CN102356070B - 制备吡唑衍生物的方法 - Google Patents
制备吡唑衍生物的方法 Download PDFInfo
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- CN102356070B CN102356070B CN201080011947.2A CN201080011947A CN102356070B CN 102356070 B CN102356070 B CN 102356070B CN 201080011947 A CN201080011947 A CN 201080011947A CN 102356070 B CN102356070 B CN 102356070B
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- Prior art keywords
- methyl
- alkyl
- haloalkyl
- alkali
- group
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- 238000000034 method Methods 0.000 title claims abstract description 36
- 150000003217 pyrazoles Chemical class 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 21
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims abstract description 20
- 150000002367 halogens Chemical class 0.000 claims abstract description 20
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 15
- 239000001257 hydrogen Substances 0.000 claims abstract description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 11
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 8
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims abstract description 5
- 150000002431 hydrogen Chemical class 0.000 claims abstract 3
- -1 R 7s (O) n Chemical group 0.000 claims description 92
- 239000003513 alkali Substances 0.000 claims description 41
- 239000002585 base Substances 0.000 claims description 31
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 29
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 claims description 18
- 239000000460 chlorine Substances 0.000 claims description 15
- 229910052801 chlorine Inorganic materials 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 150000001412 amines Chemical class 0.000 claims description 14
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 claims description 12
- BWZVCCNYKMEVEX-UHFFFAOYSA-N 2,4,6-Trimethylpyridine Chemical compound CC1=CC(C)=NC(C)=C1 BWZVCCNYKMEVEX-UHFFFAOYSA-N 0.000 claims description 10
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
- 150000003512 tertiary amines Chemical class 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 6
- 239000011707 mineral Substances 0.000 claims description 6
- 150000007530 organic bases Chemical class 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims 1
- 150000002429 hydrazines Chemical class 0.000 abstract description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 3
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 abstract 3
- SHENXRCDBJGWNU-GOSISDBHSA-N 6-(1,3-benzothiazol-6-ylamino)-4-(cyclopropylamino)-n-[(2r)-2-fluoro-3-hydroxy-3-methylbutyl]pyridine-3-carboxamide Chemical compound CC(C)(O)[C@H](F)CNC(=O)C1=CN=C(NC=2C=C3SC=NC3=CC=2)C=C1NC1CC1 SHENXRCDBJGWNU-GOSISDBHSA-N 0.000 abstract 3
- 239000011737 fluorine Substances 0.000 description 21
- 229910052731 fluorine Inorganic materials 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 229910052799 carbon Inorganic materials 0.000 description 15
