CN101583602A - Process for the sulfinylation of a pyrazole derivative - Google Patents
Process for the sulfinylation of a pyrazole derivative Download PDFInfo
- Publication number
- CN101583602A CN101583602A CNA2007800496448A CN200780049644A CN101583602A CN 101583602 A CN101583602 A CN 101583602A CN A2007800496448 A CNA2007800496448 A CN A2007800496448A CN 200780049644 A CN200780049644 A CN 200780049644A CN 101583602 A CN101583602 A CN 101583602A
- Authority
- CN
- China
- Prior art keywords
- trifluoromethyl
- amino
- acid
- chloro
- pyrazoles
- 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
Links
- 238000000034 method Methods 0.000 title claims abstract description 71
- 150000003217 pyrazoles Chemical class 0.000 title claims abstract description 11
- 230000008569 process Effects 0.000 title claims abstract description 10
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 48
- 239000002253 acid Substances 0.000 claims abstract description 40
- -1 cyclic secondary amines Chemical class 0.000 claims abstract description 28
- 239000000203 mixture Substances 0.000 claims abstract description 28
- 150000001412 amines Chemical class 0.000 claims abstract description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 4
- 238000006351 sulfination reaction Methods 0.000 claims description 67
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 claims description 58
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 56
- 150000001413 amino acids Chemical class 0.000 claims description 55
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 48
- 239000003153 chemical reaction reagent Substances 0.000 claims description 37
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 22
- 150000004820 halides Chemical class 0.000 claims description 20
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 18
- 241001465754 Metazoa Species 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 17
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical group CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 15
- 239000011541 reaction mixture Substances 0.000 claims description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 12
- 239000000460 chlorine Substances 0.000 claims description 11
- 239000008096 xylene Substances 0.000 claims description 11
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 10
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 10
- 238000005660 chlorination reaction Methods 0.000 claims description 9
- 150000003053 piperidines Chemical class 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 241000238631 Hexapoda Species 0.000 claims description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 8
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 8
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 8
- 244000045947 parasite Species 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 8
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 7
- 150000003233 pyrroles Chemical class 0.000 claims description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 6
- 239000012298 atmosphere Substances 0.000 claims description 6
- 229920006395 saturated elastomer Polymers 0.000 claims description 6
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 5
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 5
- 229940117389 dichlorobenzene Drugs 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- 230000036541 health Effects 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- 206010061217 Infestation Diseases 0.000 claims description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 4
- 241000244206 Nematoda Species 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 239000005864 Sulphur Substances 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 claims description 4
- 208000015181 infectious disease Diseases 0.000 claims description 4
- 230000000749 insecticidal effect Effects 0.000 claims description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 230000000590 parasiticidal effect Effects 0.000 claims description 4
- 239000002297 parasiticide Substances 0.000 claims description 4
- GETTZEONDQJALK-UHFFFAOYSA-N (trifluoromethyl)benzene Chemical compound FC(F)(F)C1=CC=CC=C1 GETTZEONDQJALK-UHFFFAOYSA-N 0.000 claims description 3
- LXFQSRIDYRFTJW-UHFFFAOYSA-N 2,4,6-trimethylbenzenesulfonic acid Chemical compound CC1=CC(C)=C(S(O)(=O)=O)C(C)=C1 LXFQSRIDYRFTJW-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 229910052728 basic metal Inorganic materials 0.000 claims description 3
- 150000003818 basic metals Chemical class 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000001188 haloalkyl group Chemical group 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 claims description 2
- RJWBTWIBUIGANW-UHFFFAOYSA-N 4-chlorobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Cl)C=C1 RJWBTWIBUIGANW-UHFFFAOYSA-N 0.000 claims description 2
- UZOFELREXGAFOI-UHFFFAOYSA-N 4-methylpiperidine Chemical compound CC1CCNCC1 UZOFELREXGAFOI-UHFFFAOYSA-N 0.000 claims description 2
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 claims description 2
- 241000607479 Yersinia pestis Species 0.000 claims description 2
- 238000009395 breeding Methods 0.000 claims description 2
- 230000001488 breeding effect Effects 0.000 claims description 2
- 230000012010 growth Effects 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 2
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 2
- 239000002689 soil Substances 0.000 claims description 2
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 claims description 2
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims 1
- QPZYPAMYHBOUTC-UHFFFAOYSA-N 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]pyrazole-3-carbonitrile Chemical compound NC1=CC(C#N)=NN1C1=C(Cl)C=C(C(F)(F)F)C=C1Cl QPZYPAMYHBOUTC-UHFFFAOYSA-N 0.000 abstract 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 abstract 1
- 125000001153 fluoro group Chemical group F* 0.000 abstract 1
- 230000002140 halogenating effect Effects 0.000 abstract 1
- 150000003458 sulfonic acid derivatives Chemical class 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 32
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 30
- 239000002904 solvent Substances 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- JYGXADMDTFJGBT-VWUMJDOOSA-N hydrocortisone Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 238000002425 crystallisation Methods 0.000 description 11
- 230000008025 crystallization Effects 0.000 description 10
- 229950004288 tosilate Drugs 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 9
- 239000011734 sodium Substances 0.000 description 9
- 229910052708 sodium Inorganic materials 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 8
- 229910052700 potassium Inorganic materials 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 239000006227 byproduct Substances 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000007795 chemical reaction product Substances 0.000 description 6
- 229960000890 hydrocortisone Drugs 0.000 description 6
- 150000002460 imidazoles Chemical class 0.000 description 6
- 239000001103 potassium chloride Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- 238000001291 vacuum drying Methods 0.000 description 6
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 5
- 230000003197 catalytic effect Effects 0.000 description 5
- 239000012043 crude product Substances 0.000 description 5
- 239000000543 intermediate Substances 0.000 description 5
- 239000011591 potassium Substances 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 150000008065 acid anhydrides Chemical class 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 238000005516 engineering process Methods 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 4
- 238000006277 sulfonation reaction Methods 0.000 description 4
- GWBNYWVYPASUBM-UHFFFAOYSA-N trifluoromethanesulfinyl chloride Chemical compound FC(F)(F)S(Cl)=O GWBNYWVYPASUBM-UHFFFAOYSA-N 0.000 description 4
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 3
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical class C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- 229960001701 chloroform Drugs 0.000 description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 235000011164 potassium chloride Nutrition 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- ZDLYEAYJIVUCGZ-UHFFFAOYSA-N trifluoromethanesulfinyl bromide Chemical compound FC(F)(F)S(Br)=O ZDLYEAYJIVUCGZ-UHFFFAOYSA-N 0.000 description 3
- OVRZXQJRDBWYNI-UHFFFAOYSA-N trifluoromethanesulfinyl fluoride Chemical compound FS(=O)C(F)(F)F OVRZXQJRDBWYNI-UHFFFAOYSA-N 0.000 description 3
- KFRLATLMKFFRCG-UHFFFAOYSA-N trifluoromethanesulfinyl iodide Chemical compound FC(F)(F)S(I)=O KFRLATLMKFFRCG-UHFFFAOYSA-N 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 2
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 2
- XBNGYFFABRKICK-UHFFFAOYSA-N 2,3,4,5,6-pentafluorophenol Chemical compound OC1=C(F)C(F)=C(F)C(F)=C1F XBNGYFFABRKICK-UHFFFAOYSA-N 0.000 description 2
