CN118164920A - Synthesis method of polysubstituted isoxazoline - Google Patents
Synthesis method of polysubstituted isoxazoline Download PDFInfo
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- CN118164920A CN118164920A CN202410271258.9A CN202410271258A CN118164920A CN 118164920 A CN118164920 A CN 118164920A CN 202410271258 A CN202410271258 A CN 202410271258A CN 118164920 A CN118164920 A CN 118164920A
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- Prior art keywords
- compound
- polysubstituted
- isoxazoline
- synthesizing
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- 150000002547 isoxazolines Chemical class 0.000 title claims abstract description 18
- 238000001308 synthesis method Methods 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 36
- 238000000034 method Methods 0.000 claims abstract description 18
- 150000002828 nitro derivatives Chemical class 0.000 claims abstract description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- -1 alkene compound Chemical class 0.000 claims description 20
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 13
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 11
- 230000002194 synthesizing effect Effects 0.000 claims description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 125000003118 aryl group Chemical group 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 7
- CGKPGVZMSKVVOF-UHFFFAOYSA-N chloro(nitro)methane Chemical compound [O-][N+](=O)CCl CGKPGVZMSKVVOF-UHFFFAOYSA-N 0.000 claims description 6
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 6
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 claims description 5
- DNPRVXJGNANVCZ-UHFFFAOYSA-N bromo(nitro)methane Chemical compound [O-][N+](=O)CBr DNPRVXJGNANVCZ-UHFFFAOYSA-N 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- WPHUUIODWRNJLO-UHFFFAOYSA-N 2-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=CC=C1S(Cl)(=O)=O WPHUUIODWRNJLO-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 3
- 235000017550 sodium carbonate Nutrition 0.000 claims description 3
- JXRGUPLJCCDGKG-UHFFFAOYSA-N 4-nitrobenzenesulfonyl chloride Chemical compound [O-][N+](=O)C1=CC=C(S(Cl)(=O)=O)C=C1 JXRGUPLJCCDGKG-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 claims description 2
- 229910001863 barium hydroxide Inorganic materials 0.000 claims description 2
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 claims description 2
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 claims description 2
- 239000000920 calcium hydroxide Substances 0.000 claims description 2
- 229910001861 calcium hydroxide Inorganic materials 0.000 claims description 2
- 235000011116 calcium hydroxide Nutrition 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- MCSAJNNLRCFZED-UHFFFAOYSA-N nitroethane Chemical compound CC[N+]([O-])=O MCSAJNNLRCFZED-UHFFFAOYSA-N 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 239000011736 potassium bicarbonate Substances 0.000 claims description 2
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 2
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 2
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 235000011181 potassium carbonates Nutrition 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 2
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 claims description 2
- 239000012312 sodium hydride Substances 0.000 claims description 2
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims description 2
- GRGCWBWNLSTIEN-UHFFFAOYSA-N trifluoromethanesulfonyl chloride Chemical compound FC(F)(F)S(Cl)(=O)=O GRGCWBWNLSTIEN-UHFFFAOYSA-N 0.000 claims description 2
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 10
- 238000003786 synthesis reaction Methods 0.000 abstract description 10
- 239000000543 intermediate Substances 0.000 abstract description 6
- WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical compound C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-N 0.000 abstract description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 abstract description 4
- 238000009776 industrial production Methods 0.000 abstract description 4
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 238000003860 storage Methods 0.000 abstract description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract description 2
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 2
- 239000001301 oxygen Substances 0.000 abstract description 2
- 229910052760 oxygen Inorganic materials 0.000 abstract description 2
