JP7034953B2 - ハロゲン化ピリジン誘導体の製造方法 - Google Patents
ハロゲン化ピリジン誘導体の製造方法 Download PDFInfo
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- JP7034953B2 JP7034953B2 JP2018567735A JP2018567735A JP7034953B2 JP 7034953 B2 JP7034953 B2 JP 7034953B2 JP 2018567735 A JP2018567735 A JP 2018567735A JP 2018567735 A JP2018567735 A JP 2018567735A JP 7034953 B2 JP7034953 B2 JP 7034953B2
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- 238000004519 manufacturing process Methods 0.000 title claims description 8
- 150000003222 pyridines Chemical class 0.000 title description 16
- 150000001875 compounds Chemical class 0.000 claims description 70
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 32
- 229910052736 halogen Inorganic materials 0.000 claims description 30
- 150000002367 halogens Chemical class 0.000 claims description 30
- 238000000034 method Methods 0.000 claims description 30
- 239000002585 base Substances 0.000 claims description 28
- 239000000460 chlorine Chemical group 0.000 claims description 26
- 229910052801 chlorine Chemical group 0.000 claims description 25
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 22
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 20
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 20
- 229910052794 bromium Inorganic materials 0.000 claims description 20
- -1 jiglime Chemical compound 0.000 claims description 19
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 17
- 239000011630 iodine Substances 0.000 claims description 17
- 229910052740 iodine Inorganic materials 0.000 claims description 17
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 15
- 239000011737 fluorine Substances 0.000 claims description 14
- 229910052731 fluorine Inorganic materials 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- HVZJRWJGKQPSFL-UHFFFAOYSA-N tert-Amyl methyl ether Chemical compound CCC(C)(C)OC HVZJRWJGKQPSFL-UHFFFAOYSA-N 0.000 claims description 8
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 7
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 7
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- QPFMBZIOSGYJDE-UHFFFAOYSA-N 1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)C(Cl)Cl QPFMBZIOSGYJDE-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- ZFPGARUNNKGOBB-UHFFFAOYSA-N 1-Ethyl-2-pyrrolidinone Chemical compound CCN1CCCC1=O ZFPGARUNNKGOBB-UHFFFAOYSA-N 0.000 claims description 4
- BNXZHVUCNYMNOS-UHFFFAOYSA-N 1-butylpyrrolidin-2-one Chemical compound CCCCN1CCCC1=O BNXZHVUCNYMNOS-UHFFFAOYSA-N 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 4
- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 claims description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 4
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- 229910001508 alkali metal halide Inorganic materials 0.000 claims description 3
- 229910001615 alkaline earth metal halide Inorganic materials 0.000 claims description 3
