CN106467492B - preparation method of polyfluoromethyl pyrazole compound, intermediate and preparation method - Google Patents
preparation method of polyfluoromethyl pyrazole compound, intermediate and preparation method Download PDFInfo
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- CN106467492B CN106467492B CN201510502466.6A CN201510502466A CN106467492B CN 106467492 B CN106467492 B CN 106467492B CN 201510502466 A CN201510502466 A CN 201510502466A CN 106467492 B CN106467492 B CN 106467492B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 160
- -1 pyrazole compound Chemical class 0.000 title description 11
- 238000006243 chemical reaction Methods 0.000 claims abstract description 171
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 81
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 claims abstract description 80
- 229940125904 compound 1 Drugs 0.000 claims abstract description 55
- 239000003960 organic solvent Substances 0.000 claims abstract description 48
- 229940125782 compound 2 Drugs 0.000 claims abstract description 36
- 238000004519 manufacturing process Methods 0.000 claims abstract description 26
- 239000002994 raw material Substances 0.000 claims abstract description 23
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 23
- 239000006227 byproduct Substances 0.000 claims abstract description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 219
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 152
- 150000001875 compounds Chemical class 0.000 claims description 105
- 239000000243 solution Substances 0.000 claims description 101
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 87
- 239000007864 aqueous solution Substances 0.000 claims description 86
- 239000002904 solvent Substances 0.000 claims description 75
- 238000000034 method Methods 0.000 claims description 73
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 66
- 229940126214 compound 3 Drugs 0.000 claims description 62
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical class F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 55
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 55
- 239000008096 xylene Substances 0.000 claims description 45
- 239000007788 liquid Substances 0.000 claims description 43
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 42
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 42
- 239000003513 alkali Substances 0.000 claims description 42
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 39
- 239000000203 mixture Substances 0.000 claims description 38
- 229940125898 compound 5 Drugs 0.000 claims description 36
- 238000001816 cooling Methods 0.000 claims description 35
- 239000012074 organic phase Substances 0.000 claims description 32
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 30
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 30
- 239000003054 catalyst Substances 0.000 claims description 30
- 229940125773 compound 10 Drugs 0.000 claims description 30
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 30
- 150000007530 organic bases Chemical class 0.000 claims description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- 239000002585 base Substances 0.000 claims description 24
- 239000012071 phase Substances 0.000 claims description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 20
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 20
- 150000003951 lactams Chemical class 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 19
- 238000006482 condensation reaction Methods 0.000 claims description 19
- 238000010438 heat treatment Methods 0.000 claims description 18
- 238000000926 separation method Methods 0.000 claims description 18
- 150000007529 inorganic bases Chemical class 0.000 claims description 15
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 15
- 230000002378 acidificating effect Effects 0.000 claims description 14
- 235000019439 ethyl acetate Nutrition 0.000 claims description 14
- 239000000126 substance Substances 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 13
- 239000003153 chemical reaction reagent Substances 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 12
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinon Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 claims description 10
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 10
- 238000006460 hydrolysis reaction Methods 0.000 claims description 10
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 9
- 159000000003 magnesium salts Chemical class 0.000 claims description 9
- YNQLUTRBYVCPMQ-UHFFFAOYSA-N Ethylbenzene Chemical compound CCC1=CC=CC=C1 YNQLUTRBYVCPMQ-UHFFFAOYSA-N 0.000 claims description 8
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- JBTWLSYIZRCDFO-UHFFFAOYSA-N ethyl methyl carbonate Chemical compound CCOC(=O)OC JBTWLSYIZRCDFO-UHFFFAOYSA-N 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 8
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 claims description 8
- 150000002825 nitriles Chemical group 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 7
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 7
- DAMJCWMGELCIMI-UHFFFAOYSA-N benzyl n-(2-oxopyrrolidin-3-yl)carbamate Chemical compound C=1C=CC=CC=1COC(=O)NC1CCNC1=O DAMJCWMGELCIMI-UHFFFAOYSA-N 0.000 claims description 7
- 230000035484 reaction time Effects 0.000 claims description 7
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 5
- 238000006114 decarboxylation reaction Methods 0.000 claims description 5
- 238000003682 fluorination reaction Methods 0.000 claims description 5
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 4
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 claims description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 4
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 4
- 239000012295 chemical reaction liquid Substances 0.000 claims description 4
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylaniline Chemical compound CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- YIXJRHPUWRPCBB-UHFFFAOYSA-N magnesium nitrate Chemical compound [Mg+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O YIXJRHPUWRPCBB-UHFFFAOYSA-N 0.000 claims description 4
- 229940078552 o-xylene Drugs 0.000 claims description 4
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 claims description 4
- YKYONYBAUNKHLG-UHFFFAOYSA-N propyl acetate Chemical compound CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 4
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 238000010979 pH adjustment Methods 0.000 claims description 3
- 229910000343 potassium bisulfate Inorganic materials 0.000 claims description 3
- 229910001414 potassium ion Inorganic materials 0.000 claims description 3
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 claims description 3
- 229910000342 sodium bisulfate Inorganic materials 0.000 claims description 3
- JTNCEQNHURODLX-UHFFFAOYSA-N 2-phenylethanimidamide Chemical compound NC(=N)CC1=CC=CC=C1 JTNCEQNHURODLX-UHFFFAOYSA-N 0.000 claims description 2
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 2
- 229940011051 isopropyl acetate Drugs 0.000 claims description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 2
- UEGPKNKPLBYCNK-UHFFFAOYSA-L magnesium acetate Chemical compound [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 claims description 2
- 239000011654 magnesium acetate Substances 0.000 claims description 2
- 235000011285 magnesium acetate Nutrition 0.000 claims description 2
- 229940069446 magnesium acetate Drugs 0.000 claims description 2
- OTCKOJUMXQWKQG-UHFFFAOYSA-L magnesium bromide Chemical compound [Mg+2].[Br-].[Br-] OTCKOJUMXQWKQG-UHFFFAOYSA-L 0.000 claims description 2
- 229910001623 magnesium bromide Inorganic materials 0.000 claims description 2
- BLQJIBCZHWBKSL-UHFFFAOYSA-L magnesium iodide Chemical compound [Mg+2].[I-].[I-] BLQJIBCZHWBKSL-UHFFFAOYSA-L 0.000 claims description 2
- 229910001641 magnesium iodide Inorganic materials 0.000 claims description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 claims description 2
- 235000019341 magnesium sulphate Nutrition 0.000 claims description 2
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 2
- DCKVNWZUADLDEH-UHFFFAOYSA-N sec-butyl acetate Chemical compound CCC(C)OC(C)=O DCKVNWZUADLDEH-UHFFFAOYSA-N 0.000 claims description 2
- 229910001415 sodium ion Inorganic materials 0.000 claims description 2
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 6
- 125000003158 alcohol group Chemical group 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 abstract description 16
- 238000009776 industrial production Methods 0.000 abstract description 6
- 208000012839 conversion disease Diseases 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 3
- 239000000047 product Substances 0.000 abstract description 3
- 150000003217 pyrazoles Chemical class 0.000 abstract description 2
- 235000011121 sodium hydroxide Nutrition 0.000 description 71
- 238000004128 high performance liquid chromatography Methods 0.000 description 49
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 41
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 40
- 239000007789 gas Substances 0.000 description 40
- 238000003756 stirring Methods 0.000 description 35
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 24
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 24
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 20
- 229910052757 nitrogen Inorganic materials 0.000 description 20
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 18
- 235000019441 ethanol Nutrition 0.000 description 17
- 238000004321 preservation Methods 0.000 description 15
- 235000011118 potassium hydroxide Nutrition 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 10
- FBCCMZVIWNDFMO-UHFFFAOYSA-N dichloroacetyl chloride Chemical compound ClC(Cl)C(Cl)=O FBCCMZVIWNDFMO-UHFFFAOYSA-N 0.000 description 9
- 230000020477 pH reduction Effects 0.000 description 8
- WWTULTKUWBKVGV-UHFFFAOYSA-M potassium;3-methoxy-3-oxopropanoate Chemical compound [K+].COC(=O)CC([O-])=O WWTULTKUWBKVGV-UHFFFAOYSA-M 0.000 description 8
- 150000002367 halogens Chemical group 0.000 description 7
- 238000012544 monitoring process Methods 0.000 description 7
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 6
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 230000000844 anti-bacterial effect Effects 0.000 description 6
- 239000003899 bactericide agent Substances 0.000 description 6
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- 239000011737 fluorine Substances 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 150000001335 aliphatic alkanes Chemical class 0.000 description 5
- 239000012025 fluorinating agent Substances 0.000 description 5
- JBUXDBAQTRJHNJ-UHFFFAOYSA-N methyl 4,4-dichloro-3-oxobutanoate Chemical compound COC(CC(=O)C(Cl)Cl)=O JBUXDBAQTRJHNJ-UHFFFAOYSA-N 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- PNQBEPDZQUOCNY-UHFFFAOYSA-N trifluoroacetyl chloride Chemical compound FC(F)(F)C(Cl)=O PNQBEPDZQUOCNY-UHFFFAOYSA-N 0.000 description 5
- RFFLAFLAYFXFSW-UHFFFAOYSA-N 1,2-dichlorobenzene Chemical compound ClC1=CC=CC=C1Cl RFFLAFLAYFXFSW-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- KDVPGBVZKTVEIS-UHFFFAOYSA-N ethyl 2-(ethoxymethylidene)-4,4-difluoro-3-oxobutanoate Chemical compound CCOC=C(C(=O)C(F)F)C(=O)OCC KDVPGBVZKTVEIS-UHFFFAOYSA-N 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- WVUCPRGADMCTBN-UHFFFAOYSA-M potassium;3-ethoxy-3-oxopropanoate Chemical compound [K+].CCOC(=O)CC([O-])=O WVUCPRGADMCTBN-UHFFFAOYSA-M 0.000 description 4
- BFKJFAAPBSQJPD-UHFFFAOYSA-N tetrafluoroethene Chemical group FC(F)=C(F)F BFKJFAAPBSQJPD-UHFFFAOYSA-N 0.000 description 4
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 4
- XTDZGXBTXBEZDN-UHFFFAOYSA-N 3-(difluoromethyl)-N-(9-isopropyl-1,2,3,4-tetrahydro-1,4-methanonaphthalen-5-yl)-1-methylpyrazole-4-carboxamide Chemical compound CC(C)C1C2CCC1C1=C2C=CC=C1NC(=O)C1=CN(C)N=C1C(F)F XTDZGXBTXBEZDN-UHFFFAOYSA-N 0.000 description 3
- 239000005738 Bixafen Substances 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- 239000005799 Isopyrazam Substances 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
- LDLMOOXUCMHBMZ-UHFFFAOYSA-N bixafen Chemical compound FC(F)C1=NN(C)C=C1C(=O)NC1=CC=C(F)C=C1C1=CC=C(Cl)C(Cl)=C1 LDLMOOXUCMHBMZ-UHFFFAOYSA-N 0.000 description 3
- 125000004122 cyclic group Chemical group 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000011031 large-scale manufacturing process Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000011736 potassium bicarbonate Substances 0.000 description 3
- 235000015497 potassium bicarbonate Nutrition 0.000 description 3
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 235000011181 potassium carbonates Nutrition 0.000 description 3
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 3
- 238000007127 saponification reaction Methods 0.000 description 3
- ZKKBIZXAEDFPNL-HWKANZROSA-N (e)-3-(dimethylamino)prop-2-enenitrile Chemical compound CN(C)\C=C\C#N ZKKBIZXAEDFPNL-HWKANZROSA-N 0.000 description 2
- ZPQOPVIELGIULI-UHFFFAOYSA-N 1,3-dichlorobenzene Chemical compound ClC1=CC=CC(Cl)=C1 ZPQOPVIELGIULI-UHFFFAOYSA-N 0.000 description 2
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 2
- IBSQPLPBRSHTTG-UHFFFAOYSA-N 1-chloro-2-methylbenzene Chemical compound CC1=CC=CC=C1Cl IBSQPLPBRSHTTG-UHFFFAOYSA-N 0.000 description 2
- OSOUNOBYRMOXQQ-UHFFFAOYSA-N 1-chloro-3-methylbenzene Chemical compound CC1=CC=CC(Cl)=C1 OSOUNOBYRMOXQQ-UHFFFAOYSA-N 0.000 description 2
- PFFIDZXUXFLSSR-UHFFFAOYSA-N 1-methyl-N-[2-(4-methylpentan-2-yl)-3-thienyl]-3-(trifluoromethyl)pyrazole-4-carboxamide Chemical compound S1C=CC(NC(=O)C=2C(=NN(C)C=2)C(F)(F)F)=C1C(C)CC(C)C PFFIDZXUXFLSSR-UHFFFAOYSA-N 0.000 description 2
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 2
- NPDACUSDTOMAMK-UHFFFAOYSA-N 4-Chlorotoluene Chemical compound CC1=CC=C(Cl)C=C1 NPDACUSDTOMAMK-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- CKVLFNBLOAUSQQ-UHFFFAOYSA-N CNN.CO Chemical compound CNN.CO CKVLFNBLOAUSQQ-UHFFFAOYSA-N 0.000 description 2
- OKIZRZSUAYSCKQ-UHFFFAOYSA-N COC=C(C(=O)OC)C(C(F)F)=O Chemical compound COC=C(C(=O)OC)C(C(F)F)=O OKIZRZSUAYSCKQ-UHFFFAOYSA-N 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 239000005788 Fluxapyroxad Substances 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- 239000005816 Penthiopyrad Substances 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 239000003849 aromatic solvent Substances 0.000 description 2
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 2
- HCDITHVDEPPNIL-UHFFFAOYSA-L dipotassium;propanedioate Chemical compound [K+].[K+].[O-]C(=O)CC([O-])=O HCDITHVDEPPNIL-UHFFFAOYSA-L 0.000 description 2
- SIJOCEACGCHNSI-UHFFFAOYSA-N ethyl 4,4-dichloro-3-oxobutanoate Chemical compound ClC(C(CC(=O)OCC)=O)Cl SIJOCEACGCHNSI-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- SXSGXWCSHSVPGB-UHFFFAOYSA-N fluxapyroxad Chemical compound FC(F)C1=NN(C)C=C1C(=O)NC1=CC=CC=C1C1=CC(F)=C(F)C(F)=C1 SXSGXWCSHSVPGB-UHFFFAOYSA-N 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- JDEAYEGEXSZZFO-UHFFFAOYSA-N methyl 4,4,4-trichloro-3-oxobutanoate Chemical compound COC(=O)CC(=O)C(Cl)(Cl)Cl JDEAYEGEXSZZFO-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 235000017550 sodium carbonate Nutrition 0.000 description 2
- VIANBEAUACIOKY-UHFFFAOYSA-M sodium;3-ethoxy-3-oxopropanoate Chemical compound [Na+].CCOC(=O)CC([O-])=O VIANBEAUACIOKY-UHFFFAOYSA-M 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 230000017105 transposition Effects 0.000 description 2
- PVFOMCVHYWHZJE-UHFFFAOYSA-N trichloroacetyl chloride Chemical compound ClC(=O)C(Cl)(Cl)Cl PVFOMCVHYWHZJE-UHFFFAOYSA-N 0.000 description 2
- XHILZHAQBOLGFD-UHFFFAOYSA-N 1,1-difluoropropan-2-one Chemical compound CC(=O)C(F)F XHILZHAQBOLGFD-UHFFFAOYSA-N 0.000 description 1
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 description 1
- PZHIWRCQKBBTOW-UHFFFAOYSA-N 1-ethoxybutane Chemical compound CCCCOCC PZHIWRCQKBBTOW-UHFFFAOYSA-N 0.000 description 1
- AOPDRZXCEAKHHW-UHFFFAOYSA-N 1-pentoxypentane Chemical compound CCCCCOCCCCC AOPDRZXCEAKHHW-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 238000003512 Claisen condensation reaction Methods 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- KKUKTXOBAWVSHC-UHFFFAOYSA-N Dimethylphosphate Chemical compound COP(O)(=O)OC KKUKTXOBAWVSHC-UHFFFAOYSA-N 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000003905 agrochemical Substances 0.000 description 1
- 239000005456 alcohol based solvent Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- QQQCWVDPMPFUGF-ZDUSSCGKSA-N alpinetin Chemical compound C1([C@H]2OC=3C=C(O)C=C(C=3C(=O)C2)OC)=CC=CC=C1 QQQCWVDPMPFUGF-ZDUSSCGKSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 125000006371 dihalo methyl group Chemical group 0.000 description 1
- BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- IKGLACJFEHSFNN-UHFFFAOYSA-N hydron;triethylazanium;trifluoride Chemical compound F.F.F.CCN(CC)CC IKGLACJFEHSFNN-UHFFFAOYSA-N 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 150000002561 ketenes Chemical class 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- PRWXGRGLHYDWPS-UHFFFAOYSA-L sodium malonate Chemical compound [Na+].[Na+].[O-]C(=O)CC([O-])=O PRWXGRGLHYDWPS-UHFFFAOYSA-L 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a preparation method of polyfluoromethyl pyrazole compounds, an intermediate and a preparation method. The invention provides a preparation method of a compound 1, which comprises the following steps: in an organic solvent, carrying out cyclization reaction on the compound 2 and methyl hydrazine to obtain a compound 1; wherein R is1is C1～C4alkyl groups of (a); r2Is methyl or ethyl; x is 2 or 3. The preparation method has the advantages of cheap and easily-obtained raw materials, mild reaction conditions, safe operation, environmental protection, low production cost, high reaction conversion rate, low content of by-product isomers, high reaction yield and high purity of the prepared product, and is suitable for industrial production.
