IL153412A - Method for producing 4-bromo aniline derivatives - Google Patents
Method for producing 4-bromo aniline derivativesInfo
- Publication number
- IL153412A IL153412A IL153412A IL15341202A IL153412A IL 153412 A IL153412 A IL 153412A IL 153412 A IL153412 A IL 153412A IL 15341202 A IL15341202 A IL 15341202A IL 153412 A IL153412 A IL 153412A
- Authority
- IL
- Israel
- Prior art keywords
- dihydroisoxazol
- pyridine
- bromo
- methylaniline
- alkyl
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 7
- WDFQBORIUYODSI-IDEBNGHGSA-N 4-bromoaniline Chemical class N[13C]1=[13CH][13CH]=[13C](Br)[13CH]=[13CH]1 WDFQBORIUYODSI-IDEBNGHGSA-N 0.000 title claims description 8
- -1 C1-C6-halogenalkyl Chemical group 0.000 claims abstract description 99
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims abstract description 9
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 7
- 150000002367 halogens Chemical class 0.000 claims abstract description 7
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims abstract description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 60
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 30
- 150000001875 compounds Chemical class 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 24
- 239000003795 chemical substances by application Substances 0.000 claims description 18
- 239000002904 solvent Substances 0.000 claims description 18
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 17
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 16
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 13
- ICMSGNRMZFNBLN-UHFFFAOYSA-N 4-bromo-2-(4,5-dihydro-1,2-oxazol-3-yl)-3-methylaniline Chemical compound CC1=C(Br)C=CC(N)=C1C1=NOCC1 ICMSGNRMZFNBLN-UHFFFAOYSA-N 0.000 claims description 12
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 12
- 229910052794 bromium Inorganic materials 0.000 claims description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims description 12
- 239000011877 solvent mixture Substances 0.000 claims description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000003965 isoxazolidinyl group Chemical group 0.000 claims description 3
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 125000006413 ring segment Chemical group 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 239000011593 sulfur Substances 0.000 claims description 2
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims 1
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 1
- WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical group C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-N 0.000 claims 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 abstract description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 2
- 239000000243 solution Substances 0.000 description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 238000006243 chemical reaction Methods 0.000 description 17
- WQOXQRCZOLPYPM-UHFFFAOYSA-N dimethyl disulfide Chemical compound CSSC WQOXQRCZOLPYPM-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 239000000203 mixture Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 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 description 4
- HFWVJEXKJBOUHJ-UHFFFAOYSA-N 2-(4,5-dihydro-1,2-oxazol-3-yl)-3-methylaniline Chemical compound CC1=CC=CC(N)=C1C1=NOCC1 HFWVJEXKJBOUHJ-UHFFFAOYSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000000460 chlorine Chemical group 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 125000000950 dibromo group Chemical group Br* 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- AQXNGHALTDOVHV-UHFFFAOYSA-N 4,6-dibromo-2-(4,5-dihydro-1,2-oxazol-3-yl)-3-methylaniline Chemical compound CC1=C(Br)C=C(Br)C(N)=C1C1=NOCC1 AQXNGHALTDOVHV-UHFFFAOYSA-N 0.000 description 3
- XENJLTGXGVSVRN-UHFFFAOYSA-N 6-bromo-2-(4,5-dihydro-1,2-oxazol-3-yl)-3-methylaniline Chemical compound CC1=CC=C(Br)C(N)=C1C1=NOCC1 XENJLTGXGVSVRN-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 3
- 230000031709 bromination Effects 0.000 description 3
- 238000005893 bromination reaction Methods 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- HNEGJTWNOOWEMH-UHFFFAOYSA-N 1-fluoropropane Chemical group [CH2]CCF HNEGJTWNOOWEMH-UHFFFAOYSA-N 0.000 description 2
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 2
- 125000004778 2,2-difluoroethyl group Chemical group [H]C([H])(*)C([H])(F)F 0.000 description 2
- 125000005999 2-bromoethyl group Chemical group 0.000 description 2
- 125000004780 2-chloro-2,2-difluoroethyl group Chemical group [H]C([H])(*)C(F)(F)Cl 0.000 description 2
- 125000004779 2-chloro-2-fluoroethyl group Chemical group [H]C([H])(*)C([H])(F)Cl 0.000 description 2
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 description 2
- KKZUMAMOMRDVKA-UHFFFAOYSA-N 2-chloropropane Chemical group [CH2]C(C)Cl KKZUMAMOMRDVKA-UHFFFAOYSA-N 0.000 description 2