- 239000000575 pesticide Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 16
- 239000007789 gas Substances 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical compound CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 10
- YMCWJQIZJIKFHO-UHFFFAOYSA-N 3-chloro-5,5-dimethyl-4h-1,2-oxazole Chemical compound CC1(C)CC(Cl)=NO1 YMCWJQIZJIKFHO-UHFFFAOYSA-N 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000012043 crude product Substances 0.000 description 9
- 239000008367 deionised water Substances 0.000 description 9
- 229910021641 deionized water Inorganic materials 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- OMKAMTCDOWAJAA-UHFFFAOYSA-N 3-bromo-5,5-dimethyl-4h-1,2-oxazole Chemical compound CC1(C)CC(Br)=NO1 OMKAMTCDOWAJAA-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 238000004440 column chromatography Methods 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 7
- 239000000047 product Substances 0.000 description 6
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 5
- 238000001035 drying Methods 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 230000000749 insecticidal effect Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- UKFPAGCSDWQXFT-UHFFFAOYSA-N 3-phenyl-4,5-dihydro-1,2-oxazole Chemical compound O1CCC(C=2C=CC=CC=2)=N1 UKFPAGCSDWQXFT-UHFFFAOYSA-N 0.000 description 1
- DIYSFZUJSGOINT-UHFFFAOYSA-N 5,5-dimethyl-4h-1,2-oxazole Chemical compound CC1(C)CC=NO1 DIYSFZUJSGOINT-UHFFFAOYSA-N 0.000 description 1
- UYOWAKYOTZHBRD-UHFFFAOYSA-N 5-phenyl-4,5-dihydro-1,2-oxazole Chemical compound C1C=NOC1C1=CC=CC=C1 UYOWAKYOTZHBRD-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 241000255925 Diptera Species 0.000 description 1
- 239000005779 Fenpyrazamine Substances 0.000 description 1
- 241000258937 Hemiptera Species 0.000 description 1
- 241000255777 Lepidoptera Species 0.000 description 1
- 241001414989 Thysanoptera Species 0.000 description 1
- 241000607479 Yersinia pestis Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- UTOHZQYBSYOOGC-UHFFFAOYSA-N fenpyrazamine Chemical compound O=C1N(C(C)C)N(C(=O)SCC=C)C(N)=C1C1=CC=CC=C1C UTOHZQYBSYOOGC-UHFFFAOYSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000010907 mechanical stirring Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- AWBKQZSYNWLCMW-UHFFFAOYSA-N n-(dibromomethylidene)hydroxylamine Chemical compound ON=C(Br)Br AWBKQZSYNWLCMW-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- XKLJHFLUAHKGGU-UHFFFAOYSA-N nitrous amide Chemical compound ON=N XKLJHFLUAHKGGU-UHFFFAOYSA-N 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- JIRJHEXNDQBKRZ-UHFFFAOYSA-N phosgene oxime Chemical compound ON=C(Cl)Cl JIRJHEXNDQBKRZ-UHFFFAOYSA-N 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- IYMLUHWAJFXAQP-UHFFFAOYSA-N topramezone Chemical compound CC1=C(C(=O)C2=C(N(C)N=C2)O)C=CC(S(C)(=O)=O)=C1C1=NOCC1 IYMLUHWAJFXAQP-UHFFFAOYSA-N 0.000 description 1
- 238000009333 weeding Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention belongs to the field of novel pesticide intermediate synthesis, and provides a brand-new synthesis method of polysubstituted isoxazoline, which takes a nitro compound as a nitrogen source and an oxygen source, synthesizes the isoxazoline through 3+2 reaction in one step, avoids the problems of halogenated dangerous process and difficult storage and transportation of intermediates, provides a novel, simple, efficient and environment-friendly synthesis method for the synthesis of the compound, and has the characteristics of low-cost and easily obtained raw materials, simple and convenient operation, easy industrial production, high atomic economy and the like.
Description
Technical Field
The invention belongs to the field of synthesis of novel pesticide intermediates, and provides a synthesis method of polysubstituted isoxazoline.
Background
The isoxazoline is a five-membered heterocyclic compound containing N, O elements, and the compound with the isoxazoline component generally has good weeding, sterilizing, insecticidal and antiviral activities in the field of modern agriculture. For example, registered and promoted herbicides include topramezone, fenpyrazamine, ethyl bisbenzoate and the like, and the fluorothiazole pyrazamine and the hydrazinone are good bactericides, and the like, and have broad-spectrum, efficient and safe insecticidal effects on lepidoptera, thysanoptera, diptera and hemiptera agricultural pests.
