CN108570041B - Preparation method of isoxazoline-containing uracil compound - Google Patents
Preparation method of isoxazoline-containing uracil compound Download PDFInfo
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- CN108570041B CN108570041B CN201710149117.XA CN201710149117A CN108570041B CN 108570041 B CN108570041 B CN 108570041B CN 201710149117 A CN201710149117 A CN 201710149117A CN 108570041 B CN108570041 B CN 108570041B
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- isoxazoline
- hydrogen
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- containing uracil
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- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- -1 uracil compound Chemical class 0.000 title claims abstract description 25
- WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical compound C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-N 0.000 title claims abstract description 17
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Natural products O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 229940035893 uracil Drugs 0.000 title claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 50
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 15
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims abstract description 14
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000003960 organic solvent Substances 0.000 claims abstract description 10
- 239000003513 alkali Substances 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims abstract description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 38
- 239000001257 hydrogen Substances 0.000 claims description 38
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 33
- 150000002431 hydrogen Chemical class 0.000 claims description 31
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 23
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 11
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 7
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 238000007363 ring formation reaction Methods 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 5
- 230000002378 acidificating effect Effects 0.000 claims description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 5
- 239000012312 sodium hydride Substances 0.000 claims description 5
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 5
- 238000000746 purification Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- SAVROPQJUYSBDD-UHFFFAOYSA-N formyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=CO SAVROPQJUYSBDD-UHFFFAOYSA-N 0.000 claims description 3
- 239000000741 silica gel Substances 0.000 claims description 3
- 229910002027 silica gel Inorganic materials 0.000 claims description 3
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 claims description 3
- 239000012442 inert solvent Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 5
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 3
- 230000011987 methylation Effects 0.000 abstract description 2
- 238000007069 methylation reaction Methods 0.000 abstract description 2
- 231100000086 high toxicity Toxicity 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 239000000203 mixture Substances 0.000 description 10
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 9
- 239000000243 solution Substances 0.000 description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 125000001424 substituent group Chemical group 0.000 description 6
- 125000001188 haloalkyl group Chemical group 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- YIIMEMSDCNDGTB-UHFFFAOYSA-N Dimethylcarbamoyl chloride Chemical compound CN(C)C(Cl)=O YIIMEMSDCNDGTB-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 125000004448 alkyl carbonyl group Chemical group 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 244000075634 Cyperus rotundus Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 125000004093 cyano group Chemical group *C#N 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- NRNFKRFWZQQDMD-UHFFFAOYSA-M dichloromethylidene(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=C(Cl)Cl NRNFKRFWZQQDMD-UHFFFAOYSA-M 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000002363 herbicidal effect Effects 0.000 description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 238000009333 weeding Methods 0.000 description 2