- 150000001721 carbon Chemical group 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 description 12
- 125000000217 alkyl group Chemical group 0.000 description 9
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 9
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 8
- 229910052794 bromium Inorganic materials 0.000 description 8
- HPYNZHMRTTWQTB-UHFFFAOYSA-N 2,3-dimethylpyridine Chemical compound CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 6
- JYYNAJVZFGKDEQ-UHFFFAOYSA-N 2,4-Dimethylpyridine Chemical compound CC1=CC=NC(C)=C1 JYYNAJVZFGKDEQ-UHFFFAOYSA-N 0.000 description 6
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 6
- NURQLCJSMXZBPC-UHFFFAOYSA-N 3,4-dimethylpyridine Chemical compound CC1=CC=NC=C1C NURQLCJSMXZBPC-UHFFFAOYSA-N 0.000 description 6
- HWWYDZCSSYKIAD-UHFFFAOYSA-N 3,5-dimethylpyridine Chemical compound CC1=CN=CC(C)=C1 HWWYDZCSSYKIAD-UHFFFAOYSA-N 0.000 description 6
- ITQTTZVARXURQS-UHFFFAOYSA-N 3-methylpyridine Chemical compound CC1=CC=CN=C1 ITQTTZVARXURQS-UHFFFAOYSA-N 0.000 description 6
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 6
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 5
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 5
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 5
- 235000010755 mineral Nutrition 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- GFYHSKONPJXCDE-UHFFFAOYSA-N 2,3,5-trimethylpyridine Chemical compound CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 4
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical compound CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 4
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 4
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
- 229910001413 alkali metal ion Inorganic materials 0.000 description 4
- 229910001420 alkaline earth metal ion Inorganic materials 0.000 description 4
- 125000003342 alkenyl group Chemical group 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 3
- NRGGMCIBEHEAIL-UHFFFAOYSA-N 2-ethylpyridine Chemical compound CCC1=CC=CC=N1 NRGGMCIBEHEAIL-UHFFFAOYSA-N 0.000 description 3
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 3
- NTSLROIKFLNUIJ-UHFFFAOYSA-N 5-Ethyl-2-methylpyridine Chemical compound CCC1=CC=C(C)N=C1 NTSLROIKFLNUIJ-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 150000004982 aromatic amines Chemical class 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 125000002619 bicyclic group Chemical group 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012973 diazabicyclooctane Substances 0.000 description 3
- 229930195733 hydrocarbon Natural products 0.000 description 3
- 150000002430 hydrocarbons Chemical class 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
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 2
- JIHQDMXYYFUGFV-UHFFFAOYSA-N 1,3,5-triazine Chemical compound C1=NC=NC=N1 JIHQDMXYYFUGFV-UHFFFAOYSA-N 0.000 description 2
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 2