- PDOIGRRPKSYVKH-UHFFFAOYSA-N 2,4-dinitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O.OC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O PDOIGRRPKSYVKH-UHFFFAOYSA-N 0.000 description 2
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 2
- LYWVNPSVLAFTFX-UHFFFAOYSA-N 4-methylbenzenesulfonate;morpholin-4-ium Chemical compound C1COCCN1.CC1=CC=C(S(O)(=O)=O)C=C1 LYWVNPSVLAFTFX-UHFFFAOYSA-N 0.000 description 2
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- 238000005618 Fries rearrangement reaction Methods 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- WJAQBQQLMGUUTD-UHFFFAOYSA-N S(=O)(=O)(O)C1=CC=C(C)C=C1.C=N.C=N.C=N.C=N Chemical compound S(=O)(=O)(O)C1=CC=C(C)C=C1.C=N.C=N.C=N.C=N WJAQBQQLMGUUTD-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-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
- 230000004913 activation Effects 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000002723 alicyclic group Chemical group 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical class CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical group CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 2
- OCKPCBLVNKHBMX-UHFFFAOYSA-N butylbenzene Chemical compound CCCCC1=CC=CC=C1 OCKPCBLVNKHBMX-UHFFFAOYSA-N 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000010668 complexation reaction Methods 0.000 description 2
- RWGFKTVRMDUZSP-UHFFFAOYSA-N cumene Chemical compound CC(C)C1=CC=CC=C1 RWGFKTVRMDUZSP-UHFFFAOYSA-N 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000026030 halogenation Effects 0.000 description 2
- 238000005658 halogenation reaction Methods 0.000 description 2
- 150000005826 halohydrocarbons Chemical class 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
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- 238000003760 magnetic stirring Methods 0.000 description 2
- RHNBKZXYSDSFFE-UHFFFAOYSA-N n-ethylethanamine;4-methylbenzenesulfonic acid Chemical compound CC[NH2+]CC.CC1=CC=C(S([O-])(=O)=O)C=C1 RHNBKZXYSDSFFE-UHFFFAOYSA-N 0.000 description 2
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- 239000012044 organic layer Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- IZUPBVBPLAPZRR-UHFFFAOYSA-N pentachloro-phenol Natural products OC1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl IZUPBVBPLAPZRR-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 2
- 239000003495 polar organic solvent Substances 0.000 description 2
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 2
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- ODLMAHJVESYWTB-UHFFFAOYSA-N propylbenzene Chemical compound CCCC1=CC=CC=C1 ODLMAHJVESYWTB-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 210000003491 skin Anatomy 0.000 description 2
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 238000007039 two-step reaction Methods 0.000 description 2
- ZRIPDVBVNISUFE-UHFFFAOYSA-N 1-(trifluoromethylsulfinyl)pyrazol-3-amine Chemical compound FC(S(=O)N1N=C(C=C1)N)(F)F ZRIPDVBVNISUFE-UHFFFAOYSA-N 0.000 description 1
- QQZOPKMRPOGIEB-UHFFFAOYSA-N 2-Oxohexane Chemical group CCCCC(C)=O QQZOPKMRPOGIEB-UHFFFAOYSA-N 0.000 description 1
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- PLAZTCDQAHEYBI-UHFFFAOYSA-N 2-nitrotoluene Chemical compound CC1=CC=CC=C1[N+]([O-])=O PLAZTCDQAHEYBI-UHFFFAOYSA-N 0.000 description 1
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- ZPTVNYMJQHSSEA-UHFFFAOYSA-N 4-nitrotoluene Chemical compound CC1=CC=C([N+]([O-])=O)C=C1 ZPTVNYMJQHSSEA-UHFFFAOYSA-N 0.000 description 1
- ZOCSXAVNDGMNBV-UHFFFAOYSA-N 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-[(trifluoromethyl)sulfinyl]-1H-pyrazole-3-carbonitrile Chemical compound NC1=C(S(=O)C(F)(F)F)C(C#N)=NN1C1=C(Cl)C=C(C(F)(F)F)C=C1Cl ZOCSXAVNDGMNBV-UHFFFAOYSA-N 0.000 description 1
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- 239000004215 Carbon black (E152) Substances 0.000 description 1
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- 239000005899 Fipronil Substances 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
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- 150000003973 alkyl amines Chemical group 0.000 description 1
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- 230000009286 beneficial effect Effects 0.000 description 1
- MUQHQUUOMJDHOR-UHFFFAOYSA-N benzenesulfonate;piperazin-1-ium Chemical compound C1C[NH2+]CCN1.[O-]S(=O)(=O)C1=CC=CC=C1 MUQHQUUOMJDHOR-UHFFFAOYSA-N 0.000 description 1
- VMEDQFDEBTXTJM-UHFFFAOYSA-N benzenesulfonic acid;morpholine Chemical compound C1COCCN1.OS(=O)(=O)C1=CC=CC=C1 VMEDQFDEBTXTJM-UHFFFAOYSA-N 0.000 description 1
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- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- JHIVVAPYMSGYDF-UHFFFAOYSA-N cyclohexanone Chemical group O=C1CCCCC1 JHIVVAPYMSGYDF-UHFFFAOYSA-N 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
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- 230000000694 effects Effects 0.000 description 1
- 231100000584 environmental toxicity Toxicity 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
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- 231100001261 hazardous Toxicity 0.000 description 1
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- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 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
- 238000009776 industrial production Methods 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Chemical group CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 description 1
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 1
- KXUHSQYYJYAXGZ-UHFFFAOYSA-N isobutylbenzene Chemical compound CC(C)CC1=CC=CC=C1 KXUHSQYYJYAXGZ-UHFFFAOYSA-N 0.000 description 1
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical group CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 description 1
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- 229940011051 isopropyl acetate Drugs 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
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- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Chemical group COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 235000014666 liquid concentrate Nutrition 0.000 description 1
- AUHZEENZYGFFBQ-UHFFFAOYSA-N mesitylene Substances CC1=CC(C)=CC(C)=C1 AUHZEENZYGFFBQ-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- UFXSGSYKGLMMJU-UHFFFAOYSA-N methanesulfonic acid;morpholine Chemical compound CS([O-])(=O)=O.C1COCC[NH2+]1 UFXSGSYKGLMMJU-UHFFFAOYSA-N 0.000 description 1
- ZKJKXGCLZUMGNT-UHFFFAOYSA-N methanesulfonic acid;piperazine Chemical compound CS(O)(=O)=O.C1CNCCN1 ZKJKXGCLZUMGNT-UHFFFAOYSA-N 0.000 description 1
- JUTNHVRKTLPXAE-UHFFFAOYSA-N methanimine trifluoromethanesulfonic acid Chemical compound FC(F)(F)S(=O)(=O)O.C=N.C=N.C=N.C=N JUTNHVRKTLPXAE-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- PYLWMHQQBFSUBP-UHFFFAOYSA-N monofluorobenzene Chemical compound FC1=CC=CC=C1 PYLWMHQQBFSUBP-UHFFFAOYSA-N 0.000 description 1
- OVXDLDSWRLLUJT-UHFFFAOYSA-N morpholine;trifluoromethanesulfonic acid Chemical compound C1COCC[NH2+]1.[O-]S(=O)(=O)C(F)(F)F OVXDLDSWRLLUJT-UHFFFAOYSA-N 0.000 description 1
- JIKUXBYRTXDNIY-UHFFFAOYSA-N n-methyl-n-phenylformamide Chemical compound O=CN(C)C1=CC=CC=C1 JIKUXBYRTXDNIY-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- MCSAJNNLRCFZED-UHFFFAOYSA-N nitroethane Chemical compound CC[N+]([O-])=O MCSAJNNLRCFZED-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 238000003408 phase transfer catalysis Methods 0.000 description 1
- LBYWYRWZKHZBQR-UHFFFAOYSA-N piperazin-1-ium trifluoromethanesulfonate Chemical compound FC(F)(F)S(=O)(=O)O.N1CCNCC1 LBYWYRWZKHZBQR-UHFFFAOYSA-N 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- ISYORFGKSZLPNW-UHFFFAOYSA-N propan-2-ylazanium;chloride Chemical compound [Cl-].CC(C)[NH3+] ISYORFGKSZLPNW-UHFFFAOYSA-N 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
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- 238000000926 separation method Methods 0.000 description 1
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- 229960001866 silicon dioxide Drugs 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
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- 241000894007 species Species 0.000 description 1
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Abstract
The present invention relates to a process for the sulfinylation of a pyrazole derivative, characterized in that 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1H-pyrazole-3-carbonitrile (II) is reacted with a sulfinylating agent S in the presence of at least one amine acid complex wherein the amine(s) are selected from cyclic secondary amines and the acid(s) are selected from sulfonic acid derivatives, and with the addition of a halogenating agent, wherein S is [CF3S(O)]2O; or CF3S(O)X wherein X means fluoro, chloro, bromo, iodo, a hydroxy group, or an alkaline or alkaline earth metal salt of the hydroxy group; or mixtures thereof.