Description
Technical Field
the invention particularly relates to a preparation method, an intermediate and a preparation method of polyfluoromethyl pyrazole compounds.
Background
3-difluoromethyl-1H-methylpyrazole-4-carboxylic acid is an important intermediate of agricultural chemicals, is used for synthesizing fluxapyroxad, one of the main active ingredients of a novel bactericide Priaxor of Bassfer, and can be used for producing a bactericide Bixafen (Bixafen) of Bayer and a bactericide Isopyrazam (Isopyrazam) of Pradar. 3-trifluoromethyl-1H-methylpyrazole-4-carboxylic acid is also an important pesticide intermediate, and is used for producing a bactericide Penthiopyrad (Penthiopyrad) developed by Mitsui corporation.
currently, the following methods for synthesizing 3-difluoromethyl-1H-methylpyrazole-4-carboxylic acid are mainly available:
Firstly, taking polyfluoroacetic acid ethyl ester as a raw material, and obtaining 3-difluoromethyl-1H-methylpyrazole-4-carboxylic acid through claisen condensation, ethoxyl-alkylation, cyclization, saponification and acidification (WO2011113789, EP1997808, US5093347 and WO 2010009990); or 3-trifluoromethyl-1H-methylpyrazole-4-carboxylic acid (CN103694119, US8115012, JP2010202648, JP2000212166, CN 101977889).
Secondly, difluoroacetone is used as a raw material, and after condensation by using methylhydrazine, 3-difluoromethyl-1H-methylpyrazole-4-carboxylic acid is obtained by phosphorus oxychloride cyclization and hydrogen peroxide oxidation (EP 2008996);
Adding tetrafluoroethylene serving as a raw material with dimethylamine, condensing with 3-ethoxy ethyl acrylate, and then cyclizing with methylhydrazine to obtain 3-difluoromethyl-1H-methylpyrazole-4-carboxylic acid (J.fluorinene chem.,2001, 109 (1): 25-31; CN 101720317);
fourthly, coupling trifluoroacetyl chloride serving as a raw material with 3-dimethylamino acrylonitrile, cyclizing with methylhydrazine, and finally hydrolyzing and acidifying to obtain a target product (CN 101627015);
fifthly, after trifluoroacetic acid is used as a raw material to prepare trifluoroacetyl chloride, the trifluoroacetyl chloride is coupled with 3-dimethylamino ethyl acrylate, and then the trifluoroacetyl chloride is cyclized with methylhydrazine, and finally, saponification and acidification are carried out to obtain 3-trifluoromethyl-1H-methylpyrazole-4-carboxylic acid (CN101977889)
sixthly, dichloroacetyl chloride is used as a raw material, coupled with 3-dimethylamino ethyl acrylate, cyclized with methylhydrazine (CN1871204), fluorinated with hydrogen fluoride (CN1875006), and finally saponified and acidified to obtain 3-difluoromethyl-1H-methylpyrazole-4-carboxylic acid (CN 102731402);
Among the above six methods, the former five methods use fluorine-containing compounds as starting materials to synthesize 3-polyfluoromethyl-1H-methylpyrazole-4-carboxylic acid, and since the fluorine-containing raw materials are generally expensive, and the loss of yield in the subsequent reaction significantly increases the unit consumption of raw materials, the cost is relatively high, and the method is not suitable for industrial production.
in the first method, fluorine-containing raw materials are used as starting raw materials, so that the cost of the 3-difluoromethyl-1H-methylpyrazole-4-carboxylic acid is greatly increased. Meanwhile, the inventors further repeated the experiment of the first method (specifically, see comparative example 4), and found that the ratio of the cyclic isomer is as high as 8.3% when 3-ethoxy-2-difluoroacetoacetylacrylate is used as a raw material in the cyclic closing step.
according to the patent, when NaOH is not used, the 3-ethoxy-2-difluoroacetyl acrylic acid ethyl ester is cyclized with methyl hydrazine, the content of the isomer is 8-10% (EP1997808), when NaOH is used, the 3-ethoxy-2-difluoroacetyl acrylic acid ethyl ester is cyclized with methyl hydrazine, and the content of the isomer is still as high as about 3% at least (EP 1997808); the 3-dimethylamino-2-dichloroacetyl methyl acrylate is subjected to cyclization with methylhydrazine, so that the content of the isomer is up to 6.2 percent at the low temperature of minus 50 ℃, and the maximum content of the isomer is up to 38.3 percent at other temperatures (CN 1871204). Due to the excessively high isomer content, the overall yield is further reduced and the overall cost is increased. For this reason, just the research on isomer transposition has been carried out, and it has been shown through these studies that the use of dimethyl sulfate (CN102471279, CN103052625) or dimethyl phosphate (CN1871204) can perform well the transposition of cyclic isomers, but increases the use of additional materials, and that dimethyl sulfate is a highly toxic substance, and has severe requirements on production facilities and production sites, and further, increases additional post-treatment costs.
the total yield of the second method is only 36.6 percent, and the second method also relates to the use of the highly toxic phosphorus oxychloride, increases the danger of production operation of workers, and has severe corrosion to equipment, so that the requirements on operating sites and reaction equipment of the workers are severe.
the total yield of the method III is about 48 percent, and simultaneously, the toxicity of the raw material tetrafluoroethylene is high. When the catalyst is used as gas to participate in reaction, the loss in the reaction process is large. Furthermore, tetrafluoroethylene when mixed with air forms explosive mixtures, which undoubtedly increases the production risk. More importantly, the easy polymerization characteristic of tetrafluoroethylene further increases the unit consumption of raw materials and the cost of post-reaction treatment. Due to the factors, the large-scale industrial production application of the method is limited.
in addition to the use of fluorine-containing starting material trifluoroacetyl chloride, the method increases the cost and the unit consumption, and 3-dimethylamino acrylonitrile is difficult to obtain from the market, so the method has higher cost.
the total yield of the method five is 55.7 percent, meanwhile, the raw material relates to the use of fluorine-containing compound trifluoroacetyl chloride, and in addition, the other starting material 3-dimethylamino ethyl acrylate is expensive and difficult to purchase, so the application of the method in large-scale production is limited.
Method six, according to patent CN102731402, for preparing 3-difluoromethyl-1H-methylpyrazole-4-carboxylic acid and for preparing 3-trifluoromethyl-1H-methylpyrazole-4-carboxylic acid, chlorine-containing raw materials are used as starting materials, and meanwhile, the fluorination step is carried out after ring closure, but the use of 3-dimethylamino ethyl acrylate, which is expensive and difficult to purchase, seriously affects the cost of the final product, and also definitely limits the application of the method in large-scale production. Meanwhile, according to the disclosure of patent CN1871204, using 2-dichloroacetyl-3-dimethylamino acrylate as an intermediate, when the cyclization reaction is carried out at 0 ℃, the content of 5-dichloromethyl-1H-methylpyrazole carboxylate as an isomer is up to 18.6%, when the reaction temperature is 40 ℃ as the temperature of the cyclization reaction is increased, the content of 5-dichloromethyl-1H-methylpyrazole carboxylate as an isomer is even up to 38.3%, when the temperature of the cyclization reaction is as low as-20 ℃, the content of 5-dichloromethyl-1H-methylpyrazole carboxylate as an isomer is still up to 12.7%, and when the temperature of the cyclization reaction is as low as-50 ℃, the content of the isomer can be controlled to only 6.2%. Moreover, the inventor verifies the result of the step-cycling reaction by using a substrate 2-dichloroacetyl-3-dimethylamino acrylate, and the result is consistent with the patent CN1871204, and the content of the isomer is 12.7-17.5%. Higher isomer content and too low reaction temperature will greatly increase the cost and energy consumption of production, making the process unsuitable for large-scale production.
In the reported routes to date, the production cost of 3-difluoromethyl-1H-methylpyrazole-4-carboxylic acid is relatively high, which is not suitable for industrial production. Due to the continuous increase of the demands of three bactericides of fluxapyroxad, bixafen and isopyrazam, the cost demand of 3-difluoromethyl-1H-methylpyrazole-4-carboxylic acid, which is a key intermediate for producing the three bactericides, is higher and higher, and the development of a process of 3-difluoromethyl-1H-methylpyrazole-4-carboxylic acid, which has the advantages of low cost, mild reaction conditions, high conversion rate, few byproducts, safe operation and environmental friendliness and is suitable for industrial production, is urgently required.
disclosure of Invention
The invention aims to solve the technical problem of overcoming the defects of high production cost, harsh reaction conditions, low reaction conversion rate, a plurality of byproducts, low reaction yield, use of highly toxic raw materials, low operation safety, serious environmental pollution and the like of a preparation method of 3-difluoromethyl-1H-methylpyrazole-4-carboxylic acid in the prior art, and provides a preparation method of a 3-polyfluoromethylpyrazole compound and an intermediate thereof. The preparation method has the advantages of cheap and easily-obtained raw materials, mild reaction conditions, safe operation, environmental protection, low production cost, high reaction conversion rate, low content of by-product isomers, high reaction yield and high purity of the prepared product, and is suitable for industrial production.
the invention provides a preparation method of a compound 1, which comprises the following steps: in an organic solvent, carrying out cyclization reaction on the compound 2 and methyl hydrazine to obtain a compound 1;
wherein R is1is C1～C4alkyl of (a), said C1～C4Alkyl groups such as methyl, ethyl, n-propylA group (n-Pr), isopropyl (i-Pr), n-butyl (n-Bu), isobutyl (i-Bu), sec-butyl (s-Bu) or tert-butyl (t-Bu), preferably methyl or ethyl; r2Is methyl or ethyl, preferably ethyl; x is 2 or 3.
In the preparation method of the compound 1, the organic solvent may be a conventional organic solvent for the cyclization reaction in the field, preferably one or more of an ether solvent, an aromatic solvent, an alkane solvent and a halogenated aromatic solvent; further preferred is an aromatic hydrocarbon solvent. The ether solvent is preferably one or more of diethyl ether, n-propyl ether, isopropyl ether, ethyl n-butyl ether, n-butyl ether and n-pentyl ether. The aromatic hydrocarbon solvent is preferably one or more of benzene, toluene, ethylbenzene, xylene, o-xylene, m-xylene and p-xylene, and further preferably toluene and/or xylene. The halogenated aromatic hydrocarbon solvent is preferably one or more of chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, o-chlorotoluene, p-chlorotoluene and m-chlorotoluene. The alkane solvent is preferably C1～C8The alkane solvent of (a), said C1～C8such as one or more of n-hexane, n-heptane and cyclohexane.
in the method for preparing the compound 1, the mass ratio of the organic solvent to the compound 2 is preferably 1 to 100, and more preferably 2 to 10.
in the method for preparing the compound 1, the methylhydrazine can be used directly or in the form of a solution thereof, and when the methylhydrazine is used in the form of a solution thereof, the mass concentration of the methylhydrazine solution is preferably 20% to 70%, and more preferably 30% to 60%; the mass concentration refers to the mass percentage of the methylhydrazine in the total mass of the methylhydrazine solution. When the methylhydrazine is used in the form of a solution thereof, the solvent of the methylhydrazine solution may be water, methanol or ethanol, preferably water.
In the method for producing the compound 1, the molar ratio of the compound 2 to the methylhydrazine is preferably 1:1.0 to 1:2.5, and more preferably 1:1.0 to 1: 1.5.
in the preparation method of the compound 1, the temperature of the cyclization reaction can be a conventional temperature of the cyclization reaction in the field, preferably-50 ℃ to 50 ℃, and further preferably 0 ℃ to 25 ℃.
In the preparation method of the compound 1, the progress of the cyclization reaction can be monitored by a conventional monitoring method in the art (for example, TLC, HPLC or GC), and generally the time of the cyclization reaction is preferably 1 to 5 hours, and more preferably 1 to 3 hours, with the time when the compound 2 disappears being the reaction end point.
the preparation method of the compound 1 can be carried out in the presence of a base, and when the preparation method of the compound 1 is carried out in the presence of a base, the base can be an organic base or an inorganic base, preferably an inorganic base; the inorganic base is preferably one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate, and further preferably sodium hydroxide and/or potassium hydroxide. The organic base is preferably one or more of triethylamine, tri-N-butylamine, pyridine, tetramethylethylenediamine, N-methylmorpholine and 4-dimethylaminopyridine, and is further preferably triethylamine, tri-N-butylamine or pyridine. When the inorganic base is used in the form of an aqueous solution thereof, the mass concentration of the inorganic base aqueous solution is preferably 30 to 60 percent, and the mass concentration refers to the percentage of the mass of the inorganic base to the total mass of the inorganic base aqueous solution.
the molar ratio of the base to the compound 2 is preferably 0.005 to 0.3, and more preferably 0.05 to 0.25.
The preparation method of the compound 1 preferably adopts the following steps: adding a solution formed by the compound 2 and an organic solvent into a mixture formed by methylhydrazine and the organic solvent for cyclization reaction to obtain a compound 1 or adding methylhydrazine into a solution formed by the compound 2 and the organic solvent for cyclization reaction to obtain the compound 1. Further preferably, a solution of compound 2 and an organic solvent is added to a mixture of methylhydrazine and an organic solvent to carry out a cyclization reaction to give compound 1. The addition mode is preferably dropwise, and the dropwise adding speed is based on the condition that the system temperature does not exceed 25 ℃.
The preparation method of the compound 1 preferably comprises the following post-treatment steps: after the reaction was completed, the mixture was separated, and the solvent was removed from the organic phase to obtain compound 1. The removal of the solvent can be carried out by methods conventional in the art for such procedures, for example, concentration under reduced pressure. The liquid separation can adopt the conventional method of the operation in the field, and the liquid separation can be direct liquid separation after water is added or extraction liquid separation; the solvent used for the extraction is preferably toluene and/or xylene.
In the invention, the preparation method of the compound 1 further comprises the following steps: carrying out condensation reaction on a compound 3, a compound 4 and acetic anhydride to obtain a compound 2;
Wherein R is1、R2and x are as defined above.
in the method for producing the compound 2, the compound 3 is more preferably any one of the following compounds:
In the preparation method of the compound 2, the compound 4 is trimethyl orthoformate or triethyl orthoformate, and preferably triethyl orthoformate.
in the method for preparing the compound 2, the molar ratio of the compound 3 to the compound 4 is preferably 1.0 to 5.0, and more preferably 1.0 to 3.5.
In the method for preparing the compound 2, the molar ratio of the acetic anhydride to the compound 4 is preferably 1.0 to 5.0, and more preferably 2.0 to 3.5.
In the preparation method of the compound 2, the temperature of the condensation reaction may be a temperature conventional in the field, preferably 95 to 115 ℃, and more preferably 100 to 110 ℃.
In the method for preparing the compound 2, the progress of the condensation reaction can be monitored by a monitoring method (e.g., TLC, HPLC, or GC) which is conventional in the art, and generally, the time of the condensation reaction is preferably 1 to 24 hours, and more preferably 1 to 5 hours, with the time when the compound 3 disappears being the reaction end point.
In the method for producing the compound 2, it is preferable to promote the reaction by distilling off acetic ester, which is a by-product produced during the reaction.
The preparation method of the compound 2 can be carried out in a solvent or under the condition of no solvent, and preferably is carried out under the condition of no solvent.
The preparation method of the compound 2 preferably comprises the following post-treatment steps: and after the reaction is finished, cooling to 10-35 ℃, keeping the vacuum degree of the system at 10-20 mbar, and slowly heating the temperature in the system from 10-35 ℃ to 100 ℃ to remove unreacted raw materials and byproducts, thereby obtaining the compound 2.
