JP2023063620A - Method for producing 2-(fluoroalkyl) nicotinic acid derivative - Google Patents
Method for producing 2-(fluoroalkyl) nicotinic acid derivative Download PDFInfo
- Publication number
- JP2023063620A JP2023063620A JP2020195024A JP2020195024A JP2023063620A JP 2023063620 A JP2023063620 A JP 2023063620A JP 2020195024 A JP2020195024 A JP 2020195024A JP 2020195024 A JP2020195024 A JP 2020195024A JP 2023063620 A JP2023063620 A JP 2023063620A
- Authority
- JP
- Japan
- Prior art keywords
- group
- fluoroalkyl
- acid
- ammonium
- nicotinic acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical class OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 13
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims abstract description 11
- 239000002841 Lewis acid Substances 0.000 claims abstract description 6
- 239000002253 acid Substances 0.000 claims abstract description 6
- 150000003868 ammonium compounds Chemical class 0.000 claims abstract description 6
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 6
- 229910021529 ammonia Inorganic materials 0.000 claims abstract description 5
- -1 nicotinic acid ester Chemical class 0.000 claims description 15
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 7
- 235000001968 nicotinic acid Nutrition 0.000 claims description 6
- 239000011664 nicotinic acid Substances 0.000 claims description 6
- 229960003512 nicotinic acid Drugs 0.000 claims description 5
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical group [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 241000607479 Yersinia pestis Species 0.000 abstract 1
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 238000006243 chemical reaction Methods 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 6
- 239000005695 Ammonium acetate Substances 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 229940043376 ammonium acetate Drugs 0.000 description 6
- 235000019257 ammonium acetate Nutrition 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 239000012141 concentrate Substances 0.000 description 4
- QTMDXZNDVAMKGV-UHFFFAOYSA-L copper(ii) bromide Chemical compound [Cu+2].[Br-].[Br-] QTMDXZNDVAMKGV-UHFFFAOYSA-L 0.000 description 4
- 239000012156 elution solvent Substances 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 238000010898 silica gel chromatography Methods 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000000417 fungicide Substances 0.000 description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 3
- 229940098779 methanesulfonic acid Drugs 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 229910021590 Copper(II) bromide Inorganic materials 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000003905 agrochemical Substances 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 239000001099 ammonium carbonate Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical compound O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 2
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- 239000011592 zinc chloride Substances 0.000 description 2
- 235000005074 zinc chloride Nutrition 0.000 description 2
- 125000004178 (C1-C4) alkyl group Chemical class 0.000 description 1
- KEQGZUUPPQEDPF-UHFFFAOYSA-N 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione Chemical compound CC1(C)N(Cl)C(=O)N(Cl)C1=O KEQGZUUPPQEDPF-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N 1-ethenoxybutane Chemical compound CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- XZXYQEHISUMZAT-UHFFFAOYSA-N 2-[(2-hydroxy-5-methylphenyl)methyl]-4-methylphenol Chemical compound CC1=CC=C(O)C(CC=2C(=CC=C(C)C=2)O)=C1 XZXYQEHISUMZAT-UHFFFAOYSA-N 0.000 description 1
- KWIPUXXIFQQMKN-UHFFFAOYSA-N 2-azaniumyl-3-(4-cyanophenyl)propanoate Chemical compound OC(=O)C(N)CC1=CC=C(C#N)C=C1 KWIPUXXIFQQMKN-UHFFFAOYSA-N 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 description 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 description 1
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 239000004254 Ammonium phosphate Substances 0.000 description 1
- 229910015900 BF3 Inorganic materials 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 1
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 1
- YSVZGWAJIHWNQK-UHFFFAOYSA-N [3-(hydroxymethyl)-2-bicyclo[2.2.1]heptanyl]methanol Chemical compound C1CC2C(CO)C(CO)C1C2 YSVZGWAJIHWNQK-UHFFFAOYSA-N 0.000 description 1
