NZ709742B2 - Method for producing pest controlling agent - Google Patents
Method for producing pest controlling agent Download PDFInfo
- Publication number
- NZ709742B2 NZ709742B2 NZ709742A NZ70974212A NZ709742B2 NZ 709742 B2 NZ709742 B2 NZ 709742B2 NZ 709742 A NZ709742 A NZ 709742A NZ 70974212 A NZ70974212 A NZ 70974212A NZ 709742 B2 NZ709742 B2 NZ 709742B2
- Authority
- NZ
- New Zealand
- Prior art keywords
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- formula
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- compound represented
- reaction
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- 238000004519 manufacturing process Methods 0.000 title claims abstract description 41
- 241000607479 Yersinia pestis Species 0.000 title abstract description 26
- 230000001276 controlling effect Effects 0.000 title abstract description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 212
- 238000006243 chemical reaction Methods 0.000 claims description 103
- 125000005843 halogen group Chemical group 0.000 claims description 84
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 29
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 29
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 125000003545 alkoxy group Chemical group 0.000 claims description 20
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 7
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 4
- -1 2-aminopyridine compound Chemical class 0.000 abstract description 159
- 239000003795 chemical substances by application Substances 0.000 abstract description 86
- 229910052757 nitrogen Inorganic materials 0.000 abstract description 6
- 125000004433 nitrogen atoms Chemical group N* 0.000 abstract description 6
- 230000002152 alkylating Effects 0.000 abstract description 4
- 238000005917 acylation reaction Methods 0.000 abstract description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 206
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 180
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 144
- 239000002904 solvent Substances 0.000 description 130
- 239000002585 base Substances 0.000 description 114
- 239000000203 mixture Substances 0.000 description 114
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 83
- 230000015572 biosynthetic process Effects 0.000 description 76
- 238000003786 synthesis reaction Methods 0.000 description 76
- 230000002194 synthesizing Effects 0.000 description 76
- 239000001184 potassium carbonate Substances 0.000 description 72
- 229910000027 potassium carbonate Inorganic materials 0.000 description 72
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 62
- 239000012295 chemical reaction liquid Substances 0.000 description 59
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 59
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 56
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 46
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 46
- 239000000243 solution Substances 0.000 description 45
- CTQNGGLPUBDAKN-UHFFFAOYSA-N o-xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 42
- 239000008096 xylene Substances 0.000 description 42
- XHXFXVLFKHQFAL-UHFFFAOYSA-N Phosphoryl chloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 40
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 40
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 39
- SECXISVLQFMRJM-UHFFFAOYSA-N n-methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 39
- 230000035484 reaction time Effects 0.000 description 39
- 239000003153 chemical reaction reagent Substances 0.000 description 38
- 238000003756 stirring Methods 0.000 description 37
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 36
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N Trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 36
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 35
- FXHOOIRPVKKKFG-UHFFFAOYSA-N DMA Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 30
- CTSLXHKWHWQRSH-UHFFFAOYSA-N Oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 30
- 241000238631 Hexapoda Species 0.000 description 29
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 29
- DLYUQMMRRRQYAE-UHFFFAOYSA-N Phosphorus pentoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 28
- 239000000843 powder Substances 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-Aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 26
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 26
- QWIIJVGEBIQHSW-UHFFFAOYSA-N 2-chloro-3-(chloromethyl)pyridine Chemical compound ClCC1=CC=CN=C1Cl QWIIJVGEBIQHSW-UHFFFAOYSA-N 0.000 description 24
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Carbodicyclohexylimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 24
- STSCVKRWJPWALQ-UHFFFAOYSA-N ethyl 2,2,2-trifluoroacetate Chemical compound CCOC(=O)C(F)(F)F STSCVKRWJPWALQ-UHFFFAOYSA-N 0.000 description 24
- VSCWAEJMTAWNJL-UHFFFAOYSA-K Aluminium chloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 22
- WTEOIRVLGSZEPR-UHFFFAOYSA-N Boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 22
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L MgCl2 Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 22
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 22
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 22
- 238000001914 filtration Methods 0.000 description 20
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 19
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 19
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- PSHKMPUSSFXUIA-UHFFFAOYSA-N N,N-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 16
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 15
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 15
- 239000003495 polar organic solvent Substances 0.000 description 15
- TYJJADVDDVDEDZ-UHFFFAOYSA-M Potassium bicarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 14
- PNQBEPDZQUOCNY-UHFFFAOYSA-N Trifluoroacetyl chloride Chemical compound FC(F)(F)C(Cl)=O PNQBEPDZQUOCNY-UHFFFAOYSA-N 0.000 description 14
- 238000001816 cooling Methods 0.000 description 14
- 238000000113 differential scanning calorimetry Methods 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 14
- 239000011736 potassium bicarbonate Substances 0.000 description 14
- 235000015497 potassium bicarbonate Nutrition 0.000 description 14
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 14
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- 229920000137 polyphosphoric acid Polymers 0.000 description 13
- 239000001187 sodium carbonate Substances 0.000 description 13
- 229910000029 sodium carbonate Inorganic materials 0.000 description 13
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- YWTYJOPNNQFBPC-UHFFFAOYSA-N Imidacloprid Chemical compound [O-][N+](=O)\N=C1/NCCN1CC1=CC=C(Cl)N=C1 YWTYJOPNNQFBPC-UHFFFAOYSA-N 0.000 description 12
- 239000005906 Imidacloprid Substances 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- 229940056881 imidacloprid Drugs 0.000 description 12
- KUGLJYVDCCITGB-UHFFFAOYSA-N 2,2,2-trifluoro-N-pyridin-2-ylacetamide Chemical compound FC(F)(F)C(=O)NC1=CC=CC=N1 KUGLJYVDCCITGB-UHFFFAOYSA-N 0.000 description 11
- DIZPMCHEQGEION-UHFFFAOYSA-H Aluminium sulfate Chemical compound [Al+3].[Al+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O DIZPMCHEQGEION-UHFFFAOYSA-H 0.000 description 11
- GVPFVAHMJGGAJG-UHFFFAOYSA-L Cobalt(II) chloride Chemical compound [Cl-].[Cl-].[Co+2] GVPFVAHMJGGAJG-UHFFFAOYSA-L 0.000 description 11
- ORTQZVOHEJQUHG-UHFFFAOYSA-L Copper(II) chloride Chemical compound Cl[Cu]Cl ORTQZVOHEJQUHG-UHFFFAOYSA-L 0.000 description 11
- RBTARNINKXHZNM-UHFFFAOYSA-K Iron(III) chloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 11
- RUTXIHLAWFEWGM-UHFFFAOYSA-H Iron(III) sulfate Chemical compound [Fe+3].[Fe+3].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O RUTXIHLAWFEWGM-UHFFFAOYSA-H 0.000 description 11
- QMMRZOWCJAIUJA-UHFFFAOYSA-L Nickel(II) chloride Chemical compound Cl[Ni]Cl QMMRZOWCJAIUJA-UHFFFAOYSA-L 0.000 description 11
- JIAARYAFYJHUJI-UHFFFAOYSA-L Zinc chloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 11
- 229940063656 aluminum chloride Drugs 0.000 description 11
- 229940010048 aluminum sulfate Drugs 0.000 description 11
- 238000004821 distillation Methods 0.000 description 11
- 229940032296 ferric chloride Drugs 0.000 description 11
- 229940032950 ferric sulfate Drugs 0.000 description 11
- 238000010438 heat treatment Methods 0.000 description 11
- 229910000360 iron(III) sulfate Inorganic materials 0.000 description 11
- 229910001629 magnesium chloride Inorganic materials 0.000 description 11
- 239000011592 zinc chloride Substances 0.000 description 11
- 235000005074 zinc chloride Nutrition 0.000 description 11
- 229910052736 halogen Inorganic materials 0.000 description 10
- 150000002367 halogens Chemical group 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 10
- 229910052801 chlorine Inorganic materials 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- 125000001424 substituent group Chemical group 0.000 description 9
- 238000002424 x-ray crystallography Methods 0.000 description 9
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 description 8
- 125000001309 chloro group Chemical group Cl* 0.000 description 8
- PBWZKZYHONABLN-UHFFFAOYSA-N difluoroacetic acid Chemical class OC(=O)C(F)F PBWZKZYHONABLN-UHFFFAOYSA-N 0.000 description 8
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 8
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- 150000007530 organic bases Chemical class 0.000 description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 8
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- LRMSQVBRUNSOJL-UHFFFAOYSA-N 2,2,3,3,3-pentafluoropropanoic acid Chemical compound OC(=O)C(F)(F)C(F)(F)F LRMSQVBRUNSOJL-UHFFFAOYSA-N 0.000 description 7
- OAWAZQITIZDJRB-UHFFFAOYSA-N 2-chloro-2,2-difluoroacetic acid Chemical compound OC(=O)C(F)(F)Cl OAWAZQITIZDJRB-UHFFFAOYSA-N 0.000 description 7
- AXCZMVOFGPJBDE-UHFFFAOYSA-L Calcium hydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 7
- VTHJTEIRLNZDEV-UHFFFAOYSA-L Magnesium hydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 7
- 241000209094 Oryza Species 0.000 description 7
- RQPZNWPYLFFXCP-UHFFFAOYSA-L barium dihydroxide Chemical compound [OH-].[OH-].[Ba+2] RQPZNWPYLFFXCP-UHFFFAOYSA-L 0.000 description 7
- 229910001863 barium hydroxide Inorganic materials 0.000 description 7
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 7
- 239000000920 calcium hydroxide Substances 0.000 description 7
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 7
- 239000004210 ether based solvent Substances 0.000 description 7
- 239000008079 hexane Substances 0.000 description 7
- 150000007529 inorganic bases Chemical class 0.000 description 7
- GLXDVVHUTZTUQK-UHFFFAOYSA-L lithium;dihydroxide Chemical compound [Li+].[OH-].[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-L 0.000 description 7
- 239000000347 magnesium hydroxide Substances 0.000 description 7
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 7
- SSUJUUNLZQVZMO-UHFFFAOYSA-N 1,2,3,4,8,9,10,10a-octahydropyrimido[1,2-a]azepine Chemical compound C1CCC=CN2CCCNC21 SSUJUUNLZQVZMO-UHFFFAOYSA-N 0.000 description 6
- XGINAUQXFXVBND-UHFFFAOYSA-N 1,2,6,7,8,8a-hexahydropyrrolo[1,2-a]pyrimidine Chemical compound N1CC=CN2CCCC21 XGINAUQXFXVBND-UHFFFAOYSA-N 0.000 description 6
- VZGDMQKNWNREIO-UHFFFAOYSA-N Carbon tetrachloride Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 6
- PFKFTWBEEFSNDU-UHFFFAOYSA-N Carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 6
- 241000179420 Haemaphysalis longicornis Species 0.000 description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-Bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- QDRKDTQENPPHOJ-UHFFFAOYSA-N Sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 6
- 238000007792 addition Methods 0.000 description 6
- 125000004432 carbon atoms Chemical group C* 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinone Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
- NRZBWQGUZPLSOU-UHFFFAOYSA-N ClC1=NC=CC(=N1)CN1C(C=CC=C1)=NC(C(F)(F)F)=O Chemical compound ClC1=NC=CC(=N1)CN1C(C=CC=C1)=NC(C(F)(F)F)=O NRZBWQGUZPLSOU-UHFFFAOYSA-N 0.000 description 5
- JXTHNDFMNIQAHM-UHFFFAOYSA-N Dichloroacetic acid Chemical class OC(=O)C(Cl)Cl JXTHNDFMNIQAHM-UHFFFAOYSA-N 0.000 description 5
- 206010021033 Hypomenorrhoea Diseases 0.000 description 5
- 241001470017 Laodelphax striatella Species 0.000 description 5
- 241000257159 Musca domestica Species 0.000 description 5
- 238000009833 condensation Methods 0.000 description 5
- 230000005494 condensation Effects 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 5
- 230000005712 crystallization Effects 0.000 description 5
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 5
- 238000005580 one pot reaction Methods 0.000 description 5
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 5
- 230000000704 physical effect Effects 0.000 description 5
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-Lutidine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 4
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-Methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- FOCAUTSVDIKZOP-UHFFFAOYSA-N Chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N Potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 229960004319 Trichloroacetic Acid Drugs 0.000 description 4
- YNJBWRMUSHSURL-UHFFFAOYSA-N Trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 4
- UGAPHEBNTGUMBB-UHFFFAOYSA-N acetic acid;ethyl acetate Chemical compound CC(O)=O.CCOC(C)=O UGAPHEBNTGUMBB-UHFFFAOYSA-N 0.000 description 4
- 125000005332 alkyl sulfoxy group Chemical group 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 229940106681 chloroacetic acid Drugs 0.000 description 4
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 4
- 229960005215 dichloroacetic acid Drugs 0.000 description 4
- 239000003759 ester based solvent Substances 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- RTIAQOLKVLAEAU-UHFFFAOYSA-N hexan-3-yl acetate Chemical compound CCCC(CC)OC(C)=O RTIAQOLKVLAEAU-UHFFFAOYSA-N 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 4
- 238000005191 phase separation Methods 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- ARQYNPTZSVZGDP-UHFFFAOYSA-N 1,3,5-trichlorocyclohexa-2,4-diene-1-carbonyl chloride Chemical compound ClC(=O)C1(Cl)CC(Cl)=CC(Cl)=C1 ARQYNPTZSVZGDP-UHFFFAOYSA-N 0.000 description 3
- KJCIMSSFGUGTGA-UHFFFAOYSA-N 1-methylpiperazin-2-one Chemical compound CN1CCNCC1=O KJCIMSSFGUGTGA-UHFFFAOYSA-N 0.000 description 3
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- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- OEDUIFSDODUDRK-UHFFFAOYSA-N 5-phenyl-1H-pyrazole Chemical compound N1N=CC=C1C1=CC=CC=C1 OEDUIFSDODUDRK-UHFFFAOYSA-N 0.000 description 1
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- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
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- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
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- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
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- 230000002688 persistence Effects 0.000 description 1
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- 239000012217 radiopharmaceutical Substances 0.000 description 1
- 230000002799 radiopharmaceutical Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 230000003415 tickcidal Effects 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
- A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/54—1,3-Diazines; Hydrogenated 1,3-diazines
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
- A01N43/78—1,3-Thiazoles; Hydrogenated 1,3-thiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
Abstract
Disclosed is a method for producing a 2-aminopyridine compound of formula (I) by acylating a compound represented by Formula (A) by using an acylation agent, and further alkylating a 1-position nitrogen atom of the compound represented by Formula (B) in the presence of a base. The compound is useful as a pest controlling agent. as a pest controlling agent.
Description
TITLE OF THE INVENTION
METHOD FOR PRODUCING PEST CONTROLLING AGENT
This application is a divisional application of New Zealand
Application No. 623022 the specification and drawings of which
as originally filed are incorporated herein in their entirety
by reference.
BACKGROUND OF THE INVENTION
Field of the Invention
The present invention relates to a method for producing a
novel pest control agent having a 2-acyliminopyridine structure.
Related Background Art
Although many pest control agents have been developed so
far, novel agents are still sought because of problems associated
with decreased drug sensitivity, persistence of the effects of
agents, safety of agents in use, and the like.
In particular, as shown in Masaya Matsumura et al., Pest
Management Science, 2008, Vol. 64, No. 11, pp. 1115 to 1121
(Non-Patent Document 1), wet rice cultivation in East Asia and
Southeast Asia obviously suffers damage due to planthoppers which
have developed drug resistance to major pesticides including
neonicotinoids represented by imidacloprid,
phenylpyrazole-based agents represented by fipronil, and the like.
Accordingly, specific agents against planthoppers which have
developed resistance have been expected. In addition, it is
required that such novel agents be provided in amounts required
as pest control agents stably and at low costs.
Methods described in DESCRIPTION of European Patent
Application Publication No. 432600 (Patent Document 1), Japanese
Unexamined Patent Application Publication No. Hei 05-78323
(Patent Document 2), DESCRIPTION of European Patent Application
Publication No. 268915 (Patent Document 3), and Botho Kickhofen
et al., Chemische Berichte, 1955, Vol. 88, pp. 1103 to 1108
(Non-Patent Document 2) are known as methods for producing a pest
control agent having a 2-acyliminopyridine structure. Patent
Document 1 discloses a herbicide having the same ring structure
as that of a compound represented by formula (I) described later.
Patent Documents 2 and 3 disclose pesticides having the same ring
structure as that of the compound represented by formula (I).
Non-Patent Document 2 discloses a compound having a ring structure
similar to that of the compound represented by formula (I), as
a synthetic intermediate.
However, the production methods described in Patent
Documents 1, 2, and 3, and Non-Patent Document 2 are production
methods in which a compound represented by formula (Ba) described
later is used as an intermediate, and fail to describe production
in which a compound represented by formula (B) described later
is used as an intermediate. Moreover, Patent Documents 1, 2, and
3, and Non-Patent Document 2 disclose production methods in which
a compound represented by formula (Ba) is used as an intermediate,
but do not specifically describe the production of a compound
represented by formula (Ia) described later. Further, the
structural formula of
N-[1-((6-chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide is disclosed, and a physical property
value of the compound, i.e., a refractive index nD (25.5) of 1.4818
is described (Compound No. 3 in Table 1 of Patent Document 2);
however, this compound is not included in the list of compounds
shown to have pest control activities (Tables 2 and 3 of Patent
Document 2).
Moreover, Patent Document 3 discloses the structural
formula of
N-[1-((6-chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide, and describes a physical property value
of the compound, i.e., a melting point of 60 to 62°C (Example
No. 12 in Table 7 of Patent Document 3). However, this compound
is not listed in the examples of compounds which exhibited pest
control activities in Examples. Neither Patent Document 2 nor
Patent Document 3 discloses a specific method for producing
N-[1-((6-chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide.
In addition, Wladysl, aw Pietrzycki, et al., Bulletin des
Societes Chimiques Belges, 1993, Vol. 102, No. 11-12, pp. 709
to 717 (Non-Patent Document 3) discloses
N-(pyridin-2(1H)-ylidene]-acetamide as a tautomer of
2-acetamide pyridine, but fails to describe a specific method
for producing the tautomer, or a method for producing a haloacyl
derivative thereof.
SUMMARY OF THE INVENTION
An aspect of the present invention is to provide a pest
control agent having a 2-acyliminopyridine structure and being
represented by formula (I) described later, in particular
N-[1-((6-chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide, in an amount required for a pest control
agent stably and at a low cost.
Specifically, according to a first aspect of the invention,
the present inventors have obtained a desired useful compound
represented by the following formula (I) by using a compound
represented by formula (A) as a starting substance, and a compound
represented by formula (B) as an intermediate. As a result, the
present invention has been completed.
Provided is a method for producing a compound represented
by the following formula (I):
[Chem. 1]
[where Ar represents a phenyl group which may be substituted or
a 5-to 6-membered heterocycle which may be substituted, R
represents a C alkyl group which may be substituted, and Y
represents a hydrogen atom; a halogen atom; a hydroxyl group;
a C alkyl group which may be substituted with a halogen atom;
a C alkyloxy group which may be substituted with a halogen atom;
a cyano group; a formyl group; or a nitro group],
the method comprising, as shown in the following reaction
formula:
[Chem. 2]
[where R and Y have the same meanings as those described above,
R represents (1) a trifluoroacetoxy group, (2) a C alkyloxy
2 1-6
group which may be substituted with a halogen atom or a benzyloxy
group whose phenyl group may be substituted with a halogen atom,
a methyl group, a cyano group, a nitro group, or a methoxy group,
(3) a C alkylcarbonyloxy group which may be substituted with
a halogen atom (provided that a trifluoroacetoxy group is
excluded) or a phenylcarbonyloxy group whose phenyl group may
be substituted with a halogen atom, a methyl group, a cyano group,
a nitro group, or a methoxy group,(4) a hydroxyl group, or (5)
a halogen atom, and R represents a halogen atom, a C
4 1-6
alkylsulfoxy group which may be substituted with a halogen atom,
or a phenylsulfoxy group which may be substituted with a halogen
atom or a methyl group],
the steps of:
acylating an amino group at position 2 of a compound
represented by formula (A) by use of an acylating agent
represented by R COR , to thereby produce a compound represented
by formula (B);
[Chem. 3]
; and
( ( ( ( ) ) ) )
further alkylating a nitrogen atom at position 1 of the
compound represented by formula (B) by use of Ar-CH -R .
