CN106467492A - The preparation method of polyfluoro methyl pyrazoles compound, intermediate and preparation method - Google Patents
The preparation method of polyfluoro methyl pyrazoles compound, intermediate and preparation method Download PDFInfo
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- CN106467492A CN106467492A CN201510502466.6A CN201510502466A CN106467492A CN 106467492 A CN106467492 A CN 106467492A CN 201510502466 A CN201510502466 A CN 201510502466A CN 106467492 A CN106467492 A CN 106467492A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 218
- -1 methyl pyrazoles compound Chemical class 0.000 title claims abstract description 28
- 238000006243 chemical reaction Methods 0.000 claims abstract description 178
- 229940125904 compound 1 Drugs 0.000 claims abstract description 89
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 claims abstract description 69
- 239000003960 organic solvent Substances 0.000 claims abstract description 53
- 229940125782 compound 2 Drugs 0.000 claims abstract description 40
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 37
- 239000002994 raw material Substances 0.000 claims abstract description 23
- 239000006227 byproduct Substances 0.000 claims abstract description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 200
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 152
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 122
- 150000001875 compounds Chemical class 0.000 claims description 100
- 239000000243 solution Substances 0.000 claims description 94
- 239000002904 solvent Substances 0.000 claims description 93
- 239000007864 aqueous solution Substances 0.000 claims description 85
- 235000011121 sodium hydroxide Nutrition 0.000 claims description 73
- 239000003513 alkali Substances 0.000 claims description 66
- 229940126214 compound 3 Drugs 0.000 claims description 61
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 54
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 49
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 45
- 239000000203 mixture Substances 0.000 claims description 45
- 239000007788 liquid Substances 0.000 claims description 43
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 42
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 39
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 38
- 238000000034 method Methods 0.000 claims description 37
- 229940125898 compound 5 Drugs 0.000 claims description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 35
- 208000035126 Facies Diseases 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
- 150000007530 organic bases Chemical class 0.000 claims description 30
- 239000002585 base Substances 0.000 claims description 29
- 229940125773 compound 10 Drugs 0.000 claims description 29
- 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 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- 239000002253 acid Substances 0.000 claims description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 24
- 150000003951 lactams Chemical class 0.000 claims description 24
- 239000007789 gas Substances 0.000 claims description 23
- 239000008346 aqueous phase Substances 0.000 claims description 21
- 239000000463 material Substances 0.000 claims description 21
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical group [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 20
- 239000003153 chemical reaction reagent Substances 0.000 claims description 20
- 150000007529 inorganic bases Chemical class 0.000 claims description 20
- 238000006482 condensation reaction Methods 0.000 claims description 18
- 238000003682 fluorination reaction Methods 0.000 claims description 18
- 238000012805 post-processing Methods 0.000 claims description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 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
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 150000002367 halogens Chemical group 0.000 claims description 14
- 235000011118 potassium hydroxide Nutrition 0.000 claims description 13
- PYOKUURKVVELLB-UHFFFAOYSA-N trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 claims description 12
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 11
- 150000002148 esters Chemical class 0.000 claims description 11
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 10
- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 10
- 150000001335 aliphatic alkanes 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
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- FAPDDOBMIUGHIN-UHFFFAOYSA-K antimony trichloride Chemical compound Cl[Sb](Cl)Cl FAPDDOBMIUGHIN-UHFFFAOYSA-K 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
- 159000000003 magnesium salts Chemical class 0.000 claims description 8
- 150000002825 nitriles Chemical group 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 239000004215 Carbon black (E152) Substances 0.000 claims description 7
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 7
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Substances ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 229930195733 hydrocarbon Natural products 0.000 claims description 7
- 239000000376 reactant Substances 0.000 claims description 7
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 7
- YJUUZFWMKJBVFJ-UHFFFAOYSA-N 1,3-dimethylimidazolidin-4-one Chemical compound CN1CN(C)C(=O)C1 YJUUZFWMKJBVFJ-UHFFFAOYSA-N 0.000 claims description 6
- NPDACUSDTOMAMK-UHFFFAOYSA-N 4-Chlorotoluene Chemical compound CC1=CC=C(Cl)C=C1 NPDACUSDTOMAMK-UHFFFAOYSA-N 0.000 claims description 6
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 239000000706 filtrate Substances 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 5
- 150000001298 alcohols Chemical group 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 5
- DKPFZGUDAPQIHT-UHFFFAOYSA-N butyl acetate Chemical compound CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 5
- 238000000605 extraction Methods 0.000 claims description 5
- 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 5
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 5
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-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
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 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
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 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
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 4
- 239000011736 potassium bicarbonate Substances 0.000 claims description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 235000011181 potassium carbonates Nutrition 0.000 claims description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 4
- YKYONYBAUNKHLG-UHFFFAOYSA-N propyl acetate Chemical compound CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 235000017550 sodium carbonate Nutrition 0.000 claims description 4
- 239000001117 sulphuric acid Substances 0.000 claims description 4
- 235000011149 sulphuric acid Nutrition 0.000 claims description 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 claims description 4
- ZPQOPVIELGIULI-UHFFFAOYSA-N 1,3-dichlorobenzene Chemical compound ClC1=CC=CC(Cl)=C1 ZPQOPVIELGIULI-UHFFFAOYSA-N 0.000 claims description 3
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 claims description 3
- DURPTKYDGMDSBL-UHFFFAOYSA-N 1-butoxybutane Chemical compound CCCCOCCCC DURPTKYDGMDSBL-UHFFFAOYSA-N 0.000 claims description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 3
- CMEWLCATCRTSGF-UHFFFAOYSA-N N,N-dimethyl-4-nitrosoaniline Chemical compound CN(C)C1=CC=C(N=O)C=C1 CMEWLCATCRTSGF-UHFFFAOYSA-N 0.000 claims description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- FKNQFGJONOIPTF-UHFFFAOYSA-N Sodium cation Chemical compound [Na+] FKNQFGJONOIPTF-UHFFFAOYSA-N 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 claims description 3
- 229910000343 potassium bisulfate Inorganic materials 0.000 claims description 3
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 3
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 3
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 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
- 229910001415 sodium ion Inorganic materials 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- 230000033228 biological regulation Effects 0.000 claims description 2
- 239000004202 carbamide Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- POLCUAVZOMRGSN-UHFFFAOYSA-N dipropyl ether Chemical compound CCCOCCC POLCUAVZOMRGSN-UHFFFAOYSA-N 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 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
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 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
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 3
- 125000001033 ether group Chemical group 0.000 claims 3
- PZHIWRCQKBBTOW-UHFFFAOYSA-N 1-ethoxybutane Chemical compound CCCCOCC PZHIWRCQKBBTOW-UHFFFAOYSA-N 0.000 claims 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 1
- 230000001133 acceleration Effects 0.000 claims 1
- 238000006555 catalytic reaction Methods 0.000 claims 1
- 239000012295 chemical reaction liquid Substances 0.000 claims 1
- MVPPADPHJFYWMZ-IDEBNGHGSA-N chlorobenzene Chemical group Cl[13C]1=[13CH][13CH]=[13CH][13CH]=[13CH]1 MVPPADPHJFYWMZ-IDEBNGHGSA-N 0.000 claims 1
- 150000002170 ethers Chemical class 0.000 claims 1
- HZZOEADXZLYIHG-UHFFFAOYSA-N magnesiomagnesium Chemical compound [Mg][Mg] HZZOEADXZLYIHG-UHFFFAOYSA-N 0.000 claims 1
- 239000011777 magnesium Substances 0.000 claims 1
- 229910052749 magnesium Inorganic materials 0.000 claims 1
- 239000011698 potassium fluoride Substances 0.000 claims 1
- 235000003270 potassium fluoride Nutrition 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 235000015424 sodium Nutrition 0.000 claims 1
- 229910052717 sulfur Inorganic materials 0.000 claims 1
- 239000011593 sulfur Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 13
- 239000000047 product Substances 0.000 abstract description 4
- 208000012839 conversion disease Diseases 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 49
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 40
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 30
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 24
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 24
- 238000012423 maintenance Methods 0.000 description 23
- 229910052757 nitrogen Inorganic materials 0.000 description 20
- 238000010926 purge Methods 0.000 description 20
- 238000010521 absorption reaction Methods 0.000 description 19
- 229910052799 carbon Inorganic materials 0.000 description 19
- 239000012141 concentrate Substances 0.000 description 18
- 239000007791 liquid phase Substances 0.000 description 17
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 16
- 210000004905 finger nail Anatomy 0.000 description 14
- 239000000155 melt Substances 0.000 description 13
- 238000009413 insulation Methods 0.000 description 12
- 150000003217 pyrazoles Chemical class 0.000 description 12
- 239000008096 xylene Substances 0.000 description 12
- 230000000052 comparative effect Effects 0.000 description 11
- 229960004756 ethanol Drugs 0.000 description 11
- 239000007787 solid Substances 0.000 description 11
- 125000004494 ethyl ester group Chemical group 0.000 description 10
- FBCCMZVIWNDFMO-UHFFFAOYSA-N dichloroacetyl chloride Chemical compound ClC(Cl)C(Cl)=O FBCCMZVIWNDFMO-UHFFFAOYSA-N 0.000 description 9
- WWTULTKUWBKVGV-UHFFFAOYSA-M potassium;3-methoxy-3-oxopropanoate Chemical compound [K+].COC(=O)CC([O-])=O WWTULTKUWBKVGV-UHFFFAOYSA-M 0.000 description 8
- 238000012544 monitoring process Methods 0.000 description 7
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 7
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 6
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 6
- 230000000844 anti-bacterial effect Effects 0.000 description 6
- 238000004807 desolvation Methods 0.000 description 6
- 230000000977 initiatory effect Effects 0.000 description 6
- 238000010792 warming Methods 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- 238000007796 conventional method Methods 0.000 description 4
- 150000004702 methyl esters Chemical class 0.000 description 4
- 238000002156 mixing Methods 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
- 238000011084 recovery Methods 0.000 description 4
- 238000007127 saponification reaction Methods 0.000 description 4
- BFKJFAAPBSQJPD-UHFFFAOYSA-N tetrafluoroethene Chemical compound FC(F)=C(F)F BFKJFAAPBSQJPD-UHFFFAOYSA-N 0.000 description 4
- PNQBEPDZQUOCNY-UHFFFAOYSA-N trifluoroacetyl chloride Chemical compound FC(F)(F)C(Cl)=O PNQBEPDZQUOCNY-UHFFFAOYSA-N 0.000 description 4
- AIDLAEPHWROGFI-UHFFFAOYSA-N 2-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=C(C(O)=O)C=CC=C1C(O)=O AIDLAEPHWROGFI-UHFFFAOYSA-N 0.000 description 3
- 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
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 3
- 239000005799 Isopyrazam Substances 0.000 description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 3
- 238000011031 large-scale manufacturing process Methods 0.000 description 3
- JBUXDBAQTRJHNJ-UHFFFAOYSA-N methyl 4,4-dichloro-3-oxobutanoate Chemical compound COC(CC(=O)C(Cl)Cl)=O JBUXDBAQTRJHNJ-UHFFFAOYSA-N 0.000 description 3
- 238000001291 vacuum drying Methods 0.000 description 3
- ZGOAEMCMBVUNMX-UHFFFAOYSA-N 1,1'-biphenyl;1h-pyrrole Chemical compound C=1C=CNC=1.C1=CC=CC=C1C1=CC=CC=C1 ZGOAEMCMBVUNMX-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
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 2
- MTPJEFOSTIKRSS-UHFFFAOYSA-N 3-(dimethylamino)propanenitrile Chemical compound CN(C)CCC#N MTPJEFOSTIKRSS-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- CKVLFNBLOAUSQQ-UHFFFAOYSA-N CNN.CO Chemical compound CNN.CO CKVLFNBLOAUSQQ-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
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- ONKVRLIMFCFLPP-UHFFFAOYSA-N [K].C(CC(=O)O)(=O)O.[K] Chemical compound [K].C(CC(=O)O)(=O)O.[K] ONKVRLIMFCFLPP-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012467 final product Substances 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
- 230000020477 pH reduction Effects 0.000 description 2
- 239000000575 pesticide Substances 0.000 description 2
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical class F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000005070 sampling Methods 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
- 239000000126 substance Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect 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
- YZBBUYKPTHDZHF-KNVGNIICSA-N (3R)-7,2'-dihydroxy-4'-methoxyisoflavanol Chemical compound OC1=CC(OC)=CC=C1[C@H]1C(O)C2=CC=C(O)C=C2OC1 YZBBUYKPTHDZHF-KNVGNIICSA-N 0.000 description 1
- XHILZHAQBOLGFD-UHFFFAOYSA-N 1,1-difluoropropan-2-one Chemical compound CC(=O)C(F)F XHILZHAQBOLGFD-UHFFFAOYSA-N 0.000 description 1
- 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 1
- HLYYXPDTFLUERX-UHFFFAOYSA-N 3-methyl-pyrazole-4-carboxylic acid Chemical compound CC=1NN=CC=1C(O)=O HLYYXPDTFLUERX-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 239000005738 Bixafen Substances 0.000 description 1
- UVRQIFLAQQKWKR-UHFFFAOYSA-N C(C=1C(C(=O)OC)=CC=CC1)(=O)OC.[P] Chemical compound C(C=1C(C(=O)OC)=CC=CC1)(=O)OC.[P] UVRQIFLAQQKWKR-UHFFFAOYSA-N 0.000 description 1
- 0 C*c1c[n](C)nc1C Chemical compound C*c1c[n](C)nc1C 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 238000003512 Claisen condensation reaction Methods 0.000 description 1
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical class CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- UDSJPFPDKCMYBD-UHFFFAOYSA-N Metsulfovax Chemical compound S1C(C)=NC(C)=C1C(=O)NC1=CC=CC=C1 UDSJPFPDKCMYBD-UHFFFAOYSA-N 0.000 description 1
- 101000905241 Mus musculus Heart- and neural crest derivatives-expressed protein 1 Proteins 0.000 description 1
- 239000005816 Penthiopyrad Substances 0.000 description 1
- NPYPAHLBTDXSSS-UHFFFAOYSA-N Potassium ion Chemical compound [K+] NPYPAHLBTDXSSS-UHFFFAOYSA-N 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- BZHJMEDXRYGGRV-UHFFFAOYSA-N Vinyl chloride Chemical compound ClC=C BZHJMEDXRYGGRV-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 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 1
- 230000007547 defect Effects 0.000 description 1
- 150000004816 dichlorobenzenes Chemical class 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000005553 drilling Methods 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- VCYZVXRKYPKDQB-UHFFFAOYSA-N ethyl 2-fluoroacetate Chemical class CCOC(=O)CF VCYZVXRKYPKDQB-UHFFFAOYSA-N 0.000 description 1
- SIJOCEACGCHNSI-UHFFFAOYSA-N ethyl 4,4-dichloro-3-oxobutanoate Chemical compound ClC(C(CC(=O)OCC)=O)Cl SIJOCEACGCHNSI-UHFFFAOYSA-N 0.000 description 1
- MJEMIOXXNCZZFK-UHFFFAOYSA-N ethylone Chemical compound CCNC(C)C(=O)C1=CC=C2OCOC2=C1 MJEMIOXXNCZZFK-UHFFFAOYSA-N 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 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
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 150000002561 ketenes Chemical class 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000006386 neutralization reaction Methods 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
- 239000003208 petroleum Substances 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 230000008092 positive effect Effects 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
- 229910001950 potassium oxide Inorganic materials 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 230000000630 rising effect Effects 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
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- NTJBWZHVSJNKAD-UHFFFAOYSA-N triethylazanium;fluoride Chemical class [F-].CC[NH+](CC)CC NTJBWZHVSJNKAD-UHFFFAOYSA-N 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 the preparation method of polyfluoro methyl pyrazoles compound, intermediate and preparation method.The invention provides a kind of preparation method of compound 1, it comprises the following steps：In organic solvent, compound 2 and methyl hydrazine are carried out ring-closure reaction, obtains compound 1；Wherein, R1For C1～C4Alkyl；R2For methyl or ethyl；X is 2 or 3.The product purity that the preparation method raw material of the present invention is cheap and easy to get, reaction condition gentle, safe operation, environmental friendliness, low production cost, reaction conversion ratio are high, by-product content of isomer is low, reaction yield is high, be obtained is high, be suitable for industrialized production.
Description
Technical field
Present invention relates particularly to the preparation method of polyfluoro methyl pyrazoles compound, intermediate and preparation method.
Background technology
3- difluoromethyl -1H- methylpyrazole -4- carboxylic acid is a kind of important pesticide intermediate, is used to synthesize the new of BASF
The fluxapyroxad of one of the main active of type antibacterial Priaxor, can be used to produce the antibacterial Bixafen of Bayer
(biphenyl pyrrole bacterium amine) and the antibacterial Isopyrazam (isopyrazam) first just reaching.3- Trifluoromethyl-1 H- methylpyrazole
- 4- carboxylic acid is similarly a kind of important pesticide intermediate, for producing the antibacterial Penthiopyrad of Mitsui's exploitation
(pyrrole metsulfovax).
Mainly there is the synthetic method of several 3- difluoromethyl -1H- methylpyrazole -4- carboxylic acids as follows at present：
First, with many ethyl fluoroacetates as raw material, after Claisen condensation, methylamino ethoxy alkylene, cyclization, saponification, acidifying,
Obtain 3- difluoromethyl -1H- methylpyrazole -4- carboxylic acid (WO2011113789, EP1997808, US5093347,
WO2010009990)；Or 3- Trifluoromethyl-1 H- methylpyrazole -4- carboxylic acid (CN103694119, US8115012,
JP2010202648、JP2000212166、CN101977889).