Description
The present invention relates to a kind of novel method of sulfination pyrazole derivatives, it is characterized in that making 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN (II) and sulfination agent S reacting in the presence of at least a amino acid title complex and under the adding halide reagent, wherein amine is selected from cyclic secondary amine and acid is selected from sulfonic acid, and wherein S is [CF
3S (O)]
2O; Or CF
3S (O) X, wherein X refers to the basic metal or the alkaline earth salt of fluorine, chlorine, bromine, iodine, hydroxyl or hydroxyl; Or its mixture.
The sulfination of pyrazole compound relate on the pyrazole heterocycle carbon atom hydrogen atom by RS (=O)-group replaces.
Utilize P (O) Cl
3And CF
3The mixture of S (O) ONa has been described in T.Billard with the direct sulfination of each organic molecular species (not comprising pyrazole derivatives), A.Greiner, and B.R.Langlois, Tetrahedron 55 (1999), in the 7243-7250 page or leaf.Equally, C.wakselman, M.Tordeux, C.Freslon, L.Saint-Jalmes, the direct sulfination of Synlett 2001, the 550-552 pages or leaves instruction aromatic substance passes through CF
3S (O) ONa or CF
3S (O) OK is at trifluoromethanesulfonic acid (CF
3S (O)
2OH) carry out under the existence.
5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-the direct sulfination method of 1H-pyrazoles-3-formonitrile HCN (II) has been described in EP-A 668 269, EP-A 1 331 222, CN-A 1374298 and Y.Huilong, M.Zengeng, W.Shujuan, J.Hebei University of Science ofTechnology, the the 25th (2) volume, total the 69th phase (2004) is among sequence number 1008-1542 (2004) 02-0018-03.
In EP 668 269, described and used trifluoromethanesulpacidc acidc CF
3S (O) OH and derivative CF thereof
3S (O) Cl, CF
3S (O) ONa, CF
3S (O) N (CH
3)
2Or CF
3S (O) N (CH
2CH
3)
2Sulfination 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN (II).Phosgene, chloro-formic ester, PCl have been mentioned as chlorination reagent
5And SOCl
2Described can choose wantonly in the presence of the tosic acid of equimolar amount add be selected from primary, the second month in a season or tertiary amine, tosylate, hydrochloride and the mesylate of preferred dimethylamine, pyridine, Trimethylamine 99, diethylamine or isopropylamine or the reagent (" Compound C ") of gaseous hydrogen chloride so that this react completely.Provided the example of following reactants combination:
CF
3S (O) Cl, the dimethylamine tosilate;
CF
3S (O) Cl, pyridine hydrochloride;
CF
3S (O) N (CH
3)
2, tosic acid, hydrochloric acid;
CF
3S (O) Cl, dimethylamine tosilate, hydrochloric acid; With
CF
3S (O) ONa, dimethylamine tosilate, SOCl
2
Use CF
3The reaction that S (O) Cl carries out as the sulfination agent provides the end product of maximum output.
Developed some shortcoming that the method described in the CN-A 1374298 overcomes EP 668 269 described methods.CN-A 1374298 has illustrated CF
3S (O) Cl is extremely unstable, CF
3S (O) N (CH
3)
2And CF
3The difficult preparation of SOOH, and CF
3Productive rate in the not high and inferior sulfonation reaction of the reactivity of S (O) ONa is correspondingly lower.CN-A 1374298 has described the sylvite CF that uses trifluoromethanesulpacidc acidc
3The mixture C F of S (O) OK or trifluoromethanesulpacidc acidc potassium and sodium salt
3S (O) OK/CF
3S (O) ONa sulfination 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN (II), wherein with sulfination agent and POCl
3, PCl
3, SOCl
2, COCl
2Or trichloro-methyl chloroformate combination.Choose wantonly and can add amino acid title complex dimethylamine tosilate to finish this reaction.
Provided the example of following reactants combination:
CF
3S (O) OK; The dimethylamine tosilate; POCl
3With
CF
3S (O) OK/Na; The dimethylamine tosilate; SOCl
2
Huilong etc. have described 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN (II) and trifluoromethanesulpacidc acidc sodium (CF
3S (O) ONa), dimethylamine tosilate and SOCl
2Reaction, and add the DMF (dimethyl formamide) of catalytic amount.
As described in EP-A 1 331 222; use N-trifluoromethyl sulphinyl base succinimide as the sulfination agent in the presence of the triethylamine and do not add sulfination 5-amino-1-[2 under the chlorination reagent, 6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN (II).Separation of intermediates N-trifluoromethyl sulphinyl amino-pyrazol also changes into end product 5-amino-1-[2 under the Thia-Fries rearrangement condition, 6-two chloro-4-(trifluoromethyl) phenyl]-4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN.
Therefore; 5-amino-1-[2; 6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN (II) is to end product 5-amino-1-[2; 6-two chloro-4-(trifluoromethyl) phenyl]-(popular name: sulfination sharp strength spy (fipronil)) is subjected to obvious attention to 4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN in the literature, and focus is the optimization of sulfination agent.
Yet, also as recent survey article " progress of synthetic sharp strength spy and main intermediate thereof ", Chinese Journal of Pesticides, 2004, the 43 volumes, the 12nd phase, 529-531 is described, and the sulfination of still finding the pyrazoles intermediate usually and be not suitable for large-scale commercial production.
The reaction product of sulfination of the present invention is sharp strength spy, and it is the commercially available sterilant with remarkable importance.The industrially preparing process of agricultural chemicals be owing to the profit reason should satisfy high request usually on the productive rate of product and purity, and the most important thing is for fear of there being potential deleterious by product.This is special relevant especially for sharp strength, because it also is used for the animal health product and therefore also contacts with pet.
Also require industrially preparing process to avoid the employee of factory and environmental exposure legally in the reagent that may have disadvantageous effect to employee's health or environment.Therefore, it is desirable to that the industrially preparing process of avoiding using gaseous reagent such as dimethylamine is just arranged now.
In addition, be amplified to by laboratory scale in plant-scale process, unpredictalbe problem in the laboratory may occur in technology.
-for example, and the filling of big content of starting materials and/or be dissolved in may be than needing the much longer time on extensive in small vessels, bearing reaction kinetics significantly changes, thereby transformation efficiency and production spectra are changed.
-another example that can mention is the appearance of by product, and these by products are owing to the reason of solubleness or characteristic is difficult to separate with required principal product on a large scale.The problem of extraction, filtration and filter stoppage may take place.Insoluble raw material or reaction (pair) product also may influence stirring, heat dissipation or pumping, therefore produces uneven reaction mixture.
-another difficulty is the control of temperature of reaction in the extensive technology.Temperature grade is lower usually, and this may influence the by product spectrum.Because high reaction temperature and/or aggressiveness reaction medium may cause corrosion, and since economic cause, preferred mild reaction conditions (low temperature).
-solid hygroscopic property may make the reaction of advantageously carrying out under substantially anhydrous conditions complicated.For example, acid is H when above-mentioned technology is used wherein
2SO
4Rather than the amino acid title complex of the defined acid of the inventive method is when carrying out, the reaction yield extreme difference.
-preferably non-reactive catalysts is used for the inventive method to avoid side reaction.Specific secondary amine or primary amine may and form the insoluble solid that the stirring to reaction mixture has problems with sulfination agent reaction.
-in order to be beneficial to aftertreatment, the reagent that preferred use can be removed by distillation.Solid is by removing with acidity or basic solvent washing.The reagent that use has the phase-transfer catalysis performance that is separated in the possibility obstruction last handling process is not favourable.
At this background and one of the necessary raw material of existing industrial production that faces sharp strength spy for having the CF that high environmental toxicity and the Montreal Protocol on Substances that Deplete the OzoneLayer regulation can not be used to produce
3Br (may only be used as raw material at that time) this fact (for example referring to WO 01/30760), the objective of the invention is to develop a kind of new large-scale industry method of making sharp strength spy, this method obtains sharp strength spy with high purity and productive rate, the problem of avoiding using hazardous agents simultaneously and having avoided industrial reaction to control.
Therefore, found the defined method of beginning.The sharp strength spy of products therefrom is suitable as the sterilant of agricultural application and the application of non-crop with pest control.In addition, the sharp strength spy of gained is applicable to the animal health field with control animal health insect and parasite, flea and tick on the especially long-acting control Mammals.