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 150000001448 anilines Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000009835 boiling Methods 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 125000004775 chlorodifluoromethyl group Chemical group FC(F)(Cl)* 0.000 description 2
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 125000004774 dichlorofluoromethyl group Chemical group FC(Cl)(Cl)* 0.000 description 2
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 description 2
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 2
- 125000006343 heptafluoro propyl group Chemical group 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000003971 isoxazolinyl group Chemical group 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
- 125000005246 nonafluorobutyl group Chemical group FC(F)(F)C(F)(F)C(F)(F)C(F)(F)* 0.000 description 2
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 238000010626 work up procedure Methods 0.000 description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
- 125000006018 1-methyl-ethenyl group Chemical group 0.000 description 1
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 1
- 125000004781 2,2-dichloro-2-fluoroethyl group Chemical group [H]C([H])(*)C(F)(Cl)Cl 0.000 description 1
- UENGBOCGGKLVJJ-UHFFFAOYSA-N 2-chloro-1-(2,4-difluorophenyl)ethanone Chemical compound FC1=CC=C(C(=O)CCl)C(F)=C1 UENGBOCGGKLVJJ-UHFFFAOYSA-N 0.000 description 1
- 125000004794 2-chloro-2-fluoroethoxy group Chemical group ClC(CO*)F 0.000 description 1
- MZGWAVXNYOMJDE-UHFFFAOYSA-N 4-bromo-2-(4,5-dihydro-1,2-oxazol-3-yl)-3-ethoxyaniline Chemical compound CCOC1=C(Br)C=CC(N)=C1C1=NOCC1 MZGWAVXNYOMJDE-UHFFFAOYSA-N 0.000 description 1
- WTTDTHJJRJDEED-UHFFFAOYSA-N 4-bromo-2-(4,5-dihydro-1,2-oxazol-3-yl)-3-ethylaniline Chemical compound CCC1=C(Br)C=CC(N)=C1C1=NOCC1 WTTDTHJJRJDEED-UHFFFAOYSA-N 0.000 description 1
- FHSGKRWKEGIMMB-UHFFFAOYSA-N 4-bromo-3-ethoxy-2-(1,2-oxazol-3-yl)aniline Chemical compound CCOC1=C(Br)C=CC(N)=C1C1=NOC=C1 FHSGKRWKEGIMMB-UHFFFAOYSA-N 0.000 description 1
- INBFISABYLLROR-UHFFFAOYSA-N 4-bromo-3-ethoxy-2-(3-methyl-4,5-dihydro-1,2-oxazol-5-yl)aniline Chemical compound CCOC1=C(Br)C=CC(N)=C1C1ON=C(C)C1 INBFISABYLLROR-UHFFFAOYSA-N 0.000 description 1
- DUXHISYKBAFUFL-UHFFFAOYSA-N 4-bromo-3-ethyl-2-(1,2-oxazol-3-yl)aniline Chemical compound CCC1=C(Br)C=CC(N)=C1C1=NOC=C1 DUXHISYKBAFUFL-UHFFFAOYSA-N 0.000 description 1
- QKKRSDODWKWWOZ-UHFFFAOYSA-N 4-bromo-3-ethyl-2-(3-methyl-4,5-dihydro-1,2-oxazol-5-yl)aniline Chemical compound CCC1=C(Br)C=CC(N)=C1C1ON=C(C)C1 QKKRSDODWKWWOZ-UHFFFAOYSA-N 0.000 description 1
- ATANWMLVMVFXRM-UHFFFAOYSA-N 4-bromo-3-ethyl-2-(5-methyl-1,2-oxazol-3-yl)aniline Chemical compound CCC1=C(Br)C=CC(N)=C1C1=NOC(C)=C1 ATANWMLVMVFXRM-UHFFFAOYSA-N 0.000 description 1
- UGWRKDNRBGETGQ-UHFFFAOYSA-N 4-bromo-3-methoxy-2-(1,2-oxazol-3-yl)aniline Chemical compound COC1=C(Br)C=CC(N)=C1C1=NOC=C1 UGWRKDNRBGETGQ-UHFFFAOYSA-N 0.000 description 1
- RLLNFGRGUBPTLH-UHFFFAOYSA-N 4-bromo-3-methyl-2-(1,2-oxazol-3-yl)aniline Chemical compound CC1=C(Br)C=CC(N)=C1C1=NOC=C1 RLLNFGRGUBPTLH-UHFFFAOYSA-N 0.000 description 1
- YTDUTXAVCVNGBT-UHFFFAOYSA-N 4-bromo-3-methyl-2-(3-methyl-4,5-dihydro-1,2-oxazol-5-yl)aniline Chemical compound C1C(C)=NOC1C1=C(N)C=CC(Br)=C1C YTDUTXAVCVNGBT-UHFFFAOYSA-N 0.000 description 1
- ZSUKUVJCRQGJGV-UHFFFAOYSA-N 4-bromo-3-methyl-2-(5-methyl-1,2-oxazol-3-yl)aniline Chemical compound O1C(C)=CC(C=2C(=C(Br)C=CC=2N)C)=N1 ZSUKUVJCRQGJGV-UHFFFAOYSA-N 0.000 description 1
- OFZDOFMICXMFPK-UHFFFAOYSA-N 6-amino-3-bromo-2-methoxybenzonitrile Chemical compound COC1=C(Br)C=CC(N)=C1C#N OFZDOFMICXMFPK-UHFFFAOYSA-N 0.000 description 1
- NFJSIWUQYGVKTE-UHFFFAOYSA-N 6-amino-3-bromo-2-methylbenzonitrile Chemical compound CC1=C(Br)C=CC(N)=C1C#N NFJSIWUQYGVKTE-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 125000004773 chlorofluoromethyl group Chemical group [H]C(F)(Cl)* 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000012045 crude solution Substances 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000006006 difluoroethoxy group Chemical group 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000001298 n-hexoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- BBFCIBZLAVOLCF-UHFFFAOYSA-N pyridin-1-ium;bromide Chemical compound Br.C1=CC=NC=C1 BBFCIBZLAVOLCF-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- SFLXUZPXEWWQNH-UHFFFAOYSA-K tetrabutylazanium;tribromide Chemical compound [Br-].[Br-].[Br-].CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC.CCCC[N+](CCCC)(CCCC)CCCC SFLXUZPXEWWQNH-UHFFFAOYSA-K 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyrrole Compounds (AREA)
Abstract
The invention relates to a method for producing 4-bromine-aniline derivatives of formula (I), wherein the substituents have the following meanings: R<1>: C1-C6-alkyl, C1-C6-halogenalkyl, C1-C6-alkoxy, C1-C6-halogen-alkoxy, C3-C8-cycloalkyl, halogen; R<2>: C1-C6-alkyl, C1-C6-alkoxy, C3-C8-cycloalkyl, C2-C6-alkenyl, cyano or a heterocyclic radical.