- WDJHALXBUFZDSR-UHFFFAOYSA-M acetoacetate Chemical compound CC(=O)CC([O-])=O WDJHALXBUFZDSR-UHFFFAOYSA-M 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229940090948 ammonium benzoate Drugs 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- BVCZEBOGSOYJJT-UHFFFAOYSA-N ammonium carbamate Chemical compound [NH4+].NC([O-])=O BVCZEBOGSOYJJT-UHFFFAOYSA-N 0.000 description 1
- 235000012501 ammonium carbonate Nutrition 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 229940107816 ammonium iodide Drugs 0.000 description 1
- VBIXEXWLHSRNKB-UHFFFAOYSA-N ammonium oxalate Chemical compound [NH4+].[NH4+].[O-]C(=O)C([O-])=O VBIXEXWLHSRNKB-UHFFFAOYSA-N 0.000 description 1
- 229910000148 ammonium phosphate Inorganic materials 0.000 description 1
- 235000019289 ammonium phosphates Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- SOIFLUNRINLCBN-UHFFFAOYSA-N ammonium thiocyanate Chemical compound [NH4+].[S-]C#N SOIFLUNRINLCBN-UHFFFAOYSA-N 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 1
- 229940043232 butyl acetate Drugs 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 238000012824 chemical production Methods 0.000 description 1
- XTHPWXDJESJLNJ-UHFFFAOYSA-N chlorosulfonic acid Substances OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003759 ester based solvent Substances 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 229940093499 ethyl acetate Drugs 0.000 description 1
- UAIZDWNSWGTKFZ-UHFFFAOYSA-L ethylaluminum(2+);dichloride Chemical compound CC[Al](Cl)Cl UAIZDWNSWGTKFZ-UHFFFAOYSA-L 0.000 description 1
- UQSQSQZYBQSBJZ-UHFFFAOYSA-N fluorosulfonic acid Chemical compound OS(F)(=O)=O UQSQSQZYBQSBJZ-UHFFFAOYSA-N 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 125000006343 heptafluoro propyl group Chemical group 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-M hexanoate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- SKTCDJAMAYNROS-UHFFFAOYSA-N methoxycyclopentane Chemical compound COC1CCCC1 SKTCDJAMAYNROS-UHFFFAOYSA-N 0.000 description 1
- 229940017219 methyl propionate Drugs 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000005246 nonafluorobutyl group Chemical group FC(F)(F)C(F)(F)C(F)(F)C(F)(F)* 0.000 description 1
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 229940090181 propyl acetate Drugs 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- FEONEKOZSGPOFN-UHFFFAOYSA-K tribromoiron Chemical compound Br[Fe](Br)Br FEONEKOZSGPOFN-UHFFFAOYSA-K 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
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- Pyridine Compounds (AREA)
Abstract
Description
本発明は農薬の製造中間体として有用な２－（フルオロアルキル）ニコチン酸誘導体の製造方法に関する。 The present invention relates to a method for producing 2-(fluoroalkyl)nicotinic acid derivatives useful as intermediates for the production of agricultural chemicals.
これまでに２－（フルオロアルキル）ニコチン酸アミド誘導体が農園芸分野における殺菌剤として有用であることが知られており、２－（フルオロアルキル）ニコチン酸誘導体が、それらの製造中間体であることが知られている（特許文献１～５）。 It has been known that 2-(fluoroalkyl)nicotinamide derivatives are useful as fungicides in the agricultural and horticultural fields, and 2-(fluoroalkyl)nicotinic acid derivatives are intermediates for their production. are known (Patent Documents 1 to 5).
ところで、２－（フルオロアルキル）ニコチン酸の製造方法としては、特許文献６、特許文献７、非特許文献１に、４位がフッ素置換したアセト酢酸エステルとＮ，Ｎ－ジアルキルホルムアミドから調製したＶｉｌｓｍｅｉｅｒ試薬、並びにアルキル（ビニル）エーテルを反応させた後に、アンモニアなどの窒素源試薬と反応させることによって、２－（フルオロアルキル）ニコチン酸エステルを得た後に加水分解することによって、２－（フルオロアルキル）ニコチン酸を製造できることが知られている。 By the way, as a method for producing 2-(fluoroalkyl)nicotinic acid, Patent Document 6, Patent Document 7, and Non-Patent Document 1 disclose Vilsmeier prepared from acetoacetate having a fluorine-substituted 4-position and N,N-dialkylformamide. reagent, and an alkyl (vinyl) ether followed by reaction with a nitrogen source reagent such as ammonia to give a 2-(fluoroalkyl)nicotinate ester followed by hydrolysis to give a 2-(fluoroalkyl) ) is known to produce nicotinic acid.
本発明は、農園芸分野の殺菌剤等の製造において、重要な中間体となる２－（フルオロアルキル）ニコチン酸誘導体を簡便且つ効率良く製造する製造方法を提供することを目的とする。 An object of the present invention is to provide a method for simply and efficiently producing 2-(fluoroalkyl)nicotinic acid derivatives, which are important intermediates in the production of fungicides and the like in the agricultural and horticultural fields.
本発明者は、上記課題を解決するべく、鋭意検討したところ、２－（フルオロアルキル）ニコチン酸エステル誘導体を６－（フルオロアルキル）－３，４－ジヒドロ－２Ｈ－ピラン－５－カルボン酸エステル誘導体から簡便且つ効率良く製造する方法を見出し、本発明を完成するに至った。 In order to solve the above problems, the present inventors have made intensive studies and found that a 2-(fluoroalkyl)nicotinic acid ester derivative is converted into a 6-(fluoroalkyl)-3,4-dihydro-2H-pyran-5-carboxylic acid ester. The inventors have found a simple and efficient production method from derivatives and have completed the present invention.