The isoxazoline compounds are mostly halogen oxime sources of nitrogen atoms and oxygen atoms, are active in chemical property, have strong reactivity, poor stability and difficult storage, and are strong in corrosiveness, such as notorious phosgene oxime, and have great harm to organisms and environment.
In the prior art, CN116102510A discloses a preparation method of 3-bromo-5, 5-dimethyl-4, 5-dihydroisoxazole, wherein dibromoaldoxime and isobutene are mixed in a closed reaction device to obtain a mixture; and adding an acid binding agent into the mixture to react to obtain the 3-bromo-5, 5-dimethyl-4, 5-dihydroisoxazole. The halogen atoms in the preparation method are difficult to introduce, and a key intermediate dibromoformaldoxime in the process can be decomposed under the conditions of heating or overhigh pH, so that the thermal stability is poor, and the total yield can be influenced and huge potential safety hazards exist when industrial production is carried out.
Therefore, whether to provide a method for synthesizing polysubstituted isoxazoline which is easier for industrial production is a problem to be solved urgently by the technicians in the field.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention provides a brand-new synthesis method of polysubstituted isoxazoline, which takes nitro compounds as nitrogen sources and oxygen sources, synthesizes the isoxazoline through 3+2 reaction in one step, avoids the problems of halogenated dangerous processes and difficult storage and transportation of intermediates, provides a novel, simple, efficient and environment-friendly synthesis method for synthesizing the compounds, and has the characteristics of low-cost and easily obtained raw materials, simple and convenient operation, easy industrial production, high atomic economy and the like.
The specific technical scheme of the invention is as follows:
a synthesis method of polysubstituted isoxazoline comprises the following reaction equation:
the method comprises the following specific steps:
adding alkali into anhydrous solvent, adding sulfonyl chloride compound at 0-30deg.C, stirring for half an hour, and slowly dripping nitro compound at 0-30deg.C; adding an alkene compound, stirring at 35-120 ℃ for 6-12 hours to react completely, and purifying to obtain a polysubstituted isoxazoline compound;
As a preferable scheme, the molar ratio of the nitro compound to the alkali is 1:1.0-1:4.0; the molar ratio of the nitro compound to the sulfonyl chloride compound is 1:1.0-1:4.0; the molar ratio of the nitro compound to the alkylene compound is 1:1.0-1:6.0; the concentration of the nitro compound in the anhydrous solvent is 0.8-1.2mol/L.
Preferably, the base is selected from one or more of triethylamine, diisopropylethylamine, tri-n-propylamine, piperidine, pyridine, sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydride, sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide, and potassium hexamethyldisilazide.
Further, the alkali adopts one of piperidine, sodium carbonate, sodium hydroxide and potassium hydroxide.
Preferably, the anhydrous solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tertiary butyl ether and 1, 4-dioxane.
Preferably, the sulfonyl chloride compound is selected from one of methylsulfonyl chloride, trifluoromethyl sulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride or o-nitrobenzenesulfonyl chloride.
Preferably, the nitro compound has the structure:
wherein the R 1 group may be selected from a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an alkyl group, a substituted alkyl group, an aryl group.
Further preferably, the nitro compound is one selected from nitromethane, nitroethane, chloronitromethane, bromonitromethane.
Preferably, the alkene compound has the following structural formula:
Wherein R 3、R4、R5、R6 is selected from hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl.
Preferably, the alkyl in the alkylene compound is selected from one of methyl, ethyl, propyl and isopropyl; the substituted alkyl in the alkylene compound is alkyl substituted by halogen atom, cyano, hydroxyl, amino and nitro; the aryl in the alkene compound is phenyl and heterocyclic; the substituted aromatic group in the alkene compound is an aromatic group of halogen atom, cyano group, hydroxyl group, amino group and nitro group.
Compared with the prior art, the application has the main technical effects that:
The invention uses the nitro compound and the alkene compound as raw materials, is cheap and easy to obtain, and can be obtained by simply converting the polysubstituted nitro compound; compared with the prior art, chlorine and bromine with high toxicity are not used, and an intermediate with poor thermal stability is not generated, so that obvious potential safety hazard is avoided; the whole route is mild, the operation is simple, and the strict reaction condition is not needed.