- JVVRJMXHNUAPHW-UHFFFAOYSA-N 1h-pyrazol-5-amine Chemical compound NC=1C=CNN=1 JVVRJMXHNUAPHW-UHFFFAOYSA-N 0.000 description 2
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 2
- XNMQEEKYCVKGBD-UHFFFAOYSA-N 2-butyne Chemical compound CC#CC XNMQEEKYCVKGBD-UHFFFAOYSA-N 0.000 description 2
- 125000006012 2-chloroethoxy group Chemical group 0.000 description 2
- FTZGVFCVJRQLGL-UHFFFAOYSA-N 2-chloropropanedinitrile Chemical compound N#CC(Cl)C#N FTZGVFCVJRQLGL-UHFFFAOYSA-N 0.000 description 2
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 2
- WWUVJRULCWHUSA-UHFFFAOYSA-N 2MP Natural products CCCC(C)=C WWUVJRULCWHUSA-UHFFFAOYSA-N 0.000 description 2
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- WSSSPWUEQFSQQG-UHFFFAOYSA-N 4-methyl-1-pentene Chemical compound CC(C)CC=C WSSSPWUEQFSQQG-UHFFFAOYSA-N 0.000 description 2
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- FNELVJVBIYMIMC-UHFFFAOYSA-N Ethiprole Chemical compound N1=C(C#N)C(S(=O)CC)=C(N)N1C1=C(Cl)C=C(C(F)(F)F)C=C1Cl FNELVJVBIYMIMC-UHFFFAOYSA-N 0.000 description 2
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- 125000002723 alicyclic group Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- KDKYADYSIPSCCQ-UHFFFAOYSA-N but-1-yne Chemical group CCC#C KDKYADYSIPSCCQ-UHFFFAOYSA-N 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 229960001701 chloroform Drugs 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- ZEHZNAXXOOYTJM-UHFFFAOYSA-N dicyanoacetylene Chemical group N#CC#CC#N ZEHZNAXXOOYTJM-UHFFFAOYSA-N 0.000 description 2
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 235000019439 ethyl acetate Nutrition 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000011630 iodine Chemical group 0.000 description 2
- 229910052740 iodine Chemical group 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 2
- ISRXMEYARGEVIU-UHFFFAOYSA-N n-methyl-n-propan-2-ylpropan-2-amine Chemical compound CC(C)N(C)C(C)C ISRXMEYARGEVIU-UHFFFAOYSA-N 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
- 239000003960 organic solvent Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 229920006395 saturated elastomer Polymers 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
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- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- 125000006000 trichloroethyl group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- 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
- C07D231/38—Nitrogen atoms
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Abstract
本发明涉及一种制备式(I)的吡唑衍生物的方法,其中W是氮或CR1;R1、R2、R4和R5各自独立地选自氢、卤素、C1-C6-烷基、C1-C6-卤代烷基、C1-C6-烷氧基、C1-C6-卤代烷氧基、R7S(O)n、硝基、氰基和五氟硫代;R3是氢,卤素,C1-C6-烷基,C1-C6-卤代烷基,C1-C6-烷氧基,C1-C6-卤代烷氧基,R7S(O)n,硝基,氰基,五氟硫代或苯基,苯基是未取代的或被选自以下的1-5个基团取代:卤素,C1-C6-烷基,C1-C6-卤代烷基,C1-C6-烷氧基,C1-C6-卤代烷氧基,R7S(O)n,硝基,氰基,以及五氟硫代,它们是相同或不同的;R7是C1-C6-烷基或C1-C6-卤代烷基;和n是0、1或2;其特征在于式(II)的肼与式(III)的化合物反应,其中W、R2、R3、R4和R5具有对于式(I)的吡唑衍生物所给出的定义。
Description
本发明涉及一种制备式(I)的吡唑衍生物的新方法,
其中