すなわち本出願に係る発明は、下記式（１）
本発明により、農薬製造中間体等として有用な２－（フルオロアルキル）ニコチン酸エステル誘導体の製造方法を提供することができる。 INDUSTRIAL APPLICABILITY The present invention can provide a method for producing a 2-(fluoroalkyl)nicotinate derivative useful as an intermediate for agricultural chemical production.
本発明の２－（フルオロアルキル）ニコチン酸エステル誘導体（１ａ）の製造方法について詳細に説明する。
Ｒ1又はＲ２で表されるＣ１～Ｃ６アルキル基としては、直鎖又は分枝していても良く、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、ｓｅｃ－ブチル基、イソブチル基、ｔｅｒｔ－ブチル基、ｎ－ペンチル基、ｓｅｃ－ペンチル基、ｔｅｒｔ－ペンチル基、ネオペンチル基、ｎ－ヘキシル基等を例示することができ、容易に製造できるなどの理由から、好ましくはメチル基又はエチル基等を例示することができる。 The C 1 -C 6 alkyl group represented by R 1 or R 2 may be linear or branched and includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec -Butyl group, isobutyl group, tert-butyl group, n-pentyl group, sec-pentyl group, tert-pentyl group, neopentyl group, n-hexyl group, etc., and can be easily produced. , preferably a methyl group or an ethyl group.
Ｒ３で表されるＣ１～Ｃ８アルキル基としては、直鎖又は分枝していても良く、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、ｓｅｃ－ブチル基、イソブチル基、ｔｅｒｔ－ブチル基、ｎ－ペンチル基、ｓｅｃ－ペンチル基、ｔｅｒｔ－ペンチル基、ネオペンチル基、ｎ－ヘキシル基、ｎ－ヘプチル基、ｎ－オクチル基等を例示することができ、好ましくはエチル基、ｎ－プロピル基、ｎ－ブチル基、イソブチル基等を例示することができる。 The C 1 -C 8 alkyl group represented by R 3 may be linear or branched, and includes methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group and sec-butyl group. , isobutyl group, tert-butyl group, n-pentyl group, sec-pentyl group, tert-pentyl group, neopentyl group, n-hexyl group, n-heptyl group, n-octyl group, etc., and preferably can be exemplified by ethyl group, n-propyl group, n-butyl group, isobutyl group and the like.
Ｒ３で表される置換されていてもよいフェニル基としてはフェニル基、２－フルオロフェニル基、３－フルオロフェニル基、４－フルオロフェニル基、２－クロロフェニル基、３－クロロフェニル基、４－クロロフェニル基、２－メチルフェニル基、３－メチルフェニル基、４－メチルフェニル基、２－メトキシフェニル基、３－メトキシフェニル基、４－メトキシフェニル基等を例示することができる。 The optionally substituted phenyl group represented by R 3 includes a phenyl group, a 2-fluorophenyl group, a 3-fluorophenyl group, a 4-fluorophenyl group, a 2-chlorophenyl group, a 3-chlorophenyl group and a 4-chlorophenyl group. group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group and the like.
Ｒ３で表される置換されていてもよいＣ３－Ｃ６シクロアルキル基としては、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基、４－メチルシクロヘキシル基等を例示することができる。 Examples of the optionally substituted C3-C6 cycloalkyl group represented by R 3 include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, 4-methylcyclohexyl group and the like.
Ｒｆで表されるフッ素原子が置換しているＣ１～Ｃ４アルキル基としては、モノフルオロメチル基、ジフルオロメチル基、トリフルオロメチル基、ペンタフルオロエチル基、ヘプタフルオロプロピル基、ノナフルオロブチル基等を例示することができ、好ましくはジフルオロメチル基、トリフルオロメチル基等を例示することができる。 The fluorine atom-substituted C 1 -C 4 alkyl group represented by R f includes a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a pentafluoroethyl group, a heptafluoropropyl group, and a nonafluorobutyl group. groups and the like, preferably difluoromethyl group, trifluoromethyl group and the like.
