CN113880774B - 一种苯基异恶唑啉类化合物的制备方法 - Google Patents
一种苯基异恶唑啉类化合物的制备方法 Download PDFInfo
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- CN113880774B CN113880774B CN202010634286.4A CN202010634286A CN113880774B CN 113880774 B CN113880774 B CN 113880774B CN 202010634286 A CN202010634286 A CN 202010634286A CN 113880774 B CN113880774 B CN 113880774B
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- Prior art keywords
- uracil
- compound
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- hours
- phenyl
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- -1 phenyl isoxazoline compound Chemical class 0.000 title claims abstract description 69
- 238000002360 preparation method Methods 0.000 title abstract description 16
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 claims abstract description 36
- 229940035893 uracil Drugs 0.000 claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- KENAMMSVUHVEOL-UHFFFAOYSA-N 4-chloro-2-fluoro-5-methylaniline Chemical compound CC1=CC(N)=C(F)C=C1Cl KENAMMSVUHVEOL-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 7
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 6
- 238000001308 synthesis method Methods 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 36
- 239000002904 solvent Substances 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 20
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 16
- 239000003513 alkali Substances 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 12
- 230000002140 halogenating effect Effects 0.000 claims description 12
- 239000012074 organic phase Substances 0.000 claims description 12
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- 150000004657 carbamic acid derivatives Chemical class 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 5
- 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 claims description 5
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 125000001188 haloalkyl group Chemical group 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 4
- 238000001914 filtration Methods 0.000 claims description 4
- 230000011987 methylation Effects 0.000 claims description 4
- 238000007069 methylation reaction Methods 0.000 claims description 4
- 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 claims description 4
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 3