Description
^iN i»m- nyrinn muii no ¾< Method for producing 4-bromo aniline derivatives BASF Aktiengesellschaft C. 142381 - 1 - 153412/2 The present invention provides a process for preparing 4-bromoaniline derivatives. 4-Bromoaniline derivatives are useful compounds which are used as intermediates in chemical industry. They are suitable, for example, for preparing active compounds used in the field of crop protection, or for preparing pharmaceutically active compounds. WO 99/58509 corresponds to IL 139277, for example, describes processes for preparing isoxazolin-3-ylacylbenzenes in which 4-bromoaniline derivatives are employed as intermediates for preparing herbicidally active compounds. WO 98/31681 corresponds to IL 130777 and IL 130778 ■ describes these active compounds (2- alkyl-3- (4, 5-dihydroisoxazol-3-yl) acylbenzenes) as herbicidally active compounds. , It is known from the literature that the selective bromination of anilines in the para position is impossible, or possible only with difficulty (Houben-Weyl 5/4, 241, 274 ff ) . In general, bromination with elemental bromine is not selective, but frequently associated with the formation of considerable amounts of dibromo compounds. According to experience, the selectivities for monobromo to dibromo compounds are in an order of magnitude of about 9:1, i.e. the proportion of undesired dibromo compounds is about 10%. Thus, only with expensive reagents, such as tetrabutylammonium tribromide, the compound 4-bromo-2-( 4 , 5-dihydroisoxazol-3-yl ) -3-methylaniline, for example, was obtained at -30°C in a yield of about 50% (cf.
WO 99/58509) .
It is an object of the present invention to provide an alternative process for preparing 4-bromoaniline derivatives. The preparation process described in WO 99/58509 for the 4-bromo-2-( 4 , 5-dihydroisoxazol-3-yl) -3-methylaniline derivatives gives unsatisfactory yields and an unsatisfactory purity of the products. Accordingly, the process described in WO 99/58509 is only of limited use for the industrial preparation of such compounds .
We have found that this object is achieved by a process for preparing 4-bromoaniline derivatives of the formula I where : is Ci-C6-alkyl, Ci-C6-haloalkyl, Ci-C6-alkoxy, Ci-C6-haloalkoxy, C3-C8-cycloalkyl, halogen is Ci-C6-alkyl, Gi-C6-alkoxy, C3-C8-cycloalkyl, C2-C6-alkenyl, cyano or a heterocyclic radical, which comprises reacting a compound of the formula in which R1 and R2 are as defined above with a brominating agent in the solvent pyridine or in a solvent mixture comprising at 25 least 55% by weight of pyridine. ith the aid of the process according to the invention, it is possible to obtain the aniline derivatives of the formula I in higher yields than with the prior-art preparation processes.
Thus, for example, the compound 4-bromo-2-(4,5-dihydroisoxazol-3-yl)-3-methylaniline can be obtained by the process described in WO 99/58509 (cf. Example 10 therein) in a yield of only 47%, whereas the yield in the process according to the invention is at least 60%, preferably at least 70% or 80%, and in particular at least 90%.
Moreover, the compounds of the formula I are obtained in higher purity. Here, the bromination takes place with high selectivity in the 4-position of the phenyl ring. The selectivity (ratio of 40 monobromo to dibromo compound) is at least 92:8, in particular at least 95:5. Surprisingly, the proportion of impurities, such as, for example, dibromides (these dibromides are derivatives of the formula I which are substituted in the 5— or 6—position by a further bromine atom) which are difficult to remove from the 45 resulting reaction mixture, or whose removal requires relatively high technical expenditure, is less than 5%. Accordingly, the number of further additional purification steps for isolation and work-up of the compounds I prepared by the process according to the invention can be reduced. This is particularly advantageous for the industrial production of the compounds I, since an efficient and cost-effective process can be provided.
Owing to the high selectivity and the small proportion of dibromo compounds, it is possible, if appropriate, to use the reaction product even without additional purification for the next process steps for further conversion into suitable end products .