Therefore, the invention still further relates to the 5-amino-1-[2 that contains by the inventive method preparation, 6-two chloro-4-(trifluoromethyl) phenyl]-desinsection or the parasite killing composition of 4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN.
Equally, the present invention relates to a kind of method of preventing and treating insect, acarid or nematode, comprise the 5-amino-1-[2 that makes insect, acarid or nematode or its provand source, habitat, breeding spot or its place and insecticidal effective dose, 6-two chloro-4-(trifluoromethyl) phenyl by the inventive method preparation]-4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN contact; And a kind of growing plants of protecting is with protection against insect, acarid or nematosis or the method that infects; comprise the 5-amino-1-[2 that in the soil of the blade face of plant or seed or wherein their growths or water, uses insecticidal effective dose, 6-two chloro-4-(trifluoromethyl) phenyl by the inventive method preparation]-4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN.According to these methods, 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN uses with the amount of 5-2000g/ha usually.
In addition; the present invention relates to a kind of processing, control, prevent or watch for animals to avoid the method for parasite infestation or infection; comprise to animal or its habitat per os, part or parenteral admin or use the 5-amino-1-[2 by the inventive method preparation of parasiticide significant quantity, 6-two chloro-4-(trifluoromethyl) phenyl]-4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN or its can enantiomorph for animals or salt.
The invention still further relates to a kind of preparation is used to handle, prevent and treat, prevent or watches for animals to avoid the method for compositions of parasite infestation or infection; comprising will be by the 5-amino-1-[2 of the inventive method preparation, 6-two chloro-4-(trifluoromethyl) phenyl]-4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN or its enantiomorph or can salt for animals with can mix by carrier for animals.Said composition can be enriched material or contain 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl with the parasiticide significant quantity]-4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN.
Although for having provided example in when beginning or some amino acid title complex of in the inferior sulfonation reaction process, adding, with regard to the specific nature of amino acid title complex for reaction control or the sharp strength spy's of end product the productive rate and/or the not instruction of most important property of purity.
In EP-A1 668 269, provided following preferred amines: the tosylate of dimethylamine, pyridine, Trimethylamine 99, diethylamine, Isopropylamine, hydrochloride or mesylate.Use dimethylamine tosilate and the pyridine hydrochloride example as the amino acid title complex has been described.
Similarly, at CN-A 1374298 and Huilong etc. in the two, for using the dimethylamine tosilate to provide example as the amino acid title complex.
Yet as mentioned above, the required dimethylamine of preparation dimethylamine tosilate is difficult to handle especially: it is the gas of extremely inflammable, harmful by skin contact and stimulation eyes, skin and respiratory system.Therefore, for large-scale methods, must handle the problem that environment produced because of transportation and to the employee's of factory danger.
The prior art document is not all mentioned and is advantageously used the amine of cyclic secondary amine as the amino acid title complex, and wherein acid only is selected from sulfonic acid.
Therefore new theme of the present invention is a kind of method of sulfination pyrazole derivatives, it is characterized in that making 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN (II) reacting in the presence of at least a amino acid title complex and under the adding halide reagent with sulfination agent S as defined above, and wherein amine is selected from cyclic secondary amine and acid is selected from sulfonic acid.
Reaction scheme can be described below:
The sulfination agent is preferably selected from trifluoromethyl sulphinyl fluorine, trifluoromethyl sulphinyl chlorine, trifluoromethyl sulphinyl bromine, trifluoromethyl sulphinyl iodine, trifluoromethanesulpacidc acidc, trifluoromethanesulpacidc acidc acid anhydride, trifluoromethanesulpacidc acidc sodium, trifluoromethanesulpacidc acidc potassium and composition thereof.
The sulfination agent more preferably is selected from trifluoromethanesulpacidc acidc, trifluoromethanesulpacidc acidc acid anhydride, trifluoromethanesulpacidc acidc sodium, trifluoromethanesulpacidc acidc potassium and composition thereof.
According to the preferred embodiments of the invention, with trifluoromethyl sulphinyl fluorine, trifluoromethyl sulphinyl chlorine, trifluoromethyl sulphinyl bromine or trifluoromethyl sulphinyl iodine, more preferably trifluoromethyl sulphinyl chlorine is as the sulfination agent.
According to the preferred embodiments of the invention, trifluoromethanesulpacidc acidc sodium is used as the sulfination agent.
According to another preferred embodiment of the present invention, trifluoromethanesulpacidc acidc potassium is used as the sulfination agent.
According to a preferred embodiment more of the present invention, trifluoromethanesulpacidc acidc is used as the sulfination agent.
According to another preferred embodiment of the present invention, the trifluoromethanesulpacidc acidc acid anhydride is used as the sulfination agent.
According to the preferred embodiments of the invention, be 0.01: 99.99 weight %-50 with ratio of mixture: the trifluoromethanesulpacidc acidc sodium of 50 weight % and the mixture of sylvite are as the sulfination agent.
Preferably with respect to 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN uses 1.0-1.35 molar equivalent, the most preferably sulfination agent of 1.2 molar equivalents.
In preferred embodiments, dry sulfination agent before using is up to substantially anhydrous." anhydrous " is meant that the water-content in the solid is no more than 5ppm to 100ppm.
Halide reagent is selected from thionyl chloride, thionyl bromide, phosphoryl chloride, oxalyl chloride, phosgene, triphosgene ((CCl
3)
2C (=O)), chloro-formic ester, phosphorus pentachloride, phosphorus trichloride, trichloro-methyl chloroformate (trichloromethylchloromethanoat) and xylenesulfonyl chloride.
According to the preferred embodiments of the invention, chlorination reagent is used as halide reagent.Preferably thionyl chloride or phosphoryl chloride are used as chlorination reagent.
According to another preferred embodiment of the present invention, phosphoryl chloride is used as chlorination reagent.
Most preferably thionyl chloride is used as chlorination reagent.
Preferably with respect to 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN uses 1.15-1.35 molar equivalent, the most preferably from about halide reagent of 1.2 molar equivalents.
What we found the amino acid title complex is chosen in 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-play a crucial role in the sulfination of 1H-pyrazoles-3-formonitrile HCN.The key property that influences inferior sulfonation reaction is space (volume) performance, pKs value, solubleness and molecular weight.
Inferior sulfonation reaction of the present invention is that single still of two-step reaction is synthetic.The first step relates to CF
3S (the O)-addition of group on the amino of pyrazoles ring.In second step, reset the sharp strength spy of formation via Thia-Fries:
The amino acid title complex has two kinds of functions in this two-step reaction: (1) when with the sulfination thing when the sulfination agent, it is via the activation to the sulfination thing of the formation catalytic halogenation reagent of-sulfinic acid intermediate.For this reason, the amino acid title complex that needs 0.01-1.0 molar equivalent catalytic amount with respect to pyrazole compound II.(2) it quickens the Thia-Fries rearrangement and selectivity is had remarkably influenced.In order to obtain high yield and high purity, advantageously will be used for step 2 with respect to the amino acid title complex that pyrazole compound II total amount surpasses 1 molar equivalent.
Preferably have agent of low hygroscopicity or do not have hygroscopic amino acid title complex substantially, because sulfination method of the present invention is advantageously carried out not existing substantially under the water (promptly being lower than 5-100ppm water).
The cyclic secondary amine of amino acid title complex is preferably by formula NHR
1R
2Definition, wherein R
1And R
2Form the saturated or part unsaturated heterocycle system of 3-10 person with the nitrogen-atoms that they connected, preferred 5-6 person's saturated heterocyclic system, this heterocyclic system is not substituted or by 1-3 C
1-C
8Alkyl or C
1-C
8Haloalkyl, preferred 1-3 C
1-C
3Alkyl or C
1-C
3Haloalkyl, most preferably 1-3 C
1-C
3Alkyl, most preferably 1-3 methyl substituted and can contain 1-3 and be selected from oxygen, nitrogen and sulphur is preferably selected from other heteroatomss of oxygen or nitrogen.