工程－１は、式（１）で表される６－（フルオロアルキル）－３，４－ジヒドロ－２Ｈ－ピラン－５－カルボン酸エステル誘導体（１）を酸またはルイス酸で処理した後、アンモニウム化合物又はアンモニアと反応させることによって、２－（フルオロアルキル）ニコチン酸エステル誘導体（１ａ）を製造する工程である。式（１）で表される６－（フルオロアルキル）－３，４－ジヒドロ－２Ｈ－ピラン－５－カルボン酸エステル誘導体（１）は、フッ素化された２－（アルコキシメチリデン）－β－ケトエステル誘導体とビニル化合物を反応させることによって、調製することができる。 In step-1, 6-(fluoroalkyl)-3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative (1) represented by formula (1) is treated with an acid or Lewis acid, followed by ammonium A step of producing a 2-(fluoroalkyl)nicotinic acid ester derivative (1a) by reacting with a compound or ammonia. 6-(fluoroalkyl)-3,4-dihydro-2H-pyran-5-carboxylic acid ester derivative (1) represented by formula (1) is a fluorinated 2-(alkoxymethylidene)-β- It can be prepared by reacting a ketoester derivative with a vinyl compound.
本反応で使用できる酸またはルイス酸としては、塩化水素、臭化水素、硫酸、メタンスルホン酸、トリフルオロ酢酸、トリクロロ酢酸、トリフルオロメタンスルホン酸、フルオロスルホン酸、クロロスルホン酸、過塩素酸、三フッ化ホウ素、塩化アルミニウム、塩化亜鉛、四塩化チタン、四塩化錫、塩化第二鉄、臭化第二鉄、エチル二塩化アルミニウム、臭化銅（II）等を用いることができる。酸またはルイス酸は基質に対して０．１～２０当量用いることにより目的物を得ることができ、０．５～５当量用いることにより、収率よく目的物を得ることができる。 Acids or Lewis acids that can be used in this reaction include hydrogen chloride, hydrogen bromide, sulfuric acid, methanesulfonic acid, trifluoroacetic acid, trichloroacetic acid, trifluoromethanesulfonic acid, fluorosulfonic acid, chlorosulfonic acid, perchloric acid, Boron fluoride, aluminum chloride, zinc chloride, titanium tetrachloride, tin tetrachloride, ferric chloride, ferric bromide, ethyl aluminum dichloride, copper (II) bromide and the like can be used. The target product can be obtained by using 0.1 to 20 equivalents of the acid or Lewis acid relative to the substrate, and the target product can be obtained in good yield by using 0.5 to 5 equivalents.
本反応で使用するアンモニウム化合物としては、安息香酸アンモニウム、塩化アンモニウム、カルバミン酸アンモニウム、ギ酸アンモニウム、炭酸アンモニウム、シュウ酸アンモニウム、酢酸アンモニウム、炭酸水素アンモニウム、チオシアン酸アンモニウム、ヨウ化アンモニウム、リン酸アンモニウム、リン酸にアンモニウム、硫酸アンモニウム等のアンモニウム塩、或いは、アンモニア水やアンモニアガスを用いることができる。アンモニウム化合物は基質に対して０．５～２０当量用いることにより目的物を得ることができ、１～１０当量用いることにより、収率よく目的物を得ることができる。 アンモニウム Ammonium compounds used in this reaction include ammonium benzoate, ammonium chloride, ammonium carbamate, ammonium formate, ammonium carbonate, ammonium oxalate, ammonium acetate, ammonium hydrogencarbonate, ammonium thiocyanate, ammonium iodide, ammonium phosphate, Ammonium salts such as ammonium and ammonium sulfate, or ammonia water or ammonia gas can be used for phosphoric acid. The target product can be obtained by using 0.5 to 20 equivalents of the ammonium compound relative to the substrate, and the target product can be obtained in good yield by using 1 to 10 equivalents of the ammonium compound. ammonium
本反応は無溶媒下及び溶媒存在下のどちらでも行うことができる。用いる溶媒としては、反応に害を及ぼさない溶媒であれば使用することができ、ベンゼン、トルエン、キシレン、クロロベンゼン等の芳香族炭化水素系溶媒、ペンタン、ヘキサン、オクタン等の脂肪族炭化水素系溶媒、ジエチルエーテル、ジイソプロピルエーテル、シクロペンチルメチルエーテル、テトラヒドロフラン、ジメトキシエタン、１，４－ジオキサン等のエーテル系溶媒、アセトン、メチルエチルケトン、シクロヘキサノン等のケトン類、クロロホルム、ジクロロメタン等のハロゲン系溶媒、アセトニトリル、プロピオニトリル等のニトリル系溶媒、酢酸エチル、酢酸プロピル、酢酸ブチル、プロピオン酸メチル等のエステル系溶媒、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチルピロリドン等のアミド系溶媒、メタノール、エタノール、１－プロパノール、２－プロパノール、ｔｅｒｔ－ブタノール、エチレングリコール等のアルコール系溶媒、ジメチルスルホキシド、水あるいはこれらの混合溶媒を用いることができる。 This reaction can be carried out either in the absence of a solvent or in the presence of a solvent. Any solvent can be used as long as it does not harm the reaction, and aromatic hydrocarbon solvents such as benzene, toluene, xylene and chlorobenzene, and aliphatic hydrocarbon solvents such as pentane, hexane and octane can be used. , diethyl ether, diisopropyl ether, cyclopentyl methyl ether, tetrahydrofuran, dimethoxyethane, 1,4-dioxane and other ether solvents, acetone, methyl ethyl ketone, cyclohexanone and other ketones, chloroform, dichloromethane and other halogen solvents, acetonitrile, propio Nitrile solvents such as nitrile, ester solvents such as ethyl acetate, propyl acetate, butyl acetate and methyl propionate, amide solvents such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone, methanol , ethanol, 1-propanol, 2-propanol, tert-butanol, ethylene glycol, dimethylsulfoxide, water or a mixed solvent thereof can be used.
