JPH02169579A - Production of anilinopyridazine derivative - Google Patents
Production of anilinopyridazine derivativeInfo
- Publication number
- JPH02169579A JPH02169579A JP32344888A JP32344888A JPH02169579A JP H02169579 A JPH02169579 A JP H02169579A JP 32344888 A JP32344888 A JP 32344888A JP 32344888 A JP32344888 A JP 32344888A JP H02169579 A JPH02169579 A JP H02169579A
- Authority
- JP
- Japan
- Prior art keywords
- acid
- formula
- aniline
- dihalogeno
- lower alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000004519 manufacturing process Methods 0.000 title claims description 11
- RBAQOAYHTJXKRR-UHFFFAOYSA-N n-phenylpyridazin-3-amine Chemical class C=1C=CN=NC=1NC1=CC=CC=C1 RBAQOAYHTJXKRR-UHFFFAOYSA-N 0.000 title description 3
- 239000002253 acid Substances 0.000 claims abstract description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 16
- 125000005843 halogen group Chemical group 0.000 claims abstract description 13
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 11
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 5
- 238000010494 dissociation reaction Methods 0.000 claims abstract description 5
- 230000005593 dissociations Effects 0.000 claims abstract description 5
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 34
- 238000000034 method Methods 0.000 claims description 16
- 150000001448 anilines Chemical class 0.000 claims description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- 125000001931 aliphatic group Chemical group 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- 150000007524 organic acids Chemical class 0.000 claims description 2
- KHIWWQKSHDUIBK-UHFFFAOYSA-N periodic acid Chemical compound OI(=O)(=O)=O KHIWWQKSHDUIBK-UHFFFAOYSA-N 0.000 claims description 2
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims 2
- 239000000126 substance Substances 0.000 claims 2
- 125000003118 aryl group Chemical group 0.000 claims 1
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 abstract description 42
- -1 aniline compound Chemical class 0.000 abstract description 11
- 150000001875 compounds Chemical class 0.000 abstract description 11
- ROYHWGZNGMXQEU-UHFFFAOYSA-N 3,6-dichloro-4-methylpyridazine Chemical compound CC1=CC(Cl)=NN=C1Cl ROYHWGZNGMXQEU-UHFFFAOYSA-N 0.000 abstract description 10
- 239000006227 byproduct Substances 0.000 abstract description 10
- 239000003960 organic solvent Substances 0.000 abstract description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 abstract description 6
- 238000003756 stirring Methods 0.000 abstract description 5
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 abstract description 4
- 239000003905 agrochemical Substances 0.000 abstract description 3
- 229940098779 methanesulfonic acid Drugs 0.000 abstract description 3
- 239000000203 mixture Substances 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 229910052736 halogen Inorganic materials 0.000 abstract 2
- FTZQXOJYPFINKJ-UHFFFAOYSA-N 2-fluoroaniline Chemical compound NC1=CC=CC=C1F FTZQXOJYPFINKJ-UHFFFAOYSA-N 0.000 abstract 1
- 150000002367 halogens Chemical class 0.000 abstract 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 abstract 1
- 239000002904 solvent Substances 0.000 description 18
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 238000004128 high performance liquid chromatography Methods 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 150000007513 acids Chemical class 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 230000000052 comparative effect Effects 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- CZZZABOKJQXEBO-UHFFFAOYSA-N 2,4-dimethylaniline Chemical group CC1=CC=C(N)C(C)=C1 CZZZABOKJQXEBO-UHFFFAOYSA-N 0.000 description 2
- DOLQYFPDPKPQSS-UHFFFAOYSA-N 3,4-dimethylaniline Chemical group CC1=CC=C(N)C=C1C DOLQYFPDPKPQSS-UHFFFAOYSA-N 0.000 description 2
- CXNVOWPRHWWCQR-UHFFFAOYSA-N 4-Chloro-ortho-toluidine Chemical compound CC1=CC(Cl)=CC=C1N CXNVOWPRHWWCQR-UHFFFAOYSA-N 0.000 description 2
- HRXZRAXKKNUKRF-UHFFFAOYSA-N 4-ethylaniline Chemical compound CCC1=CC=C(N)C=C1 HRXZRAXKKNUKRF-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 239000005456 alcohol based solvent Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-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
- 150000004892 pyridazines Chemical class 0.000 description 2
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- JSZOAYXJRCEYSX-UHFFFAOYSA-N 1-nitropropane Chemical compound CCC[N+]([O-])=O JSZOAYXJRCEYSX-UHFFFAOYSA-N 0.000 description 1
- DYSRXWYRUJCNFI-UHFFFAOYSA-N 2,4-dibromoaniline Chemical compound NC1=CC=C(Br)C=C1Br DYSRXWYRUJCNFI-UHFFFAOYSA-N 0.000 description 1
- KQCMTOWTPBNWDB-UHFFFAOYSA-N 2,4-dichloroaniline Chemical compound NC1=CC=C(Cl)C=C1Cl KQCMTOWTPBNWDB-UHFFFAOYSA-N 0.000 description 1
- CEPCPXLLFXPZGW-UHFFFAOYSA-N 2,4-difluoroaniline Chemical compound NC1=CC=C(F)C=C1F CEPCPXLLFXPZGW-UHFFFAOYSA-N 0.000 description 1
- FOYHNROGBXVLLX-UHFFFAOYSA-N 2,6-diethylaniline Chemical compound CCC1=CC=CC(CC)=C1N FOYHNROGBXVLLX-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- IRTONKUCLPTRNS-UHFFFAOYSA-N 2-butoxyaniline Chemical compound CCCCOC1=CC=CC=C1N IRTONKUCLPTRNS-UHFFFAOYSA-N 0.000 description 1
- HDVUPIFFKAHPJY-UHFFFAOYSA-N 2-butylaniline Chemical compound CCCCC1=CC=CC=C1N HDVUPIFFKAHPJY-UHFFFAOYSA-N 0.000 description 1
- XRAKCYJTJGTSMM-UHFFFAOYSA-N 2-chloro-4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1Cl XRAKCYJTJGTSMM-UHFFFAOYSA-N 0.000 description 1
- LNEVUNYUJNORRV-UHFFFAOYSA-N 2-chloro-4-methoxyaniline Chemical compound COC1=CC=C(N)C(Cl)=C1 LNEVUNYUJNORRV-UHFFFAOYSA-N 0.000 description 1
