5-dihydro-5, 5-diphenylisoxazole-3-carboxylic acid (I) having a purity of 99.5% in liquid phase and a yield of 91.7%.
Example 10: preparation of bisbenzoxazole acid
Into a 500 ml four-necked flask equipped with a stirrer, a thermometer and a reflux condenser, 100 g of ethanol, 13.4 g (0.05 mol) of 4, 5-dihydro-5, 5-diphenylisoxazole-3-carboxylic acid (I) obtained in example 7, 6.9 g (0.05 mol) of potassium carbonate, 10.8 g (0.07 mol) of diethyl sulfate and stirring were charged to react at 20-25℃for 3 hours. The mixture was filtered and the filter cake was washed twice with 30 grams of ethanol each time. The filtrates were combined, the ethanol was recovered by distillation of the filtrate, and the residue was recrystallized from 100 g of methyl tert-butyl ether to give 14.3 g of bisbenzoxazole acid with a liquid phase purity of 99.8% and a yield of 96.5%.
1 HNMR data (400 MHz, DMSO-d 6) of the resulting product were as follows:
1.35(t,3H),3.26(s,2H),4.31(q,2H),7.21-7.36(m,10H).
Example 11: preparation of bisbenzoxazole acid
To a 500ml stainless steel autoclave equipped with a stirrer, a thermometer and a reflux condenser, 100g of ethanol, 13.4 g (0.05 mol) of 4, 5-dihydro-5, 5-diphenylisoxazole-3-carboxylic acid (I) obtained in example 7, 6.9 g (0.05 mol) of potassium carbonate and 8.7 g (0.08 mol) of bromoethane were charged, and the reaction was stirred at 40 to 45℃for 3 hours while sealing the autoclave. Cooling to 20-25 ℃, opening the reaction kettle, filtering, washing the filter cake twice with 30g of ethanol each time. The filtrates were combined, the ethanol was recovered by distillation of the filtrate, and the residue was recrystallized from 100g of methyl tert-butyl ether to give 13.7 g of bisbenzoxazole acid with a liquid phase purity of 99.9% and a yield of 92.8%.
Example 12: preparation of isopropyl 4, 5-dihydro-5, 5-diphenylisoxazole-3-carboxylate salt
To a 500 ml stainless steel reaction vessel equipped with a stirrer, a thermometer and a reflux condenser, 100 g of acetonitrile and 13.4 g (0.05 mol) of 4, 5-dihydro-5, 5-diphenylisoxazole-3-carboxylic acid (I) obtained in example 7 were added, 5.9 g (0.1 mol) of isopropylamine were reacted under stirring at 40 to 45℃for 3 hours. Cooling to 20-25 ℃, opening the reaction kettle, filtering, and drying to obtain 15.3 g of 4, 5-dihydro-5, 5-diphenyl isoxazole-3-carboxylic acid isopropyl amine salt, wherein the purity of the liquid phase is 99.7%, and the yield is 93.9%.
1 HNMR data (400 MHz, D 2 O) of the resulting product were as follows:
1.05(d,6H),1.21(m,1H),3.23(s,2H),7.17-7.33(m,10H).
Example 13: preparation of methyl 4, 4-diphenylbutyrate (III 1)
To a 2000 ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a constant pressure dropping funnel, 600 g of tetrahydrofuran, 168.2 g (1 mol) of diphenylmethane, 112.0 g (1.3 mol) of methyl acrylate, 5.0g of DBU, heating and stirring were charged for reaction at 60-65℃for 6 hours. Cooling to 20-25 ℃, adding 300 g of water and 400 g of dichloromethane, regulating the pH value of the system to 2 by using 30% hydrochloric acid, layering, extracting the aqueous layer by using dichloromethane twice, 200 g each time, combining organic phases, drying by using 20g of anhydrous sodium sulfate for 4 hours, filtering, distilling filtrate to recover dichloromethane and tetrahydrofuran, and carrying out reduced pressure distillation (115-125 ℃/1-2 mmHg) to obtain 186.3 g of 4, 4-diphenyl methyl butyrate (III 1), wherein the gas phase purity is 96.6 percent and the yield is 73.3 percent.