2nd, with difluoro acetone as raw material, after methyl hydrazine condensation, by phosphorus oxychloride cyclization, hydrogen peroxide oxidation is to obtain
Obtain 3- difluoromethyl -1H- methylpyrazole -4- carboxylic acid (EP2008996)；
3rd, with tetrafluoroethene as raw material, after dimethylamine addition, and the condensation of 3- ethoxy ethyl acrylate, then with first
Base hydrazine cyclization obtain 3- difluoromethyl -1H- methylpyrazole -4- carboxylic acid (J.Fluorine Chem., 2001,109 (1)：25～31；
CN101720317)；
4th, with trifluoro-acetyl chloride as raw material, after being coupled with 3- dimethylaminopropionitrile, with methyl hydrazine cyclization, finally hydrolyze
After acidifying, obtain final product target product (CN101627015)；
5th, with trifluoroacetic acid as raw material, after being prepared into trifluoro-acetyl chloride, it is coupled with 3- dimethylamino ethyl acrylate, then
With methyl hydrazine cyclization, after last saponification and acidifying, obtain 3- Trifluoromethyl-1 H- methylpyrazole -4- carboxylic acid (CN101977889)
6th, with dichloroacetyl chloride as raw material, after being coupled with 3- dimethylamino ethyl acrylate, with methyl hydrazine cyclization
(CN1871204), then using fluorination hydrofluorination (CN1875006), after last saponification and acidifying, obtain 3- difluoro
Methyl isophthalic acid H- methylpyrazole -4- carboxylic acid (CN102731402)；
In above six kinds of methods, first five kind method all synthesizes 3- polyfluoro methyl isophthalic acid H- using fluorochemical for initiation material
Methylpyrazole -4- carboxylic acid, because the fluorine-containing prices of raw materials are typically relatively expensive, meanwhile, the loss of yield in follow-up reaction
Raw material consumption is caused to dramatically increase, so, comparatively relatively costly, it is not suitable for industrialized production.
Method one considerably increases the cost of 3- difluoromethyl -1H- methylpyrazole -4- carboxylic acid using fluorine-containing raw material as initiation material.
Meanwhile, the experiment of the further repetition methods of inventor one (being specifically shown in comparative example 4), finds in cyclization step, 3-
When ethyoxyl -2- difluoro acetyl group ethyl acrylate is raw material, the ratio of cyclization isomer is up to 8.3%.
According to patent report, when not using NaOH, using 3- ethyoxyl -2- difluoro acetyl group ethyl acrylate and methyl
Hydrazine cyclization, the content of isomer is in 8%～10% (EP1997808), when naoh is used, 3- ethyoxyl -2- difluoro second
Acyl group ethyl acrylate and methyl hydrazine cyclization, the content of isomer is minimum to be still up to 3% about (EP1997808)；And make
With 3- dimethylamino -2- dichloro-acetyl acrylic acid methyl ester. and methyl hydrazine cyclization, under -50 DEG C of low temperature, the content of isomer is high
Reach 6.2%, and at other temperature, content of isomer highest more reaches 38.3% (CN1871204).Due to too high different
Structure body burden, reduce further total recovery and increased totle drilling cost.Turn for this reason, first just reaching and also exclusively carrying out isomer
The research of position, is shown by these researchs, using dimethyl sulfate (CN102471279, CN103052625) or phosphorus
Dimethyl phthalate (CN1871204), although the indexing of cyclization isomer can be carried out well, increased extra material
Use, and dimethyl sulfate belongs to toxic articles, production equipment and production site is required harsh, further,
Also add extra post processing cost.
Method two total recovery only has 36.6%, has further related to the use of toxic articles phosphorus oxychloride, increased workman's production operation
Danger, meanwhile, the seriously corroded to equipment is so that the requirement to operative place and consersion unit is more harsh.
Method three total recovery about 48%, meanwhile, raw material tetrafluoroethene toxicity itself is higher.When participating in reaction as gas,
It is lost larger in course of reaction.Additionally, explosive mixture can be formed when tetrafluoroethene is mixed with air, undoubtedly increased
Production risk.Particular, it is important that the easy polymerization property of tetrafluoroethene further increases the unit consumption of raw material and anti-
Answer the cost of post processing.Many factors are so that the large-scale industrial productionization application of the method is restricted above.
Method four increased cost and unit consumption, 3- dimethylaminopropionitrile except employing fluorine-containing initiation material trifluoro-acetyl chloride
More difficult obtain from market, institute relatively costly in this way.
Method five total recovery 55.7%, meanwhile, raw material is related to the use of fluorochemical trifluoro-acetyl chloride, additionally, another
Initiation material 3- dimethylamino ethyl acrylate is not only expensive but also is difficult to purchase, and limits the method answering in large-scale production
With.
Method six, according to patent CN102731402, prepares 3- difluoromethyl -1H- methylpyrazole -4- carboxylic acid and preparation 3- tri-
Methyl fluoride -1H- methylpyrazole -4- carboxylic acid, employing chloride raw material is initiation material, meanwhile, by fluorination step in cyclization
After carry out, but, expensive and be difficult to the use of raw material 3- dimethylamino ethyl acrylate purchased, had a strong impact on final
The cost of product, also undoubtedly limits application in large-scale production for the method.Meanwhile, according to patent CN1871204
Record, with 2- dichloro-acetyl -3- dimethylamino acrylate as intermediate, when cyclization react when carrying out for 0 DEG C, different
Structure body 5- dichloromethyl -1H- methylpyrazole carboxylic acid ester content is up to 18.6%, with the rising of cyclization reaction temperature, when anti-
When to answer temperature be 40 DEG C, isomer 5- dichloromethyl -1H- methylpyrazole carboxylic acid ester content is even as high as 38.3%, works as cyclization
During as little as -20 DEG C of reaction temperature, isomer 5- dichloromethyl -1H- methylpyrazole carboxylic acid ester content still up to 12.7%, cyclization
During as little as -50 DEG C of reaction temperature, also it is only capable of controlling content of isomer 6.2%.And, inventor uses substrate 2- dichloro
The result that acetyl group -3- dimethylamino acrylate reacts to this step cyclization is verified, result and patent CN1871204
Unanimously, content of isomer is 12.7～17.5%.Higher content of isomer and too low reaction temperature, it will greatly increase
The cost producing and energy consumption, make the method should not be used in large-scale production.
Up to the present, in the route of report, produce 3- difluoromethyl -1H- methylpyrazole -4- carboxylic acid cost all relative to mistake
Height, is unfavorable for industrialized production.Due to fluxapyroxad, biphenyl pyrrole bacterium amine and these three antibacterial demands of isopyrazam
Continuous growth so that producing the one-tenth of the key intermediate 3- difluoromethyl -1H- methylpyrazole -4- carboxylic acid of these three antibacterial
This demand more and more higher, urgent needss exploitation one kind is inexpensive, reaction condition is gentle, high conversion rate, by-product are few, behaviour
Make safety, environmental friendliness, be suitable for industrialized production 3- difluoromethyl -1H- methylpyrazole -4- carboxylic acid technique.
Content of the invention
The technical problem to be solved is to overcome 3- difluoromethyl -1H- methylpyrazole -4- carboxylic acid in prior art
Preparation method production cost height, severe reaction conditions, reaction conversion ratio is low, by-product is many, reaction yield is low, use
The defect such as hypertoxic raw material, processing safety are low, environmental pollution is serious, and provide 3- polyfluoro methyl pyrazoles compound and
The preparation method of its intermediate.The preparation method raw material of the present invention is cheap and easy to get, reaction condition gentle, safe operation, ring
Border close friend, low production cost, reaction conversion ratio is high, by-product content of isomer is low, reaction yield is high, the product that is obtained
Purity is high, be suitable for industrialized production.
The invention provides a kind of preparation method of compound 1, it comprises the following steps：In organic solvent, by compound 2
Carry out ring-closure reaction with methyl hydrazine, obtain compound 1；
Wherein, R1For C1～C4Alkyl, described C1～C4Alkyl for example methyl, ethyl, n-pro-pyl (n-Pr),
Isopropyl (i-Pr), normal-butyl (n-Bu), isobutyl group (i-Bu), sec-butyl (s-Bu) or the tert-butyl group (t-Bu), excellent
Select methyl or ethyl；R2For methyl or ethyl, preferably ethyl；X is 2 or 3.
In the preparation method of described compound 1, described organic solvent can be such ring-closure reaction in this area
One of conventional organic solvent, preferably ether solvent, aromatic hydrocarbon solvent, alkane solvents and halogenated aryl hydrocarbon class solvent or
Multiple；Further preferably aromatic hydrocarbon solvent.The preferred ether of described ether solvent, positive propyl ether, diisopropyl ether, the positive fourth of ethyl
One or more of base ether, n-butyl ether and n-amylether.The preferred benzene of described aromatic hydrocarbon solvent, toluene, ethylbenzene, diformazan
One or more of benzene, o-Dimethylbenzene, meta-xylene and xylol, further preferred toluene and/or dimethylbenzene.Institute
The preferred chlorobenzene of halogenated aryl hydrocarbon class solvent stated, o-dichlorohenzene, m-dichlorobenzene, paracide, ortho-chlorotolu'ene, parachlorotoluene
One or more of with m-chlorotoluene.The preferred C of described alkane solvents1～C8Alkane solvents, described C1～C8
Alkane solvents such as one or more of normal hexane, normal heptane and hexamethylene.
In the preparation method of described compound 1, described organic solvent is excellent with the mass values of described compound 2
Select 1～100, further preferred 2～10.
In the preparation method of described compound 1, described methyl hydrazine can be with directly use or in the form of its solution
Use, when described methyl hydrazine is used in the form of its solution, the mass concentration preferably 20%～70% of methyl hydrazine solution,
Further preferred 30%～60%；Described mass concentration refers to that the quality of methyl hydrazine accounts for the percentage of methyl hydrazine solution gross mass
Than.When described methyl hydrazine is used in the form of its solution, the solvent of methyl hydrazine solution can be water, methanol or ethanol,
Preferably water.
In the preparation method of described compound 1, described compound 2 is preferred with the mol ratio of described methyl hydrazine
1:1.0～1:2.5, further preferred 1:1.0～1:1.5.
In the preparation method of described compound 1, the temperature of described ring-closure reaction can be such cyclization in this area
The ordinary temperature of reaction, preferably -50 DEG C～50 DEG C, further preferred 0～25 DEG C.
In the preparation method of described compound 1, the process of described ring-closure reaction can be using the routine in this area
Monitoring method (such as TLC, HPLC or GC) is monitored, typically with compound 2 disappear when as reaction end, institute
Preferably 1 hour～5 hours time of the ring-closure reaction stated, further preferred 1 hour～3 hours.
The preparation method of described compound 1 can be carried out in the presence of a base, when the preparation of described compound 1
When method is carried out in the presence of a base, described alkali can be organic base or inorganic base, preferably inorganic base；Described
One of the preferred sodium hydroxide of inorganic base, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate or many
Kind, further preferred sodium hydroxide and/or potassium hydroxide.The preferred triethylamine of described organic base, tri-n-butylamine, pyridine,
One or more of tetramethylethylenediamine, N-methylmorpholine and DMAP, further preferred triethylamine, three
N-butylamine or pyridine.Described inorganic base directly using or in the form of its aqueous solution use, when described inorganic base with
When the form of its aqueous solution uses, the mass concentration preferably 30%～60% of inorganic base aqueous solution, described mass concentration is
The quality referring to inorganic base accounts for the percentage ratio of inorganic base aqueous solution gross mass.
Described alkali and the mol ratio preferably 0.005～0.3, further preferred 0.05～0.25 of described compound 2.
The preparation method of described compound 1 preferably employs following steps：The solution that compound 2 is formed with organic solvent
Add in the mixture that methyl hydrazine is formed with organic solvent, carry out ring-closure reaction and obtain compound 1 or methyl hydrazine is added
In the solution being formed with organic solvent to compound 2, carry out ring-closure reaction and obtain compound 1.Further preferably by compound
2 solution being formed with organic solvent are added in the mixture that methyl hydrazine is formed with organic solvent, carry out ring-closure reaction and obtain chemical combination
Thing 1.The preferred Deca of mode of described addition, the speed of described Deca is defined less than 25 DEG C by system temperature.
The preparation method of described compound 1 preferably includes following post-processing step：After reaction terminates, point liquid, organic faciess
Remove solvent, obtain compound 1.The described solvent that removes can be using the conventional method of this generic operation in this area, such as
Concentrating under reduced pressure.Described point liquid can be using the conventional method of this generic operation in this area, and described point liquid can be for adding water
Directly divide liquid or extraction point liquid afterwards；The preferred toluene of solvent and/or dimethylbenzene that described extraction adopts.
In the present invention, the preparation method of described compound 1, further comprising the steps：By compound 3, compound
4 and acetic anhydride carry out condensation reaction, obtain described compound 2；
Wherein, R1、R2All same as above with the definition of x.
In the preparation method of described compound 2, described compound 3 further preferably arbitrary compound as follows：
In the preparation method of described compound 2, described compound 4 is trimethyl orthoformate or triethyl orthoformate,
Preferably triethyl orthoformate.
In the preparation method of described compound 2, described compound 3 is excellent with the molar ratio of described compound 4
Select 1.0～5.0, further preferred 1.0～3.5.
In the preparation method of described compound 2, described acetic anhydride is preferred with the molar ratio of described compound 4
1.0～5.0, further preferred 2.0～3.5.
In the preparation method of described compound 2, the temperature of described condensation reaction can be such condensation in this area
The ordinary temperature of reaction, preferably 95 DEG C～115 DEG C, further preferred 100 DEG C～110 DEG C.
In the preparation method of described compound 2, the process of described condensation reaction can be using the routine in this area
Monitoring method (such as TLC, HPLC or GC) is monitored, typically with compound 3 disappear when as reaction end, institute
Preferably 1 hour～24 hours time of the condensation reaction stated, further preferred 1 hour～5 hours.
The preparation method preferred side border ring of described compound 2 is distilled off the by-product acetate generating, and promotes reaction
Carrying out.
The preparation method of described compound 2 can carry out, preferably solvent-free bar in a solvent or under the conditions of solvent-free
Carry out under part.
The preparation method of described compound 2 preferably includes following post-processing step：After reaction terminates, it is cooled to 10～35 DEG C,
Make system vacuum keep 10～20mbar, slowly system interior temperature is risen to 100 DEG C of unreacted raw materials of removing by 10～35 DEG C
And by-product, obtain compound 2.
In the present invention, described compound 3 can according to document Org.Process Res.Dev., 2010,14 (1):152；Or
Synthesis,1993,(3):The method of 290. reports is obtained, or is obtained by the following method：
In the present invention, the preparation method of described compound 1, further comprising the steps：In organic solvent, inorganic
Under conditions of magnesium salt and organic base exist, compound 5 and compound 6 are carried out condensation reaction, then adjust again pH to
3～8, carry out decarboxylic reaction, obtain described compound 3；
Wherein, R1All same as above with the definition of x；M+Represent potassium ion (K+) or sodium ion (Na+), preferably potassium from
Sub (K+).
In the preparation method of described compound 3, described organic solvent can be such condensation reaction in this area
Conventional organic solvent, preferably nitrile solvents and/or esters solvent.The preferred acetonitrile of described nitrile solvents.Described esters are molten
Agent ethyl acetate, methyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, sec-butyl acetate and second
One or more of tert-butyl acrylate, further preferred ethyl acetate.
In the preparation method of described compound 3, described organic solvent is excellent with the mass values of described compound 6
Select 1～100, further preferred 5～15.
In the preparation method of described compound 3, described compound 5 is excellent with the molar ratio of described compound 6
Select 1.0～2.0, further preferred 1.0～1.5.
In the preparation method of described compound 3, described inorganic magnesium salt refers to the inorganic salt that magnesium metal is formed with acid,
Preferably one or more of magnesium chloride, magnesium acetate, magnesium nitrate, magnesium sulfate, magnesium bromide and magnesium iodide, further preferably
Magnesium chloride.
In the preparation method of described compound 3, the preferred triethylamine of described organic base, Tri-n-Propylamine, tri-n-butylamine,
Diisopropyl ethyl amine, DMA and N, one or more of N- diethylaniline, further preferred three second
Amine.
In the preparation method of described compound 3, described organic base is preferred with the molar ratio of described compound 6
1.0～5.0, further preferred 1.0～2.5.
In the preparation method of described compound 3, described organic base is preferred with the molar ratio of described compound 5
1.0～5.0, further preferred 1.5～2.5.
In the preparation method of described compound 3, described inorganic magnesium salt is excellent with the molar ratio of described compound 6
Select 1.0～5.0, further preferred 1.0～2.5.
In the preparation method of described compound 3, the temperature of described condensation reaction can be such condensation in this area
The ordinary temperature of reaction, preferably 0 DEG C～35 DEG C.
In the preparation method of described compound 3, the process of described condensation reaction can be using the routine in this area
Monitoring method (such as TLC, HPLC or GC) is monitored, typically with compound 6 disappear when as reaction end, institute
Preferably 1 hour～48 hours time of the condensation reaction stated, further preferred 15 hours～25 hours.
In the preparation method of described compound 3, described regulation pH to 3～8 preferably employs addition acidic materials and realizes,
One or more of the preferred hydrochloric acid of described acidic materials, sulphuric acid, phosphoric acid, hydrobromic acid, sodium bisulfate and potassium acid sulfate,
Further preferably hydrochloric acid.Described acidic materials can be used in the form of its solution, when described acidic materials are molten with it
When the form of liquid uses, the mass concentration preferably 1%～20%, further preferred 3%～10% of acidic materials solution, institute
The mass concentration stated refers to the quality of acidic materials and the percentage ratio of acidic materials solution gross mass.Described dilute acid soln
Mass concentration preferably 3%～10%, described mass concentration refers to that the quality of acid accounts for the percentage ratio of dilute acid soln gross mass.Institute
Acid in the diluted acid stated preferably hydrochloric acid.