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 description 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
- BAYBOFPVBRQJIW-UPHRSURJSA-N (Z)-2-amino-4,4,4-trifluorobut-2-enoic acid Chemical compound OC(=O)C(/N)=C/C(F)(F)F BAYBOFPVBRQJIW-UPHRSURJSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- 241000219144 Abutilon Species 0.000 description 1
- 244000237956 Amaranthus retroflexus Species 0.000 description 1
- 235000013479 Amaranthus retroflexus Nutrition 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- 244000037364 Cinnamomum aromaticum Species 0.000 description 1
- 235000014489 Cinnamomum aromaticum Nutrition 0.000 description 1
- 235000016854 Cyperus rotundus Nutrition 0.000 description 1
- 235000001602 Digitaria X umfolozi Nutrition 0.000 description 1
- 235000017898 Digitaria ciliaris Nutrition 0.000 description 1
- 235000005476 Digitaria cruciata Nutrition 0.000 description 1
- 235000006830 Digitaria didactyla Nutrition 0.000 description 1
- 235000005804 Digitaria eriantha ssp. eriantha Nutrition 0.000 description 1
- 235000010823 Digitaria sanguinalis Nutrition 0.000 description 1
- 244000058871 Echinochloa crus-galli Species 0.000 description 1
- 244000025670 Eleusine indica Species 0.000 description 1
- 235000014716 Eleusine indica Nutrition 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 244000234609 Portulaca oleracea Species 0.000 description 1
- 235000001855 Portulaca oleracea Nutrition 0.000 description 1
- 235000010086 Setaria viridis var. viridis Nutrition 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 235000002594 Solanum nigrum Nutrition 0.000 description 1
- 240000002307 Solanum ptychanthum Species 0.000 description 1
- 241001251949 Xanthium sibiricum Species 0.000 description 1
- 240000003307 Zinnia violacea Species 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 1
- 125000004670 alkyl amino thio carbonyl group Chemical group 0.000 description 1
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 244000230342 green foxtail Species 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
Abstract
The invention belongs to the field of organic synthesis, and provides a preparation method of an isoxazoline-containing uracil compound, which comprises the following steps: the method comprises the steps of firstly reacting a compound IV with alkali in an organic solvent, then adding N, N-dimethyl formyl chloride to react to obtain a compound III, and then reacting the compound III with a compound II in acid to obtain a target compound I. The reaction formula is as follows:
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a preparation method of an isoxazoline-containing uracil compound.
Background
Patent WO2016095768 reports isoxazoline containing uracil compounds of general formula I:
the compound with the general formula I has good weeding activity, can effectively control weeds such as barnyard grass, green bristlegrass, special-shaped nutgrass flatsedge, cyperus rotundus, crabgrass, grass, abutilon, zinnia, amaranthus retroflexus, purslane, xanthium sibiricum, black nightshade, cassia, pulp Citrulli seedlings, wild soybeans and the like, can obtain good weeding effect at low dosage, and can be used as herbicide in agriculture. Although the patent mentions a method for preparing the compound, the ring-closing reagent such as dichloromethylene dimethyl ammonium chloride used in the preparation method is not industrially produced in large scale and has high price, so that the compound shown in the general formula I is not easy to industrially produce; meanwhile, in the preparation process, the ring is closed first and then methylated, column chromatography is needed, and industrialization is not easy to realize.
In recent years, even though the isoxazoline-containing uracil compound shown in the general formula I has good herbicidal activity, the existing preparation method cannot meet the requirement of industrial production, so that popularization and application of the compound are hindered. Therefore, a new preparation method is urgently needed to avoid using the unendomized and expensive dichloromethylene dimethyl ammonium chloride so as to reduce the cost and facilitate the industrial production of the compound shown in the general formula I.
Disclosure of Invention
The invention aims to provide a preparation method of an isoxazoline-containing uracil compound.
