JP6078563B2 - フェニルが置換された3−ジフルオロメチル−1−メチル−1h−ピラゾール−4−カルボン酸n−メトキシ−[1−メチル−2−フェニルエチル]アミドを調製するためのプロセス - Google Patents
フェニルが置換された3−ジフルオロメチル−1−メチル−1h−ピラゾール−4−カルボン酸n−メトキシ−[1−メチル−2−フェニルエチル]アミドを調製するためのプロセス Download PDFInfo
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- JP6078563B2 JP6078563B2 JP2014559177A JP2014559177A JP6078563B2 JP 6078563 B2 JP6078563 B2 JP 6078563B2 JP 2014559177 A JP2014559177 A JP 2014559177A JP 2014559177 A JP2014559177 A JP 2014559177A JP 6078563 B2 JP6078563 B2 JP 6078563B2
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- phenyl
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- XKDRDLNBSRCAGQ-UHFFFAOYSA-N 3-(difluoromethyl)-n-methoxy-1-methyl-n-(1-phenylpropan-2-yl)pyrazole-4-carboxamide Chemical class C=1N(C)N=C(C(F)F)C=1C(=O)N(OC)C(C)CC1=CC=CC=C1 XKDRDLNBSRCAGQ-UHFFFAOYSA-N 0.000 title description 3
- 238000004519 manufacturing process Methods 0.000 title description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 46
- 239000000203 mixture Substances 0.000 claims description 26
- 238000006243 chemical reaction Methods 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 19
- 238000002360 preparation method Methods 0.000 claims description 15
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 claims description 5
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- GMPKIPWJBDOURN-UHFFFAOYSA-N Methoxyamine Chemical compound CON GMPKIPWJBDOURN-UHFFFAOYSA-N 0.000 claims description 3
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 2
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 2
- 125000006643 (C2-C6) haloalkenyl group Chemical group 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims description 2
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 14
- 239000002904 solvent Substances 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000012043 crude product Substances 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- SSGBVBPQZPYPSM-UHFFFAOYSA-N 1-(2,4,6-trichlorophenyl)propan-2-one Chemical compound CC(=O)CC1=C(Cl)C=C(Cl)C=C1Cl SSGBVBPQZPYPSM-UHFFFAOYSA-N 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 238000003556 assay Methods 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 7
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 7
- ONALTRORXRRIQR-UHFFFAOYSA-N n-methoxy-1-(2,4,6-trichlorophenyl)propan-2-imine Chemical compound CON=C(C)CC1=C(Cl)C=C(Cl)C=C1Cl ONALTRORXRRIQR-UHFFFAOYSA-N 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000008096 xylene Substances 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 6
- 239000012954 diazonium Substances 0.000 description 6