Preferred cyclic secondary amine is a piperidines, by C
1-C
8Alkyl or C
1-C
8Haloalkyl, preferred C
1-C
2Alkyl or C
1-C
2The piperidines that haloalkyl replaces, as pipecoline or 4-methyl piperidine, tetramethyleneimine is by C
1-C
8Alkyl or C
1-C
8The tetramethyleneimine that haloalkyl replaces is as 2-crassitude and 3-crassitude, imidazolidine, pyrroles, piperazine or morpholine.
Especially preferred morpholine, piperidines or tetramethyleneimine.
The preferred acid that is used for amino acid title complex of the present invention is sulfonic acid such as aromatic sulfonic acid, for example tosic acid, Phenylsulfonic acid, 4-ethyl phenenyl azochlorosulfonate acid, 4-chlorobenzenesulfonic acid, xylene monosulfonic acid, 2,3-acid dimethyl, 2,4-acid dimethyl, 2,5-acid dimethyl, 2, the mixture of two or more in 6-acid dimethyl, 1-naphthalene sulfonic aicd, 2-naphthene sulfonic acid, the acid dimethyl isomer, or mesitylene sulfonic acid; Or alkylsulphonic acid, for example methylsulfonic acid or camphorsulfonic acid; Or haloalkyl sulfonic acid, for example trifluoromethane sulfonic acid.Especially preferred pKs value is less than 2 acid.
In the selection that is used for amino acid title complex of the present invention, preferred pKa is less than 6, preferred 5 and greater than 10 those.
Even preferred acid is tosic acid, xylene monosulfonic acid, Phenylsulfonic acid, methylsulfonic acid, trifluoromethane sulfonic acid or mesitylene sulfonic acid.
Most preferred acid is tosic acid, xylene monosulfonic acid or Phenylsulfonic acid.
Preferred amino acid title complex Q is listed in the table below in 1.
Table 1
| Sequence number | Amine | Acid |
| Q-1 | Morpholine | Tosic acid |
| Q-2 | Morpholine | Phenylsulfonic acid |
| Q-3 | Morpholine | Xylene monosulfonic acid |
| Q-4 | Morpholine | Methylsulfonic acid |
| Q-5 | Morpholine | Trifluoromethane sulfonic acid |
| Q-6 | Piperidines | Tosic acid |
| Q-7 | Piperidines | Phenylsulfonic acid |
| Q-8 | Piperidines | Xylene monosulfonic acid |
| Q-9 | Piperidines | Methylsulfonic acid |
| Q-10 | Piperidines | Trifluoromethane sulfonic acid |
| Q-11 | Tetramethyleneimine | Tosic acid |
| Q-12 | Tetramethyleneimine | Phenylsulfonic acid |
| Q-13 | Tetramethyleneimine | Xylene monosulfonic acid |
| Q-14 | Tetramethyleneimine | Methylsulfonic acid |
| Q-15 | Tetramethyleneimine | Trifluoromethane sulfonic acid |
| Q-16 | Imidazoles | Tosic acid |
| Q-17 | Imidazoles | Phenylsulfonic acid |
| Q-18 | Imidazoles | Xylene monosulfonic acid |
| Q-19 | Imidazoles | Methylsulfonic acid |
| Q-20 | Imidazoles | Trifluoromethane sulfonic acid |
| Q-21 | Imidazoles | Trifluoromethane sulfonic acid |
| Sequence number | Amine | Acid |
| Q-22 | The pyrroles | Tosic acid |
| Q-23 | The pyrroles | Phenylsulfonic acid |
| Q-24 | The pyrroles | Xylene monosulfonic acid |
| Q-25 | The pyrroles | Methylsulfonic acid |
| Q-26 | The pyrroles | Trifluoromethane sulfonic acid |
| Q-27 | Piperazine | Tosic acid |
| Q-28 | Piperazine | Phenylsulfonic acid |
| Q-29 | Piperazine | Xylene monosulfonic acid |
| Q-30 | Piperazine | Methylsulfonic acid |
| Q-31 | Piperazine | Trifluoromethane sulfonic acid |
Especially preferred amino acid title complex Q1, Q2, Q3, Q6, Q7, Q8, Q11, Q12 or Q13.
For they purposes in the methods of the invention, the combination that especially preferred following table is given sulfination agent and amino acid title complex.
Table 2
Trifluoromethanesulpacidc acidc sodium is used as the sulfination agent, and the amino acid title complex is the delegation of table 1 in each case.
Table 3
Trifluoromethanesulpacidc acidc potassium is used as the sulfination agent, and the amino acid title complex is the delegation of table 1 in each case.
Table 4
Trifluoromethanesulpacidc acidc is used as the sulfination agent, and the amino acid title complex is the delegation of table 1 in each case.
Table 5
The trifluoromethanesulpacidc acidc acid anhydride is used as the sulfination agent, and the amino acid title complex is the delegation of table 1 in each case.
Table 6
With ratio of mixture is 0.01: 99.99 weight % to 50: the sodium salt of the trifluoromethanesulpacidc acidc of 50 weight % and sylvite mixture are as the sulfination agent, and the amino acid title complex is the delegation of table 1 in each case.
Table 7
The trifluoromethyl sulphinyl fluorine is used as the sulfination agent, and the amino acid title complex is the delegation of table 1 in each case.
Table 8
Trifluoromethyl sulphinyl chlorine is used as the sulfination agent, and the amino acid title complex is the delegation of table 1 in each case.
Table 9
The trifluoromethyl sulphinyl bromine is used as the sulfination agent, and the amino acid title complex is the delegation of table 1 in each case.
Table 10
Trifluoromethyl sulphinyl iodine is used as the sulfination agent, and the amino acid title complex is the delegation of table 1 in each case.
In addition, in another preferred embodiment of the present invention, can be with Lewis acid such as AlCl
3, FeCl
3, CaCl
2, ZnCl
2, BF
3, TiCl
4Or ZrCl
4Be used to replace above-mentioned protonic acid.
Maybe advantageously add the amino acid title complex in two batches, a collection ofly be used for step 1 and a collection of adding after the pyrazoles that adds formula II.
Maybe advantageously in reaction process, use two kinds of different amino acid title complexs.For example, can be in step 1 add the first amino acid title complex with the amount of 0.2-1 molar equivalent, with of the activation of catalytic halogenation reagent to the sulfination thing with respect to pyrazoles II.After the pyrazoles that adds formula II, in resetting, the Thia-Fries of step 2 adds the second amino acid title complex different with the amount of 0.2-1 molar equivalent with the first amino acid title complex with respect to pyrazoles II.
With respect to 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN, preferably use the 1.4-2.2 molar equivalent, most preferably the amino acid title complex of the present invention of 1.5-1.8 molar equivalent.
When the sulfination agent is a trifluoromethanesulpacidc acidc or when containing the mixture of trifluoromethanesulpacidc acidc, preferably produce the amino acid title complex that molar weight equates with the molar weight of trifluoromethanesulpacidc acidc on the spot, and add the required residue molar weight of the required 1.4-2.2 molar equivalent of acquisition as the amino acid title complex by adding amine.
In preferred embodiments, dry amino acid title complex before using is up to substantially anhydrous." anhydrous " is meant that the water-content in the solid is no more than 5ppm to 100ppm.
Can advantageously other additives be added reaction mixture, as Potassium monofluoride, Pentafluorophenol, dimethyl formamide or 2,2, 4-dinitrophenol.These additives preferably add in reaction mixture or material solution or the suspension before the reaction beginning or when the reaction beginning.Most preferably additive adds under 5-10 ℃ low temperature.
In preferred embodiments, in when beginning reaction or will be 5-10 ℃ under before the reaction beginning with respect to 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN is in the Potassium monofluoride adding reaction mixture or material solution or suspension of 0.1-1.5 molar equivalent.
Advantageously with respect to 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN adds Pentafluorophenol, dimethyl formamide or 2,2, 4-dinitrophenol with catalytic amount or 0.10 molar equivalent.
In preferred embodiments, dry additive before using is up to substantially anhydrous." anhydrous " is meant that the water-content in the solid is no more than 5ppm to 100ppm.