Drawings
FIG. 1 is a 1 H NMR spectrum of the product of example 1, 5-dimethyl-4, 5-dihydroisoxazole;
FIG. 2 is a 1 H NMR spectrum of the product of example 2, 3-bromo-5, 5-dimethyl-4, 5-dihydroisoxazole;
FIG. 3 is a 1 H NMR spectrum of the product of example 3, 3-chloro-5, 5-dimethyl-4, 5-dihydroisoxazole.
Detailed Description
The above-described aspects of the present invention will be described in further detail by way of the following embodiments, but it should not be construed that the scope of the above-described subject matter of the present invention is limited to the following examples. All techniques realized based on the above description of the invention are within the scope of the invention, and the reactants used are conventional in the art.
Example 1 Synthesis of 5, 5-dimethyl-4, 5-dihydroisoxazole:
Sodium hydroxide (8.0 g,0.2mol,2.0 equiv.) and 100mL of anhydrous 2-methyltetrahydrofuran are added to a four-necked flask with mechanical stirring, thermometer and reflux condenser, o-nitrobenzenesulfonyl chloride (22.2 g,0.1mol,1.0 equiv.) is added at 30℃and nitromethane (6.1 g,0.1mol,1.0 equiv.) is added dropwise after stirring for half an hour, isobutylene gas (gas amount 4-6 times reaction equivalent) is introduced into an oil bath at 80℃and 6 hours reaction is completed (by liquid phase monitoring, nitromethane reaction is completely ensured to be completed, the end of reaction is ensured in the same manner in the following examples), 200mL of deionized water is added to the reaction system, extraction is performed with ethyl acetate (200 mL of 3), the organic phase is combined, and after washing with 200mL of saturated saline and drying and water removal of anhydrous magnesium sulfate, crude product is obtained by precipitation under-0.1 MPa,40℃and finally colorless liquid distillation is carried out at-0.1 MPa, 5-5% by distillation under 55℃to obtain 5-2.92% by weight, and 2% by weight of the transparent product, and the purity of 2.74% by weight of the product is obtained. The 1 H NMR spectrum is shown in FIG. 1, 1 H NMR (. Delta. 7.01,2.70,1.35) spectrum.
Example 23 Synthesis of bromo-5, 5-dimethyl-4, 5-dihydroisoxazole:
sodium hydroxide (8.0 g,0.2mol,2.0 equiv.) and 100mL of tetrahydrofuran are added to a four-necked flask equipped with a mechanical stirrer, a thermometer and a reflux condenser, p-toluenesulfonyl chloride (19.1 g,0.1mol,1.0 equiv.) is added at 20℃and bromonitromethane (14.0 g,0.1mol,1.0 equiv.) is added dropwise after stirring for half an hour, isobutylene gas (the amount of gas is 4 to 6 times the reaction equivalent) is introduced at 66℃and after the reaction is completed for 8 hours, -0.1M Pa, the reaction system is desolventized under reduced pressure at 40℃and 200mL of deionized water is added, extracted with ethyl acetate (200 mL. Times.3), the organic phase is combined, washed with 200mL of saturated brine, dehydrated over anhydrous magnesium sulfate, and desolventized at-0.1 MPa,40℃to obtain a crude product, and finally silica gel is desolventized with 200 to 300 mesh petroleum ether: ethyl acetate = 5:1 column chromatography gave 3-bromo-5, 5-dimethyl-4, 5-dihydroisoxazole as a pale yellow liquid, 13.86g in weight, 96.8% in purity, and 76% in yield. The 1 H NMR spectrum is shown in FIG. 2, 1 H NMR (. Delta. 2.95,1.44) spectrum.