A second aspect of the present invention provides a useful
intermediate represented by formula (B) (provided that compounds
in which R is a methyl group or a phenyl group, and Y is a hydrogen
atom are excluded), and a salt thereof.
A third aspect of the present invention provides a method
for producing a compound represented by the following formula
(Ia):
[Chem. 4]
[where R represents a halogen atom, a cyano group, a nitro group,
or a trifluoromethyl group, X represents a carbon atom or a
nitrogen atom, and R represents a halogen-substituted C alkyl
1a 1-6
group],
the method being shown by the following reaction formula:
[Chem. 5]
[where R , R , R and X have the same meanings as those described
1a 4 3
above, R represents (1) a trifluoroacetoxy group, (2) a C
2a 1-6
alkyloxy group which may be substituted with a halogen atom or
a benzyloxy group whose phenyl group may be substituted with a
halogen atom, a methyl group, a cyano group, a nitro group, or
a methoxy group, (3) a C alkylcarbonyloxy group which may be
substituted with a halogen atom (provided that a trifluoroacetoxy
group is excluded) or a phenylcarbonyloxy group whose phenyl group
may be substituted with a halogen atom, a methyl group, a cyano
group, a nitro group, or a methoxy group, (4) a hydroxyl group,
or (5) a halogen atom].
A fourth aspect of the present invention provides a compound
represented by formula (I'), which is produced according to the
following reaction formula:
[Chem. 6]
[where the compound represented by formula (I') is
N-[1-((6-chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide which has the following physical
properties (a) and/or (b):
(a) diffraction angle peaks determined by powder X-ray
diffraction being present at least at the following diffraction
angles (2θ): 8.6±0.2°, 14.2±0.2°, 17.5±0.2°, 18.3±0.2°,
19.7±0.2°, 22.3±0.2°, 30.9±0.2°, and 35.3±0.2°;
(b) a melting point determined by differential scanning
calorimetry (DSC) of 155 to 158°C].
A fifth aspect of the present invention provides a method
for producing a compound represented by the following formula
(I):
[Chem. 1]
(I)
[where
Ar represents a phenyl group which may be substituted with
halogen atoms, C alkyl groups which may be substituted with
a halogen atom, C alkyloxy groups which may be substituted with
a halogen atom, a hydroxyl group, a cyano group, or a nitro group;
or a 5-to 6-membered heterocycle which may be substituted with
halogen atoms, C alkyl groups which may be substituted with
a halogen atom, C alkyloxy groups which may be substituted with
a halogen atom, a hydroxyl group, a cyano group or a nitro group,
-R represents a C alkyl group which may be substituted
1 1-6
with halogen atoms, C halogenated alkyloxy groups, a cyano
group, a nitro group, or a hydroxyl group, and
Y represents a hydrogen atom; a halogen atom; a hydroxyl
group; a C alkyl group which may be substituted with a halogen
atom; a C alkyloxy group which may be substituted with a halogen
atom; a cyano group; a formyl group; or a nitro group],
the method comprising, as shown in the following reaction
formula:
[Chem. 2]
the steps of:
acylating an amino group at position 2 of a compound
represented by formula (A) (Y has the same meaning as that
described above) by use of an acylating agent represented by R COR
(where R has the same meaning as that described above, and R
represents (1) a trifluoroacetoxy group, (2) a C alkyloxy group
which may be substituted with a halogen atom or a benzyloxy group
whose phenyl group may be substituted with a halogen atom, a methyl
group, a cyano group, a nitro group, or a methoxy group, (3) a
C alkylcarbonyloxy group which may be substituted with a halogen
atom (provided that a trifluoroacetoxy group is excluded) or a
phenylcarbonyloxy group whose phenyl group may be substituted
with a halogen atom, a methyl group, a cyano group, a nitro group,
or a methoxy group, (4) a hydroxyl group, or (5) a halogen atom)
in the presence or in the absence of a condensation agent,
phosphorus pentoxide, sulfuric acid, polyphosphoric acid,
thionyl chloride, phosphorus oxychloride, or oxalyl dichloride,
to thereby produce a compound represented by formula (B); and
further alkylating a nitrogen atom at position 1 of the
compound represented by formula (B) by use of Ar-CH -R (where
Ar has the same meaning as that described above, and R represents
a halogen atom, a C alkylsulfoxy group which may be substituted
with a halogen atom, or a phenylsulfoxy group which may be
substituted with a halogen atom or a methyl group)
wherein the acylation is carried out in the presence of a
base.
A sixth aspect of the present invention provides a method
for producing a compound represented by the following formula
(Ia):
[Chem. 3]
[where R represents a halogen atom, a cyano group, a nitro group,
or a trifluoromethyl group, X represents a carbon atom or a
nitrogen atom, and R represents a halogen-substituted C alkyl
1a 1-6
group],
the method comprising, as shown in the following reaction
formula:
[Chem. 4]
the steps of:
alkylating a nitrogen atom at position 1 of a compound
represented by formula (Aa) by use of a compound represented by
formula (Ca) (where R and X have the same meanings as those
described above and R represents a halogen atom, a C
4 1-6
alkylsulfoxy group which may be substituted with a halogen atom,
or a phenylsulfoxy group which may be substituted with a halogen
atom or a methyl group), to thereby produce a compound represented
by formula (Ba); and
acylating an imino group of the compound represented by
formula (Ba) by use of an acylating agent represented by R COR
1a 2a
(where R has the same meaning as that described above, and R
1a 2a
represents (1) a trifluoroacetoxy group, (2) a C alkyloxy group
which may be substituted with a halogen atom or a benzyloxy group
whose phenyl group may be substituted with a halogen atom, a methyl
group, a cyano group, a nitro group, or a methoxy group, (3) a
C alkylcarbonyloxy group which may be substituted with a halogen
atom (provided that a trifluoroacetoxy group is excluded) or a
phenylcarbonyloxy group whose phenyl group may be substituted
with a halogen atom, a methyl group, a cyano group, a nitro group,
or a methoxy group, (4) a hydroxyl group, or (5) a halogen atom)
in the presence or in the absence of a condensation agent,
phosphorus pentoxide, sulfuric acid, polyphosphoric acid,
thionyl chloride, phosphorus oxychloride, or oxalyl dichloride
wherein the acylation is carried out in the presence of a
base.
Effects of the Invention
According to the present invention, a 2-acyliminopyridine
derivative useful as a pest control agent can be produced
efficiently in a good yield and, if necessary, in a one-pot manner.
BRIEF DESCRIPTION OF THE DRAWINGS
[Fig. 1] Fig. 1 is a graph showing results of powder X-ray
crystallography conducted on crystals of
N-[1-((6-chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide prepared by a first production method.
[Fig. 2] Fig. 2 is a graph showing results of differential
scanning calorimetry conducted on crystals of
N-[1-((6-chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide prepared by the first production method.
[Fig. 3] Fig. 3 is a graph showing results of powder X-ray
crystallography conducted on crystals of
N-[1-((6-chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide prepared by a second production method.
[Fig. 4] Fig. 4 is a graph showing results of differential
scanning calorimetry conducted on crystals of
N-[1-((6-chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide prepared by the second production method.
[Fig. 5] Fig. 5 is a graph showing results of differential
scanning calorimetry conducted on crystals of
N-[1-((6-chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide prepared by a third production method.
[Fig. 6] Fig. 6 is a graph showing results of powder X-ray
crystallography conducted on crystals of
N-[1-((6-chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide prepared by a fourth production method.
[Fig. 7] Fig. 7 is a graph showing results of differential
scanning calorimetry conducted on crystals of
N-[1-((6-chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide prepared by the fourth production method.
[Fig. 8] Fig. 8 is a graph showing results of differential
scanning calorimetry conducted on crystals of
N-[1-((6-chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide prepared by a fifth production method.
[Fig. 9] Fig. 9 is a graph showing results of powder X-ray
crystallography conducted on crystals of
N-[1-((6-chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide synthesized in Synthesis Example 4.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The "alkyl" used herein either as a substituent or a portion
of a substituent means a linear, branched, or cyclic alkyl, or
an alkyl of a combination of any of these, unless otherwise
defined.
The "halogen atom" used herein means an atom selected from
fluorine, chlorine, bromine, and iodine.
The term "equivalent" of the base used herein is, for
example, as follows: when 1 mol of potassium carbonate is used
for 1 mol of a compound represented by formula (A), the potassium
carbonate is 2 equivalents; when 1 mol of sodium hydroxide or
sodium hydrogen carbonate is used therefor, the sodium hydroxide
or sodium hydrogen carbonate is 1 equivalent; and when 1 mol of
an organic base is used therefor, the organic base is 1 equivalent.
The "salt" used herein refers to an inorganic acid salt such
as a hydrochloride, a sulfuric acid salt, or a nitric acid salt;
an organic acid salt such as a trifluoroacetic acid salt, a
difluoroacetic acid salt, a dichloroacetic acid salt; or the like.
The "reagent used simultaneously with an acylating agent
R COR " used herein may be a hydrate thereof, when R represents
1 2 2
a hydroxyl group.
The "condensation agent" used herein is a reagent for
synthesis of carboxylic acid derivatives such as esters and amides,
and examples of the "condensation agent" includes
N,N'-dicyclohexylcarbodiimide,
1-ethyl(3-dimethylaminopropyl)carbodiimide hydrochloride,
1,1'-carbonyldiimidazole, dipyridyl disulfide, diimidazolyl
disulfide, 1,3,5-trichlorobenzoyl chloride,
1,3,5-trichlorobenzoyl anhydride, PyBop (registered trademark,
(benzotriazoleyloxy)tripyrrolidinophosphonium
hexafluorophosphate), and PyBrop (registered trademark,
bromotri(pyrrolidino)phosphonium hexafluorophosphate), and the
like.
The sign "C " used herein and attached to a substituent
means that the number of carbon atoms contained in the substituent
is in the range from a to b. Moreover, for example, the "C "
in a case of "C alkylcarbonyloxy" means that the number of carbon
atoms in the alkyl moiety excluding the carbon atom in the
carbonyloxy moiety is in the range from a to b.
Ar represents a phenyl group which may be substituted or
a 5-to 6-membered heterocycle which may be substituted. Examples
of the 5-to 6-membered heterocycle include pyridine, pyrimidine,
thiazole, tetrahydrofuran, furan, and the like. Preferred
examples of Ar include a 3-pyridyl group, a 5-pyrimidyl group,
a 3-thiazolyl group, a 5-thiazolyl group, and a 3-pyridyl group
is more preferable. Examples of a substituent which may be
introduced to the phenyl group or the heterocycle include halogen
atoms, C alkyl groups which may be substituted with a halogen
atom, C alkyloxy groups which may be substituted with a halogen
atom, a hydroxyl group, a cyano group, and a nitro group. Here,
halogen atoms and C alkyl groups which may be substituted with
a halogen atom are preferable, and a chlorine atom is particularly
preferable. Specific examples of the phenyl group which may be
substituted and the 5-to 6-membered heterocycle which may be
substituted include a phenyl group, a 3-chlorophenyl group, a
4-chlorophenyl group, a 3-cyanophenyl group, a 4-cyanophenyl
group, a 3-nitrophenyl group, a 4-nitrophenyl group, a
3,5-dichlorophenyl group, a 4-methylphenyl group, a
4-methoxyphenyl group, a 3,5-dibromophenyl group, a
2,4-dibromophenyl group, a 4-fluorophenyl group, a 4-bromophenyl
group, a 3-nitrobromophenyl group, a
3,5-bis(trifluoromethyl)phenyl group, a 6-chloropyridyl
group, a 2-chlorothiazolyl group, a
6-chlorofluoropyridyl group, a 6-bromopyridyl group,
a 6-fluoropyridyl group, a 5,6-dichloropyridyl group, and
a 6-trifluoromethylpyridyl group. Here, a
6-chloropyridyl group, a 6-fluoropyridyl group, a
6-chlorofluoropyridyl group, and a 6-bromopyridyl
group are preferable, and a 6-chloropyridyl group is
particularly preferable.
R represents a C alkyl group which may be substituted.
1 1-6
Examples of a substituent which may be introduced to the C alkyl
group include halogen atoms, C halogenated alkyloxy groups,
a cyano group, a nitro group, and a hydroxyl group. Specific
examples of the C alkyl group represented by R include a
1-6 1
trifluoromethyl group, a difluorochloromethyl group, a
trichloromethyl group, a pentafluoroethyl group, a
difluoromethyl group, a dichloromethyl group, a dibromomethyl
group, a chloromethyl group, a difluoroethyl group, a
dichloroethyl group, a 2,2,2-trifluoroethyl group, a
difluorocyclopropyl group, a bromodifluoromethyl group, a
trifluoromethoxymethyl group, and the like; preferred examples
thereof include a trifluoromethyl group, a difluorochloromethyl
group, a difluoromethyl group, a trichloromethyl group, and a
pentafluoroethyl group; and a more preferred example is a
trifluoromethyl group.
R represents a halogen-substituted C alkyl group.
1a 1-6
Examples thereof include a trifluoromethyl group, a
trichloromethyl group, a difluorochloromethyl group, a
difluoromethyl group, a dichloromethyl group, a dibromomethyl
group, a chloromethyl group, a difluoroethyl group, a
dichloroethyl group, a 2,2,2-trifluoroethyl group, a
pentafluoroethyl group, a difluorocyclopropyl group, and the like.
Here, a trifluoromethyl group, a trichloromethyl group, a
dichloromethyl group, a difluoromethyl group, a
difluorochloromethyl group, a chloromethyl group, and a
pentafluoroethyl group are preferable; a trifluoromethyl group,
a difluoromethyl group, a difluorochloromethyl group, a
chloromethyl group, and a pentafluoroethyl group are more
preferable; and a trifluoromethyl group is particularly
preferable.
Y represents a hydrogen atom; a halogen atom; a hydroxyl
group; a C alkyl group which may be substituted with a halogen
atom; a C alkyloxy group which may be substituted with a halogen
atom; a cyano group; a formyl group; or a nitro group. Y
preferably represents a hydrogen atom, a halogen atom, or a
hydroxyl group, and more preferably represents a hydrogen atom.
Each of R and R represents (1) a trifluoroacetoxy group,
2 2a
(2) a C alkyloxy group which may be substituted with a halogen
atom or a benzyloxy group whose phenyl group may be substituted
with a halogen atom, a methyl group, a cyano group, a nitro group,
or a methoxy group, (3) a C alkylcarbonyloxy group which may
be substituted with a halogen atom (provided that a
trifluoroacetoxy group is excluded) or a phenylcarbonyloxy group
whose phenyl group may be substituted with a halogen atom, a methyl
group, a cyano group, a nitro group, or a methoxy group, (4) a
hydroxyl group, or (5) a halogen atom.
R represents a substituent substituted on a carbon atom
of a pyridine ring or a pyrimidine ring, and it is evident that
the number of R is 0 to 4 in the case of pyridine, and 0 to 3
in the case of the pyrimidine ring. Each of the substituents
represented by R is a halogen atom, a cyano group, a nitro group,
or a trifluoromethyl group, and the substituents may be the same
or different.
R represents a halogen, a C alkylsulfoxy group which may
4 1-6
be substituted with a halogen atom, or a phenylsulfoxy group which
may be substituted with a halogen atom or a methyl group.
Preferred examples of the compound represented by formula
(I) or (Ia) include Compound No. 1:
N-[1-((6-chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide, Compound No. 2:
N-[1-((6-chlorofluoropyridinyl)methyl)pyridin-2(1H)-yl
idene]-2,2,2-trifluoroacetamide, Compound No. 19:
N-[1-((6-fluoropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide, Compound No. 3:
N-[1-((6-bromopyridinyl)methyl)pyridin-2(1H)-ylidene]-2,2
,2-trifluoroacetamide, Compound No. 8:
N-[1-((6-chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2-difluoroacetamide, Compound No. 4:
2-chloro-N-[1-((6-chloropyridinyl)methyl)pyridin-2(1H)-yl
idene]-2,2-difluoroacetamide, Compound No. 7:
N-[1-((6-chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,3,3,3-pentafluoropropanamide, and Compound No. 6:
N-[1-((2-chloropyrimidinyl)methyl)pyridin-2(1H)-ylidene]-
2,2,2-trifluoroacetamide.
Of these compounds represented by formula (I) or formula
(Ia), a particularly preferred example is a compound represented
by formula (I'), i.e.,
N-[1-((6-chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide which has the following physical
properties (a) and/or (b) (provided that the compound with
nD(25.5)=1.4818 described in Patent Document 2 is excluded):
(a) diffraction angle peaks determined by powder X-ray
diffraction being present at least at the following diffraction
angles (2θ): 8.6±0.2°, 14.2±0.2°, 17.5±0.2°, 18.3±0.2°,
19.7±0.2°, 22.3±0.2°, 30.9±0.2°, and 35.3±0.2°;
(b) a melting point determined by differential scanning
calorimetry (DSC) of 155 to 158°C.
Preferred examples of the compound represented by formula
(B) include 2,2,2-trifluoro-N-(pyridin-2(1H)-ylidene)acetamide,
2-chloro-2,2-difluoro-N-(pyridin-2(1H)-ylidene)acetamide,
2,2,3,3,3-pentafluoro-N-(pyridin-2(1H)-ylidene)propanamide,
and 2,2-difluoro-N-(pyridin-2(1H)-ylidene)acetamide; and a more
preferred example is
2,2,2-trifluoro-N-(pyridin-2(1H)-ylidene)acetamide
represented by the following formula (B1):
[Chem. 7]
( ( ( ( ) ) ) )
Production Method
The present invention will be described in further detail
according to the following scheme.
[Chem. 8]
[in the above scheme, Ar, Y, R , R , and R have the same meanings
1 2 4
as those described above].
In addition, the compound represented by formula (B) shown
in the above scheme may be used for the subsequent step, without
post treatment or isolation.
1-1: Production of Compound Represented by Formula (B) from
Compound Represented by Formula (A)
The compound represented by formula (A) can be obtained as
a commercially available compound, or can be obtained by the
method described in Journal of labeled compounds &
radiopharmaceuticals (1987), 24(2), 119-123, for example.
A method for producing a compound represented by formula
(B) from a compound represented by formula (A) is as follows.
Specifically, the compound represented by formula (B) can be
obtained by reacting the compound represented by formula (A) with
an acylating agent R COR (R and R have the same meanings as those
1 2 1 2
defined above) without a solvent or in a solvent which does not
affect the reaction in the presence of or in the absence of a
base.
Here, the numbers of equivalents of reagents are all the
numbers of equivalents to the compound represented by formula
(A).
Examples of usable solvents include aromatic
hydrocarbon-based solvents such as toluene, xylene, and
ethylbenzene; ester-based solvents such as ethyl acetate and
butyl acetate; ether-based solvents such as diethyl ether,
diisopropyl ether, tetrahydrofuran, and dioxane; aprotic polar
organic solvents such as N,N-dimethylformamide, dimethyl
sulfoxide, N,N-dimethylacetamide, N-methylpyrrolidinone,
and acetonitrile; halogen-containing solvents such as
dichloromethane and chloroform; hydrocarbon-based solvent such
as cyclohexane; ketone-based solvents such as acetone and methyl
ethyl ketone; water; and mixture solvents thereof.