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 claims description 3
- 229930195733 hydrocarbon Natural products 0.000 claims description 3
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical class FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 2
- BOSAWIQFTJIYIS-UHFFFAOYSA-N 1,1,1-trichloro-2,2,2-trifluoroethane Chemical compound FC(F)(F)C(Cl)(Cl)Cl BOSAWIQFTJIYIS-UHFFFAOYSA-N 0.000 claims description 2
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 claims description 2
- SEQRDAAUNCRFIT-UHFFFAOYSA-N 1,1-dichlorobutane Chemical compound CCCC(Cl)Cl SEQRDAAUNCRFIT-UHFFFAOYSA-N 0.000 claims description 2
- RELMFMZEBKVZJC-UHFFFAOYSA-N 1,2,3-trichlorobenzene Chemical compound ClC1=CC=CC(Cl)=C1Cl RELMFMZEBKVZJC-UHFFFAOYSA-N 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- KNKRKFALVUDBJE-UHFFFAOYSA-N 1,2-dichloropropane Chemical compound CC(Cl)CCl KNKRKFALVUDBJE-UHFFFAOYSA-N 0.000 claims description 2
- GOYDNIKZWGIXJT-UHFFFAOYSA-N 1,2-difluorobenzene Chemical compound FC1=CC=CC=C1F GOYDNIKZWGIXJT-UHFFFAOYSA-N 0.000 claims description 2
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 claims description 2
- KMTRUDSVKNLOMY-UHFFFAOYSA-N Ethylene carbonate Chemical compound O=C1OCCO1 KMTRUDSVKNLOMY-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- CYTYCFOTNPOANT-UHFFFAOYSA-N Perchloroethylene Chemical group ClC(Cl)=C(Cl)Cl CYTYCFOTNPOANT-UHFFFAOYSA-N 0.000 claims description 2
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical group ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 claims description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 2
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims description 2
- 229940117389 dichlorobenzene Drugs 0.000 claims description 2
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 claims description 2
- 150000005826 halohydrocarbons Chemical class 0.000 claims description 2
- 150000002430 hydrocarbons Chemical class 0.000 claims description 2
- 125000001827 mesitylenyl group Chemical group [H]C1=C(C(*)=C(C([H])=C1C([H])([H])[H])C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- QULYNCCPRWKEMF-UHFFFAOYSA-N parachlorobenzotrifluoride Chemical class FC(F)(F)C1=CC=C(Cl)C=C1 QULYNCCPRWKEMF-UHFFFAOYSA-N 0.000 claims description 2
- BNIXVQGCZULYKV-UHFFFAOYSA-N pentachloroethane Chemical compound ClC(Cl)C(Cl)(Cl)Cl BNIXVQGCZULYKV-UHFFFAOYSA-N 0.000 claims description 2
- RUOJZAUFBMNUDX-UHFFFAOYSA-N propylene carbonate Chemical compound CC1COC(=O)O1 RUOJZAUFBMNUDX-UHFFFAOYSA-N 0.000 claims description 2
- 229950011008 tetrachloroethylene Drugs 0.000 claims description 2
- UBOXGVDOUJQMTN-UHFFFAOYSA-N trichloroethylene Natural products ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims 3
- 125000001931 aliphatic group Chemical group 0.000 claims 1
- 150000008045 alkali metal halides Chemical class 0.000 claims 1
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 20