- XGYLSRFSXKAYCR-UHFFFAOYSA-N 2-chloro-4-methylaniline Chemical compound CC1=CC=C(N)C(Cl)=C1 XGYLSRFSXKAYCR-UHFFFAOYSA-N 0.000 description 1
- ZOQDAFBFLFFCMT-UHFFFAOYSA-N 2-chloro-4-phenoxyaniline Chemical compound C1=C(Cl)C(N)=CC=C1OC1=CC=CC=C1 ZOQDAFBFLFFCMT-UHFFFAOYSA-N 0.000 description 1
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- YWUVOJJHVFLNJA-UHFFFAOYSA-N 2-fluoro-4-methoxyaniline Chemical compound COC1=CC=C(N)C(F)=C1 YWUVOJJHVFLNJA-UHFFFAOYSA-N 0.000 description 1
- ZQEXBVHABAJPHJ-UHFFFAOYSA-N 2-fluoro-4-methylaniline Chemical compound CC1=CC=C(N)C(F)=C1 ZQEXBVHABAJPHJ-UHFFFAOYSA-N 0.000 description 1
- YOBANBIDKIFILX-UHFFFAOYSA-N 2-fluoro-4-phenoxyaniline Chemical compound FC1=C(C=CC(=C1)OC1=CC=CC=C1)N YOBANBIDKIFILX-UHFFFAOYSA-N 0.000 description 1
- UBPDKIDWEADHPP-UHFFFAOYSA-N 2-iodoaniline Chemical compound NC1=CC=CC=C1I UBPDKIDWEADHPP-UHFFFAOYSA-N 0.000 description 1
- VUCNAMPOMSVBED-UHFFFAOYSA-N 2-methoxy-4-phenoxyaniline Chemical compound C1=C(N)C(OC)=CC(OC=2C=CC=CC=2)=C1 VUCNAMPOMSVBED-UHFFFAOYSA-N 0.000 description 1
- WYWNLVJBQRJIOU-UHFFFAOYSA-N 2-methyl-4-propan-2-ylaniline Chemical compound CC(C)C1=CC=C(N)C(C)=C1 WYWNLVJBQRJIOU-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- WKURVXXDGMYSDP-UHFFFAOYSA-N 2-propyl-aniline Chemical compound CCCC1=CC=CC=C1N WKURVXXDGMYSDP-UHFFFAOYSA-N 0.000 description 1
- SDYWXFYBZPNOFX-UHFFFAOYSA-N 3,4-dichloroaniline Chemical compound NC1=CC=C(Cl)C(Cl)=C1 SDYWXFYBZPNOFX-UHFFFAOYSA-N 0.000 description 1
- AXNUZKSSQHTNPZ-UHFFFAOYSA-N 3,4-difluoroaniline Chemical compound NC1=CC=C(F)C(F)=C1 AXNUZKSSQHTNPZ-UHFFFAOYSA-N 0.000 description 1
- RQBKJQQWXNALHH-UHFFFAOYSA-N 3,6-dibromo-4-methylpyridazine Chemical compound CC1=CC(Br)=NN=C1Br RQBKJQQWXNALHH-UHFFFAOYSA-N 0.000 description 1
- YKUMFVUOUWBXTB-UHFFFAOYSA-N 3,6-dichloro-4-ethylpyridazine Chemical compound CCC1=CC(Cl)=NN=C1Cl YKUMFVUOUWBXTB-UHFFFAOYSA-N 0.000 description 1
- JRZDBBCBIQEJLA-UHFFFAOYSA-N 3,6-dichloro-4-propan-2-ylpyridazine Chemical compound CC(C)C1=CC(Cl)=NN=C1Cl JRZDBBCBIQEJLA-UHFFFAOYSA-N 0.000 description 1
- ZIZHOYOBASUITD-UHFFFAOYSA-N 3-butoxyaniline Chemical compound CCCCOC1=CC=CC(N)=C1 ZIZHOYOBASUITD-UHFFFAOYSA-N 0.000 description 1
- LVFXXXPXOSABGF-UHFFFAOYSA-N 3-chloro-2-phenoxyaniline Chemical compound NC1=CC=CC(Cl)=C1OC1=CC=CC=C1 LVFXXXPXOSABGF-UHFFFAOYSA-N 0.000 description 1
- YSEMCVGMNUUNRK-UHFFFAOYSA-N 3-chloro-4-fluoroaniline Chemical compound NC1=CC=C(F)C(Cl)=C1 YSEMCVGMNUUNRK-UHFFFAOYSA-N 0.000 description 1
- KFJFBKCMYYAWHI-UHFFFAOYSA-N 3-chloro-4-phenoxyaniline Chemical compound ClC1=CC(N)=CC=C1OC1=CC=CC=C1 KFJFBKCMYYAWHI-UHFFFAOYSA-N 0.000 description 1
- RQKFYFNZSHWXAW-UHFFFAOYSA-N 3-chloro-p-toluidine Chemical compound CC1=CC=C(N)C=C1Cl RQKFYFNZSHWXAW-UHFFFAOYSA-N 0.000 description 1
- RCYMPYMITUEHOJ-UHFFFAOYSA-N 3-fluoro-2-methoxyaniline Chemical compound COC1=C(N)C=CC=C1F RCYMPYMITUEHOJ-UHFFFAOYSA-N 0.000 description 1
- LJWAPDSCYTZUJU-UHFFFAOYSA-N 3-fluoro-4-methoxyaniline Chemical compound COC1=CC=C(N)C=C1F LJWAPDSCYTZUJU-UHFFFAOYSA-N 0.000 description 1
- MGRHBBRSAFPBIN-UHFFFAOYSA-N 3-fluoro-4-methylaniline Chemical compound CC1=CC=C(N)C=C1F MGRHBBRSAFPBIN-UHFFFAOYSA-N 0.000 description 1
- SYUZQKSUMLAOIB-UHFFFAOYSA-N 3-fluoro-4-phenoxyaniline Chemical compound FC1=CC(N)=CC=C1OC1=CC=CC=C1 SYUZQKSUMLAOIB-UHFFFAOYSA-N 0.000 description 1
- MXDRPNGTQDRKQM-UHFFFAOYSA-N 3-methylpyridazine Chemical compound CC1=CC=CN=N1 MXDRPNGTQDRKQM-UHFFFAOYSA-N 0.000 description 1
- IPWGAPCYYMTTLT-UHFFFAOYSA-N 3-propylaniline Chemical compound CCCC1=CC=CC(N)=C1 IPWGAPCYYMTTLT-UHFFFAOYSA-N 0.000 description 1
- MOYMWRBMGUKAQG-UHFFFAOYSA-N 3-tert-butylpyridazine Chemical compound CC(C)(C)C1=CC=CN=N1 MOYMWRBMGUKAQG-UHFFFAOYSA-N 0.000 description 1
- YTISFYMPVILQRL-UHFFFAOYSA-N 4-(4-chlorophenoxy)aniline Chemical compound C1=CC(N)=CC=C1OC1=CC=C(Cl)C=C1 YTISFYMPVILQRL-UHFFFAOYSA-N 0.000 description 1
- VPCGOYHSWIYEMO-UHFFFAOYSA-N 4-(4-methylphenoxy)aniline Chemical compound C1=CC(C)=CC=C1OC1=CC=C(N)C=C1 VPCGOYHSWIYEMO-UHFFFAOYSA-N 0.000 description 1
- LNKBDFVSILQKSI-UHFFFAOYSA-N 4-Chloro-3-methoxyaniline Chemical compound COC1=CC(N)=CC=C1Cl LNKBDFVSILQKSI-UHFFFAOYSA-N 0.000 description 1
- NPDACUSDTOMAMK-UHFFFAOYSA-N 4-Chlorotoluene Chemical compound CC1=CC=C(Cl)C=C1 NPDACUSDTOMAMK-UHFFFAOYSA-N 0.000 description 1
- NJLJXOXRYXXBOF-UHFFFAOYSA-N 4-[(2-methylpropan-2-yl)oxy]aniline Chemical compound CC(C)(C)OC1=CC=C(N)C=C1 NJLJXOXRYXXBOF-UHFFFAOYSA-N 0.000 description 1
- SMLYUHJGJWSUEC-UHFFFAOYSA-N 4-[4-(trifluoromethyl)phenoxy]aniline Chemical compound C1=CC(N)=CC=C1OC1=CC=C(C(F)(F)F)C=C1 SMLYUHJGJWSUEC-UHFFFAOYSA-N 0.000 description 1
- INMZDDDQLHKGPF-UHFFFAOYSA-N 4-bromo-2-chloroaniline Chemical compound NC1=CC=C(Br)C=C1Cl INMZDDDQLHKGPF-UHFFFAOYSA-N 0.000 description 1
- WDFQBORIUYODSI-UHFFFAOYSA-N 4-bromoaniline Chemical compound NC1=CC=C(Br)C=C1 WDFQBORIUYODSI-UHFFFAOYSA-N 0.000 description 1
- UBRIHZOFEJHMIT-UHFFFAOYSA-N 4-butoxyaniline Chemical compound CCCCOC1=CC=C(N)C=C1 UBRIHZOFEJHMIT-UHFFFAOYSA-N 0.000 description 1
- YLMVXQHLRLIVJD-UHFFFAOYSA-N 4-butyl-3,6-dichloropyridazine Chemical compound CCCCC1=CC(Cl)=NN=C1Cl YLMVXQHLRLIVJD-UHFFFAOYSA-N 0.000 description 1
- WOXLPNAOCCIZGP-UHFFFAOYSA-N 4-chloro-2-methoxyaniline Chemical compound COC1=CC(Cl)=CC=C1N WOXLPNAOCCIZGP-UHFFFAOYSA-N 0.000 description 1
- HIHCTGNZNHSZPP-UHFFFAOYSA-N 4-chloro-3-methylaniline Chemical compound CC1=CC(N)=CC=C1Cl HIHCTGNZNHSZPP-UHFFFAOYSA-N 0.000 description 1
- ICXDUPVIBIVMQW-UHFFFAOYSA-N 4-chloro-3-phenoxyaniline Chemical compound NC1=CC=C(Cl)C(OC=2C=CC=CC=2)=C1 ICXDUPVIBIVMQW-UHFFFAOYSA-N 0.000 description 1