Example 33 Synthesis of chloro-5, 5-dimethyl-4, 5-dihydroisoxazole:
Piperidine (25.5 g,0.3mol,3.0 equiv.) and 100mL of 1, 4-dioxane are added to a four-necked flask equipped with a mechanical stirrer, a thermometer and a reflux condenser, p-toluenesulfonyl chloride (19.1 g,0.1mol,1.0 equiv.) is added at 0℃and stirred for half an hour, chloronitromethane (9.5 g,0.1mol,1.0 equiv.) is added dropwise, isobutylene gas (the gas amount is 4 to 6 times the reaction equivalent) is introduced under an oil bath at 101℃and reacted completely for 12 hours, 200mL of deionized water is added to the reaction system, extraction (200 mL. Times.3) is performed with ethyl acetate, the organic phases are combined, washed with 200mL of saturated brine, dried over anhydrous magnesium sulfate and dehydrated, -0.1MPa, desolventized at 40℃to obtain a crude product, and finally petroleum ether is used with 200 to 300 mesh silica gel: ethyl acetate = 5:1 column chromatography gave 3-chloro-5, 5-dimethyl-4, 5-dihydroisoxazole as a pale yellow liquid, weighing 8.79g, purity 96.2%, yield 63%. The 1 H NMR spectrum is shown in FIG. 3, 1 H NMR (. Delta. 2.81,1.32) spectrum.
Example 43 Synthesis of chloro-5, 5-dimethyl-4, 5-dihydroisoxazole:
Sodium hydroxide (8.0 g,0.2mol,2.0 equiv.) and 100mL of 2-methyltetrahydrofuran are added to a four-necked flask equipped with a mechanical stirrer, a thermometer and a reflux condenser, p-toluenesulfonyl chloride (19.1 g,0.1mol,1.0 equiv.) is added at 0℃and stirred for half an hour, chloronitromethane (9.5 g,0.1mol,1.0 equiv.) is added dropwise, isobutylene gas (the gas amount is 4-6 times the reaction equivalent) is introduced under an oil bath at 80℃and after 6 hours of reaction is completed, 200mL of deionized water is added to the reaction system, extraction (200.3) with ethyl acetate is performed, the organic phases are combined, washed with 200mL of saturated brine, dried over anhydrous magnesium sulfate and dehydrated, -0.1MPa, and desolventized at 40℃to obtain a crude product, and finally 200-300 mesh silica gel is subjected to petroleum ether: ethyl acetate = 5:1 column chromatography gave 3-chloro-5, 5-dimethyl-4, 5-dihydroisoxazole as a pale yellow liquid, 10.6g in weight, 95.7% in purity and 75% in yield.
Example 53 Synthesis of chloro-5, 5-dimethyl-4, 5-dihydroisoxazole:
Piperidine (25.5 g,0.3mol,3.0 equiv.) and 100mL tetrahydrofuran are added to a four-necked flask equipped with a mechanical stirrer, a thermometer and a reflux condenser, p-toluenesulfonyl chloride (19.1 g,0.1mol,1.0 equiv.) is added at 0deg.C, chloronitromethane (9.5 g,0.1mol,1.0 equiv.) is added dropwise after stirring for half an hour, isobutylene gas (the gas amount is 4-6 times the reaction equivalent) is introduced into an oil bath pot at 66deg.C, after 7 hours of reaction is completed, 200mL deionized water is added to the reaction system, extraction (200 mL. Times.3) is performed by ethyl acetate, the organic phase is combined, washed with 200mL saturated brine, dried over anhydrous magnesium sulfate and dehydrated, -0.1MPa, and finally, the crude product is obtained by desolventizing with 200-300 mesh silica gel through petroleum ether: ethyl acetate = 5:1 column chromatography gave 3-chloro-5, 5-dimethyl-4, 5-dihydroisoxazole as a pale yellow liquid, 9.8g in weight, 94.2% in purity and 70% in yield.