- 150000001989 diazonium salts Chemical class 0.000 description 6
- YEYSNJKFDGOAAP-UHFFFAOYSA-N n-methoxy-1-(2,4,6-trichlorophenyl)propan-2-amine Chemical compound CONC(C)CC1=C(Cl)C=C(Cl)C=C1Cl YEYSNJKFDGOAAP-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- CTMHWPIWNRWQEG-UHFFFAOYSA-N 1-methylcyclohexene Chemical compound CC1=CCCCC1 CTMHWPIWNRWQEG-UHFFFAOYSA-N 0.000 description 4
- OCUAPVNNQFAQSM-UHFFFAOYSA-N 3-Methyl-3-butenyl acetate Chemical compound CC(=C)CCOC(C)=O OCUAPVNNQFAQSM-UHFFFAOYSA-N 0.000 description 4
- HETCEOQFVDFGSY-UHFFFAOYSA-N Isopropenyl acetate Chemical compound CC(=C)OC(C)=O HETCEOQFVDFGSY-UHFFFAOYSA-N 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 4
- XNXVOSBNFZWHBV-UHFFFAOYSA-N hydron;o-methylhydroxylamine;chloride Chemical compound Cl.CON XNXVOSBNFZWHBV-UHFFFAOYSA-N 0.000 description 4
- XXIKYCPRDXIMQM-UHFFFAOYSA-N isoprenyl acetate Natural products CC(C)=CCOC(C)=O XXIKYCPRDXIMQM-UHFFFAOYSA-N 0.000 description 4
- UAEPNZWRGJTJPN-UHFFFAOYSA-N methylcyclohexane Chemical compound CC1CCCCC1 UAEPNZWRGJTJPN-UHFFFAOYSA-N 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- -1 phenyl-substituted 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid Chemical class 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 3
- MZGPCLIDFPCPTI-UHFFFAOYSA-N 3-(difluoromethyl)-1-methylpyrazole-4-carbonyl chloride Chemical compound CN1C=C(C(Cl)=O)C(C(F)F)=N1 MZGPCLIDFPCPTI-UHFFFAOYSA-N 0.000 description 3
- 239000005749 Copper compound Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 229910000085 borane Inorganic materials 0.000 description 3
- 239000012267 brine Substances 0.000 description 3
- 150000001880 copper compounds Chemical class 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 238000005984 hydrogenation reaction Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- IOGXOCVLYRDXLW-UHFFFAOYSA-N tert-butyl nitrite Chemical compound CC(C)(C)ON=O IOGXOCVLYRDXLW-UHFFFAOYSA-N 0.000 description 3
- 239000012414 tert-butyl nitrite Substances 0.000 description 3
- 239000003039 volatile agent Substances 0.000 description 3
- PLTQSYGKZGRRMX-UHFFFAOYSA-N 1-(4-bromo-2,6-dichlorophenyl)propan-2-one Chemical compound CC(=O)CC1=C(Cl)C=C(Br)C=C1Cl PLTQSYGKZGRRMX-UHFFFAOYSA-N 0.000 description 2
- NATVSFWWYVJTAZ-UHFFFAOYSA-N 2,4,6-trichloroaniline Chemical compound NC1=C(Cl)C=C(Cl)C=C1Cl NATVSFWWYVJTAZ-UHFFFAOYSA-N 0.000 description 2
- DGOAXBPOVUPPEB-UHFFFAOYSA-N 3-(difluoromethyl)-N-methoxy-1-methyl-N-[1-(2,4,6-trichlorophenyl)propan-2-yl]pyrazole-4-carboxamide Chemical compound C=1N(C)N=C(C(F)F)C=1C(=O)N(OC)C(C)CC1=C(Cl)C=C(Cl)C=C1Cl DGOAXBPOVUPPEB-UHFFFAOYSA-N 0.000 description 2