In the preparation method of described compound 3, preferably 0 DEG C～15 DEG C of the temperature that described deacidification is reacted.
In the preparation method of described compound 3, the process of described deacidification reaction can be using the routine in this area
Monitoring method (such as TLC, HPLC or GC) is monitored, and with the G/C content of compound 3 more than 80% is typically
Reaction end, preferably 0.5 hour～10 hours time of described decarboxylic reaction, further preferred 0.5 hour～2 hours.
The preparation method of described compound 3 preferably includes following steps：By inorganic magnesium salt add compound 5, organic base with
In the mixture that organic solvent is formed, react 2 hours～3 hours, then lower the temperature, add compound 6, carry out condensation reaction,
Then adjust pH to 3～8, carry out decarboxylic reaction and obtain described compound 3.Described " compound 5, organic
Preferably 0～25 DEG C of the temperature of the mixture that alkali is formed with organic solvent ", further preferred 10 DEG C～25 DEG C.Described is " anti-
Answer 2 hours～3 hours " preferably 10 DEG C～35 DEG C of reaction temperature, further preferred 20 DEG C～25 DEG C.Described cooling
Preferably 0 DEG C～35 DEG C of temperature, further preferred 0 DEG C～25 DEG C, still further preferably 0 DEG C～10 DEG C.Described addition
The preferred Deca of mode, the speed of described Deca is defined less than 35 DEG C by system temperature, preferably more than 25 DEG C, enters
Preferably more than 10 DEG C of one step.
In the preparation method of compound 3, preferably include following post-processing step, after reaction terminates, point liquid, organic faciess
Described compound 3 is obtained using dilute acid soln washing, removing solvent.The mass concentration of described dilute acid soln be 3%～
10%, described mass concentration refers to that the quality of acid accounts for the percentage ratio of dilute acid soln gross mass.Acid in described diluted acid is excellent
Select hydrochloric acid.
In the present invention, the preparation method of described compound 1, further comprising the steps：In organic solvent, will change
Compound 7 and MOH carry out reacting the compound 5 described in obtaining；
Wherein, R1And M+Definition be all the same as those described above.
In the preparation method of described compound 5, described organic solvent can be the routine of such reaction in this area
Organic solvent, preferably alcohols solvent.The preferred C of described alcohols solvent1～C4Alcohols solvent, described C1～C4Alcohol
One or more of the preferred methanol of class solvent, ethanol, normal propyl alcohol, isopropanol, n-butyl alcohol and tert-butyl alcohol, excellent further
Select methanol and/or ethanol.
In the preparation method of described compound 5, described organic solvent is excellent with the mass values of described compound 7
Select 1～100, further preferred 2～10.
In the preparation method of described compound 5, described MOH is potassium hydroxide and/or sodium hydroxide, preferably hydrogen
Potassium oxide.
In the preparation method of described compound 5, described MOH is preferred with the molar ratio of described compound 7
0.5～1.5, further preferred 0.9～1.2.
In the preparation method of described compound 5, the temperature of described reaction can be the normal of such reaction in this area
Rule temperature, preferably 10 DEG C～35 DEG C.
In the preparation method of described compound 5, the process of described reaction can be using the routine monitoring in this area
Method (such as TLC, HPLC or GC) is monitored, typically with compound 7 disappear when as reaction end, described
Preferably 1 hour～10 hours time of reaction, further preferred 3 hours～5 hours.
The preparation method of described compound 5 preferably includes following steps：The mixture that MOH is formed with organic solvent
Add in the solution that compound 7 is formed with organic solvent, carry out reacting the compound 5 described in obtaining.Described adds
The preferred Deca of mode entering, the speed of Deca is defined less than 35 DEG C by system temperature.Described MOH and organic solvent
In the mixture being formed, the mass values of described organic solvent and described MOH preferably 5～15, further preferred 8～
13.In the solution that described compound 7 is formed with organic solvent, the matter of described organic solvent and described compound 7
Amount ratio preferably 2.5～4.5, further preferred 2.8～4.2.
The preparation method of described compound 5 preferably includes following post-processing step：After reaction terminates, reactant liquor is heated to
(temperature of solvent refluxing, such as solvent are that during ethanol, reflux temperature is 79 DEG C～80 DEG C for backflow；Solvent is for flowing back during methanol
Temperature is 65 DEG C～68 DEG C), heat filter, filtrate is cooled to -5 DEG C～0 DEG C, is filtrated to get described compound 5.It is filtrated to get
Filtrate after described compound 5 preferably removes partial solvent (the 70%～80% of solvent usage amount in course of reaction), then
Obtain part of compounds 5.
Present invention also offers the preparation method of compound 9, it comprises the following steps：In enclosed system, catalyst exists
Under conditions of, described compound 1 is carried out halogen exchange reaction with fluorination reagent, obtains compound 9；Described
Catalyst be one or more of alkali, lactams and Butter of antimony.；
Wherein, R1All same as above with the definition of x.
The preparation method of described compound 9 can be the conventional method of such halogen exchange reaction in this area and condition,
Particularly preferably following reaction condition in the present invention：
In the preparation method of described compound 9, the preferred organic base of described alkali, the preferred triethylamine of described organic base,
Tri-n-Propylamine, tri-n-butylamine, N, one of accelerine, pyridine, 2- picoline and 4- picoline or many
Kind, further preferred triethylamine and/or pyridine.Described alkali can also its hydrofluoride form use, such as triethylamine
Hydrogen fluoride salts or pyridine hydrogen fluoride salts.Identical rubbing can be substituted when described alkali is used in the form of its hydrofluoride
The fluorination reagent of your amount.
In the preparation method of described compound 9, described lactams refer to the chemical combination that there is intramolecular amide base group
One of urea in thing, preferably DMI, N-Methyl pyrrolidone, 2-Pyrrolidone and formyl second
Or multiple, further preferred DMI and/or N-Methyl pyrrolidone.Described lactams can also
Form use, ten hexahydro fluorate of such as DMI and/or the N- crassitude of its hydrofluoride
Five hydrofluorides of ketone.The fluorine of same molar can be substituted when described lactams are used in the form of its hydrofluoride
Change reagent.
In the preparation method of described compound 9, described catalyst is preferred with the molar ratio of described compound 1
0.005～5.0.When the hydrofluoride form that described catalyst is alkali, described catalyst and described compound 1
Molar ratio preferably 1.0～3.0.When the hydrofluoride form that described catalyst is alkali rather than alkali, described catalyst
Molar ratio preferably 0.1～0.5 with described compound 1.When described catalyst is lactams, described catalyst
Molar ratio preferably 0.05～0.5, further preferred 0.05～0.2 with described compound 1.When described catalyst is
During Butter of antimony., the molar ratio preferably 0.005～0.05 of described catalyst and described compound 1, further preferably
0.01～0.02.When described catalyst is lactams hydrofluoride, described catalyst is rubbed with described compound 1
That ratio preferably 0.01～1, further preferred 0.2～0.8.
In the preparation method of described compound 9, described fluorination reagent preferred fluorinated hydrogen (HF), the hydrogen of organic base
One or more of fluorate, the hydrofluoride of lactams, potassium fluoride (KF) and cesium fluoride, are further preferably fluorinated
Hydrogen (HF), ten hexahydro fluorate of 1,3- dimethyl-2-imidazolinone, five hydrofluorides of N-Methyl pyrrolidone, three
One or more of hydrogen fluoride salts of the hydrogen fluoride salts of ethamine and pyridine.Described fluohydric acid gas is gas form.Described
Ten hexahydro fluorate of the hydrofluoride of lactams, such as DMI and/or N-Methyl pyrrolidone
Five hydrofluorides.The hydrogen fluoride salts of the preferred triethylamine of hydrofluoride of described alkali and/or the hydrogen fluoride salts of pyridine.
The preparation method of described compound 9 when fluorination reagent is for the hydrofluoride of the hydrofluoride of organic base or lactams,
Reaction can be carried out under conditions of there is no catalyst.
In the preparation method of described compound 9, described fluorination reagent is excellent with the molar ratio of described compound 1
Select 1.0～5.0, further preferred 1.0～4.0.When the hydrofluoride of the hydrofluoride using organic base and/or lactams is made
During for fluorination reagent, in the described hydrofluoride of organic base and/or the hydrofluoride of lactams contained HF with described
The molar ratio of compound 1 preferably 1.0～5.0, further preferred 1.0～4.0.
In the preparation method of described compound 9, described compound 1 can be prepared according to preceding method.
In the preparation method of described compound 9, the temperature of described halogen exchange reaction can in this area such
The ordinary temperature of nucleophilic substitution, preferably 80 DEG C～180 DEG C, further preferred 100 DEG C～160 DEG C, further excellent
Select 130 DEG C～155 DEG C.
In the preparation method of described compound 9, the process of described halogen exchange reaction can be using in this area
Routine monitoring method (such as TLC, HPLC or GC) is monitored, and is typically more than 85% with the G/C content of compound 9
When be reaction end, preferably 1 hour～24 hours time of described halogen exchange reaction, further preferred 5 hours～
15 hours.
The preparation method of described compound 9, can be carried out, preferably solvent-free in a solvent or under condition of no solvent
Under conditions of carry out.When carrying out in a solvent, the preferred ether solvent of described solvent, esters solvent, aromatic hydrocarbon solvent
One or more of with nitrile solvents.The preferred ether of described ether solvent, oxolane, diisopropyl ether and methyl- tert
One or more of butyl ether.One of the preferred methyl acetate of described esters solvent, ethyl acetate and butyl acetate
Or it is multiple.The preferred toluene of described aromatic hydrocarbon solvent, ethylbenzene, dimethylbenzene, o-Dimethylbenzene, meta-xylene, xylol
One or more of.The preferred acetonitrile of described nitrile solvents and/or propionitrile.
The preparation method of described compound 9, it is preferred to use following steps：Fluorination reagent is added to alkali and compound 1
In the mixture being formed, carry out halogen exchange reaction, obtain compound 9.The preferred Deca of mode of described addition,
Described rate of addition so that system temperature maintains is advisable between 130 DEG C～155 DEG C, described " alkali and compound 1 shape
Preferably 125 DEG C～130 DEG C of the temperature of the mixture becoming ".
The preparation method of described compound 9, it is preferred to use following post-processing step：After reaction terminates, pressure release of exitting,
Nitrogen purges, and reactant liquor is not directly used in the reaction of prepare compound 10 after further treatment.Reactant liquor can also first use alkali
Neutralization, is used further to the reaction of prepare compound 10.The preferred inorganic base of described alkali, the preferred sodium hydroxide of described inorganic base,
One or more of potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate, further preferred hydroxide
Sodium.Described inorganic base can be used directly to use or in the form of its aqueous solution, is preferably made in the form of its aqueous solution
With.When described inorganic base is used in the form of its aqueous solution, the mass concentration of the described aqueous solution of inorganic base is preferred
20%～60%, described mass concentration refers to that the quality of inorganic base accounts for the percentage ratio of inorganic base aqueous solution gross mass.
Present invention also offers the preparation method of compound 10, it comprises the following steps：In solvent, by compound 9 in alkali
Be hydrolyzed under conditions of presence reaction, obtains compound 10；
Wherein, R1All same as above with the definition of x.
The preparation method of described compound 10 can be using the conventional method of such hydrolysis in this area and condition, this
Particularly preferably following reaction condition in invention：
In the preparation method of described compound 10, described solvent preferable organic solvent and/or water.Described is organic
One of solvent preferred aromatic hydrocarbons class solvent, halogenated aryl hydrocarbon class solvent, alcohols solvent, alkane solvents and ether solvent or
Multiple.The preferred benzene of described aromatic hydrocarbon solvent, toluene, ethylbenzene, dimethylbenzene, o-Dimethylbenzene, meta-xylene and to diformazan
One or more of benzene, further preferred toluene and/or dimethylbenzene.The described preferred chlorobenzene of halogenated aryl hydrocarbon class solvent, neighbour
One or more of dichloro-benzenes, m-dichlorobenzene, paracide, ortho-chlorotolu'ene, parachlorotoluene and m-chlorotoluene.Described
Alcohols solvent methanol, ethanol, one or more of isopropanol and n-butyl alcohol.Described alkane solvents are preferably just own
One or more of alkane, normal heptane and petroleum ether.The preferred methyl tertiary butyl ether(MTBE) of described ether solvent and/or diisopropyl ether.
In the preparation method of described compound 10, the mass values of described solvent and described compound 9 preferably 1～
100.
In the preparation method of described compound 10, the preferred inorganic base of described alkali, the preferred potassium carbonate of described inorganic base,
One or more of sodium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide, further preferred hydrogen-oxygen
Change sodium and/or potassium hydroxide.Described alkali can also be used in the form of its aqueous solution, when described alkali is with its aqueous solution
When form uses, the mass concentration preferably 10%～80%, further preferred 10%～30% of the aqueous solution of alkali, described
Mass concentration refers to that the quality of alkali accounts for the percentage ratio of the aqueous solution gross mass of alkali.
In the preparation method of described compound 10, the molar ratio of described alkali and described compound 9 preferably 1.0～
5.0, further preferred 1.0～3.0.
In the preparation method of described compound 10, preferably 0 DEG C～130 DEG C of the temperature of described hydrolysis, further
Preferably 20 DEG C～80 DEG C, still further preferably 50 DEG C～70 DEG C.
In the preparation method of described compound 10, the process of described hydrolysis can be using the routine in this area
Monitoring method (such as TLC, HPLC or GC) is monitored, typically with compound 9 disappear when as reaction end, institute
Preferably 1 hour～10 hours time of the hydrolysis stated, further preferred 1 hour～3 hours.
The preparation method of described compound 10 preferably employs following steps：By the aqueous solution of alkali add compound 9 with organic
In the mixture that solvent is formed, be hydrolyzed reaction, obtains compound 10.The preferred Deca of mode of described addition, institute
The speed of the Deca stated is defined for 50～70 DEG C by maintenance system temperature.
The preparation method of described compound 10, preferably includes following post-processing step：Reaction divides liquid, aqueous phase to adjust after terminating
Section pH to 1.0 about, is cooled to 10 DEG C～25 DEG C, filters, is dried to obtain compound 10.Adjust pH to preferably use no
Machine acid, one of the preferred hydrochloric acid of described mineral acid, sulphuric acid, phosphoric acid, hydrobromic acid, sodium bisulfate and potassium acid sulfate or
Multiple, further preferred hydrochloric acid and sulphuric acid.Described hydrochloric acid can be conventional commercial hydrochloric acid reagent, described hydrochloric acid reagent
Mass concentration preferably 25%～40%, described mass concentration refers to that the quality of hydrogen chloride accounts for the hundred of hydrochloric acid reagent gross mass
Divide ratio.
Present invention also offers a kind of preparation method of compound 9, it comprises the following steps：In enclosed system, catalyst
Under conditions of presence, compound 1 and fluorination reagent are carried out halogen exchange reaction, obtains compound 9；Described
Catalyst is one or more of alkali, lactams and Butter of antimony.；
Wherein, R1All same as above with the definition of x.Each reaction condition is all same as above.
Present invention also offers compound 2, its structure is as follows：
Wherein, R1、R2All same as above with the definition of x.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, can combination in any, obtain final product the present invention each preferably
Example.
Agents useful for same of the present invention and raw material are all commercially available.
In the present invention, described room temperature refers to ambient temperature and is 10 DEG C～35 DEG C.
The positive effect of the present invention is：
1st, the preparation method of the present invention, cyclization step is carried out under gentle reaction condition, using 3- alkoxyl -2- two chloroethene
Acyl group acrylate and methyl hydrazine cyclization, isomer proportion can control below 6%, minimum can as little as less than 1%.
2nd, report, dihalomethyl alkoxy acrylic ester need to be by dihalo acetyl according to Bayer patent (CN1871204)
Acetass preparation, dihalo acetoacetic ester can not industrially obtain, and needs the technology (using ketenes) of complexity,
So this patent thinks that dihalomethyl alkoxy acrylic ester can not be prepared in an economical manner.And the preparation side of the present invention
Method, with cheap raw material malonate, is easily obtained the potassium salt of malonic acid monoester, enters one by selectivity saponification
Step ground, in the presence of magnesium chloride, using organic base and dichloroacetyl chloride be successfully made dihalo acetoacetic ester low become
This preparation, can prepare dihalomethyl alkoxy acrylic ester in an economical manner, and then synthesizes 3- difluoro at low cost
Methyl isophthalic acid H- methylpyrazole -4- carboxylic acid, solves the problems, such as to be previously mentioned in patent CN1871204.
3rd, the preparation method route of the present invention is novel, it is to avoid the use of fluorine-containing raw material, using malonate and dichloroacetyl
Chlorine (or trichloro-acetic chloride) is initiation material, obtains 3- difluoromethyl -1H- methyl by six step synthetic reaction low costs
Pyrazoles -4- carboxylic acid (or 3- Trifluoromethyl-1 H- methylpyrazole -4- carboxylic acid), is dropped compared with the current technique of report significantly
Low production cost.
Specific embodiment
Further illustrate the present invention below by the mode of embodiment, but therefore do not limit the present invention to described enforcement
Among example scope.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or according to
Catalogue selects.
Embodiment 1
Add the dehydrated alcohol of 100g diethyl malonate (0.625mol) and 315.0g in reaction bulb, be thoroughly mixed
At 10～35 DEG C, after dissolving, it is slowly added dropwise ethanol solution (the potassium hydroxide of potassium hydroxide：35.0g (0.624mol),
Ethanol：315.0g), white solid is gradually had to separate out during Deca.After completion of dropping, reactant liquor continues at 10～35 DEG C
Stir about 3.5 hours.Be warming up to 79～80 DEG C make system flow back after, filtered while hot is to remove malonic acid di-potassium.Gained is filtered
After liquid is cooled to 0 DEG C, filters, obtain potassium ethyl malonate salt.