- RJWBTWIBUIGANW-UHFFFAOYSA-N 4-chlorobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Cl)C=C1 RJWBTWIBUIGANW-UHFFFAOYSA-N 0.000 description 1
- XXMPNQYDAJKFBU-UHFFFAOYSA-N 4-ethoxy-2-methoxyaniline Chemical compound CCOC1=CC=C(N)C(OC)=C1 XXMPNQYDAJKFBU-UHFFFAOYSA-N 0.000 description 1
- AWFVTWKQFZGFDS-UHFFFAOYSA-N 4-ethyl-2-methylaniline Chemical compound CCC1=CC=C(N)C(C)=C1 AWFVTWKQFZGFDS-UHFFFAOYSA-N 0.000 description 1
- KMHLGVTVACLEJE-UHFFFAOYSA-N 4-fluoro-2-methylaniline Chemical compound CC1=CC(F)=CC=C1N KMHLGVTVACLEJE-UHFFFAOYSA-N 0.000 description 1
- XXXIQAJCXZONOI-UHFFFAOYSA-N 4-fluoro-2-phenoxyaniline Chemical compound NC1=CC=C(F)C=C1OC1=CC=CC=C1 XXXIQAJCXZONOI-UHFFFAOYSA-N 0.000 description 1
- XAACOEWSHBIFGJ-UHFFFAOYSA-N 4-fluoro-3-methoxyaniline Chemical compound COC1=CC(N)=CC=C1F XAACOEWSHBIFGJ-UHFFFAOYSA-N 0.000 description 1
- NYMDPDNETOLVBS-UHFFFAOYSA-N 4-fluoro-3-methylaniline Chemical compound CC1=CC(N)=CC=C1F NYMDPDNETOLVBS-UHFFFAOYSA-N 0.000 description 1
- MJVMMFGDESDAAL-UHFFFAOYSA-N 4-fluoro-3-phenoxyaniline Chemical compound NC1=CC=C(F)C(OC=2C=CC=CC=2)=C1 MJVMMFGDESDAAL-UHFFFAOYSA-N 0.000 description 1
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical compound NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 description 1
- VLVCDUSVTXIWGW-UHFFFAOYSA-N 4-iodoaniline Chemical compound NC1=CC=C(I)C=C1 VLVCDUSVTXIWGW-UHFFFAOYSA-N 0.000 description 1
- WOYZXEVUWXQVNV-UHFFFAOYSA-N 4-phenoxyaniline Chemical compound C1=CC(N)=CC=C1OC1=CC=CC=C1 WOYZXEVUWXQVNV-UHFFFAOYSA-N 0.000 description 1
- DWOIGSLSPPLRKO-UHFFFAOYSA-N 4-propoxyaniline Chemical compound CCCOC1=CC=C(N)C=C1 DWOIGSLSPPLRKO-UHFFFAOYSA-N 0.000 description 1
- OAPDPORYXWQVJE-UHFFFAOYSA-N 4-propylaniline Chemical compound CCCC1=CC=C(N)C=C1 OAPDPORYXWQVJE-UHFFFAOYSA-N 0.000 description 1
- ZPWRNXCIWFCXOL-UHFFFAOYSA-N 4-tert-butyl-2-methylaniline Chemical compound CC1=CC(C(C)(C)C)=CC=C1N ZPWRNXCIWFCXOL-UHFFFAOYSA-N 0.000 description 1
- DTUZXHRABOWYAE-UHFFFAOYSA-N 4-tert-butyl-3,6-dichloropyridazine Chemical compound CC(C)(C)C1=CC(Cl)=NN=C1Cl DTUZXHRABOWYAE-UHFFFAOYSA-N 0.000 description 1
- ODGIMMLDVSWADK-UHFFFAOYSA-N 4-trifluoromethylaniline Chemical compound NC1=CC=C(C(F)(F)F)C=C1 ODGIMMLDVSWADK-UHFFFAOYSA-N 0.000 description 1
- HWTDMFJYBAURQR-UHFFFAOYSA-N 80-82-0 Chemical compound OS(=O)(=O)C1=CC=CC=C1[N+]([O-])=O HWTDMFJYBAURQR-UHFFFAOYSA-N 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 1
- QGJOPFRUJISHPQ-NJFSPNSNSA-N carbon disulfide-14c Chemical compound S=[14C]=S QGJOPFRUJISHPQ-NJFSPNSNSA-N 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000003759 ester based solvent Substances 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000010813 internal standard method Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- SLFVYFOEHHLHDW-UHFFFAOYSA-N n-(trifluoromethyl)aniline Chemical compound FC(F)(F)NC1=CC=CC=C1 SLFVYFOEHHLHDW-UHFFFAOYSA-N 0.000 description 1
- NSBIQPJIWUJBBX-UHFFFAOYSA-N n-methoxyaniline Chemical compound CONC1=CC=CC=C1 NSBIQPJIWUJBBX-UHFFFAOYSA-N 0.000 description 1
- BGUPWXNCOACHRQ-UHFFFAOYSA-N n-propoxyaniline Chemical compound CCCONC1=CC=CC=C1 BGUPWXNCOACHRQ-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- MCSAJNNLRCFZED-UHFFFAOYSA-N nitroethane Chemical compound CC[N+]([O-])=O MCSAJNNLRCFZED-UHFFFAOYSA-N 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
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- RNVCVTLRINQCPJ-UHFFFAOYSA-N o-toluidine Chemical compound CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 1
- LRTFPLFDLJYEKT-UHFFFAOYSA-N para-isopropylaniline Chemical compound CC(C)C1=CC=C(N)C=C1 LRTFPLFDLJYEKT-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- STCOOQWBFONSKY-UHFFFAOYSA-N tributyl phosphate Chemical compound CCCCOP(=O)(OCCCC)OCCCC STCOOQWBFONSKY-UHFFFAOYSA-N 0.000 description 1
- DQWPFSLDHJDLRL-UHFFFAOYSA-N triethyl phosphate Chemical compound CCOP(=O)(OCC)OCC DQWPFSLDHJDLRL-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Abstract
Description
【発明の詳細な説明】 〔産業上の利用分野〕 本発明はピリダジン誘導体の製造方法に関する。[Detailed description of the invention] [Industrial application field] The present invention relates to a method for producing pyridazine derivatives.
さらに詳しくは農薬等の中間体として利用価値の高い6
−アニソツー3−ハロゲノ−4−アルキルピリダジン類
の改良された製造方法を提供するものである。For more details, see 6, which has high utility value as an intermediate for agricultural chemicals, etc.
-An improved method for producing aniso2-3-halogeno-4-alkylpyridazines is provided.
一般式(II)
(式中、Rは低級アルキル基を示し、R1,Hlはそれ
ぞれ独立に水素原子、ハロゲン原子、低級アルキル基、
低級アルコキシ基または置換または無置換のフェノキシ
基を示し、Xはハロゲン原子を示す、)で表される6−
アニソツー3−ハロゲン−4−アルキルピリダジン類は
、農薬の中間体として有用な化合物であり、例えば特開
昭60−185768号または特開昭60−18576
9号によれば式(n)の化合物から誘導される下式(I
)
(式中、R3は水素原子、ハロゲン原子、低級アルキル
基、低級アルコキシ基またはフェノキシ基を示し、nば
1〜5の整数を示し、またR4は低級(ハロ)アルケニ
ル基または低級(ハロ)アルキニル基を示す、)で表さ
れるピリダジン誘導体が除草剤として活性が高いことが
知られている。General formula (II) (wherein R represents a lower alkyl group, R1 and Hl are each independently a hydrogen atom, a halogen atom, a lower alkyl group,
6-, which represents a lower alkoxy group or a substituted or unsubstituted phenoxy group, and X represents a halogen atom)
Aniso2-3-halogen-4-alkylpyridazines are compounds useful as intermediates for agricultural chemicals, and are described, for example, in JP-A-60-185768 or JP-A-60-18576.
According to No. 9, compounds of formula (I) derived from compounds of formula (n)
) (In the formula, R3 represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, or a phenoxy group, n represents an integer of 1 to 5, and R4 represents a lower (halo)alkenyl group or a lower (halo) It is known that pyridazine derivatives represented by ), which represent an alkynyl group, are highly active as herbicides.