また、０～２００度の反応温度の範囲で反応させることによって、目的物を得ることができ、２０～１６０度の範囲で反応させることによって、目的物をさらに収率良く得ることができる。 Further, the desired product can be obtained by reacting at a reaction temperature of 0 to 200°C, and the desired product can be obtained in a higher yield by reacting at a reaction temperature of 20 to 160°C.
反応終了後は、通常の後処理操作により目的物を得ることができるが、必要であれば、蒸留あるいはカラムクロマトグラフィー等により精製することもできる。 After completion of the reaction, the target product can be obtained by a normal post-treatment operation, but if necessary, it can be purified by distillation, column chromatography, or the like.
次に実施例をあげて本発明を具体的に説明するが、本発明の範囲はこれらに限定されるものではない。 EXAMPLES Next, the present invention will be specifically described with reference to Examples, but the scope of the present invention is not limited to these.
〔実施例１〕
２－ジフルオロメチルニコチン酸エチルの合成
エチル ２－ブトキシ－６－（ジフルオロメチル）－４－エトキシ－３，４－ジヒドロ－２Ｈ－ピラン－５－カルボキシラート（１．１０ｇ，３．３５ｍｍｏｌ）にエタノール（１．００ｍＬ）、メタンスルホン酸（３２２ｍｇ，３．３５ｍｍｏｌ）を加え、５０℃で２時間反応させた。反応溶液を２５℃まで放冷後、酢酸アンモニウム(９０５ｍｇ，１１．７ｍｍｏｌ)を加え、２５℃で２時間撹拌した。反応溶液を減圧下濃縮し、水（３．００ｍＬ）、酢酸エチル（５．００ｍＬ）を加えて抽出し、有機層を飽和食塩水（３．００ｍＬ）で洗浄後、硫酸ナトリウムで乾燥後、減圧下濃縮した。濃縮物をシリカゲルカラムクロマトグラフィ－（溶出溶剤：酢酸エチル／ｎ－ヘキサン＝１/３）により精製して、橙色透明液体の標記化合物（収量３５０ｍｇ、収率５２％）を得た。
[Example 1]
Synthesis of ethyl 2-difluoromethylnicotinate Ethyl 2-butoxy-6-(difluoromethyl)-4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (1.10 g, 3.35 mmol) was dissolved in ethanol. (1.00 mL) and methanesulfonic acid (322 mg, 3.35 mmol) were added and reacted at 50° C. for 2 hours. After allowing the reaction solution to cool to 25°C, ammonium acetate (905 mg, 11.7 mmol) was added, and the mixture was stirred at 25°C for 2 hours. The reaction solution is concentrated under reduced pressure, water (3.00 mL) and ethyl acetate (5.00 mL) are added for extraction, and the organic layer is washed with saturated brine (3.00 mL), dried over sodium sulfate, and evaporated under reduced pressure. It was concentrated down. The concentrate was purified by silica gel column chromatography (elution solvent: ethyl acetate/n-hexane=1/3) to obtain the title compound as an orange transparent liquid (yield: 350 mg, yield: 52%).