In the present invention, said compound 3 can be prepared according to the documents org.process res.dev.,2010,14(1): 152; or Synthesis,1993, (3):290. obtained by the method reported in (1) or according to the following method:
in the invention, the preparation method of the compound 1 further comprises the following steps: in an organic solvent, in the presence of an inorganic magnesium salt and an organic base, carrying out a condensation reaction on a compound 5 and a compound 6, then adjusting the pH value to 3-8, and carrying out a decarboxylation reaction to obtain a compound 3;
wherein R is1and x are as defined above; m+Represents potassium ion (K)+) Or sodium ion (Na)+) Preferably potassium ion (K)+)。
in the preparation method of the compound 3, the organic solvent can be a conventional organic solvent for condensation reaction in the field, preferably a nitrile solvent and/or an ester solvent. The nitrile solvent is preferably acetonitrile. The ester solvent is preferably one or more of ethyl acetate, methyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, sec-butyl acetate and tert-butyl acetate, and further preferably ethyl acetate.
In the method for preparing the compound 3, the mass ratio of the organic solvent to the compound 6 is preferably 1 to 100, and more preferably 5 to 15.
In the method for preparing the compound 3, the molar ratio of the compound 5 to the compound 6 is preferably 1.0 to 2.0, and more preferably 1.0 to 1.5.
In the preparation method of the compound 3, the inorganic magnesium salt is an inorganic salt formed by metal magnesium and acid, preferably one or more of magnesium chloride, magnesium acetate, magnesium nitrate, magnesium sulfate, magnesium bromide and magnesium iodide, and more preferably magnesium chloride.
In the preparation method of the compound 3, the organic base is preferably one or more of triethylamine, tri-N-propylamine, tri-N-butylamine, diisopropylethylamine, N-dimethylaniline and N, N-diethylaniline, and is more preferably triethylamine.
In the method for preparing the compound 3, the molar ratio of the organic base to the compound 6 is preferably 1.0 to 5.0, and more preferably 1.0 to 2.5.
in the method for preparing the compound 3, the molar ratio of the organic base to the compound 5 is preferably 1.0 to 5.0, and more preferably 1.5 to 2.5.
In the method for producing the compound 3, the molar ratio of the inorganic magnesium salt to the compound 6 is preferably 1.0 to 5.0, and more preferably 1.0 to 2.5.
in the preparation method of the compound 3, the temperature of the condensation reaction can be the conventional temperature of the condensation reaction in the field, and is preferably 0-35 ℃.
in the method for preparing the compound 3, the progress of the condensation reaction can be monitored by a monitoring method (e.g., TLC, HPLC, or GC) which is conventional in the art, and generally, the time of the condensation reaction is preferably 1 hour to 48 hours, and more preferably 15 hours to 25 hours, when the compound 6 disappears as a reaction end point.
In the preparation method of the compound 3, the pH adjustment to 3-8 is preferably realized by adding an acidic substance, and the acidic substance is preferably one or more of hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, sodium bisulfate and potassium bisulfate, and is further preferably hydrochloric acid. The acidic substance may be used in the form of a solution thereof, and when the acidic substance is used in the form of a solution thereof, the mass concentration of the acidic substance solution is preferably 1% to 20%, more preferably 3% to 10%, and the mass concentration refers to the percentage of the mass of the acidic substance to the total mass of the acidic substance solution. The mass concentration of the dilute acid solution is preferably 3-10%, and the mass concentration refers to the mass percentage of acid in the total mass of the dilute acid solution. The acid in the dilute acid is preferably hydrochloric acid.
In the method for producing compound 3, the temperature of the deacidification reaction is preferably 0 to 15 ℃.
In the preparation method of the compound 3, the progress of the deacidification reaction can be monitored by a conventional monitoring method in the field (such as TLC, HPLC or GC), the reaction end point is generally the GC content of the compound 3 of more than 80%, and the decarboxylation reaction time is preferably 0.5 to 10 hours, and more preferably 0.5 to 2 hours.
The preparation method of the compound 3 preferably comprises the following steps: adding inorganic magnesium salt into a mixture formed by a compound 5, organic base and an organic solvent, reacting for 2-3 hours, cooling, adding a compound 6, performing condensation reaction, adjusting the pH value to 3-8, and performing decarboxylation reaction to obtain a compound 3. The temperature of the "mixture of the compound 5, the organic base and the organic solvent" is preferably 0 to 25 ℃, and more preferably 10 to 25 ℃. The reaction temperature of the "reaction for 2 to 3 hours" is preferably 10 to 35 ℃ and more preferably 20 to 25 ℃. The temperature of the temperature reduction is preferably 0 ℃ to 35 ℃, more preferably 0 ℃ to 25 ℃, and still more preferably 0 ℃ to 10 ℃. The adding mode is preferably dropwise adding, and the dropwise adding speed is based on that the system temperature is not more than 35 ℃, preferably not more than 25 ℃, and further preferably not more than 10 ℃.
the method for producing compound 3 preferably includes a post-treatment step of separating the reaction mixture after the completion of the reaction, washing the organic phase with a dilute acid solution, and removing the solvent to obtain compound 3. The mass concentration of the dilute acid solution is 3-10%, and the mass concentration refers to the mass percentage of acid in the total mass of the dilute acid solution. The acid in the dilute acid is preferably hydrochloric acid.
In the invention, the preparation method of the compound 1 further comprises the following steps: reacting a compound 7 with MOH in an organic solvent to obtain a compound 5;
wherein R is1And M+The definitions of (A) and (B) are as described above.
in the preparation method of the compound 5, the organic solvent can be a conventional organic solvent in the reaction in the field, and preferably an alcohol solvent. The alcohol solvent is preferably C1～C4The alcohol solvent of (1), the alcohol solvent of (C)1～C4the alcohol solvent (b) is preferably one or more selected from methanol, ethanol, n-propanol, isopropanol, n-butanol and tert-butanol, and more preferably methanol and/or ethanol.
in the method for preparing the compound 5, the mass ratio of the organic solvent to the compound 7 is preferably 1 to 100, and more preferably 2 to 10.
In the preparation method of the compound 5, the MOH is potassium hydroxide and/or sodium hydroxide, and potassium hydroxide is preferred.
In the method for preparing the compound 5, the molar ratio of the MOH to the compound 7 is preferably 0.5 to 1.5, and more preferably 0.9 to 1.2.
in the preparation method of the compound 5, the temperature of the reaction can be a temperature conventional in the art for such a reaction, and preferably 10 to 35 ℃.
In the method for preparing the compound 5, the progress of the reaction can be monitored by a conventional monitoring method in the art (e.g., TLC, HPLC, or GC), and the reaction time is preferably 1 to 10 hours, more preferably 3 to 5 hours, with the end point being generally the time when the compound 7 disappears.
The preparation method of the compound 5 preferably comprises the following steps: and adding a mixture formed by MOH and an organic solvent into a solution formed by the compound 7 and the organic solvent, and reacting to obtain the compound 5. The addition mode is preferably dropwise, and the dropwise adding speed is based on the condition that the system temperature does not exceed 35 ℃. In the mixture formed by the MOH and the organic solvent, the mass ratio of the organic solvent to the MOH is preferably 5-15, and more preferably 8-13. In the solution formed by the compound 7 and the organic solvent, the mass ratio of the organic solvent to the compound 7 is preferably 2.5-4.5, and more preferably 2.8-4.2.
The preparation method of the compound 5 preferably comprises the following post-treatment steps: after the reaction, the reaction solution is heated to reflux (the reflux temperature is 79 to 80 ℃ in the case of ethanol as a solvent and 65 to 68 ℃ in the case of methanol as a solvent), and the compound 5 is obtained by heat-filtering, cooling the filtrate to-5 to 0 ℃ and filtering. The filtrate after filtration to obtain the compound 5 is preferably subjected to removal of a part of the solvent (70% to 80% of the amount of the solvent used in the reaction process) to obtain a part of the compound 5.
The present invention also provides a process for the preparation of compound 9, comprising the steps of: in a closed system, in the presence of a catalyst, carrying out halogen exchange reaction on the compound 1 and a fluorinating reagent to obtain a compound 9; the catalyst is one or more of alkali, lactam and antimony trichloride;
Wherein R is1And x are as defined above.
The preparation method of the compound 9 can be a conventional method and conditions of halogen exchange reaction in the field, and the following reaction conditions are particularly preferred in the invention:
in the preparation method of the compound 9, the base is preferably an organic base, and the organic base is preferably one or more of triethylamine, tri-N-propylamine, tri-N-butylamine, N-dimethylaniline, pyridine, 2-methylpyridine and 4-methylpyridine, and is further preferably triethylamine and/or pyridine. The base may also be used in the form of its hydrofluoride, for example the hydrogen fluoride salt of triethylamine or pyridine. The base may be used in place of the same molar amount of the fluorinating agent when used in the form of its hydrofluoride.
In the method for preparing the compound 9, the lactam refers to a compound in which a lactam group exists in a molecule, preferably one or more of 1, 3-dimethyl-2-imidazolidinone, N-methylpyrrolidone, 2-pyrrolidone and formylhydantoin, and more preferably 1, 3-dimethyl-2-imidazolidinone and/or N-methylpyrrolidone. The lactams can also be used in the form of their hydrofluorides, for example hexadecahydrofluoride salt of 1, 3-dimethyl-2-imidazolidinone and/or pentahydrofluoride salt of N-methylpyrrolidone. The lactam can be substituted for the same molar amount of the fluorinating agent when it is used in the form of its hydrofluoride.
In the preparation method of the compound 9, the molar ratio of the catalyst to the compound 1 is preferably 0.005-5.0. When the catalyst is in the form of a base hydrofluoride, the molar ratio of the catalyst to the compound 1 is preferably 1.0-3.0. When the catalyst is in the form of a base instead of the base hydrofluoride, the molar ratio of the catalyst to the compound 1 is preferably 0.1-0.5. When the catalyst is lactam, the molar ratio of the catalyst to the compound 1 is preferably 0.05 to 0.5, and more preferably 0.05 to 0.2. When the catalyst is antimony trichloride, the molar ratio of the catalyst to the compound 1 is preferably 0.005-0.05, and more preferably 0.01-0.02. When the catalyst is lactam hydrofluoride, the mole ratio of the catalyst to the compound 1 is preferably 0.01-1, and more preferably 0.2-0.8.
in the method for producing the compound 9, the fluorinating agent is preferably one or more of Hydrogen Fluoride (HF), a hydrofluoride salt of an organic base, a hydrofluoride salt of a lactam, potassium fluoride (KF) and cesium fluoride, and more preferably one or more of Hydrogen Fluoride (HF), a hexadecahydrofluoride salt of 1, 3-dimethyl-2-imidazolidinone, a pentahydrofluoride salt of N-methylpyrrolidone, a hydrogen fluoride salt of triethylamine and a hydrogen fluoride salt of pyridine. The hydrogen fluoride is in gaseous form. The hydrofluoride salt of a lactam, for example the hexadecahydrofluoride salt of 1, 3-dimethyl-2-imidazolidinone and/or the pentafluoroacid salt of N-methylpyrrolidone. The hydrofluoride salt of the base is preferably the hydrogen fluoride salt of triethylamine and/or the hydrogen fluoride salt of pyridine.
said compound 9 preparation method when the fluorinating agent is the hydrofluoride salt of organic base or the hydrofluoride salt of lactam, the reaction can be carried out in the absence of catalyst.
In the method for preparing the compound 9, the molar ratio of the fluorinating agent to the compound 1 is preferably 1.0 to 5.0, and more preferably 1.0 to 4.0. When the hydrofluoric acid salt of an organic base and/or the hydrofluoric acid salt of a lactam are used as the fluorination agent, the molar ratio of HF contained in the hydrofluoric acid salt of an organic base and/or the hydrofluoric acid salt of a lactam to the compound 1 is preferably 1.0 to 5.0, and more preferably 1.0 to 4.0.
In the preparation method of the compound 9, the compound 1 can be prepared according to the aforementioned method.
In the preparation method of the compound 9, the temperature of the halogen exchange reaction may be a temperature conventional in such nucleophilic substitution reaction in the art, preferably 80 ℃ to 180 ℃, further preferably 100 ℃ to 160 ℃, and further preferably 130 ℃ to 155 ℃.
in the preparation method of the compound 9, the progress of the halogen exchange reaction can be monitored by a conventional monitoring method in the art (such as TLC, HPLC or GC), and generally the time of the halogen exchange reaction is preferably 1 hour to 24 hours, and more preferably 5 hours to 15 hours, with the GC content of the compound 9 being greater than 85% as a reaction endpoint.
The process for producing the compound 9 may be carried out in a solvent or without a solvent, and preferably without a solvent. When carried out in a solvent, the solvent is preferably one or more of an ether solvent, an ester solvent, an aromatic hydrocarbon solvent and a nitrile solvent. The ether solvent is preferably one or more of diethyl ether, tetrahydrofuran, diisopropyl ether and methyl tert-butyl ether. The ester solvent is preferably one or more of methyl acetate, ethyl acetate and butyl acetate. The aromatic hydrocarbon solvent is preferably one or more of toluene, ethylbenzene, xylene, o-xylene, m-xylene and p-xylene. The nitrile solvents are preferably acetonitrile and/or propionitrile.
The preparation method of the compound 9 preferably adopts the following steps: adding a fluorinating reagent into a mixture formed by alkali and the compound 1, and carrying out halogen exchange reaction to obtain a compound 9. The addition is preferably carried out dropwise, the dropping speed is preferably such that the temperature of the system is maintained between 130 ℃ and 155 ℃, and the temperature of the mixture of the base and the compound 1 is preferably 125 ℃ to 130 ℃.
The preparation method of the compound 9 preferably adopts the following post-treatment steps: after the reaction is finished, the gas is discharged and the pressure is released, the nitrogen is used for purging, and the reaction liquid is directly used for the reaction for preparing the compound 10 without further treatment. The reaction solution may be neutralized with a base before the reaction for producing compound 10. The alkali is preferably inorganic alkali, the inorganic alkali is preferably one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate, and further preferably sodium hydroxide. The inorganic base may be used as it is or in the form of an aqueous solution thereof, preferably in the form of an aqueous solution thereof. When the inorganic base is used in the form of an aqueous solution thereof, the mass concentration of the aqueous solution of the inorganic base is preferably 20 to 60%, and the mass concentration refers to the mass percentage of the inorganic base to the total mass of the aqueous solution of the inorganic base.
The present invention also provides a process for the preparation of compound 10, comprising the steps of: in a solvent, carrying out hydrolysis reaction on the compound 9 in the presence of alkali to obtain a compound 10;
Wherein R is1and x are as defined above.
the preparation method of the compound 10 can adopt the conventional method and conditions of the hydrolysis reaction in the field, and the following reaction conditions are particularly preferred in the invention:
in the preparation method of the compound 10, the solvent is preferably an organic solvent and/or water. The organic solvent is preferably one or more of aromatic hydrocarbon solvents, halogenated aromatic hydrocarbon solvents, alcohol solvents, alkane solvents and ether solvents. The aromatic hydrocarbon solvent is preferably one or more of benzene, toluene, ethylbenzene, xylene, o-xylene, m-xylene and p-xylene, and further preferably toluene and/or xylene. The halogenated aromatic hydrocarbon solvent is preferably one or more of chlorobenzene, o-dichlorobenzene, m-dichlorobenzene, p-dichlorobenzene, o-chlorotoluene, p-chlorotoluene and m-chlorotoluene. The alcohol solvent is one or more of methanol, ethanol, isopropanol and n-butanol. The alkane solvent is preferably one or more of n-hexane, n-heptane and petroleum ether. The ether solvent is preferably methyl tert-butyl ether and/or diisopropyl ether.
in the method for preparing the compound 10, the mass ratio of the solvent to the compound 9 is preferably 1 to 100.
in the preparation method of the compound 10, the base is preferably an inorganic base, and the inorganic base is preferably one or more of potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide, and further preferably sodium hydroxide and/or potassium hydroxide. The alkali can also be used in the form of its aqueous solution, when the alkali is used in the form of its aqueous solution, the mass concentration of the alkali aqueous solution is preferably 10% to 80%, more preferably 10% to 30%, and the mass concentration refers to the mass percentage of the alkali to the total mass of the alkali aqueous solution.
in the method for producing the compound 10, the molar ratio of the base to the compound 9 is preferably 1.0 to 5.0, and more preferably 1.0 to 3.0.
In the method for producing the compound 10, the temperature of the hydrolysis reaction is preferably 0 to 130 ℃, more preferably 20 to 80 ℃, and still more preferably 50 to 70 ℃.
In the preparation method of the compound 10, the progress of the hydrolysis reaction can be monitored by a conventional monitoring method in the art (e.g., TLC, HPLC, or GC), and generally the time when the compound 9 disappears is taken as a reaction end point, and the hydrolysis reaction time is preferably 1 hour to 10 hours, and more preferably 1 hour to 3 hours.