Ci-C6-Alkyl is a straight-chain or branched alkyl group having 1 - 6 carbon atoms, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl; preference is given to Ci-Cj-alkyl, such as, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
Ci-C6-Haloalkyl is a straight-chain or branched Cx-C6-alkyl group as mentioned above which is partially or fully substituted by fluorine, chlorine, bromine and/or iodine, i.e., for example, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2 , 2-difluoroethyl, 2, 2, 2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2, 2-difluoroethyl, 2 , 2-dichloro-2-fluoroethyl, 2.2.2-trichloroethyl, pentafluoroethyl , 2-fluoropropyl, 3-fluoropropyl, 2 , 2-difluoropropyl, 2 , 3-difluoropropyl, 2-chloropropyl, 3-chloropropyl, 2 , 3-dichloropropyl, 2-bromopropyl, 3-bromopropyl, 3 , 3 , 3-trifluoropropyl, 3.3.3-trichloropropy1 , 2,2,3,3,3-pentafluoropropyl , heptafluoropropyl, l-( fluoromethyl) -2-fluoroethyl, 1- (chloromethyl ) -2-chloroethyl , 1- ( bromomethyl ) -2-bromoethyl , 4-fluorobutyl, 4-chlorobutyl, 4-bromobutyl , nonafluorobutyl, 5-fluoropentyl, 5-chloropentyl, 5-bromopentyl, 5-iodopentyl, undecafluoropentyl, 6-fluorohexyl, 6-chlorohexyl, 6-bromohexyl, 6-iodohexyl or dodecafluorohexyl; preferably Ci-C4-haloalkyl, such as chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorfluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2 , 2-difluoroethyl, 2,2, 2-trifluoroethyl, 2-chloro-2-fluoroethyl, 2-chloro-2, 2-difluoroethyl, 2 , 2-di-chloro-2-fluoroethyl, 2 , 2 , 2-trichloroethyl, pentafluoroethyl, 2-fluoropropyl, 3-fluoropropyl, 2 , 2-difluoropropyl, 2 , 3-difluoropropyl, 2-chloropropyl, 3-chloropropyl, 2, 3-dichloropropyl, 2-bromopropyl, 3-bromopropyl, 3 , 3 , 3-trifluoropropyl, 3,3, 3-trichloropropyl, 2,2,3,3 , 3-pentafluoropropyl, heptafluoropropyl, l-( fluoromethyl ) -2-fluoroethyl , 1- ( chloromethy1 ) -2-chloroethy1 , 1- (bromomethy1 ) -2-bromoethy1 , 4-fluorobutyl, 4-chlorobutyl, 4-bromobutyl or nonafluorobutyl ; Ci-C6-alkoxy is a straight-chain or branched alkyl group having 1 - 6 carbon atoms, such as, for example, methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, tert-butyloxy, n-pentyloxy or n-hexyloxy; preferably C1-C4-alkoxy such as, for example, methoxy, ethoxy, n-propyloxy, n-butyloxy, isobutyloxy or tert-butyloxy; Ci-C6-haloalkoxy is a straight-chain or branched Ci-C6-alkoxy group as mentioned above which is partially or fully substituted. by fluorine, chlorine, bromine and/or iodine, i.e., for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, bromodifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2 , 2-difluoroethoxy, 2 , 2 , 2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2 , 2-difluoroethoxy, 2 , 2-dichloro-2-fluoroethoxy, 2.2.2-trichloroethoxy, pentafluoroethoxy, 2-fluoropropoxy, 3-fluoropropoxy, 2-chloropropoxy, 3-chloropropoxy, 2-bromopropoxy, 3-bromopropoxy, 2 , 2-difluoropropoxy, 2 , 3-difluoropropoxy, 2 , 3-dichloropropoxy, 3,3, 3-trifluoropropoxy, 3 , 3 , 3-trichloropropoxy, 2 , 2 , 3 , 3-pentafluoropropoxy, heptafluoropropoxy, 1- ( fluoromethyl ) -2-fluoroethoxy, 1- ( chloromethy1 ) -2-chloroethoxy, 1- (bromomethyl ) -2-bromoethoxy, 4-fluorobutoxy, 4-chlorobutoxy, 4-bromobutoxy, nonafluorobutoxy, -fluoropentoxy, 5-chloropentoxy, 5-bromopentoxy, 5-iodopentoxy, undecafluoropentoxy, 6-fluorohexoxy, 6-chlorohexoxy, 6-bromohexoxy, 6-iodohexoxy or dodecafluorohexoxy; preferably Ci-C4-haloalkoxy, such as fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorodifluoromethoxy, bromodifluoromethoxy, 2-fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 2 , 2-difluoroethoxy, 2 , 2 , 2-trifluoroethoxy, 2-chloro-2-fluoroethoxy, 2-chloro-2 , 2 ,difluoroethoxy, 2 , 2-dichloro-2-fluoroethoxy, 2 , 2 , 2-trichloroethoxy, pentafluoroethoxy, 2-fluoropropoxy, 3-fluoropropoxy, 2-chloropropoxy, 3-chloropropoxy, 2-bromopropoxy, 3-bromopropoxy, 2 , 2-difluoropropoxy, 2 , 3-difluoropropoxy, 