In order to achieve the above purpose, the invention adopts the technical scheme that:
a preparation method of an isoxazoline-containing uracil compound is characterized by comprising the following steps: the reaction formula is as follows:
carrying out ring closure reaction on the compound III and the compound II under an acidic condition to obtain a target compound I;
in the method, in the process of the invention,
R 1 selected from hydrogen, C 1 -C 4 Alkyl or C 1 -C 4 A haloalkyl group;
R 2 、R 3 may be the same or different and are each selected from hydrogen, fluorine, chlorine or methyl;
R 4 selected from hydrogen or C 1 -C 4 An alkyl group;
R 5 selected from hydrogen, C 1 -C 4 Alkyl, CO 2 R 8 Or CH (CH) 2 OR 9 ；
R 6 Selected from hydrogen, cyano, C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, CO 2 R 8 Or CH (CH) 2 OR 9 ；
R 7 Selected from hydrogen, C 1 -C 4 Alkyl or C 1 -C 4 A haloalkyl group;
R 8 selected from hydrogen, C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, C 3 -C 4 Alkenyl, C 3 -C 4 Alkynyl, C 1 -C 4 Alkoxy C 1 -C 4 Alkyl, C 1 -C 4 Alkylcarbonyloxy C 2 -C 3 Alkyl, benzyl, furanmethylene or tetrahydrofuranmethylene, unsubstituted or substituted with 1 to 4 groups independently selected from the group consisting of: halogen, CN, NO 2 、C 1 -C 4 Alkyl or C 1 -C 4 A haloalkyl group;
R 9 selected from hydrogen, C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxycarbonyl group, C 1 -C 4 Alkylcarbonyl, C 1 -C 4 Haloalkylcarbonyl, C 3 -C 6 Cycloalkyl carbonyl, C 3 -C 6 Halogenated cycloalkyl carbonyl, C 1 -C 4 Alkylsulfonyl, C 1 -C 4 Haloalkyl sulfonyl, C 1 -C 3 Alkylaminosulfonyl, di (C) 1 -C 3 ) Alkylaminosulfonyl, C 1 -C 3 Alkylaminocarbonyl, di (C) 1 -C 3 ) Alkylaminocarbonyl, di (C) 1 -C 3 ) Alkylaminothiocarbonyl, C 1 -C 2 Alkylthio C 2 -C 4 Alkylcarbonyl, phenyl C which is unsubstituted or substituted by 1 to 4 radicals independently selected from 1 -C 2 Alkyl, phenylcarbonyl, phenyl C 1 -C 2 Alkylcarbonyl, phenyl C 2 -C 4 Alkenylcarbonyl, phenoxy C 1 -C 2 Alkylcarbonyl, thiophenecarbonyl and pyrazolecarbonylQuinoline carbonyl: halogen, CN, NO 2 、C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy, C 1 -C 4 Haloalkoxy, C 1 -C 4 Alkoxycarbonyl group, C 1 -C 4 Alkylthio, C 1 -C 4 Alkylsulfonyl or substituted by 1-4 halogens, CN, NO 2 、C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, C 1 -C 4 Alkoxy or C 1 -C 4 A haloalkoxy group is independently substituted.
The preferred scheme for the preparation of compound I is: carrying out ring closure reaction on the compound III and the compound II under an acidic condition at 25-150 ℃ to obtain a target compound I;
the acid is acetic acid or hydrochloric acid; the amount of acid is 1-20 times of the weight of the compound III; the feeding mole ratio of the compound II to the compound III is 1:1-1:1.5.
A further preferred scheme for preparing compound I is: the ring closure reaction is carried out under the condition of acetic acid at 100-120 ℃, and the dosage of acid is 1-10 times of the weight of the compound III; the feeding mole ratio of the compounds II to III is 1:1-1:1.2;
the compound III is obtained by reacting a compound IV with N, N-dimethylformamide chloride in an organic solvent at a temperature of between 0 and 120 ℃ under an alkaline condition; wherein R in formula IV 1 Selected from hydrogen, C 1 -C 4 Alkyl or C 1 -C 4 A haloalkyl group.
The organic solvent is an inert solvent, and the dosage of the organic solvent is 1-20 times of the weight of the compound IV.
The preferred scheme for the preparation of compound III is: the compound III is obtained by reacting a compound IV with N, N-dimethylformamide chloride in an organic solvent at a temperature of between 0 and 80 ℃ under an alkaline condition;
wherein the organic solvent is benzene, toluene, tetrahydrofuran, dioxane, N-Dimethylformamide (DMF), N-Dimethylacetamide (DMA), dimethyl sulfoxide (DMSO) or hexamethylphosphoric triamide (HMPA), and the dosage of the organic solvent is 2-10 times of the weight of the compound IV; the alkali is sodium hydroxide, potassium hydroxide, sodium hydride, sodium amide, sodium methoxide, potassium carbonate, potassium tert-butoxide or triethylamine, and the feeding mole ratio of the compound IV to the alkali is 1:1-1:3; the feeding mole ratio of the compound IV to the N, N-dimethyl formyl chloride is 1:1-1:3.