〔実施例２〕
２－ジフルオロメチルニコチン酸エチルの合成
エチル ２－ブトキシ－６－（ジフルオロメチル）－４－エトキシ－３，４－ジヒドロ－２Ｈ－ピラン－５－カルボキシラート（１．１１ｇ，３．４５ｍｍｏｌ）にエタノール（１．００ｍＬ）、３５％塩酸（３５９ｍｇ，３．４５ｍｍｏｌ）を加え、５０℃で２時間反応させた。反応溶液を２５℃まで放冷後、酢酸アンモニウム(９３０ｍｇ，１２．１ｍｍｏｌ)を加え、２５℃で２時間撹拌した。反応溶液を減圧下濃縮し、水（３．００ｍＬ）、酢酸エチル（５．００ｍＬ）を加えて抽出し、有機層を飽和食塩水（３．００ｍＬ）で洗浄後、硫酸ナトリウムで乾燥後、減圧下濃縮した。濃縮物をシリカゲルカラムクロマトグラフィ－（溶出溶剤：酢酸エチル／ｎ－ヘキサン＝１/３）により精製して、橙色透明液体の標記化合物（収量２７３ｍｇ、収率３９％）を得た。
[Example 2]
Synthesis of ethyl 2-difluoromethylnicotinate Ethyl 2-butoxy-6-(difluoromethyl)-4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (1.11 g, 3.45 mmol) was dissolved in ethanol. (1.00 mL) and 35% hydrochloric acid (359 mg, 3.45 mmol) were added and reacted at 50° C. for 2 hours. After allowing the reaction solution to cool to 25°C, ammonium acetate (930 mg, 12.1 mmol) was added, and the mixture was stirred at 25°C for 2 hours. The reaction solution is concentrated under reduced pressure, water (3.00 mL) and ethyl acetate (5.00 mL) are added for extraction, and the organic layer is washed with saturated brine (3.00 mL), dried over sodium sulfate, and evaporated under reduced pressure. It was concentrated down. The concentrate was purified by silica gel column chromatography (elution solvent: ethyl acetate/n-hexane=1/3) to obtain the title compound as an orange transparent liquid (yield: 273 mg, yield: 39%).
〔実施例３〕
２－ジフルオロメチルニコチン酸エチルの合成
エチル ２－ブトキシ－６－（ジフルオロメチル）－４－エトキシ－３，４－ジヒドロ－２Ｈ－ピラン－５－カルボキシラート（１．０５ｇ，３．１９ｍｍｏｌ）にエタノール（１．００ｍＬ）、塩化亜鉛（１３０ｍｇ，０．９６ｍｍｏｌ）を加え、５０℃で２時間反応させた。反応溶液を２５℃まで放冷後、酢酸アンモニウム(８６０ｍｇ，１１．２ｍｍｏｌ)を加え、２５℃で２時間撹拌した。反応溶液を減圧下濃縮し、水（３．００ｍＬ）、酢酸エチル（５．００ｍＬ）を加えて抽出し、有機層を飽和食塩水（３．００ｍＬ）で洗浄後、硫酸ナトリウムで乾燥後、減圧下濃縮した。濃縮物をシリカゲルカラムクロマトグラフィ－（溶出溶剤：酢酸エチル／ｎ－ヘキサン＝１/３）により精製して、橙色透明液体の標記化合物（収量２８０ｍｇ、収率３５％）を得た。
[Example 3]
Synthesis of ethyl 2-difluoromethylnicotinate Ethyl 2-butoxy-6-(difluoromethyl)-4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (1.05 g, 3.19 mmol) was dissolved in ethanol. (1.00 mL) and zinc chloride (130 mg, 0.96 mmol) were added and reacted at 50° C. for 2 hours. After allowing the reaction solution to cool to 25°C, ammonium acetate (860 mg, 11.2 mmol) was added, and the mixture was stirred at 25°C for 2 hours. The reaction solution is concentrated under reduced pressure, water (3.00 mL) and ethyl acetate (5.00 mL) are added for extraction, and the organic layer is washed with saturated brine (3.00 mL), dried over sodium sulfate, and evaporated under reduced pressure. It was concentrated down. The concentrate was purified by silica gel column chromatography (elution solvent: ethyl acetate/n-hexane=1/3) to obtain the title compound as an orange transparent liquid (yield: 280 mg, yield: 35%).
〔実施例４〕
２－ジフルオロメチルニコチン酸エチルの合成
エチル ２－ブトキシ－６－（ジフルオロメチル）－４－エトキシ－３，４－ジヒドロ－２Ｈ－ピラン－５－カルボキシラート（１．０５ｇ，３．２０ｍｍｏｌ）にエタノール（１．００ｍＬ）、臭化銅（II）（７１６ｍｇ，３．２０ｍｍｏｌ）を加え、５０℃で２時間反応させた。反応溶液を２５℃まで放冷後、酢酸アンモニウム(８６４ｍｇ，１１．２ｍｍｏｌを)加え、２５℃で２時間撹拌した。反応溶液を減圧下濃縮し、水（３．００ｍＬ）、酢酸エチル（５．００ｍＬ）を加えて抽出し、有機層を飽和食塩水（３．００ｍＬ）で洗浄後、硫酸ナトリウムで乾燥後、減圧下濃縮した。濃縮物をシリカゲルカラムクロマトグラフィ－（溶出溶剤：酢酸エチル／ｎ－ヘキサン＝１/３）により精製して、橙色透明液体の標記化合物（収量１６３ｍｇ、収率２５％）を得た。
[Example 4]
Synthesis of ethyl 2-difluoromethylnicotinate Ethyl 2-butoxy-6-(difluoromethyl)-4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (1.05 g, 3.20 mmol) was dissolved in ethanol. (1.00 mL) and copper (II) bromide (716 mg, 3.20 mmol) were added and reacted at 50° C. for 2 hours. After cooling the reaction solution to 25° C., ammonium acetate (864 mg, 11.2 mmol) was added and stirred at 25° C. for 2 hours. The reaction solution is concentrated under reduced pressure, water (3.00 mL) and ethyl acetate (5.00 mL) are added for extraction, and the organic layer is washed with saturated brine (3.00 mL), dried over sodium sulfate, and evaporated under reduced pressure. It was concentrated down. The concentrate was purified by silica gel column chromatography (elution solvent: ethyl acetate/n-hexane=1/3) to obtain the title compound as an orange transparent liquid (163 mg, 25% yield).