2 , 3-dichloropropoxy, 3.3.3-trifluoropropoxy, 3 , 3 , 3-trichloropropoxy, 2,2,3, 3-pentafluoropropoxy, heptafluoropropoxy, 1- ( fluoromethyl ) -2-fluoroethoxy, 1- ( chloromethyl ) -2-chloroethoxy, l-( bromomethyl) -2-bromoethoxy, 4-fluorobutoxy, 4-chlorobutoxy, 4-bromobutoxy or nonafluorobutoxy; C3-C8-cycloalkyl is an unsubstituted or substituted cycloalkyl ring having 3 - 8 carbon atoms, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Suitable substituents are, for example: Ci-C6-alkyl, Ci-C6-alkoxy or halogen; preference is given to unsubstituted C3-C6-cycloalkyl, such as, for example, cyclopropyl, cyclopentyl or cyclohexyl; C2-C6-alkenyl is a straight-chain or branched alkenyl group having 2 - 6 carbon atoms, where the double bond is at the point of attachment, such as, for example, ethenyl, prop-l-en-l-yl, 1-methylethenyl, buten-l-yl, 1-methylprop-l-en-l-yl, 2-methylprop-l-en-l-yl, penten-l-yl, l-methylbut-l-en-l-yl, 2-methylbut-l-en-l-yl, 3-methylbut-l-en-l-yl, 1 , 2-dimethylprop-l-en-l-yl, hex-l en-l-yl, 1-methylpent-l-en-l-yl, 2-methylpent-l-en-l-yl, 3-methylpent-l-en-l-yl, 4-methylpent-l-en-l-yl, 1, 2-dimethylbut-l-en-l-yl, 1 , 3-dimethylbut-l-en-l-yl, 2 , 3-dimethylbut-l-en-l-yl, 3, 3-dimethylbut-l-en-l-yl, 1-ethylbut-l-en-l-yl, 2-ethylbut-l-en-l-yl or l-ethyl-2-methylprop-l-en-yl; Halogen is fluorine, chlorine, bromine, in particular chlorine or bromine.
"Heterocyclic ring" is a saturated, unsaturated or partially unsaturated heterocycle having 3 — 8 ring atoms and one, two or three oxygen, sulfur or nitrogen atoms. Preference is given to heterocycles which contain at least one oxygen and/or one nitrogen atom. Preference is furthermore given to heterocycles having 5 or 6 ring atoms. The heterocycle can be attached to the phenyl ring at any site of the heterocycle, for example via a heterocylic nitrogen ring atom or a carbon ring atom. The heterocycles are unsubstituted or mono-, di- or trisubstituted. Suitable substituents are radicals which are chemically inert under the chosen reaction conditions, such as, for example, Ci-Ce-alkyl, Ci-C6-alkoxy or halogen. Suitable heterocyclic rings in the context of the present invention are, for example, the following heterocycles: pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, piperidinyl, morpholinyl, oxazinyl, isoxazolinyl, isoxazolidinyl, etc.
Preference is given to the following heterocycles: isoxazolyl, isoxazolinyl or isoxazolidinyl, in particular 4 , 5-dihydroisoxazol-3-yl or 4 , 5-dihydroisoxazol-5-yl .
The process according to the invention is preferably suitable for preparing compounds of the formula I where the substituents are as defined below: R1 is Ci-C6-alkyl, Ci-C6-alkoxy, C3-C8-cycloalkyl, halogen, R2 is Ci-C6-alkyl, Ci-C6-alkoxy, .C3-C8-cycloalkyl, cyano or a heterocyclic radical.
The process according to the invention is furthermore preferably suitable for preparing the following compounds of the formula I: 4-bromo-2- ( 4 , 5-dihydroisoxazol-3-yl ) -3-methylaniline , 4-bromo-2- ( 4 , 5-dihydroisoxazol-3-yl ) -3-ethylaniline, 4-bromo-2- ( 4 , 5-dihydroisoxazol-3-yl- ) 3-methoxyaniline , 4-bromo-2-(4,5-dihydroisoxazol-3-yl)-3-ethoxyaniline, 4-bromo-2- ( 3-methyl-4 , 5-dihydroisoxazol-5-yl ) -3-methylaniline , 4-bromo-2- ( 3-methyl-4 , 5-dihydroisoxazol-5-yl ) -3-ethylaniline , 4-bromor2- ( 3-methyl-4 , 5-dihydroisoxazol-5-yl- ) 3-methoxyaniline , 4-bromo-2-(3-methyl-4 , 5-dihydroisoxazol-5-yl)-3-ethoxyaniline, 4-bromo-2-( isoxazol-3-yl) -3-methylaniline, 4-bromo-2- ( isoxazol-3-yl ) -3-ethylaniline , 4-bromo-2- ( isoxazol-3-yl ) -3-methoxyaniline, 4-bromo-2- ( isoxazol-3-yl ) -3-ethoxyaniline , 4-bromo-2-( 5-methylisoxazol-3-yl) -3-methylaniline, 4-bromo-2-(5-methylisoxazol-3-yl) -3-ethylaniline, 4-bromo-2- ( 5-methylisoxazol-3-yl- ) 3-methoxyaniline, 4-bromo-2- ( 5-methylisoxazol-3-y1 ) -3-ethoxyaniline, 4-bromo-2-cyano-3-methylaniline , 4-brom-2-cyano-3-methoxyaniline.