This reaction can be carried out in inert organic solvents, and described solvent is preferably selected from:
The optional halohydrocarbon such as the organic hydrocarbon of aromatics of-aliphatic, alicyclic or aromatics, for example toluene, dimethylbenzene, trifluoromethylbenzene, benzene, oil of mirbane, mono chloro benzene, dichlorobenzene and ethylbenzene, preferred toluene and dimethylbenzene, most preferably toluene; Aliphatic or alicyclic optional halohydrocarbon such as hexane, hexanaphthene, benzene, 1,2-ethylene dichloride, methylene dichloride, trichloromethane (chloroform), tetracol phenixin, preferred 1,2-ethylene dichloride, methylene dichloride, trichloromethane; With
-ethers, as ether, diox, tetrahydrofuran (THF), 2-methyltetrahydrofuran or ethylene glycol dimethyl-or Anaesthetie Ether; With
-ketone, as acetone or butanone and
-nitrile, as acetonitrile or propionitrile and
-amides is as dimethyl formamide, DMI (1,3-dimethyl-2-imidazolidone), N,N-DIMETHYLACETAMIDE, N-methyl formyl aniline, N-Methyl pyrrolidone or HMPA; With
-sulfoxide is as methyl-sulphoxide.
In preferred embodiments, use substantially anhydrous solvent." anhydrous " is meant that the water-content in the solvent is no more than 5ppm to 100ppm.Most preferred solvent is a dry toluene.
This is reflected under the inert gas atmosphere and carries out, and for example carries out under argon gas or nitrogen atmosphere.
In preferred embodiments,, 6-two chloro-4-(trifluoromethyl) phenyl with respect to 5-amino-1-[2]-1H-pyrazoles-3-formonitrile HCN uses 3.0-8.0 molar equivalent altogether, more preferably 4.0-7.5 molar equivalent, the most preferably solvent of 4.5-6.5 molar equivalent.The raw material of this higher concentration makes the conversion maximization to the sulfinyl amine intermediate.
Raw material its in conjunction with before respectively separately under dissolving and/or the situation about suspending, will about 25-40% solvent be used for dissolving and/or suspension 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN.
Usually can freely select to add raw material 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-order of 1H-pyrazoles-3-formonitrile HCN, amino acid title complex, sulfination agent and halide reagent.
Before preferably in adding reaction mixture each raw material is dissolved respectively or be suspended in the reaction solvent.
Preferably in reaction mixture, do not exist and halide reagent do not added 5-amino-1-[2 under amino acid title complex or the sulfination agent, 6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN in.In preferred embodiments, halide reagent is dissolved in the solvent and adds contain 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-reaction mixture of 1H-pyrazoles-3-formonitrile HCN, amino acid title complex and sulfination agent in, back three is all dissolved or is suspended in the solvent.
In preferred embodiments, with 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN (II) and the mixture merging that contains sulfination agent, amino acid title complex and halide reagent.Maybe advantageously (equal first part to about 1 molar equivalent this moment, with respect to Compound I I) halide reagent be included in the mixture that contains sulfination agent, amino acid title complex and halide reagent, adding Compound I I and adding second section (equaling about 0.1-0.2 molar equivalent) after stir about 30-60 minute and before temperature is risen to 30-50 ℃ immediately then with respect to Compound I I.
When the sulfination agent is trifluoromethanesulpacidc acidc, preferably trifluoromethanesulpacidc acidc and halide reagent are added in the solution or suspension of amino acid title complex simultaneously, then with 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN solution adds in the reaction mixture.
In another preferred embodiment, sulfination agent, amino acid title complex and halide reagent dissolving or the suspended mixture in solvent (preferred toluene) is cooled to about 3-10 ℃, and will be heated to 5-amino-1-[2 of about 90-110 ℃, 6-two chloro-4-(trifluoromethyl) phenyl]-solution of 1H-pyrazoles-3-formonitrile HCN in solvent (preferred toluene) combines with this cooling mixture.
In preferred embodiments, with 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-after 1H-pyrazoles-3-formonitrile HCN, sulfination agent, amino acid title complex and chlorination reagent merge, in 5-60 minute, temperature is risen to 30-55 ℃.
Also preferably temperature of reaction was kept 5-60 minute down at-20 ℃ to 10 ℃ at first, preferred 20-40 minute, the speed with 5-45 ℃/min rose to 30-55 ℃ with temperature then.Preferably, reaction mixture is risen to temperature be no more than 35 ℃ in order to obtain high-purity product.When the sulfination agent for or contain CF
3During S (O) OH, initial reaction temperature is preferably-20 ℃ to 5 ℃, and under the situation of trifluoromethanesulpacidc acidc basic metal or alkaline earth salt, initial reaction temperature is preferably-5 ℃ to 10 ℃.
Reaction times is depended on temperature control and different reagent and the solvents in temperature of reaction, this procedure.Those of skill in the art can determine in order to obtain the suitable reactions time of required productive rate and purity.Reaction times is generally about 5-15 hour, preferred 10-15 hour.
In another preferred embodiment, this is reflected at 1.013 crust (1 normal atmosphere) and carries out in pressurizing vessel to the pressure of about 4 crust.
After reaction was finished, sharp strength spy can separate by using ordinary method, and these methods are as using supercarbonate such as NaHCO
3, carbonate such as NaCO
3Or oxyhydroxide such as NaOH termination reaction, extract sharp strength spy with non-polar organic solvent such as ethyl acetate or methyl tertiary butyl ether, for example use supercarbonate such as NaHCO
3The washing extraction liquid concentrates extract, vacuum concentration for example, the sharp strength top grade of crystallization.The special necessary words of isolating sharp strength can be purified by the technology such as chromatography, recrystallization etc.
End product 5-amino-1-[2; 6-two chloro-4-(trifluoromethyl) phenyl]-crystallization of 4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN undertaken by the solution in following solvent usually: nonpolar; inertia; preferred aromatic solvent, it has non-reacted substituting group such as chlorine, fluorine, cyano group, nitro, C
1-C
8Alkyl or C
1-C
8Haloalkyl; Especially undertaken by the solution in following solvent: benzene, ethylbenzene, mono chloro benzene, phenyl-monofluoride, 1, the 2-dichlorobenzene, 1, the 3-dichlorobenzene, 1, the 4-dichlorobenzene, toluene, o-Xylol, m-xylene, p-Xylol, vinylbenzene, isopropyl benzene, n-propylbenzene, the 2-toluene(mono)chloride, the 3-toluene(mono)chloride, the 4-toluene(mono)chloride, tert.-butylbenzene, sec-butylbenzene, isobutyl-benzene, n-butylbenzene, 1, the 3-diisopropyl benzene, 1, the 4-diisopropyl benzene, the 2-nitrotoluene, the 3-nitrotoluene, the 4-nitrotoluene, oil of mirbane, benzonitrile, mesitylene, trifluoromethylbenzene, 1, the 2-ethylene dichloride, acetonitrile, methyl-sulphoxide, tetrahydrofuran (THF), acetone, alcohols is (as methyl alcohol, ethanol, n-propyl alcohol, Virahol, propyl carbinol, isopropylcarbinol, the 2-butanols or the trimethyl carbinol); Preferably undertaken by the solution in mono chloro benzene, dichlorobenzene, ethylbenzene or toluene.
Preferably by the mono chloro benzene crystallization.
Preferably by the dichlorobenzene crystallization.
Preferably by the ethylbenzene crystallization.
Preferably by the toluene crystallization.
Maybe advantageously add about 1-30% polar solvent such as ketone, acid amides, alcohols, ester class or ethers, preferred ester class, ketone or ethers, as acetone, methyl ethyl ketone, penta-2-ketone, metacetone, 4-methyl-2 pentanone, 3-methyl-2-butanone, tertiary butyl methyl ketone, pimelinketone, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, diethyl carbonate, acetate 2-butoxy ethyl ester, dimethyl formamide, N,N-DIMETHYLACETAMIDE, methyl-sulphoxide, Nitromethane 99Min., nitroethane, water, ethanol, methyl alcohol, the 1-propyl alcohol, the 2-propyl alcohol, the 1-butanols, the 2-butanols, the trimethyl carbinol, 2-methyl isophthalic acid-propyl alcohol, 2-methyl-2-propyl alcohol, the 3-amylalcohol, 2-methyl-1-butene alcohol, 3-methyl isophthalic acid-butanols, 1,2-ethylene glycol, 1, ammediol, 1, the 2-propylene glycol, hexalin diox, tetrahydrofuran (THF), ether, methyl tertiary butyl ether, the 2-methyltetrahydrofuran, acetonitrile, propionitrile or its mixture.