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical class OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 239000012022 methylating agents Substances 0.000 claims description 3
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 claims description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 3
- 239000000376 reactant Substances 0.000 claims description 3
- 229920002554 vinyl polymer Polymers 0.000 claims description 3
- VTWKXBJHBHYJBI-VURMDHGXSA-N (nz)-n-benzylidenehydroxylamine Chemical compound O\N=C/C1=CC=CC=C1 VTWKXBJHBHYJBI-VURMDHGXSA-N 0.000 claims description 2
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 2
- 125000004670 alkyl amino thio carbonyl group Chemical group 0.000 claims description 2
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 230000001590 oxidative effect Effects 0.000 claims description 2
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 4
- 150000002547 isoxazolines Chemical class 0.000 claims 1
- 125000003971 isoxazolinyl group Chemical group 0.000 abstract description 4
- 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 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 17
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 16
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 description 9
- 235000011181 potassium carbonates Nutrition 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 239000011736 potassium bicarbonate Substances 0.000 description 7
- 235000015497 potassium bicarbonate Nutrition 0.000 description 7
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 7
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 239000003444 phase transfer catalyst Substances 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- 235000017550 sodium carbonate Nutrition 0.000 description 6
- 235000011121 sodium hydroxide Nutrition 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical group ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical group N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 235000011118 potassium hydroxide Nutrition 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- SUPCQIBBMFXVTL-UHFFFAOYSA-N ethyl 2-methylprop-2-enoate Chemical compound CCOC(=O)C(C)=C SUPCQIBBMFXVTL-UHFFFAOYSA-N 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical group IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 229920006395 saturated elastomer Chemical class 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- KGFYBSLNHAYQLY-UHFFFAOYSA-N 2-(dimethylamino)-4-(trifluoromethyl)-1,3-oxazin-6-one Chemical compound CN(C)C1=NC(C(F)(F)F)=CC(=O)O1 KGFYBSLNHAYQLY-UHFFFAOYSA-N 0.000 description 2