As can be seen from the example, the addition mode of methyl acrylate affects the yield and the product purity, if methyl acrylate is added at one time, polymerization side reaction of methyl acrylate under the action of an alkaline catalyst can be generated, the conversion rate of diphenylmethane is reduced, the reaction selectivity is reduced, and the product yield and the product purity are reduced.
Example 14: preparation of 4, 5-dihydro-5, 5-diphenylisoxazole-3-carboxylic acid (I)
To a 500ml four-necked flask equipped with a stirrer, a thermometer, a reflux condenser and a constant pressure dropping funnel, 200 g of ethanol, 28.9 g (0.1 mol) of 4-chloro-4, 4-diphenyl-2-oxobutanoic acid (V) obtained in example 5, 10.5 g (0.15 mol) of hydroxylamine hydrochloride, 35.9 g (0.26 mol) of potassium carbonate were charged, and the mixture was heated and reacted at 40 to 45℃for 3 hours and 50 to 55℃for 2 hours with stirring, cooled to 20 to 25℃and filtered, and the cake was washed with ethanol twice with 30 g of ethanol each time. The filtrates were combined, the ethanol was recovered by distillation, and the residue was recrystallized from 120 g of 75% ethanol and dried to give 18.6 g of 4, 5-dihydro-5, 5-diphenylisoxazole-3-carboxylic acid (I) having a liquid phase purity of 97.3% and a yield of 69.6%.
As is clear from the present example, the manner of adding the base affects the yield and the purity of the product in this step, and if the base is added at one time, the remaining base causes hydrolysis side reaction of the 4-position chlorine atom and substitution side reaction of the hydroxylamine nitrogen atom after neutralizing the hydroxylamine salt, which is disadvantageous for the progress of cyclization reaction, resulting in a decrease in the yield and purity of the product.
The foregoing description and examples illustrate the basic principles and features of the invention and the advantages of the invention. The present invention is not limited to the above-described embodiments, and the above-described embodiments and descriptions are merely illustrative of the principles of the present invention, and various changes and modifications may be made therein without departing from the spirit of the invention, which is within the scope of the invention as claimed.
Claims (10)
1. A preparation method of 4, 5-dihydro-5, 5-diphenyl isoxazole-3-formic acid comprises the following steps:
(1) In a solvent A, under the action of a catalyst 1, carrying out addition reaction on a compound of a formula II and acrylic ester to obtain a compound of a formula III;
The solvent A is one or more than two of N, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, acetonitrile, 1, 2-dichloroethane, alkane with 6 to 8 carbon atoms, benzene, toluene, ethanol or xylene; the catalyst 1 is one or a combination of more than two of piperidine, 4-dimethylaminopyridine, tri-n-butylamine, 1, 8-diazabicyclo undec-7-ene (DBU), 1, 4-diazabicyclo [2, 2] octane (DABCO), 1, 8-bis-dimethylaminonaphthalene, tetramethyl guanidine, sodium methoxide, sodium ethoxide or potassium tert-butoxide;
wherein, the substituent R in the compound of the formula III is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl or benzyl;
(2) In a solvent B, under the action of a catalyst 2, preparing a compound of a formula IV by chlorination reaction of the compound of the formula III and chlorine; then, carrying out hydrolysis reaction and acidification under the action of alkali 1 to obtain a compound of a formula V;
The solvent B is one or more of dichloromethane, chloroform, carbon tetrachloride, 1, 2-dichloroethane, trichloroethane, cyclohexane, petroleum ether with the boiling range of 60-90 ℃, n-hexane or chlorobenzene; the catalyst 2 is one or the combination of more than two of phosphorus trichloride, organic phosphorus phosphite or organic amine; the alkali 1 is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate or lithium hydroxide;