The preparation method of the compound 10 preferably adopts the following steps: adding an aqueous solution of a base to a mixture of the compound 9 and an organic solvent to carry out a hydrolysis reaction to obtain a compound 10. The adding mode is preferably dropwise adding, and the dropwise adding speed is based on the maintenance of the system temperature of 50-70 ℃.
the preparation method of the compound 10 preferably comprises the following post-treatment steps: after the reaction is finished, liquid separation and water phase pH adjustment are carried out to about 1.0, the temperature is reduced to 10-25 ℃, and the compound 10 is obtained after filtration and drying. The pH is preferably adjusted using an inorganic acid, and the inorganic acid is preferably one or more of hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, sodium hydrogen sulfate, and potassium hydrogen sulfate, and further preferably hydrochloric acid and sulfuric acid. The hydrochloric acid can be a conventional commercially available hydrochloric acid reagent, the mass concentration of the hydrochloric acid reagent is preferably 25-40%, and the mass concentration refers to the mass percentage of hydrogen chloride in the total mass of the hydrochloric acid reagent.
The invention also provides a preparation method of the compound 9, which comprises the following steps: in a closed system, in the presence of a catalyst, carrying out halogen exchange reaction on the compound 1 and a fluorination reagent to obtain a compound 9; the catalyst is one or more of alkali, lactam and antimony trichloride;
wherein R is1And x are as defined above. The reaction conditions were the same as described above.
The present invention also provides compound 2, the structure of which is shown below:
Wherein R is1、R2and x are as defined above.
the above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
In the invention, the room temperature refers to the environment temperature of 10-35 ℃.
the positive progress effects of the invention are as follows:
1. according to the preparation method, the cyclization step is carried out under mild reaction conditions, 3-alkoxy-2-dichloroacetyl acrylate and methyl hydrazine are used for cyclization, and the isomer ratio can be controlled to be below 6% and can be as low as below 1% at least.
2. According to the Bayer patent (CN1871204) it is reported that dihalomethylalkoxyacrylates need to be prepared from dihaloacetoacetates, which are not industrially available and require complicated techniques (using ketenes), so the patent states that dihalomethylalkoxyacrylates cannot be prepared in an economical manner. The preparation method of the present invention, however, easily obtains potassium salt of malonic acid monoester by selective saponification from inexpensive raw material malonic acid ester, and further, successfully performs low-cost preparation of dihalo acetoacetate ester using organic base and dichloroacetyl chloride in the presence of magnesium chloride, and can economically prepare dihalo methyl alkoxy acrylate, and further synthesize 3-difluoromethyl-1H-methylpyrazole-4-carboxylic acid at low cost, solving the problem mentioned in patent CN 1871204.
3. the preparation method has novel route, avoids the use of fluorine-containing raw materials, uses malonate and dichloroacetyl chloride (or trichloroacetyl chloride) as starting raw materials, obtains the 3-difluoromethyl-1H-methylpyrazole-4-carboxylic acid (or the 3-trifluoromethyl-1H-methylpyrazole-4-carboxylic acid) by six-step synthesis reaction at low cost, and greatly reduces the production cost compared with the currently reported process.
Detailed Description
the invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1
100g diethyl malonate (0.625mol) and 315.0g absolute ethyl alcohol are added into a reaction bottle, after complete mixing and dissolution, an ethanol solution of potassium hydroxide (35.0 g (0.624mol) of potassium hydroxide and 315.0g of ethanol) is slowly dripped at 10-35 ℃, and white solid is gradually precipitated in the dripping process. After the dropwise addition, the reaction solution is continuously stirred at 10-35 ℃ for about 3.5 hours. And (3) heating to 79-80 ℃ to reflux the system, and filtering while the system is hot to remove the dipotassium malonate. And cooling the obtained filtrate to 0 ℃, and filtering to obtain the potassium monoethyl malonate.
After the filtrate was concentrated and about 500g of ethanol was further distilled off, the resulting concentrated solution was cooled to 0 ℃ and filtered, and the obtained two portions of potassium monoethyl malonate were combined and dried under vacuum to finally obtain 92.06g of potassium monoethyl malonate (HPLC purity: 98.8%, yield: 85.50%).
Example 2
100g of dimethyl malonate (0.757mol) and 350.0g of anhydrous methanol are added into a reaction bottle, after complete mixing and dissolution, a methanol solution of potassium hydroxide (42.3 g of potassium hydroxide (0.754mol) and 350.0g of methanol) is slowly dripped at the temperature of 10-35 ℃, and white solids are gradually separated out in the dripping process. After the dropwise addition, the reaction solution is continuously stirred at 10-35 ℃ for about 3.5 hours. And (3) heating to 65-68 ℃ to reflux the system, and filtering while the system is hot to remove the dipotassium malonate. And cooling the obtained filtrate to 0 ℃, and filtering to obtain the potassium monomethyl malonate.
after the filtrate was concentrated and about 550g of methanol was further distilled off, the resulting concentrated solution was cooled to 0 ℃ and filtered, and the obtained two portions of potassium monomethyl malonate were combined and dried under vacuum to finally obtain 98.78g of potassium monomethyl malonate (HPLC purity: 99.1%, yield: 82.80%).
Example 3
100g diethyl malonate (0.625mol) and 315.0g absolute ethyl alcohol are added into a reaction bottle, after complete mixing and dissolution, an ethanol solution of sodium hydroxide (25.0 g (0.624mol) of sodium hydroxide and 315.0g of ethanol) is slowly dripped at the temperature of 10-35 ℃, and white solid is gradually and slowly separated out in the dripping process. After the dropwise addition, the reaction solution is continuously stirred at 10-35 ℃ for about 3.5 hours. And (3) heating to 79-80 ℃ to reflux the system, and filtering while the system is hot to remove the disodium malonate. About 500g of ethanol was distilled off from the filtrate, the concentrated solution was cooled to 0 ℃ and filtered, and the obtained sodium monoethyl malonate salt was dried in vacuo to obtain 34.30g of sodium monoethyl malonate salt (HPLC purity: 98.6%, yield: 35.12%).
Example 4 (all examples for the preparation of Compound 3, yield in dichloroacetyl chloride)
100g of monomethyl malonate potassium salt (HPLC purity: 99.1%, 0.634mol) obtained in example 2 and 750g of acetonitrile were mixed in a reaction flask while keeping the internal temperature at 10 to 25 ℃, 96.23g of triethylamine (0.951mol) was added while keeping the system internal temperature at 10 to 25 ℃, and 72.40g of magnesium chloride solid (0.760mol) was slowly added. And after the feeding is finished, naturally heating, and keeping the temperature in the system at 20-25 ℃ for 2-3 hours. The temperature is reduced to 0 to 10 ℃, and 70.10g of dichloroacetyl chloride (0.476mol) is slowly dropped. After dripping, naturally heating to 20-25 ℃ and preserving the temperature for 18 hours.
after completion of the reaction, 240g of ethyl acetate was added to dilute the reaction solution. And cooling to 0-15 ℃, slowly and dropwise adding 455g of 5% hydrochloric acid aqueous solution for acidification (the mass concentration refers to the mass percentage of hydrogen chloride in the total mass of the hydrochloric acid aqueous solution). After the dropwise addition is finished, the temperature is kept at 0-15 ℃ for 30min, and liquid is separated. The organic phase obtained was washed twice with a 5% aqueous hydrochloric acid solution (200g × 2). After the solvent was removed from the organic phase, 76.95g of methyl dichloroacetoacetate (GC purity: 97.5%, yield: 85.2%) was obtained.
example 5
100g of monoethyl malonate potassium salt (HPLC purity: 98.8%, 0.581mol) obtained in example 1 and 700g of acetonitrile were mixed in a reaction flask while maintaining the internal temperature at 10 to 25 ℃, and then 96.23g of triethylamine (0.951mol) was added while maintaining the internal temperature at 10 to 25 ℃, followed by slow addition of 66.35g of magnesium chloride solid (0.696 mol). And after the feeding is finished, naturally heating, and keeping the temperature in the system at 20-25 ℃ for 2-3 hours. The temperature is reduced to 0 to 10 ℃, and 64.24g of dichloroacetyl chloride (0.436mol) is slowly dropped. After dripping, naturally heating to 20-25 ℃ and preserving the temperature for 18 hours.
After the reaction was completed, 220g of ethyl acetate was added to dilute the reaction solution. And cooling to 0-15 ℃, and slowly adding 420g of 5% hydrochloric acid aqueous solution dropwise for acidification (the mass concentration refers to the mass percentage of hydrogen chloride in the total mass of the hydrochloric acid aqueous solution). After the dropwise addition is finished, the temperature is kept at 0-15 ℃ for 30min, and liquid is separated. The obtained organic phase was washed twice with a 5% aqueous hydrochloric acid solution (180g × 2). After the solvent was removed from the organic phase, 76.12g of ethyl dichloroacetoacetate was obtained (GC purity: 97.7%, yield: 85.7%).
Example 6
after 100g of potassium monomethyl malonate (HPLC purity: 99.1%, 0.634mol) obtained in example 2 and 950g of ethyl acetate were mixed in a reaction flask while maintaining the internal temperature at 10 to 25 ℃, 96.23g of triethylamine (0.951mol) was added while maintaining the system internal temperature at 10 to 15 ℃, and 72.40g of magnesium chloride solid (0.760mol) was slowly added. And after the feeding is finished, naturally heating, and keeping the temperature in the system at 30-35 ℃ for 8-10 hours. The temperature is reduced to 0 to 10 ℃, and 70.10g of dichloroacetyl chloride (0.476mol) is slowly dropped. After dripping, naturally heating to 20-25 ℃ and preserving the temperature for 22 hours.
after the reaction is finished, cooling to 0-15 ℃, slowly adding 455g of hydrochloric acid aqueous solution with the mass concentration of 5% dropwise for acidification (the mass concentration refers to the mass percentage of hydrogen chloride in the total mass of the hydrochloric acid aqueous solution). After the dropwise addition is finished, the temperature is kept at 0-15 ℃ for 30min, and liquid is separated. The organic phase obtained was washed twice with a 5% aqueous hydrochloric acid solution (200g × 2). After the solvent was removed from the organic phase, 74.78g of methyl dichloroacetoacetate (GC purity: 97.5%, yield: 82.8%) was obtained.
Example 7
After 100g of potassium monomethyl malonate (HPLC purity: 99.1%, 0.634mol) obtained in example 2 and 750g of acetonitrile were mixed in a reaction flask while keeping the internal temperature at 10 to 25 ℃, 96.23g of triethylamine (0.951mol) was added while keeping the system internal temperature at 10 to 25 ℃, and 72.40g of magnesium chloride solid (0.760mol) was gradually added. And after the feeding is finished, naturally heating, and keeping the temperature in the system at 20-25 ℃ for 2-3 hours. The temperature is reduced to 0 to 10 ℃, and 86.55g of trichloroacetyl chloride (0.476mol) is slowly dropped. After dripping, naturally heating to 20-25 ℃ and preserving the temperature for 18 hours.
after completion of the reaction, 240g of ethyl acetate was added to dilute the reaction solution. And cooling to 0-15 ℃, slowly and dropwise adding 455g of 5% hydrochloric acid aqueous solution for acidification (the mass concentration refers to the mass percentage of hydrogen chloride in the total mass of the hydrochloric acid aqueous solution). After the dropwise addition is finished, the temperature is kept at 0-15 ℃ for 30min, and liquid is separated. The organic phase obtained was washed twice with a 5% aqueous hydrochloric acid solution (200g × 2). After the solvent was removed from the organic phase, 97.94g of methyl trichloroacetoacetate (GC purity: 97.7%, yield: 86.1%) was obtained.
Example 8
after 100g of methyl dichloroacetoacetate (GC purity: 97.5%, 0.527mol) prepared in example 4, 68.34g of trimethyl orthoformate (0.644mol) and 161.41g of acetic anhydride (1.581mol) were mixed in a reaction flask, the temperature in the system was gradually raised to 100 to 110 ℃ and the mixture was distilled while maintaining the temperature for 3 to 5 hours to remove methyl acetate formed by the reaction. After the reaction is finished, the temperature is reduced to 10-35 ℃, the vacuum degree of the system is kept at 10-20 mbar, and the temperature in the system is slowly increased from 10-35 ℃ to 100 ℃ to remove residual methyl acetate, unreacted trimethyl orthoformate and acetic anhydride, so that 118.29g of 3-methoxy-2-dichloroacetyl methyl acrylate (GC purity: 96.6%, yield: 95.5%) is obtained.
example 9
100g of ethyl dichloroacetoacetate prepared in example 5 (GC purity: 97.7%, 0.405mol), 73.35g of triethyl orthoformate (0.495mol) and 124.04g of acetic anhydride (1.215mol) were mixed in a reaction flask, and the temperature in the system was gradually raised to 100 to 110 ℃ and distilled for 3 to 5 hours while maintaining the temperature, to remove ethyl acetate formed by the reaction. After the reaction is finished, the temperature is reduced to 10-35 ℃, the vacuum degree of the system is kept at 10-20 mbar, and the temperature in the system is slowly increased from 10-35 ℃ to 100 ℃ to remove residual ethyl acetate, unreacted triethyl orthoformate and acetic anhydride, so that 102.78g of 3-ethoxy-2-dichloroacetyl ethyl acrylate (GC purity: 96.6%, yield: 96.1%) is obtained.
Example 10
After 100g of methyl trichloroacetoacetate prepared in example 7 (GC purity: 97.7%, 0.445mol), 57.73g of trimethyl orthoformate (0.544mol) and 136.29g of acetic anhydride (1.335mol) were mixed in a reaction flask, the temperature in the system was gradually raised to 100 to 110 ℃ and the mixture was distilled for 3 to 5 hours while maintaining the temperature, to remove methyl acetate formed by the reaction. After the reaction is finished, the temperature is reduced to 10-35 ℃, the vacuum degree of the system is kept at 10-20 mbar, and the temperature in the system is slowly increased from 10-35 ℃ to 100 ℃ to remove residual methyl acetate, unreacted trimethyl orthoformate and acetic anhydride, so that 114.55g of 3-methoxy-2-trichloroacet methyl acrylate (GC purity: 96.6%, yield: 95.1%) is obtained.
Example 11
after 45.00g of a 40% by mass aqueous methylhydrazine solution (0.391mol) (the mass concentration is defined as the mass percentage of methylhydrazine to the total mass of the aqueous methylhydrazine solution) and 70.00g of xylene were mixed in a reaction flask, the temperature in the system was controlled to 0 to 25 ℃, and the xylene solution of methyl 3-methoxy-2-dichloroacetyl acrylate prepared in example 8 (methyl 3-methoxy-2-dichloroacetyl acrylate: 83.54g, GC purity: 96.6%, 0.355 mol; xylene: 140.00g) was slowly added dropwise. After dripping, maintaining the temperature of the system between 0 and 25 ℃, and stirring for 1 hour under heat preservation.
After the reaction, 5.00g of water was added, followed by liquid separation and concentration of the organic phase to obtain 70.45g of methyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate (GC purity: 91.6%, yield: 81.5%, wherein GC purity of the isomer methyl 5-dichloromethyl-1H-methylpyrazole-4-carboxylate: 5.2%).
Example 12
after 30.02g of a 60% by mass aqueous solution of methylhydrazine (0.391mol) (the mass concentration is the mass percentage of methylhydrazine to the total mass of the aqueous solution of methylhydrazine) and 70.00g of toluene were mixed in a reaction flask, the temperature in the system was controlled to 0 to 25 ℃, and the toluene solution of methyl 3-methoxy-2-dichloroacetyl acrylate prepared in example 8, methyl 3-methoxy-2-dichloroacetyl acrylate: 83.54g, GC purity: 96.6 percent and 0.355 mol; toluene: 140.00 g). After dripping, maintaining the temperature of the system between 0 and 25 ℃, and stirring for 1 hour under heat preservation.
After the reaction was completed, 20.00g of water was added thereto, followed by liquid separation and concentration of the organic phase to obtain 71.36g of methyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate (GC purity: 91.1%, yield: 82.1%, wherein GC purity of the isomer methyl 5-dichloromethyl-1H-methylpyrazole-4-carboxylate: 5.3%).
example 13
After 45.00g of a 40% methylhydrazine aqueous solution (0.391mol) (the mass concentration means the mass percentage of methylhydrazine to the total mass of the methylhydrazine aqueous solution) and 70.00g of xylene were mixed in a reaction flask, the temperature in the system was controlled to 0 to 25 ℃, and a xylene solution of ethyl 3-ethoxy-2-dichloroacetyl acrylate prepared in example 9 (93.75 g of ethyl 3-ethoxy-2-dichloroacetyl acrylate, GC purity: 96.6%, 0.355 mol; xylene: 160.00g) was slowly added dropwise. After dripping, maintaining the temperature of the system between 0 and 25 ℃, and stirring for 1 hour under heat preservation.