- HNOIAPRHNXBCAE-UHFFFAOYSA-N 2-chloro-4-fluoro-5-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC(C=O)=C(Cl)C=C1F HNOIAPRHNXBCAE-UHFFFAOYSA-N 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- SOGAXMICEFXMKE-UHFFFAOYSA-N Butylmethacrylate Chemical group CCCCOC(=O)C(C)=C SOGAXMICEFXMKE-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- BYYPTWNMZJLHCD-UHFFFAOYSA-N ClC1=C(C=C(C(=C1)F)N1C(NC(=CC1=O)C(F)(F)F)=O)C1=NOC(C1)(C(=O)OCC)C Chemical compound ClC1=C(C=C(C(=C1)F)N1C(NC(=CC1=O)C(F)(F)F)=O)C1=NOC(C1)(C(=O)OCC)C BYYPTWNMZJLHCD-UHFFFAOYSA-N 0.000 description 2
- XASPCJRBQSRJBH-UHFFFAOYSA-N ClC1=C(C=C(C(=C1)F)[N+](=O)[O-])C1=NOC(C1)(C(=O)OCC)C Chemical compound ClC1=C(C=C(C(=C1)F)[N+](=O)[O-])C1=NOC(C1)(C(=O)OCC)C XASPCJRBQSRJBH-UHFFFAOYSA-N 0.000 description 2
- MXJSOUALMQDXIQ-UHFFFAOYSA-N ClC1=C(C=NO)C=C(C(=C1)F)[N+](=O)[O-] Chemical compound ClC1=C(C=NO)C=C(C(=C1)F)[N+](=O)[O-] MXJSOUALMQDXIQ-UHFFFAOYSA-N 0.000 description 2
- 244000075634 Cyperus rotundus Species 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- PSRVQQFHOLSZLL-UHFFFAOYSA-N NC=1C(=CC(=C(C=1)C1=NOC(C1)(C(=O)OCC)C)Cl)F Chemical compound NC=1C(=CC(=C(C=1)C1=NOC(C1)(C(=O)OCC)C)Cl)F PSRVQQFHOLSZLL-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- SHFJWMWCIHQNCP-UHFFFAOYSA-M hydron;tetrabutylazanium;sulfate Chemical compound OS([O-])(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC SHFJWMWCIHQNCP-UHFFFAOYSA-M 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 2
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin(II) chloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 2
- IPILPUZVTYHGIL-UHFFFAOYSA-M tributyl(methyl)azanium;chloride Chemical compound [Cl-].CCCC[N+](C)(CCCC)CCCC IPILPUZVTYHGIL-UHFFFAOYSA-M 0.000 description 2
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 2
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 238000009333 weeding Methods 0.000 description 2
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 description 1