Examples of usable bases include inorganic bases such as
sodium carbonate, potassium carbonate, sodium hydrogen carbonate,
potassium hydrogen carbonate, sodium hydroxide, magnesium
hydroxide, calcium hydroxide, lithium hydroxide, and barium
hydroxide; organic bases such as
1,8-diazabicyclo[5.4.0]undecene,
1,5-diazabicyclo[4.3.0]nonene, triethylamine,
diisopropylethylamine, pyridine, picoline, and
dimethylaminopyridine; and alcoholates such as sodium ethoxide,
sodium methoxide, and potassium tert-butoxide. The base does not
necessarily need to be used; however, when the reaction is carried
out in the presence of a base, the base can be used in an amount
of 0.01 to 20.0 equivalents.
Examples of the acylating agent R COR include
trifluoroacetic anhydride, trifluoroacetic acid, ethyl
trifluoroacetate, trifluoroacetyl chloride, and mixed acid
anhydrides. In addition, these acylating agents may be used
alone or in combination of two or more. Of these acylating agents,
trifluoroacetic anhydride, trifluoroacetic acid, ethyl
trifluoroacetate, or trifluoroacetyl chloride can be preferably
used. In addition, when R represents a hydroxyl group, the
reaction can be carried out by simultaneously using a condensation
agent such as N,N'-dicyclohexylcarbodiimide,
1-ethyl(3-dimethylaminopropyl)carbodiimide hydrochloride,
1,1'-carbonyldiimidazole, dipyridyl disulfide, diimidazolyl
disulfide, 1,3,5-trichlorobenzoyl chloride,
1,3,5-trichlorobenzoyl anhydride, PyBop (registered trademark,
(benzotriazoleyloxy)tripyrrolidinophosphonium
hexafluorophosphate), or PyBrop(registered trademark,
bromotri(pyrrolidino) phosphonium hexafluorophosphate); or a
reagent such as phosphorus pentoxide, sulfuric acid,
polyphosphoric acid, thionyl chloride, phosphorus oxychloride,
oxalyl dichloride, boron trifluoride, p-toluenesulfonic acid, or
a halide, a sulfate, a nitrate, or an oxide of iron, cobalt, copper,
nickel, zinc, aluminum, lithium, or magnesium. In addition,
these reagents may be used alone or in combination of two or more.
Preferred examples of the halide, the sulfate, the nitrate, or
the oxide of iron, cobalt, copper, nickel, zinc, aluminum, lithium,
or magnesium include zinc chloride, copper chloride, magnesium
chloride, cobalt chloride, nickel chloride, ferric chloride,
aluminum chloride, ferric sulfate, and aluminum sulfate. These
compounds of metals may be anhydrides or hydrates thereof. The
amount of the acylating agent used is preferably 0.5 to 10.0
equivalents, and more preferably 1.0 to 5.0 equivalents.
The reaction temperature is preferably in a range from -80°C
to 200°C. The reaction time is preferably in a range from 0.1
hours to 7 days.
Preferred modes are as follows:
(1) When R represents a trifluoroacetoxy group,
specifically, when trifluoroacetic anhydride is used as the
acylating agent, examples of preferred solvents include
ester-based solvents such as ethyl acetate and butyl acetate;
halogen-containing solvents such as dichloromethane and
chloroform; and aromatic hydrocarbon-based solvents such as
toluene, xylene, and ethylbenzene. Here, toluene is more
preferable. The reaction is preferably carried out in the
absence of a base; however, when a base is used, preferred examples
of the base include sodium carbonate, potassium carbonate,
potassium hydrogen carbonate, triethylamine, pyridine, and the
like. Here, potassium carbonate is more preferable. The amount
of the acylating agent used is preferably 1.0 to 5.0 equivalents,
and more preferably 1.0 to 1.5 equivalents. When the base is used,
the amount of the base used is preferably 1.0 to 4.5 equivalents,
and more preferably 1.0 to 3.0 equivalents. The reaction
temperature is preferably in a range from -20°C to 50°C, and more
preferably from -10°C to 30°C. The reaction time is preferably
in a range from 0.1 hours to 7 days, and more preferably in a
range from 0.5 hours to 4 hours. Particularly preferred
conditions are as follows: trifluoroacetic anhydride is used as
the acylating agent; toluene is used as the solvent; the amount
of the acylating agent used is 1.0 to 1.5 equivalents; the reaction
temperature is -10°C to 30°C; and the reaction time is 0.5 to
4 hours. Regarding the base, no base is used, or when a base is
used, potassium carbonate is used in an amount of 1.0 to 3.0
equivalents.
(2) When R represents a C alkyloxy group which may be
2 1-6
substituted with a halogen atom or a benzyloxy group whose phenyl
group may be substituted with a halogen atom, a methyl group,
a cyano group, a nitro group, or a methoxy group, specifically
when ethyl trifluoroacetate, methyl trifluoroacetate, or propyl
trifluoroacetate is used, particularly preferably when ethyl
trifluoroacetate or the like is used, preferred examples of the
solvent include aprotic polar organic solvents such as
N,N-dimethylformamide, dimethyl sulfoxide,
N,N-dimethylacetamide, N-methylpyrrolidinone, and
acetonitrile; ether-based solvents such as diethyl ether,
diisopropyl ether, tetrahydrofuran, and dioxane; and mixture
solvents of any of these solvents with an aromatic
hydrocarbon-based solvent such as toluene, xylene, or
ethylbenzene. Here, N,N-dimethylformamide or a mixture solvent
of N,N-dimethylformamide with toluene is more preferable. The
reaction is preferably carried out in the absence of a base;
however, when a base is used, preferred examples of the base
include potassium carbonate, triethylamine,
dimethylaminopyridine, and the like. Here, potassium carbonate
and dimethylaminopyridine are more preferable. The amount of the
acylating agent used is preferably 1.0 to 5.0 equivalents, and
more preferably 1.5 to 5.0 equivalents. When the base is used,
the amount of the base used is preferably 0.01 to 3.0 equivalents,
and more preferably 0.01 to 2.0 equivalents. The reaction
temperature is preferably in a range from 20°C to 100°C, and more
preferably from 40°C to 80°C. The reaction time is preferably
in a range from 0.1 hours to 7 days, and more preferably in a
range from 1 hour to 2 days.
Particularly preferred conditions are as follows: ethyl
trifluoroacetate is used as the acylating agent;
N,N-dimethylformamide or a mixture solvent of
N,N-dimethylformamide with toluene is used as the solvent; the
amount of the acylating agent used is 1.5 to 5.0 equivalents;
the reaction temperature is 40°C to 80°C; and the reaction time
is 2 hours to 2 days. Regarding the base, no base is used, or
when a base is used, potassium carbonate or dimethylaminopyridine
is used in an amount of 0.01 to 2.0 equivalents.
(3) When R represents a C alkylcarbonyloxy group which
2 1-6
may be substituted with a halogen atom (provided that a
trifluoroacetoxy group is excluded) or a phenylcarbonyloxy group
whose phenyl group may be substituted with a halogen atom, a methyl
group, a cyano group, a nitro group, or a methoxy group, a specific
example is a pivaloyl group. The reaction temperature is
preferably in a range from -20°C to 50°C, and more preferably
from -10°C to 30°C. The reaction time is preferably in a range
from 0.1 hours to 7 days, and more preferably in a range from
0.5 hours to 4 hours.
(4) When R represents a hydroxyl group, specific examples
of the acylating agent include trifluoroacetic acid,
difluorochloroacetic acid, trichloroacetic acid, difluoroacetic
acid, dichloroacetic acid, dibromoacetic acid, chloroacetic acid,
difluoropropionic acid, dichloropropionic acid,
2,2,2-trifluoropropionic acid, pentafluoropropionic acid,
difluorocyclopropanecarboxylic acid, and the like. Here,
trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid,
difluoroacetic acid, difluorochloroacetic acid, chloroacetic
acid, and pentafluoropropionic acid are preferable;
trifluoroacetic acid, difluoroacetic acid, difluorochloroacetic
acid, and pentafluoropropionic acid are more preferable; and
trifluoroacetic acid is particularly preferable. When
trifluoroacetic acid is used, preferred examples of the solvent
include aromatic hydrocarbon-based solvents such as toluene,
xylene, and ethylbenzene; and aprotic polar organic solvents such
as N,N-dimethylformamide, dimethyl sulfoxide,
N,N-dimethylacetamide, N-methylpyrrolidinone, and
acetonitrile. Here, toluene, xylene, N,N-dimethylformamide,
N-methylpyrrolidinone, N,N-dimethylacetamide, a mixture
solvent of toluene with N,N-dimethylformamide, a mixture solvent
of xylene with N,N-dimethylformamide, a mixture solvent of xylene
with N-methylpyrrolidinone, or a mixture solvent of xylene
with N,N-dimethylacetamide is more preferable. Examples of the
reagent used simultaneously include
N,N'-dicyclohexylcarbodiimide,
1-ethyl(3-dimethylaminopropyl)carbodiimide hydrochloride,
phosphorus pentoxide, sulfuric acid, polyphosphoric acid,
thionyl chloride, phosphorus oxychloride, oxalyl dichloride, and
the like. The reagent is preferably used in an amount of 0.2 to
.0 equivalents. In addition, when zinc chloride, copper
chloride, magnesium chloride, cobalt chloride, nickel chloride,
ferric chloride, aluminum chloride, ferric sulfate, aluminum
sulfate, boron trifluoride, p-toluenesulfonic acid, or the like
is used as the reagent used simultaneously, the reagent is
preferably used in an amount of 0.0001 to 1.0 equivalents. The
reaction is preferably carried out in the absence of a base, when
phosphorus pentoxide, sulfuric acid, polyphosphoric acid,
thionyl chloride, phosphorus oxychloride, oxalyl dichloride,
zinc chloride, copper chloride, magnesium chloride, cobalt
chloride, nickel chloride, ferric chloride, aluminum chloride,
ferric sulfate, aluminum sulfate, boron trifluoride, or
p-toluenesulfonic acid is used. Meanwhile, the reaction is
preferably carried out in the presence of a base, when
N,N'-dicyclohexylcarbodiimide or
1-ethyl(3-dimethylaminopropyl)carbodiimide hydrochloride is
used. When a base is used, preferred examples of the base include
sodium carbonate, potassium carbonate, potassium hydrogen
carbonate, triethylamine, pyridine, dimethylaminopyridine, and
the like. Here, triethylamine is more preferable. The amount
of the acylating agent used is preferably 1.0 to 5.0 equivalents,
and more preferably 1.0 to 3.0 equivalents. When thionyl
chloride, phosphorus oxychloride, or oxalyl dichloride is used,
the reagent is preferably used in an amount of 0.2 to 5.0
equivalents, and the reaction temperature is preferably in a range
from -30°C to 80°C, and more preferably from -10°C to 40°C. When
phosphorus pentoxide, sulfuric acid, or polyphosphoric acid is
used, the reagent is preferably used in an amount of 0.2 to 5.0
equivalents, and the reaction temperature is preferably in a range
from -30°C to 200°C, and more preferably from -10°C to 160°C.
When N,N'-dicyclohexylcarbodiimide or
1-ethyl(3-dimethylaminopropyl)carbodiimide hydrochloride is
used, the following conditions are preferable: the reagent is
used in an amount of 0.2 to 5.0 equivalents; the reaction
temperature is preferably in a range from -30°C to 80°C, and more
preferably from -10°C to 40°C; and triethylamine is used as the
base in an amount of 0.2 to 5.0 equivalents. When zinc chloride,
copper chloride, magnesium chloride, cobalt chloride, nickel
chloride, ferric chloride, aluminum chloride, ferric sulfate,
aluminum sulfate, boron trifluoride, or p-toluenesulfonic acid
is used, the following conditions are preferable: the reagent
is used in an amount of 0.0001 to 1.0 equivalents; the reaction
temperature is preferably in a range from 20°C to 200°C, and more
preferably from 80°C to 160°C. The reaction time is preferably
in a range from 0.1 hours to 7 days, and more preferably in a
range from 0.5 hours to 2 days.
Particularly preferred conditions are as follows:
trifluoroacetic acid is used as the acylating agent; toluene,
N,N-dimethylformamide, xylene, N-methylpyrrolidinone,
N,N-dimethylacetamide, a mixture solvent of
N,N-dimethylformamide with toluene, a mixture solvent of xylene
with N,N-dimethylformamide, a mixture solvent of xylene with
N-methylpyrrolidinone, or a mixture solvent of xylene with
N,N-dimethylacetamide is used as the solvent; and the amount of
the acylating agent used is 1.0 to 3.0 equivalents. When thionyl
chloride, phosphorus oxychloride, or oxalyl dichloride is used,
particularly preferred conditions are as follows: the reagent
is used in an amount of 0.3 to 3.0 equivalents; no base is used;
the reaction temperature is -10°C to 40°C; and the reaction time
is 0.5 hours to 1 day. When phosphorus pentoxide, sulfuric acid,
or polyphosphoric acid is used, particularly preferred conditions
are as follows: the reagent is used in an amount of 0.2 to 2.0
equivalents; the reaction temperature is -10°C to 160°C; and the
reaction time is 0.5 hours to 1 day. When
N,N'-dicyclohexylcarbodiimide or
1-ethyl(3-dimethylaminopropyl)carbodiimide hydrochloride is
used, particularly preferred conditions are as follows: the
reagent is used in an amount of 0.5 to 3 equivalents;, the reaction
temperature is -10°C to 40°C; triethylamine is used as the base
in an amount of 0.5 to 3.0 equivalents; and the reaction time
is 0.5 to 1 day. When zinc chloride, copper chloride, magnesium
chloride, cobalt chloride, nickel chloride, ferric chloride,
aluminum chloride, ferric sulfate, aluminum sulfate, boron
trifluoride, or p-toluenesulfonic acid is used, particularly
preferred conditions are as follows: the reagent is used in an
amount of 0.0001 to 0.5 equivalents; no base is used; the reaction
temperature is 80°C to 160°C; and the reaction time is 2 hours
to 2 days.
(5) When R represents a halogen atom, specifically when
trifluoroacetyl chloride or trifluoroacetyl bromide is used,
preferably when trifluoroacetyl chloride is used, preferred
examples of the solvent include halogen-containing solvents such
as chloroform and dichloromethane; aromatic hydrocarbon-based
solvents such as toluene, xylene, and ethylbenzene; and aprotic
polar organic solvents such as N,N-dimethylformamide, dimethyl
sulfoxide, N,N-dimethylacetamide, N-methylpyrrolidinone,
and acetonitrile. Here, toluene, N,N-dimethylformamide,
N-methylpyrrolidinone, or a mixture solvent of any of these
is more preferable. The reaction is preferably carried out in
the absence of a base; however, when a base is used, preferred
examples of the base include sodium carbonate, potassium
carbonate, potassium hydrogen carbonate, triethylamine,
pyridine, and the like. Here, potassium carbonate is more
preferable. The amount of the acylating agent used is preferably
1.0 to 5.0 equivalents, and more preferably 1.0 to 3.0 equivalents.
When the base is used, the amount of the base used is preferably
1.0 to 5.0 equivalents, and more preferably 1.0 to 3.0 equivalents.
The reaction temperature is preferably in a range from -80°C to
40°C, and more preferably from -30°C to 30°C. The reaction time
is preferably in a range from 0.1 hours to 7 days, and more
preferably in a range from 0.5 hours to 8 hours. Meanwhile, when
R represents a chlorine atom, it is also possible to use R COCl
generated in advance by simultaneously using trifluoroacetic acid
with thionyl chloride, phosphorus oxychloride, oxalic acid
dichloride, or the like outside the reaction system in which the
reaction of the compound represented by formula (A) is carried
out.
Particularly preferred conditions are as follows:
trifluoroacetyl chloride is used as the acylating agent; toluene,
N,N-dimethylformamide, N-methylpyrrolidinone, or a mixture
solvent of any of these is used as the solvent; the amount of
the acylating agent used is 1.0 to 3.0 equivalents; the reaction
temperature is -30°C to 30°C; and the reaction time is 0.5 hours
to 8 hours. Regarding the base, particularly preferred
conditions are as follows: no base is used; or when a base is
used, potassium carbonate is used in an amount of 1.0 to 3.0
equivalents.
After the compound represented by formula (B) is
synthesized from the compound represented by formula (A), the
compound represented by formula (B) may be neutralized by use
of a base. Examples of usable bases include inorganic bases such
as sodium carbonate, potassium carbonate, sodium hydrogen
carbonate, potassium hydrogen carbonate, sodium hydroxide,
magnesium hydroxide, calcium hydroxide, lithium hydroxide, and
barium hydroxide; organic bases such as
1,8-diazabicyclo[5.4.0]undecene,
1,5-diazabicyclo[4.3.0]nonene, triethylamine,
diisopropylethylamine, pyridine, picoline, and
dimethylaminopyridine; and alcoholates such as sodium ethoxide,
sodium methoxide, and potassium tert-butoxide. Here, potassium
carbonate, sodium ethoxide, or triethylamine is preferable.
1-2: Production of Compound Represented by Formula (I) or
Formula (I') from Compound Represented by Formula (B) or Formula
(B')
A method for producing a compound represented by formula
(I) or formula (I') from a compound represented by formula (B)
or formula (B') is as follows. Specifically, the compound
represented by formula (I) or formula (I') can be obtained by
reacting the compound represented by formula (B) or formula (B')
with Ar-CH -R (Ar and R have the same meanings as those defined
2 4 4
above) without a solvent or in a solvent which does not affect
the reaction in the presence of a base.
Examples of usable solvents include ether-based solvents
such as diethyl ether, diisopropyl ether, tetrahydrofuran, and
dioxane; aprotic polar organic solvents such as
N,N-dimethylformamide, dimethyl sulfoxide,
N,N-dimethylacetamide, acetonitrile, N-methylpyrrolidinone,
N-methylpiperazinone, N,N-dimethylimidazolidinone, and
acetonitrile; halogen-containing solvents such as
dichloromethane and chloroform; aromatic hydrocarbon-based
solvents such as toluene, xylene, and ethylbenzene; and mixture
solvents thereof; and preferred examples thereof include aprotic
polar organic solvents. Here, N,N-dimethylformamide,
N,N-dimethylacetamide, N-methylpyrrolidinone,
N,N-dimethylimidazolidinone, acetonitrile, or a mixture
solvent of N,N-dimethylformamide, N,N-dimethylacetamide,
N-methylpyrrolidinone, N,N-dimethylimidazolidinone, or
acetonitrile with an aromatic hydrocarbon-based solvent is more
preferable; and N,N-dimethylformamide or a mixture solvent of
N,N-dimethylformamide with toluene is particularly preferable.
When the reaction is carried out in the presence of a base,
examples of usable bases include inorganic bases such as sodium
carbonate, potassium carbonate, sodium hydrogen carbonate,
potassium hydrogen carbonate, sodium hydroxide, magnesium
hydroxide, calcium hydroxide, lithium hydroxide, and barium
hydroxide; and organic bases such as
1,8-diazabicyclo[5.4.0]undecene,
1,5-diazabicyclo[4.3.0]nonene, triethylamine,
diisopropylethylamine, pyridine, lutidine, collidine,
N,N-dimethylaniline, and N,N-diethylaniline; preferred examples
thereof include potassium carbonate, potassium hydrogen
carbonate, pyridine, triethylamine, and the like; and more
preferred examples thereof include potassium carbonate and
triethylamine.