After the reaction, 5.00g of water was added, followed by liquid separation and concentration of the organic phase to obtain 74.82g of ethyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate (GC purity: 92.8%, yield: 82.5%, wherein GC purity of ethyl 5-dichloromethyl-1H-methylpyrazole-4-carboxylate as an isomer: 4.2%).
example 14
After 45.00g of a 40% methylhydrazine aqueous solution (0.391mol) (the mass concentration means the mass percentage of methylhydrazine to the total mass of the methylhydrazine aqueous solution) and 70.00g of xylene were mixed in a reaction flask, the temperature in the system was controlled to 0 to 25 ℃, and a xylene solution of methyl 3-methoxy-2-trichloroacetylacrylate prepared in example 10 (96.09 g of methyl 3-methoxy-2-trichloroacetylacrylate, 96.6% GC purity, 0.355 mol; 160.00g of xylene) was slowly added dropwise. After dripping, maintaining the temperature of the system between 0 and 25 ℃, and stirring for 1 hour under heat preservation.
After the reaction was completed, 5.00g of water was added, followed by liquid separation and concentration of the organic phase to obtain 81.85g of methyl 3-trichloromethyl-1H-methylpyrazole-4-carboxylate (GC purity: 91.8%, yield: 82.2%, wherein GC purity of the isomer, methyl 5-trichloromethyl-1H-methylpyrazole-4-carboxylate, 5.4%).
example 15
After 90.00g of a 40% methylhydrazine aqueous solution (0.782mol) (the mass concentration means the mass percentage of methylhydrazine to the total mass of the methylhydrazine aqueous solution) and 70.00g of xylene were mixed in a reaction flask, the temperature in the system was controlled to 0 to 25 ℃, and a xylene solution of methyl 3-methoxy-2-dichloroacetyl acrylate prepared in example 8 (methyl 3-methoxy-2-dichloroacetyl acrylate: 83.54g, GC purity: 96.6%, 0.355 mol; xylene: 140.00g) was slowly added dropwise. After dripping, maintaining the temperature of the system between 0 and 25 ℃, and stirring for 1 hour under heat preservation.
after the reaction was completed, the organic phase was separated and concentrated to obtain 70.12g of methyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate (GC purity: 93.5%, yield: 82.8%, wherein GC purity of the isomer methyl 5-dichloromethyl-1H-methylpyrazole-4-carboxylate: 4.3%).
Example 16
After 45.00g of a 40% by mass aqueous methylhydrazine solution (0.391mol) (the mass concentration is defined as the percentage of methylhydrazine based on the total mass of the aqueous methylhydrazine solution), 6.7g of a 30% by mass aqueous sodium hydroxide solution (0.050mol) (the mass concentration is defined as the percentage of sodium hydroxide based on the total mass of the aqueous sodium hydroxide solution) and 70.00g of xylene were mixed in a reaction flask, the temperature in the system was controlled to 0 to 25 ℃, and the xylene solution of methyl 3-methoxy-2-dichloroacetylacrylate prepared in example 8 (methyl 3-methoxy-2-dichloroacetylacrylate: 83.54g, GC purity: 96.6%, 0.355 mol; xylene: 140.00g) was slowly added dropwise. After dripping, maintaining the temperature of the system between 0 and 25 ℃, and stirring for 1 hour under heat preservation.
after the reaction was completed, the organic phase was separated and concentrated to obtain 69.74g of methyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate (GC purity: 97.3%, yield: 85.7%, wherein GC purity of the isomer, methyl 5-dichloromethyl-1H-methylpyrazole-4-carboxylate, was 0.85%).
Example 17
after 45.00g of a 40% by mass aqueous methylhydrazine solution (0.391mol) (the mass concentration is defined as the percentage of methylhydrazine based on the total mass of the aqueous methylhydrazine solution), 1.6g of KOH solid (0.028mol) and 70.00g of xylene were mixed in a reaction flask, the temperature in the system was controlled to 0 to 25 ℃, and a xylene solution of methyl 3-methoxy-2-dichloroacetyl acrylate prepared in example 8 (83.54 g of methyl 3-methoxy-2-dichloroacetyl acrylate, GC purity: 96.6%, 0.355 mol; xylene: 140.00g) was slowly added dropwise thereto. After dripping, maintaining the temperature of the system between 0 and 25 ℃, and stirring for 1 hour under heat preservation.
After the reaction, 5.00g of water was added, followed by liquid separation and concentration of the organic phase to obtain 69.06g of methyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate (GC purity: 97.8%, yield: 85.3%, wherein GC purity of the isomer methyl 5-dichloromethyl-1H-methylpyrazole-4-carboxylate: 0.63%).
example 18
After 45.00g of a 40% methylhydrazine aqueous solution (0.391mol) (the mass concentration means the mass percentage of methylhydrazine to the total mass of the methylhydrazine aqueous solution), 2.1g of NaOH solid (0.070mol) and 70.00g of xylene were mixed in a reaction flask, the temperature in the system was controlled to 0 to 25 ℃, and a xylene solution of methyl 3-methoxy-2-dichloroacetyl acrylate prepared in example 8 (83.54 g of methyl 3-methoxy-2-dichloroacetyl acrylate, GC purity: 96.6%, 0.355 mol; xylene: 140.00g) was slowly added dropwise. After dripping, maintaining the temperature of the system between 0 and 25 ℃, and stirring for 1 hour under heat preservation.
After the reaction, 5.00g of water was added, followed by liquid separation and concentration of the organic phase to obtain 68.73g of methyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate (GC purity: 97.7%, yield: 84.8%, wherein GC purity of the isomer methyl 5-dichloromethyl-1H-methylpyrazole-4-carboxylate: 0.91%).
Example 19
After 45.00g of a 40% by mass aqueous methylhydrazine solution (0.391mol) (the mass concentration is defined as the percentage of methylhydrazine based on the total mass of the aqueous methylhydrazine solution), 6.07g of triethylamine (0.060mol) and 70.00g of xylene were mixed in a reaction flask, the temperature in the system was controlled to 0 to 25 ℃, and a xylene solution of methyl 3-methoxy-2-dichloroacetyl acrylate prepared in example 8 (83.54 g of methyl 3-methoxy-2-dichloroacetyl acrylate, GC purity: 96.6%, 0.355 mol; xylene: 140.00g) was slowly added dropwise thereto. After dripping, maintaining the temperature of the system between 0 and 25 ℃, and stirring for 1 hour under heat preservation.
After the reaction was completed, the organic phase was separated and concentrated to obtain 69.38g of methyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate (GC purity: 96.1%, yield: 84.2%, wherein GC purity of the isomer methyl 5-dichloromethyl-1H-methylpyrazole-4-carboxylate: 2.5%).
Example 20
after 45.00g of a 40% methylhydrazine aqueous solution (0.391mol) (the mass concentration means the mass percentage of methylhydrazine to the total mass of the methylhydrazine aqueous solution), 13.90g of tri-n-butylamine (0.075mol) and 70.00g of xylene were mixed in a reaction flask, the temperature in the system was controlled to 0 to 25 ℃, and a xylene solution of methyl 3-methoxy-2-dichloroacetyl acrylate prepared in example 8 (83.54 g of methyl 3-methoxy-2-dichloroacetyl acrylate, GC purity: 96.6%, 0.355 mol; xylene: 140.00g) was slowly added dropwise thereto. After dripping, maintaining the temperature of the system between 0 and 25 ℃, and stirring for 1 hour under heat preservation.
after the reaction was completed, the organic phase was separated and concentrated to obtain 69.40g of methyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate (GC purity: 96.3%, yield: 84.4%, wherein GC purity of the isomer, methyl 5-dichloromethyl-1H-methylpyrazole-4-carboxylate, 2.2%).
Example 21
after 45.00g of a 40% methylhydrazine aqueous solution (0.391mol) (the mass concentration means the percentage of methylhydrazine based on the total mass of the methylhydrazine aqueous solution), 5.14g of pyridine (0.065mol) and 70.00g of xylene were mixed in a reaction flask, the temperature in the system was controlled to 0 to 25 ℃, and a xylene solution of methyl 3-methoxy-2-dichloroacetoacetate prepared in example 8 (83.54 g of methyl 3-methoxy-2-dichloroacetoacetate, 96.6%, 0.355 mol; 140.00g) was slowly added dropwise. After dripping, maintaining the temperature of the system between 0 and 25 ℃, and stirring for 1 hour under heat preservation.
After the reaction was completed, the organic phase was separated and concentrated to obtain 69.10g of methyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate (GC purity: 95.8%, yield: 83.6%, and GC purity: 3.1% of the isomer, methyl 5-dichloromethyl-1H-methylpyrazole-4-carboxylate).
example 22
200g of methyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate (GC purity: 97.3%, 0.872mol) prepared in example 16 was charged into a high-pressure reactor, and then the temperature was gradually increased to 125 to 130 ℃ to melt methyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate. 22.00g of pyridine (0.278mol) and 3-dichloromethyl-1H-methylpyrazole-4-carboxylic acid methyl ester were uniformly mixed in an autoclave, and then the temperature was further raised to 130 ℃ to 155 ℃. When the temperature in the system reaches 130 to 155 ℃, the temperature is maintained, 48.00g of HF (2.399mol) is slowly dropped for about 4 to 5 hours, and then the temperature is maintained at 130 to 155 ℃ for 5 to 8 hours.
After the reaction is finished, the gas is discharged and the pressure is released, the nitrogen is blown and swept, and the tail gas is absorbed by alkali liquor. Cooling to 60-80 ℃, adding 350g of dimethylbenzene and 60g of water to dilute the reaction solution, slowly dripping 145.00g of sodium hydroxide aqueous solution with the mass concentration of 30% (the mass concentration refers to the mass percentage of the sodium hydroxide in the total mass of the sodium hydroxide aqueous solution), keeping the temperature at 50-70 ℃, stirring for 1 hour, separating liquid, and acidifying the water phase by using concentrated hydrochloric acid with the mass concentration of 36% (the mass concentration refers to the mass percentage of the hydrogen chloride in the total mass of the concentrated hydrochloric acid) to the pH value of 1.0. The temperature is reduced to 10 ℃ to 25 ℃, and then the mixture is filtered and dried in vacuum, 136.33g of 3-difluoromethyl-1H-methylpyrazole-4-carboxylic acid (yield: 88.0%, HPLC purity: 99.7%; isomer 5-difluoromethyl-1H-methylpyrazole-4-carboxylic acid HPLC purity: less than 0.01%) is obtained.
example 23
200g of methyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate (GC purity: 97.3%, 0.872mol) prepared in example 16 was charged into a high-pressure reactor, and then the temperature was gradually increased to 125 to 130 ℃ to melt methyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate. 35.00g of triethylamine (0.346mol) and 3-dichloromethyl-1H-methylpyrazole-4-carboxylic acid methyl ester were uniformly mixed in an autoclave, and then the temperature was further raised to 130 ℃ to 155 ℃. When the temperature in the system reaches 130 to 155 ℃, the temperature is maintained, 48.00g of HF (2.399mol) is slowly dropped for about 4 to 5 hours, and then the temperature is maintained at 130 to 155 ℃ for 5 to 8 hours.
After the reaction is finished, the gas is discharged and the pressure is released, the nitrogen is blown and swept, and the tail gas is absorbed by alkali liquor. Cooling to 60-80 ℃, adding 350g of dimethylbenzene and 60g of water to dilute the reaction solution, slowly dripping 145.00g of sodium hydroxide aqueous solution with the mass concentration of 30% (the mass concentration refers to the mass percentage of the sodium hydroxide in the total mass of the sodium hydroxide aqueous solution), keeping the temperature at 50-70 ℃, stirring for 1 hour, separating liquid, and acidifying the water phase by using concentrated hydrochloric acid with the mass concentration of 36% (the mass concentration refers to the mass percentage of the hydrogen chloride in the total mass of the concentrated hydrochloric acid) to the pH value of 1.0. The temperature is reduced to 10 ℃ to 25 ℃, and the mixture is filtered and dried in vacuum to obtain 137.24g of 3-difluoromethyl-1H-methylpyrazole-4-carboxylic acid (the yield: 88.5%, the HPLC purity: 99.6%, and the HPLC purity of the isomer 5-difluoromethyl-1H-methylpyrazole-4-carboxylic acid: less than 0.01%).
Example 24
200g of methyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate (GC purity: 97.3%, 0.872mol) prepared in example 16 was charged into a high-pressure reactor, and then the temperature was gradually increased to 125 to 130 ℃ to melt methyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate. 8.82g of triethylamine (0.0872mol) and 3-dichloromethyl-1H-methylpyrazole-4-carboxylic acid methyl ester were uniformly mixed in an autoclave, and then the temperature was further raised to 130 ℃ to 155 ℃. When the temperature in the system reaches 130 to 155 ℃, the temperature is maintained, 48.00g of HF (2.399mol) is slowly dropped for about 4 to 5 hours, and then the temperature is maintained at 130 to 155 ℃ for 5 to 8 hours.
After the reaction is finished, the gas is discharged and the pressure is released, the nitrogen is blown and swept, and the tail gas is absorbed by alkali liquor. Cooling to 60-80 ℃, adding 350g of dimethylbenzene and 60g of water to dilute the reaction solution, slowly dripping 145.00g of sodium hydroxide aqueous solution with the mass concentration of 30% (the mass concentration refers to the mass percentage of the sodium hydroxide in the total mass of the sodium hydroxide aqueous solution), keeping the temperature at 50-70 ℃, stirring for 1 hour, separating liquid, and acidifying the water phase by using concentrated hydrochloric acid with the mass concentration of 36% (the mass concentration refers to the mass percentage of the hydrogen chloride in the total mass of the concentrated hydrochloric acid) to the pH value of 1.0. The temperature is reduced to 10 ℃ to 25 ℃, and the mixture is filtered and dried in vacuum, thus obtaining 126.71g of 3-difluoromethyl-1H-methylpyrazole-4-carboxylic acid (yield: 81.6%, HPLC purity: 98.9%; isomer 5-difluoromethyl-1H-methylpyrazole-4-carboxylic acid HPLC purity: less than 0.01%).
Example 25
200g of methyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate (GC purity: 97.3%, 0.872mol) prepared in example 16 was charged into a high-pressure reactor, and then the temperature was gradually increased to 125 to 130 ℃ to melt methyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate. 20.02g of N-methylpyrrolidone (0.202mol) and methyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate were uniformly mixed in an autoclave, and then the temperature was further raised to 130 ℃ to 155 ℃. When the temperature in the system reaches 130 to 155 ℃, the temperature is maintained, 48.00g of HF (2.399mol) is slowly dropped for about 4 to 5 hours, and then the temperature is maintained at 130 to 155 ℃ for 10 to 15 hours.
after the reaction is finished, the gas is discharged and the pressure is released, the nitrogen is blown and swept, and the tail gas is absorbed by alkali liquor. Cooling to 60-80 ℃, adding 350g of dimethylbenzene and 60g of water to dilute the reaction solution, slowly dripping 145.00g of sodium hydroxide aqueous solution with the mass concentration of 30% (the mass concentration refers to the mass percentage of the sodium hydroxide in the total mass of the sodium hydroxide aqueous solution), keeping the temperature at 50-70 ℃, stirring for 1 hour, separating liquid, and acidifying the water phase by using concentrated hydrochloric acid with the mass concentration of 36% (the mass concentration refers to the mass percentage of the hydrogen chloride in the total mass of the concentrated hydrochloric acid) to the pH value of 1.0. The temperature is reduced to 10 ℃ to 25 ℃, and then the mixture is filtered and dried in vacuum, thus 127.75g of 3-difluoromethyl-1H-methylpyrazole-4-carboxylic acid (yield: 82.1%, HPLC purity: 98.7%; isomer 5-difluoromethyl-1H-methylpyrazole-4-carboxylic acid HPLC purity: less than 0.01%) is obtained.