- VFTFKUDGYRBSAL-UHFFFAOYSA-N 15-crown-5 Chemical compound C1COCCOCCOCCOCCO1 VFTFKUDGYRBSAL-UHFFFAOYSA-N 0.000 description 1
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- LXQPBCHJNIOMQU-UHFFFAOYSA-N 2,4-dimethylpent-1-ene Chemical group CC(C)CC(C)=C LXQPBCHJNIOMQU-UHFFFAOYSA-N 0.000 description 1
- RCBGGJURENJHKV-UHFFFAOYSA-N 2-methylhept-1-ene Chemical group CCCCCC(C)=C RCBGGJURENJHKV-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- NUXLDNTZFXDNBA-UHFFFAOYSA-N 6-bromo-2-methyl-4h-1,4-benzoxazin-3-one Chemical group C1=C(Br)C=C2NC(=O)C(C)OC2=C1 NUXLDNTZFXDNBA-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
- 239000004342 Benzoyl peroxide Substances 0.000 description 1
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 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
- 229920000858 Cyclodextrin Polymers 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
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- 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
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- 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
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
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Abstract
本发明属于有机合成领域,本发明提供了一种苯基异噁唑啉类化合物的合成方法,以2‑氟‑4‑氯‑5‑甲基苯胺为起始原料先合成脲嘧啶在合成异噁唑啉环,得到目标化合物苯基异恶唑啉化合物(VII)。本发明提供的制备方法可以广泛的用于含脲嘧啶的苯基异噁唑啉的合成,大幅度提高了收率且有效的降低成本并易于工业化生产。
Description
技术领域
本发明属于有机合成领域,具体涉及一种苯基异恶唑啉类化合物的制备方法。
背景技术
专利WO2016095768报道了如通式I所示的苯基异恶唑啉类化合物:
通式I化合物具有很好的除草活性,可以有效地控制稗草、狗尾草、异型莎草、水莎草、马唐、荩草、苘麻、百日草、反枝苋、马齿苋、苍耳、龙葵、决明、野西瓜苗、野大豆等杂草,在低剂量下就可以获得很好的除草效果,在农业上可用作除草剂。专利WO2016095768和CN108570041中也均涉及该类化合物的制备,但其合成均是先合成异恶唑啉环后合成脲嘧啶环。
这种合成方法的缺点是:先合成的异噁唑啉环稳定性不好,对脲嘧啶合环时的温度以及碱要求均比较高,容易造成副产,导致反应时间长且收率不高。
发明内容
本发明目的在于提供一种原料廉价易得、合成工艺简单的苯基异恶唑啉类化合物的制备方法。
为实现上述目的,本发明采用技术方案为:
一种苯基异恶唑啉类化合物的合成方法:
1)以2-氟-4-氯-5-甲基苯胺和氯甲酸酯类化合物为原料反应生成氨基甲酸酯类化合物;
2)将步骤1)生成的氨基甲酸酯与三氟氨基巴豆酸酯反应后经甲基化试剂得到脲嘧啶;
3)将步骤2)生成的脲嘧啶经过氧化或二卤化水解的方式得到脲嘧啶苯甲醛;
4)将步骤3)生成的脲嘧啶苯甲醛(IV)经过与盐酸羟胺反应得到脲嘧啶苯甲醛肟;
5)将步骤4)生成的脲嘧啶苯甲醛肟经过NCS氯化后与烯类化合物合环得到苯基异恶唑啉化合物。
所述合成路线如下:
式中,
R1选自甲基、乙基、苯基、4-硝基苯基或苄基;
R2选自氢、C1-C4烷基、CO2R4或CH2OR5;
R3选自氢、氰基、C1-C4烷基、C1-C4卤代烷基、CO2R4或CH2OR5;
R4选自氢、C1-C4烷基、C1-C4卤代烷基、C3-C4烯基、C3-C4炔基、C1-C4烷氧基C1-C4烷基、C1-C4烷羰基氧基C2-C3烷基,未取代或者被1-4个独立选自以下基团取代的苄基、呋喃亚甲基或四氢呋喃亚甲基,以下基团为卤素、CN、NO2、C1-C4烷基或C1-C4卤代烷基;