Wherein the substituent R in the compound of formula IV is the same as the substituent R in the compound of formula III;
(3) In a solvent C, under the action of alkali 2, cyclizing the compound shown in the formula V and hydroxylamine salt to obtain 4, 5-dihydro-5, 5-diphenyl isoxazole-3-formic acid I;
The solvent C is one or more than two of methanol, ethanol, saturated monohydric alcohol with 3 to 5 carbon atoms, dichloromethane, 1, 2-dichloroethane, acetonitrile or water; the alkali 2 is one or the combination of more than two of sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, triethylamine, isopropyl diethylamine, diisopropyl ethylamine or pyridine;
2. The process for the preparation of 4, 5-dihydro-5, 5-diphenylisoxazole-3-carboxylic acid according to claim 1, characterized in that in step (1) one or more of the following conditions are included:
i. the mass ratio of the solvent A to the compound of the formula II is 2-7:1;
ii. The mass of the catalyst 1 is 0.5-5.0% of the mass of the compound of the formula II;
iii, the acrylic ester is methyl acrylate, ethyl acrylate, n-propyl acrylate, isopropyl acrylate, n-butyl acrylate, isobutyl acrylate, sec-butyl acrylate, tert-butyl acrylate or benzyl acrylate; the molar ratio of the acrylic ester to the compound of the formula II is (1.0-1.5): 1;
iv, the temperature of the addition reaction is 50-100 ℃.
3. The process for the preparation of 4, 5-dihydro-5, 5-diphenylisoxazole-3-carboxylic acid according to claim 1, characterized in that in step (1) one or more of the following conditions are included:
i. The compound of the formula III is methyl 4, 4-diphenyl butyrate, ethyl 4, 4-diphenyl butyrate or tert-butyl 4, 4-diphenyl butyrate;
ii. The acrylic ester is added into a system containing a solvent A, a catalyst 1 and a compound of a formula II in a dropwise manner;
The post-treatment steps of the reaction liquid obtained by the addition reaction of the compound of the formula II and the acrylic ester are as follows: adding water and dichloromethane into the reaction solution, regulating the pH value of the system to 1-3, layering, extracting the water layer with dichloromethane, merging the organic phases, drying the organic phases through anhydrous sodium sulfate, filtering, distilling the filtrate to recover the organic solvent, and distilling under reduced pressure to obtain the compound shown in the formula III.
4. The process for the preparation of 4, 5-dihydro-5, 5-diphenylisoxazole-3-carboxylic acid according to claim 1, characterized in that in step (2) one or more of the following conditions are included:
i. The mass ratio of the solvent B to the compound of the formula III is 2-10:1;
ii. The organophosphorus phosphite is trimethyl phosphite, triethyl phosphite, tripropyl phosphite or tributyl phosphite; the organic amine is tri-N-butylamine, 4-dimethylaminopyridine, N-methylpiperidine or pyridine; the mass of the catalyst 2 is 0.1-5.0% of that of the compound of the formula III;
iii the molar ratio of chlorine to the compound of formula III is (3.0-5.0): 1;
iv, the chlorination reaction temperature is 50-100 ℃.
5. The process for the preparation of 4, 5-dihydro-5, 5-diphenylisoxazole-3-carboxylic acid according to claim 1, characterized in that in step (2) one or more of the following conditions are included:
i. the molar ratio of base 1 to compound of formula III is (2.0-8.0): 1;
ii. The hydrolysis reaction is carried out in the presence of water, the mass of the water is 1-10:1 of that of the compound of formula III;
iii, the hydrolysis reaction temperature is 20-60 ℃;
iv, acidifying with hydrochloric acid to a pH of the system of 2-3;
v, post-treatment of reaction liquid obtained by hydrolysis reaction comprises the following steps: the reaction solution is layered, the solid phase and the organic phase in the system are washed by water, the water phase is combined, the pH value of the obtained water phase is acidified to 2-3 by hydrochloric acid, and then the compound of the formula V is obtained through filtration, water washing and drying.