Example 26
200g of methyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate (GC purity: 97.3%, 0.872mol) prepared in example 16 was charged into a high-pressure reactor, and then the temperature was gradually increased to 125 to 130 ℃ to melt methyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate. 9.95g of 1, 3-dimethyl-2-imidazolidinone (0.0872mol) and 3-dichloromethyl-1H-methylpyrazole-4-carboxylic acid methyl ester were mixed uniformly in an autoclave, and then the temperature was further raised to 130 ℃ to 155 ℃. When the temperature in the system reaches 130 to 155 ℃, the temperature is maintained, 48.00g of HF (2.399mol) is slowly dropped for about 4 to 5 hours, and then the temperature is maintained at 130 to 155 ℃ for 7 to 12 hours.
after the reaction is finished, the gas is discharged and the pressure is released, the nitrogen is blown and swept, and the tail gas is absorbed by alkali liquor. Cooling to 60-80 ℃, adding 350g of dimethylbenzene and 60g of water to dilute the reaction solution, slowly dripping 145.00g of sodium hydroxide aqueous solution with the mass concentration of 30% (the mass concentration refers to the mass percentage of the sodium hydroxide in the total mass of the sodium hydroxide aqueous solution), keeping the temperature at 50-70 ℃, stirring for 1 hour, separating liquid, and acidifying the water phase by using concentrated hydrochloric acid with the mass concentration of 36% (the mass concentration refers to the mass percentage of the hydrogen chloride in the total mass of the concentrated hydrochloric acid) to the pH value of 1.0. The temperature is reduced to 10 ℃ to 25 ℃, and then the mixture is filtered and dried in vacuum, 133.53g of 3-difluoromethyl-1H-methylpyrazole-4-carboxylic acid (yield: 86.6%, HPLC purity: 99.6%; isomer 5-difluoromethyl-1H-methylpyrazole-4-carboxylic acid HPLC purity: less than 0.01%) is obtained.
Example 27
200g of methyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate (GC purity: 97.3%, 0.872mol) prepared in example 16 was charged into a high-pressure reactor, and then the temperature was gradually increased to 125 to 130 ℃ to melt methyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate. 5.71g of 1, 3-dimethyl-2-imidazolidinone (0.0500mol) and 3-dichloromethyl-1H-methylpyrazole-4-carboxylic acid methyl ester were mixed uniformly in an autoclave, and then the temperature was further raised to 130 ℃ to 155 ℃. When the temperature in the system reaches 130 to 155 ℃, the temperature is maintained, 48.00g of HF (2.399mol) is slowly dropped for about 4 to 5 hours, and then the temperature is maintained at 130 to 155 ℃ for 7 to 12 hours.
After the reaction is finished, the gas is discharged and the pressure is released, the nitrogen is blown and swept, and the tail gas is absorbed by alkali liquor. Cooling to 60-80 ℃, adding 350g of dimethylbenzene and 60g of water to dilute the reaction solution, slowly dripping 145.00g of sodium hydroxide aqueous solution with the mass concentration of 30% (the mass concentration refers to the mass percentage of the sodium hydroxide in the total mass of the sodium hydroxide aqueous solution), keeping the temperature at 50-70 ℃, stirring for 1 hour, separating liquid, and acidifying the water phase by using concentrated hydrochloric acid with the mass concentration of 36% (the mass concentration refers to the mass percentage of the hydrogen chloride in the total mass of the concentrated hydrochloric acid) to the pH value of 1.0. The temperature is reduced to 10 ℃ to 25 ℃, and then the mixture is filtered and dried in vacuum, 130.89g of 3-difluoromethyl-1H-methylpyrazole-4-carboxylic acid (yield: 84.8%, HPLC purity: 99.5%; isomer 5-difluoromethyl-1H-methylpyrazole-4-carboxylic acid HPLC purity: less than 0.01%) is obtained.
Example 28
200g of methyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate (GC purity: 97.3%, 0.872mol) prepared in example 16 was charged into a high-pressure reactor, and then the temperature was gradually increased to 125 to 130 ℃ to melt methyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate. 5.71g of 1, 3-dimethyl-2-imidazolidinone (0.0500mol), 8.82g of triethylamine (0.0872mol) and 3-dichloromethyl-1H-methylpyrazole-4-carboxylic acid methyl ester were mixed uniformly in an autoclave, and then the temperature was further raised to 130 ℃ to 155 ℃. When the temperature in the system reaches 130 to 155 ℃, the temperature is maintained, 48.00g of HF (2.399mol) is slowly dropped for about 4 to 5 hours, and then the temperature is maintained at 130 to 155 ℃ for 6 to 10 hours.
after the reaction is finished, the gas is discharged and the pressure is released, the nitrogen is blown and swept, and the tail gas is absorbed by alkali liquor. Cooling to 60-80 ℃, adding 350g of dimethylbenzene and 60g of water to dilute the reaction solution, slowly dripping 145.00g of sodium hydroxide aqueous solution with the mass concentration of 30% (the mass concentration refers to the mass percentage of the sodium hydroxide in the total mass of the sodium hydroxide aqueous solution), keeping the temperature at 50-70 ℃, stirring for 1 hour, separating liquid, and acidifying the water phase by using concentrated hydrochloric acid with the mass concentration of 36% (the mass concentration refers to the mass percentage of the hydrogen chloride in the total mass of the concentrated hydrochloric acid) to the pH value of 1.0. The temperature is reduced to 10 ℃ to 25 ℃, and then the mixture is filtered and dried in vacuum, thus 138.93g of 3-difluoromethyl-1H-methylpyrazole-4-carboxylic acid (yield: 90.1%, HPLC purity: 99.6%; isomer 5-difluoromethyl-1H-methylpyrazole-4-carboxylic acid HPLC purity: less than 0.01%) is obtained.
Example 29
200g of methyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate (GC purity: 97.3%, 0.872mol) prepared in example 16 was charged into a high-pressure reactor, and then the temperature was gradually increased to 125 to 130 ℃ to melt methyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate, and further increased to 130 to 155 ℃. When the temperature in the system reaches 130 to 155 ℃, the temperature is maintained, 48.00g of HF (2.399mol) is slowly dropped for about 4 to 5 hours, and then the temperature is maintained at 130 to 155 ℃ for 10 to 15 hours.
After the reaction is finished, the gas is discharged and the pressure is released, the nitrogen is blown and swept, and the tail gas is absorbed by alkali liquor. Cooling to 60-80 ℃, adding 350g of dimethylbenzene and 60g of water to dilute the reaction solution, slowly dripping 145.00g of sodium hydroxide aqueous solution with the mass concentration of 30% (the mass concentration refers to the mass percentage of the sodium hydroxide in the total mass of the sodium hydroxide aqueous solution), keeping the temperature at 50-70 ℃, stirring for 1 hour, separating liquid, and acidifying the water phase by using concentrated hydrochloric acid with the mass concentration of 36% (the mass concentration refers to the mass percentage of the hydrogen chloride in the total mass of the concentrated hydrochloric acid) to the pH value of 1.0. The temperature is reduced to 10 ℃ to 25 ℃, and the mixture is filtered and dried in vacuum, thus obtaining 121.65g of 3-difluoromethyl-1H-methylpyrazole-4-carboxylic acid (yield: 78.1%, HPLC purity: 98.6%; isomer 5-difluoromethyl-1H-methylpyrazole-4-carboxylic acid HPLC purity: less than 0.01%).
example 30
200g of methyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate (GC purity: 97.3%, 0.872mol) prepared in example 16 was charged into a high-pressure reactor, and then slowly heated to 125 to 130 ℃ to melt methyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate, 4.10g of antimony trichloride (0.0180mol) was charged into the high-pressure reactor, and further heated to 130 to 155 ℃. When the temperature in the system reaches 130 to 155 ℃, the temperature is maintained, 48.00g of HF (2.399mol) is slowly dropped for about 4 to 5 hours, and then the temperature is maintained at 130 to 155 ℃ for 10 to 15 hours.
After the reaction is finished, the gas is discharged and the pressure is released, the nitrogen is blown and swept, and the tail gas is absorbed by alkali liquor. Cooling to 60-80 ℃, adding 350g of dimethylbenzene and 60g of water to dilute the reaction solution, slowly dripping 145.00g of sodium hydroxide aqueous solution with the mass concentration of 30% (the mass concentration refers to the mass percentage of the sodium hydroxide in the total mass of the sodium hydroxide aqueous solution), keeping the temperature at 50-70 ℃, stirring for 1 hour, separating liquid, and acidifying the water phase by using concentrated hydrochloric acid with the mass concentration of 36% (the mass concentration refers to the mass percentage of the hydrogen chloride in the total mass of the concentrated hydrochloric acid) to the pH value of 1.0. The temperature is reduced to 10 ℃ to 25 ℃, and then the mixture is filtered and dried in vacuum, 137.12g of 3-difluoromethyl-1H-methylpyrazole-4-carboxylic acid (yield: 88.3%, HPLC purity: 98.9%; isomer 5-difluoromethyl-1H-methylpyrazole-4-carboxylic acid HPLC purity: less than 0.01%) is obtained.
Example 31
200g of methyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate (GC purity: 97.3%, 0.872mol) prepared in example 16 was charged into a high-pressure reactor, and then the temperature was gradually increased to 125 to 130 ℃ to melt methyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate. 16.00g of pyridine (0.202mol) and 3-dichloromethyl-1H-methylpyrazole-4-carboxylic acid methyl ester were uniformly mixed in an autoclave, and then the temperature was further raised to 130 ℃ to 155 ℃. When the temperature in the system reaches 130 to 155 ℃, the temperature is maintained, 26.32g of HF (1.315mol) is slowly dropped for about 2 to 3 hours, and then the temperature is maintained at 130 to 155 ℃ for 5 to 8 hours.
after the reaction is finished, the gas is discharged and the pressure is released, the nitrogen is blown and swept, and the tail gas is absorbed by alkali liquor. Cooling to 60-80 ℃, adding 350g of dimethylbenzene and 60g of water to dilute the reaction solution, slowly dripping 145.00g of sodium hydroxide aqueous solution with the mass concentration of 30% (the mass concentration refers to the mass percentage of the sodium hydroxide in the total mass of the sodium hydroxide aqueous solution), keeping the temperature at 50-70 ℃, stirring for 1 hour, separating liquid, and acidifying the water phase by using concentrated hydrochloric acid with the mass concentration of 36% (the mass concentration refers to the mass percentage of the hydrogen chloride in the total mass of the concentrated hydrochloric acid) to the pH value of 1.0. The temperature is reduced to 10 ℃ to 25 ℃, and then the mixture is filtered and dried in vacuum, 145.98g of 3-monofluoro-chloromethyl-1H-methylpyrazole-4-carboxylic acid is obtained (the yield: 83.5%, the HPLC purity: 96.6%, and the isomer 5-monofluoro-chloromethyl-1H-methylpyrazole-4-carboxylic acid HPLC purity: less than 0.01%).
Example 32
200g of methyl 3-trichloromethyl-1H-methylpyrazole-4-carboxylate (GC purity: 91.8%, 0.713mol) prepared in example 14 was charged in a high-pressure reactor, and then the temperature was slowly raised to 125 to 130 ℃ to melt the methyl 3-trichloromethyl-1H-methylpyrazole-4-carboxylate. After 13.00g of pyridine (0.164mol) and 3-trichloromethyl-1H-methylpyrazole-4-carboxylic acid methyl ester were mixed uniformly in an autoclave, the temperature was further raised to 130 ℃ to 155 ℃. When the temperature in the system reaches 130 to 155 ℃, the temperature is maintained, 55.00g of HF (2.749mol) is slowly dropped for about 5 to 6 hours, and then the temperature is maintained at 130 to 155 ℃ for 5 to 8 hours.
after the reaction is finished, the gas is discharged and the pressure is released, the nitrogen is blown and swept, and the tail gas is absorbed by alkali liquor. Cooling to 60-80 ℃, adding 350g of dimethylbenzene and 60g of water to dilute the reaction solution, slowly dripping 125.00g of sodium hydroxide aqueous solution with the mass concentration of 30% (the mass concentration refers to the mass percentage of the sodium hydroxide in the total mass of the sodium hydroxide aqueous solution), keeping the temperature at 50-70 ℃, stirring for 1 hour, separating liquid, and acidifying the water phase by using concentrated hydrochloric acid with the mass concentration of 36% (the mass concentration refers to the mass percentage of the hydrogen chloride in the total mass of the concentrated hydrochloric acid) to the pH value of 1.0. The temperature was reduced to 10 ℃ to 25 ℃, filtered and vacuum-dried to obtain 119.75g of 3-trifluoromethyl-1H-methylpyrazole-4-carboxylic acid (yield: 85.7%, HPLC purity: 99.1%; isomer 5-trifluoromethyl-1H-methylpyrazole-4-carboxylic acid HPLC purity: 0.05%).
Example 33
200g of methyl 3-trichloromethyl-1H-methylpyrazole-4-carboxylate (GC purity: 91.8%, 0.713mol) prepared in example 14 was charged in a high-pressure reactor, and then the temperature was slowly raised to 125 to 130 ℃ to melt the methyl 3-trichloromethyl-1H-methylpyrazole-4-carboxylate. After 13.00g of pyridine (0.164mol) and 3-trichloromethyl-1H-methylpyrazole-4-carboxylic acid methyl ester were mixed uniformly in an autoclave, the temperature was further raised to 130 ℃ to 155 ℃. When the temperature in the system reaches 130 to 155 ℃, the temperature is maintained, 35.00g of HF (1.749mol) is slowly dropped into the system for about 5 to 6 hours, and then the system is kept at 130 to 155 ℃ for 5 to 8 hours.
After the reaction is finished, the gas is discharged and the pressure is released, the nitrogen is blown and swept, and the tail gas is absorbed by alkali liquor. Cooling to 60-80 ℃, adding 350g of dimethylbenzene and 60g of water to dilute the reaction solution, slowly dripping 125.00g of sodium hydroxide aqueous solution with the mass concentration of 30% (the mass concentration refers to the mass percentage of the sodium hydroxide in the total mass of the sodium hydroxide aqueous solution), keeping the temperature at 50-70 ℃, stirring for 1 hour, separating liquid, and acidifying the water phase by using concentrated hydrochloric acid with the mass concentration of 36% (the mass concentration refers to the mass percentage of the hydrogen chloride in the total mass of the concentrated hydrochloric acid) to the pH value of 1.0. The temperature was reduced to 10 ℃ to 25 ℃, and the mixture was filtered and vacuum-dried to obtain 132.43g of 3-difluorochloromethyl-1H-methylpyrazole-4-carboxylic acid (yield: 83.5%, HPLC purity: 94.7%, isomer 5-difluorochloromethyl-1H-methylpyrazole-4-carboxylic acid content: 0.04%).
Example 34
200g of methyl 3-trichloromethyl-1H-methylpyrazole-4-carboxylate (GC purity: 91.8%, 0.713mol) prepared in example 14 was charged in a high-pressure reactor, and then the temperature was slowly raised to 125 to 130 ℃ to melt the methyl 3-trichloromethyl-1H-methylpyrazole-4-carboxylate. 10.00g of pyridine (0.127mol) and 3-trichloromethyl-1H-methylpyrazole-4-carboxylic acid methyl ester were uniformly mixed in an autoclave, and then the temperature was further raised to 130 ℃ to 155 ℃. When the temperature in the system reaches 130 to 155 ℃, the temperature is maintained, 20.00g of HF (1.000mol) is slowly dropped for about 4 to 5 hours, and then the temperature is maintained at 130 to 155 ℃ for 5 to 8 hours.
after the reaction is finished, the gas is discharged and the pressure is released, the nitrogen is blown and swept, and the tail gas is absorbed by alkali liquor. Cooling to 60-80 ℃, adding 350g of dimethylbenzene and 60g of water to dilute the reaction solution, slowly dripping 125.00g of sodium hydroxide aqueous solution with the mass concentration of 30% (the mass concentration refers to the mass percentage of the sodium hydroxide in the total mass of the sodium hydroxide aqueous solution), keeping the temperature at 50-70 ℃, stirring for 1 hour, separating liquid, and acidifying the water phase by using concentrated hydrochloric acid with the mass concentration of 36% (the mass concentration refers to the mass percentage of the hydrogen chloride in the total mass of the concentrated hydrochloric acid) to the pH value of 1.0. The temperature was reduced to 10 ℃ to 25 ℃, and the mixture was filtered and vacuum-dried to obtain 142.56g of 3-fluorodichloromethyl-1H-methylpyrazole-4-carboxylic acid (yield: 84.6%, HPLC purity: 96.1%; isomer 5-fluorodichloromethyl-1H-methylpyrazole-4-carboxylic acid HPLC purity: 0.04%).
Example 35
200g of ethyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate (GC purity: 92.8%, 0.783mol) prepared in example 13 and 172.06g of triethylamine trihydrofluoride (1.067mol) were put into a high-pressure reactor, and then the temperature was slowly raised to 130 ℃ to 155 ℃. When the temperature in the system reaches 130-155 ℃, maintaining the temperature, and keeping the temperature at 130-155 ℃ for 5-8 hours.