R5选自氢、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基羰基、C1-C4烷基羰基、C1-C4卤代烷基羰基、C3-C6环烷基羰基、C3-C6卤代环烷基羰基、C1-C4烷基磺酰基、C1-C4卤代烷基磺酰基、C1-C3烷基氨基磺酰基、二(C1-C3)烷基氨基磺酰基、C1-C3烷基氨基羰基、二(C1-C3)烷基氨基羰基、二(C1-C3)烷基氨基硫代羰基、C1-C2烷硫基C2-C4烷基羰基,未取代或者被1-4个独立选自以下基团取代的苯基C1-C2烷基、苯基羰基、苯基C1-C2烷基羰基、苯基C2-C4烯基羰基、苯氧基C1-C2烷基羰基、噻吩羰基、吡唑羰基、喹啉羰基;以下基团为卤素、CN、NO2、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4卤代烷氧基、C1-C4烷氧基羰基、C1-C4烷硫基、C1-C4烷基磺酰基或被1-4个卤素、CN、NO2、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基或C1-C4卤代烷氧基独立取代的苯氧基。
进一步,通式II和VII中,
R1选自甲基、乙基、苯基、4-硝基苯基或苄基;
R2选自氢、C1-C4烷基、CO2R4或CH2OR5;
R3选自氢、C1-C4烷基或C1-C4卤代烷基;
R3选自氢、C1-C4烷基或C1-C4卤代烷基;
R4选自氢、C1-C4烷基、C1-C4卤代烷基、C3-C4烯基、C3-C4炔基、C1-C4烷氧基C1-C4烷基、C1-C4烷羰基氧基C2-C3烷基、苄基、呋喃亚甲基或四氢呋喃亚甲基;
R5选自氢、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基羰基、C1-C4烷基羰基、C1-C4卤代烷基羰基、C3-C6环烷基羰基、C3-C6卤代环烷基羰基、C1-C4烷基磺酰基、C1-C4卤代烷基磺酰基。
更进一步,通式II和VII中,
R1选自甲基或乙基;
R2选自氢、C1-C4烷基、CO2R4或CH2OR5;
R3选自氢、C1-C4烷基或C1-C4卤代烷基;
R4选自氢、C1-C4烷基、C1-C4卤代烷基、C3-C4烯基、C3-C4炔基、C1-C4烷氧基C1-C4烷基、C1-C4烷羰基氧基C2-C3烷基、苄基、呋喃亚甲基或四氢呋喃亚甲基;
R5选自氢、C1-C4烷基羰基或C3-C6环烷基羰基。
优选的,通式II和VII中,
R1选自乙基;
R2选自氢、氰基、甲基、乙基、正丙基、正丁基、异丙基、异丁基、叔丁基、三氟乙基、三氟甲基或CO2R4;
R3选自氢、甲基、乙基、丙基、异丙基、叔丁基或三氟甲基;
R4选自氢、甲基、乙基、正丙基、正丁基、异丙基、异丁基、叔丁基、三氟乙基、烯丙基、炔丙基、甲氧基乙基、乙氧基乙基、甲基羰基氧基乙基、2-四氢呋喃亚甲基或3-四氢呋喃亚甲基。
进一步的说,所述步骤1)将2-氟-4-氯-5-甲基苯胺(I)在溶剂中、碱性条件下加热至60-100℃,滴加氯甲酸酯类化合物反应1-4h生成氨基甲酸酯类化合物(II);其中,2-氟-4-氯-5-甲基苯胺(I)、碱和氯甲酸酯类化合物的摩尔比为1:(1-4):(1-2)。
所述步骤2)为将步骤1)所得产物氨基甲酸酯类化合物(II)与三氟氨基巴豆酸酯在溶剂中、碱性条件下,利用催化剂于100-140℃反应3-8小时,反应后降至室温加入甲基化试剂并补加碱,在20-80℃下反应2-8小时得到脲嘧啶(III)。
其中,氨基甲酸酯(II)、三氟氨基巴豆酸酯、碱、催化剂和甲基化试剂的摩尔比为1:(1-1.2):(1.5-3):(0.01-0.1):(1-2)。
所述步骤3)为将步骤2)获得脲嘧啶(III)、卤化试剂、溶剂、催化剂混合,在50-150℃下反应2-10小时,反应后降至室温后通过萃取,收集有机相减压蒸馏后得到二卤化物,加入酸水解,在50-100℃下反应4-12小时,而后减压蒸馏,中和体系pH至中性,过滤得脲嘧啶苯甲醛(IV);
其中,脲嘧啶(III)、卤化试剂、催化剂、酸摩尔比为1:(2.5-3.5):(0.01-0.1):(10-30)。
所述步骤4)为将脲嘧啶苯甲醛(IV)与盐酸羟胺在醇中,室温下反应1-6小时,经过滤得脲嘧啶苯甲醛肟(V);其中,脲嘧啶苯甲醛(IV)与盐酸羟胺的摩尔比为1:(1-1.5)。
所述步骤5)为将步骤4)所得脲嘧啶苯甲醛肟(V)加入到溶剂中,在20-40℃下加入卤化试剂,在此温度下反应1-2小时,降温至0-15℃,在此温度下加入烯类化合物(VI)及碱,保持1-4小时,反应物经萃取分层,有机相经洗涤后减压蒸馏得产品苯基异恶唑啉化合物(VII);
其中,脲嘧啶苯甲醛肟(V)、卤化试剂、烯类化合物(VI)及碱的摩尔比为1:(1-1.5):1:(1-2)。
所述步骤1)中溶剂选自乙腈、四氢呋喃、1,4-二氧六环、乙二醇二甲醚、乙酸乙酯、2-丁酮、N,N-二甲基甲酰胺或二甲基亚砜等;所述碱选自碳酸钾、碳酸钠、碳酸氢钾、碳酸氢钠、氢氧化钠、氢氧化钾、氢氧化锂、叔丁醇钠、叔丁醇钾、乙醇钠、甲醇钠、三乙胺、吡啶或4-二甲氨基吡啶。
优选的所述步骤1)所述2-氟-4-氯-5-甲基苯胺(I)、碱和氯甲酸酯类化合物的摩尔比1:(1.5~3):(1~1.5);所述溶剂选自乙腈、乙酸乙酯或2-丁酮;所述碱选自碳酸钾、碳酸钠、碳酸氢钾或碳酸氢钠;
所述步骤2)中溶剂选自乙腈、四氢呋喃、1,4-二氧六环、乙二醇二甲醚、乙酸乙酯、2-丁酮、N,N-二甲基甲酰胺或二甲基亚砜中的一种或两种;所述碱环境和补加碱均选自碳酸钾、碳酸钠、碳酸氢钾、碳酸氢钠、氢氧化钠、氢氧化钾、氢氧化锂、叔丁醇钠、叔丁醇钾、乙醇钠、甲醇钠、三乙胺、吡啶或4-二甲氨基吡啶;所述催化剂选自聚醚类相转移催化剂、环状冠醚类相转移催化剂、季铵盐类相转移催化剂、叔胺类相转移催化剂、季铵碱类相转移催化剂、季膦盐类相转移催化剂中的一种或两种;所述甲基化试剂选自碘甲烷、硫酸二甲酯或氯甲烷。