A further preferred scheme for the preparation of compound III is: the reaction temperature is 0-30 ℃; the solvent is N, N-Dimethylformamide (DMF), N-Dimethylacetamide (DMA) or dimethyl sulfoxide (DMSO); the alkali is sodium hydride, sodium amide or potassium tert-butoxide; the feeding molar ratio of the compound IV to the alkali is 1:1-1:2; the feeding mole ratio of the compound IV to the N, N-dimethyl formyl chloride is 1:1-1:1.5.
The preparation method of the isoxazoline-containing uracil compound also comprises the following steps: and (3) carrying out ring closure reaction on the compound III and the compound II under acidic conditions to obtain a target compound I, and then purifying the compound I from the preparation.
The preparation method of the isoxazoline-containing uracil compound also comprises the following steps: a step of purifying the compound IIII after the compound III is produced and before the compound III is reacted with the compound II.
The purification step is that silica gel or diatomite is adopted for purification, and meanwhile, the preferable substituent groups in the reaction formula are as follows:
R 1 selected from hydrogen, C 1 -C 4 An alkyl group;
R 2 、R 3 may be the same or different and are each selected from hydrogen, fluorine or chlorine;
R 4 、R 5 are all selected from hydrogen;
R 6 selected from hydrogen, cyano, C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, CO 2 R 8 Or CH (CH) 2 OR 9 ；
R 7 Selected from hydrogen, C 1 -C 4 Alkyl or C 1 -C 4 A haloalkyl group;
R 8 selected from hydrogen, C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl, C 3 -C 4 Alkenyl, C 3 -C 4 Alkynyl, C 1 -C 4 Alkoxy C 1 -C 4 Alkyl, C 1 -C 4 Alkylcarbonyloxy C 2 -C 3 Alkyl or tetrahydrofuran methylene;
R 9 selected from hydrogen, C 1 -C 4 Alkyl, C 1 -C 4 Haloalkyl or C 1 -C 4 An alkylcarbonyl group;
further preferred substituents of the formula are:
R 1 selected from hydrogen, methyl;
R 2 、R 3 may be the same or different and are each selected from hydrogen, fluorine or chlorine;
R 4 、R 5 are all selected from hydrogen;
R 6 selected from hydrogen, C 1 -C 4 Alkyl, CO 2 R 8 Or CH (CH) 2 OR 9 ；
R 7 Selected from hydrogen, methyl, ethyl, t-butyl or trifluoromethyl;
R 8 selected from hydrogen, methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, t-butyl, trifluoroethyl, allyl, propargyl, methoxyethyl, ethoxyethyl, methylcarbonyloxyethyl, 2-tetrahydrofurane or 3-tetrahydrofurane;
R 9 selected from acetyl;
still further preferred substituents of the formula are:
R 1 selected from hydrogen, methyl;
R 2 、R 3 may be the same or different and are each selected from hydrogen, fluorine or chlorine;
R 4 、R 5 are all selected from hydrogen;
R 6 selected from hydrogen, cyano, methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, tert-butyl, trifluoroethyl, trifluoromethyl or CO 2 R 8 ；
R 7 Selected from hydrogen, methyl, ethyl, t-butyl or trifluoromethyl;
R 8 selected from hydrogen, methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, t-butyl, trifluoroethyl, allyl, propargyl, methoxyethyl, ethoxyethyl, methylcarbonyloxyethyl, 2-tetrahydrofurane or 3-tetrahydrofurane;
the most preferred substituents of the formula are:
R 1 selected from hydrogen, methyl;
R 2 、R 3 may be the same or different and are each selected from hydrogen, fluorine or chlorine;
R 4 、R 5 are all selected from hydrogen;
R 6 selected from hydrogen, cyano, methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, tert-butyl, trifluoroethyl, trifluoromethyl or CO 2 R 8 ；
R 7 Selected from hydrogen, methyl, ethyl, t-butyl or trifluoromethyl;
R 8 selected from hydrogen, methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, t-butyl, trifluoroethyl, allyl, propargyl, methoxyethyl, ethoxyethyl, methylcarbonyloxyethyl, 2-tetrahydrofurane or 3-tetrahydrofurane.