Example 63 Synthesis of chloro-5, 5-dimethyl-4, 5-dihydroisoxazole:
Triethylamine (15.15 g,0.15mol,1.5 equiv.) and 100mL tetrahydrofuran are added to a four-necked flask equipped with a mechanical stirrer, a thermometer and a reflux condenser, p-toluenesulfonyl chloride (19.1 g,0.1mol,1.0 equiv.) is added at 0℃and after stirring for half an hour, chloronitromethane (9.5 g,0.1mol,1.0 equiv.) is added dropwise, isobutylene gas (the amount of gas is 4 to 6 times the reaction equivalent) is introduced under an oil bath at 66℃and after completion of the reaction for 7 hours, 200mL of deionized water is added to the reaction system, extracted with ethyl acetate (200 mL. Times.3), the organic phase is combined, washed with 200mL of saturated brine, dried over anhydrous magnesium sulfate and dehydrated, -0.1MPa, and finally desolventized with 200 to 300 mesh silica gel under petroleum ether to obtain a crude product: ethyl acetate = 5:1 column chromatography gave 3-chloro-5, 5-dimethyl-4, 5-dihydroisoxazole as a pale yellow liquid, 9.04g in weight, 92.4% in purity and 62% in yield.
Example 7 5 Synthesis of phenyl-4, 5-dihydroisoxazole:
Sodium hydroxide (8.0 g,0.2mol,2.0 equiv.) and 100mL of 2-methyltetrahydrofuran are added to a four-necked flask equipped with a mechanical stirrer, a thermometer and a reflux condenser, 11.5g,0.1mol,1.0 equiv.) of methylsulfonyl chloride is added at 0deg.C, nitromethane (6.1 g,0.1mol,1.0 equiv.) and styrene (10.4 g,0.1mol,1.0 equiv.) are added dropwise after stirring for half an hour, the reaction is completed in an oil bath at 80deg.C, the solution is removed under reduced pressure, 200mL of deionized water is added to the reaction system, extracted with ethyl acetate (200.3), the organic phases are combined, and after washing with 200mL of saturated saline water, drying with anhydrous magnesium sulfate, -0.1MPa, the solution is removed at 40deg.C to obtain a crude product, and finally 200-300 mesh silica gel is removed with petroleum ether: ethyl acetate=7: column chromatography was carried out on 1 to obtain oily liquid 5-phenyl-4, 5-dihydroisoxazole, 12.4g in weight, 96.2% in purity and 81% in yield.
Comparative example:
on the basis of example 2, 3-bromo-5, 5-dimethyl-4, 5-dihydroisoxazole can likewise be obtained by varying the solvent, in particular by the following reaction procedure:
Comparative example 1 toluene was used as the solvent
Sodium hydroxide (8.0 g,0.2mol,2.0 equiv.) and 100mL of toluene are added to a four-necked flask equipped with a mechanical stirrer, a thermometer and a reflux condenser, p-toluenesulfonyl chloride (19.1 g,0.1mol,1.0 equiv.) is added at 20℃and after stirring for half an hour, bromonitromethane (14.0 g,0.1mol,1.0 equiv.) is added dropwise, isobutylene gas (the amount of gas is 4 to 6 times the reaction equivalent) is introduced at 66℃and after completion of the reaction for 8 hours, -0.1M Pa, and reduced pressure at 40℃is used to dissolve the mixture, 200mL of deionized water is added to the reaction system, extracted with ethyl acetate (200 mL of 3), the organic phases are combined, and after washing with 200mL of saturated brine, drying over anhydrous magnesium sulfate, the crude product is obtained by removing the solvent at-0.1 MPa and 40℃under reduced pressure, and finally 200 to 300 mesh silica gel is purified by petroleum ether: ethyl acetate = 5:1 column chromatography gave 3-bromo-5, 5-dimethyl-4, 5-dihydroisoxazole as a pale yellow liquid, weighing 5.41g, purity 91.3%, yield 28%.
Comparative example 2 solvent used dichloroethane
Sodium hydroxide (8.0 g,0.2mol,2.0 equiv.) and 100mL of toluene are added to a four-necked flask equipped with a mechanical stirrer, a thermometer and a reflux condenser, p-toluenesulfonyl chloride (19.1 g,0.1mol,1.0 equiv.) is added at 20℃and after stirring for half an hour, bromonitromethane (14.0 g,0.1mol,1.0 equiv.) is added dropwise, isobutylene gas (the amount of gas is 4 to 6 times the reaction equivalent) is introduced at 66℃and after completion of the reaction for 8 hours, -0.1M Pa, and reduced pressure at 40℃is used to dissolve the mixture, 200mL of deionized water is added to the reaction system, extracted with ethyl acetate (200 mL of 3), the organic phases are combined, and after washing with 200mL of saturated brine, drying over anhydrous magnesium sulfate, the crude product is obtained by removing the solvent at-0.1 MPa and 40℃under reduced pressure, and finally 200 to 300 mesh silica gel is purified by petroleum ether: ethyl acetate = 5:1 column chromatography gave 3-bromo-5, 5-dimethyl-4, 5-dihydroisoxazole as a pale yellow liquid, weighing 6.28g, purity 92.7%, yield 33%.