The reaction of the compounds II with a brominating agent is preferably carried out by the following process steps: According to the invention, the reaction is carried out in the solvent pyridine, or in solvent mixtures comprising at least 55% by weight, preferably 80% by weight of pyridine. In the case of solvent mixtures, suitable additional solvents in the mixture with pyridine are, for example, alcohols, such as methanol or ethanol, in particular methanol; esters, such as ethyl acetate or butyl acetate, in particular ethyl acetate or butyl acetate; amides, such as, for example, Ν,Ν-dimethylformamide or Ν,Ν-dimethylacetamide; or water.
Initially, the compound II is charged in pyridine or a pyridine-containing solvent mixture, as solution or suspension. The brominating agent is then added over a period of 5 minutes — hours. The brominating agent is added either directly, i.e. without solvent, or together with a suitable solvent.
Preferred brominating agents are elemental bromine or a mixture 5 of HBr and hydrogen peroxide. In the case of bromine, the bromine is preferably added together with a suitable solvent, such as, for example, pyridine, with formation of pyridinium perbromide. In this case, a particularly high selectivity in the ratio of monobromo to dibromo compound is achieved.
In a preferred embodiment of the process, the brominating agent and the compound II are employed in a molar ratio of from 1:1 to 2:1. The brominating agent is preferably employed in equimolar amounts, or in a slight excess.
The reaction is carried out at temperatures of from 20°C to the boiling point of the solvent, preferably in the range from 60°C to 85°C. In a further preferred embodiment, the reaction is carried out at temperatures of from 50°C to 100°C, preferably in the range 20 from 80°C to 100°C, with particular preference at about 100°C.
The reaction time is 1 - 24 hours, preferably 2 - 12 hours, in particular 5 — 8 hours. In a further preferred embodiment, the reaction time is 30 min - 10 h, preferably 30 min - 5 hours.
If the brominating agent used is a mixture of HBr and hydrogen peroxide, the brominating agent is added to the solution of II over a period of preferably from 10 minutes to 3 hours. The molar ratio of HBr to compound II is preferably in the range from 1:1 to 1.5:1. The addition is carried out at temperatures of 0 — 50°C, preferably 20 — 40°C. The hydrogen peroxide is then added. The molar ratio of Η202 to HBr is from 1:1 to 1.5:1. The addition is carried out at temperatures of from 10°C to the boiling point of the solvent, preferably from 50°C to 120°C, with preference from 80°C to 100°C, with particular preference at about 100°C; in a' further preferred embodiment, the addition is preferably carried out at from 60°C to 85°C. The solution is then stirred for a period of 10 min - 36 hours, preferably 10 min - 8 hours. In a further embodiment, the solution is stirred for a period, of 1 - 40 36 hours, preferably 2 - 8 hours. In a further embodiment, the solution is stirred for a period of from 10 min to 3 hours, preferably from 10 min to 2 hours. Subsequently, the product is worked up and purified. To this end, the solution is concentrated. The crude product is dissolved in a suitable 45 solvent, preferably pyridine or a solvent mixture comprising at least 50% pyridine, and water is added. Filtration and washing of the residue or crystallization using a suitable solvent (for example water) gives the product in good yield and high purity.
However, it is also possible to take up the crude product in dimethyl disulfide and to wash the product with water and/or aqueous sodium hydroxide solution. The organic solution can then be used for subsequent steps .
In a preferred embodiment, the compound of the formula II is initially charged in pyridine or in a mixture of pyridine and water. In the latter case, the ratio of pyridine to water is in the range from 80 to 98% by weight to 20 to 5% by weight, preferably in a range of from 90 to 95% by weight to 10 to 5% by weight .
The ratio of the compound of the formula II to pyridine or pyridine/water is chosen such that a 5 - 25% strength solution, preferably a 10 - 15% strength solution, is formed. Above 0.8 to 1.1 molar equivalents, preferably 0.9 to 1.0 molar equivalents, of HBr are then added to the resulting solution. The water is removed by azeotropic distillation and hydrogen peroxide is added to the solution that remains over a period of 1 - 3 hours, preferably 1.5 - 2.5 hours, at 50 - 120°C, preferably 80 - 110°C, in particular at about 100°C. The hydrogen peroxide is Usually employed in a 20% strength to 50% strength, preferably 30 to 50% strength, aqueous solution.
The mixture is then stirred for about 10 min to 2 h, preferably 30 min to 1 h.
This is followed by work-up of the product. To this end, the reaction solution is cooled to about room temperature and, if required, washed with aqueous sodium sulfite solution, and the organic phase is concentrated. The resulting product can be used without further purification for subsequent reactions. However, it is also possible to take up the residue in dimethyl disulfide, to wash the resulting solution with water or aqueous sodium hydroxide solution and to use the resulting organic phase for subsequent reactions .