W是氮或CR1,
R1、R2、R4和R5各自独立地选自氢、卤素、C1-C6-烷基、C1-C6-卤代烷基、C1-C6-烷氧基、C1-C6-卤代烷氧基、R7S(O)n、硝基、氰基和五氟硫代;
R3是氢,卤素,C1-C6-烷基,C1-C6-卤代烷基,C1-C6-烷氧基,C1-C6-卤代烷氧基,R7S(O)n,硝基,氰基,五氟硫代或苯基,苯基是未取代的或被选自以下的1-5个基团取代:卤素,C1-C6-烷基,C1-C6-卤代烷基,C1-C6-烷氧基,C1-C6-卤代烷氧基,R7S(O)n,硝基,氰基,以及五氟硫代,它们是相同或不同的;
R7是C1-C6-烷基或C1-C6-卤代烷基;和
n是0、1或2;
其特征在于式(II)的肼与式(III)的化合物反应:
其中W、R2、R3、R4和R5具有对于式(I)的吡唑衍生物所给出的定义,
所得的吡唑(I)是在生产农药活性5-氨基-1-苯基-3-氰基-吡唑衍生物中的重要中间体。一种特别重要的5-氨基-1-苯基-3-氰基-吡唑衍生物是市售的杀虫剂氟虫腈。
一种从相应肼制备一些式(I)吡唑的方式尤其描述在WO 98/39302中。根据此文件的描述,在第一步中,肼与富马腈(反-CN-CH=CH-CN)反应得到中间体2-芳基肼基琥珀腈。这些2-芳基肼基琥珀腈可以在第二步中氧化成2-芳基亚腈基琥珀腈,然后在第三步中环化,得到式(I)的吡唑。
此反应顺序具有以下缺点:
(a)此反应包括三个步骤,对于此产品的潜在工业化生产必须考虑相当的投资成本;
(b)第一步的产率以及总产率差(根据实施例,第一步的产率仅仅是45-63%);
(c)用于第二步的优选氧化剂是过渡金属盐,其难以从反应产物除去达到符合农业化学产品例如氟虫腈的法规规定。
WO 99/54288目的在于从肼制备开链的3-芳基亚肼基丙腈。后者可以任选地衍生化并尤其转变成5-氨基吡唑。这种转变需要三个额外的反应步骤:
(a)加入HCN以将氰基引入链中,得到2-芳基肼基琥珀腈化合物,然后
(b)氧化成氰基取代的2-芳基亚腈基琥珀腈,和
(c)环化得到吡唑。
这种制备式(I)吡唑的四步法的缺点尤其是其产率差,例如与HCN的反应仅仅达到约40%产率。
DE 3612939教导了合成吡唑衍生物的两步法,其中与式(I)的吡唑相比,此衍生物在吡唑环的3位中不带氰基。这种两步法包括肼与CH2=CH-CN在第一步中反应,并在第二步中在碱的存在下进行氧化和环化。其中没有暗示或教导(a)怎样避免氧化步骤,和(b)怎样将氰基引入吡唑环的3位。
WO 04/005245涉及制备丙二腈和富马腈的衍生物的方法,其目的是减少从肼获得4-亚磺酰化5-氨基吡唑的合成步骤的数目的方法。同样,在实施例1中,描述了从相应的肼与二氰基乙炔按照一步法合成5-氨基-3-氰基吡唑衍生物。虽然此步骤的产率是满意的,但是反应物二氰基乙炔的制备通常伴随着低产率,并且需要非常低的温度和防止***的措施(参见例如J.Org.Chem.1945,10,p.149,和J.Org.Chem.1957,22,p.1171)。这在可能的规模化方面是十分不利的。
本发明的目的是提供新的和改进的制备吡唑化合物(I)的方法。具体而言,目的是提供新的和改进的制备吡唑化合物(I)的方法,其涉及的合成步骤的数目降低。此外,本发明的目的是提供新的和改进的制备吡唑化合物(I)的方法,其具有提高的总产率。本发明的目的也是提供新的和改进的制备吡唑化合物(I)的方法,其中使用可获得的原料。
因此,发现了在本文开头定义的本发明方法。惊奇的是,肼衍生物(II)与化合物(III)的反应在一步法中获得了所需的吡唑衍生物(I)并具有优异的总产率。
化合物(III)可以以顺式异构体(氯代丙二腈)或反式异构体(氯代富马腈)或它们的混合物的形式使用。关于本发明方法,优选使用氯代丙二腈和氯代富马腈的混合物。
取代基具有以下含义:
术语卤素在每种情况下表示氟、溴、氯或碘,尤其是氟、氯或溴,优选是氯或氟。
这里使用的术语″C1-C6-烷基″表示饱和的直链或支化的具有1-6个碳原子、尤其1-4个碳原子的烃基,例如甲基,乙基,丙基,1-甲基乙基,丁基,1-甲基丙基,2-甲基丙基,1,1-二甲基乙基,戊基,1-甲基丁基,2-甲基丁基,3-甲基丁基,2,2-二甲基丙基,1-乙基丙基,己基,1,1-二甲基丙基,1,2-二甲基丙基,1-甲基戊基,2-甲基戊基,3-甲基戊基,4-甲基戊基,1,1-二甲基丁基,1,2-二甲基丁基,1,3-二甲基丁基,2,2-二甲基丁基,2,3-二甲基丁基,3,3-二甲基丁基,1-乙基丁基,2-乙基丁基,1,1,2-三甲基丙基,1,2,2-三甲基丙基,1-乙基-1-甲基丙基,1-乙基-2-甲基丙基和它们的异构体。C1-C4-烷基表示例如甲基,乙基,丙基,1-甲基乙基,丁基,1-甲基丙基,2-甲基丙基或1,1-二甲基乙基。
这里使用的术语″C1-C6-卤代烷基″表示直链或支化的饱和的具有1-6个碳原子的烷基(如上所述),其中在这些基团中的部分或全部氢原子可以被上述卤素原子取代,例如C1-C4-卤代烷基,例如氯甲基,溴甲基,二氯甲基,三氯甲基,氟甲基,二氟甲基,三氟甲基,氯氟甲基,二氯氟甲基,氯二氟甲基,1-氯乙基,1-溴乙基,1-氟乙基,2-氟乙基,2,2-二氟乙基,2,2,2-三氟乙基,2-氯-2-氟乙基,2-氯-2,2-二氟乙基,2,2-二氯-2-氟乙基,2,2,2-三氯乙基,五氟乙基等。
这里使用的术语“C1-C6-烷氧基”表示直链或支化的饱和的具有1-6个碳原子(如上所述)并且经由氧原子连接的烷基。例子包括C1-C6-烷氧基,例如甲氧基,乙氧基,OCH2-C2H5,OCH(CH3)2,正丁氧基,OCH(CH3)-C2H5,OCH2-CH(CH3)2,OC(CH3)3,正戊氧基,1-甲基丁氧基,2-甲基丁氧基,3-甲基丁氧基,1,1-二甲基丙氧基,1,2-二甲基丙氧基,2,2-二甲基-丙氧基,1-乙基丙氧基,正己氧基,1-甲基戊氧基,2-甲基戊氧基,3-甲基戊氧基,4-甲基戊氧基,1,1-二甲基丁氧基,1,2-二甲基丁氧基,1,3-二甲基丁氧基,2,2-二甲基丁氧基,2,3-二甲基丁氧基,3,3-二甲基丁氧基,1-乙基丁氧基,2-乙基丁氧基,1,1,2-三甲基丙氧基,1,2,2-三甲基丙氧基,1-乙基-1-甲基丙氧基,1-乙基-2-甲基丙氧基等。
这里使用的术语″C1-C6-卤代烷氧基″表示上述定义的C1-C6-烷氧基,其中氢原子部分地或全部地被氟、氯、溴和/或碘取代,即例如C1-C6-卤代烷氧基,例如氯甲氧基,二氯甲氧基,三氯甲氧基,氟甲氧基,二氟甲氧基,三氟甲氧基,氯氟甲氧基,二氯氟甲氧基,氯二氟甲氧基,2-氟乙氧基,2-氯乙氧基,2-溴乙氧基,2-碘乙氧基,2,2-二氟乙氧基,2,2,2-三氟乙氧基,2-氯-2-氟乙氧基,2-氯-2,2-二氟乙氧基,2,2-二氯-2-氟乙氧基,2,2,2-三氯乙氧基,五氟乙氧基,2-氟丙氧基,3-氟丙氧基,2,2-二氟丙氧基,2,3-二氟丙氧基,2-氯丙氧基,3-氯丙氧基,2,3-二氯丙氧基,2-溴丙氧基,3-溴丙氧基,3,3,3-三氟丙氧基,3,3,3-三氯丙氧基,2,2,3,3,3-五氟丙氧基,七氟丙氧基,1-(氟甲基)-2-氟乙氧基,1-(氯甲基)-2-氯乙氧基,1-(溴甲基)-2-溴乙氧基,4-氟丁氧基,4-氯丁氧基,4-溴丁氧基,九氟丁氧基,5-氟-1-戊氧基,5-氯-1-戊氧基,5-溴-1-戊氧基,5-碘-1-戊氧基,5,5,5-三氯-1-戊氧基,十一氟戊氧基,6-氟-1-己氧基,6-氯-1-己氧基,6-溴-1-己氧基,6-碘-1-己氧基,6,6,6-三氯-1-己氧基或十二氟己氧基,尤其是氯甲氧基,氟甲氧基,二氟甲氧基,三氟甲氧基,2-氟乙氧基,2-氯乙氧基或2,2,2-三氟乙氧基。