After filtrate concentrates and steams about 500g ethanol further, gained concentrated solution is cooled to 0 DEG C, filters, gained two parts
After potassium ethyl malonate salt merges, vacuum drying, final potassium ethyl malonate salt 92.06g (HPLC purity：
98.8%, yield：85.50%).
Embodiment 2
Add the absolute methanol of 100g dimethyl malenate (0.757mol) and 350.0g in reaction bulb, be thoroughly mixed
At 10～35 DEG C, after dissolving, it is slowly added dropwise methanol solution (the potassium hydroxide of potassium hydroxide：42.3g (0.754mol),
Methanol：350.0g), white solid is gradually had to separate out during Deca.After completion of dropping, reactant liquor continues at 10～35 DEG C
Stir about 3.5 hours.Be warming up to 65～68 DEG C make system flow back after, filtered while hot is to remove malonic acid di-potassium.Gained
After filtrate is cooled to 0 DEG C, filters, obtain malonic acid monomethyl ester potassium salt.
After filtrate concentrates and steams about 550g methanol further, gained concentrated solution is cooled to 0 DEG C, filters, gained two parts
After malonic acid monomethyl ester potassium salt merges, vacuum drying, final malonic acid monomethyl ester potassium salt 98.78g (HPLC purity：
99.1%, yield：82.80%).
Embodiment 3
Add the dehydrated alcohol of 100g diethyl malonate (0.625mol) and 315.0g in reaction bulb, be thoroughly mixed
At 10～35 DEG C, after dissolving, it is slowly added dropwise ethanol solution (the sodium hydroxide of sodium hydroxide：25.0g (0.624mol),
Ethanol：315.0g), white solid is gradually slowly had to separate out during Deca.After completion of dropping, reactant liquor continues at 10～35 DEG C
Stir about 3.5 hours.Be warming up to 79～80 DEG C make system flow back after, filtered while hot is to remove malonic acid disodium salt.Gained is filtered
After liquid steams about 500g ethanol, gained concentrated solution is cooled to 0 DEG C, filters, and gained monoethyl malonate sodium salt is vacuum dried
Afterwards, obtain monoethyl malonate sodium salt 34.30g (HPLC purity：98.6%, yield：35.12%).
Embodiment 4 (embodiment of all prepare compounds 3, yield is in terms of dichloroacetyl chloride)
Keep 10～25 DEG C of interior temperature, malonic acid monomethyl ester potassium salt (the HPLC purity that the embodiment 2 of 100g is obtained：
99.1%, 0.634mol) and 750g acetonitrile mix in reaction bulb after, 10 DEG C～25 DEG C of maintenance system interior temperature, add
After 96.23g triethylamine (0.951mol), it is slowly added to 72.40g magnesium chloride solids (0.760mol).After the completion of charging,
Naturally heat up, and keep 20 DEG C～25 DEG C of system interior temperature to be incubated 2～3 hours.It is cooled to 0～10 DEG C, be slowly added dropwise 70.10g
Dichloroacetyl chloride (0.476mol).Drip and finish, warm naturally to 20 DEG C～25 DEG C and in this temperature 18 hours.
After reaction terminates, add 240g ethyl acetate with dilute reaction solution.It is cooled to 0～15 DEG C, be slowly added dropwise 455g
Mass concentration be 5% aqueous hydrochloric acid solution acidifying (it is total that described mass concentration refers to that the quality of hydrogen chloride accounts for aqueous hydrochloric acid solution
The percentage ratio of quality).After being added dropwise to complete, it is incubated 30min at 0～15 DEG C, point liquid.Gained organic faciess use quality concentration
Aqueous hydrochloric acid solution (200g × 2) for 5% washes twice.After gained organic faciess desolvation, obtain dichloroacetyl acetic acid
Methyl ester 76.95g (GC purity：97.5%, yield：85.2%).
Embodiment 5
Keep 10 DEG C～25 DEG C of interior temperature, potassium ethyl malonate salt (the HPLC purity that the embodiment 1 of 100g is obtained：
98.8%, 0.581mol) and 700g acetonitrile mix in reaction bulb after, 10 DEG C～25 DEG C of maintenance system interior temperature, add
After 96.23g triethylamine (0.951mol), it is slowly added to 66.35g magnesium chloride solids (0.696mol).After the completion of charging,
Naturally heat up, and keep 20 DEG C～25 DEG C of system interior temperature to be incubated 2～3 hours.It is cooled to 0～10 DEG C, be slowly added dropwise 64.24g
Dichloroacetyl chloride (0.436mol).Drip and finish, warm naturally to 20 DEG C～25 DEG C and in this temperature 18 hours.
After reaction terminates, add 220g ethyl acetate with dilute reaction solution.It is cooled to 0～15 DEG C, be slowly added dropwise 420g
Mass concentration be 5% aqueous hydrochloric acid solution acidifying (it is total that described mass concentration refers to that the quality of hydrogen chloride accounts for aqueous hydrochloric acid solution
The percentage ratio of quality).After being added dropwise to complete, it is incubated 30min at 0～15 DEG C, point liquid.Gained organic faciess use quality concentration
Aqueous hydrochloric acid solution (180g × 2) for 5% washes twice.After gained organic faciess desolvation, obtain dichloroacetyl acetic acid
Ethyl ester 76.12g (GC purity：97.7%, yield：85.7%).
Embodiment 6
Keep 10～25 DEG C of interior temperature, malonic acid monomethyl ester potassium salt (the HPLC purity that the embodiment 2 of 100g is obtained：
99.1%, 0.634mol) and 950g ethyl acetate mix in reaction bulb after, 10 DEG C～15 DEG C of maintenance system interior temperature,
After adding 96.23g triethylamine (0.951mol), it is slowly added to 72.40g magnesium chloride solids (0.760mol).Feed
Cheng Hou, heats up naturally, and keeps 30 DEG C～35 DEG C of system interior temperature to be incubated 8～10 hours.It is cooled to 0～10 DEG C, be slowly added dropwise
70.10g dichloroacetyl chloride (0.476mol).Drip and finish, warm naturally to 20 DEG C～25 DEG C and in this temperature 22 hours.
After reaction terminates, it is cooled to 0～15 DEG C, the mass concentration being slowly added dropwise 455g is 5% aqueous hydrochloric acid solution acidifying (institute
The mass concentration stated refers to that the quality of hydrogen chloride accounts for the percentage ratio of aqueous hydrochloric acid solution gross mass).After being added dropwise to complete, at 0～15 DEG C
Insulation 30min, point liquid.Gained organic faciess use quality concentration is 5% aqueous hydrochloric acid solution (200g × 2) washing two
Secondary.After gained organic faciess desolvation, obtain dichloroacetyl methyl acetate 74.78g (GC purity：97.5%, yield：82.8%).
Embodiment 7
Keep 10 DEG C～25 DEG C of interior temperature, malonic acid monomethyl ester potassium salt (the HPLC purity that the embodiment 2 of 100g is obtained：
99.1%, 0.634mol) and 750g acetonitrile mix in reaction bulb after, maintenance system interior temperature at 10 DEG C～25 DEG C, so
After adding 96.23g triethylamine (0.951mol) afterwards, it is slowly added to 72.40g magnesium chloride solids (0.760mol).Charging
After the completion of, naturally heat up, and keep 20 DEG C～25 DEG C of system interior temperature to be incubated 2～3 hours.It is cooled to 0～10 DEG C, slow
Plus 86.55g trichloro-acetic chloride (0.476mol).Drip and finish, warm naturally to 20 DEG C～25 DEG C and little in this temperature 18
When.
After reaction terminates, add 240g ethyl acetate with dilute reaction solution.It is cooled to 0～15 DEG C, be slowly added dropwise 455g
Mass concentration be 5% aqueous hydrochloric acid solution acidifying (it is total that described mass concentration refers to that the quality of hydrogen chloride accounts for aqueous hydrochloric acid solution
The percentage ratio of quality).After being added dropwise to complete, it is incubated 30min at 0～15 DEG C, point liquid.Gained organic faciess use quality concentration
Aqueous hydrochloric acid solution (200g × 2) for 5% washes twice.After gained organic faciess desolvation, obtain tribromo-acetyl acetic acid
Methyl ester 97.94g (GC purity：97.7%, yield：86.1%).
Embodiment 8
By dichloroacetyl methyl acetate (the GC purity prepared by the embodiment 4 of 100g：97.5%, 0.527mol), 68.34
After g trimethyl orthoformate (0.644mol) and 161.41g acetic anhydride (1.581mol) mix in reaction bulb, by body
It is that interior temperature is slowly increased to 100 DEG C～110 DEG C, distill 3～5 hours methyl acetates to generate except dereaction in insulation.Instead
After should terminating, it is cooled to 10～35 DEG C, make system vacuum keep 10～20mbar, slowly by system interior temperature by 10～35 DEG C
Rise to 100 DEG C to remove the methyl acetate remaining, unreacted completely trimethyl orthoformate and acetic anhydride, obtain 118.29g's
3- methoxyl group -2- dichloro-acetyl acrylic acid methyl ester. (GC purity：96.6%, yield 95.5%).
Embodiment 9
By dichloroacetyl ethyl acetate (the GC purity prepared by the embodiment 5 of 100g：97.7%, 0.405mol), 73.35
After g triethyl orthoformate (0.495mol) and 124.04g acetic anhydride (1.215mol) mix in reaction bulb, by body
It is that interior temperature is slowly increased to 100 DEG C～110 DEG C, distill 3～5 hours ethyl acetate to generate except dereaction in insulation.Instead
After should terminating, it is cooled to 10～35 DEG C, make system vacuum keep 10～20mbar, slowly by system interior temperature by 10～35 DEG C
Rise to 100 DEG C to remove the ethyl acetate remaining, unreacted completely triethyl orthoformate and acetic anhydride, obtain 102.78g
3- ethyoxyl -2- dichloro-acetyl ethyl acrylate (GC purity：96.6%, yield 96.1%).
Embodiment 10
By tribromo-acetyl methyl acetate (the GC purity prepared by the embodiment 7 of 100g：97.7%, 0.445mol), 57.73
After g trimethyl orthoformate (0.544mol) and 136.29g acetic anhydride (1.335mol) mix in reaction bulb, by body
It is that interior temperature is slowly increased to 100 DEG C～110 DEG C, distill 3～5 hours methyl acetates to generate except dereaction in insulation.Instead
After should terminating, it is cooled to 10～35 DEG C, make system vacuum keep 10～20mbar, slowly by system interior temperature by 10～35 DEG C
Rise to 100 DEG C to remove the methyl acetate remaining, unreacted completely trimethyl orthoformate and acetic anhydride, obtain 114.55g
3- methoxyl group -2- tribromo-acetyl base acrylic acid methyl ester. (GC purity：96.6%, yield 95.1%).
Embodiment 11
(described mass concentration is fingernail to the methyl hydrazine aqueous solution (0.391mol) that the mass concentration of 45.00g is 40%
The quality of base hydrazine accounts for the percentage ratio of methyl hydrazine aqueous solution gross mass) and 70.00g dimethylbenzene mix in reaction bulb after, will
System interior temperature controls between 0～25 DEG C, is slowly added dropwise the 3- methoxyl group -2- dichloro-acetyl acrylic acid prepared by embodiment 8
Xylene solution (3- methoxyl group -2- dichloro-acetyl the acrylic acid methyl ester. of methyl ester：83.54g, GC purity：96.6%, 0.355
mol；Dimethylbenzene：140.00g).Drip finish, maintenance system temperature between 0～25 DEG C, insulated and stirred 1 hour.
After reaction terminates, add the water of 5.00g, point liquid, concentrate the 3- dichloromethyl -1H- methyl that organic faciess obtain 70.45g
Pyrazoles -4- carboxylate methyl ester (GC purity：91.6%, yield：81.5%, wherein isomer 5- dichloromethyl -1H- methyl pyrrole
Azoles -4- carboxylate methyl ester GC purity：5.2%).
Embodiment 12
(described mass concentration is fingernail to the methyl hydrazine aqueous solution (0.391mol) that the mass concentration of 30.02g is 60%
The quality of base hydrazine accounts for the percentage ratio of methyl hydrazine aqueous solution gross mass) and 70.00g toluene mix in reaction bulb after, by body
It is that interior temperature controls between 0～25 DEG C, be slowly added dropwise the 3- methoxyl group -2- dichloro-acetyl acrylic acid first prepared by embodiment 8
The toluene solution 3- methoxyl group -2- dichloro-acetyl acrylic acid methyl ester. of ester：83.54g, GC purity：96.6%, 0.355mol；
Toluene：140.00g).Drip finish, maintenance system temperature between 0～25 DEG C, insulated and stirred 1 hour.
After reaction terminates, add the water of 20.00g, point liquid, concentrate the 3- dichloromethyl -1H- first that organic faciess obtain 71.36g
Base pyrazoles -4- carboxylate methyl ester (GC purity：91.1%, yield：82.1%, wherein isomer 5- dichloromethyl -1H- methyl
Pyrazoles -4- carboxylate methyl ester GC purity：5.3%).
Embodiment 13
(described mass concentration is fingernail to the methyl hydrazine aqueous solution (0.391mol) that the mass concentration of 45.00g is 40%
The quality of base hydrazine accounts for the percentage ratio of methyl hydrazine aqueous solution gross mass) and 70.00g dimethylbenzene mix in reaction bulb after, will
System interior temperature controls between 0～25 DEG C, is slowly added dropwise the 3- ethyoxyl -2- dichloro-acetyl acrylic acid prepared by embodiment 9
Xylene solution (3- ethyoxyl -2- dichloro-acetyl the ethyl acrylate of ethyl ester：93.75g, GC purity：96.6%, 0.355
mol；Dimethylbenzene：160.00g).Drip finish, maintenance system temperature between 0～25 DEG C, insulated and stirred 1 hour.
After reaction terminates, add the water of 5.00g, point liquid, concentrate the 3- dichloromethyl -1H- methyl that organic faciess obtain 74.82g
Pyrazoles -4- carboxylic acid, ethyl ester (GC purity：92.8%, yield：82.5%, wherein isomer 5- dichloromethyl -1H- methyl pyrrole
Azoles -4- carboxylic acid, ethyl ester GC purity：4.2%).
Embodiment 14
(described mass concentration is fingernail to the methyl hydrazine aqueous solution (0.391mol) that the mass concentration of 45.00g is 40%
The quality of base hydrazine accounts for the percentage ratio of methyl hydrazine aqueous solution gross mass) and 70.00g dimethylbenzene mix in reaction bulb after, will
System interior temperature controls between 0～25 DEG C, is slowly added dropwise the 3- methoxyl group -2- tribromo-acetyl base propylene prepared by embodiment 10
Xylene solution (3- methoxyl group -2- tribromo-acetyl base the acrylic acid methyl ester. of sour methyl ester：96.09g, GC purity：96.6%,
0.355mol；Dimethylbenzene：160.00g).Drip finish, maintenance system temperature between 0～25 DEG C, insulated and stirred 1 hour.
After reaction terminates, add the water of 5.00g, point liquid, concentrate the 3- trichloromethyl -1H- methyl that organic faciess obtain 81.85g
Pyrazoles -4- carboxylate methyl ester (GC purity：91.8%, yield：82.2%, wherein isomer 5- trichloromethyl -1H- methyl pyrrole
Azoles -4- carboxylate methyl ester GC purity：5.4%).
Embodiment 15
(described mass concentration is fingernail to the methyl hydrazine aqueous solution (0.782mol) that the mass concentration of 90.00g is 40%
The quality of base hydrazine accounts for the percentage ratio of methyl hydrazine aqueous solution gross mass) and 70.00g dimethylbenzene mix in reaction bulb after, will
System interior temperature controls between 0～25 DEG C, is slowly added dropwise the 3- methoxyl group -2- dichloro-acetyl acrylic acid prepared by embodiment 8
Xylene solution (3- methoxyl group -2- dichloro-acetyl the acrylic acid methyl ester. of methyl ester：83.54g, GC purity：96.6%, 0.355
mol；Dimethylbenzene：140.00g).Drip finish, maintenance system temperature between 0～25 DEG C, insulated and stirred 1 hour.
After reaction terminates, point liquid, concentrate the 3- dichloromethyl -1H- methylpyrazole -4- carboxylate methyl ester (GC that organic faciess obtain 70.12g
Purity：93.5%, yield：82.8%, wherein isomer 5- dichloromethyl -1H- methylpyrazole -4- carboxylate methyl ester GC purity：
4.3%).
Embodiment 16
(described mass concentration is fingernail to the methyl hydrazine aqueous solution (0.391mol) that the mass concentration of 45.00g is 40%
The quality of base hydrazine accounts for the percentage ratio of methyl hydrazine aqueous solution gross mass), the mass concentration of 6.7g be 30% sodium hydroxide water-soluble
Liquid (0.050mol) (described mass concentration refers to that the quality of sodium hydroxide accounts for the percentage ratio of sodium hydrate aqueous solution gross mass)
After mixing in reaction bulb with the dimethylbenzene of 70.00g, system interior temperature is controlled between 0～25 DEG C, is slowly added dropwise embodiment
Xylene solution (3- methoxyl group -2- the dichloro-acetyl third of the 3- methoxyl group -2- dichloro-acetyl acrylic acid methyl ester. prepared by 8
E pioic acid methyl ester：83.54g, GC purity：96.6%, 0.355mol；Dimethylbenzene：140.00g).Drip and finish, maintenance system
Temperature between 0～25 DEG C, insulated and stirred 1 hour.