After the reaction is finished, the gas is discharged and the pressure is released, the nitrogen is blown and swept, and the tail gas is absorbed by alkali liquor. Cooling to 60-80 ℃, adding 350g of dimethylbenzene and 60g of water to dilute the reaction solution, slowly dripping 125.00g of sodium hydroxide aqueous solution with the mass concentration of 30% (the mass concentration refers to the mass percentage of the sodium hydroxide in the total mass of the sodium hydroxide aqueous solution), keeping the temperature at 50-70 ℃, stirring for 1 hour, separating liquid, and acidifying the water phase by using concentrated hydrochloric acid with the mass concentration of 36% (the mass concentration refers to the mass percentage of the hydrogen chloride in the total mass of the concentrated hydrochloric acid) to the pH value of 1.0. The temperature was reduced to 10 ℃ to 25 ℃, and the mixture was filtered and vacuum-dried to obtain 106.61g of 3-difluoromethyl-1H-methylpyrazole-4-carboxylic acid (yield: 76.1%, HPLC purity: 98.5%; isomer 5-difluoromethyl-1H-methylpyrazole-4-carboxylic acid HPLC purity: 0.05%).
example 36
200g of ethyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate (GC purity: 92.8%, 0.783mol) prepared in example 13 and 248.32g of pyridine hydrofluoride (2.505mol) were put into a high-pressure reactor, and then the temperature was slowly raised to 130 ℃ to 155 ℃. When the temperature in the system reaches 130-155 ℃, maintaining the temperature, and keeping the temperature at 130-155 ℃ for 5-8 hours.
After the reaction is finished, the gas is discharged and the pressure is released, the nitrogen is blown and swept, and the tail gas is absorbed by alkali liquor. Cooling to 60-80 ℃, adding 350g of dimethylbenzene and 60g of water to dilute the reaction solution, slowly dripping 125.00g of sodium hydroxide aqueous solution with the mass concentration of 30% (the mass concentration refers to the mass percentage of the sodium hydroxide in the total mass of the sodium hydroxide aqueous solution), keeping the temperature at 50-70 ℃, stirring for 1 hour, separating liquid, and acidifying the water phase by using concentrated hydrochloric acid with the mass concentration of 36% (the mass concentration refers to the mass percentage of the hydrogen chloride in the total mass of the concentrated hydrochloric acid) to the pH value of 1.0. The temperature was reduced to 10 ℃ to 25 ℃, and the mixture was filtered and vacuum-dried to obtain 104.21g of 3-difluoromethyl-1H-methylpyrazole-4-carboxylic acid (yield: 74.4%, HPLC purity: 98.5%; isomer 5-difluoromethyl-1H-methylpyrazole-4-carboxylic acid HPLC purity: 0.05%).
Example 37
200g of ethyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate (GC purity: 92.8%, 0.783mol) prepared in example 13 and 120.90g of N-methylpyrrolidone pentafluoroate (0.607mol) were put into a high-pressure reactor, and then the temperature was slowly raised to 130 ℃ to 155 ℃. When the temperature in the system reaches 130-155 ℃, maintaining the temperature, and keeping the temperature at 130-155 ℃ for 10-15 hours.
After the reaction is finished, the gas is discharged and the pressure is released, the nitrogen is blown and swept, and the tail gas is absorbed by alkali liquor. Cooling to 60-80 ℃, adding 350g of dimethylbenzene and 60g of water to dilute the reaction solution, slowly dripping 125.00g of sodium hydroxide aqueous solution with the mass concentration of 30% (the mass concentration refers to the mass percentage of the sodium hydroxide in the total mass of the sodium hydroxide aqueous solution), keeping the temperature at 50-70 ℃, stirring for 1 hour, separating liquid, and acidifying the water phase by using concentrated hydrochloric acid with the mass concentration of 36% (the mass concentration refers to the mass percentage of the hydrogen chloride in the total mass of the concentrated hydrochloric acid) to the pH value of 1.0. The temperature is reduced to 10 ℃ to 25 ℃, and the mixture is filtered and dried in vacuum, thus obtaining 104.00g of 3-difluoromethyl-1H-methylpyrazole-4-carboxylic acid (yield: 74.5%, HPLC purity: 98.8%; isomer 5-difluoromethyl-1H-methylpyrazole-4-carboxylic acid HPLC purity: 0.05%).
Example 38
200g of ethyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate (GC purity: 92.8%, 0.783mol) prepared in example 13 and 69.50g of 1, 3-dimethyl-2-imidazolidinone hexadecahydrofluoride (0.160mol) were put into a high-pressure reactor, and then the temperature was slowly raised to 130 ℃ to 155 ℃. When the temperature in the system reaches 130-155 ℃, maintaining the temperature, and keeping the temperature at 130-155 ℃ for 7-12 hours.
After the reaction is finished, the gas is discharged and the pressure is released, the nitrogen is blown and swept, and the tail gas is absorbed by alkali liquor. Cooling to 60-80 ℃, adding 350g of dimethylbenzene and 60g of water to dilute the reaction solution, slowly dripping 125.00g of sodium hydroxide aqueous solution with the mass concentration of 30% (the mass concentration refers to the mass percentage of the sodium hydroxide in the total mass of the sodium hydroxide aqueous solution), keeping the temperature at 50-70 ℃, stirring for 1 hour, separating liquid, and acidifying the water phase by using concentrated hydrochloric acid with the mass concentration of 36% (the mass concentration refers to the mass percentage of the hydrogen chloride in the total mass of the concentrated hydrochloric acid) to the pH value of 1.0. The temperature is reduced to 10 ℃ to 25 ℃, and the mixture is filtered and dried in vacuum to obtain 117.60g of 3-difluoromethyl-1H-methylpyrazole-4-carboxylic acid (yield: 84.5%, HPLC purity: 99.1%; isomer 5-difluoromethyl-1H-methylpyrazole-4-carboxylic acid HPLC purity: 0.05%).
Comparative examples
comparative example 1
After 100g of monomethyl malonate potassium salt (HPLC purity: 99.1%, 0.634mol) obtained in example 2 and 750g of acetonitrile were mixed in a reaction flask while maintaining the internal temperature at 0 to 5 ℃, 96.23g of triethylamine (0.951mol) was added while maintaining the system internal temperature at 0 to 5 ℃, and 72.40g of magnesium chloride solid (0.760mol) was gradually added. And after the feeding is finished, naturally heating, and keeping the temperature in the system at 20-25 ℃ for 2-3 hours. The temperature is reduced to 0 to 10 ℃, and 70.10g of dichloroacetyl chloride (0.476mol) is slowly dropped. After dripping, naturally heating to 20-25 ℃ and preserving the temperature for 18 hours.
After completion of the reaction, 240g of ethyl acetate was added to dilute the reaction solution. And cooling to 0-15 ℃, slowly and dropwise adding 455g of 5% hydrochloric acid aqueous solution for acidification (the mass concentration refers to the mass percentage of hydrogen chloride in the total mass of the hydrochloric acid aqueous solution). After the dropwise addition is finished, the temperature is kept at 0-15 ℃ for 30min, and liquid is separated. The organic phase obtained was washed twice with a 5% aqueous hydrochloric acid solution (200g × 2). After the solvent was removed from the organic phase, 26.47g of methyl dichloroacetoacetate (GC purity: 83.5%, yield: 25.1%) was obtained.
comparative example 2
100g of monomethyl malonate potassium salt (HPLC purity: 99.1%, 0.634mol) obtained in example 2 and 750g of acetonitrile were mixed in a reaction flask while maintaining the internal temperature at 10 to 25 ℃, and then 77.00g of triethylamine (0.761mol) was added while maintaining the system internal temperature at 10 to 25 ℃, and then 72.40g of magnesium chloride solid (0.760mol) was gradually added. And after the feeding is finished, naturally heating, and keeping the temperature in the system at 20-25 ℃ for 2-3 hours. The temperature is reduced to 0 to 10 ℃, and 70.10g of dichloroacetyl chloride (0.476mol) is slowly dropped. After dripping, naturally heating to 20-25 ℃ and preserving the temperature for 18 hours.
after completion of the reaction, 240g of ethyl acetate was added to dilute the reaction solution. And cooling to 0-15 ℃, slowly and dropwise adding 455g of 5% hydrochloric acid aqueous solution for acidification (the mass concentration refers to the mass percentage of hydrogen chloride in the total mass of the hydrochloric acid aqueous solution). After the dropwise addition is finished, the temperature is kept at 0-15 ℃ for 30min, and liquid is separated. The organic phase obtained was washed twice with a 5% aqueous hydrochloric acid solution (200g × 2). After the solvent was removed from the organic phase, 76.95g of methyl dichloroacetoacetate (GC purity: 82.6%, yield: 35.3%) was obtained.
comparative example 3
After 45.00g of a 40% by mass aqueous methylhydrazine solution (0.391mol) (the mass concentration is the mass percentage of methylhydrazine to the total mass of the aqueous methylhydrazine solution) and 70.00g of methanol were mixed in a reaction flask, the temperature in the system was controlled to 0 to 25 ℃, and a methanol solution of methyl 3-methoxy-2-dichloroacetyl acrylate prepared in example 8 (methyl 3-methoxy-2-dichloroacetyl acrylate: 83.54g, GC purity: 96.6%, 0.355 mol; methanol: 60.00g) was slowly added dropwise. After dripping, maintaining the internal temperature of the system between 0 and 25 ℃, and stirring for 1 hour under heat preservation.
After the reaction, the mixture was extracted with 100g × 2 of toluene, and the organic phase was separated and concentrated to obtain 62.06g of methyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate (GC purity: 55.5%, yield: 43.5%, and GC purity: 42.1% of the isomer, methyl 5-dichloromethyl-1H-methylpyrazole-4-carboxylate).
Comparative example 4
After 45.00g of a 40% methylhydrazine aqueous solution (0.391mol) (the mass concentration means the mass percentage of methylhydrazine to the total mass of the methylhydrazine aqueous solution) and 70.00g of xylene were mixed in a reaction flask, a xylene solution of ethyl 3-ethoxy-2-difluoroacetylacrylate (80.08 g of ethyl 3-ethoxy-2-difluoroacetylacrylate, GC purity: 98.5%, 0.355 mol; xylene: 140.00g) was slowly added dropwise while controlling the temperature in the system to 0 to 25 ℃. After dripping, maintaining the temperature of the system between 0 and 25 ℃, and stirring for 1 hour under heat preservation.
after the reaction was completed, 5.00g of water was added, followed by liquid separation and concentration of the organic phase to obtain 60.26g of ethyl 3-difluoromethyl-1H-methylpyrazole-4-carboxylate (GC purity: 88.5%, yield: 79.0%, wherein GC purity of the isomer ethyl 5-difluoromethyl-1H-methylpyrazole-4-carboxylate: 8.3%).
Comparative example 5
Dissolving 100g of 2-dichloroacetyl-3-dimethylamino ethyl acrylate (GC purity: 98.5%, 0.388mol) in 450g of toluene, cooling to an internal temperature of 0-5 ℃, starting to dropwise add 44.0g of a 60% methylhydrazine aqueous solution (0.573mol) (the mass concentration refers to the mass of methylhydrazine in percentage of the total mass of the methylhydrazine aqueous solution), completing dropwise addition within about 40-70 minutes, keeping the system temperature between 0-5 ℃, and stirring for 1-2 hours under heat preservation.
After the reaction, 8.8g of water was added, followed by liquid separation and concentration of the organic phase, whereby 86.35g of ethyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate (GC purity: 86.5%, yield: 81.2%, and GC purity: 12.7% for the isomer, methyl 5-dichloromethyl-1H-methylpyrazole-4-carboxylate) was obtained.
Comparative example 6
dissolving 100g of methyl 2-dichloroacetyl-3-dimethylamino acrylate (GC purity: 98.5%, 0.410mol) in 500g of chlorobenzene, cooling to an internal temperature of 0-5 ℃, starting to dropwise add 46.5g of methyl hydrazine methanol solution (0.605mol) with the mass concentration of 60% (the mass concentration refers to the mass percentage of methyl hydrazine in the total mass of the methyl hydrazine methanol solution), completing dropwise adding within about 40-70 minutes, keeping the temperature of the system between 0-5 ℃ after dropwise adding, and stirring for 1-2 hours at the maintained temperature.
after the reaction, 18.0g of water was added, and the organic phase was separated and concentrated to obtain 89.53g of methyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate (GC purity: 80.8%, yield: 79.1%, wherein GC purity of the isomer, methyl 5-dichloromethyl-1H-methylpyrazole-4-carboxylate, 17.5%).
comparative example 7
after 45.00g of a 40% by mass methylhydrazine aqueous solution (0.391mol) (the mass concentration is the mass percentage of methylhydrazine to the total mass of the methylhydrazine aqueous solution), 6.7g of a 30% by mass sodium hydroxide aqueous solution (0.050mol) (the mass concentration is the mass percentage of sodium hydroxide to the total mass of the sodium hydroxide aqueous solution) and 70.00g of xylene were mixed in a reaction flask, the temperature in the system was controlled to 0 to 25 ℃, and a xylene solution of methyl 3-methoxy-2-difluoroacetylacrylate (69.97 g of methyl 3-methoxy-2-difluoroacetylacrylate, 98.5%, 0.355 mol; xylene: 140.00g) was slowly added dropwise. After dripping, maintaining the temperature of the system between 0 and 25 ℃, and stirring for 1 hour under heat preservation.
After the reaction was completed, the organic phase was separated and concentrated to obtain 59.27g of methyl 3-difluoromethyl-1H-methylpyrazole-4-carboxylate (GC purity: 92.6%, yield: 81.3%, wherein GC purity of the isomer, methyl 5-difluoromethyl-1H-methylpyrazole-4-carboxylate, 4.3%).
comparative example 8
35g of methyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate (GC purity: 97.3%, 0.153mol) prepared in example 16, 4.10g of antimony trichloride (0.0180mol) and 200g of xylene were put into a high-pressure reactor, and then the temperature was slowly raised to 130 ℃ to 155 ℃. When the temperature in the system reaches 130 to 155 ℃, the temperature is maintained, 9.0g of HF (0.450mol) is slowly dropped for about 4 to 5 hours, and then the temperature is maintained at 130 to 155 ℃ for 10 to 15 hours.
After the reaction is finished, the gas is discharged and the pressure is released, the nitrogen is blown and swept, and the tail gas is absorbed by alkali liquor. Cooling to 60-80 deg.c, adding 45g of water to dilute the reaction liquid, slowly dropping 25.00g of 30 wt% concentration sodium hydroxide aqua, stirring at 50-70 deg.c for 1 hr, separating liquid, sampling water phase, and other steps.
comparative example 9
35g of methyl 3-dichloromethyl-1H-methylpyrazole-4-carboxylate (GC purity: 97.3%, 0.153mol) prepared in example 16 and 200g of xylene were put into an autoclave, and then the temperature was slowly raised to 130 ℃ to 155 ℃. When the temperature in the system reaches 130 to 155 ℃, the temperature is maintained, 9.0g of HF (0.450mol) is slowly dropped for about 4 to 5 hours, and then the temperature is maintained at 130 to 155 ℃ for 10 to 15 hours.
after the reaction is finished, the gas is discharged and the pressure is released, the nitrogen is blown and swept, and the tail gas is absorbed by alkali liquor. Cooling to 60-80 deg.c, adding 45g of water to dilute the reaction liquid, slowly dropping 25.00g of 30 wt% concentration sodium hydroxide aqua, stirring at 50-70 deg.c for 1 hr, separating liquid, sampling water phase, and other steps.
Claims (15)
1. A process for the preparation of compound 9, characterized in that it comprises the following steps:
Under the condition of alkali existence, adding a solution formed by the compound 2 and an organic solvent into a mixture formed by methylhydrazine and the organic solvent, and carrying out cyclization reaction to obtain a compound 1; the alkali is sodium hydroxide and/or potassium hydroxide; the temperature of the cyclization reaction is 0-25 ℃; the molar ratio of the compound 2 to the methylhydrazine is 1: 1.0-1: 2.5; the mass ratio of the organic solvent to the compound 2 is 2-10; the methyl hydrazine is used in the form of an aqueous solution thereof; the organic solvent is one or more of benzene, toluene, ethylbenzene, xylene, o-xylene, m-xylene and p-xylene;
Then, in a closed system, under the condition of the existence of a catalyst, carrying out halogen exchange reaction on the compound 1 and a fluorinating reagent to obtain a compound 9; the catalyst is one or more of alkali, lactam and antimony trichloride;
Wherein R is1Is methyl; r2Is methyl; x is 2.
2. A process for the preparation of compound 9 according to claim 1, characterized in that:
In the preparation method of the compound 1, the molar ratio of the compound 2 to the methylhydrazine is 1: 1.0-1: 1.5;
And/or the presence of a gas in the gas,
In the preparation method of the compound 1, the time of the cyclization reaction is 1 to 5 hours;
And/or the presence of a gas in the gas,
the preparation method of the compound 1 comprises the following post-treatment steps: after the reaction was completed, the mixture was separated, and the solvent was removed from the organic phase to obtain compound 1.