〔参考例１〕
エチル ２－ブトキシ－６－（ジフルオロメチル）－４－エトキシ－３，４－ジヒドロ－２Ｈ－ピラン－５－カルボキシラートの合成
２－（エトキシメチレン）－４，４－ジフルオロ－３－オキソ酪酸エチル（５００ｇ，２．３０ｍｏｌ）にブチル（ビニル）エーテル（２７１ｇ，２．７０ｍｏｌ）を加え、９４℃で１時間半撹拌した。得られた反応溶液を減圧濃縮して、黄色油状の標記化合物（収量７４７ｇ、収率１００％）で得た。
１ＨＮＭＲスペクトル（ＣＤＣｌ３） σ：７．１４（０．７Ｈ，ｔ，Ｊ＝５４．２Ｈｚ），７．０８（０．３Ｈ，ｔ，Ｊ＝５４．２Ｈｚ），５．３３（０．７Ｈ，ｔ，Ｊ＝２．６Ｈｚ），５．１４（０．３Ｈ，ｄｄ，Ｊ１＝１０．０Ｈｚ，Ｊ２＝２．４Ｈｚ），４．３５－４．１５（３Ｈ，ｍ），４．０２（０．３Ｈ，ｄｔ，Ｊ１＝９．６Ｈｚ，Ｊ２＝６．６Ｈｚ）， ３．８７（０．７Ｈ，ｄｔ，Ｊ１＝１０．０Ｈｚ，Ｊ２＝６．６Ｈｚ），３．７０－３．６０（１Ｈ，ｍ）， ３．５７－３．４４（２Ｈ，ｍ），２．３６（０．７Ｈ， ｄｔ，Ｊ１＝１４．４Ｈｚ，Ｊ２＝２．７Ｈｚ）， ２．２１（０．３Ｈ， ｄｔ，Ｊ１＝１４．０Ｈｚ，Ｊ２＝２．５Ｈｚ），１．９２（０．７Ｈ，ｄｄｄ， Ｊ１＝１４．５Ｈｚ，Ｊ２＝５．７Ｈｚ，Ｊ３＝３．３Ｈｚ），１．７７－１．７０（０．３Ｈ，ｍ），１．６３－１．５０（２Ｈ，ｍ），１．４３－１．３４（２Ｈ，ｍ），１．４４－１．３０（３Ｈ，ｍ），１．２２－１．１７（３Ｈ，ｍ），０．９６－０．８９（３Ｈ，ｍ）．
[Reference Example 1]
Synthesis of ethyl 2-butoxy-6-(difluoromethyl)-4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate Ethyl 2-(ethoxymethylene)-4,4-difluoro-3-oxobutyrate Butyl (vinyl) ether (271 g, 2.70 mol) was added to (500 g, 2.30 mol) and stirred at 94°C for 1.5 hours. The resulting reaction solution was concentrated under reduced pressure to obtain the title compound as a yellow oil (yield: 747 g, yield: 100%).
1 H NMR spectrum (CDCl 3 ) σ: 7.14 (0.7H, t, J = 54.2 Hz), 7.08 (0.3H, t, J = 54.2 Hz), 5.33 (0.7H , t, J = 2.6 Hz), 5.14 (0.3H, dd, J1 = 10.0 Hz, J2 = 2.4 Hz), 4.35-4.15 (3H, m), 4.02 ( 0.3H, dt, J1 = 9.6Hz, J2 = 6.6Hz), 3.87 (0.7H, dt, J1 = 10.0Hz, J2 = 6.6Hz), 3.70-3.60 ( 1H, m), 3.57-3.44 (2H, m), 2.36 (0.7H, dt, J1 = 14.4Hz, J2 = 2.7Hz), 2.21 (0.3H, dt , J1 = 14.0 Hz, J2 = 2.5 Hz), 1.92 (0.7H, ddd, J1 = 14.5 Hz, J2 = 5.7 Hz, J3 = 3.3 Hz), 1.77-1.70 (0.3H, m), 1.63-1.50 (2H, m), 1.43-1.34 (2H, m), 1.44-1.30 (3H, m), 1.22 -1.17 (3H, m), 0.96-0.89 (3H, m).