优选的所述步骤2)可利用精馏装置分出反应中的水分及低沸点溶剂;所述氨基甲酸酯(II)、三氟氨基巴豆酸酯和碱的摩尔比为1:(1~1.1):(1~2.5);所述溶剂选自乙腈、2-丁酮、N,N-二甲基甲酰胺或二甲基亚砜的一种或两种;所述碱环境和补加碱均选自碳酸钾、碳酸钠、碳酸氢钾或碳酸氢钠;所述催化剂选自PEG-200、PEG-400、PEG-600、18冠-6、15冠-5、环糊精、苄基三乙基氯化铵、四丁基溴化铵、四丁基氯化铵、四丁基硫酸氢铵、四甲基溴化铵、三丁基甲基氯化铵、三辛基甲基氯化铵、十二烷基三甲基氯化铵、十四烷基三甲基氯化铵、吡啶、三丁胺、1,8-二氮杂二环十一碳-7-烯(DBU)或三乙烯二胺中的一种或两种。
进一步优选的所述步骤2)中催化剂选自四丁基溴化铵、三丁基甲基氯化铵或DBU中的一种或两种。
所述步骤3)中卤化试剂选自NBS、NCS、氯气或溴素;所述溶剂选自四氯化碳、三氯甲烷、乙腈、乙酸乙酯、乙酸异丙酯、四氢呋喃、1,4-二氧六环、乙二醇二甲醚或苯;所述催化剂选自偶氮二异丁腈或过氧化苯甲酰;所述酸选自盐酸、硫酸、甲酸;所述碱选自氢氧化钠、碳酸钠、碳酸氢钠、氢氧化钾、碳酸钾或碳酸氢钾。
优选的所述步骤3)中卤化试剂选自NBS;所述溶剂选自四氯化碳或1,4-二氧六环;所述碱选自氢氧化钠或氢氧化钾。
所述步骤4)中醇选自甲醇、乙醇或异丙醇。
优选的,步骤4)所述反应时间为1~3小时。
所述步骤5)反应物经萃取分层,有机相依次用1N盐酸、饱和食盐水洗,减压蒸馏得产品苯基异恶唑啉化合物(VII);所述卤化试剂选自NBS、NCS、氯气或溴素;所述碱选自碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、三乙胺或者吡啶;所述溶剂选自二氯甲烷、三氯甲烷、乙二醇二甲醚、乙酸乙酯或N,N-二甲基甲酰胺中的一种或两种;
优选的所述步骤5)所述卤化试剂选自NCS或溴素;所述碱选自碳酸氢钠、碳酸氢钾或三乙胺。
上述制备过程中对于产物的含量以高效液相色谱采用外标法测定。
另外,本发明所采用的原料氯甲酸酯、2-氟-4-氯-5-甲基苯胺、3-氨基-4,4,4-三氟巴豆酸乙酯及烯类化合物(VI)可以通过市售得到。
一种合成苯基异恶唑啉类化合物的中间体化合物,中间体化合物其结构式如反应式中的式V所示。其取代基的选择如上述记载。
所述化合物在合成含有脲嘧啶的异噁唑啉类化合物中的应用。
本发明所具有的优点:
本发明所提供的制备方法,合成脲嘧啶环,最后合成异恶唑啉环,采用的原料易得,成本低廉,可有效降低工艺成本;而且本发明方法所涉及反应均为常规操作单元,操作简单,易于工业化;反应过程中相关中间体均比较稳定,不易产生副产;反应过程中部分中间体无需特意纯化,直接用于下一步反应,利于工业的连续化操作;收率明显高于现有技术,总收率提高了3倍之多。
具体实施方式
以下具体实施例用来进一步说明本发明,但本发明绝非仅限于这些例子;并且下述实施例中所涉及的百分比均为质量百分比,如含量、纯度等。
实施例1中间体V的合成
将2-氟-4-氯-5-甲基苯胺63.8g(0.4mol)和碳酸氢钠67.2g(0.8mol)依次加入到装有300ml乙酸乙酯中升温至微回流状态下,滴加氯甲酸乙酯48.8g(0.45mol),保持回流4小时,HPLC反应完全,冷至室温加入水,萃取分层,饱和食盐水洗有机相,减压蒸馏得中间体II 94.2g,为油状物,含量98%(HPLC归一,下同)。
将上述油状物和200ml乙腈加入到装有200ml DMF、56.6g(0.41mol)碳酸钾、75g(0.41mol)、3-氨基-4,4,4-三氟巴豆酸乙酯和4.98g四丁基溴化铵(15.46mmol)并配有精馏柱和冷凝器的反应瓶中,升温至回流并分离出低沸点溶剂,4小时后,HPLC反应结束,降至室温后,补加56.6g(0.41mol)碳酸钾,并滴加85.2g(0.6mol)碘甲烷,保持在室温搅拌6小时,HPLC反应完全,将反应液慢慢倒入水中,搅拌30分钟,过滤并干燥得128g中间体III,为浅黄色固体,含量97.8%,收率93%(以2-氟-4-氯-5-甲基苯胺计),熔点117-119℃。
将68.8g(0.2mol)II、78.5g(0.44mol)NBS、3.5g(21.3mmol)偶氮二异丁腈、300ml四氯化碳依次加入到反应瓶中,升温至回流反应,2小时后补加11g(0.06mol)和0.5g(3.05mmol)偶氮二异丁腈,继续反应2小时,HPLC反应完全,二溴化物含量91.8%,一溴化物含量3.85%。降至室温,加入1N HCl100ml,分出有机相,水相加入200ml二氯甲烷萃取分出有机相,合并有机相,减压脱溶后加入150ml 88%甲酸,并升至回流,保温8小时,减压蒸除溶剂,小心加入到水中,用氢氧化钠调节pH至9,搅拌15分钟,过滤并干燥得IV,为浅黄色固体66.7g,含量94.5%,收率89.9%,熔点176-177℃。
将66.4g(0.18mol)IV加入到200ml乙醇中,室温搅拌10分钟,随后滴加14.4g(0.207mol)和50ml水的混合液,并在室温下搅拌,逐渐形成浅黄色浑浊液,反应1小时后HPLC反应结束,停止反应,静置,过滤,再用50mL水洗涤,干燥,得到V为浅黄色固体64.9g,含量96.1%,收率94.8%,熔点182-185℃。