关于本发明方法,式(I)和(II)化合物中的取代基优选具有以下含义:
W是氮或CR1,优选是CR1。
R1和R5是优选选自氢、卤素、C1-C6-烷基、C1-C6-卤代烷基,更优选选自卤素和C1-C4-卤代烷基,甚至更优选选自氯、氟和三氟甲基,最优选是氯。
R2和R4优选是氢。
R3优选是卤素,C1-C6-烷基、C1-C6-卤代烷基、C1-C6-烷氧基、C1-C6-卤代烷氧基或五氟硫代,更优选是C1-C6烷基、C1-C6-卤代烷基或五氟硫代,甚至更优选是C1-C4-卤代烷基,最优选是三氟甲基。
其它优选的取代基是:
W是氮或CR1,
R1和R5各自独立地选自氢、卤素、C1-C4-烷基和C1-C4-卤代烷基;
R2和R4是氢;和
R3是卤素、C1-C4-烷基、C1-C4-卤代烷基或五氟硫代。
最优选是,式(I)和(II)化合物的取代基具有以下含义:
W是C-Cl,
R1和R5是卤素,优选是氯;
R2和R4是氢;和
R3是C1-C4-卤代烷基,优选是三氟甲基。
在一个尤其优选的实施方案中,提供一种通过化合物(III)与(2,6-二氯-4-三氟甲基苯基)-肼反应制备5-氨基-1-(2,6-二氯-4-三氟甲基苯基)-1H-吡唑-3-甲腈的方法。
此反应优选在无机碱或有机碱的存在下进行。
合适的无机碱是例如碱金属和碱土金属的氢氧化物,例如氢氧化锂、氢氧化钠、氢氧化钾和氢氧化钙;碱金属和碱土金属的氧化物,例如氧化锂、氧化钠、氧化钙和氧化镁;碱金属和碱土金属的氢化物,例如氢化锂、氢化钠、氢化钾和氢化钙;碱金属和碱土金属的碳酸盐,例如碳酸锂、碳酸钾和碳酸钙;以及碱金属碳酸氢盐,例如碳酸氢钠。优选的无机碱是碱金属或碱土金属的醇盐。在一个更优选的实施方案中,无机碱选自钠或钾的甲醇盐或乙醇盐。最优选使用甲醇钠。
当碱是无机碱时,优选醇用做溶剂。
碱也可以是路易斯碱,例如三正丁基膦、三苯基膦、三苯基氧化膦或亚磷酸三乙酯,优选三苯基氧化膦。
优选,碱是有机碱。
有机碱有利地是胺碱,即其中碱性点是氮原子的碱。
优选,胺碱是仲或叔的烷基-、链烯基-或炔基胺或芳基胺或杂环芳族胺。更优选是,胺碱是烷基-、链烯基-或炔基-叔胺或芳基胺或杂环芳族胺。
这里的“烷基胺”定义为氮原子带有1、2或3个直链或支化的具有1-10个碳原子的烷基,它们可以是相同或不同的。
这里的“链烯基胺”定义为氮原子带有1、2或3个直链或支化的具有2-10个碳原子的链烯基,它们可以是相同或不同的。
这里的“炔基胺”表示氮原子带有1、2或3个直链或支化的具有2-10个碳原子的炔基,它们可以是相同或不同的。
具有1-10个碳原子的烷基是支化的或未支化的、具有1-10个碳原子的饱和烃基,例如和优选是C1-C6-烷基,例如甲基,乙基,丙基,1-甲基乙基,丁基,1-甲基丙基,2-甲基丙基,1,1-二甲基乙基,戊基,1-甲基丁基,2-甲基丁基,3-甲基丁基,2,2-二甲基丙基,1-乙基丙基,己基,1,1-二甲基丙基,1,2-二甲基丙基,1-甲基戊基,2-甲基戊基,3-甲基戊基,4-甲基戊基,1,1-二甲基丁基,1,2-二甲基丁基,1,3-二甲基丁基,2,2-二甲基丁基,2,3-二甲基丁基,3,3-二甲基丁基,1-乙基丁基,2-乙基丁基,1,1,2-三甲基丙基,1,2,2-三甲基丙基,1-乙基-1-甲基丙基和1-乙基-2-甲基丙基。
具有2-10个碳原子的链烯基是直链或支化的具有2-10个碳原子和在任何位置具有双键的不饱和烃基,例如和优选是C2-C6-链烯基,例如乙烯基,1-丙烯基,2-丙烯基,1-甲基-乙烯基,1-丁烯基,2-丁烯基,3-丁烯基,1-甲基-1-丙烯基,2-甲基-1-丙烯基,1-甲基-2-丙烯基,2-甲基-2-丙烯基;1-戊烯基,2-戊烯基,3-戊烯基,4-戊烯基,1-甲基-1-丁烯基,2-甲基-1-丁烯基,3-甲基-1-丁烯基,1-甲基-2-丁烯基,2-甲基-2-丁烯基,3-甲基-2-丁烯基,1-甲基-3-丁烯基,2-甲基-3-丁烯基,3-甲基-3-丁烯基,1,1-二甲基-2-丙烯基,1,2-二甲基-1-丙烯基,1,2-二甲基-2-丙烯基,1-乙基-1-丙烯基,1-乙基-2-丙烯基,1-己烯基,2-己烯基,3-己烯基,4-己烯基,5-己烯基,1-甲基-1-戊烯基,2-甲基-1-戊烯基,3-甲基-1-戊烯基,4-甲基-1-戊烯基,1-甲基-2-戊烯基,2-甲基-2-戊烯基,3-甲基-2-戊烯基,4-甲基-2-戊烯基,1-甲基-3-戊烯基,2-甲基-3-戊烯基,3-甲基-3-戊烯基,4-甲基-3-戊烯基,1-甲基-4-戊烯基,2-甲基-4-戊烯基,3-甲基-4-戊烯基,4-甲基-4-戊烯基,1,1-二甲基-2-丁烯基,1,1-二甲基-3-丁烯基,1,2-二甲基-1-丁烯基,1,2-二甲基-2-丁烯基,1,2-二甲基-3-丁烯基,1,3-二甲基-1-丁烯基,1,3-二甲基-2-丁烯基,1,3-二甲基-3-丁烯基,2,2-二甲基-3-丁烯基,2,3-二甲基-1-丁烯基,2,3-二甲基-2-丁烯基,2,3-二甲基-3-丁烯基,3,3-二甲基-1-丁烯基,3,3-二甲基-2-丁烯基,1-乙基-1-丁烯基,1-乙基-2-丁烯基,1-乙基-3-丁烯基,2-乙基-1-丁烯基,2-乙基-2-丁烯基,2-乙基-3-丁烯基,1,1,2-三甲基-2-丙烯基,1-乙基-1-甲基-2-丙烯基,1-乙基-2-甲基-1-丙烯基和1-乙基-2-甲基-2-丙烯基。
具有2-10个碳原子的炔基是直链或支化的具有2-10个碳原子并且在任何位置具有三键的不饱和烃基,例如和优选是C2-C6-炔基,例如乙炔基,1-丙炔基,2-丙炔基,1-丁炔基,2-丁炔基,3-丁炔基,1-戊炔基,2-戊炔基,3-戊炔基,4-戊炔基,1-己炔基,2-己炔基,3-己炔基,4-己炔基和5-己炔基。
烷基或链烯基与和它们连接的氮原子一起可以形成不饱和或部分不饱和的、环状或双环的3-10元环体系,其中除了氮原子外还可以含有1-3个选自氧、氮或硫的其它杂原子,优选是氮,例如吡咯烷、哌啶、吗啉、哌嗪、DABCO(1,4-二氮杂双环[2.2.2]辛烷)、DBU(1,8-二氮杂双环[5.4.0]十一碳-7-烯)或DBN(1,5-二氮杂双环[4.3.0]壬-5-烯),最优选是双环体系,例如DBU(1,8-二氮杂双环[5.4.0]十一碳-7-烯)和DBN(1,5-二氮杂双环[4.3.0]壬-5-烯)。