The amount of Ar-CH -R (Ar and R have the same meanings
2 4 4
as those defined above) used is preferably 0.7 to 2.0 equivalents,
and more preferably 0.8 to 1.5 equivalents, to the compound
represented by formula (B) or formula (B'). When the base is used,
the amount of the base used is preferably 1.0 to 10.0 equivalents,
and more preferably 1.0 to 5.0 equivalents, to the compound
represented by formula (B) or formula (B').
The reaction temperature is preferably in a range from 20°C
to 100°C, and more preferably from 40°C to 80°C. The reaction
time is preferably in a range from 0.1 hours to 3 days, and more
preferably in a range from 1 hour to 2 days.
Particularly preferred conditions are as follows: R is a
chlorine atom; N,N-dimethylformamide, N-methylpyrrolidinone,
N,N-dimethylacetamide, a mixture solvent of
N,N-dimethylformamide with toluene, a mixture solvent of
N,N-dimethylformamide with xylene, a mixture solvent of xylene
with N-methylpyrrolidinone, or a mixture solvent of xylene
with N,N-dimethylacetamide is used as the solvent; the amount
of Ar-CH -R used is 0.8 to 1.5 equivalents to the compound
represented by formula (B) or formula (B'); the reaction
temperature is 40°C to 80°C; the reaction time is 1 hour to 2
days; and potassium carbonate or triethylamine is used as the
base in an amount of 1.0 to 5.0 equivalents.
One-Pot Production for Obtaining Compound Represented by
Formula (I) or Formula (I') from Compound Represented by Formula
(A) or Formula (A') through Compound Represented by Formula (B)
or (B')
When the compound represented by formula (I) or formula (I')
is synthesized from the compound represented by formula (A) or
formula (A'), the compound represented by formula (I) or formula
(I') can be obtained by conducting the subsequent step, without
isolation of the compound represented by formula (B) or formula
(B').
Specifically, the compound represented by formula (I) or
formula (I') can be obtained by a reaction in which the reaction
product represented by formula (B) or formula (B') is used as
it is or after the excessive reagent is removed under reduced
pressure; Ar-CH -R (Ar and R have the same meanings as those
2 4 4
described above) and the base are added thereto; and a reaction
therebetween is allowed to proceed under the above-described
conditions.
A preferred example of the method for obtaining the compound
represented by formula (I) or formula (I') from the compound
represented by formula (A) or formula (A') through the compound
represented by formula (B) or formula (B') is a method in which
a compound represented by formula (A) or formula (A') is reacted
with an acylating agent R COR by use of an aromatic
hydrocarbon-based solvent, an aprotic polar solvent, or a mixture
solvent thereof in the absence of a base, to thereby obtain a
compound represented by formula (B) or formula (B'); then
Ar-CH -R , a base, and an aromatic hydrocarbon-based solvent, an
aprotic polar organic solvent, or a mixture solvent thereof are
added; and a reaction therebetween is allowed to proceed, as it
is or while the aromatic hydrocarbon-based solvent is distilled
off under reduced pressure, to thereby obtain a compound
represented by formula (I) or formula (I').
Production of Compound Represented by Formula (B) or (B')
from Compound Represented by Formula (A) or Formula (A') in
One-Pot Production
Here, the numbers of equivalents of reagents are all the
numbers of equivalents to the compound represented by formula
(A) or formula (A'). To obtain a compound represented by formula
(B) or formula (B') from a compound represented by formula (A)
or formula (A'), it is particularly preferable to use R COR or
CF COR in which R is a CF COO group, an OEt group, a hydroxyl
3 2 2 3
group, or a chlorine atom.
When R is a CF COO group (for example, trifluoroacetic
anhydride), particularly preferred conditions are as follow:
toluene is used as the solvent; the amount of the acylating agent
used is 1.0 to 1.5 equivalents, the reaction temperature is -10°C
to 30°C; the reaction time is 0.5 to 4 hours; and regarding the
base, no base is used, or when a base is used, potassium carbonate
is used in an amount of 1.0 to 3.0 equivalents. When R is an
OEt group (ethyl trifluoroacetate), particularly preferred
conditions are as follows: N,N-dimethylformamide or a mixture
solvent of N,N-dimethylformamide with toluene is used as the
solvent; the amount of the acylating agent used is 1.5 to 5.0
equivalents; the reaction temperature is 40 to 80°C; the reaction
time is 2 hours to 2 days; and regarding the base, no base is
used, or when a base is used, potassium carbonate or
dimethylaminopyridine is used in an amount of 0.01 to 2.0
equivalents.
When R is a hydroxyl group (for example, trifluoroacetic
acid), particularly preferred conditions are as follows: toluene,
N,N-dimethylformamide, xylene, N-methylpyrrolidinone,
N,N-dimethylacetamide, a mixture solvent of
N,N-dimethylformamide with toluene, a mixture solvent of
N,N-dimethylformamide with xylene, a mixture solvent of xylene
with N-methylpyrrolidinone, or a mixture solvent of xylene
with N,N-dimethylacetamide is used as the solvent; and the amount
of the acylating agent used is 1.0 to 3.0 equivalents. When
thionyl chloride, phosphorus oxychloride, or oxalyl dichloride
is used, particularly preferred conditions are as follows: the
reagent is used in an amount of 0.3 to 3.0 equivalents; no a base
is used; the reaction temperature is -10°C to 40°C; and the
reaction time is 0.5 hours to 1 day. When phosphorus pentoxide,
sulfuric acid, or polyphosphoric acid is used, particularly
preferred conditions are as follows: the reagent is used in an
amount of 0.5 to 2.0 equivalents; the reaction temperature is
-10°C to 160°C; and the reaction time is 0.5 hours to 1 day. When
N,N'-dicyclohexylcarbodiimide or
1-ethyl(3-dimethylaminopropyl)carbodiimide hydrochloride is
used, particularly preferred conditions are as follows: the
reagent is used in an amount of 0.5 to 3.0 equivalents; the
reaction temperature is -10°C to 40°C; triethylamine is used as
the base in an amount of 0.5 to 3.0 equivalents; and the reaction
time is 0.5 to 1 day. When zinc chloride, copper chloride,
magnesium chloride, cobalt chloride, nickel chloride, ferric
chloride, aluminum chloride, ferric sulfate, aluminum sulfate,
boron trifluoride, or p-toluenesulfonic acid is used,
particularly preferred conditions are as follows: the reagent
is used in an amount of 0.0001 to 0.5 equivalents; no base is
used; the reaction temperature is 80°C to 160°C; and the reaction
time is 2 hours to 2 days.
When R is a chlorine atom (for example, trifluoroacetyl
chloride), the conditions are as follows: toluene,
N,N-dimethylformamide, N-methylpyrrolidinone, or a mixture
solvent of any of these is used as the solvent; the amount of
the acylating agent used is 1.0 to 3.0 equivalents; the reaction
temperature is -30°C to 30°C; and the reaction time is 0.5 hours
to 8 hours. Regarding the base, the following conditions are
particularly preferable: no base is used, or when a base is used,
potassium carbonate is used in an amount of 1.0 to 3.0 equivalents.
Production of Compound Represented by Formula (I) or (I')
from Compound Represented by Formula (B) or Formula (B') in
One-Pot Production
Conditions particularly preferable for obtaining a
compound represented by formula (I) or formula (I') from a
compound represented by formula (B) or formula (B') are as
follows: R is a chlorine atom; N,N-dimethylformamide,
N-methylpyrrolidinone, N,N-dimethylacetamide, a mixture
solvent of N,N-dimethylformamide with toluene, a mixture solvent
of xylene with N,N-dimethylformamide, a mixture solvent of xylene
with N-methylpyrrolidinone, or a mixture solvent of xylene
with N,N-dimethylacetamid is used as the solvent; the amount of
Ar-CH -R used is 0.8 to 1.5 equivalents to the compound
represented by formula (B) or formula (B'); the reaction
temperature is 40°C to 80°C; the reaction time is 1 hour to 2
days; and regarding the base, potassium carbonate or
triethylamine is used in an amount of 1.0 to 5.0 equivalents.
Step of Producing Compound Represented by Formula (Ia) from
Compound Represented by Formula (Ba)
A method for obtaining a compound represented by formula
(Ia) from a compound represented by formula (Ba) is as follows.
Specifically, the compound represented by formula (Ia) can be
obtained reacting the compound represented by formula (Ba) with
an acylating agent R COR (R and R have the same meanings as
1a 2a 1a 2a
those defined above) without a solvent or in a solvent which does
not affect the reaction in the presence of or in the absence of
a base. Here, the numbers of equivalents of reagents herein are
all the numbers of equivalents to the compound represented by
formula (Ba).
Examples of usable solvents include aromatic
hydrocarbon-based solvents such as toluene, xylene, and
ethylbenzene; ester-based solvents such as ethyl acetate and
butyl acetate; ether-based solvents such as diethyl ether,
diisopropyl ether, tetrahydrofuran, and dioxane; aprotic polar
organic solvents such as N,N-dimethylformamide, dimethyl
sulfoxide, N,N-dimethylacetamide, N-methylpyrrolidinone,
and acetonitrile; halogen-containing solvents such as
dichloromethane and chloroform; hydrocarbon-based solvents such
as cyclohexane; ketone-based solvents such as acetone and methyl
ethyl ketone; water; and mixture solvents thereof.
Examples of usable bases include inorganic bases such as
sodium carbonate, potassium carbonate, sodium hydrogen carbonate,
potassium hydrogen carbonate, sodium hydroxide, magnesium
hydroxide, calcium hydroxide, lithium hydroxide, and barium
hydroxide; organic bases such as
1,8-diazabicyclo[5.4.0]undecene,
1,5-diazabicyclo[4.3.0]nonene, triethylamine,
diisopropylethylamine, pyridine, picoline, and
dimethylaminopyridine; and alcoholates such as sodium ethoxide,
sodium methoxide, and potassium tert-butoxide. The base does not
necessarily need to be used; however, when the reaction is carried
out in the presence of a base, the base can be used in an amount
of 0.01 to 20.0 equivalents.
Examples of the acylating agent R COR include
trifluoroacetic anhydride, trifluoroacetic acid, ethyl
trifluoroacetate, trifluoroacetyl chloride, and mixed acid
anhydrides. In addition, these acylating agents may be used
alone or in combination of two or more. Of these acylating agents,
trifluoroacetic anhydride, trifluoroacetic acid, ethyl
trifluoroacetate, or trifluoroacetyl chloride can be preferably
used. Moreover, when R represents a hydroxyl group, the reaction
can be carried out by simultaneously using a reagent such as
N,N'-dicyclohexylcarbodiimide,
1-ethyl(3-dimethylaminopropyl)carbodiimide hydrochloride,
1,1'-carbonyldiimidazole, dipyridyl disulfide, diimidazolyl
disulfide, 1,3,5-trichlorobenzoyl chloride,
1,3,5-trichlorobenzoyl anhydride, PyBop (registered trademark),
PyBrop (registered trademark), phosphorus pentoxide, sulfuric
acid, polyphosphoric acid, thionyl chloride, phosphorus
oxychloride, oxalyl dichloride, zinc chloride, copper chloride,
magnesium chloride, cobalt chloride, nickel chloride, ferric
chloride, aluminum chloride, ferric sulfate, aluminum sulfate,
boron trifluoride, or p-toluenesulfonic acid. The amount of the
acylating agent used is preferably 0.5 to 10.0 equivalents.
The reaction temperature is preferably in a range from -80°C
to 200°C. The reaction time is preferably in a range from 0.1
hours to 7 days.
Preferred modes are as follows:
(1) When R represents a trifluoroacetoxy group,
specifically when trifluoroacetic anhydride is used as the
acylating agent, preferred examples of the solvent include
ester-based solvents such as ethyl acetate and butyl acetate;
halogen-containing solvents such as dichloromethane and
chloroform; and aromatic hydrocarbon-based solvents such as
toluene, xylene, and ethylbenzene. Here, toluene is more
preferable. The reaction is preferably carried out in the
absence of a base; however, when a base is used, preferred examples
of the base include sodium carbonate, potassium carbonate,
potassium hydrogen carbonate, triethylamine, pyridine, and the
like, and potassium carbonate is more preferable. The amount of
the acylating agent used is preferably 1.0 to 5.0 equivalents,
and more preferably 1.0 to 1.5 equivalents. When a base is used,
the amount of the base used is preferably 1.0 to 4.5 equivalents,
and more preferably 1.0 to 3.0 equivalents. The reaction
temperature is preferably in a range from -20°C to 50°C, and more
preferably from -10°C to 30°C. The reaction time is preferably
in a range from 0.1 hours to 7 days, and more preferably in a
range from 0.5 hours to 4 hours.
Particularly preferred conditions are as follows:
trifluoroacetic anhydride is used as the acylating agent; toluene
is used as the solvent; the amount of the acylating agent used
is 1.0 to 1.5 equivalents; the reaction temperature is -10°C to
°C; and the reaction time is 0.5 to 4 hours. Regarding the base,
no base is used, or when a base is used, potassium carbonate is
used in an amount of 1.0 to 3.0 equivalents.
(2) When R represents a C alkyloxy group which may be
2 1-6
substituted with a halogen atom or a benzyloxy group whose phenyl
group may be substituted with a halogen atom, a methyl group,
a cyano group, a nitro group, or a methoxy group, specifically
when ethyl trifluoroacetate, methyl trifluoroacetate, or propyl
trifluoroacetate is used, particularly preferably when ethyl
trifluoroacetate or the like is used, preferred solvents include
aprotic polar organic solvents such as N,N-dimethylformamide,
dimethyl sulfoxide, N,N-dimethylacetamide,
N-methylpyrrolidinone, and acetonitrile; ether-based
solvents such as diethyl ether, diisopropyl ether,
tetrahydrofuran, and dioxane; and mixture solvents of any of these
solvents with an aromatic hydrocarbon-based solvent such as
toluene, xylene, or ethylbenzene; and more preferred solvents
include N,N-dimethylformamide, and a mixture solvent of
N,N-dimethylformamide with toluene. The reaction is preferably
carried out in the absence of a base; however, when a base is
used, preferred examples of the base include potassium carbonate,
triethylamine, dimethylaminopyridine, and the like, and more
preferred examples thereof include potassium carbonate and
dimethylaminopyridine. The amount of the acylating agent used
is preferably 1.0 to 5.0 equivalents, and more preferably 1.5
to 5.0 equivalents. When a base is used, the amount of the base
used is preferably 0.01 to 3.0 equivalents, and more preferably
0.01 to 2.0 equivalents. The reaction temperature is preferably
in a range from 20°C to 100°C, and more preferably from 40°C to
80°C. The reaction time is preferably in a range from 0.1 hours
to 7 days, and more preferably in a range from 1 hour to 2 days.
Particularly preferred conditions are as follows: ethyl
trifluoroacetate is used as the acylating agent;
N,N-dimethylformamide or a mixture solvent of
N,N-dimethylformamide with toluene is used as the solvent; the
amount of the acylating agent used is 1.0 to 5.0 equivalents;
the reaction temperature is 40°C to 80°C; and the reaction time
is 2 hours to 2 days. Regarding the base, no base is used, or
when a base is used, potassium carbonate or dimethylaminopyridine
is used in an amount of 0.01 to 2.0 equivalents.
(3) When R represents a C alkylcarbonyloxy group which
2 1-6
may be substituted with a halogen atom (provided that a
trifluoroacetoxy group is excluded) or a phenylcarbonyloxy group
whose phenyl group may be substituted with a halogen atom, a methyl
group, a cyano group, a nitro group, or a methoxy group, a specific
example thereof is a pivaloyl group. The reaction temperature
is preferably in a range from -20°C to 50°C, and more preferably
from -10°C to 30°C. The reaction time is preferably in a range
from 0.1 hours to 7 days, and more preferably in a range from
0.5 hours to 4 hours.
(4) When R represents a hydroxyl group, specific examples
of the acylating agent include trifluoroacetic acid,
difluorochloroacetic acid, trichloroacetic acid, difluoroacetic
acid, dichloroacetic acid, dibromoacetic acid, chloroacetic acid,
difluoropropionic acid, dichloropropionic acid,
2,2,2-trifluoropropionic acid, pentafluoropropionic acid,
difluorocyclopropanecarboxylic acid, and the like. Here,
trifluoroacetic acid, trichloroacetic acid, dichloroacetic acid,
difluoroacetic acid, difluorochloroacetic acid, chloroacetic
acid, and pentafluoropropionic acid are preferable;
trifluoroacetic acid, difluoroacetic acid, difluorochloroacetic
acid, and pentafluoropropionic acid are more preferable; and
trifluoroacetic acid is particularly preferable. When
trifluoroacetic acid is used, preferred examples of the solvent
include aromatic hydrocarbon-based solvents such as toluene,
xylene, and ethylbenzene; and aprotic polar organic solvents such
as N,N-dimethylformamide, dimethyl sulfoxide,
N,N-dimethylacetamide, N-methylpyrrolidinone, and
acetonitrile. Here, toluene, xylene, N,N-dimethylformamide,
N-methylpyrrolidinone, a mixture solvent of toluene with
N,N-dimethylformamide, a mixture solvent of xylene with
N,N-dimethylformamide, or a mixture solvent of xylene with
N-methylpyrrolidinone is more preferable. Examples of the
reagent used simultaneously include
N,N'-dicyclohexylcarbodiimide,
1-ethyl(3-dimethylaminopropyl)carbodiimide hydrochloride,
phosphorus pentoxide, sulfuric acid, polyphosphoric acid,
thionyl chloride, phosphorus oxychloride, oxalyl dichloride, and
the like. The reagent is preferably used in an amount of 0.2 to
5.0 equivalents. In addition, when zinc chloride, copper
chloride, magnesium chloride, cobalt chloride, nickel chloride,
ferric chloride, aluminum chloride, ferric sulfate, aluminum
sulfate, boron trifluoride, p-toluenesulfonic acid, or the like
is used as the reagent used simultaneously, the reagent is
preferably used in an amount of 0.0001 to 1.0 equivalents. The
reaction is preferably carried out in the absence of a base, when
phosphorus pentoxide, sulfuric acid, polyphosphoric acid,
thionyl chloride, phosphorus oxychloride, oxalyl dichloride,
zinc chloride, copper chloride, magnesium chloride, cobalt
chloride, nickel chloride, ferric chloride, aluminum chloride,
ferric sulfate, aluminum sulfate, boron trifluoride, or
p-toluenesulfonic acid is used. Meanwhile, The reaction is
preferably carried out in the presence of a base, when
N,N'-dicyclohexylcarbodiimide or
1-ethyl(3-dimethylaminopropyl)carbodiimide hydrochloride is
used. When a base is used, preferred examples of the base include
sodium carbonate, potassium carbonate, potassium hydrogen
carbonate, triethylamine, pyridine, dimethylaminopyridine, and
the like. Here, triethylamine is more preferable. The amount
of the acylating agent used is preferably 1.0 to 5.0 equivalents,
and more preferably 1.0 to 3.0 equivalents. When thionyl
chloride, phosphorus oxychloride, or oxalyl dichloride is used,
the reagent is preferably used in an amount of 0.2 to 5.0
equivalents, and the reaction temperature is preferably in a range
from -30°C to 80°C, and more preferably -10°C to 40°C. When
phosphorus pentoxide, sulfuric acid, or polyphosphoric acid is
used, the reagent is preferably used in an amount of 0.2 to 5.0
equivalents, and the reaction temperature is preferably in a range
from -30°C to 200°C, and more preferably from -10°C to 160°C.