After reaction terminates, point liquid, concentrate the 3- dichloromethyl -1H- methylpyrazole -4- carboxylate methyl ester (GC that organic faciess obtain 69.74g
Purity：97.3%, yield：85.7%, wherein isomer 5- dichloromethyl -1H- methylpyrazole -4- carboxylate methyl ester GC purity：
0.85%).
Embodiment 17
(described mass concentration is fingernail to the methyl hydrazine aqueous solution (0.391mol) that the mass concentration of 45.00g is 40%
The quality of base hydrazine accounts for the percentage ratio of methyl hydrazine aqueous solution gross mass), the KOH solid (0.028mol) of 1.6g and 70.00g
Dimethylbenzene mix in reaction bulb after, system interior temperature is controlled between 0～25 DEG C, is slowly added dropwise prepared by embodiment 8
3- methoxyl group -2- dichloro-acetyl acrylic acid methyl ester. xylene solution (3- methoxyl group -2- dichloro-acetyl acrylic acid methyl ester.：
83.54g, GC purity：96.6%, 0.355mol；Dimethylbenzene：140.00g).Drip and finish, maintenance system temperature is at 0～25 DEG C
Between, insulated and stirred 1 hour.
After reaction terminates, add the water of 5.00g, point liquid, concentrate the 3- dichloromethyl -1H- methyl that organic faciess obtain 69.06g
Pyrazoles -4- carboxylate methyl ester (GC purity：97.8%, yield：85.3%, wherein isomer 5- dichloromethyl -1H- methyl pyrrole
Azoles -4- carboxylate methyl ester GC purity：0.63%).
Embodiment 18
(described mass concentration is fingernail to the methyl hydrazine aqueous solution (0.391mol) that the mass concentration of 45.00g is 40%
The quality of base hydrazine accounts for the percentage ratio of methyl hydrazine aqueous solution gross mass), the NaOH solid (0.070mol) of 2.1g and 70.00g
Dimethylbenzene mix in reaction bulb after, system interior temperature is controlled between 0～25 DEG C, is slowly added dropwise prepared by embodiment 8
3- methoxyl group -2- dichloro-acetyl acrylic acid methyl ester. xylene solution (3- methoxyl group -2- dichloro-acetyl acrylic acid methyl ester.：
83.54g, GC purity：96.6%, 0.355mol；Dimethylbenzene：140.00g).Drip and finish, maintenance system temperature is at 0～25 DEG C
Between, insulated and stirred 1 hour.
After reaction terminates, add the water of 5.00g, point liquid, concentrate the 3- dichloromethyl -1H- methyl that organic faciess obtain 68.73g
Pyrazoles -4- carboxylate methyl ester (GC purity：97.7%, yield：84.8%, wherein isomer 5- dichloromethyl -1H- methyl pyrrole
Azoles -4- carboxylate methyl ester GC purity：0.91%).
Embodiment 19
(described mass concentration is fingernail to the methyl hydrazine aqueous solution (0.391mol) that the mass concentration of 45.00g is 40%
The quality of base hydrazine accounts for the percentage ratio of methyl hydrazine aqueous solution gross mass), the triethylamine (0.060mol) of 6.07g and 70.00g
Dimethylbenzene mix in reaction bulb after, system interior temperature is controlled between 0～25 DEG C, is slowly added dropwise prepared by embodiment 8
3- methoxyl group -2- dichloro-acetyl acrylic acid methyl ester. xylene solution (3- methoxyl group -2- dichloro-acetyl acrylic acid methyl ester.：
83.54g, GC purity：96.6%, 0.355mol；Dimethylbenzene：140.00g).Drip and finish, maintenance system temperature is at 0～25 DEG C
Between, insulated and stirred 1 hour.
After reaction terminates, point liquid, concentrate the 3- dichloromethyl -1H- methylpyrazole -4- carboxylate methyl ester (GC that organic faciess obtain 69.38g
Purity：96.1%, yield：84.2%, wherein isomer 5- dichloromethyl -1H- methylpyrazole -4- carboxylate methyl ester GC purity：
2.5%).
Embodiment 20
(described mass concentration is fingernail to the methyl hydrazine aqueous solution (0.391mol) that the mass concentration of 45.00g is 40%
The quality of base hydrazine accounts for the percentage ratio of methyl hydrazine aqueous solution gross mass), the tri-n-butylamine (0.075mol) and 70.00 of 13.90g
After the dimethylbenzene of g mixes in reaction bulb, system interior temperature is controlled between 0～25 DEG C, be slowly added dropwise embodiment 8 made
Xylene solution (3- methoxyl group -2- dichloro-acetyl acrylic acid the first of standby 3- methoxyl group -2- dichloro-acetyl acrylic acid methyl ester.
Ester：83.54g, GC purity：96.6%, 0.355mol；Dimethylbenzene：140.00g).Drip and finish, maintenance system temperature exists
Between 0～25 DEG C, insulated and stirred 1 hour.
After reaction terminates, point liquid, concentrate the 3- dichloromethyl -1H- methylpyrazole -4- carboxylate methyl ester (GC that organic faciess obtain 69.40g
Purity：96.3%, yield：84.4%, wherein isomer 5- dichloromethyl -1H- methylpyrazole -4- carboxylate methyl ester GC purity：
2.2%).
Embodiment 21
(described mass concentration is fingernail to the methyl hydrazine aqueous solution (0.391mol) that the mass concentration of 45.00g is 40%
The quality of base hydrazine accounts for the percentage ratio of methyl hydrazine aqueous solution gross mass), the pyridine (0.065mol) of 5.14g and 70.00g
After dimethylbenzene mixes in reaction bulb, system interior temperature is controlled between 0～25 DEG C, be slowly added dropwise prepared by embodiment 8
Xylene solution (3- methoxyl group -2- dichloro-acetyl the acrylic acid methyl ester. of 3- methoxyl group -2- dichloro-acetyl acrylic acid methyl ester.：
83.54g, GC purity：96.6%, 0.355mol；Dimethylbenzene：140.00g).Drip and finish, maintenance system temperature is at 0～25 DEG C
Between, insulated and stirred 1 hour.
After reaction terminates, point liquid, concentrate the 3- dichloromethyl -1H- methylpyrazole -4- carboxylate methyl ester (GC that organic faciess obtain 69.10g
Purity：95.8%, yield：83.6%, wherein isomer 5- dichloromethyl -1H- methylpyrazole -4- carboxylate methyl ester GC purity：
3.1%).
Embodiment 22
By 3- dichloromethyl -1H- methylpyrazole -4- carboxylate methyl ester (the GC purity prepared by the embodiment 16 of 200g：97.3%,
After 0.872mol) putting into autoclave, it is to slowly warm up to 125 DEG C～130 DEG C so that 3- dichloromethyl -1H- methylpyrazole -4-
Carboxylate methyl ester melts.By 22.00g pyridine (0.278mol) with 3- dichloromethyl -1H- methylpyrazole -4- carboxylate methyl ester in height
After mix homogeneously in pressure kettle, further heat up to 130 DEG C～155 DEG C.When system interior temperature reaches 130 DEG C～155 DEG C, maintain
This temperature, is slowly dropped into the HF (2.399mol) of 48.00g, drips off within about 4～5 hours, afterwards, at 130 DEG C～155 DEG C
Insulation 5～8 hours.
After reaction terminates, pressure release of exitting, nitrogen purges, and tail gas uses alkali liquor absorption.It is cooled to 60 DEG C～80 DEG C, add
, with dilute reaction solution, the mass concentration being slowly dropped into 145.00g is 30% sodium hydroxide for 350g dimethylbenzene and 60g water
Aqueous solution (described mass concentration refers to that the quality of sodium hydroxide accounts for the percentage ratio of sodium hydrate aqueous solution gross mass), at 50 DEG C
～70 DEG C of insulated and stirred, after 1 hour, divide liquid, and aqueous phase use quality concentration is 36% concentrated hydrochloric acid acidifying (described mass concentration
Refer to that the quality of hydrogen chloride accounts for the percentage ratio of concentrated hydrochloric acid gross mass) to pH=1.0.It is cooled to 10 DEG C～25 DEG C, filter, very
Empty dry, obtain the 3- difluoromethyl -1H- methylpyrazole -4- carboxylic acid (yield of 136.33g：88.0%, HPLC purity：99.7%；
Isomer 5- difluoromethyl -1H- methylpyrazole -4- carboxylic acid HPLC purity：＜ 0.01%).
Embodiment 23
By 3- dichloromethyl -1H- methylpyrazole -4- carboxylate methyl ester (the GC purity prepared by the embodiment 16 of 200g：97.3%,
After 0.872mol) putting into autoclave, it is to slowly warm up to 125 DEG C～130 DEG C so that 3- dichloromethyl -1H- methylpyrazole -4-
Carboxylate methyl ester melts.35.00g triethylamine (0.346mol) and 3- dichloromethyl -1H- methylpyrazole -4- carboxylate methyl ester are existed
After mix homogeneously in autoclave, further heat up to 130 DEG C～155 DEG C.When system interior temperature reaches 130 DEG C～155 DEG C, dimension
Hold this temperature, be slowly dropped into the HF (2.399mol) of 48.00g, drip off within about 4～5 hours, afterwards, at 130 DEG C～155 DEG C
Insulation 5～8 hours.
After reaction terminates, pressure release of exitting, nitrogen purges, and tail gas uses alkali liquor absorption.It is cooled to 60 DEG C～80 DEG C, add
, with dilute reaction solution, the mass concentration being slowly dropped into 145.00g is 30% sodium hydroxide for 350g dimethylbenzene and 60g water
Aqueous solution (described mass concentration refers to that the quality of sodium hydroxide accounts for the percentage ratio of sodium hydrate aqueous solution gross mass), at 50 DEG C
～70 DEG C of insulated and stirred, after 1 hour, divide liquid, and aqueous phase use quality concentration is 36% concentrated hydrochloric acid acidifying (described mass concentration
Refer to that the quality of hydrogen chloride accounts for the percentage ratio of concentrated hydrochloric acid gross mass) to pH=1.0.It is cooled to 10 DEG C～25 DEG C, filter, very
Empty dry, obtain the 3- difluoromethyl -1H- methylpyrazole -4- carboxylic acid (yield of 137.24g：88.5%, HPLC purity：99.6%；
Isomer 5- difluoromethyl -1H- methylpyrazole -4- carboxylic acid HPLC purity：＜ 0.01%).
Embodiment 24
By 3- dichloromethyl -1H- methylpyrazole -4- carboxylate methyl ester (the GC purity prepared by the embodiment 16 of 200g：97.3%,
After 0.872mol) putting into autoclave, it is to slowly warm up to 125 DEG C～130 DEG C so that 3- dichloromethyl -1H- methylpyrazole -4-
Carboxylate methyl ester melts.8.82g triethylamine (0.0872mol) and 3- dichloromethyl -1H- methylpyrazole -4- carboxylate methyl ester are existed
After mix homogeneously in autoclave, further heat up to 130 DEG C～155 DEG C.When system interior temperature reaches 130 DEG C～155 DEG C, dimension
Hold this temperature, be slowly dropped into the HF (2.399mol) of 48.00g, drip off within about 4～5 hours, afterwards, at 130 DEG C～155 DEG C
Insulation 5～8 hours.
After reaction terminates, pressure release of exitting, nitrogen purges, and tail gas uses alkali liquor absorption.It is cooled to 60 DEG C～80 DEG C, add
, with dilute reaction solution, the mass concentration being slowly dropped into 145.00g is 30% sodium hydroxide for 350g dimethylbenzene and 60g water
Aqueous solution (described mass concentration refers to that the quality of sodium hydroxide accounts for the percentage ratio of sodium hydrate aqueous solution gross mass), at 50 DEG C
～70 DEG C of insulated and stirred, after 1 hour, divide liquid, and aqueous phase use quality concentration is 36% concentrated hydrochloric acid acidifying (described mass concentration
Refer to that the quality of hydrogen chloride accounts for the percentage ratio of concentrated hydrochloric acid gross mass) to pH=1.0.It is cooled to 10 DEG C～25 DEG C, filter, very
Empty dry, obtain the 3- difluoromethyl -1H- methylpyrazole -4- carboxylic acid (yield of 126.71g：81.6%, HPLC purity：98.9%；
Isomer 5- difluoromethyl -1H- methylpyrazole -4- carboxylic acid HPLC purity：＜ 0.01%).
Embodiment 25
By 3- dichloromethyl -1H- methylpyrazole -4- carboxylate methyl ester (the GC purity prepared by the embodiment 16 of 200g：97.3%,
After 0.872mol) putting into autoclave, it is to slowly warm up to 125 DEG C～130 DEG C so that 3- dichloromethyl -1H- methylpyrazole -4-
Carboxylate methyl ester melts.By the N-Methyl pyrrolidone (0.202mol) of 20.02g and 3- dichloromethyl -1H- methylpyrazole -4-
After carboxylate methyl ester mix homogeneously in autoclave, further heat up to 130 DEG C～155 DEG C.When system interior temperature reaches 130 DEG C
When～155 DEG C, maintain this temperature, be slowly dropped into the HF (2.399mol) of 48.00g, drip off within about 4～5 hours, afterwards,
It is incubated 10～15 hours at 130 DEG C～155 DEG C.
After reaction terminates, pressure release of exitting, nitrogen purges, and tail gas uses alkali liquor absorption.It is cooled to 60 DEG C～80 DEG C, add
, with dilute reaction solution, the mass concentration being slowly dropped into 145.00g is 30% sodium hydroxide for 350g dimethylbenzene and 60g water
Aqueous solution (described mass concentration refers to that the quality of sodium hydroxide accounts for the percentage ratio of sodium hydrate aqueous solution gross mass), at 50 DEG C
～70 DEG C of insulated and stirred, after 1 hour, divide liquid, and aqueous phase use quality concentration is 36% concentrated hydrochloric acid acidifying (described mass concentration
Refer to that the quality of hydrogen chloride accounts for the percentage ratio of concentrated hydrochloric acid gross mass) to pH=1.0.It is cooled to 10 DEG C～25 DEG C, filter, very
Empty dry, obtain the 3- difluoromethyl -1H- methylpyrazole -4- carboxylic acid (yield of 127.75g：82.1%, HPLC purity：98.7%；
Isomer 5- difluoromethyl -1H- methylpyrazole -4- carboxylic acid HPLC purity：＜ 0.01%).
Embodiment 26
By 3- dichloromethyl -1H- methylpyrazole -4- carboxylate methyl ester (the GC purity prepared by the embodiment 16 of 200g：97.3%,
After 0.872mol) putting into autoclave, it is to slowly warm up to 125 DEG C～130 DEG C so that 3- dichloromethyl -1H- methylpyrazole -4-
Carboxylate methyl ester melts.By the 1,3- dimethyl-2-imidazolinone (0.0872mol) of 9.95g and 3- dichloromethyl -1H- methyl
After pyrazoles -4- carboxylate methyl ester mix homogeneously in autoclave, further heat up to 130 DEG C～155 DEG C.When system interior temperature reaches
When 130 DEG C～155 DEG C, maintain this temperature, be slowly dropped into the HF (2.399mol) of 48.00g, drip off within about 4～5 hours,
Afterwards, it is incubated 7～12 hours at 130 DEG C～155 DEG C.
After reaction terminates, pressure release of exitting, nitrogen purges, and tail gas uses alkali liquor absorption.It is cooled to 60 DEG C～80 DEG C, add
, with dilute reaction solution, the mass concentration being slowly dropped into 145.00g is 30% sodium hydroxide for 350g dimethylbenzene and 60g water
Aqueous solution (described mass concentration refers to that the quality of sodium hydroxide accounts for the percentage ratio of sodium hydrate aqueous solution gross mass), at 50 DEG C
～70 DEG C of insulated and stirred, after 1 hour, divide liquid, and aqueous phase use quality concentration is 36% concentrated hydrochloric acid acidifying (described mass concentration
Refer to that the quality of hydrogen chloride accounts for the percentage ratio of concentrated hydrochloric acid gross mass) to pH=1.0.It is cooled to 10 DEG C～25 DEG C, filter, very
Empty dry, obtain the 3- difluoromethyl -1H- methylpyrazole -4- carboxylic acid (yield of 133.53g：86.6%, HPLC purity：99.6%；
Isomer 5- difluoromethyl -1H- methylpyrazole -4- carboxylic acid HPLC purity：＜ 0.01%).
Embodiment 27
By 3- dichloromethyl -1H- methylpyrazole -4- carboxylate methyl ester (the GC purity prepared by the embodiment 16 of 200g：97.3%,
After 0.872mol) putting into autoclave, it is to slowly warm up to 125 DEG C～130 DEG C so that 3- dichloromethyl -1H- methylpyrazole -4-
Carboxylate methyl ester melts.By the 1,3- dimethyl-2-imidazolinone (0.0500mol) of 5.71g and 3- dichloromethyl -1H- methyl
After pyrazoles -4- carboxylate methyl ester mix homogeneously in autoclave, further heat up to 130 DEG C～155 DEG C.When system interior temperature reaches
When 130 DEG C～155 DEG C, maintain this temperature, be slowly dropped into the HF (2.399mol) of 48.00g, drip off within about 4～5 hours,
Afterwards, it is incubated 7～12 hours at 130 DEG C～155 DEG C.