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 15
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- 0 CI(C)*c(nc1*)ccc1N Chemical compound CI(C)*c(nc1*)ccc1N 0.000 description 8
- 239000011701 zinc Substances 0.000 description 8
- 229910052725 zinc Inorganic materials 0.000 description 6
- YAXWOADCWUUUNX-UHFFFAOYSA-N 1,2,2,3-tetramethylpiperidine Chemical compound CC1CCCN(C)C1(C)C YAXWOADCWUUUNX-UHFFFAOYSA-N 0.000 description 5
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-Tetramethylpiperidine Substances CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- MINXERMPCQJEFL-UHFFFAOYSA-N 6-chloro-3-fluoro-2-iodopyridine Chemical compound FC1=CC=C(Cl)N=C1I MINXERMPCQJEFL-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- 238000001465 metallisation Methods 0.000 description 4
- JMWYSMBTMNOYFN-UHFFFAOYSA-N methyl 5-fluoro-6-iodopyridine-2-carboxylate Chemical compound COC(=O)C1=NC(=C(C=C1)F)I JMWYSMBTMNOYFN-UHFFFAOYSA-N 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- HLFVDGPBZNIAAD-UHFFFAOYSA-N 6-bromo-3-fluoro-2-iodopyridine Chemical compound BrC1=CC=C(C(=N1)I)F HLFVDGPBZNIAAD-UHFFFAOYSA-N 0.000 description 3
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 3
- IIEWJVIFRVWJOD-UHFFFAOYSA-N ethyl cyclohexane Natural products CCC1CCCCC1 IIEWJVIFRVWJOD-UHFFFAOYSA-N 0.000 description 3
- 238000000589 high-performance liquid chromatography-mass spectrometry Methods 0.000 description 3
- 229910052744 lithium Inorganic materials 0.000 description 3
- 229910052749 magnesium Inorganic materials 0.000 description 3
- 239000011777 magnesium Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 125000002524 organometallic group Chemical group 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 3
- 235000019345 sodium thiosulphate Nutrition 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 239000003905 agrochemical Substances 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 230000005595 deprotonation Effects 0.000 description 2
- 238000010537 deprotonation reaction Methods 0.000 description 2
- 150000004820 halides Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 150000008040 ionic compounds Chemical class 0.000 description 2
- 239000011572 manganese Substances 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000011592 zinc chloride Substances 0.000 description 2
- 235000005074 zinc chloride Nutrition 0.000 description 2
- UODINHBLNPPDPD-UHFFFAOYSA-N 2-bromo-5-fluoropyridine Chemical compound FC1=CC=C(Br)N=C1 UODINHBLNPPDPD-UHFFFAOYSA-N 0.000 description 1
- QOGXQLSFJCIDNY-UHFFFAOYSA-N 2-chloro-5-fluoropyridine Chemical compound FC1=CC=C(Cl)N=C1 QOGXQLSFJCIDNY-UHFFFAOYSA-N 0.000 description 1
- XNZJNHAYFLTPGN-UHFFFAOYSA-N 3-fluoro-2-iodo-6-nitropyridine Chemical compound [O-][N+](=O)c1ccc(F)c(I)n1 XNZJNHAYFLTPGN-UHFFFAOYSA-N 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- 101001073211 Solanum lycopersicum Suberization-associated anionic peroxidase 2 Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000010960 commercial process Methods 0.000 description 1