When N,N'-dicyclohexylcarbodiimide or
1-ethyl(3-dimethylaminopropyl)carbodiimide hydrochloride is
used, preferred conditions are as follows: the reagent is used
in an amount of 0.2 to 5.0 equivalents; the reaction temperature
is preferably in a range from -30°C to 80°C, and more preferably
from -10°C to 40°C; and triethylamine is used as the base in an
amount of 0.2 to 5.0 equivalents. When zinc chloride, copper
chloride, magnesium chloride, cobalt chloride, nickel chloride,
ferric chloride, aluminum chloride, ferric sulfate, aluminum
sulfate, boron trifluoride, or p-toluenesulfonic acid is used,
the following conditions are preferable: the reagent is used in
an amount of 0.0001 to 1.0 equivalents; the reaction temperature
is preferably in a range from 20°C to 200°C, and more preferably
from 80°C to 160°C. The reaction time is preferably in a range
from 0.1 hours to 7 days, and more preferably in a range from
0.5 hours to 2 days.
Particularly preferred conditions are as follows:
trifluoroacetic acid is used as the acylating agent; toluene,
N,N-dimethylformamide, xylene, N-methylpyrrolidinone,
N,N-dimethylacetamide, a mixture solvent of
N,N-dimethylformamide with toluene, a mixture solvent of xylene
with N,N-dimethylformamide, a mixture solvent of xylene with
N-methylpyrrolidinone, or a mixture solvent of xylene with
N,N-dimethylacetamide is used as the solvent; and the amount of
the acylating agent used is 1.0 to 3.0 equivalents. When thionyl
chloride, phosphorus oxychloride, or oxalyl dichloride is used,
particularly preferred conditions are as follows: the reagent
is used in an amount of 0.3 to 3.0 equivalents; no base is used;
the reaction temperature is -10°C to 40°C; and the reaction time
is 0.5 hours to 1 day. When phosphorus pentoxide, sulfuric acid,
or polyphosphoric acid is used, particularly preferred conditions
are as follows: the reagent is used in an amount of 0.2 to 2.0
equivalents; the reaction temperature is -10°C to 160°C; and the
reaction time is 0.5 hours to 1 day. When
N,N'-dicyclohexylcarbodiimide or
1-ethyl(3-dimethylaminopropyl)carbodiimide hydrochloride is
used, particularly preferred conditions are as follows: the
reagent is used in an amount of 0.5 to 3.0 equivalents; the
reaction temperature is -10°C to 40°C; triethylamine is used as
a base in an amount of 0.5 to 3.0 equivalents; and the reaction
time is 0.5 to 1 day. When zinc chloride, copper chloride,
magnesium chloride, cobalt chloride, nickel chloride, ferric
chloride, aluminum chloride, ferric sulfate, aluminum sulfate,
boron trifluoride, or p-toluenesulfonic acid is used,
particularly preferred conditions are as follows: the reagent
is used in an amount of 0.0001 to 0.5 equivalents; no base is
used; the reaction temperature is 80°C to 160°C; and the reaction
time is 2 hours to 2 days.
(5) When R represents a halogen atom, specifically when
trifluoroacetyl chloride or trifluoroacetyl bromide is used,
preferably when trifluoroacetyl chloride is used, preferred
examples of the solvent include aromatic hydrocarbon-based
solvents such as toluene, xylene, and ethylbenzene;
halogen-containing solvents such as dichloromethane and
chloroform; and aprotic polar organic solvents such as
N,N-dimethylformamide, dimethyl sulfoxide,
N,N-dimethylacetamide, N-methylpyrrolidinone, and
acetonitrile. Here, toluene, N,N-dimethylformamide,
N-methylpyrrolidinone, or a mixture solvent of any of these
is more preferable. The reaction is preferably carried out in
the absence of a base; however, when a base is used, preferred
examples of the base include sodium carbonate, potassium
carbonate, potassium hydrogen carbonate, triethylamine,
pyridine, and the like. Here, potassium carbonate is more
preferable. The amount of the acylating agent used is preferably
1.0 to 5.0 equivalents, and more preferably 1.0 to 3.0 equivalents.
When a base is used, the amount of the base used is preferably
1.0 to 5.0 equivalents, and more preferably 1.0 to 3.0 equivalents.
The reaction temperature is preferably in a range from -80°C to
40°C, and more preferably from -30°C to 30°C. The reaction time
is preferably in a range from 0.1 hours to 7 days, and more
preferably in a range from 0.5 hours to 8 hours.
Moreover, when R represents a chlorine atom, it is also
possible to use R COCl generated in advance by simultaneously
using trifluoroacetic acid with thionyl chloride, phosphorus
oxychloride, oxalic acid dichloride, or the like outside the
reaction system in which the reaction of the compound represented
by formula (Aa) is carried out.
Particularly preferred conditions are as follows:
trifluoroacetyl chloride is used as the acylating agent; toluene,
N,N-dimethylformamide, N-methylpyrrolidinone, or a mixture
solvent thereof is used as the solvent; the amount of the acylating
agent used is 1.0 to 3.0 equivalents; the reaction temperature
is -30°C to 30°C; and the reaction time is 0.5 hours to 8 hours.
Regarding the base, particularly preferred conditions are as
follows: no base is used, or when a base is used, potassium
carbonate is used in an amount of 1.0 to 3.0 equivalents.
The compound represented by formula (Ba) can be obtained
by the method described in Patent Document 3, or the like.
Specifically, in a method for producing a compound represented
by formula (Ba) from a compound represented by formula (Aa), the
compound represented by formula (Ba) can be obtained by reacting
a compound represented by formula (Aa) with a compound represented
by formula (Ca) (X, R , and R have the same meanings as those
defined above) without a solvent or in a solvent which does not
affect the reaction in the presence of or in the absence of a
base.
[Chem. 9]
Examples of usable solvents include ether-based solvents
such as diethyl ether, diisopropyl ether, tetrahydrofuran, and
dioxane; aprotic polar organic solvents such as
N,N-dimethylformamide, dimethyl sulfoxide,
N,N-dimethylacetamide, acetonitrile, N-methylpyrrolidinone,
N-methylpiperazinone, and N,N-dimethylimidazolidinone;
halogen-containing solvents such as dichloromethane and
chloroform; aromatic hydrocarbon-based solvents such as toluene,
xylene, and ethylbenzene; and mixture solvents of any of these;
and preferred examples thereof include aprotic polar organic
solvents. Here, N,N-dimethylformamide, N,N-dimethylacetamide,
or toluene is more preferable.
The reaction can be carried out even when no base is used;
however, when a base is used, examples of usable bases include
inorganic bases such as sodium carbonate, potassium carbonate,
sodium hydrogen carbonate, potassium hydrogen carbonate, sodium
hydroxide, potassium hydroxide, magnesium hydroxide, calcium
hydroxide, lithium hydroxide, and barium hydroxide; and organic
bases such as 1,8-diazabicyclo[5.4.0]undecene,
1,5-diazabicyclo[4.3.0]nonene, triethylamine,
diisopropylethylamine, pyridine, lutidine, N,N-dimethylaniline,
N,N-diethylaniline, and dimethylaminopyridine; preferred
examples thereof include potassium carbonate, triethylamine,
pyridine, and the like; and more preferred examples thereof
include triethylamine and potassium carbonate.
When a base is used, the amount of the base used is preferably
1.0 to 3.0 equivalents, and more preferably 1.1 to 2.5 equivalents,
relative to the compound represented by formula (Aa). The
reaction temperature is preferably in a range from -20°C to 150°C,
and more preferably from -10°C to 100°C.
The reaction time is preferably in a range from 0.1 hours
to 7 days, and more preferably from 1 hour to 2 days.
[Chem. 10]
Another example of the method for obtaining the compound
represented by formula (Ba) is a method in which a compound
represented by formula (Ib) is hydrolyzed, to thereby produce
a compound represented by formula (Ba) (in the formula, R , R ,
and X have the same meanings as those defined above).
Examples of usable solvents include ether-based solvents
such as diethyl ether, diisopropyl ether, tetrahydrofuran, and
dioxane; aprotic polar organic solvents such as
N,N-dimethylformamide, dimethyl sulfoxide,
N,N-dimethylacetamide, acetonitrile, N-methylpyrrolidinone,
N-methylpiperazinone, and N,N-dimethylimidazolidinone;
halogen-containing solvents such as dichloromethane and
chloroform; aromatic hydrocarbon-based solvents such as toluene,
xylene, and ethylbenzene; alcohol-based solvents such as methanol
and ethanol; water; and mixture solvents of any of these;
preferred examples thereof include aromatic hydrocarbon-based
solvents, aprotic polar organic solvents, and mixture solvents
of water with an alcohol-based solvent. Here, a mixture solvent
of water with N,N-dimethylformamide, methanol, or toluene is more
preferable. As the acid, a mineral acid such as hydrochloric acid,
sulfuric acid, phosphoric acid, or nitric acid can be used. As
the base, an inorganic base such as sodium carbonate, potassium
carbonate, sodium hydrogen carbonate, potassium hydrogen
carbonate, sodium hydroxide, magnesium hydroxide, calcium
hydroxide, lithium hydroxide, or barium hydroxide can be used.
The reaction temperature is preferably in a range from -20°C to
150°C, and more preferably from 70°C to 100°C. The reaction time
is preferably in a range from 0.1 hours to 7 days, and more
preferably from 1 hour to 8 hours.
When a compound represented by formula (Ia) is synthesized
from a compound represented by formula (Aa) through a compound
represented by formula (Ba), the compound represented by formula
(Ia) can be obtained by conducting the subsequent step, without
isolation of the compound represented by formula (Ba).
When a compound represented by formula (I) or formula (Ia)
is synthesized from a compound represented by formula (A) or
formula (Aa), the compound represented by formula (I) or formula
(Ia) can be obtained by a reaction of the acylating agent, the
solvent, Ar-CH -R , and the base at once.
When a compound represented by formula (I) or formula (Ia)
is obtained from a compound represented by formula (A) or formula
(Aa) by a reaction using the acylating agent, the solvent,
Ar-CH -R , and the base at once, a preferred example is as follows.
Specifically, a reaction of a compound represented by formula
(A) or formula (Aa) is allowed to proceed at 20°C to 100°C for
2 hours to 3 days by using an aromatic hydrocarbon-based solvent
such as toluene, xylene, or ethylbenzene; an aprotic solvent such
as N,N-dimethylformamide, dimethyl sulfoxide,
N,N-dimethylacetamide, acetonitrile, or
N-methylpyrrolidinone; or a mixture solvent thereof, an
acylating agent in which R represents a C alkoxy group which
2 1-6
may be substituted with a halogen atom and which is used in an
amount of 1.0 to 5.0 equivalents to the compound represented by
formula (A) or (Aa), and a base in an amount of 1.0 to 10.0
equivalents to the compound represented by formula (A) or (Aa),
and adding Ar-CH -R in an amount of 0.8 to 1.5 equivalents to
the compound represented by formula (A) or (Aa), to thereby obtain
the compound represented by formula (I) or formula (Ia). Here,
specific examples of the acylating agent include ethyl
trifluoroacetate, methyl trifluoroacetate, propyl
trifluoroacetate, and the like. Moreover, examples of the base
used include inorganic bases such as sodium carbonate, potassium
carbonate, sodium hydrogen carbonate, potassium hydrogen
carbonate, sodium hydroxide, magnesium hydroxide, calcium
hydroxide, lithium hydroxide, and barium hydroxide; organic bases
such as 1,8-diazabicyclo[5.4.0]undecene,
1,5-diazabicyclo[4.3.0]nonene, triethylamine,
diisopropylethylamine, pyridine, picoline, and
dimethylaminopyridine; and alcoholates such as sodium ethoxide,
sodium methoxide, and potassium tert-butoxide.
Particularly preferred conditions are as follows: toluene,
N,N-dimethylformamide, or a mixture solvent of toluene with
N,N-dimethylformamide is used as the solvent; ethyl
trifluoroacetate is used as the acylating agent; R in Ar-CH -R
4 2 4
is a chlorine atom; potassium carbonate is used as the base;
the amount of the acylating agent is preferably 1.0 to 5.0
equivalents, and more preferably 1.5 to 5.0 equivalents, the
amount of Ar-CH -R is 0.8 to 1.5 equivalents, and the amount of
the base is 1.0 to 5.0 equivalents, relative to the compound
represented by formula (I) or formula (Ia); the reaction
temperature is 40°C to 80°C; and the reaction time is 4 hours
to 2 days.
Method for Purifying and Isolating Compound Represented by
Formula (I) or Compound Represented by Formula (Ia) from Crude
Product
The compound represented by formula (I) and the compound
represented by formula (Ia) can be purified and isolated by any
one of or a combination of crystallization, solvent extraction,
column chromatography, and the like, which are ordinarily
employed. The solvent used for the solvent extraction is not
particularly limited, as long as the solvent is immiscible with
water, and specific examples thereof include ethyl acetate, butyl
acetate, toluene, ethylbenzene, diethyl ether, diisopropyl ether,
dichloromethane, chloroform, and the like. Examples of the
solvent used for the crystallization include water, hexane,
toluene, acetone, N,N-dimethylformamide, methanol, 2-propanol,
dichloromethane, chloroform, ethyl acetate, diethyl ether,
xylene, N-methylpyrrolidinone, N,N-dimethylacetamide, and
the like; as well as mixture solvents of any of these.
A preferred method for purifying and isolating the compound
represented by formula (I) and the compound represented by formula
(Ia) is crystallization. Here, one of or a combination of acetone,
toluene, water, N,N-dimethylformamide, methanol, xylene,
N-methylpyrrolidinone, and N,N-dimethylacetamide is
preferably used as a crystallization solvent, and combinations
of any of water, N,N-dimethylformamide, methanol,
N-methylpyrrolidinone, and N,N-dimethylacetamide are more
preferable.
Examples
Specific examples of the present invention are shown below;
however, the present invention is not limited thereto.
Synthesis Example 1: Synthesis of
N-[1-((6-Chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide (Compound 1)
(1) In 200 ml of anhydrous dichloromethane, 25 g (270 mmol)
of 2-aminopyridine was dissolved, and 41 ml (30 g, 300 mmol) of
triethylamine was added thereto, followed by cooling to 0°C. To
this mixture, 38 ml (57 g, 270 mmol) of trifluoroacetic anhydride
was added dropwise over 15 minutes, followed by stirring at room
temperature for 2 hours. After completion of the reaction, the
reaction liquid was poured into approximately 100 ml of ice-water,
followed by stirring for 10 minutes. The mixture was transferred
to a separatory funnel, and phase separation was conducted. The
organic layer was washed twice with 150 ml of water, and twice
with 150 ml of a 1% aqueous HCL solution, then dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure.
Thus, 36 g of
2,2,2-trifluoro-N-(pyridin-2(1H)-ylidene)acetamide was
obtained (Percentage Yield: 71%).
1H-NMR (CDCl3, δ, ppm):
7.20 (1H, m), 7.83 (1H, m), 8.20 (1H, d), 8.35 (1H, d), 10.07
(1H, brs)
13C-NMR (CDCl3, δ, ppm): 115.3, 115.5 (q), 121.6, 139.1, 147.9,
149.5, 155.3 (q)
MS: m/z=191(M+H).
(2) In 200 ml of anhydrous acetonitrile, 20 g (126 mmol)
of 2-chlorochloromethylpyridine was dissolved. Then, 24 g
(126 mmol) of the
2,2,2-trifluoro-N-(pyridin-2(1H)-ylidene)acetamide obtained by
the above-described method and 21 g (151 mmol) of potassium
carbonate were added to the solution. The mixture was heated
under reflux for 6 hours, followed by stirring at room temperature
for 10 hours. After completion of the reaction, the reaction
liquid was filtered, and the filtrate was concentrated under
reduced pressure. Diethyl ether was added to the residue for
crystallization. The crystals formed were collected by
filtration, and thoroughly washed with diethyl ether and water.
The obtained crystals were dried under reduced pressure at 60°C
for 1 hour. Thus, the target substance was obtained. Yield: 26
g (Percentage Yield: 66%).
1H-NMR (CDCl3, δ, ppm):
.57 (2H, s), 6.92 (1H, td), 7.31 (1H, d), 7.80 (1H, td), 7.87
(1H, dd), 7.99 (1H, dd), 8.48 (2H, m)
13C-NMR (CDCl3, δ, ppm):
53.8, 115.5, 117.2 (q), 122.1, 124.7, 130.0, 139.2, 140.0, 142.5,
149.7, 151.8, 158.9, 163.5 (q)
MS: m/z=316(M+H).
(3) Powder X-ray crystallography
Powder X-ray diffraction measurement was carried out under
the following conditions;
Apparatus name: RINT-2200 (Rigaku Corporation)
X-ray: Cu-Kα (40 kV, 20 mA)
Scan Range: 4 to 40°, Sampling width: 0.02°, Scan rate: 1°/minute
The results are as follows (Fig. 1).
Diffraction angles (2θ): 8.7°, 14.2°, 17.5°, 18.3°, 19.8°, 22.4°,
30.9°, 35.3°.
(4) Differential Scanning Calorimetry (DSC)
Differential scanning calorimetry was carried out under the
following conditions:
Apparatus name: DSC-60
Sample cell: aluminum
Temperature range: 50°C to 250°C (Temperature rise: 10°C/minute)
Fig. 2 shows the results.
(5) Moreover, crystals of the same quality were obtained
by recrystallization according to the methods (second to fifth
production methods) described in the following (i) to (iv).
These kinds of crystals were subjected to powder X-ray
crystallography and differential scanning calorimetry under the
same measurement conditions as described above.
(i) Second Production Method
To Compound 1 (700 mg), approximately 25 ml of hexane and
approximately 25 ml of ethyl acetate were added, and Compound
1 was completely dissolved therein by being heated at 65°C in
a hot-water bath. The solution was slowly returned to room
temperature, and allowed to stand overnight. The crystals
precipitated were collected by filtration, and washed with a small
amount of a solution of hexane:ethyl acetate=95:5. The crystals
were dried in a desiccator under reduced pressure for 2 hours.
Thus, 349 mg of white crystals were obtained.
The results of the powder X-ray crystallography are as
follows (Fig. 3).
Diffraction angle (2θ): 8.5°, 14.0°, 17.3°, 18.1°, 19.6°, 22.2°,
.8°, 35.2°
Fig. 4 shows the results of the differential scanning
calorimetry.
(ii) Third Production Method
To Compound 1 (1.0 g), 28 ml of 2-propanol was added, and
Compound 1 was completely dissolved by being heated at 65°C in
a hot-water bath. The solution was slowly returned to room
temperature, and allowed to stand overnight. The crystals
precipitated were collected by filtration, then washed with a
small amount of 2-propanol, and then dried in a desiccator under
reduced pressure for 2 hours. Thus, 695 mg of white crystals were
obtained.
Fig. 5 shows the results of the differential scanning
calorimetry.
(iii) Fourth Production Method
To Compound 1 (700 mg), approximately 30 ml of toluene was
added, and Compound 1 was completely dissolved by being heated
at 65°C in a hot-water bath. The mixture was slowly returned to
room temperature, and allowed to stand overnight. The crystals
precipitated were collected by filtration, washed with a small
amount of toluene, and then dried in a desiccator under reduced
pressure for 2 hours. Thus, 440 mg of white crystals were
obtained.
The results of the powder X-ray crystallography are as
follows (Fig. 6).
Diffraction angle (2θ): 8.6°, 14.2°, 17.5°, 18.3°, 19.7°, 22.3°,
.9°, 35.3°
Fig. 7 shows the results of the differential scanning
calorimetry.
(iv) Fifth Production Method
To Compound 1 (50 mg), approximately 2 ml of methanol and
approximately 2 ml of water were added, and Compound 1 was
dissolved by being heated at 65°C in a hot-water bath. This
solution was returned to room temperature, and allowed to stand
overnight. The crystals precipitated were collected by
filtration. Thus, 16 mg of white crystals ware obtained.
Fig. 8 shows the results of the differential scanning
calorimetry.
Table 1 shows specific examples of compounds which are pest
control agents represented by formula (I), and were produced by
methods similar to the method of Synthesis Example 1, and also
shows physical properties of the compounds.