After reaction terminates, pressure release of exitting, nitrogen purges, and tail gas uses alkali liquor absorption.It is cooled to 60 DEG C～80 DEG C, add
, with dilute reaction solution, the mass concentration being slowly dropped into 145.00g is 30% sodium hydroxide for 350g dimethylbenzene and 60g water
Aqueous solution (described mass concentration refers to that the quality of sodium hydroxide accounts for the percentage ratio of sodium hydrate aqueous solution gross mass), at 50 DEG C
～70 DEG C of insulated and stirred, after 1 hour, divide liquid, and aqueous phase use quality concentration is 36% concentrated hydrochloric acid acidifying (described mass concentration
Refer to that the quality of hydrogen chloride accounts for the percentage ratio of concentrated hydrochloric acid gross mass) to pH=1.0.It is cooled to 10 DEG C～25 DEG C, filter, very
Empty dry, obtain the 3- difluoromethyl -1H- methylpyrazole -4- carboxylic acid (yield of 130.89g：84.8%, HPLC purity：99.5%；
Isomer 5- difluoromethyl -1H- methylpyrazole -4- carboxylic acid HPLC purity：＜ 0.01%).
Embodiment 28
By 3- dichloromethyl -1H- methylpyrazole -4- carboxylate methyl ester (the GC purity prepared by the embodiment 16 of 200g：97.3%,
After 0.872mol) putting into autoclave, it is to slowly warm up to 125 DEG C～130 DEG C so that 3- dichloromethyl -1H- methylpyrazole -4-
Carboxylate methyl ester melts.Triethylamine (0.0872 by the 1,3- dimethyl-2-imidazolinone (0.0500mol) of 5.71g, 8.82g
Mol, after) mixing homogeneously in autoclave with 3- dichloromethyl -1H- methylpyrazole -4- carboxylate methyl ester, further heat up to 130 DEG C
～155 DEG C.When system interior temperature reaches 130 DEG C～155 DEG C, maintain this temperature, be slowly dropped into the HF (2.399mol) of 48.00g,
Drip off within about 4～5 hours, afterwards, be incubated 6～10 hours at 130 DEG C～155 DEG C.
After reaction terminates, pressure release of exitting, nitrogen purges, and tail gas uses alkali liquor absorption.It is cooled to 60 DEG C～80 DEG C, add
, with dilute reaction solution, the mass concentration being slowly dropped into 145.00g is 30% sodium hydroxide for 350g dimethylbenzene and 60g water
Aqueous solution (described mass concentration refers to that the quality of sodium hydroxide accounts for the percentage ratio of sodium hydrate aqueous solution gross mass), at 50 DEG C
～70 DEG C of insulated and stirred, after 1 hour, divide liquid, and aqueous phase use quality concentration is 36% concentrated hydrochloric acid acidifying (described mass concentration
Refer to that the quality of hydrogen chloride accounts for the percentage ratio of concentrated hydrochloric acid gross mass) to pH=1.0.It is cooled to 10 DEG C～25 DEG C, filter, very
Empty dry, obtain the 3- difluoromethyl -1H- methylpyrazole -4- carboxylic acid (yield of 138.93g：90.1%, HPLC purity：99.6%；
Isomer 5- difluoromethyl -1H- methylpyrazole -4- carboxylic acid HPLC purity：＜ 0.01%).
Embodiment 29
By 3- dichloromethyl -1H- methylpyrazole -4- carboxylate methyl ester (the GC purity prepared by the embodiment 16 of 200g：97.3%,
After 0.872mol) putting into autoclave, it is to slowly warm up to 125 DEG C～130 DEG C so that 3- dichloromethyl -1H- methylpyrazole -4-
Carboxylate methyl ester melts, and is further warming up to 130 DEG C～155 DEG C.When system interior temperature reaches 130 DEG C～155 DEG C, maintaining should
Temperature, is slowly dropped into the HF (2.399mol) of 48.00g, drips off within about 4～5 hours, afterwards, protects at 130 DEG C～155 DEG C
Temperature 10～15 hours.
After reaction terminates, pressure release of exitting, nitrogen purges, and tail gas uses alkali liquor absorption.It is cooled to 60 DEG C～80 DEG C, add
, with dilute reaction solution, the mass concentration being slowly dropped into 145.00g is 30% sodium hydroxide for 350g dimethylbenzene and 60g water
Aqueous solution (described mass concentration refers to that the quality of sodium hydroxide accounts for the percentage ratio of sodium hydrate aqueous solution gross mass), at 50 DEG C
～70 DEG C of insulated and stirred, after 1 hour, divide liquid, and aqueous phase use quality concentration is 36% concentrated hydrochloric acid acidifying (described mass concentration
Refer to that the quality of hydrogen chloride accounts for the percentage ratio of concentrated hydrochloric acid gross mass) to pH=1.0.It is cooled to 10 DEG C～25 DEG C, filter, very
Empty dry, obtain the 3- difluoromethyl -1H- methylpyrazole -4- carboxylic acid (yield of 121.65g：78.1%, HPLC purity：98.6%；
Isomer 5- difluoromethyl -1H- methylpyrazole -4- carboxylic acid HPLC purity：＜ 0.01%).
Embodiment 30
By 3- dichloromethyl -1H- methylpyrazole -4- carboxylate methyl ester (the GC purity prepared by the embodiment 16 of 200g：97.3%,
After 0.872mol) putting into autoclave, it is to slowly warm up to 125 DEG C～130 DEG C so that 3- dichloromethyl -1H- methylpyrazole -4-
Carboxylate methyl ester melts, and then the Butter of antimony. (0.0180mol) of 4.10g is put into autoclave, further heats up
To 130 DEG C～155 DEG C.When system interior temperature reaches 130 DEG C～155 DEG C, maintain this temperature, be slowly dropped into the HF of 48.00g
(2.399mol), drip off within about 4～5 hours, afterwards, be incubated 10～15 hours at 130 DEG C～155 DEG C.
After reaction terminates, pressure release of exitting, nitrogen purges, and tail gas uses alkali liquor absorption.It is cooled to 60 DEG C～80 DEG C, add
, with dilute reaction solution, the mass concentration being slowly dropped into 145.00g is 30% sodium hydroxide for 350g dimethylbenzene and 60g water
Aqueous solution (described mass concentration refers to that the quality of sodium hydroxide accounts for the percentage ratio of sodium hydrate aqueous solution gross mass), at 50 DEG C
～70 DEG C of insulated and stirred, after 1 hour, divide liquid, and aqueous phase use quality concentration is 36% concentrated hydrochloric acid acidifying (described mass concentration
Refer to that the quality of hydrogen chloride accounts for the percentage ratio of concentrated hydrochloric acid gross mass) to pH=1.0.It is cooled to 10 DEG C～25 DEG C, filter, very
Empty dry, obtain the 3- difluoromethyl -1H- methylpyrazole -4- carboxylic acid (yield of 137.12g：88.3%, HPLC purity：98.9%；
Isomer 5- difluoromethyl -1H- methylpyrazole -4- carboxylic acid HPLC purity：＜ 0.01%).
Embodiment 31
By 3- dichloromethyl -1H- methylpyrazole -4- carboxylate methyl ester (the GC purity prepared by the embodiment 16 of 200g：97.3%,
After 0.872mol) putting into autoclave, it is to slowly warm up to 125 DEG C～130 DEG C so that 3- dichloromethyl -1H- methylpyrazole -4-
Carboxylate methyl ester melts.By 16.00g pyridine (0.202mol) with 3- dichloromethyl -1H- methylpyrazole -4- carboxylate methyl ester in height
After mix homogeneously in pressure kettle, further heat up to 130 DEG C～155 DEG C.When system interior temperature reaches 130 DEG C～155 DEG C, maintain
This temperature, is slowly dropped into the HF (1.315mol) of 26.32g, drips off within about 2～3 hours, afterwards, at 130 DEG C～155 DEG C
Insulation 5～8 hours.
After reaction terminates, pressure release of exitting, nitrogen purges, and tail gas uses alkali liquor absorption.It is cooled to 60 DEG C～80 DEG C, add
, with dilute reaction solution, the mass concentration being slowly dropped into 145.00g is 30% sodium hydroxide for 350g dimethylbenzene and 60g water
Aqueous solution (described mass concentration refers to that the quality of sodium hydroxide accounts for the percentage ratio of sodium hydrate aqueous solution gross mass), at 50 DEG C
～70 DEG C of insulated and stirred, after 1 hour, divide liquid, and aqueous phase use quality concentration is 36% concentrated hydrochloric acid acidifying (described mass concentration
Refer to that the quality of hydrogen chloride accounts for the percentage ratio of concentrated hydrochloric acid gross mass) to pH=1.0.It is cooled to 10 DEG C～25 DEG C, filter, very
Empty dry, obtain the 3- mono- fluorine chloromethyl -1H- methylpyrazole -4- carboxylic acid (yield of 145.98g：83.5%, HPLC purity：
96.6%；Isomer 5- mono- fluorine chloromethyl -1H- methylpyrazole -4- carboxylic acid HPLC purity：＜ 0.01%).
Embodiment 32
By 3- trichloromethyl -1H- methylpyrazole -4- carboxylate methyl ester (the GC purity prepared by the embodiment 14 of 200g：91.8%,
After 0.713mol) putting into autoclave, it is to slowly warm up to 125 DEG C～130 DEG C so that 3- trichloromethyl -1H- methylpyrazole -4-
Carboxylate methyl ester melts.By 13.00g pyridine (0.164mol) with 3- trichloromethyl -1H- methylpyrazole -4- carboxylate methyl ester in height
After mix homogeneously in pressure kettle, further heat up to 130 DEG C～155 DEG C.When system interior temperature reaches 130 DEG C～155 DEG C, maintain
This temperature, is slowly dropped into the HF (2.749mol) of 55.00g, drips off within about 5～6 hours, afterwards, at 130 DEG C～155 DEG C
Insulation 5～8 hours.
After reaction terminates, pressure release of exitting, nitrogen purges, and tail gas uses alkali liquor absorption.It is cooled to 60 DEG C～80 DEG C, add
, with dilute reaction solution, the mass concentration being slowly dropped into 125.00g is 30% sodium hydroxide for 350g dimethylbenzene and 60g water
Aqueous solution (described mass concentration refers to that the quality of sodium hydroxide accounts for the percentage ratio of sodium hydrate aqueous solution gross mass),
50～70 DEG C of insulated and stirred, after 1 hour, divide liquid, and aqueous phase use quality concentration is that (described quality is dense for 36% concentrated hydrochloric acid acidifying
Degree refers to that the quality of hydrogen chloride accounts for the percentage ratio of concentrated hydrochloric acid gross mass) to pH=1.0.It is cooled to 10 DEG C～25 DEG C, filter,
Vacuum drying, obtains the 3- Trifluoromethyl-1 H- methylpyrazole -4- carboxylic acid (yield of 119.75g：85.7%, HPLC purity：
99.1%；Isomer 5- Trifluoromethyl-1 H- methylpyrazole -4- carboxylic acid HPLC purity：0.05%).
Embodiment 33
By 3- trichloromethyl -1H- methylpyrazole -4- carboxylate methyl ester (the GC purity prepared by the embodiment 14 of 200g：91.8%,
After 0.713mol) putting into autoclave, it is to slowly warm up to 125 DEG C～130 DEG C so that 3- trichloromethyl -1H- methylpyrazole -4-
Carboxylate methyl ester melts.By 13.00g pyridine (0.164mol) with 3- trichloromethyl -1H- methylpyrazole -4- carboxylate methyl ester in height
After mix homogeneously in pressure kettle, further heat up to 130 DEG C～155 DEG C.When system interior temperature reaches 130 DEG C～155 DEG C, maintain
This temperature, is slowly dropped into the HF (1.749mol) of 35.00g, drips off within about 5～6 hours, afterwards, at 130 DEG C～155 DEG C
Insulation 5～8 hours.
After reaction terminates, pressure release of exitting, nitrogen purges, and tail gas uses alkali liquor absorption.It is cooled to 60 DEG C～80 DEG C, add
, with dilute reaction solution, the mass concentration being slowly dropped into 125.00g is 30% sodium hydroxide for 350g dimethylbenzene and 60g water
Aqueous solution (described mass concentration refers to that the quality of sodium hydroxide accounts for the percentage ratio of sodium hydrate aqueous solution gross mass), at 50 DEG C
～70 DEG C of insulated and stirred, after 1 hour, divide liquid, and aqueous phase use quality concentration is 36% concentrated hydrochloric acid acidifying (described mass concentration
Refer to that the quality of hydrogen chloride accounts for the percentage ratio of concentrated hydrochloric acid gross mass) to pH=1.0.It is cooled to 10 DEG C～25 DEG C, filter, very
Empty dry, obtain the 3- difluoro chloromethyl -1H- methylpyrazole -4- carboxylic acid (yield of 132.43g：83.5%, HPLC purity：
94.7%；Isomer 5- difluoro chloromethyl -1H- methylpyrazole -4- carboxylic acid content：0.04%).
Embodiment 34
By 3- trichloromethyl -1H- methylpyrazole -4- carboxylate methyl ester (the GC purity prepared by the embodiment 14 of 200g：91.8%,
After 0.713mol) putting into autoclave, it is to slowly warm up to 125 DEG C～130 DEG C so that 3- trichloromethyl -1H- methylpyrazole -4-
Carboxylate methyl ester melts.By 10.00g pyridine (0.127mol) with 3- trichloromethyl -1H- methylpyrazole -4- carboxylate methyl ester in height
After mix homogeneously in pressure kettle, further heat up to 130 DEG C～155 DEG C.When system interior temperature reaches 130 DEG C～155 DEG C, maintain
This temperature, is slowly dropped into the HF (1.000mol) of 20.00g, drips off within about 4～5 hours, afterwards, at 130 DEG C～155 DEG C
Insulation 5～8 hours.
After reaction terminates, pressure release of exitting, nitrogen purges, and tail gas uses alkali liquor absorption.It is cooled to 60 DEG C～80 DEG C, add
, with dilute reaction solution, the mass concentration being slowly dropped into 125.00g is 30% sodium hydroxide for 350g dimethylbenzene and 60g water
Aqueous solution (described mass concentration refers to that the quality of sodium hydroxide accounts for the percentage ratio of sodium hydrate aqueous solution gross mass), at 50 DEG C
～70 DEG C of insulated and stirred, after 1 hour, divide liquid, and aqueous phase use quality concentration is 36% concentrated hydrochloric acid acidifying (described mass concentration
Refer to that the quality of hydrogen chloride accounts for the percentage ratio of concentrated hydrochloric acid gross mass) to pH=1.0.It is cooled to 10 DEG C～25 DEG C, filter, very
Empty dry, obtain the 3- mono- fluorine dichloromethyl -1H- methylpyrazole -4- carboxylic acid (yield of 142.56g：84.6%, HPLC purity：
96.1%；Isomer 5- mono- fluorine dichloromethyl -1H- methylpyrazole -4- carboxylic acid HPLC purity：0.04%).
Embodiment 35
By 3- dichloromethyl -1H- methylpyrazole -4- carboxylic acid, ethyl ester (the GC purity prepared by the embodiment 13 of 200g：92.8%,
0.783mol) and after triethylamine trihydrofluoride (1.067mol) the input autoclave of 172.06g, slow intensification
To 130 DEG C～155 DEG C.When system interior temperature reaches 130 DEG C～155 DEG C, maintain this temperature, be incubated 5～8 at 130 DEG C～155 DEG C
Hour.
After reaction terminates, pressure release of exitting, nitrogen purges, and tail gas uses alkali liquor absorption.It is cooled to 60 DEG C～80 DEG C, add
, with dilute reaction solution, the mass concentration being slowly dropped into 125.00g is 30% sodium hydroxide for 350g dimethylbenzene and 60g water
Aqueous solution (described mass concentration refers to that the quality of sodium hydroxide accounts for the percentage ratio of sodium hydrate aqueous solution gross mass), at 50 DEG C
～70 DEG C of insulated and stirred, after 1 hour, divide liquid, and aqueous phase use quality concentration is 36% concentrated hydrochloric acid acidifying (described mass concentration
Refer to that the quality of hydrogen chloride accounts for the percentage ratio of concentrated hydrochloric acid gross mass) to pH=1.0.It is cooled to 10 DEG C～25 DEG C, filter, very
Empty dry, obtain the 3- difluoromethyl -1H- methylpyrazole -4- carboxylic acid (yield of 106.61g：76.1%, HPLC purity：98.5%；
Isomer 5- difluoromethyl -1H- methylpyrazole -4- carboxylic acid HPLC purity：0.05%).
Embodiment 36
By 3- dichloromethyl -1H- methylpyrazole -4- carboxylic acid, ethyl ester (the GC purity prepared by the embodiment 13 of 200g：92.8%,
0.783mol) and after pyridine hydrofluoride (2.505mol) the input autoclave of 248.32g, it is to slowly warm up to 130 DEG C
～155 DEG C.When system interior temperature reaches 130 DEG C～155 DEG C, maintain this temperature, be incubated 5～8 hours at 130 DEG C～155 DEG C.
After reaction terminates, pressure release of exitting, nitrogen purges, and tail gas uses alkali liquor absorption.It is cooled to 60 DEG C～80 DEG C, add
, with dilute reaction solution, the mass concentration being slowly dropped into 125.00g is 30% sodium hydroxide for 350g dimethylbenzene and 60g water
Aqueous solution (described mass concentration refers to that the quality of sodium hydroxide accounts for the percentage ratio of sodium hydrate aqueous solution gross mass), at 50 DEG C
～70 DEG C of insulated and stirred, after 1 hour, divide liquid, and aqueous phase use quality concentration is 36% concentrated hydrochloric acid acidifying (described mass concentration
Refer to that the quality of hydrogen chloride accounts for the percentage ratio of concentrated hydrochloric acid gross mass) to pH=1.0.It is cooled to 10 DEG C～25 DEG C, filter, very
Empty dry, obtain the 3- difluoromethyl -1H- methylpyrazole -4- carboxylic acid (yield of 104.21g：74.4%, HPLC purity：98.5%；
Isomer 5- difluoromethyl -1H- methylpyrazole -4- carboxylic acid HPLC purity：0.05%).