In another embodiment, sharp strength spy chooses the about 1-30% polar organic solvent of adding wantonly by crystallization in the water.
The purification of crude product can also or wash with water and carries out via the filtration on charcoal or silicon-dioxide.
When obtaining according to the inventive method, the sharp strength spy of the products therefrom in crude product mixture is at the compound F 17-hydroxy-corticosterone that contains before the crystallization less than 3.0 weight % (not having to calculate under the solvent), and the latter is a common biological activity by product during sharp strength spy synthesizes.
By suitable method as the washing and (again) crystallization and purification crude product after, sharp strength spy obtained by the method for the present invention is contained the compound F 17-hydroxy-corticosterone less than 1.0 weight %.
In addition, the sharp strength spy of products therefrom does not contain Compound D, and the latter is the common by product of existing large-scale industry method as described in WO 01/30760 for example, even also exists after purifying.The sharp strength spy who is prepared under inert atmosphere by the inventive method is contained and is contained the compound of sulphur less than 300ppm with its oxidation state (IV).It does not contain the compd E that may occur with the by product of existing commercial run usually yet.
In addition, the sharp strength spy of products therefrom does not contain the trifluoroacetic acid as agents useful for same in the existing commercial run yet.
In addition, when with chlorination reagent when the halide reagent, the sharp strength special product of gained thing is not brominated substantially, this means that it does not contain bromine above 5-20ppm.
Embodiment
HPLC is being equipped with J ' Sphere ODS-H80,4m, 4.6 the HewlettPackard HP 1200 of * 250mm (YMC) post, carry out on the Chemstation, eluent A:90 weight % water+10 weight % acetonitriles, eluent B:10 weight % water+90 weight % acetonitriles, flow velocity: 0.85ml/min, detect: 235nm
Gradient: the time [minute] 02 17 25 35
A[％] 60 60 25 0 0
B[％] 40 40 75 100 100。
Following productive rate is the molecular fraction of the crystallized product of aftertreatment gained purification afterwards.Purity provides with gained solid weight percentage.
Embodiment 1: with morpholine tosylate, trifluoromethanesulpacidc acidc sodium and thionyl chloride sulfination 5-amino-1-[2 in 6.5 molar equivalent toluene, 6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN
Under argon gas atmosphere, be equipped with in the 50mL three neck round-bottomed flasks of magnetic stirring bar and thermometer and putting into vacuum drying trifluoromethanesulpacidc acidc sodium (4.29g, 27.5mmol), vacuum drying morpholine tosylate (37.5g) and 13mL dry toluene (6.5 molar equivalents, with respect to 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN).Be cooled to ice bath after 0-5 ℃, and slow adding thionyl chloride when keeping temperature of reaction to be lower than 5 ℃ (3.57g, 30mmol).Behind the restir 30 minutes, 5 ℃ add down vacuum drying 5-amino-1-(2,6-dichlor-4-trifluoromethyl phenyl)-1H-pyrazoles-3-formonitrile HCNs (8.03g, 25mmol, 99% purity) and the water-bath by preheating with reaction mixture at 5 minutes internal heating to 50 ℃.50 ℃ temperature were kept 6 hours again, use the saturated NaHCO of 50mL then
3The solution termination reaction.
Gained suspension dilutes with the 30mL ethyl acetate.Be separated afterwards the saturated NaHCO of organic layer
372%) and be evaporated to dried solution washing is (thick productive rate in the organic phase of being measured by quantitative HPLC: once.Crude product obtains white crystalline powder shape title compound (66% productive rate, recording purity by quantitative HPLC is 97%, 0.9 weight % compound F 17-hydroxy-corticosterone) by backflow toluene crystallization (100g).
Embodiment 2: with tetramethyleneimine tosylate, trifluoromethanesulpacidc acidc potassium and thionyl chloride sulfination 5-amino-1-[2 in 6.5 molar equivalent toluene, 6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN
Under argon gas atmosphere, be equipped with in the 50mL three neck round-bottomed flasks of magnetic stirring bar and thermometer and putting into vacuum drying trifluoromethanesulpacidc acidc sodium (4.29g, 27.5mmol), vacuum drying tetramethyleneimine tosylate (37.5g) and 13mL dry toluene (6.5 molar equivalents, with respect to 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN).Be cooled to ice bath after 0-5 ℃, and slow adding thionyl chloride when keeping temperature of reaction to be lower than 5 ℃ (3.57g, 30mmol).Behind the restir 30 minutes, 5 ℃ add down vacuum drying 5-amino-1-(2,6-dichlor-4-trifluoromethyl phenyl)-1H-pyrazoles-3-formonitrile HCNs (8.03g, 25mmol, 99% purity) and the water-bath by preheating with reaction mixture at 5 minutes internal heating to 50 ℃.50 ℃ temperature were kept 6 hours again, use the saturated NaHCO of 50mL then
3The solution termination reaction.
Gained suspension dilutes with the 30mL ethyl acetate.Be separated afterwards the saturated NaHCO of organic layer
377%) and be evaporated to dried solution washing is (thick productive rate in the organic phase of being measured by quantitative HPLC: once.
Crude product obtains white crystalline powder shape title compound (68% productive rate, recording purity by quantitative HPLC is 96%, 1.4 weight % compound F 17-hydroxy-corticosterone) by backflow toluene crystallization (100g).
Embodiment 3: with piperidines tosylate, trifluoromethanesulpacidc acidc potassium and thionyl chloride sulfination 5-amino-1-[2 in 6.5 molar equivalent toluene, 6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN
As above in the face of embodiment 2 described being prepared, obtain white crystalline powder shape title compound (76% thick productive rate, productive rate is 68% behind the recrystallize, recording purity by quantitative HPLC is 96%, 1.7 weight % compound F 17-hydroxy-corticosterone).
Comparative Examples
The secondary alkylamine such as dimethylamine, diethylamine and the Diisopropylamine that form the amino acid title complex with hydrofluoric acid or hydrochloric acid provide infusible precipitate, and it is retained in the product in whole aftertreatment and recrystallization process.
For Comparative Examples, select the diethylamine tosylate as the amino acid title complex, because it has relevant to a certain extent structure and molecular weight with some cyclic secondary amine of the present invention.
Embodiment C 1: with diethylamine tosylate, trifluoromethanesulpacidc acidc potassium and thionyl chloride sulfination 5-amino-1-[2 in 6.5 molar equivalent toluene, 6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN
As above in the face of embodiment 2 described being prepared, obtain white crystalline powder shape title compound (71% thick productive rate, productive rate is 65% behind the recrystallize, recording purity by quantitative HPLC is 94%, 1.8 weight % compound F 17-hydroxy-corticosterone).
Therefore, showing in this test that the inventive method is compared with sulfination method described in the prior art obtains more high yield and more high purity.
Claims (26)
1. the method for sulfination pyrazole derivatives, it is characterized in that making 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN (II) and sulfination agent S reacting in the presence of at least a amino acid title complex and under the adding halide reagent, wherein said amine is selected from cyclic secondary amine and described acid is selected from sulfonic acid, and wherein S is [CF
3S (O)]
2O; Or CF
3S (O) X, wherein X refers to the basic metal or the alkaline earth salt of fluorine, chlorine, bromine, iodine, hydroxyl or hydroxyl; Or its mixture.
2. according to the process of claim 1 wherein that described halide reagent is selected from thionyl chloride, thionyl bromide, phosphoryl chloride, oxalyl chloride, phosgene, triphosgene ((CCl
3)
2C (=O)), chloro-formic ester, phosphorus pentachloride, phosphorus trichloride, trichloro-methyl chloroformate and xylenesulfonyl chloride.
3. according to the method for claim 1 or 2, wherein said halide reagent is the chlorination reagent that is selected from thionyl chloride and phosphoryl chloride.
4. according to each method among the claim 1-3, the described cyclic secondary amine of wherein said amino acid title complex is by formula NHR
1R
2Definition, wherein R
1And R
2Form the saturated or part unsaturated heterocycle system of 3-10 person with the nitrogen-atoms that they connected, described heterocyclic system is not substituted or by 1-3 C
1-C
8Alkyl or C
1-C
8Haloalkyl replaces and can contain 1-3 other heteroatomss that are selected from oxygen, nitrogen and sulphur.