[Table 1]
Synthesis Example 2: Synthesis of
2,2,2-trifluoro-N-(pyridin-2(1H)-ylidene)acetamide
In 10 ml of ethyl acetate, 1.0 g (10.6 mmol) of
2-aminopyridine was dissolved, and 1.78 ml (12.7 mmol) of
triethylamine was added thereto. Then, under ice-cooling, 1.62
ml (11.7 mmol) of trifluoroacetic anhydride was added thereto.
After that, the mixture was stirred at room temperature for 2
hours, and then 10 ml of ethyl acetate and 10 ml of water were
added to this mixture. The resultant mixture was stirred, and
then phase separation was conducted. The ethyl acetate layer was
further washed twice with 10 ml of water, then dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure.
Thus, 1.56 g of
2,2,2-trifluoro-N-(pyridin-2(1H)-ylidene)acetamide was
obtained (77.2%).
Synthesis Example 3: Synthesis of
2,2,2-Trifluoro-N-(pyridin-2(1H)-ylidene)acetamide
In 25 ml of N,N-dimethylformamide, 4.7 g (50 mmol) of
2-aminopyridine was dissolved, and 35.5 g (250 mmol) of ethyl
trifluoroacetate was added thereto. After that, the mixture was
stirred at 55 to 60°C for 15 hours, and then 100 ml of ethyl acetate
and 100 ml of water were added thereto. The resultant mixture
was stirred, and then phase separation was conducted. The ethyl
acetate layer was further washed with 100 ml of water and with
100 mL of aqueous sodium chloride, then dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure.
Thus, 9.05 g of
2,2,2-trifluoro-N-(pyridin-2(1H)-ylidene)acetamide was
obtained (95.6%).
1H-NMR (CDCl3, δ, ppm):
7.20 (1H, ddd), 7.83 (1H, td), 8.20 (1H, d), 8.35 (1H, d), 10.07
(1H, brs).
Synthesis Example 4: Synthesis of
N-[1-((6-chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide
In 400 ml of toluene, 50.0 g (0.53 mol) of 2-aminopyridine
was dissolved, and then 88.6 ml (0.64 mol) of trifluoroacetic
anhydride was added to the mixture dropwise over 30 minutes under
cooling to 5°C. After the dropwise addition, the mixture was
stirred at room temperature for 30 minutes, and 20 ml of toluene
was distilled off under reduced pressure. To the reaction liquid,
250 ml of dimethylformamide was added, and 88.2 g (0.64 mol) of
potassium carbonate powder was gradually added to the reaction
liquid under ice-cooling. After that, 89.2 g (0.557 mol) of
2-chlorochloromethylpyridine was added to the reaction liquid.
Under a reduced pressure (50 to 60 hPa) at 40 to 45°C, toluene
was gradually distilled off, and the mixture was heated for 1
hour. Distillation by heating was further conducted at 60 to 70°C
and 35 hPa for 2.5 hours. Then, 5.0 g (0.036 mol) of potassium
carbonate powder was added, and water was removed at 50 to 60°C
and 35 hPa for further 1 hour. The reaction liquid was added to
2 L of water of 50°C, and after completion of the addition, the
mixture was stirred for 30 minutes. After that, the mixture was
filtered, and the crystals were subjected to slurry washing with
200 ml of water and subsequently with 500 ml of water. After the
filtration, the crystals were washed with 100 ml of toluene, while
being pressed. Further, the crystals were subjected to slurry
washing with 400 ml of toluene. The obtained crystals were dried
under reduced pressure at 60°C overnight with a vacuum pump. Thus,
147.78 g of the target compound
N-[1-((6-chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide was obtained (88.1%). Then, 8.21 g of the
obtained title compound was sampled, and dissolved in 100 mL of
acetone. To this solution, 300 mL of water was added, and the
mixture was stirred at room temperature. The crystals
precipitated were collected by filtration, and the obtained
crystals were dried under reduced pressure at 60°C overnight with
a vacuum pump. Thus, 7.28 g of crystals were obtained. The
results of powder X-ray crystallography conducted on the obtained
crystals are as follows (Fig. 9).
Diffraction angles (2θ): 8.8°, 14.3°, 17.6°, 18.3°, 19.9°, 22.5°,
31.0°, 35.4°
Synthesis Example 5: Synthesis of
N-[1-((6-Chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide
In 250 ml of toluene, 50.0 g (0.53 mol) of 2-aminopyridine
was dissolved, and then 88.6 ml (0.64 mol) of trifluoroacetic
anhydride was added dropwise over 30 minutes to the solution under
cooling to 5°C. After the dropwise addition, the mixture was
stirred at room temperature for 30 minutes, and 20 ml of toluene
was distilled off under reduced pressure. To the reaction liquid,
250 ml of dimethylformamide was added, and then 88.2 g (0.64 mol)
of potassium carbonate powder was added gradually to the reaction
liquid under ice-cooling. After that, 87.0 g (0.54 mol) of
2-chlorochloromethylpyridine was added, and toluene was
gradually distilled off under a reduced pressure (50 to 60 hPa)
at 50 to 60°C, followed by heating at 35 hPa. One hour later,
5.0 g (0.036 mol) of potassium carbonate powder was added, and
water was removed at 50 to 60°C and 35 hPa. Four hours later,
the reaction liquid was added to 1.1 L of water of 50°C. The
reaction vessel was washed with 150 ml of methanol, and the washing
liquid was also added to the water. After the completion of the
addition, the mixture was heated at 50°C for 10 minutes, cooled
gradually, and stirred at 15 to 20°C for 30 minutes. Then, the
crystals were filtered, and washed with 150 ml of water, and
subsequently with 150 ml of toluene. The obtained crystals were
dried under reduced pressure at 60°C for 11 hours with a vacuum
pump. Thus, 147.32 g of the target compound
N-[1-((6-chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide was obtained (87.8%).
Synthesis Example 6: Synthesis of
N-[1-((6-Chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide
In 10 ml of toluene, 1.0 g (10.6 mmol) of 2-aminopyridine
was dissolved. After the solution was cooled to 5°C, 1.18 ml (15.9
mmol) of trifluoroacetic acid and 0.99 ml (10.6 mmol) of
phosphorus oxychloride were added thereto, followed by stirring
at room temperature for 6.5 hours. To the reaction liquid, 5.0
ml of dimethylformamide, 5.87 g (42.5 mmol) of potassium carbonate
powder, and 1.72 g (10.6 mmol) of 2-chlorochloromethylpyridine
were added, and distillation was conducted under reduced pressure
(60 to 35 hPa) at 50 to 60°C. Two and a half hours later, the
reaction liquid was added to 100 ml of water, and the crystals
were filtered, and washed with 30 ml of water and 15 ml of toluene.
The obtained crystals were dried under reduced pressure at 60°C.
Thus, 2.09 g of the target compound
N-[1-((6-chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide was obtained (62.3%).
Synthesis Example 7: Synthesis of
N-[1-((6-Chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide
In 100 ml of toluene, 10.0 g (0.106 mol) of 2-aminopyridine
was dissolved. After the solution was cooled to 5°C, 11.8 ml
(0.159 mol) of trifluoroacetic acid and 9.9 ml (0.106 mol) of
phosphorus oxychloride were added, followed by stirring at room
temperature overnight. Then, 20 ml of toluene was distilled off
under reduced pressure. To the reaction liquid, 50 ml of
dimethylformamide, 35.28 g (0.256 mol) of potassium carbonate
powder, and 17.22 g (0.106 mol) of
2-chlorochloromethylpyridine were added under ice-cooling.
Then, distillation was conducted under reduced pressure (60 to
hPa) at 50 to 60°C. Two hours later, 25 ml of dimethylformamide,
ml of toluene, and 7.35 g (0.053 mol) of potassium carbonate
powder were further added, and then distillation was conducted
under reduced pressure (60 to 35 hPa) at 50 to 60°C for 2 hours.
To the reaction liquid, 60 ml of methanol and 50 ml of water were
added, and the reaction liquid was added to 300 ml of water, while
the vessel was also washed. Thirty minutes later, the crystals
were filtered, and washed with 70 ml of water and 40 ml of toluene.
The obtained crystals were dried under reduced pressure at 60°C.
Thus, 25.75 g of the target compound was obtained (76.9%).
Synthesis Example 8: Synthesis of
N-[1-((6-Chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide
In 100 ml of toluene, 10.0 g (0.106 mol) of 2-aminopyridine
was dissolved. After the solution was cooled to 5°C, 11.8 ml
(0.159 mol) of trifluoroacetic acid and 7.7 ml (0.106 mol) of
thionyl chloride were added thereto, followed by stirring at room
temperature overnight. Then, 20 ml of toluene was distilled off
under reduced pressure. To the reaction liquid, 50 ml of
dimethylformamide, 35.28 g (0.256 mol) of potassium carbonate
powder, and 17.22 g (0.106 mol) of
2-chlorochloromethylpyridine were added under ice-cooling.
Then, distillation was conducted under reduced pressure (36 hPa)
at 50 to 60°C for 1 hour. To the reaction liquid, 60 ml of methanol
and 50 ml of water were added, and the reaction liquid was added
to 300 ml of water, while the vessel was also washed. Thirty
minutes later, the crystals were filtered, and washed with 70
ml of water and 40 ml of toluene. The obtained crystals were dried
under reduced pressure at 60°C. Thus, 22.31 g of the target
compound was obtained (66.6%).
Synthesis Example 9: Synthesis of
N-[1-((6-Chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide
In 50 ml of toluene, 5.0 g (0.053 mol) of 2-aminopyridine
was dissolved, and 8.86 ml (0.064 mol) of trifluoroacetic
anhydride was added dropwise thereto over 10 minutes under cooling
to 5°C. After the dropwise addition, the mixture was stirred at
room temperature for 30 minutes, and 10 ml of toluene was distilled
off under reduced pressure. To the reaction liquid, 25 ml of
dimethylformamide was added, and then 8.82 g of potassium
carbonate powder was gradually added thereto under ice-cooling.
After that, 11.78 g (0.053 mol) of
2-chloromethanesulfonyloxymethylpyridine was added, and
toluene was gradually distilled off under reduced pressure (50
to 60 hPa) at 50 to 60°C, followed by heating at 35 hPa. Thirty
minutes later, 30 ml of dimethylformamide, 30 ml of toluene, and
1.18 g (0.0053 mol) of
2-chloromethanesulfonyloxymethylpyridine were added, and
reduced pressure distillation was conducted at 50 to 60°C and
55 hPa. Four hours later, the reaction liquid was added to 250
ml of water. Then, the reaction vessel was washed with 30 ml of
methanol and 20 ml of water, and the washing liquids were also
added to the water. After completion of the addition, the mixture
was stirred at room temperature for 30 minutes. Then, the
crystals were filtered, and washed with 50 ml of water, and
subsequently with 40 ml of toluene. The obtained crystals were
dried under reduced pressure at 80°C for 11 hours with a vacuum
pump. Thus, 11.63 g of the target compound
N-[1-((6-chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide was obtained (69.4%).
Synthesis Example 10: Synthesis of
N-[1-((6-Chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide
In 100 ml of toluene, 10.0 g (0.106 mol) of 2-aminopyridine
was dissolved. After the solution was cooled to 5°C, 11.84 ml
(0.159 mol) of trifluoroacetic acid and subsequently 5.94 ml
(0.064 mol) of phosphorus oxychloride were added thereto,
followed by stirring at room temperature overnight. Then, 20 ml
of toluene was distilled off under reduced pressure. To the
reaction liquid, 50 ml of dimethylformamide, 22.03 g (0.16 mol)
of potassium carbonate powder, and 17.56 g (0.108 mol) of
2-chlorochloromethylpyridine were added under ice-cooling.
Then, distillation was conducted under reduced pressure (60 to
hPa) at 50 to 60°C. One hour later, 20 ml of dimethylformamide,
ml of toluene, and 4.41 g (0.032 mol) of potassium carbonate
powder were further added thereto, and distillation was conducted
under reduced pressure (60 to 35 hPa) and 50 to 60°C for 1.5 hours.
The reaction liquid to which 30 ml of methanol was added was added
to 250 ml of water of 50°C. Then, 50 ml of water was added thereto,
while the vessel was also washed therewith. After being cooled
to room temperature, the mixture was stirred for 30 minutes. The
crystals were filtered, and washed with 50 ml of water and 30
ml of toluene. The obtained crystals were dried under reduced
pressure at 60°C. Thus, 23.69 g of the target compound was
obtained (70.6%).
Synthesis Example 11: Synthesis of
N-[1-((6-Chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide
In 100 ml of toluene, 10.0 g (0.106 mol) of 2-aminopyridine
was dissolved. After the solution was cooled to 5°C, 11.8 ml
(0.159 mol) of trifluoroacetic acid and subsequently 7.76 ml
(0.106 mol) of thionyl chloride were added thereto portionwise,
followed by stirring at room temperature overnight. Then, 50 ml
of toluene was distilled off under reduced pressure. To the
reaction liquid, 50 ml of toluene was added. Then, 50 ml of
dimethylformamide, 22.03 g (0.16 mol) of potassium carbonate
powder, and 17.56 g (0.108 mol) of
2-chlorochloromethylpyridine were added thereto under
ice-cooling. Then, distillation was conducted under reduced
pressure (90 to 36 hPa) at 60°C for 1.5 hours. To the reaction
liquid, 30 ml of methanol and 20 ml of water were added. The
reaction liquid was added to 300 ml of water of 50°C, while the
vessel was also washed. The mixture was stirred at room
temperature for 30 minutes, and then the crystals were filtered,
and washed with 50 ml of water and 30 ml of toluene. The obtained
crystals were dried under reduced pressure at 60°C. Thus, 21.45
g of the target compound was obtained (64.1%).
Synthesis Example 12: Synthesis of
N-[1-((6-Chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide
In 500 mL of dimethylformamide, 94 g (1 mol) of
2-aminopyridine was dissolved, and 284 g (2 mol) of ethyl
trifluoroacetate was added thereto, followed by stirring at 55
to 60°C for 24 hours. To the reaction liquid, 82.8 g (0.6 mol)
of potassium carbonate powder, 153.9 g (0.95 mol) of
2-chlorochloromethylpyridine, and 300 mL of toluene were added,
followed by stirring under reduced pressure (36 hPa) at 50 to
60°C for 3 hours. To the reaction liquid, 200 mL of methanol was
added. Then, the reaction liquid was added to 2 L of hot water
of 50°C. After being cooled to room temperature, the mixture was
stirred for 3 hours. The crystals were filtered, and washed with
400 mL of water and 450 mL of toluene. The obtained crystals were
dried under reduced pressure at 45°C. Thus, 228.9 g of the target
compound was obtained (Percentage Yield: 72.7%).
Synthesis Example 13: Synthesis of
N-[1-((6-Chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide
In a mixture solvent of 30 mL of dimethylformamide and 20
ml of toluene, 9.4 g (0.1 mol) of 2-aminopyridine was dissolved,
and 28.4 g (0.2 mol) of ethyl trifluoroacetate was added thereto,
followed by stirring at 60 to 65°C for 8 hours. To the reaction
liquid, 16.6 g (0.12 mol) of potassium carbonate powder and 16.2
g (0.1 mol) of 2-chlorochloromethylpyridine were added,
followed by stirring at 60 to 65°C for 15 hours. To the reaction
liquid, 15 mL of methanol was added, and then the reaction liquid
was added to 120 mL of hot water of 50°C. After being cooled to
room temperature, the mixture was stirred for 2 hours. The
crystals were filtered, and washed with 50 mL of water and 100
mL of toluene. The obtained crystals were dried under reduced
pressure at 45°C. Thus, 25.6 g of the target compound was obtained
(Percentage Yield: 81.2%).
Synthesis Example 14: Synthesis of
N-[1-((6-Chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide
To 13.68 g (0.12 mol) of trifluoroacetic acid, 1.5 mL of
dimethylformamide was added. Then, 14.28 g (0.12 mol) of thionyl
chloride was added to the mixture, which was heated to 65°C.
Trifluoroacetyl chloride generated therefrom was bubbled into
a solution which was obtained by dissolving 9.4 g (0.1 mol) of
2-aminopyridine in 50 mL of N-methylpyrrolidone, and which was
cooled to -10°C, and the mixture was stirred for 1 hour. To the
reaction liquid, 100 mL of toluene, 48.3 g (0.35 mol) of potassium
carbonate powder, and 16.52 g (0.102 mol) of
2-chlorochloromethylpyridine were added, and distillation
was conducted under reduced pressure (36 hPa) at 50 to 60°C for
3 hours. To the reaction liquid, 20 mL of methanol was added,
and the mixture was added to 300 ml of water heated to 50°C, while
the vessel was also washed. The mixture was stirred at room
temperature for 1.5 hours. Then, the crystals were filtered, and
washed with 100 mL of water and 150 mL of toluene. The obtained
crystals were dried under reduced pressure at 45°C. Thus, 16.8
g of the target compound was obtained (Percentage Yield: 53.3%).
Synthesis Example 15: Synthesis of
N-[1-((6-Chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide
To 18.24 g (0.16 mol) of trifluoroacetic acid, 8.76 g (0.12
mol) of dimethylformamide was added. While the mixture was
heated to 65°C, 12.26 g (0.08 mol) of phosphorus oxychloride was
added to this mixture. Trifluoroacetyl chloride generated
therefrom was bubbled into a solution which was obtained by
dissolving 9.4 g (0.1 mol) of 2-aminopyridine in 80 mL of
N-methylpyrrolidinone, and which was cooled to -15°C, and the
mixture was stirred for 2 hours. While being cooled to -10°C,
the reaction liquid was neutralized by adding 14.9 g (0.22 mol)
of sodium ethoxide powder thereto. To this reaction liquid, 13.8
g (0.1 mol) of potassium carbonate powder and 16.2 g (0.1 mol)
of 2-chlorochloromethylpyridine were added, and distillation
was conducted under reduced pressure (36 hPa) at 50 to 60°C for
2 hours. To the reaction liquid, 20 mL of methanol was added,
and the mixture was added to 400 ml of water heated to 50°C, while
the vessel was also washed. After the mixture was stirred at room
temperature for 30 minutes, the crystals were filtered, and washed
with 100 mL of water and 50 mL of toluene. The obtained crystals
were dried under reduced pressure at 45°C. Thus, 22.5 g of the
target compound was obtained (Percentage Yield: 71.4%).
Synthesis Example 16: Synthesis of
N-[1-((6-Chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide
In 20 ml of dimethylformamide, 3.00 g (18.6 mmol) of
2-chlorochloromethylpyridine was dissolved, and 1.75 g (18.6
mmol) of 2-aminopyridine was added thereto, followed by stirring
at 80°C for 8 hours, and at room temperature for 5 hours. After
completion of the reaction, dimethylformamide was distilled off
under reduced pressure, and acetonitrile was added. As a result,
a solid was precipitated. The solid was collected by filtration,
thoroughly washed with acetonitrile, and then dried. Thus, 2.07
g of 1-[(6-chloropyridinyl)methyl] pyridine-2(1H)-imine
hydrochloride was obtained (Percentage Yield: 44%).
1H-NMR (DMSO-d6, δ, ppm):
.65 (2H, s), 6.96 (1H, t), 7.23 (1H, m), 7.57 (1H, d), 7.80 (1H,
m), 7.91 (1H, m), 8.28 (1H, m), 8.49 (1H, d)
In 5 ml of anhydrous dichloromethane, 50 mg (0.20 mmol) of
1-[(6-chloropyridinyl)methyl] pyridine-2(1H)-imine
hydrochloride obtained by the above-described method was
suspended. Then, 122 mg (1.00 mmol) of dimethylaminopyridine and
50 mg (0.24 mmol) of trifluoroacetic anhydride were added in this
order to the suspension under ice-cooling, followed by stirring
at room temperature for 1 hour. After completion of the reaction,
the reaction liquid was diluted with dichloromethane, washed with
1% hydrochloric acid, and then dried over anhydrous magnesium
sulfate. The dichloromethane was distilled off under reduced
pressure. Thus, the target substance was obtained. Yield: 42
mg (Percentage Yield: 67%).