ところで、式(II)の6−アニソツー3−ハロゲノ−
4−アルキルピリダジン類(以下AXAPと略記する)
は従来、式(I)
(式中、Rは低級アルキル基を示し、Xはハロゲン原子
を示す、)で表される3、6−ジハロゲノ−4−アルキ
ルピリダジンとアニリン類を縮合させることによって製
造できることが知られている。By the way, 6-aniso-3-halogeno- of formula (II)
4-alkylpyridazines (hereinafter abbreviated as AXAP)
is conventionally produced by condensing 3,6-dihalogeno-4-alkylpyridazine represented by formula (I) (wherein R represents a lower alkyl group and X represents a halogen atom) with aniline. It is known that it can be done.
例えば特開昭58−77866号によれば3,6−ジク
ロロ−4−メチルピリダジンを無溶媒または溶媒中、ア
ニリンと縮合させる方法が開示されており、必要あれば
適当な酸受容体(炭酸ナトリウム、炭酸カリウム、トリ
エチルアミン他)の存在下に実施できるとしている。具
体的には3.6−ジクaロー4−メチルピリダジンのn
−ブタノール溶液中に還流下で等モルのアニリンを滴下
し、さらに1時間加熱還流したのち冷却し、水に排出し
て得られる結晶を濾取し、エタノールから再結晶精製す
ることにより、収率47.3χで6−アニリノ−3−ク
ロロ−4−メチルピリダジンを得ている。For example, JP-A-58-77866 discloses a method of condensing 3,6-dichloro-4-methylpyridazine with aniline without a solvent or in a solvent. , potassium carbonate, triethylamine, etc.). Specifically, n of 3,6-dichlor 4-methylpyridazine
- Equimolar amount of aniline is added dropwise to the butanol solution under reflux, heated under reflux for 1 hour, cooled, drained into water, the resulting crystals are collected by filtration, and recrystallized from ethanol to improve the yield. 6-anilino-3-chloro-4-methylpyridazine was obtained at 47.3χ.
前述したように3.6−ジハロゲノ−4−アルキルピリ
ダジンとアニリン類を溶媒中、直接加熱縮合して式(I
I)のAXAPを製造する方法では、AXAPの収率が
低い。加えて本発明者らの検討に基づけば、3.6−ジ
ハロゲノ−4−アルキルピリダジンとアニリン類との反
応では目的の6−アニリノ−3ハロゲノー4−アルキル
ピリダジンの他に異性体の3−アニリノ−4−アルキル
−6−バロゲノビリタジンならびに3.6−ピスアニリ
ノー4−アルキルピリダジンが多量副生すること、さら
には、これら以外の化合物の副生もあることがわかった
。As mentioned above, 3,6-dihalogeno-4-alkylpyridazine and anilines are directly heated and condensed in a solvent to form the formula (I
In method I) for producing AXAP, the yield of AXAP is low. In addition, based on studies by the present inventors, in the reaction of 3,6-dihalogeno-4-alkylpyridazine with anilines, in addition to the target 6-anilino-3halogeno-4-alkylpyridazine, the isomer 3-anilino-4-alkylpyridazine is produced. It was found that large amounts of -4-alkyl-6-valogenobilitadine and 3,6-pisanilino-4-alkylpyridazine were produced as by-products, and that compounds other than these were also produced as by-products.
因みに本発明者らの追試の結果、3,6−ジクロロ4−
メチルピリダジンとアニリンとをn−ブタノール中還流
下に反応させる方法では、後述の比較例から明らかな様
に、反応液を高速液体クロマトグラフィーにて分析の結
果、3.6−ジクロロ−4−メチルピリダジンの転化率
は90%程度と高いものの、異性体である3−アニリノ
−6−クロロ−4−メチルピリダジンならびに3,6−
ピスアニリノー4−メチルピリダジン、更にはその他側
生物が合計で50%以上副生じ、目的の6−アニソツー
3−クロロ−4〜メチルピリダジンの生成は30%程度
に過ぎないことがわかった。また3、6−ビスアニリノ
体等の副生を抑制すべく反応温度を70〜80°Cに下
げた場合には反応が著しく緩慢になり、反応完結までに
著しく長時間を要し、しかも6−アニリノ休の顕著な収
率向上には至らないことがわかった。Incidentally, as a result of additional tests by the present inventors, 3,6-dichloro4-
In the method of reacting methylpyridazine and aniline under reflux in n-butanol, as is clear from the comparative example described below, as a result of analyzing the reaction solution by high performance liquid chromatography, 3,6-dichloro-4-methyl Although the conversion rate of pyridazine is high at around 90%, the isomers 3-anilino-6-chloro-4-methylpyridazine and 3,6-
It was found that a total of more than 50% of pisanilino-4-methylpyridazine and other side products were formed as by-products, while the production of the desired 6-aniso2-3-chloro-4-methylpyridazine was only about 30%. Furthermore, when the reaction temperature is lowered to 70 to 80°C in order to suppress by-products such as 3,6-bisanilino, the reaction becomes extremely slow and takes an extremely long time to complete. It was found that this method did not result in a significant improvement in the yield of anilino-reactive.
このように3,6−ジハロゲノ−4−アルキルピリダジ
ンとアニリン類を有機溶媒中、直接加熱縮合する公知の
方法は、異性体等の副生が多く、目的化合物であるAX
APの収率が低く、工業的には満足し得る方法とは言い
難い。In this way, the known method of directly heating and condensing 3,6-dihalogeno-4-alkylpyridazine and anilines in an organic solvent produces many by-products such as isomers, and the target compound AX
The yield of AP is low, and it is difficult to say that this method is industrially satisfactory.
前述のような従来技術の現状に鑑み、本発明者らは3.
6−ジハロゲノ−4−アルキルピリダジンとアニリン類
を縮合して一般式(n)で表されるアニリノピリダジン
誘導体を効率良く製造する方法を鋭意検討した。In view of the current state of the prior art as described above, the present inventors have proposed 3.
A method for efficiently producing an anilinopyridazine derivative represented by the general formula (n) by condensing 6-dihalogeno-4-alkylpyridazine and aniline was intensively investigated.
その結果、当該反応を塩酸または硫酸等の酸を予め共存
させた条件下に実施することにより、温和な条件下で円
滑に反応が進行し、しかも3−アニリノ体及び3.6−
ビスアニリノ体の副生が顕著に抑制でき、その結果6−
アニリノ体の選択率ならびに収率の改善につながること
を見出した。As a result, by carrying out the reaction in the presence of an acid such as hydrochloric acid or sulfuric acid in advance, the reaction proceeds smoothly under mild conditions, and moreover, it is possible to proceed smoothly with the 3-anilino form and the 3.6-
The by-product of bisanilinino bodies can be significantly suppressed, and as a result, 6-
It has been found that this leads to improvements in the selectivity and yield of the anilino compound.
例えば等モル量の3,6−ジクロル−4−メチルピリダ
ジンとアニリンとをn−ブタノール中、0.1モル比の
塩酸存在下に反応を行ったところ、反応は75°Cで円
滑に進行し6−アニリノ体の収率が65%程度に向上す
ることがわかった。For example, when equimolar amounts of 3,6-dichloro-4-methylpyridazine and aniline were reacted in n-butanol in the presence of hydrochloric acid at a molar ratio of 0.1, the reaction proceeded smoothly at 75°C. It was found that the yield of 6-anilino compound was improved to about 65%.
本発明はこのような知見にもとづいて成されたものであ
る。即ち本発明は式(I)
(式中、Rは低級アルキル基を示し、Xはハロゲン原子
を示す、)で表される3、6−ジハロゲノ−4アルキル
ピリダジンとアニリン類を反応させて式(式中、Rおよ
びXは式(I)のそれと同じ意味を示し、またR1およ
びR2はそれぞれ独立に水素原子、ハロゲン原子、低級
アルキル基、低級アルコキシ基、或いは置換または無宜
換のフェノキシ基を示す、)で表されるアニリノピリダ
ジン誘導体の製造方法において、当該反応を酸の存在下
に行うことを特徴とする式(H)で表されるアニリノピ
リダジン誘導体の製造方法である。The present invention has been made based on this knowledge. That is, the present invention provides compounds of the formula (I) (wherein R represents a lower alkyl group and X represents a halogen atom) by reacting 3,6-dihalogeno-4 alkylpyridazine with anilines. In the formula, R and X have the same meaning as in formula (I), and R1 and R2 each independently represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, or a substituted or unsubstituted phenoxy group. The method for producing an anilinopyridazine derivative represented by formula (H) is characterized in that the reaction is carried out in the presence of an acid.