这些包含环状或双环体系的烷基、链烯基或炔基可以进一步被选自以下的1-5个基团取代:卤素,羟基,C1-C6-烷基,C1-C6-卤代烷基,C1-C6-烷氧基,C1-C6-卤代烷氧基,和二(C1-C6-烷基)胺,或苯基,吡啶基,1-萘基,或2-萘基,其中芳基可以被1-3个选自以下的基团取代:卤素、羟基、C1-C6-烷基、C1-C6-卤代烷基、C1-C6-烷氧基、C1-C6-卤代烷氧基或二(C1-C6-烷基)胺。
“芳基胺”表示氮原子被至少一个芳基取代,尤其被苯基、联苯基、吡啶基、1-萘基或2-萘基取代,这些基团可以进一步被选自以下的1-3个基团取代:卤素、羟基、C1-C6-烷基、C1-C6-卤代烷基、C1-C6-烷氧基、C1-C6-卤代烷氧基和二(C1-C6-烷基)胺。
杂环芳族胺是芳族的5-10元的单环体系和双环体系,其中除了胺碱氮原子外还可以含有1-3个选自氧、氮、硫的杂原子,其中至少一个碳原子必须被引入环体系中,例如:吡咯,咪唑,吡唑,1,3,4-二唑,1,3,4-噻二唑,1,3,4-***,1,2,4-二唑,1,2,4-噻二唑,1,2,4-***,1,2,3-***,1,2,3,4-四唑,吲哚,吲唑,异吲哚,苯并咪唑,苯并异唑,苯并异噻唑,苯并吡唑,苯并噻二唑,苯并***,咔唑,吡啶,4-(二甲基氨基)吡啶,2-甲基吡啶,3-甲基吡啶,4-甲基吡啶,5-乙基-2-甲基吡啶,2-乙基吡啶,2,3-二甲基吡啶,2,4-二甲基吡啶,2,5-二甲基吡啶,2,6-二甲基吡啶,3,4-二甲基吡啶,3,5-二甲基吡啶,2,4,6-三甲基吡啶,2,3,5-三甲基吡啶,吡嗪,嘧啶,哒嗪,1,3,5-三嗪,1,2,4-三嗪,1,2,4,5-四嗪,喹啉,异喹啉,喹喔啉,喹唑啉,噌啉,1,5-萘啶,1,6-萘啶,1,7-萘啶,1,8-萘啶,酞嗪,吡啶并嘧啶,嘌呤或喋啶。
杂环芳族胺碱优选是未取代的,但可以被1-3个选自以下的基团取代:卤素,羟基,C1-C6-烷基,C1-C6-卤代烷基,C1-C6-烷氧基,C1-C6-卤代烷氧基,和二(C1-C6-烷基)胺,或苯基,联苯基,吡啶基,1-萘基,或2-萘基,其中芳基可以被选自以下的1-3个基团取代:卤素,羟基,C1-C6-烷基,C1-C6-卤代烷基,C1-C6-烷氧基,C1-C6-卤代烷氧基,或二(C1-C6-烷基)胺),优选被C1-C3-烷基取代。
优选的杂环芳族胺碱是吡啶,4-(二甲基氨基)吡啶,2-甲基吡啶,3-甲基吡啶,4-甲基吡啶,5-乙基-2-甲基吡啶,2-乙基吡啶,2,3-二甲基吡啶,2,4-二甲基吡啶,2,5-二甲基吡啶,2,6-二甲基吡啶,3,4-二甲基吡啶,3,5-二甲基吡啶,2,4,6-三甲基吡啶,2,3,5-三甲基吡啶,嘧啶,吡嗪,哌嗪,1,3,5-三嗪,喹啉,异喹啉,N-甲基咪唑和N-甲基吡唑。
更优选的杂环芳族胺碱是2-甲基吡啶,3-甲基吡啶,4-甲基吡啶,5-乙基-2-甲基吡啶,2-乙基吡啶,2,3-二甲基吡啶,2,4-二甲基吡啶,2,5-二甲基吡啶,2,6-二甲基吡啶,3,4-二甲基吡啶,3,5-二甲基吡啶,2,4,6-三甲基吡啶和2,3,5-三甲基吡。最优选的碱是选自2,6-二甲基吡啶和2,4,6-三甲基吡啶.
优选,胺碱是选自仲胺或叔胺(包括杂环芳族胺),最优选叔胺(包括杂环芳族胺)。也优选的是,碱是叔胺碱,其中氮原子不带或仅仅带有一个选自甲基或乙基的取代基。
优选的叔胺碱是例如:三甲基胺,三乙基胺,三丙基胺,三异丙基胺,N,N-二异丙基甲基胺,三丁基胺,N,N-二甲基乙基胺,N,N-二乙基甲基胺,N,N-二甲基丙基胺,N,N-二甲基环己基胺,N,N-二甲基苄基胺,N,N-二异丙基乙基胺,三乙醇胺,N-甲基二乙醇胺,N-乙基二乙醇胺,N-丁基二乙醇胺,N,N-二甲基乙醇胺,N,N-二乙基乙醇胺,DABCO(1,4-二氮杂双环[2.2.2]辛烷),DBU(1,8-二氮杂双环[5.4.0]十一碳-7-烯),DBN(1,5-二氮杂双环[4.3.0]壬-5-烯),N,N-二甲基苯胺,N,N-二乙基苯胺,N-甲基吡咯烷,N-甲基哌啶,N-甲基吗啉,或N-乙基吗啉。
甚至更优选的叔胺碱是三乙基胺,三丙基胺,三异丙基胺,N,N-二异丙基甲基胺,N,N-二异丙基乙基胺,DABCO(1,4-二氮杂双环[2.2.2]辛烷),DBU(1,8-二氮杂双环[5.4.0]十一碳-7-烯)或DBN(1,5-二氮杂双环[4.3.0]壬-5-烯)。
最优选的叔胺碱是N,N-二异丙基乙基胺,DBU(1,8-二氮杂双环[5.4.0]十一碳-7-烯)或DBN(1,5-二氮杂双环[4.3.0]壬-5-烯)。
也优选的是,碱是位阻碱。
位阻碱定义为具有至少一个与它们的碱性点之一直接连接的仲、叔或季碳原子,或这样的化合物:其中碱性点是双键的一部分。优选,位阻碱是位阻胺碱,其中碱性点是氮原子。最优选,位阻碱是选自叔胺。
另外,在一个非常优选的实施方案中,碱性氮原子被引入芳族的6或10电子π-体系中,导致氮原子的较低碱性。
最优选的碱是选自杂环芳族胺。
也可以使用上述碱的混合物。
一般而言,式(II)化合物:碱的摩尔比是约1∶0.01至约1∶10。优选,使用相对于化合物(II)计的0.5-7摩尔当量的碱,更优选使用0.75-5摩尔当量,最优选1.0-2摩尔当量。碱也可以作为溶剂。
此反应可以按照式(II)肼/式(III)化合物的摩尔比为1∶0.1至1∶10进行。优选,使用0.5-5摩尔当量的化合物(III)。最优选,使用1-2摩尔当量的化合物(III)。
式(II)的化合物可以例如参见WO 08/113660和WO 08/113661以及其中引用的文献制备。化合物(III)可以如文献所述制备,例如参见US 2,443,494。
此反应一般在溶剂中进行。合适的溶剂优选是选自:
-水;
-醇类,例如甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇和叔丁醇,优选甲醇和乙醇,最优选甲醇;
-脂族、脂环族或芳族的、任选卤化的烃,例如芳族有机烃,例如甲苯、二甲苯、三氟甲基苯、苯、硝基苯、单氯苯、二氯苯和乙基苯,或脂族或脂环族、任选卤代的烃,例如戊烷、己烷、庚烷、环己烷、1,2-二氯乙烷、二氯甲烷、三氯甲烷(氯仿)、四氯化碳,优选是甲苯和己烷,最优选是己烷。
-醚类,例如***、二异丙基醚、叔丁基甲基醚、1,4-二烷、四氢呋喃、2-甲基-四氢呋喃、环戊基甲基醚或乙二醇二甲基-或二乙基醚;优选是四氢呋喃和叔丁基甲基醚,最优选是THF;
-酮类,例如丙酮或丁酮,优选丙酮。
-腈类,例如乙腈、丙腈或苯甲腈;优选是乙腈。
-酰胺类,例如N,N-二甲基甲酰胺,N,N-二甲基乙酰胺,DMI(1,3-二甲基-2-咪唑烷二酮),N-甲基N-甲酰苯胺,N-甲基甲酰胺,N-甲基吡咯烷酮或六甲基磷酸三酰胺;优选是N,N-二甲基甲酰胺和N-甲基吡咯烷酮,最优选是N-甲基吡咯烷酮。
-亚砜类,例如二甲基亚砜;
或它们的混合物。
优选的溶剂是选自醇,最优选是甲醇。