Synthesis Example 17: Synthesis of
N-[1-((6-Chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide
In 15 mL of N,N-dimethylformamide, 4.6 g (0.02 mol) of
1-((6-chloropyridinyl)methyl)pyridine-2(1H)-imine obtained
by being synthesized according to the method of Synthesis Example
16, and then being neutralized was dissolved, and 5.7 g (0.04
mol) of ethyl trifluoroacetate was added thereto. After
stirring at 56°C overnight, 60 mL of water was added to the mixture.
The crystals precipitated were collected by filtration. The
obtained crystals were dried under reduced pressure at 45°C.
Thus, 5.85 g of the target compound was obtained (Percentage
Yield: 92.8%).
Synthesis Example 18: Synthesis of
N-[1-((6-Chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide
In 6 mL of N,N-dimethylformamide, 2.2 g (0.01 mol) of
1-((6-chloropyridinyl)methyl)pyridine-2(1H)-imine obtained
by being synthesized according to the method of Synthesis Example
16, and then being neutralized was dissolved. Then, 828 mg (0.006
mol) of potassium carbonate and 2.52 g (0.012 mol) of
trifluoroacetic anhydride were added to the solution under
ice-cooling. After stirring at room temperature for 1 hour, 30
mL of water was added to the mixture. The crystals precipitated
were collected by filtration. The obtained crystals were washed
with 20 mL of water, and dried under reduced pressure at 45°C.
Thus, 2.38 g of the target compound was obtained (Percentage
Yield: 75.6%).
Synthesis Example 19: Synthesis of
N-[1-((6-Chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide
To 4.56 g (0.04 mol) of trifluoroacetic acid, 3 mL of
N,N-dimethylformamide was added. Then, 3.12 g (0.02 mol) of
phosphorus oxychloride was added to the mixture, which was heated
to 60°C. Trifluoroacetyl chloride generated therefrom was
bubbled into a solution obtained by dissolving, in 25 mL of
N-methylpyrrolidinone, 4.38 g (0.02 mol) of
1-((6-chloropyridinyl)methyl)pyridine-2(1H)-imine, which
was obtained by being synthesized according to the method of
Synthesis Example 16, and then being neutralized, and the reaction
was allowed to proceed at -10°C for 45 minutes. Crystals
precipitated by adding 125 mL of water were collected by
filtration. The obtained crystals were dried under reduced
pressure at 45°C. Thus, 2.58 g of the target compound was obtained
(Percentage Yield: 40.9%).
Synthesis Example 20: Synthesis of
N-[1-((6-Chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide
In 3 mL of N,N-dimethylformamide, 4.38 g (0.02 mol) of
1-((6-chloropyridinyl)methyl)pyridine-2(1H)-imine, which
was obtained by being synthesized according to the method of
Synthesis Example 16, and then neutralized, was dissolved. To
this solution, 2.7 g (0.024 mol) of trifluoroacetic acid and 2.8
g (0.02 mol) of phosphorus pentoxide were added. The mixture was
stirred at 120°C for 3 hours, and then returned to room temperature.
Crystals precipitated by adding 50 mL of water were collected
by filtration. The obtained crystals were dried under reduced
pressure at 45°C. Thus, 2.12 g of the target compound was obtained
(Percentage Yield: 33.7%).
Synthesis Example 21: Synthesis of
N-[1-((6-Chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide
In 50 mL of dimethylformamide, 9.4 g (0.1 mol) of
2-aminopyridine was dissolved. To this solution, 28.8 g (0.2
mol) of ethyl trifluoroacetate, 16.2 g (0.1 mol) of
2-chlorochloromethylpyridine, and 13.8 g (0.1 mol) of
potassium carbonate were added, followed by stirring at 55 to
60°C for 20 hours. To the reaction liquid, 1.38 g (0.1 mol) of
potassium carbonate powder, 3.24(0.02 mol) of
2-chlorochloromethylpyridine, and 5.68 g (0.04 mol) of ethyl
trifluoroacetate were further added, followed by stirring at 55
to 60°C for 6 hours. To the reaction liquid, 40 mL of methanol
was added, and then the reaction liquid was added to 300 mL of
hot water of 50°C. After being cooled to room temperature, the
mixture was stirred for 1 hour. The crystals were filtered, and
washed with 100 mL of water and 75 mL of toluene. The obtained
crystals were dried under reduced pressure at 45°C. Thus, 24.0
g of the target compound was obtained (Percentage Yield: 76%).
Synthesis Example 22: Synthesis of
N-[1-((6-Chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide
In 30 mL of dimethylformamide and 20 mL of toluene, 9.4 g
(0.1 mol) of 2-aminopyridine was dissolved. To this solution,
28.8 g (0.2 mol) of ethyl trifluoroacetate, 16.2 g (0.1 mol) of
2-chlorochloromethylpyridine, and 16.6 g (0.12 mol) of
potassium carbonate were added, followed by stirring at 60 to
65°C for 18 hours. To the reaction liquid, 15 mL of methanol was
added, and then the reaction liquid was added to 120 mL of hot
water of 50°C. After being cooled to room temperature, the
mixture was stirred for 1 hour. Crystals were filtered, and
washed with 50 mL of water and 100 mL of toluene. The obtained
crystals were dried under reduced pressure at 45°C. Thus, 23.9
g of the target compound was obtained (Percentage Yield: 75.9%).
Synthesis Example 23: Synthesis of
N-[1-((6-Chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide
In a mixture solvent of 25 mL of N,N-dimethylformamide and
ml of toluene, 4.7 g (0.05 mol) of 2-aminopyridine was dissolved.
To the solution, 35.5 g (0.25 mol) of ethyl trifluoroacetate,
9.72 g (0.06 mol) of 2-chlorochloromethylpyridine, and 8.28
g (0.06 mol) of potassium carbonate powder were added, followed
by stirring at 65°C for 18 hours. To the reaction liquid, 10 mL
of methanol was added, and then the reaction liquid was added
to 150 mL of hot water of 50°C. After being cooled to room
temperature, the mixture was stirred for 1 hour. Crystals were
filtered, and washed with 50 mL of water and 50 mL of toluene.
The obtained crystals were dried under reduced pressure at 45°C.
Thus, 13.78 g of the target compound was obtained (Percentage
Yield: 87.5%).
Synthesis Example 24: Synthesis of
N-[1-((6-Chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide
In 30 mL of dimethylformamide and 20 mL of toluene, 9.4 g
(0.1 mol) of 2-aminopyridine was dissolved. To this solution,
14.2 g (0.1 mol) of ethyl trifluoroacetate was added, followed
by stirring at 60 to 65°C for 7 hours. Subsequently, 16.2 g (0.1
mol) of 2-chlorochloromethylpyridine and 16.6 g (0.12 mol)
of potassium carbonate were added thereto, followed by stirring
at 60 to 65°C for 18 hours. To the reaction liquid, 15 mL of
methanol was added. Then the reaction liquid was added to 150
mL of hot water of 50°C, and the mixture was cooled to room
temperature. Crystals were filtered, and washed with 50 mL of
water and 75 mL of toluene. The obtained crystals were dried under
reduced pressure at 60°C. Thus, 20.6 g of the target compound
was obtained (Percentage Yield: 65.4%).
Synthesis Example 25: Synthesis of
N-[1-((6-Chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide
In 30 mL of dimethylformamide and 20 mL of toluene, 9.4 g
(0.1 mol) of 2-aminopyridine was dissolved. To the solution, 7.1
g (0.05 mol) of ethyl trifluoroacetate was added, followed by
stirring at 60 to 65°C for 7.5 hours. After concentration under
reduced pressure (90 hPa, 40°C), the residue was cooled on ice,
and 20 mL of toluene and 10.5 g (0.05 mol) of trifluoroacetic
anhydride were added to the residue, followed by stirring at room
temperature for 1 hour. Subsequently, 16.2 g (0.1 mol) of
2-chlorochloromethylpyridine, 20 mL of dimethylformamide,
and 16.6 g (0.12 mol) of potassium carbonate were added, followed
by stirring under a reduced pressure of 110 hPa at 60 to 65°C
for 4 hours. After concentration under reduced pressure (90 hPa,
50°C), 25 mL of methanol was added to the reaction liquid, and
this mixture was added to 250 mL of hot water of 50°C. The mixture
was cooled to room temperature with stirring. Crystals were
filtered, and washed with 90 mL of water and 90 mL of toluene.
The obtained crystals were dried under reduced pressure at 60°C.
Thus, 19.8 g of the target compound was obtained (Percentage
Yield: 62.9%).
Synthesis Example 26: Synthesis of
N-[1-((6-Chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide
In 30 mL of dimethylformamide and 20 mL of toluene, 9.4 g
(0.1 mol) of 2-aminopyridine was dissolved. To the solution,
21.3 g (0.15 mol) of ethyl trifluoroacetate was added, followed
by stirring at 60 to 65°C for 7.5 hours. After concentration under
reduced pressure (90 hPa, 40°C), the residue was cooled on ice,
and 20 mL of toluene and 10.5 g (0.05 mol) of trifluoroacetic
anhydride were added to the residue, followed by stirring at room
temperature for 1 hour. Subsequently, 16.2 g (0.1 mol) of
2-chlorochloromethylpyridine, 20 mL of dimethylformamide,
and 16.6 g (0.12 mol) of potassium carbonate were added , followed
by stirring under a reduced pressure of 110 hPa at 60 to 65°C
for 4 hours. After concentration under reduced pressure (90 hPa,
50°C), 25 mL of methanol was added to the reaction liquid, and
the mixture was added to 250 mL of hot water of 50°C. Then, the
mixture was cooled to room temperature with stirring. Crystals
were filtered, and washed with 90 mL of water and 90 mL of toluene.
The obtained crystals were dried under reduced pressure at 60°C.
Thus, 22.68 g of the target compound was obtained (Percentage
Yield: 72.0%).
Synthesis Example 27: Synthesis of
N-[1-((6-Chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,2-trifluoroacetamide
In 40 ml of xylene, 2.35 g (0.025 mol) of 2-aminopyridine
was suspended. To this mixture, 2.85 g (0.025 mmol) of
trifluoroacetic acid and 135 mg of ferric chloride hexahydrate
were added, and attached a Dean-Stark trap. The mixture was
stirred at 150°C for 16 hours, removing the resulting water by
the Dean-Stark trap. After the solution was cooled to 60°C, 4.05
g (0.025 mol) of 2-chlorochloromethylpyridine, 16 mL of
dimethylformamide, and 2.42 g (0.0175 mol) of potassium carbonate
were added, followed by stirring under a reduced pressure of
60-110 hPa at 60 to 65°C for 3 hours. Then, 10 mL of methanol
was added to the reaction mixture, and this mixture was added
to 80 mL of hot water of 50°C. The mixture was cooled to room
temperature with stirring. Crystals were filtered, and washed
with 20 mL of water and 20 mL of toluene. The obtained crystals
were dried under reduced pressure at 60°C. Thus, 6.32 g of the
target compound was obtained (Percentage Yield: 80.3%).
Synthesis Example 28: Synthesis of
N-[1-((6-Chlorofluoropyridinyl)methyl)pyridin-2(1H)-yl
idene]-2,2,2-trifluoroacetamide (Compound 2)
In 80 ml of carbon tetrachloride, 4.00 g (27.6 mmol) of
2-chlorofluoromethylpyridine was dissolved. To this
solution, 7.37 g (41.4 mmol) of N-bromosuccinimide and 20 mg of
benzoyl peroxide were added, and the mixture was heated under
reflux overnight. After completion of the reaction, the reaction
liquid was returned to room temperature, and concentrated under
reduced pressure. Then, the residue was purified by silica gel
column chromatography (hexane:ethyl acetate=19:1). Thus, 3.06
g of 5-(bromomethyl)chlorofluoropyridine was obtained
(Percentage Yield: 51%).
1H-NMR (CDCl3, δ, ppm): 4.45 (2H, s), 7.54 (1H, dd), 8.23 (1H,
In 5 ml of anhydrous acetonitrile, 50 mg (0.22 mmol) of
-(bromomethyl)chlorofluoropyridine obtained by the
above-described method was dissolved. To this solution, 42 mg
(0.22 mmol) of
2,2,2-trifluoro-N-(pyridin-2(1H)-ylidene)acetamide obtained by
the above-described method and 36 mg (0.26 mmol) of potassium
carbonate were added in this order, followed by heating under
reflux for 7 hours. After completion of the reaction, the
reaction liquid was returned to room temperature. The insoluble
matters were filtered, and the filtrate was concentrated under
reduced pressure. To the residue, diethyl ether was added. As
a result, a solid was precipitated. The solid was collected by
filtration, washed with diethyl ether, and dried in a desiccator
under reduced pressure. Thus, the target substance was obtained.
Yield: 29 mg (Percentage Yield: 40%).
1H-NMR (CDCl3, δ, ppm): 5.54 (2H, s), 6.89 (1H, td), 7.76 (1H,
dd), 7.80 (1H, td), 7.85 (1H, d), 8.29 (1H, d), 8.57 (1H, d)
MS: m/z = 334 (M+H)
Synthesis Example 29: Synthesis of
N-[1-((6-Bromopyridinyl)methyl)pyridin-2(1H)-ylidene]-2,2
,2-trifluoroacetamide (Compound 3)
In 15 ml of carbon tetrachloride, 500 mg (2.92 mmol) of
2-bromomethylpyridine was dissolved. To this solution, 623
mg (3.50 mmol) of N-bromosuccinimide and 10 mg of benzoyl peroxide
were added, followed by heating under reflux for 19 hours. After
completion of the reaction, the reaction liquid was returned to
room temperature, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=19:1). Thus, 143 mg of
2-bromobromomethylpyridine was obtained (Percentage Yield:
%).
1H-NMR (CDCl3, δ, ppm): 4.42 (2H, s), 7.47 (1H, d), 7.59 (1H,
dd), 8.38 (1H, d)
In 10 ml of anhydrous acetonitrile, 70 mg (0.28 mmol) of
2-bromobromomethylpyridine obtained by the above-described
method was dissolved. To this solution, 54 mg (0.28 mmol) of
2,2,2-trifluoro-N-(pyridin-2(1H)-ylidene)acetamide
synthesized by the above-described method and 46 mg (0.34 mmol)
of potassium carbonate were added in this order, followed by
heating under reflux for 6 hours. After completion of the
reaction, the reaction liquid was returned to room temperature.
Then, the insoluble matters were filtered, and the filtrate was
concentrated under reduced pressure. To the residue, diethyl
ether was added. As a result, a solid was precipitated. The
solid was collected by filtration, washed with diethyl ether,
and then dried in a desiccator under reduced pressure. Thus, the
target substance was obtained. Yield: 81 mg (Percentage Yield:
82%).
1H-NMR (CDCl3, δ, ppm): 5.52 (2H, s), 6.88 (1H, t), 7.48 (1H,
d), 7.78 (2H, m), 7.84 (1H, d), 8.44 (1H, d), 8.53 (1H, d)
MS: m/z = 360 (M+H)
Synthesis Example 30: Synthesis of
2-chloro-N-[1-((6-Chloropyridinyl)methyl)pyridin-2(1H)-yl
idene]-2,2-difluoroacetamide (Compound 4)
In 5 ml of dichloromethane, 200 mg (2.13 mmol) of
2-aminopyridine was dissolved. To this solution, 491 mg (2.55
mmol) of EDC-HCl, 311 mg (2.55 mmol) of dimethylaminopyridine,
and 187 µl (2.23 mmol, 290 mg) of chlorodifluoroacetic acid were
added in this order, followed by stirring overnight. After
completion of the reaction, the reaction liquid was diluted with
dichloromethane, washed with water and with 1% hydrochloric acid,
and then dried over anhydrous magnesium sulfate. Thus, 105 mg
of 2-chloro-2,2-difluoro-N-(pyridin-2(1H)-ylidene)acetamide
was obtained (Percentage Yield: 24%).
1H-NMR (CDCl3, δ, ppm): 7.19 (1H, dd), 7.82 (1H, m), 8.18 (1H,
d), 8.36 (1H, d), 9.35 (1H, br s)
To 68 mg (0.33 mmol) of 2-chloro-2,
2-difluoro-N-(pyridin-2(1H)-ylidene)acetamide synthesized by
the above-described method, 53 mg (0.33 mmol) of
2-chlorochloromethylpyridine dissolved in 6 ml of anhydrous
acetonitrile was added. Subsequently, 50 mg (0.36 mmol) of
potassium carbonate was added to the mixture, followed by heating
under reflux for 1 hour. After completion of the reaction, the
reaction liquid was returned to room temperature, and then
concentrated under reduced pressure. Diethyl ether was added to
the residue. As a result, a solid was precipitated. The solid
was collected by filtration, and dried. Thus, the target
substance was obtained. Yield: 49 mg (Percentage Yield: 45%).
1H-NMR (CDCl3, δ, ppm): 5.56 (2H, s), 6.92 (1H, t), 7.33 (1H,
d), 7.82 (1H, m), 7.91 (1H, dd), 8.02 (1H, d), 8.45 (1H, d), 8.48
(1H, d)
13C-NMR (CDCl3, δ, ppm): 53.8, 115.2, 120.1 (t), 122.1, 124.8,
139.0, 140.0, 142.3, 150.0, 151.9, 159.1, 159.1, 165.8 (t)
MS: m/z = 332 (M+H)
Synthesis Example 31: Synthesis of
2,2,2-Trichloro-N-[1-((6-chloropyridinyl)methyl)pyridin-2
(1H)-ylidene]acetamide (Compound 5)
In 4 ml of anhydrous dichloromethane, 70 mg (0.27 mmol) of
1-[(6-chloropyridinyl)methyl] pyridine-2(1H)-imine
hydrochloride obtained by the method of Synthesis Example 16 was
suspended. To this suspension, 94 µl (0.68 mmol, 68 mg) of
triethylamine and 33 µg (0.27 mmol, 49 mg) of trichloroacetyl
chloride were added in this order, followed by stirring at room
temperature for 1 hour. After completion of the reaction, the
reaction was quenched by adding water, and phase separation was
conducted by using dichloromethane and water. The organic layer
was washed once with water, and twice with 1% hydrochloric acid,
then dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. Diethyl ether was added to the residue.
As a result, a solid was precipitated. The solid was collected
by filtration, and dried. Thus, the target substance was
obtained. Yield: 61 mg (Percentage Yield: 62%).
1H-NMR (CDCl3, δ, ppm): 5.59 (2H, s), 6.86 (1H, t), 7.32 (1H,
d), 7.78 (1H, td), 7.91 (2H, m), 8.43 (1H, d), 8.50 (1H, d)
MS: m/z = 364 (M+H)
Synthesis Example 32: Synthesis of
N-[1-((2-Chloropyrimidinyl)methyl)pyridin-2(1H)-ylidene]-
2,2,2-trifluoroacetamide (Compound 6)
In 30 ml of carbon tetrachloride, 1.04 g (8.13 mmol) of
2-chloromethylpyrimidine was dissolved. To this solution,
1.73 g (9.75 mmol) of N-bromosuccinimide and 20 mg of benzoyl
peroxide were added, followed by heating under reflux for 6 hours.
After completion of the reaction, the reaction liquid was returned
to room temperature, and concentrated under reduced pressure.