3.6−シハロゲノビリダジン化合物とアニリン類を酸
の存在下に反応させる方法は、従来全く知られておらず
、新規な方法である。The method of reacting a 3.6-cyhalogenoviridazine compound and aniline in the presence of an acid has not been previously known and is a novel method.
本発明で使用される式(I)の3.6−ジハロゲノ−4
−アルキルピリダジンとしては、具体的には36−ジク
ロロ−4−メチルピリダジン、3.6−ジブロム4−メ
チルピリダジン、3,6−ジクロロ−4−エチルピリダ
ジン、3.6−ジプロムー4−エチルピリダジン、3.
6−ジクロロ−4−ロープロピルピリダジン、3.6−
ジプロムー4−n−プロピルピリダジン、3.6−ジク
ロロ4−iso−プロピルピリダジン、36−ジプロム
ー4−iSO−プロピルピリダジン、3,6−ジクロロ
−4−n−ブチルピリダジン、3.6−ジプロムー4−
tert−ブチルピリダジン、3.6−ジプロムー4−
tert−ブチルピリダジンなどを挙げることができる
。3,6-dihalogeno-4 of formula (I) used in the present invention
-Alkylpyridazine specifically includes 36-dichloro-4-methylpyridazine, 3,6-dibromo-4-methylpyridazine, 3,6-dichloro-4-ethylpyridazine, 3,6-dipromo-4-ethylpyridazine, 3.
6-dichloro-4-lopropylpyridazine, 3.6-
Dipromo-4-n-propylpyridazine, 3,6-dichloro-4-iso-propylpyridazine, 36-dipromo-4-iSO-propylpyridazine, 3,6-dichloro-4-n-butylpyridazine, 3.6-dipromo-4-
tert-butylpyridazine, 3,6-dipromo-4-
Examples include tert-butylpyridazine.
本発明で使用されるアニリン類としては具体的には、ア
ニリン、0−フルオロアニリン、トヨ−ドアニリン、P
−フルオロアニリン、0−クロロアニリン、トヨ−ドア
ニリン、ρ−クロロアニリン、0−ブロモアニリン、m
−プルモアニリン、p−ブロモアニリン、0−ヨードア
ニリン、トヨ−ドアニリン、p−ヨードアニリン、o−
トルイジン、横−トルイジン、ρ−トルイジン、d−ト
リフルオロメチルアニリン、トドリフルオロメチルアニ
リン、p−トリフルオロメチルアニリン、0−エチルア
ニリン、トヨ−ドアニリン、p−エチルアニリン、o−
n−プロピルアニリン、m−n−プロピルアニリン、p
−n−プロピルアニリン、0−イソプロピルアニリン、
トイソブロビルアニリン、p−イソプロピルアニリン、
o−n−ブチルアニリン、m−n−フチルアニリン、ρ
−n−ブチルアニリン、〇−第第三ジプチルアニリント
第三級ブチルアニリン、ρ−第第三ジプチルアニリン0
−アニシジン、p−アニシジン、0−フェネチジン、ト
フェネチジン、ρ−フェネチジン、o−n−プロポキシ
アニリン、Inプロポキシアニリン、p−n−プロポキ
シアニリン、0−インプロポキシアニリン、トイソプロ
ボキシアニリン、p−インプロポキシアニリン、o−n
−ブトキシアニリン、m−n−ブトキシアニリン、・p
−n−ブトキシアニリン、〇−−三級ブトキシアニリン
、訃第三級ブトキシアニリン、p−第三級ブトキシアニ
リン、0−フェノキシアニリン、−フェノキシアニリン
、p−フェノキシアニリン、p−(4−クロロフェノキ
シ)アニリン、p−(4−メチルフェノキシ)アニリン
、p−(4−トリフルオロメチルフェノキシ)アニリン
、ト(2−クロロ−4−トリフルオロメチルフェノキシ
)アニリン、2.4−ジフルオロアニリン、2.6−ジ
フルオロアニリン、3,4−ジフルオロアニリン、3.
5−ジフルオロアニリン、2.4−ジクロロアニリン、
2.6−ジクロロアニリン、3.4−ジクロロアニリン
、3.5−ジクロロアニリン、2.4−ジブロモアニリ
ン、2.6−ジブロモアニリン、3.4−ジブロモアニ
リン、3.5−ジブロモアニリン、2.4−ジエチルア
ニリン、3.4シヨートアニリン、3.5−ジエチルア
ニリン、4−ブロモ−2−クロロアニリン、2−クロロ
−4−フルオロアニリン、3−クロロ−4−フルオロア
ニリン、2,4−キシリジン、2.6−キシリジン、3
,4−キシリジン、3.5−キシリジン、2.4−ジエ
チルアニリン、2.6−ジエチルアニリン、4−エチル
−2−メチルアニリン、4−イソプロピル−2−メチル
アニリン、4−第三級ブチル−2−メチルアニリン、2
.4−ジメトキシアニリン、2.6−ジメトキシアニリ
ン、3.4−ジメトキシアニリン、3.5−ジメトキシ
アニリン、2,4−ジェトキシアニリン、2,6−ジェ
トキシアニリン、4−エトキシ−2−メトキシアニリン
、4−インプロポキシ−2メトキシアニリン、4−第三
級ブトキシ−2−メトキシアニリン、2−メトキシ−4
−フェノキシアニリン、4−フルオロ−2−メチルアニ
リン、4−フルオロ−3−メチルアニリン、2−フルオ
ロ−4−メチルアニリン、3−フルオロ−4−メチルア
ニリン、3−フルオロ−2−メトキシアニリン、4−フ
ルオロ−3−メトキシアニリン、2−フルオロ−4−メ
トキシアニリン、3−フルオロ−4−メトキシアニリン
、4−フルオロ−2−フェノキシアニリン、4−フルオ
ロ−3−フェノキシアニリン、2−フルオロ−4−フェ
ノキシアニリン、3−フルオロ−4−フェノキシアニリ
ン、4−クロロ−2−メチルアニリン、4−クロロ−3
−メチルアニリン、2−クロロ−4−メチルアニリン、
3−クロロ−4−メチルアニリン、4−クロロ−2−メ
トキシアニリン、4−クロロ−3−メトキシアニリン、
2−クロロ−4−メトキシアニリン、3−クロロ−4−
メトキシアニリン、3−クロロ−2−フェノキシアニリ
ン、4−クロロ−3−フェノキシアニリン、2−クロロ
−4−フェノキシアニリン、3−クロロ−4−フェノキ
シアニリン等を挙げることができる。Specifically, the anilines used in the present invention include aniline, 0-fluoroaniline, toiodoaniline, P
-Fluoroaniline, 0-chloroaniline, toiodoaniline, ρ-chloroaniline, 0-bromoaniline, m
-Pulmoaniline, p-bromoaniline, o-iodoaniline, toiodoaniline, p-iodoaniline, o-
Toluidine, lateral-toluidine, ρ-toluidine, d-trifluoromethylaniline, trifluoromethylaniline, p-trifluoromethylaniline, 0-ethylaniline, toiodoaniline, p-ethylaniline, o-
n-propylaniline, m-n-propylaniline, p
-n-propylaniline, 0-isopropylaniline,
Toisobrobylaniline, p-isopropylaniline,
o-n-butylaniline, m-n-phthylaniline, ρ
-n-Butylaniline, 〇-Tertiary diptylaniline, ρ-Tertiary diptylaniline 0
- Anisidine, p-anisidine, 0-phenetidine, tophenetidine, ρ-phenetidine, on-propoxyaniline, In-propoxyaniline, p-n-propoxyaniline, 0-inpropoxyaniline, toisoproboxyaniline, p-in Propoxyaniline, o-n
-butoxyaniline, m-n-butoxyaniline, ・p
-n-butoxyaniline, 〇--tert-butoxyaniline, tertiary-butoxyaniline, p-tert-butoxyaniline, 0-phenoxyaniline, -phenoxyaniline, p-phenoxyaniline, p-(4-chlorophenoxy ) Aniline, p-(4-methylphenoxy)aniline, p-(4-trifluoromethylphenoxy)aniline, tho(2-chloro-4-trifluoromethylphenoxy)aniline, 2.4-difluoroaniline, 2.6 -difluoroaniline, 3,4-difluoroaniline, 3.