5. according to each method among the claim 1-4, the described amine of wherein said amino acid title complex is selected from the cyclic secondary amine piperidines, by C
1-C
8Alkyl or C
1-C
8Haloalkyl, as pipecoline or 4-methyl piperidine, tetramethyleneimine is by C
1-C
8Alkyl or C
1-C
8The tetramethyleneimine that haloalkyl replaces, as 2-crassitude or 3-crassitude, imidazolidine, pyrroles, piperazine or morpholine, preferred morpholine, piperidines or tetramethyleneimine.
6. according to each method among the claim 1-5, the described acid of wherein said amino acid title complex is selected from tosic acid, Phenylsulfonic acid, 4-ethyl phenenyl azochlorosulfonate acid, 4-chlorobenzenesulfonic acid, xylene monosulfonic acid, 2,3-acid dimethyl, 2,4-acid dimethyl, 2,5-acid dimethyl, 2, the mixture of two or more, mesitylene sulfonic acid, methylsulfonic acid, camphorsulfonic acid or trifluoromethane sulfonic acid in 6-acid dimethyl, 1-naphthalene sulfonic aicd, 2-naphthene sulfonic acid, the acid dimethyl isomer, preferred tosic acid, Phenylsulfonic acid or xylene monosulfonic acid.
7. according to each method among the claim 1-6, wherein said sulfination agent S is selected from CF
3S (O) Cl, CF
3S (O) OH, [CF
3S (O)]
2O, CF
3S (O) ONa, CF
3S (O) OK and composition thereof.
8. according to each method among the claim 1-7, wherein said being reflected in the organic solvent that is selected from toluene, benzene, dimethylbenzene, trifluoromethylbenzene, mono chloro benzene, dichlorobenzene and ethylbenzene carried out.
9. according to each method among the claim 1-8,, 6-two chloro-4-(trifluoromethyl) phenyl wherein with 5-amino-1-[2]-solution of 1H-pyrazoles-3-formonitrile HCN adds in the reaction mixture of described sulfination agent, described amino acid title complex and described halide reagent.
10. according to each method among the claim 1-9,, 6-two chloro-4-(trifluoromethyl) phenyl wherein with respect to 5-amino-1-[2]-1H-pyrazoles-3-formonitrile HCN uses the described amino acid title complex of 1.4-2.2 molar equivalent.
11.,, 6-two chloro-4-(trifluoromethyl) phenyl wherein with respect to 5-amino-1-[2 according to each method among the claim 1-10]-1H-pyrazoles-3-formonitrile HCN uses the described halide reagent of 1.15-1.35 molar equivalent.
12.,, 6-two chloro-4-(trifluoromethyl) phenyl wherein with respect to 5-amino-1-[2 according to each method among the claim 1-11]-1H-pyrazoles-3-formonitrile HCN uses the described sulfination agent of 1.0-1.3 molar equivalent.
13. according to each method among the claim 1-12, wherein merging 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-1H-pyrazoles-3-formonitrile HCN, described sulfination agent, described amino acid title complex and described halide reagent after, in 5-60 minute, temperature is risen to 30-55 ℃, preferred 30-39 ℃.
14. by the 5-amino-1-[2 as the method preparation that each limited among the claim 1-13,6-two chloro-4-(trifluoromethyl) phenyl]-4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN.
15. by the 5-amino-1-[2 as the method preparation that each limited among the claim 3-13,6-two chloro-4-(trifluoromethyl) phenyl]-4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN, it contains the bromine less than 20ppm.
16. by as the preparation of each limited among the claim 1-13 method or according to the 5-amino-1-[2 of claim 15; 6-two chloro-4-(trifluoromethyl) phenyl]-4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN, it contains the Compound D less than 10ppm:
17. by as the preparation of each limited among the claim 1-13 method or according to 5-amino-1-[2 claim 15 or 16 and that be arranged in inert atmosphere; 6-two chloro-4-(trifluoromethyl) phenyl]-4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN, it contains and contains the compound of sulphur less than 200pm with its oxidation state (IV).
18. desinsection or parasite killing composition contain just like each defined 5-amino-1-[2 among the claim 14-17,6-two chloro-4-(trifluoromethyl) phenyl]-4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN.
19. by as the preparation of each limited among the claim 1-13 method or as each defined 5-amino-1-[2 among the claim 14-17,6-two chloro-4-(trifluoromethyl) phenyl]-4-(trifluoromethyl sulphinyl base) pyrazoles-purposes of 3-formonitrile HCN in pest control.
20. by as the preparation of each limited among the claim 1-13 method or as each defined 5-amino-1-[2 among the claim 14-17,6-two chloro-4-(trifluoromethyl) phenyl]-purposes of 4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN in preventing and treating animal health insect and parasite.
21. method of preventing and treating insect, acarid or nematode; comprise make insect, acarid or nematode or its provand source, habitat, breeding spot or its place and insecticidal effective dose by as the preparation of each limited among the claim 1-13 method or as each defined 5-amino-1-[2 among the claim 14-17,6-two chloro-4-(trifluoromethyl) phenyl]-4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN contacts.
22. protect growing plants with protection against insect, acarid or nematosis or the method that infects for one kind; comprise that the method by each limited in as claim 1-13 of using insecticidal effective dose in the soil of the blade face of plant or seed or wherein their growths or water prepares or as claim 14-17 in each defined 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN.
23., 5-amino-1-[2 wherein, 6-two chloro-4-(trifluoromethyl) phenyl as claim 22 or 21 desired methods]-4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN uses with the amount of 5-2000g/ha.
24. handle, prevent and treat, prevent or watch for animals to avoid the method for parasite infestation or infection for one kind; comprise to animal or its habitat per os, part or parenteral admin or use the parasiticide significant quantity by each limited in as claim 1-13 method preparation or as claim 14-17 in each defined 5-amino-1-[2,6-two chloro-4-(trifluoromethyl) phenyl]-4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN or its can enantiomorph for animals or salt.
25. one kind prepares and is used to handle, prevent and treat, prevent or watches for animals to avoid the method for compositions of parasite infestation or infection; comprise will by as the preparation of each limited among the claim 1-13 method or as each defined 5-amino-1-[2 among the claim 14-17,6-two chloro-4-(trifluoromethyl) phenyl]-4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN or its can enantiomorph for animals or salt with can mix by carrier for animals.
26., 5-amino-1-[2 wherein, 6-two chloro-4-(trifluoromethyl) phenyl according to the method for claim 25]-4-(trifluoromethyl sulphinyl base) pyrazoles-3-formonitrile HCN or its can enantiomorph for animals or salt exist with the parasiticide significant quantity.
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|---|---|---|---|
| US86517806P | 2006-11-10 | 2006-11-10 | |
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| CNA2007800496448A Pending CN101583602A (en) | 2006-11-10 | 2007-11-05 | Process for the sulfinylation of a pyrazole derivative |
| CNA2007800496452A Pending CN101589027A (en) | 2006-11-10 | 2007-11-05 | Process for the sulfinylation of a pyrazole derivative |
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| CN107963993A (en) * | 2018-01-06 | 2018-04-27 | 江苏托球农化股份有限公司 | A kind of preparation method of high-purity ethiprole |
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| CN104557713B (en) * | 2013-10-22 | 2018-08-21 | 江苏托球农化股份有限公司 | High-purity ethiprole preparation method |
| CN104926729B (en) * | 2014-03-18 | 2018-01-19 | 上海泰禾国际贸易有限公司 | A kind of method for synthesizing ethiprole |
| CN113825743A (en) * | 2019-03-19 | 2021-12-21 | 格哈达化工有限公司 | Method for synthesizing fipronil |
| CN111004155A (en) * | 2019-09-11 | 2020-04-14 | 浙江埃森化学有限公司 | Preparation method of trifluoromethyl sulfuryl halide |
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2007
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| CN107963993A (en) * | 2018-01-06 | 2018-04-27 | 江苏托球农化股份有限公司 | A kind of preparation method of high-purity ethiprole |
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| UA98474C2 (en) | 2012-05-25 |
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| CN101589027A (en) | 2009-11-25 |
| UA98628C2 (en) | 2012-06-11 |
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