Embodiment 37
By 3- dichloromethyl -1H- methylpyrazole -4- carboxylic acid, ethyl ester (the GC purity prepared by the embodiment 13 of 200g：92.8%,
0.783mol) and after N-Methyl pyrrolidone five hydrofluoride (0.607mol) the input autoclave of 120.90g,
It is to slowly warm up to 130 DEG C～155 DEG C.When system interior temperature reaches 130 DEG C～155 DEG C, maintain this temperature, at 130 DEG C～155 DEG C
Insulation 10～15 hours.
After reaction terminates, pressure release of exitting, nitrogen purges, and tail gas uses alkali liquor absorption.It is cooled to 60 DEG C～80 DEG C, add
, with dilute reaction solution, the mass concentration being slowly dropped into 125.00g is 30% sodium hydroxide for 350g dimethylbenzene and 60g water
Aqueous solution (described mass concentration refers to that the quality of sodium hydroxide accounts for the percentage ratio of sodium hydrate aqueous solution gross mass), at 50 DEG C
～70 DEG C of insulated and stirred, after 1 hour, divide liquid, and aqueous phase use quality concentration is 36% concentrated hydrochloric acid acidifying (described mass concentration
Refer to that the quality of hydrogen chloride accounts for the percentage ratio of concentrated hydrochloric acid gross mass) to pH=1.0.It is cooled to 10 DEG C～25 DEG C, filter, very
Empty dry, obtain the 3- difluoromethyl -1H- methylpyrazole -4- carboxylic acid (yield of 104.00g：74.5%, HPLC purity：98.8%；
Isomer 5- difluoromethyl -1H- methylpyrazole -4- carboxylic acid HPLC purity：0.05%).
Embodiment 38
By 3- dichloromethyl -1H- methylpyrazole -4- carboxylic acid, ethyl ester (the GC purity prepared by the embodiment 13 of 200g：92.8%,
0.783mol) put into reaction under high pressure with the 1,3- dimethyl-2-imidazolinone ten hexahydro fluorate (0.160mol) of 69.50g
After kettle, it is to slowly warm up to 130 DEG C～155 DEG C.When system interior temperature reaches 130 DEG C～155 DEG C, maintain this temperature, at 130 DEG C
～155 DEG C are incubated 7～12 hours.
After reaction terminates, pressure release of exitting, nitrogen purges, and tail gas uses alkali liquor absorption.It is cooled to 60 DEG C～80 DEG C, add
, with dilute reaction solution, the mass concentration being slowly dropped into 125.00g is 30% sodium hydroxide for 350g dimethylbenzene and 60g water
Aqueous solution (described mass concentration refers to that the quality of sodium hydroxide accounts for the percentage ratio of sodium hydrate aqueous solution gross mass), at 50 DEG C
～70 DEG C of insulated and stirred, after 1 hour, divide liquid, and aqueous phase use quality concentration is 36% concentrated hydrochloric acid acidifying (described mass concentration
Refer to that the quality of hydrogen chloride accounts for the percentage ratio of concentrated hydrochloric acid gross mass) to pH=1.0.It is cooled to 10 DEG C～25 DEG C, filter, very
Empty dry, obtain the 3- difluoromethyl -1H- methylpyrazole -4- carboxylic acid (yield of 117.60g：84.5%, HPLC purity：99.1%；
Isomer 5- difluoromethyl -1H- methylpyrazole -4- carboxylic acid HPLC purity：0.05%).
Comparative example
Comparative example 1
Keep 0～5 DEG C of interior temperature, malonic acid monomethyl ester potassium salt (the HPLC purity that the embodiment 2 of 100g is obtained：99.1%,
After 0.634mol) mixing in reaction bulb with the acetonitrile of 750g, 0～5 DEG C of maintenance system interior temperature, add 96.23g tri- second
After amine (0.951mol), it is slowly added to 72.40g magnesium chloride solids (0.760mol).After the completion of charging, naturally heat up,
And keep 20 DEG C～25 DEG C of system interior temperature to be incubated 2～3 hours.It is cooled to 0～10 DEG C, be slowly added dropwise 70.10g dichloroacetyl chloride
(0.476mol).Drip and finish, warm naturally to 20 DEG C～25 DEG C and in this temperature 18 hours.
After reaction terminates, add 240g ethyl acetate with dilute reaction solution.It is cooled to 0～15 DEG C, be slowly added dropwise 455g
Mass concentration be 5% aqueous hydrochloric acid solution acidifying (it is total that described mass concentration refers to that the quality of hydrogen chloride accounts for aqueous hydrochloric acid solution
The percentage ratio of quality).After being added dropwise to complete, it is incubated 30min at 0～15 DEG C, point liquid.Gained organic faciess use quality concentration
Aqueous hydrochloric acid solution (200g × 2) for 5% washes twice.After gained organic faciess desolvation, obtain dichloroacetyl acetic acid
Methyl ester 26.47g (GC purity：83.5%, yield：25.1%).
Comparative example 2
Keep 10 DEG C～25 DEG C of interior temperature, malonic acid monomethyl ester potassium salt (the HPLC purity that the embodiment 2 of 100g is obtained：
99.1%, 0.634mol) and 750g acetonitrile mix in reaction bulb after, maintenance system interior temperature at 10 DEG C～25 DEG C, plus
After entering the triethylamine (0.761mol) of 77.00g, it is slowly added to 72.40g magnesium chloride solids (0.760mol).Feed
Cheng Hou, heats up naturally, and keeps 20 DEG C～25 DEG C of system interior temperature to be incubated 2～3 hours.It is cooled to 0～10 DEG C, be slowly added dropwise
70.10g dichloroacetyl chloride (0.476mol).Drip and finish, warm naturally to 20 DEG C～25 DEG C and in this temperature 18 hours.
After reaction terminates, add 240g ethyl acetate with dilute reaction solution.It is cooled to 0～15 DEG C, be slowly added dropwise 455g
Mass concentration be 5% aqueous hydrochloric acid solution acidifying (it is total that described mass concentration refers to that the quality of hydrogen chloride accounts for aqueous hydrochloric acid solution
The percentage ratio of quality).After being added dropwise to complete, it is incubated 30min at 0～15 DEG C, point liquid.Gained organic faciess use quality concentration
Aqueous hydrochloric acid solution (200g × 2) for 5% washes twice.After gained organic faciess desolvation, obtain dichloroacetyl acetic acid
Methyl ester 76.95g (GC purity：82.6%, yield：35.3%).
Comparative example 3
(described mass concentration is fingernail to the methyl hydrazine aqueous solution (0.391mol) that the mass concentration of 45.00g is 40%
The quality of base hydrazine accounts for the percentage ratio of methyl hydrazine aqueous solution gross mass) and 70.00g methanol mix in reaction bulb after, by body
It is that interior temperature controls between 0～25 DEG C, be slowly added dropwise the 3- methoxyl group -2- dichloro-acetyl acrylic acid first prepared by embodiment 8
Methanol solution (3- methoxyl group -2- dichloro-acetyl the acrylic acid methyl ester. of ester：83.54g, GC purity：96.6%, 0.355mol；
Methanol：60.00g).Drip finish, maintenance system internal temperature between 0～25 DEG C, insulated and stirred 1 hour.
After reaction terminates, using the toluene extraction of 100g × 2, point liquid, concentrate organic faciess, obtain the 3- dichloro of 62.06g
Methyl isophthalic acid H- methylpyrazole -4- carboxylate methyl ester (GC purity：55.5%, yield：43.5%, wherein isomer 5- dichloromethane
Base -1H- methylpyrazole -4- carboxylate methyl ester GC purity：42.1%).
Comparative example 4
(described mass concentration is fingernail to the methyl hydrazine aqueous solution (0.391mol) that the mass concentration of 45.00g is 40%
The quality of base hydrazine accounts for the percentage ratio of methyl hydrazine aqueous solution gross mass) and 70.00g dimethylbenzene mix in reaction bulb after, will
System interior temperature controls between 0～25 DEG C, is slowly added dropwise the xylene solution of 3- ethyoxyl -2- difluoro acetyl group ethyl acrylate
(3- ethyoxyl -2- difluoro acetyl group ethyl acrylate：80.08g, GC purity：98.5%, 0.355mol；Dimethylbenzene：
140.00g).Drip finish, maintenance system temperature between 0～25 DEG C, insulated and stirred 1 hour.
After reaction terminates, add the water of 5.00g, point liquid, concentrate the 3- difluoromethyl -1H- methyl that organic faciess obtain 60.26g
Pyrazoles -4- carboxylic acid, ethyl ester (GC purity：88.5%, yield：79.0%, wherein isomer 5- difluoromethyl -1H- methyl pyrrole
Azoles -4- carboxylic acid, ethyl ester GC purity：8.3%).
Comparative example 5
2- dichloro-acetyl -3- dimethylamino ethyl acrylate (GC purity by 100g：98.5%, 0.388mol) molten
In the toluene of 450g, be cooled to 0～5 DEG C of interior temperature, start Deca 44.0g mass concentration be 60% methyl hydrazine water-soluble
Liquid (0.573mol) (described mass concentration refers to that the quality of methyl hydrazine accounts for the percentage ratio of methyl hydrazine aqueous solution gross mass),
About 40-70 minute is added dropwise to complete, drip finish, maintenance system temperature between 0～5 DEG C, insulated and stirred 1～2 hour.
After reaction terminates, add 8.8g water, point liquid, concentrate organic faciess, obtain the 3- dichloromethyl -1H- methyl of 86.35g
Pyrazoles -4- carboxylic acid, ethyl ester (GC purity：86.5%, yield：81.2%, wherein isomer 5- dichloromethyl -1H- methyl pyrrole
Azoles -4- carboxylate methyl ester GC purity：12.7%).
Comparative example 6
2- dichloro-acetyl -3- dimethylamino acrylic acid methyl ester. (GC purity by 100g：98.5%, 0.410mol) molten
In the chlorobenzene of 500g, it is cooled to 0～5 DEG C of interior temperature, the mass concentration starting Deca 46.5g is 60% methyl hydrazine methanol
Solution (0.605mol) (described mass concentration refers to that the quality of methyl hydrazine accounts for the percentage ratio of methyl hydrazine methanol solution gross mass),
About 40-70 minute is added dropwise to complete, drip finish, maintenance system temperature between 0～5 DEG C, insulated and stirred 1～2 hour.
After reaction terminates, add 18.0g water, point liquid, concentrate organic faciess, obtain the 3- dichloromethyl -1H- methyl of 89.53g
Pyrazoles -4- carboxylate methyl ester (GC purity：80.8%, yield：79.1%, wherein isomer 5- dichloromethyl -1H- methyl pyrrole
Azoles -4- carboxylate methyl ester GC purity：17.5%).
Comparative example 7
(described mass concentration is fingernail to the methyl hydrazine aqueous solution (0.391mol) that the mass concentration of 45.00g is 40%
The quality of base hydrazine accounts for the percentage ratio of methyl hydrazine aqueous solution gross mass), the mass concentration of 6.7g be 30% sodium hydroxide water-soluble
Liquid (0.050mol) (described mass concentration refers to that the quality of sodium hydroxide accounts for the percentage ratio of sodium hydrate aqueous solution gross mass)
After mixing in reaction bulb with the dimethylbenzene of 70.00g, system interior temperature is controlled between 0～25 DEG C, is slowly added dropwise 3- methoxy
Xylene solution (3- methoxyl group -2- difluoro acetyl group the acrylic acid methyl ester. of base -2- difluoro acetyl group acrylic acid methyl ester.：69.97g,
GC purity：98.5%, 0.355mol；Dimethylbenzene：140.00g).Drip finish, maintenance system temperature between 0～25 DEG C,
Insulated and stirred 1 hour.
After reaction terminates, point liquid, concentrate the 3- difluoromethyl -1H- methylpyrazole -4- carboxylate methyl ester (GC that organic faciess obtain 59.27g
Purity：92.6%, yield：81.3%, wherein isomer 5- difluoromethyl -1H- methylpyrazole -4- carboxylate methyl ester GC purity：
4.3%).
Comparative example 8
By 3- dichloromethyl -1H- methylpyrazole -4- carboxylate methyl ester (the GC purity prepared by the embodiment 16 of 35g：97.3%,
0.153mol), after the dimethylbenzene of the Butter of antimony. (0.0180mol) of 4.10g and 200g puts into autoclave, slowly
It is warming up to 130 DEG C～155 DEG C.When system interior temperature reaches 130 DEG C～155 DEG C, maintain this temperature, be slowly dropped into 9.0g's
HF (0.450mol), drips off for about 4～5 hours, afterwards, is incubated 10～15 hours at 130 DEG C～155 DEG C.
After reaction terminates, pressure release of exitting, nitrogen purges, and tail gas uses alkali liquor absorption.It is cooled to 60 DEG C～80 DEG C, add
With dilute reaction solution, the mass concentration being slowly dropped into 25.00g is 30% sodium hydrate aqueous solution (described matter to 45g water
Amount concentration refers to that the quality of sodium hydroxide accounts for the percentage ratio of sodium hydrate aqueous solution gross mass), in 50 DEG C～70 DEG C insulated and stirred
After 1 hour, point liquid, aqueous phase sampling detection, system is sufficiently complex, does not carry out further acidification.
Comparative example 9
By 3- dichloromethyl -1H- methylpyrazole -4- carboxylate methyl ester (the GC purity prepared by the embodiment 16 of 35g：97.3%,
0.153mol) and after the dimethylbenzene input autoclave of 200g, it is to slowly warm up to 130 DEG C～155 DEG C.When system interior temperature
When reaching 130 DEG C～155 DEG C, maintain this temperature, be slowly dropped into the HF (0.450mol) of 9.0g, drip off within about 4～5 hours,
Afterwards, it is incubated 10～15 hours at 130 DEG C～155 DEG C.
After reaction terminates, pressure release of exitting, nitrogen purges, and tail gas uses alkali liquor absorption.It is cooled to 60 DEG C～80 DEG C, add
With dilute reaction solution, the mass concentration being slowly dropped into 25.00g is 30% sodium hydrate aqueous solution (described matter to 45g water
Amount concentration refers to that the quality of sodium hydroxide accounts for the percentage ratio of sodium hydrate aqueous solution gross mass), in 50 DEG C～70 DEG C insulated and stirred
After 1 hour, point liquid, aqueous phase sampling detection, system is sufficiently complex, does not carry out further acidification.
Claims (18)
1. a kind of preparation method of compound 1 is it is characterised in that it comprises the following steps：In organic solvent, by compound
2 carry out ring-closure reaction with methyl hydrazine, obtain compound 1；
Wherein, R1For C1～C4Alkyl；R2For methyl or ethyl；X is 2 or 3.
2. compound 1 as claimed in claim 1 preparation method it is characterised in that：Described C1～C4Alkyl
For methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl or the tert-butyl group；
And/or,
In the preparation method of described compound 1, described organic solvent is ether solvent, aromatic hydrocarbon solvent, alkane
One or more of class solvent and halogenated aryl hydrocarbon class solvent；
And/or,
In the preparation method of described compound 1, described organic solvent with the mass values of described compound 2 is
1～100；
And/or,
In the preparation method of described compound 1, described methyl hydrazine is directly used or is used in the form of its solution；
And/or,
In the preparation method of described compound 1, described compound 2 is 1 with the mol ratio of described methyl hydrazine:1.0～
1:2.5；
And/or,
In the preparation method of described compound 1, the temperature of described ring-closure reaction is -50 DEG C～50 DEG C；
And/or,
In the preparation method of described compound 1, the time of described ring-closure reaction is 1 hour～5 hours；
And/or,
The preparation method of described compound 1 is carried out in the presence of a base；
And/or,
The preparation method of described compound 1 adopts following steps：The solution that compound 2 is formed with organic solvent adds
In the mixture that methyl hydrazine and organic solvent are formed, carry out ring-closure reaction and obtain compound 1 or by being added to of methyl hydrazine
In the solution that compound 2 is formed with organic solvent, carry out ring-closure reaction and obtain compound 1；
And/or,
The preparation method of described compound 1 includes following post-processing step：After reaction terminates, point liquid, organic faciess remove
Solvent, obtains compound 1.
3. compound 1 as claimed in claim 2 preparation method it is characterised in that：
In the preparation method of described compound 1, when described organic solvent is ether solvent, described ethers is molten
Agent is one or more of ether, positive propyl ether, diisopropyl ether, ethyl n-butyl ether, n-butyl ether and n-amylether；
And/or,
In the preparation method of described compound 1, when described organic solvent is aromatic hydrocarbon solvent, described aromatic hydrocarbons
Class solvent is one or more of benzene, toluene, ethylbenzene, dimethylbenzene, o-Dimethylbenzene, meta-xylene and xylol；
And/or,
In the preparation method of described compound 1, when described organic solvent is alkane solvents, described alkane
Class solvent is C1～C8Alkane solvents；
And/or,
In the preparation method of described compound 1, when described organic solvent is halogenated aryl hydrocarbon class solvent, described
Halogenated aryl hydrocarbon class solvent is chlorobenzene, o-dichlorohenzene, m-dichlorobenzene, paracide, ortho-chlorotolu'ene, parachlorotoluene and m-chloro
One or more of toluene；
And/or,
In the preparation method of described compound 1, described organic solvent with the mass values of described compound 2 is
2～10；
And/or,
In the preparation method of described compound 1, when described methyl hydrazine is used in the form of its solution, methyl hydrazine
The mass concentration of solution is 20%～70%, and described mass concentration refers to that the quality of methyl hydrazine accounts for methyl hydrazine solution gross mass
Percentage ratio；
And/or,
In the preparation method of described compound 1, when described methyl hydrazine is used in the form of its solution, methyl hydrazine
The solvent of solution is water, methanol or ethanol；
And/or,
In the preparation method of described compound 1, described compound 2 is 1 with the mol ratio of described methyl hydrazine:1.0～
1:1.5；
And/or,
In the preparation method of described compound 1, the temperature of described ring-closure reaction is 0～25 DEG C；
And/or,
In the preparation method of described compound 1, the time of described ring-closure reaction is 1 hour～3 hours；
And/or,
When the preparation method of described compound 1 is carried out in the presence of a base, described alkali is organic base or inorganic
Alkali；
And/or,
When the preparation method of described compound 1 is carried out in the presence of a base, described alkali and described compound 2
Mol ratio be 0.005～0.3；
And/or,
In the step that the preparation method of described compound 1 adopts, the mode of described addition is Deca, described Deca
Speed be defined less than 25 DEG C by system temperature；
And/or,
In the described post-processing step of compound 1, the mode of described removing solvent concentrating under reduced pressure；Described point liquid
For after adding water, directly point liquid or extraction divide liquid.