The content of the product in the preparation process is measured by adopting an external standard method through high performance liquid chromatography; and the compounds obtained are important intermediates for the preparation of highly herbicidally active compounds (WO 2016095768).
The raw material N, N-dimethylformamide used in the present invention can be obtained commercially. Compound IV can be prepared by methods commercially available or reported in reference US20030216594 or WO2002053518, compound II being synthesized by reference to patent WO 2016095768.
The invention has the advantages that:
the preparation method provided by the invention has the advantages that the adopted raw materials are easy to obtain, the cost is low, and the process cost can be effectively reduced; compared with the existing preparation process, the method has the advantages that the method can be obtained by directly jointing the rings by the compounds II and III, the methylation is omitted, and the steps such as column chromatography are not needed, so that the process operation difficulty is effectively reduced; in addition, in the preparation process, the compounds III and I can be purified by adopting silica gel or diatomite to extract products with purity and high yield, and the process is simple and efficient, is easy for industrial production and can meet the requirement of industrial production.
Detailed Description
The following specific examples serve to further illustrate the invention, but the invention is by no means limited to these examples; and the percentages referred to in the following examples are mass percentages, such as content, purity, etc.
EXAMPLE 1 Synthesis of Compound I-1 (1)
Sodium hydride (60%, 80g,2 mol) was added to 500mL of DMF, a mixed solution of trifluoroaminocrotonate (compound IV-1, 98%,186g,1 mol) and 120mL of DMF was added dropwise under ice-bath, the dropwise addition was completed over 1.5 hours, and the mixture was stirred for 1 hour at room temperature (20-25 ℃ C.), dimethylcarbamoyl chloride (97%, 166g,1.5 mol) was added dropwise under ice-bath conditions, and the mixture was stirred for 3-4 hours at room temperature, and TLC monitored to complete the reaction. The vast majority of DMF is distilled off under reduced pressure, poured into 500mL of saturated aqueous sodium bicarbonate solution, extracted twice with 600mL of ethyl acetate in sequence, the ethyl acetate phases are combined, 100g of celite is added to a Buchner funnel for filtration, and then distilled under reduced pressure to obtain 238g of oily substance, namely compound III-1, with a purity of 96.7% (HPLC normalized content), yield of 90.6%.
238g of compound III-1 (96.7%, 0.906 mol) and 274g of compound II-1 (synthesized by referring to WO2016095768, 90%,0.82 mol) are sequentially added into a reaction bottle filled with 680mL of acetic acid, the temperature is raised to 110 ℃ for reaction to form a dark solution, the reaction is kept at the temperature for 4 hours, about 500mL of acetic acid is obtained after decompression and is poured into 500mL of water, the mixture is stirred at room temperature for 30 minutes and filtered to obtain crude product, 285g of white solid is obtained after ethanol recrystallization, namely compound I-1, the content of 94.5%, the yield of 70.9%, and the melting point of 105.2 ℃. 1 H-NMR (300 MHz, internal standard TMS, solvent CDCl) 3 )δ(ppm):1.33(t,3H)，1.71(s,3H)，3.34(d,1H)，3.89(d,1H)，4.27(m,2H)，6.21(s,1H)，7.36(d,1H)，7.71(d,1H)。
EXAMPLE 2 Synthesis of Compound I-1 (2)
Potassium tert-butoxide (98%, 172g,1.5 mol) was added to 650mL of DMF, followed by trifluoroaminocrotonate (compound IV-1, 98%,186g,1 mol), stirred at room temperature (20-25 ℃) for 1 hour, dimethylcarbamoyl chloride (97%, 166g,1.5 mol) was added dropwise, and stirred at room temperature for 5 hours, and TLC monitored the reaction was complete. The vast majority of DMF is distilled off under reduced pressure, poured into 500mL of water and extracted twice with 600mL of ethyl acetate in sequence, the ethyl acetate phases are combined, 100g of celite is added to a Buchner funnel for filtration, and then 228g of oily substance is obtained by distillation under reduced pressure, namely the compound III-1, the purity is 95% (HPLC normalized content), and the yield is 85.3%.