In a further embodiment, it is possible to add HBr to the pyridine which, if appropriate, comprises up to 10% of water, and then to remove the water azeotropically . The compound of the formula II is then dissolved in the reaction mixture and the hydrogen peroxide is added dropwise. Both the quantitative ratios of the substances employed and time and temperature conditions correspond to the conditions mentioned above.
In a further embodiment, it is also possible to use pyridinium hydrobromide instead of pyridine and HBr.
If the brominating agent used is elemental bromine, the brominating agent is preferably added to the solution of II a little at a time or continuously over a period of from about 30 minutes to 6 hours . The molar ratio of bromine to the compound II is preferably in the range from 1:1 to 1.5:1. The addition is carried out at temperatures of 0 — 50°C, preferably at room temperature. The solution is then stirred for a period of 1 — 24 hours, preferably 2 — 8 hours. Subsequently, the product is worked up and purified. To this end, the solution is concentrated and the crude product is dissolved in a suitable solvent, preferably pyridine or a solvent mixture comprising at least 50% pyridine, and admixed with water. Filtration and washing of the residue or crystallization using a suitable solvent (for example water) gives the product in good yield and high purity.
Furthermore, the product can also be obtained from the reaction solution by extraction. To this end, the reaction solution is initially concentrated and the residue is taken up in a suitable solvent or solvent mixture, the components being selected, for example, from water, ethyl acetate and dimethyl disulfide (DMDS), in particular water, ethyl acetate, water/ethyl acetate or water/DMDS. Suitable for the extraction are water-immiscible solvents or the corresponding solvent mixtures, such as, for example, ethyl acetate, butyl acetate, toluene or methyl tert-butyl ether (MTBE). Concentration of the solution gives the product in good yield and high purity.
The crude product is purified either by washing the residue obtained, or by crystallization. Suitable for washing are, for example, water and aqueous solvents. Suitable for recrystallization are, for example, toluene and benzene.
In principle, in the context of further reaction for preparing active compounds, the crude product obtained can also be used for the next reaction step without further purification of the reaction solution. To this end, the reaction solution which contains the compounds of the formula I can be diluted with further solvents and thus be employed as crude solution for the next process step. Alternatively, it is also possible to concentrate the reaction solution and to transfer the resulting residue directly or as a melt into the next process step.
The compounds of the formula II to be used as starting materials are known from the literature and/or commercially available. They can be prepared by processes known per se, such as, for example, described in more detail in WO 98/31681 or WO 99/58509.
The invention is illustrated in more detail in the working examples below.
Example 1 4-Bromo-2- ( 4 , 5-dihydroisoxazol-3-yl) -3-methylaniline Brominating agent: HBr/H202 100.5 g of 2- ( 4, 5-dihydroisoxazol-3-yl) -3-methylaniline are initially charged in 2000 g of pyridine, and 98.2 g of HBr are added dropwise at 20-35°C. At 78-84°C, 64.6 g of hydrogen peroxide are then added dropwise over 0.5 h. The mixture is stirred at 25°C for a further 12 hours and then concentrated until an oily residue remains. The crude product is, at 50°C, dissolved in 100 ml of pyridine and admixed with 1000 ml of water. The mixture is stirred at 0°C for 1 h and then filtered off, and the filter residue is washed twice with 200 ml of water and dried.
This gives 141 g (yield: 92%) of a yellow solid (HPLC: 94.6% of 4-bromo-2-( 4 , 5-dihydroisoxazol-3-yl) -3-methylaniline, 1.8% of 6-bromo-2-( 4, 5-dihydroisoxazol-3-yl) -3-methylaniline, 3.4% of 4 , 6-dibromo-2- ( 4 , 5-dihydroisoxazol-3-yl ) -3-methylaniline ) .
Example 2 4-Bromo-2-( 4 , 5-dihydroisoxazol-3-yl) -3-methylaniline Brominating agent: bromine 100 g of 2- ( 4, 5-dihydroisoxazol-3-yl) -3-methylaniline are initially charged in 1000 g of pyridine, and a solution of altogether 96.19 g of bromine in 1000 g of pyridine is added dropwise at 20°C in five freshly prepared portions, over 3 hours.
The mixture is stirred for a further 12 hours. Pyridine is distilled off at 150 mbar and a bath temperature of 75°C. The residue is dissolved in 2 1 of water and extracted repeatedly with in each case 250 ml of ethyl acetate. Concentration gives 4-bromo-2- ( 4 , 5-dihydroisoxazol-3-yl ) -3-methylaniline, 2.7% of 6-bromo-2-(4,5-dihydroisoxazol-3-yl)-3-methylaniline, 4.1% of 4 , 6-dibromo-2- ( 4 , 5-dihydroisoxazol-3-yl) -3-methylaniline ) .
Example 3 4-Bromo-2- ( 4 , 5-dihydroisoxazol-3-yl) -3-methylaniline Brominating agent: bromine g of the compound 2- ( 4, 5-dihydroisoxazol-3-yl) -3-methylaniline are initially charged in 50 g of pyridine, and a solution of altogether 4.89 g of bromine in 50 g of pyridine (mixture to be prepared at 0°C) is added dropwise at 20°C over 5 h. The mixture is stirred at 25°C for a further 12 hours. The batch is poured into 250 ml of water and extracted three times with in each case 100 ml of MTBE. The combined organic phases are washed twice with in each case 100' ml of water, dried over sodium sulfate and concentrated.