一般而言,反应物的摩尔浓度是约0.01-10mol/l。优选使用的浓度是0.1-5mol/l,更优选的浓度是0.2-2mol/l,最优选的浓度是0.5-0.9mol/l。
此反应可以任选地在惰性气体气氛下进行,例如氩气或氮气。
有利的是按小份加入碱。
一般而言,有利的是将化合物(III)加入相应芳基肼和碱的预混合溶液中。优选,相应的原料在加入反应混合物中之前分别预溶解或悬浮在反应溶剂中。
反应温度一般是约-20℃至65℃,优选0℃至40℃,最优选是10℃至25℃。
反应时间取决于反应温度、在工艺期间的温度控制以及不同的试剂和溶剂。本领域技术人员能确定合适的反应时间以达到所需的产率和通过HPLC、TLC或GC检测的纯度。通常,反应时间将是约2-24小时,优选12-16小时。
在完成反应之后,5-氨基-1-(2,6-二氯-4-三氟甲基-苯基)-1H-吡唑-3-甲腈可以通过常规方法分离,例如用水稀释反应混合物,用有机溶剂萃取式(I)化合物,有机溶剂是例如乙酸乙酯、叔丁基甲基醚或二氯甲烷,洗涤萃取物,例如用稀酸例如10%柠檬酸,浓缩萃取物,使式(I)化合物结晶等。分离的式(I)化合物可以通过例如色谱、重结晶等技术在必要时提纯。
实施例
HPLC是在Hewlett Packard HP 1200上进行(Chemstation),配备有J′Sphere ODS-H80,4m,4.6×250mm(YMC)柱,洗脱剂A:90重量%水+10重量%乙腈,洗脱剂B:10重量%水+90重量%乙腈,流速:0.85ml/min,检测:235nm,
梯度:时间[分钟]0 2 17 25 35
A[%] 60 60 25 0 0
B[%] 40 40 75 100 100.
下面给出的产率的单位是纯度>95%的分离产物的摩尔百分比。实施例1:5-氨基-1-(2,6-二氯-4-三氟甲基-苯基)-1H-吡唑-3-甲腈(其它命名:“5-氨基-1-(2,6-二氯-4-三氟甲基-苯基)-3-氰基-吡唑”)向50ml圆底烧瓶加入(2,6-二氯-4-三氟甲基-苯基)-肼(1.2g,4.84mmol)、2,6-二甲基吡啶(0.57g,5.32mmol,1.1当量)和甲醇(10mL)。于20-25℃缓慢加入氯丙二腈和氯富马腈的混合物(0.82g,7.29mmol)。搅拌在此温度下继续进行约16小时。然后将溶液于50毫巴压力下浓缩。残余物通过快速色谱提纯(二氧化硅,己烷/EtOAc 100∶0→70∶30),得到产物,是灰白色固体(1.1g,3.43mmol,71%),熔点是117-118℃,
1H-NMR(360MHz,CDCl3):[ppm]=7.78(d,2H,J=0.4Hz);6.04(s,1H);3.83(bs,2H),13C-NMR(125MHz,DMSO-d6):.[ppm]=150.0;136.0;135.9;132.7(q,J=34Hz);126.43;126.42;122.4(q,J=273Hz);114.6;90.8。
对比实施例
为了证明本发明方法的优点,检测在WO 98/39302的实施例1/2、3和5中所述的以下反应的产率:
吡唑的总产率是11%。
由此证明本发明方法获得了比WO 98/39302所述方法显著更高的产率。
Claims (10)
1.一种制备式(I)的吡唑衍生物的新方法,
其中
W是氮或CR1,
R1、R2、R4和R5各自独立地选自氢、卤素、C1-C6-烷基、C1-C6-卤代烷基、C1-C6-烷氧基、C1-C6-卤代烷氧基、R7S(O)n、硝基、氰基和五氟硫代;
R3是氢,卤素,C1-C6-烷基,C1-C6-卤代烷基,C1-C6-烷氧基,C1-C6-卤代烷氧基,R7S(O)n,硝基,氰基,五氟硫代或苯基,苯基是未取代的或被选自以下的1-5个基团取代:卤素,C1-C6-烷基,C1-C6-卤代烷基,C1-C6-烷氧基,C1-C6-卤代烷氧基,R7S(O)n,硝基,氰基,以及五氟硫代,它们是相同或不同的;
R7是C1-C6-烷基或C1-C6-卤代烷基;和
n是0、1或2;
其特征在于式(II)的肼与式(III)的化合物反应:
其中W、R2、R3、R4和R5具有对于式(I)的吡唑衍生物所给出的定义,
2.权利要求1的方法,其中:
W是CR1;
R1和R5各自独立地选自卤素;
R2和R4是氢;和
R3是C1-C4-卤代烷基。
3.权利要求1或2的方法,其中:
W是CR1;
R1和R5是氯;
R2和R4是氢;和
R3是三氟甲基。
4.权利要求1或2的方法,其中此方法在无机碱或有机碱的存在下进行。
5.权利要求4的方法,其中此方法在有机胺碱的存在下进行。
6.权利要求4的方法,其中此方法在位阻有机胺碱的存在下进行。
7.权利要求4的方法,其中此方法在叔胺碱或杂芳族有机胺碱的存在下进行。
8.权利要求4的方法,其中碱是2,6-二甲基吡啶或2,4,6-三甲基吡啶。
9.权利要求4的方法,其中使用相对于式(II)肼计的0.01-10摩尔当量的有机碱。
10.权利要求1或2的方法,其中此方法在-20℃至65℃的温度下在溶剂中进行。
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PCT/EP2010/053146 WO2010105969A1 (en) | 2009-03-16 | 2010-03-12 | Process for the preparation of pyrazole derivatives |
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EP (1) | EP2443093B8 (zh) |
JP (1) | JP5540067B2 (zh) |
CN (1) | CN102356070B (zh) |
BR (1) | BRPI1006408A2 (zh) |
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WO2011051284A1 (en) | 2009-10-30 | 2011-05-05 | Basf Se | Process for the preparation of 4-sulfinyl-pyrazole derivatives |
MX2013000374A (es) * | 2010-07-12 | 2013-03-05 | Irvita Plant Prot A Branch Of Celsius Property B V | Proceso de produccion de fipronilo. |
CN103396366B (zh) * | 2013-08-06 | 2015-12-02 | 盐城工学院 | 5-氨基-3-氰基-1-(2,6-二氯-4-三氟甲基苯基)吡唑的生产方法 |