228g of compound III-1 (96.7%, 0.853 mol) and 270g of compound II-1 (synthesized by referring to WO2016095768, 90%,0.81 mol) are sequentially added into a reaction bottle filled with 600mL of acetic acid, the temperature is raised to 110 ℃ for reaction to form dark solution, the reaction is kept at the temperature for 4 hours, about 500mL of acetic acid is obtained after decompression and is poured into 500mL of water, the mixture is stirred at room temperature for 30 minutes, the mixture is filtered to obtain crude product, 245g of pale yellow solid is obtained after ethanol recrystallization, namely compound I-1, the content of which is 95.2%, the yield of which is 62%, and the melting point of which is 103.8 ℃.
EXAMPLE 3 Synthesis of Compound I-2 (1)
Sodium hydride (60%, 80g,2 mol) was added to 500mL of DMF, a mixed solution of trifluoro-aminocrotonate (compound IV-2, 97%,203g,1 mol) and 120mL of DMF was added dropwise under ice bath, the dropwise addition was completed over 1.5 hours, the mixture was stirred for 1 hour at room temperature (20-25 ℃ C.), dimethylcarbamoyl chloride (97%, 166g,1.5 mol) was added dropwise under ice bath, and the mixture was stirred for 3-4 hours at room temperature, and TLC monitored to complete the reaction. The vast majority of DMF was distilled off under reduced pressure, poured into 500mL of saturated aqueous sodium bicarbonate solution, extracted twice with 600mL of ethyl acetate in sequence, the ethyl acetate phases were combined, 100g of celite was added to a Buchner funnel and filtered, and then distilled under reduced pressure to give 253g of oil as Compound III-2, 97.2% purity (HPLC normalized content), 91.8% yield.
253g of compound III-2 (97.2%, 0.918 mol) and 274g of compound II-1 (synthesized by reference to WO2016095768, 90%,0.82 mol) were sequentially added into a reaction flask containing 680mL of acetic acid, the temperature was raised to 110℃to react to form a dark solution, the reaction was maintained at that temperature for 8 hours, all the acetic acid was distilled off under reduced pressure, 800mL of ethyl acetate was added, and the mixture was washed twice with 500mL of saturated aqueous sodium bicarbonate solution, and once with 500mL of saturated salt, 150g of celite was added to a Buchner funnel to filter the ethyl acetate phase, and then distilled under reduced pressure to obtain 328g of compound I-2 as an oil having a content of 92.1% and a yield of 77.1%. 1 H-NMR (300 MHz, internal standard TMS, solvent CDCl) 3 )δ(ppm):1.35(t,3H)，1.68(s,3H)，3.38(d,1H)，3.60(s,3H)，3.90(d,1H)，4.30(m,2H)，6.25(s,1H)，7.38(d,1H)，7.79(d,1H)。
EXAMPLE 4 Synthesis of Compound I-2 (2)
Potassium tert-butoxide (98%, 172g,1.5 mol) was added to 650mL of DMF, followed by addition of trifluoro-amino crotonate (compound IV-2, 97%,203g,1 mol), stirring at room temperature (20-25 ℃) for 1 hour, dropwise dimethylcarbamoyl chloride (97%, 166g,1.5 mol), stirring at room temperature for 5 hours, and TLC monitoring was complete. The vast majority of DMF is distilled off under reduced pressure, poured into 500mL of water and extracted twice with 600mL of ethyl acetate in sequence, the ethyl acetate phases are combined, 100g of celite is added to a Buchner funnel for filtration, and then distilled under reduced pressure to obtain 246g of oily substance, namely compound III-2, with purity of 95.8% (HPLC normalized content) and yield of 87.9%.