Then, the residue was purified by silica gel column chromatography
(hexane:ethyl acetate=3:1). Thus, 641 mg of
-bromomethylchloropyrimidine was obtained (Percentage
Yield: 38%).
1H-NMR (CDCl3, δ, ppm): 4.42 (2H, s), 8.66 (2H, s)
In 6 ml of anhydrous acetonitrile, 104 mg (0.50 mmol) of
-bromomethylchloropyrimidine obtained by the
above-described method was dissolved. To this solution, 96 mg
(0.50 mmol) of
2,2,2-trifluoro-N-(pyridin-2(1H)-ylidene)acetamide obtained by
the above-described method and 76 mg (0.55 mmol) of potassium
carbonate were added, followed by heating under reflux for 1 hour.
After completion of the reaction, the reaction liquid was returned
to room temperature. The insoluble matters were removed by
filtration, and the filtrate was concentrated under reduced
pressure. Diethyl ether was added to the residue. As a result,
a solid was precipitated. The solid was collected by filtration,
washed with diethyl ether, and then dried in a desiccator under
reduced pressure. Thus, the target substance was obtained.
Yield: 92 mg (Percentage Yield: 58%).
1H-NMR (CDCl3, δ, ppm): 5.54 (2H, s), 6.98 (1H, m), 7.87 (1H,
m), 8.18 (1H, m), 8.48 (1H, m), 8.83 (2H, m)
13C-NMR (CDCl3, δ, ppm): 60.0, 115.6, 117.1 (q), 122.1, 127.5,
139.2, 142.9, 158.8, 160.3 (2C), 161.4, 163.8 (q)
MS: m/z = 317 (M+H)
Synthesis Example 33: Synthesis of
N-[1-((6-Chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2,3,3,3-pentafluoropropanamide (Compound 7)
In 15 ml of anhydrous dichloromethane, 300 mg (3.19 mmol)
of 2-aminopyridine was dissolved. To this solution, 919 mg (4.78
mmol) of EDC-HCl, 583 mg (4.78 mmol) of DMAP, and 397 µl (628
mg, 3.83 mmol) of pentafluoropropionic acid were added in this
order, followed by stirring at room temperature overnight. After
completion of the reaction, the reaction liquid was diluted with
dichloromethane, washed once with water, and twice with 1%
hydrochloric acid, then dried over anhydrous magnesium sulfate,
and concentrated under reduced pressure. Thus, 85 mg of
2,2,3,3,3-pentafluoro-N-(pyridin-2(1H)-ylidene)propanamide
was obtained (Percentage Yield: 11%).
To 77 mg (0.32 mmol) of
2,2,3,3,3-pentafluoro-N-(pyridin-2(1H)-ylidene)propanamide
obtained by the above-described method, 52 mg (0.32 mmol) of
2-chlorochloromethylpyridine dissolved in 8 ml of anhydrous
acetonitrile and 49 mg (0.35 mmol) of potassium carbonate were
added, followed by heating under reflux for 11 hours. After
completion of the reaction, the reaction liquid was returned to
room temperature, and the insoluble matters were filtered. The
filtrate was concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (hexane:ethyl
acetate=1:3). Thus, the target substance was obtained. Yield:
12 mg (Percentage Yield: 10%).
1H-NMR (CDCl3, δ, ppm): 5.56 (2H, s), 6.90 (1H, td), 7.32 (1H,
d), 7.79 (2H, m), 7.84 (1H, d), 8.43 (1H, d), 8.56 (1H, d)
MS: m/z = 366 (M+H)
Synthesis Example 34: Synthesis of
N-[1-((6-Chloropyridinyl)methyl)pyridin-2(1H)-ylidene]-2,
2-difluoroacetamide (Compound 8)
In 10 ml of anhydrous dichloromethane, 400 mg (4.26 mmol)
of 2-aminopyridine was dissolved. To this solution, 322 µl (490
mg, 5.11 mmol) of difluoroacetic acid, 982 mg (5.10 mmol) of
EDC-HCl, and 622 mg (5.11 mmol) of DMAP were added, followed by
stirring at room temperature for 61 hours. After completion of
the reaction, the reaction liquid was diluted with
dichloromethane, and washed once with water, and twice with 1%
HCl aq., then dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. Thus, 102 mg of
2,2-difluoro-N-(pyridin-2(1H)-ylidene)acetamide was obtained
(Percentage Yield: 14%).
1H-NMR (CDCl3, δ, ppm): 6.03 (1H, t), 7.15 (1H, m), 7.78 (1H,
td), 8.20 (1H, d), 8.34 (1H, dd), 8.72 (1H, br s)
In 10 ml of anhydrous acetonitrile, 100 mg (0.58 mmol) of
2,2-difluoro-N-(pyridin-2(1H)-ylidene)acetamide obtained by
the above-described method was dissolved. To this solution, 94
mg (0.58 mmol) of 2-chlorochloromethylpyridine dissolved in
ml of anhydrous acetonitrile was added, and subsequently 84
mg (0.63 mmol) of potassium carbonate was added thereto, followed
by heating under reflux for 140 minutes. After completion of the
reaction, the reaction liquid was returned to room temperature,
and the insoluble matters were removed by filtration, and the
filtrate was concentrated under reduced pressure. Ether was
added to the residue. As a result, a solid was precipitated. The
solid was collected by filtration, and dried well. Thus, the
target substance was obtained. Yield: 63 mg (Percentage Yield:
37%).
1H-NMR (CDCl3, δ, ppm): 5.52 (2H, s), 5.90 (1H, t), 6.79 (1H,
td), 7.33 (1H, d), 7.71 (1H, m), 7.77 (1H, dd), 7.85 (1H, dd),
8.45 (1H, d), 8.50 (1H, d)
13C-NMR (DMSO-d6, δ, ppm): 53.0, 111.0 (t), 115.2, 120.7, 124.7,
131.7, 140.6, 141.6, 143.2, 150.4, 150.9, 158.3, 169.4 (t)
MS: m/z = 298 (M+H)
Test Example 1
Test for Control of Diamondback Moth (Plutella xylostella)
A leaf disk having a diameter of 5.0 cm was cut out from
cabbage grown in a pot. Then, a liquid agent prepared to be 50%
acetone-water (to which 0.05% Tween20 was added) and to contain
500 ppm of a compound represented by formula (I) was spread over
the leaf disk. After the leaf disk was air dried, second instar
larvae were released on the leaf disk. After that, the leaf disk
was allowed to stand in a thermostatic chamber at 25°C (16-hour
light period and 8-hour dark period). Three days after the
release, the insects were observed for their mortality, and the
mortality rate was calculated in accordance with the following
formula. The test was duplicated.
Mortality rate (%) = [Number of dead insects/(Number of survived
insects + Number of dead insects)] × 100
Test Example 2
Test for Control of Cotton Aphid (Aphis gossypii)
A leaf disk having a diameter of 2.0 cm was cut out from
cucumber (Cucumis sativus L.) grown in a pot. Then, a liquid agent
prepared to be 50% acetone-water (to which 0.05% Tween20 was
added) and to contain 500 ppm of a compound represented by formula
(I) was spread over the leaf disk. After the leaf disk was air
dried, first instar larvae were released on the leaf disk. After
that, the leaf disk was allowed to stand in a thermostatic chamber
at 25°C (16-hour light period and 8-hour dark period). Three days
after the release, the insects were observed for their mortality,
and the mortality rate was calculated in accordance with the
following formula. The test was duplicated.
Mortality rate (%) = [Number of dead insects/(Number of survived
insects + Number of dead insects)] × 100
Test Example 3
Test for Control of Laodelphax striatellus
Roots of wheat seedlings 48 hours after seeding were each
treated with 200 µL of a liquid agent prepared to be 10%
acetone-water, and to contain 100 ppm of a compound represented
by formula (I). The agent was absorbed through the roots for 72
hours, and then 10 second instar larvae of Laodelphax striatellus
were released on each wheat seedling. After that, the wheat
seedlings were allowed to stand in a thermostatic chamber at 25°C
(16-hour light period and 8-hour dark period). Four days after
the release, the insects were observed for their mortality, and
the mortality rate was calculated in accordance with the following
formula. The test was duplicated.
Mortality rate (%) = [Number of dead insects/(Number of survived
insects + Number of dead insects)] × 100
Table 2 shows the results of Test Examples 1 to 3, i.e., specific
bioactivities (mortality rates (%)) of pest control agents
represented by formula (I).
[Table 2]
<Effect against insecticide resistant pests>
Reference Example Test for Control of Nilaparvata lugens
Rice plant seedlings grown in a pot were treated by soil
drench with a liquid agent prepared to be 10% acetone-water, and
to contain a predetermined concentration of a compound of the
present invention. Three days after the treatment, 10 sensitive
or resistant strain of second instar larvae of Nilaparvata lugens
were released on each of the rice plant seedlings. After that,
the rice plant seedlings were allowed to stand in a thermostatic
chamber at 25°C (16-hour light period and 8-hour dark period).
Three days after the release, the insects were observed for their
mortality, and the mortality rate was calculated in accordance
with the following formula. The test was duplicated.
Mortality rate (%) = [Number of dead insects/(Number of survived
insects + Number of dead insects)] × 100
Note that the pests tested were as follows: Insects bred
for generations in a room for a long period (sensitive strain),
(I) Insects collected in Kumamoto Prefecture in 2007, and bred
for generations in a room (field-collected strain: resistant
strain), or (II) Insects collected in Fukuoka Prefecture in 2005,
and bred for generations in a room (field-collected strain).
As a result, treatments with Compound 1 at 0.05 mg/seedling
achieved mortality rates of 100% for all the strains, and
treatments with Compound 1 at 0.005 mg/seedling achieved
mortality rates of 90% or higher for all the strains. In addition,
treatments with Compound 2 at 0.01 mg/seedling achieved mortality
rates of 72% for the sensitive strain and 70% for the strain (II).
Treatments with Compound 19 at 0.01 mg/seedling achieved
mortality rates of 100% for the sensitive strain and 93% for the
strain (II). On the other hand, treatments with imidacloprid at
0.05 mg/seedling achieved mortality rates of 100% for the
sensitive strain, 40% for the strain (I), and 60% for the strain
(II).
These results indicate that Compound 1 has a high
insecticidal activity against Nilaparvata lugens resistant to
imidacloprid.
Reference Example Test for Control of Laodelphax
striatellus
Rice plant seedlings grown in a pot were treated by soil
drench with a liquid agent prepared to be 10% acetone-water, and
to contain a predetermined concentration of a compound of the
present invention. Three days after the treatment, 10 sensitive
or resistant strain of second instar larvae of Laodelphax
striatellus were released on each of the rice plant seedlings.
After that the rice plant seedlings were allowed to stand in a
thermostatic chamber at 25°C (16-hour light period and 8-hour
dark period). Three days after the release, the insects were
observed for their mortality, and the mortality rate was
calculated in accordance with the following formula. The test
was duplicated.
Mortality rate (%) = [Number of dead insects/(Number of survived
insects + Number of dead insects)] × 100
Note that the pests tested were insects bred for generations
in a room for a long period (sensitive strain), and insects
collected in Kumamoto Prefecture in 2006, and bred for generations
in a room (field-collected strain: resistant strain).
As a result, treatments with Compound 1 at 0.01 mg/seedling
achieved mortality rates of 100% for all the strains, treatments
with Compound 1 at 0.005 mg/seedling achieved mortality rates
of 90% or higher for all the strains. Meanwhile, treatments with
Compound 3 at 0.01 mg/seedling achieved mortality rates of 100%
for the sensitive strain and 90% for the field-collected strain.
On the other hand, treatments with imidacloprid at 0.01
mg/seedling achieved mortality rates of 100% for the sensitive
strain and 50% for the field-collected strain. In addition,
treatments with fipronil at 0.01 mg/seedling achieved mortality
rates of 100% for the sensitive strain and 70% for the
field-collected strain.
These results indicate that Compounds 1 and 3 have high
inseciticidal activities against Laodelphax striatellus
resistant to imidacloprid and fipronil.
Reference Example In Vitro Metabolism Test of Compound 1
and Imidacloprid Using Crude Enzyme Extraction Liquid of Housefly
(Musca domestica)
As described in Pest Management Science (2003), 59(3),
347-352, and Journal of Pesticide Science (2004), 29(2), 110-116,
imidacloprid is known to be inactivated by oxidative metabolism,
which is thought to be one of the mechanisms for the acquisition
of the resistance. To investigate effects on insects acquiring
such resistance, the following experiment was carried out.
To adult housefly (Musca domestica) (0.645 g), 10 ml of a
potassium phosphate buffer (pH 7.4, containing 1 mM EDTA) was
added, and the adult housefly was sufficiently ground with
Physcotron (Nichion Irika Kikai Seisakusho). After that, the
ground material was centrifuged under conditions of 10,000 g and
minutes. The obtained supernatant was further centrifuged
under conditions of 100,000 g and 60 minutes. Thus, precipitates
were obtained. The precipitates were dissolved in 1 ml of a
potassium phosphate buffer, and this solution was used as a crude
enzyme solution. The enzyme extraction operations were all
conducted on ice or under a condition of 4°C.
Reagents were mixed with each other at the following ratio
in a tube having a capacity of 1.5 mL, and allowed to react with
each other at 25°C for 40 hours. After the reaction, 1 mL of
acetone was added to the mixture, followed by stirring. Then,
the formed precipitates were removed by centrifugation at 12000
rpm for 5 minutes. The acetone in the supernatant was distilled
off, and the residue was injected into a LC/MS for analysis.
The above-described crude enzyme extraction liquid: 300 µL
Solution of Compound 1 in DMSO: 5 µL
Glucose 6-phosphate solution: 5 µL
NADP solution: 5 µL
Glucose 6-phosphate dehydrogenase solution: 5 µL
Potassium phosphate buffer (pH 7.4, containing 1 mM EDTA): 180
<Analysis Conditions>
Column: CAPCELL PAK C18 MG
Mobile phase composition:
0 to 3 minutes: 85% water, 5% acetonitrile, 10% aqueous formic
acid solution (0.1 v/v%)
3 to 30 minutes: 85→25% water, 5→65% acetonitrile, 10% aqueous
formic acid solution (0.1 v/v%)
.1 to 36 minutes: 90% acetonitrile, 10% aqueous formic acid
solution (0.1 v/v%)
Column temperature: 40°C, Flow rate: 0.35 mL/minute, Injection
amount: 100 µL
UV wavelength: 325 nm for Compound 1, 300 nm for imidacloprid.
As a result, the total area percentage of metabolites was
0.08 for Compound 1. In contrast, the total area percentage of
metabolites was 2.55 for imidacloprid. The amount of metabolites
of Compound 1 was smaller than that of imidacloprid. These
results indicate that Compound 1 can be used effectively for pest
control of resistant pests which inactivate imidacloprid by
metabolism.
<Controlling Effect on Animal-Parasitic Pests>
Reference Example Test for Control of Haemaphysalis
longicornis
Into a glass vial having a capacity of 4 mL, 30 µL of an
acetone solution containing 200 ppm or 10 ppm of a compound of
the present invention was introduced. The vial was placed on a
shaker, and air dried, while being rotated. Thus, a dry film of
the compound was formed on the inner wall of the vial. After the
vial was dried for 24 hours or longer, 10 larvae of Haemaphysalis
longicornis were released in the vial, and then the vial was capped.
The vial was allowed to stand in a thermostatic chamber under
conditions of 25°C, a humidity of 85%, and total darkness. One
day after the release, the larvae were observed for their
mortality, and the mortality rate was calculated in accordance
with the following formula. The test was duplicated.
Mortality rate (%) = [Number of dead insects/(Number of survived
insects + Number of dead insects)] × 100
As a result, Compound 1 and Compound 9 in treatment amounts
of 200 ppm showed tickcidal effects with mortality rates of 80%
or higher.
Compound 1 and Compound 9 in treatment amounts of 10 ppm
showed acaricidal effects with mortality rates of 80% or higher.
In a similar test, imidacloprid in a treatment amount of
ppm achieved a mortality rate of 4%.
Reference Example Effect of Controlling Haemaphysalis
longicornis on Body Surface of Mouse
Hair on the back of a mouse (ICR, male, 5-weeks old) in a
region having a diameter of approximately 2 cm was shaved, and
a 15-mL polystyrene conical tube cut to have a height of
approximately 1.5 cm was bonded to this region with an instant
adhesive.
Then, 20 µL of a 1000-fold diluted liquid of a pest control
agent prepared according to the following formulation was added
dropwise onto the body surface of the mouse within the bonded
tube. After sufficient drying, 10 or more larvae of
Haemaphysalis longicornis were released into the tube, and the
tube was capped. Three days after the release, the larvae of
Haemaphysalis longicornis were observed for their mortality, and
the blood-sucking inhibition rate was calculated in accordance
with the following formula.
Formulation [Drop Preparation]
Compound 1 48% by weight
Ethanol 52% by weight
The components were uniformly mixed with each other, and
a drop preparation was obtained.
blood-sucking inhibition rate (%) = 100 - [Number of
allodermanyssus /(Number of survived ticks + Number of dead
ticks)] × 100
As a result, Compound 1 showed an effect of controlling
Haemaphysalis longicornis with a blood-sucking inhibition rate
of 91%.
[Industrial Applicability]
As described above, according to the present invention, it
is possible to produce a 2-acyliminopyridine derivative
represented by formula (I), which is useful as a pest control
agent, in a good yield and, if necessary, effectively in a one-pot
manner, and in turn to provide the 2-acyliminopyridine derivative
in an amount required as a tick control agent stably and at a
low cost. Accordingly, the present invention greatly
contributes to the field of pest control.
The reference in this specification to any prior
publication (or information derived from it), or to any matter
which is known, is not, and should not be taken as an
acknowledgment or admission or any form of suggestion that that
prior publication (or information derived from it) or known matter
forms part of the common general knowledge in the field of
endeavour to which this specification relates.
Throughout this specification and the claims which follow,
unless the context requires otherwise, the word "comprise", and
variations such as "comprises" and "comprising", will be
understood to imply the inclusion of a stated integer or step
or group of integers or steps but not the exclusion of any other
integer or step or group of integers or steps.
Claims (1)
1. A method for producing a compound represented by the following formula (I): 5 [Chem. 1] [where Ar represents a phenyl group which may be substituted with halogen atoms, C alkyl groups which may be substituted with 10 a halogen atom, C alkyloxy groups which may be substituted with a halogen atom, a hydroxyl group, a cyano group, or a nitro group; or a 5-to 6-membered heterocycle which may be substituted with halogen atoms, C alkyl groups which may be substituted with a halogen atom, C alkyloxy groups which may be substituted with 15 a halogen atom, a hydroxyl group, a cyano group or a nitro group, -R represents a C alkyl group which may be substituted 1 1-6 with halogen atoms, C halogenated alkyloxy groups, a cyano group, a nitro group, or a hydroxyl group, and Y represents a hydrogen atom; a halogen atom; a hydroxyl 20 group; a C alkyl group which may be substituted with a halogen atom; a C alkyloxy group which may be substituted with a halogen atom; a cyano group; a formyl group; or a nitro group], the method comprising, as shown in the following reaction formula: H:¥rbr¥Interwoven¥NRPortbl¥DCC¥RBR¥8015438_1.doc-
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JPPCT/JP2011/069352 | 2011-08-26 | ||
PCT/JP2011/069352 WO2012029672A1 (en) | 2010-08-31 | 2011-08-26 | Noxious organism control agent |
JP2012043880 | 2012-02-29 | ||
JP2012-043880 | 2012-02-29 | ||
NZ623022A NZ623022B2 (en) | 2011-08-26 | 2012-08-24 | Method for producing pest controlling agent |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ709742A NZ709742A (en) | 2015-10-30 |
NZ709742B2 true NZ709742B2 (en) | 2016-02-02 |
Family
ID=
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