- 238000006880 cross-coupling reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000009815 homocoupling reaction Methods 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- ULKSWZAXQDJMJT-UHFFFAOYSA-M magnesium;2,2,6,6-tetramethylpiperidin-1-ide;chloride Chemical compound [Cl-].CC1(C)CCCC(C)(C)N1[Mg+] ULKSWZAXQDJMJT-UHFFFAOYSA-M 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- KCMBKUFSDZMQEM-UHFFFAOYSA-N methyl 5-fluoropyridine-2-carboxylate Chemical compound COC(=O)C1=CC=C(F)C=N1 KCMBKUFSDZMQEM-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 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
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000012038 nucleophile Substances 0.000 description 1
- 239000003791 organic solvent mixture Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- 150000003752 zinc compounds Chemical class 0.000 description 1
Classifications
-
- 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
- C07D213/61—Halogen atoms or nitro radicals
-
- 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
-
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- 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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Description
Q及びWは、それぞれ独立にハロゲンであり、
Yはハロゲン、CO2R1又はNO2であり、R1は(C1-C6)-アルキル又は(C1-C6)-ハロアルキルである。]の製造方法であって、
第1の工程段階a)で、式(I)の化合物:
構造(NR3R4)-Zn-R2又は(NR3R4)2-Znの有機亜鉛塩基
[式中、
R2はハロゲン又は-O-ピバロイルであり、
R3及びR4が一緒になって、-(CH2)4-、-(CH2)5-又は-(CH2)2O(CH2)2-基を形成しており、これらの基のそれぞれは、1、2、3若しくは4個のR5基によって置換されていても良く、R5はメチル、エチル、n-プロピル及びi-プロピルからなる群から選択される。]と反応させて、
式(IIIa)又は下記式(IIIb)の化合物:
この式(IIIa)又は(IIIb)の化合物を、第2の工程段階b)で、構造Q-Xの化合物[Xはハロゲンであり、Qは、上記の定義を有する。]と反応させて、式(II)の化合物を得ることを特徴とする方法を提供する。
Q及びXは同じ定義を有し、それぞれ好ましくはヨウ素又は臭素であり、
Wは好ましくはフッ素又は塩素であり、
R2は好ましくはハロゲン、特別には塩素、臭素又はヨウ素であり、
Yは好ましくは塩素、臭素、CO2R1又はNO2であり、R1は(C1-C4)-アルキルである。
Q及びXは同じ定義を有し、それぞれ特に好ましくはヨウ素であり、
Wは特に好ましくはフッ素であり、
R2は特に好ましくは塩素であり、
Yは特に好ましくは塩素、臭素、CO2R1又はNO2であり、R1はメチルである。
本発明の文脈において、別段の定義がない限り、ハロゲン(Hal)という用語は、フッ素、塩素、臭素及びヨウ素からなる群から選択される元素を包含する。
R2は上記で定義の通りであり(構成1)(従って、ハロゲン又は-O-ピバロイルである)、
R3及びR4が一緒になって、-(CH2)4-、-(CH2)5-又は-(CH2)2O(CH2)2-基を形成しており、これらの基のそれぞれは、1、2、3若しくは4個のR5基によって置換されていても良く、
R5は、メチル、エチル、n-プロピル及びi-プロピルからなる群から選択される。
R2が、好ましいと上記で定義の通りであり(構成2)(従って、ハロゲン、特別には塩素、臭素又はヨウ素である)、
R3及びR4が一緒になって、-(CH2)5-基を形成しており、これらの基のそれぞれは、1、2、3若しくは4個のR5基によって置換されていても良く、
R5がメチル及びエチルからなる群から選択されることが好ましい。
R2が、特に好ましいと上記で定義の通りであり(構成3)(従って、塩素である)、
R3及びR4が一緒になって、4個のメチル基によって置換された-(CH2)5-基を形成していることが特に好ましい。
Wはハロゲンであり、
Yはハロゲン、CO2R1又はNO2であり、R1は(C1-C6)-アルキル又は(C1-C6)-ハロアルキルであり、
R2はハロゲン又は-O-ピバロイルである。
Yは好ましくは塩素、臭素、CO2R1又はNO2であり、R1は(C1-C4)-アルキルであり、
R2は好ましくはハロゲン、特別には塩素、臭素及びヨウ素である。
Yは特に好ましくは塩素、臭素、CO2R1又はNO2であり、R1はメチルであり、
R2は特に好ましくは塩素である。
Wはハロゲンであり、
Yはハロゲン、CO2R1又はNO2であり、R1は(C1-C6)-アルキル又は(C1-C6)-ハロアルキルである。
Yは好ましくは塩素、臭素、CO2R1又はNO2であり、R1は(C1-C4)-アルキルである。
Yは特に好ましくは塩素、臭素、CO2R1又はNO2であり、R1はメチルである。