5-difluoroaniline, 2,4-dichloroaniline,
2.6-dichloroaniline, 3.4-dichloroaniline, 3.5-dichloroaniline, 2.4-dibromoaniline, 2.6-dibromoaniline, 3.4-dibromoaniline, 3.5-dibromoaniline, 2 .4-diethylaniline, 3.4-shotoaniline, 3.5-diethylaniline, 4-bromo-2-chloroaniline, 2-chloro-4-fluoroaniline, 3-chloro-4-fluoroaniline, 2,4 -xylidine, 2.6-xylidine, 3
, 4-xylidine, 3.5-xylidine, 2.4-diethylaniline, 2.6-diethylaniline, 4-ethyl-2-methylaniline, 4-isopropyl-2-methylaniline, 4-tert-butyl- 2-methylaniline, 2
.. 4-dimethoxyaniline, 2.6-dimethoxyaniline, 3.4-dimethoxyaniline, 3.5-dimethoxyaniline, 2,4-jethoxyaniline, 2,6-jethoxyaniline, 4-ethoxy-2-methoxyaniline , 4-inpropoxy-2-methoxyaniline, 4-tert-butoxy-2-methoxyaniline, 2-methoxy-4
-Phenoxyaniline, 4-fluoro-2-methylaniline, 4-fluoro-3-methylaniline, 2-fluoro-4-methylaniline, 3-fluoro-4-methylaniline, 3-fluoro-2-methoxyaniline, 4 -Fluoro-3-methoxyaniline, 2-fluoro-4-methoxyaniline, 3-fluoro-4-methoxyaniline, 4-fluoro-2-phenoxyaniline, 4-fluoro-3-phenoxyaniline, 2-fluoro-4- Phenoxyaniline, 3-fluoro-4-phenoxyaniline, 4-chloro-2-methylaniline, 4-chloro-3
-methylaniline, 2-chloro-4-methylaniline,
3-chloro-4-methylaniline, 4-chloro-2-methoxyaniline, 4-chloro-3-methoxyaniline,
2-chloro-4-methoxyaniline, 3-chloro-4-
Examples include methoxyaniline, 3-chloro-2-phenoxyaniline, 4-chloro-3-phenoxyaniline, 2-chloro-4-phenoxyaniline, and 3-chloro-4-phenoxyaniline.
本発明の方法は弐(+)の3.6−ジハロゲノ−4−ア
ルキルピリダジンとアニリン類を無溶媒下に反応させる
ことも可能であるが、通常は有機溶媒の中、或いは有機
溶媒と水との混合溶媒中で実施される。使用される有機
溶媒としては、反応に不活性な溶媒であれば特に限定さ
れるものではない。Although it is possible to react the 2(+) 3,6-dihalogeno-4-alkylpyridazine and aniline without a solvent in the method of the present invention, it is usually carried out in an organic solvent or in combination with an organic solvent and water. carried out in a mixed solvent of The organic solvent used is not particularly limited as long as it is inert to the reaction.
具体的には、n−ヘキサン、n−へブタン、ベンゼン、
トルエン、キシレンまたはエチルベンゼン等の炭化水素
系溶媒、クロルベンゼン、0−ジクロルベンゼン、トル
エン、0−クロルトルエンまたはpクロルトルエン等の
芳香族炭化水素系溶媒、メタノール、エタノール、n−
プロパツール、イソプロパツール、n−ブタノール、イ
ソブタノール、第二級ブタノール、第三級ブタノール、
ペンタノールまたはヘプタツール等のアルコール系溶媒
、ジイソプロピルエーテル、ジオキサンまたはテトラヒ
ドロフラン等のエーテル系溶媒、酢酸エチルまたは酢酸
ブチル等のエステル系溶媒、エチレングリコール、エチ
レングリコールモノメチルエーテル、エチレングリコー
ルモノエチルエーテル、エチレングリコールジエチルエ
ーテル、ジエチレングリコール、プロピレングリコール
またはグリセリン等の多価アルコール系溶媒、酢酸また
はプロピオン酸等のカルボン酸系溶媒、ニトロメタン、
ニトロエタン、ニトロプロパン、ニトロベンゼン、ホル
ムアミド、N、N−ジメチルホルムアミド、アセトニト
リル、ピリジン、ピコリン、キノリン、Nメチルピロリ
ドンまたはN、N”−ジメチルイミダゾリジノン等の含
窒素系溶媒、二硫化炭素、ジメチルスルホキシド、リン
酸トリエチルまたはリン酸トリブチル等の含イオウまた
は含リン系溶媒など広範囲の溶媒を挙げることができる
。勿論ここに具体的に例示した溶媒は一例であり、本発
明の方法に使用される溶媒がこれらに限定されるもので
はないことは明らかである。またこれらの有機熔媒は通
常は単独で用いられるが、2種類以上の溶媒を併用する
ことも何ら問題はない。Specifically, n-hexane, n-hebutane, benzene,
Hydrocarbon solvents such as toluene, xylene or ethylbenzene, aromatic hydrocarbon solvents such as chlorobenzene, 0-dichlorobenzene, toluene, 0-chlorotoluene or p-chlorotoluene, methanol, ethanol, n-
Proper tool, isoproper tool, n-butanol, isobutanol, secondary butanol, tertiary butanol,
Alcohol solvents such as pentanol or heptatool, ether solvents such as diisopropyl ether, dioxane or tetrahydrofuran, ester solvents such as ethyl acetate or butyl acetate, ethylene glycol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol Polyhydric alcohol solvents such as diethyl ether, diethylene glycol, propylene glycol or glycerin, carboxylic acid solvents such as acetic acid or propionic acid, nitromethane,
Nitrogen-containing solvents such as nitroethane, nitropropane, nitrobenzene, formamide, N,N-dimethylformamide, acetonitrile, pyridine, picoline, quinoline, N-methylpyrrolidone or N,N''-dimethylimidazolidinone, carbon disulfide, dimethylsulfoxide A wide range of solvents can be mentioned, such as sulfur-containing or phosphorus-containing solvents such as triethyl phosphate or tributyl phosphate.Of course, the solvents specifically illustrated here are just examples, and the solvents used in the method of the present invention It is clear that the organic solvents are not limited to these.Although these organic solvents are usually used alone, there is no problem in using two or more solvents in combination.
溶媒を使用する場合においてその使用量は特に限定され
るものではないが、反応の容積効率等を考慮して通常は
原料の3,6−ジハロ・ゲラ−4−アルキルピリダジン
とアニリン類の合計量に対して20重量倍以下が好まし
い。When using a solvent, the amount used is not particularly limited, but in consideration of the volumetric efficiency of the reaction, etc., it is usually the total amount of the raw materials 3,6-dihalo Geller-4-alkylpyridazine and anilines. It is preferably 20 times or less by weight.
本発明の方法において、一方の原料であるアニリン類は
、あまり過剰に用いると3.6−ジハロゲノ−4−アル
キルピリダジンの3位ならびに6位のハロゲン原子がア
ニリン類と置換した3、6−ビスアニリノ体の副生が増
加し、目的化合物のAχAPの収率の低下につながるこ
とから、その使用量は式%式%
に対して1.5モル比以下、好ましくは1.2モル比以
下が良い、使用量の下限については特に制限はないが、
経済的見地より3,6−ジハロゲノ−4−アルキルピリ
ダジンに対して0,8モル比以上で使用するのが良い。In the method of the present invention, if one of the raw materials, aniline, is used in excess, 3,6-bisanilino may be substituted with anilines in the 3- and 6-position halogen atoms of 3,6-dihalogeno-4-alkylpyridazine. Since this increases by-products in the body and leads to a decrease in the yield of the target compound AχAP, the amount used should be at most 1.5 molar ratio, preferably at most 1.2 molar ratio with respect to formula%. , there is no particular restriction on the lower limit of usage, but
From an economic standpoint, it is preferable to use it in a molar ratio of 0.8 or more to 3,6-dihalogeno-4-alkylpyridazine.
通常はほぼ等モル量の3,6−ジハロゲノ−4−アルキ
ルピリダジンとアニリン類が使用される。Generally, approximately equimolar amounts of 3,6-dihalogeno-4-alkylpyridazine and aniline are used.