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- GYNNXHKOJHMOHS-UHFFFAOYSA-N methyl-cycloheptane Natural products CC1CCCCCC1 GYNNXHKOJHMOHS-UHFFFAOYSA-N 0.000 description 2
- PHFFANVCGVJLOM-UHFFFAOYSA-N n-diethylboranylethanamine Chemical compound CCNB(CC)CC PHFFANVCGVJLOM-UHFFFAOYSA-N 0.000 description 2
- 150000002826 nitrites Chemical class 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- JXCNBASKFCBVAN-UHFFFAOYSA-N 2-methylbutan-2-yl nitrite Chemical compound CCC(C)(C)ON=O JXCNBASKFCBVAN-UHFFFAOYSA-N 0.000 description 1
- RLOHOBNEYHBZID-UHFFFAOYSA-N 3-(difluoromethyl)-1-methylpyrazole-4-carboxylic acid Chemical compound CN1C=C(C(O)=O)C(C(F)F)=N1 RLOHOBNEYHBZID-UHFFFAOYSA-N 0.000 description 1
- NPQBZKNXJZARBJ-UHFFFAOYSA-N 4-bromo-2,6-dichloroaniline Chemical compound NC1=C(Cl)C=C(Br)C=C1Cl NPQBZKNXJZARBJ-UHFFFAOYSA-N 0.000 description 1
- NTSLROIKFLNUIJ-UHFFFAOYSA-N 5-Ethyl-2-methylpyridine Chemical compound CCC1=CC=C(C)N=C1 NTSLROIKFLNUIJ-UHFFFAOYSA-N 0.000 description 1
- KNCHDRLWPAKSII-UHFFFAOYSA-N 5-ethyl-2-methylpyridine Natural products CCC1=CC=NC(C)=C1 KNCHDRLWPAKSII-UHFFFAOYSA-N 0.000 description 1
- 0 C*C(c1c[n](C)nc1*)=O Chemical compound C*C(c1c[n](C)nc1*)=O 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- XSMGYUYCDXVGNV-UHFFFAOYSA-N N-methoxy-1-methyl-N-[1-(2,4,6-trichlorophenyl)propan-2-yl]pyrazole-4-carboxamide Chemical compound CON(C(=O)C=1C=NN(C1)C)C(CC1=C(C=C(C=C1Cl)Cl)Cl)C XSMGYUYCDXVGNV-UHFFFAOYSA-N 0.000 description 1
- XAUNPSJKPFCUCD-UHFFFAOYSA-N N-methoxy-N-[1-(2,4,6-trichlorophenyl)propan-2-yl]-1H-pyrazole-4-carboxamide Chemical compound CON(C(=O)C=1C=NNC=1)C(CC1=C(C=C(C=C1Cl)Cl)Cl)C XAUNPSJKPFCUCD-UHFFFAOYSA-N 0.000 description 1
- IOVCWXUNBOPUCH-UHFFFAOYSA-N Nitrous acid Chemical compound ON=O IOVCWXUNBOPUCH-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- UORVGPXVDQYIDP-BJUDXGSMSA-N borane Chemical class [10BH3] UORVGPXVDQYIDP-BJUDXGSMSA-N 0.000 description 1
- VEWFZHAHZPVQES-UHFFFAOYSA-N boron;n,n-diethylethanamine Chemical compound [B].CCN(CC)CC VEWFZHAHZPVQES-UHFFFAOYSA-N 0.000 description 1
- 150000003857 carboxamides Chemical class 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 description 1
- JZCCFEFSEZPSOG-UHFFFAOYSA-L copper(II) sulfate pentahydrate Chemical compound O.O.O.O.O.[Cu+2].[O-]S([O-])(=O)=O JZCCFEFSEZPSOG-UHFFFAOYSA-L 0.000 description 1
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 description 1