This gives 6.0 g of product (yield 79.8%; 94.3% of 4-bromo-2- ( 4 , 5-dihydroisoxazol-3-yl) -3-methylaniline, 1.8% of 6-bromo-2-( 4 , 5-dihydroisoxazol-3-yl) -3-methylaniline, 3.5% of 4 , 6-dibromo-2- ( 4 , 5-dihydroisoxazol-3-yl) -3-methylaniline ) .
Example 4 4-Bromo-2- ( 4 , 5-dihydroisoxazole-3-yl ) -3-methylaniline Brominating agent: HBr, H2O2 500.0 g of 2- ( 4, 5-dihydroisoxazol-3-yl) -3-methylaniline are initially charged in 4 500 g of pyridine, and at 25 - 35°C, 467.4 g of 47% strength HBr are added dropwise. Under reflux, the water is distilled off azeotropically at atmospheric pressure. At 100°C, 199.2 g of 50% strength H202 are then added dropwise over a period of 2 hours . The reaction mixture is stirred for another hour and then cooled to room temperature and washed with sodium sulfite solution, and the solvent is then distilled off (T<100°C) . The residue is taken up in 3 220 g of dimethyl disulfide and, at 60°C, washed with 1 500 g of water. The resulting solution is used for a subsequent reaction.
This gives about 83% of the desired product.
Claims (7)
1. A process for preparing 4-bromoaniline derivatives of the formula I where : R1 is C1-Ce-alkyl, d-Cg-haloalkyl, d-Cg-alkoxy,' C1-C6-haloalkoxy, C3-C8-cycloalkyl , halogen R2 . .is C1-C8-alkyl, d-Cg-alkoxy, C3-C8-cycloalkyl , C2_C6-alkenyl, cyano or a heterocyclic radical selected from saturated, unsaturated or partially unsaturated heterocycle having 3-8 ring atoms and one, two or three oxygen, sulfur or nitrogen atoms; which comprises reacting a compound of the formula II in which R1 and R2 are as defined above with a brominating agent in the solvent pyridine or a solvent mixture comprising at least 55% by weight of pyridine.
2. A process as claimed in claim 1, wherein the brominating agent used is bromine.
3. A process as claimed in claim 1, wherein the brominating agent used is hydrogen bromide and hydrogen peroxide.
4. A process as claimed in any of claims 1 - 3, wherein the solvent used is pyridine.
5. A process as claimed in any of claims 1 - 4, wherein R1 is Ci-C6-alkyl. ,
6. A process as claimed in claim 5, wherein R1 is methyl or ethyl.
7. A process as claimed in any of claims 1 - 6, wherein R2 is a heterocyclic ring. A process as claimed in claim 7, where R2 is an isoxazole, isoxazoline or isoxazolidine ring. A process as claimed in claim 8, where R2 is 4 , 5-dihydroisoxazol-3-yl or 4 , 5-dihydroisoxazol-5-yl . A process as claimed in any of claims 1 — 8 for preparing 4-bromo-2- ( 4 , 5-dihydroisoxazol-3-yl ) -3-methylaniline . For the Applicants
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| DE10030975 | 2000-06-30 | ||
| PCT/EP2001/007482 WO2002002537A1 (en) | 2000-06-30 | 2001-06-29 | Method for producing 4-bromine-aniline derivatives |
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| CZ (1) | CZ301413B6 (en) |
| DE (1) | DE50107619D1 (en) |
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| EA (1) | EA006293B1 (en) |
| ES (1) | ES2250425T3 (en) |
| HU (1) | HUP0301741A3 (en) |
| IL (2) | IL153412A0 (en) |
| MX (1) | MXPA02012483A (en) |
| NO (1) | NO324408B1 (en) |
| NZ (1) | NZ523825A (en) |
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| SK (1) | SK285627B6 (en) |
| WO (1) | WO2002002537A1 (en) |
| ZA (1) | ZA200300816B (en) |
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| US8975431B2 (en) * | 2010-05-19 | 2015-03-10 | Rhodia Operations | Process for preparing an ortho-substituted 5-halophenol and a synthesis intermediate thereof |
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| JPS6377844A (en) * | 1986-09-18 | 1988-04-08 | Nippon Kayaku Co Ltd | Production of p-bromoanilines |
| JPH0816085B2 (en) * | 1988-06-07 | 1996-02-21 | 日本化薬株式会社 | Method for producing 2-bromo-4-fluoroaniline |
| IL108630A0 (en) * | 1993-02-18 | 1994-05-30 | Fmc Corp | Insecticidal substituted 2,4-diaminoquinazolines |
| EP0923509A1 (en) * | 1996-08-30 | 1999-06-23 | Aventis Research & Technologies GmbH & Co. KG | Bromination of aromatic compounds with ozone |
| DE59914392D1 (en) * | 1998-05-11 | 2007-08-09 | Basf Ag | PROCESS FOR THE PREPARATION OF ISOXAZOLIN-3-YL-ACYLBENZOLENE |
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