〔参考例２〕２－ジフルオロメチルニコチン酸の合成
エチル ２－ブトキシ－６－（ジフルオロメチル）－４－エトキシ－３，４－ジヒドロ－２Ｈ－ピラン－５－カルボキシラート（２．００ｇ，６．２１ｍｍｏｌ）にエタノール（２．００ｍＬ）、メタンスルホン酸（５９６ｍｇ，６．２１ｍｍｏｌ）を加え、５０℃で２時間反応させた。反応溶液を２５℃まで放冷後、酢酸アンモニウム(１．６７ｇ，２１．７ｍｍｏｌ)を加え、５０℃で４時間撹拌した。その後、４８％水酸化ナトリウム水溶液（２．５９ｇ，３１．０ｍｍｏｌ）を氷浴で冷却しながら１０～３０℃で加えた後、２５℃で１時間撹拌した。反応溶液を減圧下濃縮し、水（５ｍＬ）、トルエン（５ｍＬ）を加えて洗浄した後、水層に３５％塩酸（３．８８ｇ，３７．２ｍｏｌ）を氷浴で冷却しながら加えた。析出した固体をろ過し、水（５ｍＬ）で洗浄した後に、減圧下乾燥することで、白色固体の標記化合物（収量３１０ｍｇ，収率２９％）を得た
１ＨＮＭＲスペクトル（ＤＭＳＯ－ｄ） σ：１３．９（１Ｈ，ｂｒｓ）８．８５（１．０Ｈ， ｄｄ，Ｊ１＝４．５６Ｈｚ，Ｊ２＝１．８４Ｈｚ），８．３３（１Ｈ，ｄ，Ｊ＝７．８０Ｈｚ），７．６９（１Ｈ，ｄｄ，Ｊ１＝８．２０Ｈｚ，Ｊ２＝４．８０Ｈｚ），７．５０（１．０Ｈ，ｔ，Ｊ＝５４．０Ｈｚ）
[Reference Example 2] Synthesis of 2-difluoromethylnicotinic acid Ethyl 2-butoxy-6-(difluoromethyl)-4-ethoxy-3,4-dihydro-2H-pyran-5-carboxylate (2.00g, 6.00g, 6.00g, 6.00g, 6.00g, 6.00g, 6.00g) 21 mmol), ethanol (2.00 mL) and methanesulfonic acid (596 mg, 6.21 mmol) were added and reacted at 50° C. for 2 hours. After allowing the reaction solution to cool to 25°C, ammonium acetate (1.67 g, 21.7 mmol) was added, and the mixture was stirred at 50°C for 4 hours. After that, a 48% sodium hydroxide aqueous solution (2.59 g, 31.0 mmol) was added at 10 to 30°C while cooling in an ice bath, and the mixture was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure, washed with water (5 mL) and toluene (5 mL), and then 35% hydrochloric acid (3.88 g, 37.2 mol) was added to the aqueous layer while cooling in an ice bath. The precipitated solid was filtered, washed with water (5 mL), and dried under reduced pressure to obtain the title compound as a white solid (yield: 310 mg, yield: 29%).
1 H NMR spectrum (DMSO-d) σ: 13.9 (1H, brs) 8.85 (1.0H, dd, J = 4.56 Hz, J = 1.84 Hz), 8.33 (1H, d, J = 7.80Hz), 7.69 (1H, dd, J1 = 8.20Hz, J2 = 4.80Hz), 7.50 (1.0H, t, J = 54.0Hz)
本発明によれば、農園芸場面用殺菌剤の中間体である２－（フッ素置換アルキル）ニコチン酸誘導体を効率的に製造、提供することができる。
INDUSTRIAL APPLICABILITY According to the present invention, 2-(fluorine-substituted alkyl)nicotinic acid derivatives, which are intermediates of fungicides for agricultural and horticultural scenes, can be efficiently produced and provided.
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| TW110111141A TW202146395A (en) | 2020-03-27 | 2021-03-26 | 6-(fluoroalkyl)-3,4-dihydro-2h-pyran-5-carboxylic acid ester derivative, method for producing derivative, method for producing 2-(fluoroalkyl)nicotinic acid ester derivative, and method for producing 2-(fluoroalkyl)nicotinic acid derivative |
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