本発明は3,6−ジハロゲノ−4−アルキルピリダジン
とアニリン類との反応を酸の存在下に行うことによりA
XMPの収率向上を達成するものである。In the present invention, A
This achieves an improvement in the yield of XMP.
使用される酸としては25°Cにおける解離定数がPK
値で2.2より小さい無機または有機の酸が好ましい。The acid used has a dissociation constant of PK at 25°C.
Inorganic or organic acids with a value of less than 2.2 are preferred.
解離定数がPK値で2.2より大きい酸、例えば、酢酸
のような弱酸の存在下での反応では本発明の目的を達成
するには至らない。A reaction in the presence of an acid with a dissociation constant greater than 2.2 in terms of PK value, for example a weak acid such as acetic acid, will not achieve the object of the present invention.
本発明で使用される酸を具体的に例示すれば、塩化水素
(または塩酸)、硫酸、臭化水素酸、沃化水素酸、過塩
素酸、過沃素酸またはリン酸などの無機酸、またはメタ
ンスルホン酸、トリフルオロメタンスルホン酸、ベンゼ
ンスルホンM、p4ルエンスルホン酸、p−クロルベン
ゼンスルホン酸、0−二トロベンゼンスルホン酸、p−
二トロベンゼンスルホン酸またはナフタレンスルホン酸
などの脂肪族または芳香族のスルホン酸類、或いはトリ
フルオロ酢酸またはトリクロロ酢酸などの脂肪酸類など
を挙げることができる。Specific examples of acids used in the present invention include inorganic acids such as hydrogen chloride (or hydrochloric acid), sulfuric acid, hydrobromic acid, hydriodic acid, perchloric acid, periodic acid, or phosphoric acid; Methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfone M, p4 luenesulfonic acid, p-chlorobenzenesulfonic acid, 0-nitrobenzenesulfonic acid, p-
Examples include aliphatic or aromatic sulfonic acids such as nitrobenzenesulfonic acid or naphthalenesulfonic acid, or fatty acids such as trifluoroacetic acid or trichloroacetic acid.
勿論、前述の条件、即ち解離定数でPK値2.2より小
さい酸で条件を満たせば、ここに例示した酸に限定され
るものではない。これらの酸は通常は単独で用いられる
が、2種以上の酸を併用することも可能である。Of course, the above-mentioned conditions are not limited to the acids exemplified here, as long as the conditions are satisfied with an acid having a dissociation constant and PK value of less than 2.2. These acids are usually used alone, but it is also possible to use two or more kinds of acids in combination.
酸の使用量は、あまり少なすぎても本願発明の目的を達
成することはできず、また多量使用すると前述の副反応
以外の副反応を誘起し易くなり、その為、弐N)の3.
6−ジハロゲノ−4−アルキルピリダジンに対して0.
01乃至2モル比、好ましくは0.02乃至1モル比の
範囲が良く、これにより本発明の目的が達成される。If the amount of acid used is too small, the object of the present invention cannot be achieved, and if too large is used, side reactions other than those mentioned above are likely to be induced.
0.0 for 6-dihalogeno-4-alkylpyridazine.
The molar ratio ranges from 0.01 to 2, preferably from 0.02 to 1, which achieves the object of the present invention.
本発明で使用される酸は3.6−シハロゲノビリダジン
とアニリン類との反応の初期、好ましくは予め添加して
おくのが良い。The acid used in the present invention is preferably added at the beginning of the reaction between 3,6-cyhalogenoviridazine and aniline, preferably in advance.
本発明において原料、酸ならびに溶媒の装入順序は特に
限定されるものではない。具体的実施態様の一例を示せ
ば以下の通りである。In the present invention, the order of charging raw materials, acids, and solvents is not particularly limited. An example of a specific embodiment is as follows.
3.6−ジハロゲノ−4−アルキルピリダジン、酸なら
びに溶媒を装入したのちさらにアニリン類を一括または
滴下装入し、攪拌下に昇温し反応させる。After charging 3.6-dihalogeno-4-alkylpyridazine, an acid, and a solvent, aniline is added either all at once or dropwise, and the mixture is heated and reacted with stirring.
反応温度は50°C以上、溶媒の沸点以下、好ましくは
100 ’C以下がよい0反応の終点は薄層クロマトグ
ラフィーまたは高速液体クロマトグラフィー等の手段を
用いて容易に知ることができる。The reaction temperature is preferably 50° C. or above and below the boiling point of the solvent, preferably 100° C. or below. The end point of the reaction can be easily determined by means such as thin layer chromatography or high performance liquid chromatography.
以下実施例により本発明の詳細な説明する。尚、実施例
中の高速液体クロマトグラフィー(内部標準法)での分
析条件は以下の通りである。The present invention will be explained in detail below with reference to Examples. The analysis conditions for high performance liquid chromatography (internal standard method) in Examples are as follows.
〈高速液体クロマトグラフィー分析条件〉実施例1
100d4ツロフラスコに3.6−ジクロロ−4−メチ
ルピリダジン16.3g (0,1モル)、n−ブタノ
−−ル53−及び濃塩酸1.0g (0,01モル)を
装入し、攪拌下、に50’Cに昇温、溶解した。この?
8液にアニリン9゜3g(0,1モル)を滴下装入した
のち75°Cに昇温し、同温度で8時間反応させた0反
応後室温まで冷却したのち、高速液体クロマトグラフィ
ーにて分析の結果、反応成績は以下の通りであった。<High performance liquid chromatography analysis conditions> Example 1 16.3 g (0.1 mol) of 3,6-dichloro-4-methylpyridazine, 53-n-butanol, and 1.0 g (0.1 mol) of concentrated hydrochloric acid were placed in a 100 d4 flask. , 01 mol) was charged, and the temperature was raised to 50'C while stirring to dissolve. this?
9.3 g (0.1 mol) of aniline was added dropwise to liquid 8, the temperature was raised to 75°C, and the reaction was carried out at the same temperature for 8 hours. As a result of the analysis, the reaction results were as follows.
を1時間かけて滴下した。その後さらに1時間還流下に
反応させた。得られた反応液を高速液体クロマトグラフ
ィーにて分析の結果、反応成績は以下の通りであった。was added dropwise over 1 hour. Thereafter, the reaction was continued under reflux for an additional hour. The obtained reaction solution was analyzed by high performance liquid chromatography, and the reaction results were as follows.
次に反応液を減圧下で溶媒の大部分を留去したのち、水
30Od中に排出し、析出した結晶を濾過、水洗後、さ
らにエタノールから再結晶することにより白色の6−ア
ニソツー3−クロロ−4−メチルピリダジン12.8g
を得た。 収率58.3χ(対3,6−ジクロ#−メチ
ルピリダジン)融点;175.5〜176.5°C比較
例1 (特開昭58−77866号の合成例の方法)1
00d4ツロフラスコに3.6−ジクロロ−4−メチル
ピリダジン16.3g (0,1モル)とn−ブタノー
ル50dを装入し、加熱還流下にアニリン9.3g(0
,1モル)比較例2
実施例1において塩酸の添加を行わず、その他は実施例
1と同様に行った結果、反応成績は以下の通りであった
。Next, most of the solvent was distilled off from the reaction solution under reduced pressure, and then it was discharged into 30 Od of water. -4-methylpyridazine 12.8g
I got it. Yield 58.3χ (vs. 3,6-dichloro#-methylpyridazine) Melting point: 175.5-176.5°C Comparative Example 1 (Method of Synthesis Example in JP-A-58-77866) 1
00d4 A Tulo flask was charged with 16.3 g (0.1 mol) of 3,6-dichloro-4-methylpyridazine and 50 d of n-butanol, and 9.3 g (0.0 mol) of aniline was charged under heating under reflux.
, 1 mol) Comparative Example 2 The reaction was carried out in the same manner as in Example 1 except that no hydrochloric acid was added, and the reaction results were as follows.
実施例2〜8、比較例3
実施例1において酸の種類および使用量、ならびに反応
温度、時間を変えて3.6−ジクロロ−4−メチルピリ
ダジンとアニリンとの反応を行った結果を表−1に示す
。Examples 2 to 8, Comparative Example 3 Table 1 shows the results of reacting 3,6-dichloro-4-methylpyridazine with aniline by changing the type and amount of acid used, reaction temperature, and time in Example 1. Shown in 1.