246g of Compound III-1 (95.8%, 0.879 mol) and 267g of Compound II-1 (synthesized with reference to WO2016095768, 90%,0.80 mol) were successively added to a reaction flask containing 620mL of acetic acid, the temperature was raised to 110℃to react to form a dark solution, the reaction was maintained at that temperature for 8 hours, all the acetic acid was distilled off under reduced pressure, 700mL of ethyl acetate was added, the mixture was washed twice with 500mL of saturated aqueous sodium bicarbonate, and once with 500mL of saturated salt, 150g of celite was added to a Buchner funnel to filter the ethyl acetate phase, and then the mixture was distilled under reduced pressure to give 332g of Compound I-2 as an oil having a content of 91.5% and a yield of 79.5%.
Table 1 below describes the compounds of formula I other than the compounds I-1 and I-2 prepared in the manner described in examples 1, 2, 3 and 4, and the nuclear magnetic data of these compounds, in particular as follows:
TABLE 1
In addition, by changing different substituents of the raw materials in the reaction formula, and according to the description of the preparation process, the compound of the formula I shown by the different substituents can be obtained, which also shows the application universality of the method.
Claims (5)
1. A preparation method of an isoxazoline-containing uracil compound is characterized by comprising the following steps: the reaction formula is as follows:
carrying out ring closure reaction on the compound III and the compound II under an acidic condition at 100-120 ℃ to obtain a target compound I;
the acid is acetic acid; the amount of acid is 1-3 times of the weight of the compound III; the feeding mole ratio of the compounds II to III is 1:1-1:1.2;
the compound III is obtained by reacting a compound IV with N, N-dimethylformamide chloride in an organic solvent at a temperature of between 0 and 30 ℃ under an alkaline condition;
the organic solvent is an inert solvent, and the dosage of the organic solvent is 1-20 times of the weight of the compound IV;
in the method, in the process of the invention,
R 1 selected from methyl;
R 2 、R 3 may be the same or different and are each selected from hydrogen,Fluorine or chlorine;
R 4 、R 5 are all selected from hydrogen;
R 6 selected from hydrogen, methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, tert-butyl, trifluoroethyl, trifluoromethyl or CO 2 R 8 ；
R 7 Selected from hydrogen, methyl, ethyl, t-butyl or trifluoromethyl;
R 8 selected from methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, t-butyl, trifluoroethyl.
2. The process for producing an isoxazoline-containing uracil compound according to claim 1, characterized in that: the solvent is N, N-Dimethylformamide (DMF), N-Dimethylacetamide (DMA) or dimethyl sulfoxide (DMSO); the alkali is sodium hydride, sodium amide or potassium tert-butoxide; the feeding molar ratio of the compound IV to the alkali is 1:1-1:2; the feeding mole ratio of the compound IV to the N, N-dimethyl formyl chloride is 1:1-1:1.5.
3. The process for producing an isoxazoline-containing uracil compound according to claim 1, characterized in that: the preparation method of the isoxazoline-containing uracil compound also comprises the following steps: and (3) carrying out ring closure reaction on the compound III and the compound II under acidic conditions to obtain a target compound I, and then purifying the compound I from the preparation.
4. The process for producing an isoxazoline-containing uracil compound according to claim 1, characterized in that: the preparation method of the isoxazoline-containing uracil compound also comprises the following steps: and (3) purifying the compound II after preparing the compound III and before reacting the compound III with the compound II.
5. The process for preparing isoxazoline-containing uracil compounds according to claim 3 or 4, wherein: the purification step is to adopt silica gel or diatomite for purification.
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