Yはハロゲン、CO2R1又はNO2であり、R1は(C1-C6)-アルキル又は(C1-C6)-ハロアルキルである。
Wは好ましくはフッ素又は塩素であり、
Yは好ましくは塩素、臭素、CO2R1又はNO2であり、R1は(C1-C4)-アルキルである。
Wは特に好ましくはフッ素であり、
Yは特に好ましくは塩素、臭素、CO2R1又はNO2であり、R1はメチルである。
これらの式(II-1)~(II-4)の化合物は、本発明による方法の式(I)の随伴する反応物(I-1~I-4)を生じるものであり、それらは各場合で、特別に好ましい式(I)の化合物である。
メチル5-フルオロ-6-ヨードピリジン-2-カルボキシレートの合成:
THF(2mL)に溶かしたメチル5-フルオロピリジン-2-カルボキシレート(155mg、1.0mmol)に、60℃でアルゴン下に、TMPZnCl・LiCl(1.31M THF中溶液、0.84mL、1.1mmol)を加える。この反応溶液を30分間攪拌する。次に、ヨウ素(THF 4mL中355mg)を25℃で加え、得られた溶液をさらに30分間攪拌する。一般的な後処理及びカラムクロマトグラフィー(酢酸エチル/シクロヘキサン)による精製後に、メチル5-フルオロ-6-ヨードピリジン-2-カルボキシレート(197mg、70%)が黄色固体として得られる。HPLC-MS:log=1.85;質量(m/z):281.9;1H-NMR(D6-DMSO):δ8.10(m、1H)、7.86(m、1H)、3.89(s、3H)。
6-ブロモ-3-フルオロ-2-ヨードピリジンの合成:
THF(5mL)に溶かした2-ブロモ-5-フルオロピリジン(880mg、5.0mmol)に、アルゴン下に60℃でTMPZnCl・LiCl(1.31M THF中溶液、4.2mL、5.5mmol)を加える。この反応溶液を30分間攪拌する。次に、ヨウ素(THF 4mL中1.78g)を25℃で加え、得られた溶液をさらに30分間攪拌する。飽和塩化アンモニウム溶液及びチオ硫酸ナトリウム溶液を加えることによる一般的な後処理後に、反応混合物を酢酸エチルで抽出し、合わせた有機相をNa2SO4で脱水し、膜ポンプ真空で濃縮する。カラムクロマトグラフィー(酢酸エチル/シクロヘキサン)による精製後に、6-ブロモ-3-フルオロ-2-ヨードピリジン(1.31g、87%)が黄色固体として得られる。HPLC-MS:logP=2.67;質量(m/z):イオン化なし;1H-NMR(D6-DMSO):δ7.72(m、2H)。
Claims (16)
- 下記式(II)の化合物:
Q及びWは、それぞれ独立にハロゲンであり、
Yはハロゲン、CO2R1又はNO2であり、R1は(C1-C6)-アルキル又は(C1-C6)-ハロアルキルである。]の製造方法であって、
第1の工程段階a)で、式(I)の化合物:
構造(NR3R4)-Zn-R2又は(NR3R4)2-Znの有機亜鉛塩基
[式中、
R2はハロゲン又は-O-ピバロイルであり、
R3及びR4が一緒になって、-(CH2)4-、-(CH2)5-又は-(CH2)2O(CH2)2-基を形成しており、これらの基のそれぞれは、1、2、3若しくは4個のR5基によって置換されていても良く、R5はメチル、エチル、n-プロピル及びi-プロピルからなる群から選択される。]と反応させて、
式(IIIa)又は下記式(IIIb)の化合物:
この式(IIIa)又は(IIIb)の化合物を、第2の工程段階b)で、構造Q-Xの化合物[Xはハロゲンであり、Qは、上記の定義を有する。]と反応させて、式(II)の化合物を得ることを特徴とし、
ここで、工程段階a)を30℃~80℃の温度で行う、式(II)の化合物の製造方法。 - Q及びXが同一の定義を有し、それぞれヨウ素又は臭素であり、
Wがフッ素又は塩素であり、
R2がハロゲンであり、
Yが塩素、臭素、CO2R1又はNO2であり、R1が(C1-C4)-アルキルである請求項1に記載の方法。 - R3及びR4が一緒になって、-(CH2)5-基を形成しており、これらの基のそれぞれが1、2、3若しくは4個のR5基によって置換されていても良く、
R5が、メチル及びエチルからなる群から選択される請求項1及び2のいずれかに記載の方法。 - Q及びXが同じ定義を有し、それぞれヨウ素であり、
Wがフッ素であり、
R2が塩素であり、
Yが塩素、臭素、CO2R1又はNO2であり、R1がメチルである、請求項1~3のいずれか1項に記載の方法。 - R3及びR4が一緒になって、4個のメチル基によって置換された-(CH2)5-基を形成している、請求項1~4のいずれか1項に記載の方法。
- 前記有機亜鉛塩基が、アルカリ金属ハライド若しくはアルカリ土類金属ハライドとともに存在する、請求項1~6のいずれか1項に記載の方法。
- 前記有機亜鉛塩基を、式(I)の化合物基準で0.5~5当量の合計量で使用する、請求項1~7のいずれか1項に記載の方法。
- 前記化合物Q-Xが元素ハロゲンである、請求項1~8のいずれか1項に記載の方法。
- 前記化合物Q-Xを、式(I)の化合物基準で0.5~10.0当量の合計量で使用する、請求項1~9のいずれか1項に記載の方法。
- テトラヒドロフラン(THF)、1,4-ジオキサン、ジエチルエーテル、ジグライム、メチルtert-ブチルエーテル(MTBE)、tert-アミルメチルエーテル(TAME)、2-メチル-THF、トルエン、キシレン、メシチレン、エチレンカーボネート、プロピレンカーボネート、N,N-ジメチルアセトアミド、N,N-ジメチルホルムアミド(DMF)、N-メチルピロリドン(NMP)、N-エチル-2-ピロリドン(NEP)、N-ブチル-2-ピロリドン(NBP);N,N′-ジメチルプロピレン尿素(DMPU)、ハロ炭化水素、芳香族炭化水素、クロロ炭化水素、テトラクロロエチレン、テトラクロロエタン、ジクロロプロパン、塩化メチレン、ジクロロブタン、クロロホルム、四塩化炭素、トリクロロエタン、トリクロロエチレン、ペンタクロロエタン、ジフルオロベンゼン、1,2-ジクロロエタン、クロロベンゼン、ブロモベンゼン、ジクロロベンゼン、1,2-ジクロロベンゼン、クロロトルエン、トリクロロベンゼン;4-メトキシベンゼン、フッ素化脂肪族、フッ素化芳香族、トリクロロトリフルオロエタン、ベンゾトリフルオリド及び4-クロロベンゾトリフルオリド、又はこれら溶媒の少なくとも二つの互いとの混合物からなる群から選択される溶媒の存在下に行われる、請求項1~10のいずれか1項に記載の方法。
- 前記溶媒がTHF又はN,N-ジメチルホルムアミド(DMF)である、請求項11に記載の方法。
- 工程段階b)を0℃~80℃の温度で行う、請求項1~12のいずれか1項に記載の方法。
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