- 229940112669 cuprous oxide Drugs 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000002638 heterogeneous catalyst Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- REIPDEIPEOYEDO-UHFFFAOYSA-N n-methoxy-1-phenylpropan-2-amine Chemical compound CONC(C)CC1=CC=CC=C1 REIPDEIPEOYEDO-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006277 sulfonation reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
Description
R1は、水素、ハロゲンまたはC1〜C6アルキルであり、
R2は、水素、ハロゲン、C1〜C6アルキル、C2〜C6アルケニル、C3〜C6アルキニル、C3〜C6シクロアルキル−C3〜C6アルキニル、ハロフェノキシ、ハロフェニル−C3〜C6アルキニル、C(C1〜C4アルキル)=NO−C1〜C4アルキル、C1〜C6ハロアルキル、C1〜C6ハロアルコキシ、C2〜C6ハロアルケニルまたはC2〜C6ハロアルケニルオキシであり、
R3は、水素、ハロゲンまたはC1〜C6アルキルである)の化合物を調製するためのプロセスであって、
a)式II:
R4−O−N=O (III)
(式中、R4は、C1〜C8アルキルである)の有機亜硝酸エステル、式IV:
b)結果として得られた式V:
H2N−O−CH3 (VI)
のO−メチル−ヒドロキシルアミンと反応させることにより式VII:
c)式VIIの化合物を式VIII:
d)式VIIIの化合物を式IX:
を含むプロセスが提供される。
実施例P1:1−(2,4,6−トリクロロ−フェニル)−プロパン−2−オン(化合物CAS 1228284−86−3)の調製
1H NMR(400MHz,CDCl3):δ2.26(s,3H,CH3),4.05(s,2H,CH2),7.34(s,2H,Ar−H)。
1H NMR(400MHz,CDCl3):δ2.25(s,3H,CH3),4.06(s,2H,CH2),7.50(s,2H,Ar−H)。
1H NMR(400MHz,DMSO−d6):δ1.51(s,3H,副異性体),1.82(s,3H,主異性体),3.62(s,3H,主異性体),3.74(s,2H,主異性体),3.80(s,3H,副異性体),3.89(s,2H,副異性体),7.64(s,2H,主異性体),7.70(s,2H,副異性体)。
実施例P4に記載した通りに調製した1−(2,4,6−トリクロロ−フェニル)−プロパン−2−オンO−メチル−オキシムの粗生成物(12.3g、0.046mol)の酢酸(120ml)溶液を撹拌しながら、シアノ水素化ホウ素ナトリウム(6.1g、0.097mol)を少量ずつ12〜15℃で加えた。反応マスを周囲温度で18時間撹拌した。TLCにより反応が完了したことを確認した後、溶媒を減圧蒸発(トルエンと一緒に2回共蒸発)させた。得られた残渣を1Nの水酸化ナトリウム溶液(150ml)に注ぎ、ジクロロメタン(2×100ml)で抽出した。有機層を合一して水(2×100ml)で洗浄した後、無水硫酸ナトリウムで乾燥させ、次いで溶媒を蒸発させることによってO−メチル−N−[1−メチル−2−(2,4,6−トリクロロ−フェニル)−エチル]−ヒドロキシルアミンの粗生成物(12.3g、100%)を得た。
1H NMR(400MHz,CDCl3):δ0.91−0.93(d,3H),2.72−2.77(dd,1H),2.98−3.03(dd,1H),3.25−3.30(m,1H),3.93(s,3H),7.15(s,2H)。
実施例P4に記載した通りに調製された1−(2,4,6−トリクロロ−フェニル)−プロパン−2−オンO−メチル−オキシム(53.9g、99%assay、0.20mol)のメタノール(100g)溶液を、外部冷却を行うことにより内部温度を20〜30℃に維持しながら塩化水素ガス(22.0g、0.60mol)を加えた。無色の懸濁液が得られた。反応混合物を15℃に冷却し、トリエチルアミノボラン(ボラン−トリエチルアミン錯体、27.6g、96%assay、0.23mol)を60分間かけて添加し、その間、内部温度を15℃に維持した。反応マスをさらに2時間撹拌することにより混合物を周囲温度まで昇温させた。その後のHPLCでは出発物質をほとんど検出することができなくなった。次いで反応混合物を予備加熱した(85℃)水(126g)に30分間かけて添加した。一定のペースで気体流が発生した。同時に溶媒を蒸留した。加熱を継続し、温度をさらに1時間85〜90℃に維持した。最終的に気体が生成しなくなった。得られた混合物を20〜25℃に冷却した。水酸化ナトリウム(30%水溶液、56.5g、0.42mol)をpHが7.2〜7.7になるように慎重に加えた。得られた混合物をtert−ブチルメチルエーテル(125ml)で抽出した。相を分離させた。(下層の)水相を分離した。(上層の)有機相を水(2×100g)で洗浄し、蒸発させた。O−メチル−N−[1−メチル−2−(2,4,6−トリクロロ−フェニル)−エチル]−ヒドロキシルアミン(53.9g、97.8%assay、収率98.0%)を透明な油状物として得た。
実施例P3に記載された通りに調製された1−(2,4,6−トリクロロ−フェニル)−プロパン−2−オンO−メチル−オキシム(54.2g、98.4%assay、0.20mol)の酢酸(115g、1.92mol)溶液に、硫酸(22.5g、96%assay、0.22mol)を、混合物が20〜23℃を維持することができるような速度で加えた。炭素上白金(5.9g、Evonik F101 N/W 5%、水湿潤品、Pt2.32%assay)を加えた。得られた混合物をオートクレーブに移し替えた後、密閉して水素(0.8MPa)で加圧した。オートクレーブの撹拌機を始動させ、水素圧を0.8MPaに維持した。水素がそれ以上消費されなくなったら(通常は5時間後)、撹拌を停止することにより水素化を停止した。圧力を解放し、オートクレーブを窒素雰囲気に変えた。不均一触媒を除去するために水素化混合物を濾過した。濾液に水(220g)を加えてpHプローブを取り付けた。水酸化ナトリウム水溶液(304g、30%assay、2.28mol)をpHが9を超えるまで加えた。得られた混合物をtert−ブチルメチルエーテル(300ml)で抽出した。相を分離させた。(下層の)水相を分離して廃棄した。有機相を水(2×250g)で洗浄して蒸発乾固させた。O−メチル−N−[1−メチル−2−(2,4,6−トリクロロ−フェニル)−エチル]−ヒドロキシルアミン(53.0g、93.7%assay、収率92.4%)の粗生成物を透明な油状物として得た。