3. A process for the preparation of compound 9 according to claim 2, characterized in that:
In the preparation method of the compound 1, when the methylhydrazine is used in the form of an aqueous solution, the mass concentration of the methylhydrazine solution is 20-70%, and the mass concentration refers to the percentage of the mass of the methylhydrazine in the total mass of the methylhydrazine solution;
And/or the presence of a gas in the gas,
in the preparation method of the compound 1, the time of the cyclization reaction is 1 to 3 hours;
And/or the presence of a gas in the gas,
The molar ratio of the alkali to the compound 2 is 0.005-0.3;
And/or the presence of a gas in the gas,
In the steps adopted by the preparation method of the compound 1, the adding mode is dropwise adding, and the dropwise adding speed is subject to the condition that the system temperature does not exceed 25 ℃;
And/or the presence of a gas in the gas,
In the post-treatment step of the compound 1, the solvent removal is performed by concentration under reduced pressure; the liquid separation is direct liquid separation or extraction liquid separation after water is added.
4. A process for the preparation of compound 9 according to claim 3, characterized in that:
In the preparation method of the compound 1, when the methylhydrazine is used in the form of an aqueous solution thereof, the mass concentration of the methylhydrazine solution is 30-60%, wherein the mass concentration refers to the mass percentage of the methylhydrazine in the total mass of the methylhydrazine solution;
and/or the presence of a gas in the gas,
the molar ratio of the alkali to the compound 2 is 0.05-0.25;
And/or the presence of a gas in the gas,
In the post-treatment step of the compound 1, the solvent adopted for extraction is toluene and/or xylene.
5. A process for the preparation of compound 9 according to claim 1, characterized in that: the preparation method of the compound 1 further comprises the following steps: carrying out condensation reaction on a compound 3, a compound 4 and acetic anhydride to obtain a compound 2;
Wherein R is1and R2Is defined as in claim 1, and x is defined as in claim 1.
6. a process for the preparation of compound 9 according to claim 5, characterized in that:
In the preparation method of the compound 2, the molar ratio of the compound 3 to the compound 4 is 1.0-5.0;
And/or the presence of a gas in the gas,
In the preparation method of the compound 2, the molar ratio of the acetic anhydride to the compound 4 is 1.0-5.0;
And/or the presence of a gas in the gas,
in the preparation method of the compound 2, the temperature of the condensation reaction is 95-115 ℃;
And/or the presence of a gas in the gas,
in the method for producing the compound 2, the condensation reaction is carried out for 1 to 24 hours;
In the preparation method of the compound 2, the reaction is carried out while distilling to remove the generated by-product acetic ester;
And/or the presence of a gas in the gas,
The preparation method of the compound 2 is carried out in a solvent or under the condition of no solvent;
And/or the presence of a gas in the gas,
The preparation method of the compound 2 comprises the following post-treatment steps: and after the reaction is finished, cooling to 10-35 ℃, keeping the vacuum degree of the system at 10-20 mbar, and slowly heating the temperature in the system from 10-35 ℃ to 100 ℃ to remove unreacted raw materials and byproducts, thereby obtaining the compound 2.
7. a process for the preparation of compound 9 according to claim 5, characterized in that: the preparation method of the compound 1 further comprises the following steps: in an organic solvent, in the presence of an inorganic magnesium salt and an organic base, carrying out a condensation reaction on a compound 5 and a compound 6, then adjusting the pH value to 3-8, and carrying out a decarboxylation reaction to obtain a compound 3;
Wherein R is1Is defined as in claim 1, x is defined as in claim1, the preparation method comprises the following steps of; m+represents potassium ion or sodium ion.
8. A process for the preparation of compound 9 according to claim 7, characterized in that:
in the preparation method of the compound 3, the organic solvent is a nitrile solvent and/or an ester solvent;
and/or the presence of a gas in the gas,
in the preparation method of the compound 3, the mass ratio of the organic solvent to the compound 6 is 1-100;
And/or the presence of a gas in the gas,
in the preparation method of the compound 3, the molar ratio of the compound 5 to the compound 6 is 1.0-2.0;
and/or the presence of a gas in the gas,
in the preparation method of the compound 3, the inorganic magnesium salt is one or more of magnesium chloride, magnesium acetate, magnesium nitrate, magnesium sulfate, magnesium bromide and magnesium iodide;
And/or the presence of a gas in the gas,
In the preparation method of the compound 3, the organic base is one or more of triethylamine, tri-N-propylamine, tri-N-butylamine, diisopropylethylamine, N-dimethylaniline and N, N-diethylaniline;
and/or the presence of a gas in the gas,
in the preparation method of the compound 3, the molar ratio of the organic base to the compound 6 is 1.0-5.0;
and/or the presence of a gas in the gas,
In the preparation method of the compound 3, the molar ratio of the organic base to the compound 5 is 1.0-5.0;
And/or the presence of a gas in the gas,
In the preparation method of the compound 3, the molar ratio of the inorganic magnesium salt to the compound 6 is 1.0-5.0;
And/or the presence of a gas in the gas,
In the preparation method of the compound 3, the condensation reaction temperature is 0-35 ℃;
And/or the presence of a gas in the gas,
In the method for producing the compound 3, the condensation reaction is carried out for 1 to 48 hours;
And/or the presence of a gas in the gas,
in the preparation method of the compound 3, the pH is adjusted to 3-8 by adding an acidic substance;
And/or the presence of a gas in the gas,
In the preparation method of the compound 3, the temperature of the deacidification reaction is 0-15 ℃;
And/or the presence of a gas in the gas,
In the preparation method of the compound 3, the deacidification reaction time is 0.5 to 10 hours;
And/or the presence of a gas in the gas,
the preparation method of the compound 3 comprises the following steps: adding an inorganic magnesium salt into a mixture formed by a compound 5, an organic base and an organic solvent, reacting for 2-3 hours, cooling, adding a compound 6, performing a condensation reaction, adjusting the pH to 3-8, and performing a decarboxylation reaction to obtain a compound 3;
and/or the presence of a gas in the gas,
the preparation method of the compound 3 comprises the following post-treatment steps, after the reaction is finished, liquid separation, washing of an organic phase by using a dilute acid solution, and solvent removal are carried out to obtain the compound 3.
9. A process for the preparation of compound 9 according to claim 8, characterized in that:
In the method for producing the compound 3, when the organic solvent is a nitrile solvent, the nitrile solvent is acetonitrile;
and/or
In the preparation method of the compound 3, when the organic solvent is an ester solvent, the ester solvent is one or more of ethyl acetate, methyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, sec-butyl acetate and tert-butyl acetate;
and/or the presence of a gas in the gas,
in the preparation method of the compound 3, the mass ratio of the organic solvent to the compound 6 is 5-15;
And/or the presence of a gas in the gas,
In the preparation method of the compound 3, the molar ratio of the compound 5 to the compound 6 is 1.0-1.5;
And/or the presence of a gas in the gas,
in the preparation method of the compound 3, the molar ratio of the organic base to the compound 6 is 1.0-2.5;
and/or the presence of a gas in the gas,
In the preparation method of the compound 3, the molar ratio of the inorganic magnesium salt to the compound 6 is 1.0-2.5;
And/or the presence of a gas in the gas,
In the preparation method of the compound 3, the molar ratio of the organic base to the compound 5 is 1.5-2.5;
And/or the presence of a gas in the gas,
in the method for producing the compound 3, the condensation reaction is carried out for 15 to 25 hours;
and/or the presence of a gas in the gas,
in the preparation method of the compound 3, the acidic substance is one or more of hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, sodium bisulfate and potassium bisulfate;
And/or the presence of a gas in the gas,
in the method for preparing the compound 3, the acidic substance is used in the form of a solution, and when the acidic substance is used in the form of a solution, the mass concentration of the acidic substance solution is 1-20%, wherein the mass concentration refers to the percentage of the mass of the acidic substance to the total mass of the acidic substance solution;
and/or the presence of a gas in the gas,
in the preparation method of the compound 3, the deacidification reaction time is 0.5 to 2 hours;
And/or the presence of a gas in the gas,
The preparation method of the compound 3 comprises the following steps that the temperature of a mixture formed by the compound 5, the organic base and the organic solvent is 0-25 ℃;
And/or the presence of a gas in the gas,
the preparation method of the compound 3 comprises the following steps that the reaction temperature for reacting for 2 to 3 hours is 10 to 35 ℃;
And/or the presence of a gas in the gas,
The preparation method of the compound 3 comprises the following steps that the temperature for reducing the temperature is 0-35 ℃;
and/or the presence of a gas in the gas,
the preparation method of the compound 3 comprises the steps that the adding mode is dropwise adding, and the dropwise adding speed is subject to the condition that the system temperature does not exceed 35 ℃;
And/or the presence of a gas in the gas,
In the post-treatment step of the preparation method of the compound 3, the mass concentration of the dilute acid solution is 3-10%, and the mass concentration refers to the mass percentage of acid in the total mass of the dilute acid solution;
and/or the presence of a gas in the gas,
In the post-treatment step included in the preparation method of the compound 3, the acid in the dilute acid is hydrochloric acid.
10. a process for the preparation of compound 9 according to claim 7, characterized in that: the preparation method of the compound 1 further comprises the following steps: reacting a compound 7 with MOH in an organic solvent to obtain a compound 5;
wherein R is1is as defined in claim 1, M+Are as defined in claim 7.
11. A process for the preparation of compound 9 according to claim 10, characterized in that:
In the preparation method of the compound 5, the organic solvent is an alcohol solvent;
and/or the presence of a gas in the gas,
in the preparation method of the compound 5, the mass ratio of the organic solvent to the compound 7 is 1-100;
and/or the presence of a gas in the gas,
In the preparation method of the compound 5, the MOH is potassium hydroxide and/or sodium hydroxide;
And/or the presence of a gas in the gas,
in the preparation method of the compound 5, the molar ratio of the MOH to the compound 7 is 0.5-1.5;
And/or the presence of a gas in the gas,
in the preparation method of the compound 5, the reaction temperature is 10-35 ℃;
and/or the presence of a gas in the gas,
In the method for producing the compound 5, the reaction time is 1 to 10 hours;
And/or the presence of a gas in the gas,
the preparation method of the compound 5 comprises the following steps: adding a mixture formed by MOH and an organic solvent into a solution formed by a compound 7 and the organic solvent, and reacting to obtain a compound 5;
And/or the presence of a gas in the gas,
The preparation method of the compound 5 comprises the following post-treatment steps: after the reaction is finished, heating the reaction solution to reflux, carrying out heat filtration, cooling the filtrate to-5-0 ℃, and filtering to obtain the compound 5.
12. a process for the preparation of compound 9 according to claim 1, characterized in that: in the preparation method of the compound 9, the base is an organic base;
And/or the presence of a gas in the gas,
In the preparation method of the compound 9, the molar ratio of the catalyst to the compound 1 is 0.005-5.0;
And/or the presence of a gas in the gas,
in the process for the preparation of said compound 9, said base is used in the form of its hydrofluoride salt;
And/or the presence of a gas in the gas,
in the preparation method of the compound 9, the lactam is one or more of 1, 3-dimethyl-2-imidazolidinone, N-methylpyrrolidone, 2-pyrrolidone and formylhydantoin;
And/or the presence of a gas in the gas,
In the process for the preparation of said compound 9, said lactam is used in the form of its hydrofluoride salt;
And/or the presence of a gas in the gas,
in the preparation method of the compound 9, the fluorinating reagent is hydrofluoric acid;
and/or the presence of a gas in the gas,
In the preparation method of the compound 9, the molar ratio of the fluorination reagent to the compound 1 is 1.0-5.0; and/or the presence of a gas in the gas,
in the preparation method of the compound 9, the temperature of the halogen exchange reaction is 80-180 ℃;
And/or the presence of a gas in the gas,
in the method for producing the compound 9, the time of the halogen exchange reaction is 1 to 24 hours;
And/or the presence of a gas in the gas,
the preparation method of the compound 9 is carried out in a solvent or under the condition of no solvent;
and/or the presence of a gas in the gas,
the preparation method of the compound 9 comprises the following steps: adding a fluorinating reagent into a mixture formed by alkali and a compound 1, and carrying out halogen exchange reaction to obtain a compound 9;
and/or the presence of a gas in the gas,
The preparation method of the compound 9 adopts the following post-treatment steps: after the reaction is finished, the gas is discharged and the pressure is relieved, and the reaction liquid is directly used for the reaction for preparing the compound 10 without further treatment.
13. A process for the preparation of compound 9 according to claim 12, characterized in that:
In the preparation method of the compound 9, the organic base is one or more of triethylamine, tri-N-propylamine, tri-N-butylamine, N-dimethylaniline, pyridine, 2-methylpyridine and 4-methylpyridine;
And/or the presence of a gas in the gas,
in the preparation method of the compound 9, when the base is used in the form of the hydrofluoride salt thereof, the hydrofluoride salt of the base is the hydrofluoride salt of triethylamine and/or the hydrofluoride salt of pyridine;
And/or the presence of a gas in the gas,
In the preparation method of the compound 9, when the lactam is used in the form of its hydrofluoride salt, the hydrofluoride salt of the lactam is the hexadecahydrofluoride salt of 1, 3-dimethyl-2-imidazolidinone and/or the pentahydrofluoride salt of N-methylpyrrolidone;
And/or the presence of a gas in the gas,
In the preparation method of the compound 9, when the catalyst is in the form of alkali hydrofluoride, the molar ratio of the catalyst to the compound 1 is 1.0-3.0; when the catalyst is in the form of a base instead of a base hydrofluoride, the molar ratio of the catalyst to the compound 1 is 0.1-0.5; when the catalyst is lactam, the molar ratio of the catalyst to the compound 1 is 0.05-0.5; when the catalyst is antimony trichloride, the molar ratio of the catalyst to the compound 1 is 0.005-0.05; when the catalyst is hydrofluoride of lactam, the molar ratio of the catalyst to the compound 1 is 0.01-1;
And/or the presence of a gas in the gas,
in the preparation method of the compound 9, the molar ratio of the fluorination reagent to the compound 1 is 1.0-4.0;
And/or the presence of a gas in the gas,
in the preparation method of the compound 9, the temperature of the halogen exchange reaction is 100-160 ℃;
And/or the presence of a gas in the gas,
in the method for producing the compound 9, the time of the halogen exchange reaction is 5 to 15 hours;
and/or the presence of a gas in the gas,
In the preparation method of the compound 9, when the reaction is carried out in a solvent, the solvent is one or more of an ether solvent, an ester solvent, an aromatic hydrocarbon solvent and a nitrile solvent;
And/or the presence of a gas in the gas,
In the steps adopted in the preparation method of the compound 9, the temperature of the mixture of the alkali and the compound 1 is 125-130 ℃;
And/or the presence of a gas in the gas,
In the steps adopted by the preparation method of the compound 9, the adding mode is dropping, and the dropping speed is to maintain the system temperature at 130-155 ℃.
14. a process for the preparation of compound 10, characterized in that it comprises the following steps: the compound 9 is prepared by the preparation method of any one of claims 1 to 13; then in a solvent, carrying out hydrolysis reaction on the compound 9 in the presence of alkali to obtain a compound 10;
wherein R is1Are defined as in claim 1, and x is defined as in claim 1.
15. a process for the preparation of compound 10 according to claim 14, wherein:
In the preparation method of the compound 10, the solvent is an organic solvent and/or water;
And/or the presence of a gas in the gas,
In the preparation method of the compound 10, the mass ratio of the solvent to the compound 9 is 1-100;
and/or the presence of a gas in the gas,
in the preparation method of the compound 10, the base is an inorganic base;
And/or the presence of a gas in the gas,
In the preparation method of the compound 10, the base is used in the form of an aqueous solution thereof;
and/or the presence of a gas in the gas,
in the preparation method of the compound 10, the molar ratio of the alkali to the compound 9 is 1.0-5.0;
and/or the presence of a gas in the gas,
In the preparation method of the compound 10, the temperature of the hydrolysis reaction is 0-130 ℃;
And/or the presence of a gas in the gas,
In the preparation method of the compound 10, the hydrolysis reaction time is 1 to 10 hours;
And/or the presence of a gas in the gas,
the preparation method of the compound 10 adopts the following steps: adding an aqueous solution of alkali into a mixture formed by the compound 9 and an organic solvent for hydrolysis reaction to obtain a compound 10;
And/or the presence of a gas in the gas,
The preparation method of the compound 10 comprises the following post-treatment steps: after the reaction is finished, liquid separation and water phase pH adjustment are carried out to about 1.0, the temperature is reduced to 10-25 ℃, and the compound 10 is obtained after filtration and drying.
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