6. The process for the preparation of 4, 5-dihydro-5, 5-diphenylisoxazole-3-carboxylic acid according to claim 1, characterized in that in step (3) one or more of the following conditions are included:
i. the mass ratio of the solvent C to the compound of the formula V is 3-10:1;
ii. The hydroxylamine salt is hydroxylamine hydrochloride or hydroxylamine sulfate;
iii the molar ratio of hydroxylamine salt, base 2 to compound of formula V is (0.5-1.5): 1.5-4.0): 1;
iv, the cyclization reaction temperature is 20-80 ℃.
7. The process for producing 4, 5-dihydro-5, 5-diphenylisoxazole-3-carboxylic acid according to claim 1, wherein in step (3), the base 2 is added to the reaction system in portions.
8. The process for the preparation of 4, 5-dihydro-5, 5-diphenylisoxazole-3-carboxylic acid according to claim 1, wherein in step (3), the process for the preparation of 4, 5-dihydro-5, 5-diphenylisoxazole-3-carboxylic acid I comprises the steps of: dissolving a compound of a formula V, hydroxylamine salt and alkali 2a in a solvent C, and carrying out cyclization reaction at 20-80 ℃; then adding alkali 2b, and continuing cyclization reaction at 20-80 ℃ to obtain 4, 5-dihydro-5, 5-diphenyl isoxazole-3-formic acid I; the alkali 2a and the alkali 2b are selected from one or more of sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, triethylamine, isopropyl diethylamine, diisopropyl ethylamine or pyridine, the types of the alkali 2a and the alkali 2b are the same or different, the molar ratio of the alkali 2a to the alkali 2b is 1:0.5-2, and the sum of the dosage of the alkali 2a and the dosage of the alkali 2b is the same as the dosage of the alkali 2.
9. The process for producing 4, 5-dihydro-5, 5-diphenylisoxazole-3-carboxylic acid according to claim 1, wherein in the step (3), the post-treatment of the reaction solution obtained by the cyclization reaction of the compound of formula V and hydroxylamine salt comprises the steps of: filtering the reaction solution, washing a filter cake by using a solvent C, merging filtrate, distilling the filtrate to recover the solvent C, recrystallizing residues, and drying to obtain the 4, 5-dihydro-5, 5-diphenyl isoxazole-3-carboxylic acid I.
10. The process for the preparation of 4, 5-dihydro-5, 5-diphenylisoxazole-3-carboxylic acid according to claim 1, wherein 4, 5-dihydro-5, 5-diphenylisoxazole-3-carboxylic acid I is reacted with an ethylating reagent or salified with isopropylamine to give bisbenzoxazole acid or isopropylamine salt of 4, 5-dihydro-5, 5-diphenylisoxazole-3-carboxylic acid.
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| WO1995022533A1 (en) * | 1994-02-16 | 1995-08-24 | Shionogi & Co., Ltd. | Process for producing 3-isoxazolecarboxylic acid |
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| CN112409284A (en) * | 2020-11-28 | 2021-02-26 | 南京艾普特生物医药有限公司 | Synthetic method of 5-methyl-3, 4-diphenyl isoxazole |
| CN113024480A (en) * | 2021-03-03 | 2021-06-25 | 河南省农业科学院植物保护研究所 | 4, 5-dihydro-5, 5-diphenyl isoxazole-3-formamide compound and application thereof |
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| WO1995022533A1 (en) * | 1994-02-16 | 1995-08-24 | Shionogi & Co., Ltd. | Process for producing 3-isoxazolecarboxylic acid |
| US5760244A (en) * | 1994-02-16 | 1998-06-02 | Shionogi & Co., Ltd. | Process for the preparation of 3-isoxazolecarboxylic acid |
| CN103172582A (en) * | 2013-03-25 | 2013-06-26 | 江苏省农用激素工程技术研究中心有限公司 | Method for preparing isoxadifen |
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| CN113024480A (en) * | 2021-03-03 | 2021-06-25 | 河南省农业科学院植物保护研究所 | 4, 5-dihydro-5, 5-diphenyl isoxazole-3-formamide compound and application thereof |
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