実施例P5aに記載された通りに調製されたO−メチル−N−[1−メチル−2−(2,4,6−トリクロロ−フェニル)−エチル]−ヒドロキシルアミン(12.3g、0.046mol)のジクロロメタン(120ml)溶液にトリエチルアミン(7.7ml、0.055mol)を加えた後、3−ジフルオロメチル−1−メチル−1H−ピラゾール−4−カルボニルクロリド(9.1g、0.046mol)のジクロロメタン(10ml)溶液を0℃で滴下した。酸塩化物の添加が完了した後、混合物を周囲温度で5時間撹拌した。TLCで反応が完了したことを確認した後、反応マスを1NのHCl(100ml)、次いで1NのNaOH(100ml)、次いで水(2×100ml)、最後に食塩水(50ml)で洗浄した後、硫酸ナトリウムで乾燥させ、溶媒を蒸発させた。結果として得られた粗生成物である粘着性を有する暗色油状物20.5gを60〜120μメッシュのシリカゲルカラムクロマトグラフィーで精製し、生成物をヘキサン中40%酢酸エチルで溶出液として回収することにより3−ジフルオロメチル−1−メチル−1H−ピラゾール−4−カルボン酸メトキシ−[1−メチル−2−(2,4,6−トリクロロ−フェニル)−エチル]−アミド(7.9g、41%)をオフホワイト色の固体として得た。m.p:110〜112℃。
1H NMR(400MHz,CDCl3):δ1.38−1.39(d,3H),3.20−3.26(dd,1H),3.32−3.37(dd,1H),3.70(s,3H),3.97(s,3H),4.88−4.93(m,1H),7.02−7.29(t,1H),7.27(s,2H),7.81(s,1H)。
MS[M+H]+426/428/430。
実施例P5aに記載された通りに調製されたO−メチル−N−[1−メチル−2−(2,4,6−トリクロロ−フェニル)−エチル]−ヒドロキシルアミン(12.3g、0.046mol)のキシレン(90g)溶液にトリエチルアミン(5.6g、0.055mol)を加えた後、3−ジフルオロメチル−1−メチル−1H−ピラゾール−4−カルボニルクロリド(40.1g、0.046mol)を70℃で2時間かけて加えた。酸塩化物の添加が完了した後、混合物を70℃で2時間撹拌した。この溶液を水で2回洗浄し、揮発性物質を有機層から減圧除去した。結果として得られた粗生成物23.6g(粘着性を有する暗褐色の油状物)をキシレン16gおよびメチルシクロヘキセン36gの混合物から結晶化させることにより精製することによって3−ジフルオロメチル−1−メチル−1H−ピラゾール−4−カルボン酸メトキシ−[1−メチル−2−(2,4,6−トリクロロ−フェニル)−エチル]−アミド(17.0g、91.5%)をオフホワイト色の固体として得た。m.p:115〜116℃。
実施例P5aに記載された通りに調製されたO−メチル−N−[1−メチル−2−(2,4,6−トリクロロ−フェニル)−エチル]−ヒドロキシルアミン(3.92g、0.014mol)のキシレン(30g)溶液に、水酸化ナトリウム水溶液(30%、2.3g、0.017mol)を、3−ジフルオロメチル−1−メチル−1H−ピラゾール−4−カルボニルクロリド(3.2g、0.046mol)をキシレン(10g)に溶解した溶液と同時に56℃で2時間かけて添加した。酸塩化物の添加が完了した後、混合物を56℃で2時間撹拌した。溶液を水で2回(10gおよび5g)洗浄し、有機層から揮発性物質を減圧除去した。得られた粗生成物7.4g(粘着性を有する暗褐色の油状物)をキシレン(7g)およびメチルシクロヘキセン(14g)の混合物から結晶化させることにより精製することによって3−ジフルオロメチル−1−メチル−1H−ピラゾール−4−カルボン酸メトキシ−[1−メチル−2−(2,4,6−トリクロロ−フェニル)−エチル]−アミド(5.3g、87.8%)をオフホワイト色の固体として得た。m.p:115〜116℃。
Claims (5)
- 式I:
R1は、水素、ハロゲンまたはC1〜C6アルキルであり、
R2は、水素,ハロゲン、C1〜C6アルキル、C2〜C6アルケニル、C3〜C6アルキニル、C3〜C6シクロアルキル−C3〜C6アルキニル、ハロフェノキシ、ハロフェニル−C3〜C6アルキニル、C(C1〜C4アルキル)=NO−C1〜C4アルキル、C1〜C6ハロアルキル、C1〜C6ハロアルコキシ、C2〜C6ハロアルケニルまたはC2〜C6ハロアルケニルオキシであり、
R3は、水素、ハロゲンまたはC1〜C6アルキルである)の化合物を調製するための方法であって、
a)式II:
R4−O−N=O (III)
(式中、R4はC1〜C8アルキルである)の有機亜硝酸エステル、式IV:
b)結果として得られた式V:
H2N−O−CH3 (VI)
のO−メチル−ヒドロキシルアミンと反応させることにより式VII:
c)式VIIの化合物を式VIII:
d)式VIIIの化合物を式IX:
を含む方法。 - R1、R2およびR3の少なくとも1種が水素とは異なる、式Iの化合物を調製するための請求項1に記載の方法。
- R1、R2およびR3の少なくとも1種がハロゲンである、式Iの化合物を調製するための請求項1に記載の方法。
- R1、R2およびR3がクロロである、式Iの化合物を調製するための請求項1に記載の方法。
- R 4 がC4〜C7アルキルである、式Iの化合物を調製するための請求項1に記載の方法。
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