实施例2化合物VII-1的合成
将0.76g(2mmol)脲嘧啶苯甲醛肟(V)溶于20ml二氯甲烷和5ml N,N-二甲基甲酰胺中,升温至35℃,在该温度下小心加入0.28g(2.1mol)NCS,保持在此温度下反应1小时。降至0~5℃,滴加0.23g(2mmol)甲代丙烯酸乙酯和0.22g(2.2mol)三乙胺以及5ml二氯甲烷的混合液,保持在该温度下反应1.5小时,HPLC监测反应结束,依次1N盐酸、水、饱和食盐水洗,有机相用无水硫酸镁干燥,脱溶得浅黄色油状物0.81g,含量96.7%,收率81.7%。1H-NMR(300MHz,内标TMS,溶剂CDCl3)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)。
以2-氟-4-氯-5-甲基苯胺计,总收率64.8%。
对比例1化合物VII-1的制备(WO2016095768)
1)2-氯-4-氟-5-硝基苯甲醛肟的制备
将42g(0.206mol)2-氯-4-氟-5-硝基苯甲醛溶于200ml乙醇中,降至0℃,搅拌下滴加17.4g(0.25mol)盐酸羟胺的水溶液,随后升至室温搅拌反应。2小时后,TLC监测反应完全。倒入水中,过滤得白色固体38.3g(98%)。
2)3-(2-氯-4-氟-5-硝基苯基)-5-甲基-4,5-二氢异恶唑-5-羧酸乙酯的制备
将43.7g(0.2mol)2-氯-4-氟-5-硝基苯甲醛肟溶于150ml N,N-二甲基甲酰胺中,升温至30℃,在该温度下分批加入32g(0.24mol)NCS,形成浅黄色溶液,保持在35℃下反应1小时。降至室温,加入300ml二氯甲烷,随后用1N盐酸洗两次,饱和食盐水洗两次,无水硫酸镁干燥,抽滤,将二氯甲烷溶液降至0-5℃,滴加34.2g(0.3mol)甲代丙烯酸乙酯和31g(0.3mol)三乙胺的混合液,保持在该温度下反应1小时。依次用1N盐酸和饱和食盐水洗,有机相用无水硫酸镁干燥,脱溶后柱层析(乙酸乙酯:石油醚=1:3)得浅黄色固体57g(97%)。
3)3-(2-氯-4-氟-5-氨基苯基)-5-甲基-4,5-二氢异恶唑-5-羧酸乙酯的制备
将57g(0.18mol)3-(2-氯-4-氟-5-硝基苯基)-5-甲基-4,5-二氢异恶唑-5-羧酸乙酯溶于300ml乙酸乙酯中,加热下分批加入163g(0.72mol)二水合氯化亚锡,随后在回流下反应8小时。TLC监测反应完全。冷至室温,加入到冰水中,用氢氧化钠调节pH至8,乙酸乙酯萃取,饱和食盐水洗,无水硫酸镁干燥后减压蒸馏得31g油状物,未经提纯直接用于下一步反应。
4)2-二甲氨基-4-三氟甲基-6H-1,3-恶嗪-6-酮的制备
将25g(0.15mol)二氯亚甲基二甲基氯化铵加入到100ml氯仿中,升温至60℃滴加25g(0.14mol)3-氨基-4,4,4-三氟巴豆酸乙酯和15ml氯仿的混合液,继续回流反应,溶液逐渐由浅黄色混浊变澄清,4小时后TLC监测反应完全。冷至室温加入饱和碳酸氢钠水溶液,分离有机相,用饱和食盐水洗,有机相用无水硫酸镁干燥,减压蒸馏得浅黄色固体30.8g。
5)3-(2-氯-5-(2,6-二氧-4-三氟甲基-3,6-二氢嘧啶-1(2H)-基)-4-氟苯基)-5-甲基-4,5-二氢异恶唑-5-羧酸乙酯的制备
依次将13.2g(0.046mol)3-(2-氯-4-氟-5-氨基苯基)-5-甲基-4,5-二氢异恶唑-5-羧酸乙酯和9.8g(0.047mol)2-二甲氨基-4-三氟甲基-6H-1,3-恶嗪-6-酮加入到装有100ml乙酸的反应瓶中,升温至回流反应,形成深色溶液,保持在该温度下反应6h,减压整除溶剂,加入碳酸氢钠水溶液调节pH至7,乙酸乙酯萃取,无水硫酸镁干燥后减压整除溶剂得粗品,经乙醇重结晶得白色固体14.5g(95%)。
6)化合物VII-1的制备
将14g(0.031mol)3-(2-氯-5-(2,6-二氧-4-三氟甲基-3,6-二氢嘧啶-1(2H)-基)-4-氟苯基)-5-甲基-4,5-二氢异恶唑-5-羧酸乙酯、12.9g(0.094mol)碳酸钾依次加入到装有150ml N,N-二甲基甲酰胺的反应瓶中,冷至0℃,滴加8.9g(0.062mol)碘甲烷,随后升至室温搅拌反应6h。TLC监测反应完全,倒入水中,乙酸乙酯萃取,饱和食盐水洗,有机相无水硫酸镁干燥,减压蒸馏,柱层析(乙酸乙酯:石油醚=1:5)得13.2g油状物(94%)。
以2-氯-4-氟-5-硝基苯甲醛计,总收率19.6%。
按照上述实施例1和2记载的方法,将合成实施例2中甲代丙烯酸乙酯替换为甲代丙烯酸甲酯、甲代丙烯酸异丙酯、甲代丙烯酸正丁酯、甲代丙烯酸正丙酯、甲代丙烯酸叔丁酯、甲基丙烯酸-2-乙氧基乙酯、2-(三氟甲基)丙烯酸甲酯、丙烯酸乙酯、2-甲基-1-庚烯、2,4-二甲基-1-戊烯,即可制备的除化合物VII-1以外其他属于式VII所示的化合物,具体其他式VII所示的化合物的核磁数据及收率如表1所示:
表1
另外,将反应式中通过改变原料的不同取代基,并依照上述制备过程的记载,还可以获得不同取代基所示的式I化合物,这也显示出了本发明方法应用的广泛性。
Claims (3)
1.一种苯基异恶唑啉类化合物的合成方法,其特征在于:
1)以2-氟-4-氯-5-甲基苯胺和氯甲酸酯类化合物为原料反应生成氨基甲酸酯类化合物;
2)将步骤1)生成的氨基甲酸酯与三氟氨基巴豆酸酯反应后经甲基化试剂得到脲嘧啶;