(以下余白)
実施例9
100d4ツロフラスコに3.6−ジクロロ−4−メチ
ルピリダジン16.3g (0,1モル)、アニリン1
0.2g(0,11モル)、エタノール60.dおよび
P−)ルエンスルホン酸−水和物1.9g (0,01
モル)を装入し、撹拌下に80°Cに昇温した。その後
同温度で7時間反応させたのち室温まで冷却した後、反
応液を分取し高速液体クロマトグラフィーにて分析した
結果、3.6−ジクロロ−4−メチルピリダジンの転化
率は98.7χであり、6−アニソツー3−クロロ−4
−メチルピリダジンの収率は68.5χ(対3.6−ジ
クロロー4メチルピリダジン)であった。(Left below) Example 9 16.3 g (0.1 mol) of 3,6-dichloro-4-methylpyridazine, 1 aniline in a 100 d4 flask
0.2 g (0.11 mol), ethanol 60. d and P-) luenesulfonic acid hydrate 1.9 g (0,01
mol) and the temperature was raised to 80°C while stirring. After that, the reaction was allowed to proceed at the same temperature for 7 hours, and after cooling to room temperature, the reaction solution was separated and analyzed by high performance liquid chromatography. As a result, the conversion rate of 3.6-dichloro-4-methylpyridazine was 98.7χ. Yes, 6-aniso2-3-chloro-4
The yield of -methylpyridazine was 68.5x (vs. 3,6-dichloro-4-methylpyridazine).
実施例10
100d4ツロフラスコに3.6−ジプロムー4−メチ
ルピリダジン19.2g (0,1モル)、アニリン9
.3g(0,1モル)、n−ブタノール50dおよびメ
タンスルホン酸0.96g(0,01モル)を装入し、
攪拌下に70゛cに昇温し、同温度で4時間反応させた
。その後、室温まで冷却し、反応液を一部採取し高速液
体クロマトグラフィーにて分析の結果、6−アニソツー
3−ブロム−4−メチルピリダジンの収率は69,2χ
(対3.6−ジプロムー4−メチルピリダジン)であっ
た。Example 10 19.2 g (0.1 mol) of 3,6-dipromo-4-methylpyridazine, 9 aniline in a 100d4 Turow flask
.. 3 g (0.1 mol), 50 d of n-butanol and 0.96 g (0.01 mol) of methanesulfonic acid,
The temperature was raised to 70°C while stirring, and the reaction was continued at the same temperature for 4 hours. After that, it was cooled to room temperature, and a portion of the reaction solution was collected and analyzed by high-performance liquid chromatography. As a result, the yield of 6-aniso2-3-bromo-4-methylpyridazine was 69.2χ
(vs. 3,6-dipromo-4-methylpyridazine).
実施例11
実施例1において3.6−ジクロロ−4−メチルピリダ
ジンの代わりに3.6−ジクロロ−4−第三級プチルピ
リダジン20.5gを用いる他は実施例1と同様に反応
を行い、反応液を高速液体クロマトグラフィーにて分析
の結果、収率73.8χの収率で6−アニソツー3−ク
ロロ−4−ブチルピリダジンが生成した。Example 11 The reaction was carried out in the same manner as in Example 1, except that 20.5 g of 3,6-dichloro-4-tertiary butylpyridazine was used instead of 3,6-dichloro-4-methylpyridazine. As a result of analyzing the reaction solution by high performance liquid chromatography, 6-aniso2-3-chloro-4-butylpyridazine was produced at a yield of 73.8χ.
実施例12〜16
実施例1においてアニリンの代わりに種々の置換アニリ
ンの0.1モルを用いる他は実施例1と同様に反応を行
った。結果を表−2に示す。Examples 12 to 16 Reactions were carried out in the same manner as in Example 1, except that 0.1 mol of various substituted anilines was used instead of aniline. The results are shown in Table-2.
(以下余白)
〔発明の効果〕
本発明の方法によれば3.6−ジハロゲノ−4−アルキ
ルピリダジンとアニリン類との反応が温和な条件下に円
滑に進行するだけでなく、従来の方法に比較して異性体
等の副生成物の抑制が可能である。(Left below) [Effects of the Invention] According to the method of the present invention, the reaction between 3,6-dihalogeno-4-alkylpyridazine and anilines not only proceeds smoothly under mild conditions, but also improves the efficiency of conventional methods. In comparison, by-products such as isomers can be suppressed.
それ故、目的とする6−アニリンピリダジン誘導体の収
率の向上につながるもので、工業的にも意義の高い6−
アリニノビリダジン誘導体の製造方法である。Therefore, it leads to an improvement in the yield of the target 6-aniline pyridazine derivative, and is of great industrial significance.
This is a method for producing an alininoviridazine derivative.
特許出願人 三井東圧化学株式会社Patent applicant: Mitsui Toatsu Chemical Co., Ltd.
Claims (1)
を示す。) で表される3,6−ジハロゲノ−4−ピリダジンとアニ
リン類を反応させて式(II) ▲数式、化学式、表等があります▼(II) (式中、Rは低級アルキル基を示し、Xはハロゲン原子
を示し、R^1およびR^2はそれぞれ独立に水素原子
、ハロゲン原子、低級アルキル基、低級アルコキシ基ま
たはフェノキシ基を示す。)で表される6−アニリノ−
3−ハロゲノ−4−低級アルキルピリダジン類を製造す
る方法において、当該反応を酸の存在下に行うことを特
徴とする式(II)の6−アニリノ−3−ハロゲノ−4−
低級アルキルピリダジン類の製造方法。 2、酸が25℃における解離定数でPK値2.2より小
さい無機または有機の酸である請求項1記載の製造方法
。 3、酸が塩化水素(または塩酸)、硫酸、臭化水素酸、
沃化水素酸、過塩素酸、過沃素酸またはリン酸から選ば
れる無機酸である請求項1記載の製造方法。 4、酸が脂肪族スルホン酸または芳香族スルホン酸であ
る請求項1記載の製造方法。 5、酸がトリフルオロ酢酸またはトリクロロ酢酸である
請求項1記載の製造方法。 6、酸の使用量が式( I )の3,6−ジハロゲノ−4
−低級アルキルピリダジン1モルに対して0.01乃至
2モル比の範囲である請求項1記載の製造方法。[Claims] 1. Formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R represents a lower alkyl group and X represents a halogen atom.) 3 , 6-dihalogeno-4-pyridazine and anilines are reacted to form the formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, R represents a lower alkyl group and X represents a halogen atom. , R^1 and R^2 each independently represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a phenoxy group.) 6-anilino-
6-anilino-3-halogeno-4- of formula (II) in a method for producing 3-halogeno-4-lower alkylpyridazines, characterized in that the reaction is carried out in the presence of an acid.
A method for producing lower alkylpyridazines. 2. The manufacturing method according to claim 1, wherein the acid is an inorganic or organic acid having a dissociation constant at 25° C. and a PK value of less than 2.2. 3. The acid is hydrogen chloride (or hydrochloric acid), sulfuric acid, hydrobromic acid,
2. The method according to claim 1, wherein the inorganic acid is selected from hydriodic acid, perchloric acid, periodic acid, or phosphoric acid. 4. The manufacturing method according to claim 1, wherein the acid is an aliphatic sulfonic acid or an aromatic sulfonic acid. 5. The manufacturing method according to claim 1, wherein the acid is trifluoroacetic acid or trichloroacetic acid. 6. The amount of acid used is 3,6-dihalogeno-4 of formula (I)
- The method according to claim 1, wherein the molar ratio is in the range of 0.01 to 2 per mole of lower alkylpyridazine.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP32344888A JPH02169579A (en) | 1988-12-23 | 1988-12-23 | Production of anilinopyridazine derivative |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP32344888A JPH02169579A (en) | 1988-12-23 | 1988-12-23 | Production of anilinopyridazine derivative |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH02169579A true JPH02169579A (en) | 1990-06-29 |
Family
ID=18154781
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP32344888A Pending JPH02169579A (en) | 1988-12-23 | 1988-12-23 | Production of anilinopyridazine derivative |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH02169579A (en) |
-
1988
- 1988-12-23 JP JP32344888A patent/JPH02169579A/en active Pending
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