As can be seen from comparison, the comparative example replaces a different reaction solvent system compared with example 2, and other materials such as the feeding ratio, the reaction condition and the operation steps are the same as those of example 2, but the yields of comparative examples 1 and 2 are obviously reduced, which shows that the solvent system provided by the application is the optimal choice for the reaction after the solvent is replaced.
The foregoing embodiments illustrate and describe the basic principles of the invention, product features, and advantages of the methods of the invention. The present invention is not limited to the above embodiments, and various changes and modifications can be made without departing from the scope of the invention, and the invention is intended to be included in the scope of protection.
Claims (10)
1. A synthesis method of polysubstituted isoxazoline is characterized in that the reaction equation is as follows:
the method comprises the following specific steps:
Adding alkali into anhydrous solvent, adding sulfonyl chloride compound at 0-30deg.C, stirring for half an hour, and slowly dripping nitro compound at 0-30deg.C; adding the alkene compound, stirring at 35-120 ℃ for 6-12 hours to react completely, and purifying to obtain the polysubstituted isoxazoline compound.
2. The method for synthesizing the polysubstituted isoxazoline according to claim 1, wherein: the molar ratio of the nitro compound to the alkali is 1:1.0-1:4.0; the molar ratio of the nitro compound to the sulfonyl chloride compound is 1:1.0-1:4.0; the molar ratio of the nitro compound to the alkylene compound is 1:1.0-1:6.0; the concentration of the nitro compound in the anhydrous solvent is 0.8-1.2mol/L.
3. The method for synthesizing the polysubstituted isoxazoline according to claim 1, wherein: wherein the alkali is selected from one or more of triethylamine, diisopropylethylamine, tri-n-propylamine, piperidine, pyridine, sodium hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydride, sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, sodium hexamethyldisilazide and potassium hexamethyldisilazide.
4. The method for synthesizing the polysubstituted isoxazoline according to claim 1, wherein: the anhydrous solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tertiary butyl ether and 1, 4-dioxane.
5. The method for synthesizing the polysubstituted isoxazoline according to claim 1, wherein: the sulfonyl chloride compound is selected from one of methylsulfonyl chloride, trifluoromethyl sulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride or o-nitrobenzenesulfonyl chloride.
6. The method for synthesizing polysubstituted isoxazoline according to claim 3, wherein: the alkali adopts one of piperidine, sodium carbonate, sodium hydroxide and potassium hydroxide.
7. The method for synthesizing the polysubstituted isoxazoline according to claim 1, wherein: the structure of the nitro compound is as follows:
wherein the R 1 group may be selected from a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an alkyl group, a substituted alkyl group, an aryl group.
8. The method for synthesizing the polysubstituted isoxazoline according to claim 7, wherein: the nitro compound is selected from one of nitromethane, nitroethane, chloronitromethane and bromonitromethane.
9. The method for synthesizing the polysubstituted isoxazoline according to claim 1, wherein: the structural formula of the alkylene compound is as follows:
Wherein R 3、R4、R5、R6 is selected from hydrogen, alkyl, substituted alkyl, aryl, or substituted aryl.
10. The method for synthesizing the polysubstituted isoxazoline according to claim 9, wherein: the alkyl in the alkylene compound is selected from one of methyl, ethyl, propyl and isopropyl;
the substituted alkyl in the alkylene compound is alkyl substituted by halogen atom, cyano, hydroxyl, amino and nitro;
the aryl in the alkene compound is phenyl and heterocyclic;
the substituted aromatic group in the alkene compound is an aromatic group of halogen atom, cyano group, hydroxyl group, amino group and nitro group.
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