EP3412658A1 (en) * | 2017-06-09 | 2018-12-12 | Solvay Sa | Processes for the manufacture of sulfur-substitued pyrazole derivatives |
CN114292234B (zh) * | 2021-12-06 | 2024-05-14 | 南方海洋科学与工程广东省实验室(湛江) | 一种吡唑衍生物的制备方法 |
CN114989142A (zh) * | 2022-05-09 | 2022-09-02 | 沈阳万菱生物技术有限公司 | 一种吡唑类化合物的制备方法 |
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US2443494A (en) | 1944-10-21 | 1948-06-15 | Du Pont | Preparation of unsaturated chloronitriles |
DE3612939A1 (de) | 1986-04-17 | 1987-10-22 | Bayer Ag | Verfahren zur herstellung von 1-aryl-5-amino-pyrazolen |
GB9604691D0 (en) * | 1996-03-05 | 1996-05-01 | Rhone Poulenc Agriculture | New processes for preparing pesticidal intermediates |
HU228183B1 (en) | 1997-03-03 | 2013-01-28 | Merial Ltd | Process for preparing intermediates of pesticidally active compounds, the novel intermediates using in this process and preparation thereof |
MXPA00010156A (es) | 1998-04-20 | 2002-08-06 | Aventis Agriculture Ltd | Proceso para la preparacion de intermediarios de pesticidas. |
FR2789387B1 (fr) * | 1999-02-04 | 2001-09-14 | Aventis Cropscience Sa | Nouveau procede de preparation d'intermediaires pesticides |
EP1378506B1 (en) | 2002-07-05 | 2006-07-26 | BASF Agro B.V., Arnhem (NL), Wädenswil-Branch | Process for the preparation of phenyl pyrazole compounds |
GB0329314D0 (en) * | 2003-12-18 | 2004-01-21 | Pfizer Ltd | Substituted arylpyrazoles |
WO2008113661A2 (en) | 2007-03-16 | 2008-09-25 | Basf Se | Process for preparing substituted phenylhydrazines |
JP2010521432A (ja) | 2007-03-16 | 2010-06-24 | ビーエーエスエフ ソシエタス・ヨーロピア | ジクロロ−フルオロ−トリフルオロメチルベンゼンの混合物を用いた2,6−ジクロロ−4−(トリフルオロメチル)フェニルヒドラジンの調製方法 |
WO2009077590A1 (de) | 2007-12-19 | 2009-06-25 | Basf Se | Verfahren zur herstellung von 2,2-dichlorcyclopropancarbonsäureestern |
BRPI0911767A2 (pt) | 2008-05-05 | 2015-07-28 | Basf Se | Processo, e, composto. |
DK2349987T3 (da) | 2008-10-02 | 2013-03-11 | Basf Se | Fremgangsmåde til fremstilling og oprensning af trifluormethansulfinsyre |
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Jay A. Markwalder et al..Synthesis and Biological Evaluation of 1-Aryl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-one Inhibitors of Cyclin-Dependent Kinases.《J. Med. Chem.》.2004,第47卷5894-5911. |
Synthesis and Biological Evaluation of 1-Aryl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-4-one Inhibitors of Cyclin-Dependent Kinases;Jay A. Markwalder et al.;《J. Med. Chem.》;20041027;第47卷;5894-5911 * |
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US8288563B2 (en) | 2012-10-16 |
EP2443093B8 (en) | 2013-10-09 |
JP2012520338A (ja) | 2012-09-06 |
BRPI1006408A2 (pt) | 2016-02-10 |
CN102356070A (zh) | 2012-02-15 |
IL214764A (en) | 2014-09-30 |
ES2433427T3 (es) | 2013-12-11 |
EP2443093A1 (en) | 2012-04-25 |
WO2010105969A1 (en) | 2010-09-23 |
JP5540067B2 (ja) | 2014-07-02 |
EP2443093B1 (en) | 2013-07-03 |
US20120004421A1 (en) | 2012-01-05 |
PL2443093T3 (pl) | 2014-04-30 |
IL214764A0 (en) | 2011-11-30 |
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