3)将步骤2)生成的脲嘧啶经过氧化或二卤化水解的方式得到脲嘧啶苯甲醛;
4)将步骤3)生成的脲嘧啶苯甲醛(IV)经过与盐酸羟胺反应得到脲嘧啶苯甲醛肟;
5)将步骤4)生成的脲嘧啶苯甲醛肟经过NCS氯化后与烯类化合物合环得到苯基异恶唑啉化合物;
所述合成路线如下:
式中,
R1选自甲基、乙基、苯基、4-硝基苯基或苄基;
R2选自氢、C1-C4烷基、CO2R4或CH2OR5;
R3选自氢、氰基、C1-C4烷基、C1-C4卤代烷基、CO2R4或CH2OR5;
R4选自氢、C1-C4烷基、C1-C4卤代烷基、C3-C4烯基、C3-C4炔基、C1-C4烷氧基C1-C4烷基、C1-C4烷羰基氧基C2-C3烷基,未取代或者被1-4个独立选自以下基团取代的苄基、呋喃亚甲基或四氢呋喃亚甲基,以下基团为卤素、CN、NO2、C1-C4烷基或C1-C4卤代烷基;
R5选自氢、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基羰基、C1-C4烷基羰基、C1-C4卤代烷基羰基、C3-C6环烷基羰基、C3-C6卤代环烷基羰基、C1-C4烷基磺酰基、C1-C4卤代烷基磺酰基、C1-C3烷基氨基磺酰基、二(C1-C3)烷基氨基磺酰基、C1-C3烷基氨基羰基、二(C1-C3)烷基氨基羰基、二(C1-C3)烷基氨基硫代羰基、C1-C2烷硫基C2-C4烷基羰基,未取代或者被1-4个独立选自以下基团取代的苯基C1-C2烷基、苯基羰基、苯基C1-C2烷基羰基、苯基C2-C4烯基羰基、苯氧基C1-C2烷基羰基、噻吩羰基、吡唑羰基、喹啉羰基;以下基团为卤素、CN、NO2、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基、C1-C4卤代烷氧基、C1-C4烷氧基羰基、C1-C4烷硫基、C1-C4烷基磺酰基或被1-4个卤素、CN、NO2、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基或C1-C4卤代烷氧基独立取代的苯氧基;
所述步骤1)将2-氟-4-氯-5-甲基苯胺(I)在溶剂中、碱性条件下加热至60-100℃,滴加氯甲酸酯类化合物反应1-4h生成氨基甲酸酯类化合物(II);其中,2-氟-4-氯-5-甲基苯胺(I)、碱和氯甲酸酯类化合物的摩尔比为1:(1-4):(1-2);
所述步骤2) 为将步骤1)所得产物氨基甲酸酯类化合物(II)与三氟氨基巴豆酸酯在溶剂中、碱性条件下,利用催化剂于100-140℃反应3-8小时,反应后降至室温加入甲基化试剂并补加碱,在20-80℃下反应2-8小时得到脲嘧啶(III);
其中,氨基甲酸酯(II)、三氟氨基巴豆酸酯、碱、催化剂和甲基化试剂的摩尔比为1:(1-1.2):(1.5-3):(0.01-0.1):(1-2);
所述步骤3) 为将步骤2)获得脲嘧啶(III)、卤化试剂、溶剂、催化剂混合,在50-150℃下反应2-10小时,反应后降至室温后通过萃取,收集有机相减压蒸馏后得到二卤化物,加入酸水解,在50-100℃下反应4-12小时,而后减压蒸馏,中和体系pH至中性,过滤得脲嘧啶苯甲醛(IV);
其中,脲嘧啶(III)、卤化试剂、催化剂、酸摩尔比为1:(2.5-3.5):(0.01-0.1):(10-30);
所述步骤4) 为将脲嘧啶苯甲醛(IV)与盐酸羟胺在醇中,室温下反应1-6小时,经过滤得脲嘧啶苯甲醛肟(V);其中,脲嘧啶苯甲醛(IV)与盐酸羟胺的摩尔比为1:(1-1.5);
所述步骤5) 为将步骤4)所得脲嘧啶苯甲醛肟(V)加入到溶剂中,在20-40℃下加入卤化试剂,在此温度下反应0.5-2小时,降温至0-15℃,在此温度下加入烯类化合物(VI)及碱,保持1-4小时,反应物经萃取分层,有机相经洗涤后减压蒸馏得产品苯基异恶唑啉化合物(VII);
其中,脲嘧啶苯甲醛肟(V)、卤化试剂、烯类化合物(VI)及碱的摩尔比为1:(1-1.5):1:(1-2)。
2.一种合成苯基异恶唑啉类化合物的中间体化合物,其特征在于:中间体化合物其结构式如权利要求1中的式V所示。
3.按权利要求2所述化合物在合成含有脲嘧啶的异噁唑啉类化合物中的应用。
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BR112023000029A BR112023000029A2 (pt) | 2020-07-02 | 2021-06-30 | Método de preparação do composto de fenilisoxazolina |
CA3184706A CA3184706A1 (en) | 2020-07-02 | 2021-06-30 | Preparation method of phenylisoxazoline compound |
US18/003,906 US20230303545A1 (en) | 2020-07-02 | 2021-06-30 | Preparation method of phenylisoxazoline compound |
AU2021302173A AU2021302173B2 (en) | 2020-07-02 | 2021-06-30 | Preparation method for phenylisoxazoline compound |
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