4. compound 1 as claimed in claim 3 preparation method it is characterised in that：System in described compound 1
In Preparation Method, when described organic solvent is C1～C8Alkane solvents when, described C1～C8Alkane solvents be
One or more of normal hexane, normal heptane and hexamethylene；
And/or,
In the preparation method of described compound 1, when described methyl hydrazine is used in the form of its solution, methyl hydrazine
The mass concentration of solution is 30%～60%, and described mass concentration refers to that the quality of methyl hydrazine accounts for methyl hydrazine solution gross mass
Percentage ratio；
And/or,
When the preparation method of described compound 1 is carried out under conditions of inorganic base presence, described inorganic base is hydrogen-oxygen
Change one or more of sodium, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate；
And/or,
When the preparation method of described compound 1 is carried out under conditions of organic base presence, described organic base is three second
One or more of amine, tri-n-butylamine, pyridine, tetramethylethylenediamine, N-methylmorpholine and DMAP；
And/or,
When the preparation method of described compound 1 is carried out in the presence of a base, described alkali and described compound 2
Mol ratio be 0.05～0.25；
And/or,
In the described post-processing step of compound 1, the solvent that described extraction adopts is toluene and/or dimethylbenzene.
5. compound 1 as claimed in claim 1 preparation method it is characterised in that：The preparation of described compound 1
Method, further comprising the steps：Compound 3, compound 4 and acetic anhydride are carried out condensation reaction, obtains described
Compound 2；
Wherein, R1And R2Definition as claimed in claim 1 or 2, the definition of x is as claimed in claim 1.
6. compound 1 as claimed in claim 5 preparation method it is characterised in that：
In the preparation method of described compound 2, described compound 4 is trimethyl orthoformate or triethyl orthoformate；
And/or,
In the preparation method of described compound 2, described compound 3 with the molar ratio of described compound 4 is
1.0～5.0；
And/or,
In the preparation method of described compound 2, described acetic anhydride with the molar ratio of described compound 4 is
1.0～5.0；
And/or,
In the preparation method of described compound 2, the temperature of described condensation reaction is 95 DEG C～115 DEG C；
And/or,
In the preparation method of described compound 2, the time of described condensation reaction is 1 hour～24 hours；
The preparation method of described compound 2, side border ring is distilled off the by-product acetate generating；
And/or,
The preparation method of described compound 2 is carried out in a solvent or under the conditions of solvent-free；
And/or,
The preparation method of described compound 2 includes following post-processing step：After reaction terminates, it is cooled to 10～35 DEG C,
Make system vacuum keep 10～20mbar, slowly system interior temperature is risen to 100 DEG C of unreacted raw materials of removing by 10～35 DEG C
And by-product, obtain compound 2.
7. compound 1 as claimed in claim 5 preparation method it is characterised in that：The preparation of described compound 1
Method, further comprising the steps：In organic solvent, under conditions of inorganic magnesium salt and organic base presence, by compound 5
Carry out condensation reaction with compound 6, then adjust pH to 3～8 again, carry out decarboxylic reaction, obtain described compound 3
?；
Wherein, R1Definition as claimed in claim 1 or 2, the definition of x is as claimed in claim 1；M+Represent potassium from
Son or sodium ion.
8. compound 1 as claimed in claim 7 preparation method it is characterised in that：
In the preparation method of described compound 3, described organic solvent is nitrile solvents and/or esters solvent；
And/or,
In the preparation method of described compound 3, described organic solvent with the mass values of described compound 6 is
1～100；
And/or,
In the preparation method of described compound 3, described compound 5 with the molar ratio of described compound 6 is
1.0～2.0；
And/or,
In the preparation method of described compound 3, described inorganic magnesium salt is magnesium chloride, magnesium acetate, magnesium nitrate, sulfur
One or more of sour magnesium, magnesium bromide and magnesium iodide；
And/or,
In the preparation method of described compound 3, described organic base is triethylamine, Tri-n-Propylamine, tri-n-butylamine,
Diisopropyl ethyl amine, N, accelerine and N, one or more of N- diethylaniline；
And/or,
In the preparation method of described compound 3, described organic base with the molar ratio of described compound 6 is
1.0～5.0；
And/or,
In the preparation method of described compound 3, described organic base with the molar ratio of described compound 5 is
1.0～5.0；
And/or,
In the preparation method of described compound 3, the molar ratio of described inorganic magnesium salt magnesium and described compound 6
For 1.0～5.0；
And/or,
In the preparation method of described compound 3, the temperature of described condensation reaction is 0 DEG C～35 DEG C；
And/or,
In the preparation method of described compound 3, the time of described condensation reaction is 1 hour～48 hours；
And/or,
In the preparation method of described compound 3, described regulation pH to 3～8 is realized using addition acidic materials；
And/or,
In the preparation method of described compound 3, the temperature of described deacidification reaction is 0 DEG C～15 DEG C；
And/or,
In the preparation method of described compound 3, the time of described deacidification reaction is 0.5 hour～10 hours；
And/or,
The preparation method of described compound 3 comprises the following steps：By inorganic magnesium salt add compound 5, organic base with organic
In the mixture that solvent is formed, react 2 hours～3 hours, then lower the temperature, add compound 6, carry out condensation reaction, so
Adjust pH to 3～8 afterwards, carry out decarboxylic reaction and obtain described compound 3；
And/or,
The preparation method of described compound 3 includes following post-processing step, and after reaction terminates, point liquid, organic faciess adopt
Dilute acid soln washing, removing solvent obtain described compound 3.
9. compound 1 as claimed in claim 8 preparation method it is characterised in that：
In the preparation method of described compound 3, when described organic solvent is nitrile solvents, described nitrile is molten
Agent is acetonitrile；
And/or
In the preparation method of described compound 3, when described organic solvent is esters solvent, described esters are molten
Agent is ethyl acetate, methyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, sec-butyl acetate and acetic acid
One or more of tert-butyl ester；
And/or,
In the preparation method of described compound 3, described organic solvent with the mass values of described compound 6 is
5～15；
And/or,
In the preparation method of described compound 3, described compound 5 with the molar ratio of described compound 6 is
1.0～1.5；
And/or,
In the preparation method of described compound 3, described organic base with the molar ratio of described compound 6 is
1.0～2.5；
And/or,
In the preparation method of described compound 3, described inorganic magnesium salt with the molar ratio of described compound 6 is
1.0～2.5；
And/or,
In the preparation method of described compound 3, described organic base with the molar ratio of described compound 5 is
1.5～2.5；
And/or,
In the preparation method of described compound 3, the time of described condensation reaction is 15 hours～25 hours；
And/or,
In the preparation method of described compound 3, described acidic materials are hydrochloric acid, sulphuric acid, phosphoric acid, hydrobromic acid,
One or more of sodium bisulfate and potassium acid sulfate；
And/or,
In the preparation method of described compound 3, described acidic materials are used, when described in the form of its solution
When acidic materials are used in the form of its solution, the mass concentration of acidic materials solution is 1%～20%, and described quality is dense
Degree refers to the quality of acidic materials and the percentage ratio of acidic materials solution gross mass；
And/or,
In the preparation method of described compound 3, the time of described deacidification reaction is 0.5 hour～2 hours；
And/or,
In the step that the preparation method of described compound 3 includes, described " compound 5, organic base and organic solvent shape
The temperature of the mixture becoming " is 0～25 DEG C；
And/or,
In the step that the preparation method of described compound 3 includes, the reaction temperature of described " reaction 2 hours～3 hours "
Spend for 10 DEG C～35 DEG C；
And/or,
In the step that the preparation method of described compound 3 includes, the temperature of described cooling is 0 DEG C～35 DEG C；
And/or,
In the step that the preparation method of described compound 3 includes, the mode of described addition is Deca, described Deca
Speed be defined less than 35 DEG C by system temperature；
And/or,
In the post-processing step that the preparation method of described compound 3 includes, the mass concentration of described dilute acid soln is
3%～10%, described mass concentration refers to that the quality of acid accounts for the percentage ratio of dilute acid soln gross mass；
And/or,
In the post-processing step that the preparation method of described compound 3 includes, the acid in described diluted acid is hydrochloric acid.
10. compound 1 as claimed in claim 7 preparation method it is characterised in that：The system of described compound 1
Preparation Method, further comprising the steps：In organic solvent, compound 7 and MOH are carried out reacting obtain described
Compound 5；
Wherein, R1Definition as claimed in claim 1 or 2, M+Definition all as claimed in claim 7.
The preparation method of 11. compounds 1 as claimed in claim 10 it is characterised in that：
In the preparation method of described compound 5, described organic solvent is alcohols solvent；
And/or,
In the preparation method of described compound 5, described organic solvent with the mass values of described compound 7 is
1～100；
And/or,
In the preparation method of described compound 5, described MOH is potassium hydroxide and/or sodium hydroxide；
And/or,
In the preparation method of described compound 5, the molar ratio of described MOH and described compound 7 is 0.5～
1.5；
And/or,
In the preparation method of described compound 5, the temperature of described reaction is 10 DEG C～35 DEG C；
And/or,
In the preparation method of described compound 5, the time of described reaction is 1 hour～10 hours；
And/or,
The preparation method of described compound 5 comprises the following steps：The mixture that MOH is formed with organic solvent adds
In the solution that compound 7 is formed with organic solvent, carry out reacting the compound 5 described in obtaining；
And/or,
The preparation method of described compound 5 includes following post-processing step：Reaction terminate after, reactant liquor be heated to backflow,
Heat filter, filtrate are cooled to -5 DEG C～0 DEG C, are filtrated to get described compound 5.
A kind of 12. preparation methoies of compound 9 are it is characterised in that it comprises the following steps：According to claim 1～13
Preparation method described in any one is obtained compound 1；Then in enclosed system, under conditions of catalyst exists, will be described
Compound 1 carry out halogen exchange reaction with fluorination reagent, obtain compound 9；Described catalyst is alkali, interior
One or more of amide and Butter of antimony.；
Wherein, R1Definition as claimed in claim 1 or 2；The definition of x is as claimed in claim 1.
The preparation method of 13. compounds 9 as claimed in claim 12 it is characterised in that：In described compound 9
In preparation method, described alkali is organic base；
And/or,
In the preparation method of described compound 9, described catalyst with the molar ratio of described compound 1 is
0.005～5.0；
And/or,
In the preparation method of described compound 9, described alkali is used in the form of its hydrofluoride；
And/or,
In the preparation method of described compound 9, described lactams are DMI, N- methyl
One or more of urea in ketopyrrolidine, 2-Pyrrolidone and formyl second；
And/or,
In the preparation method of described compound 9, described lactams are used in the form of its hydrofluoride；
And/or,
In the preparation method of described compound 9, described fluorination reagent is fluohydric acid gas, the hydrofluoride of organic base,
One or more of the hydrofluoride of lactams, potassium fluoride and cesium fluoride；
And/or,
In the preparation method of described compound 9, described fluorination reagent with the molar ratio of described compound 1 is
1.0～5.0；When being used the hydrofluoride of organic base and/or the hydrofluoride of lactams as fluorination reagent, described has
In the hydrofluoride of the hydrofluoride of machine alkali and/or lactams, contained HF and the molar ratio of described compound 1 are
1.0～5.0；
And/or,
In the preparation method of described compound 9, the temperature of described halogen exchange reaction is 80 DEG C～180 DEG C；
And/or,
In the preparation method of described compound 9, the time of described halogen exchange reaction is 1 hour～24 hours；
And/or,
The preparation method of described compound 9, is carried out in a solvent or under condition of no solvent；
And/or,
The preparation method of described compound 9, using following steps：Fluorination reagent is added to alkali formed with compound 1
Mixture in, carry out halogen exchange reaction, obtain compound 9；
And/or,
The preparation method of described compound 9, using following post-processing step：After reaction terminates, pressure release of exitting, reaction
Liquid is not directly used in the reaction of prepare compound 10 after further treatment.
The preparation method of 14. compounds 9 as claimed in claim 13 it is characterised in that：
In the preparation method of described compound 9, described organic base is triethylamine, Tri-n-Propylamine, tri-n-butylamine,
N, one or more of accelerine, pyridine, 2- picoline and 4- picoline；
And/or,
In the preparation method of described compound 9, when described alkali is used in the form of its hydrofluoride, described
The hydrofluoride of alkali is the hydrogen fluoride salts of triethylamine and/or the hydrogen fluoride salts of pyridine；
And/or,
In the preparation method of described compound 9, when described lactams are used in the form of its hydrofluoride, institute
The hydrofluoride of the lactams stated is ten hexahydro fluorate and/or the N-Methyl pyrrolidone of 1,3- dimethyl-2-imidazolinone
Five hydrofluorides；
And/or,
In the preparation method of described compound 9, when the hydrofluoride form that described catalyst is alkali, described
The molar ratio with described compound 1 of catalyst is 1.0～3.0；The hydrogen fluorine being alkali rather than alkali when described catalyst
During acid salts, described catalyst is 0.1～0.5 with the molar ratio of described compound 1；When described catalyst is
During lactams, described catalyst is 0.05～0.5 with the molar ratio of described compound 1；When described catalyst is
During Butter of antimony., described catalyst is 0.005～0.05 with the molar ratio of described compound 1；When described catalysis
When agent is the hydrofluoride of lactams, described catalyst is 0.01～1 with the molar ratio of described compound 1；
And/or,
In the preparation method of described compound 9, described fluorination reagent with the molar ratio of described compound 1 is
1.0～4.0；When being used the hydrofluoride of organic base and/or the hydrofluoride of lactams as fluorination reagent, described has
In the hydrofluoride of the hydrofluoride of machine alkali and/or lactams, contained HF and the molar ratio of described compound 1 are
1.0～4.0；
And/or,
In the preparation method of described compound 9, the temperature of described halogen exchange reaction is 100 DEG C～160 DEG C；
And/or,
In the preparation method of described compound 9, the time of described halogen exchange reaction is 5 hours～15 hours；
And/or,
In the preparation method of described compound 9, when described reaction is carried out in a solvent, described solvent is ether
One or more of class solvent, esters solvent, aromatic hydrocarbon solvent and nitrile solvents；
And/or,
In the step that the preparation method of described compound 9 adopts, described " mixture that alkali is formed with compound 1 "
Temperature be 125 DEG C～130 DEG C；
And/or,
In the step that the preparation method of described compound 9 adopts, the mode of described addition is Deca, and described drips
Acceleration is so that system temperature maintains 130 DEG C～155 DEG C.
A kind of 15. preparation methoies of compound 10 are it is characterised in that it comprises the following steps：According to claim 14～17
Preparation method described in any one prepares compound 9；Then, again in solvent, described compound 9 is existed in alkali
Under the conditions of be hydrolyzed reaction, obtain compound 10；
Wherein, R1Definition all as claimed in claim 1 or 2, the definition of x is all as claimed in claim 1.
The preparation method of 16. compounds 10 as claimed in claim 15 it is characterised in that：
In the preparation method of described compound 10, described solvent is organic solvent and/or water；
And/or,
In the preparation method of described compound 10, the mass values of described solvent and described compound 9 are 1～
100；
And/or,
In the preparation method of described compound 10, described alkali is inorganic base；
And/or,
In the preparation method of described compound 10, described alkali is used in the form of its aqueous solution；
And/or,
In the preparation method of described compound 10, the molar ratio of described alkali and described compound 9 is 1.0～
5.0；
And/or,
In the preparation method of described compound 10, the temperature of described hydrolysis is 0 DEG C～130 DEG C；
And/or,
In the preparation method of described compound 10, the time of described hydrolysis is 1 hour～10 hours；
And/or,
The preparation method of described compound 10 adopts following steps：The aqueous solution of alkali is added compound 9 and organic solvent
Be hydrolyzed in the mixture being formed reaction, obtains compound 10；
And/or,
The preparation method of described compound 10, including following post-processing step：Reaction divides liquid, aqueous phase to adjust pH after terminating
To 1.0 about, it is cooled to 10 DEG C～25 DEG C, filters, be dried to obtain compound 10.
A kind of 17. preparation methoies of compound 9, it comprises the following steps：In enclosed system, the condition that catalyst exists
Under, compound 1 and fluorination reagent are carried out halogen exchange reaction, obtains compound 9；Described catalyst be alkali,
One or more of lactams and Butter of antimony.；
Wherein, R1Definition as claimed in claim 1 or 2；The definition of x is as claimed in claim 1；Each reaction is as weighed
Profit requires described in 12～14 any one.
A kind of 18. compounds 2, its structure is as follows：
Wherein, R1And R2Definition as claimed in claim 1 or 2, the definition of x is as claimed in claim 1.
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|---|---|---|---|---|
| CN108395404A (en) * | 2018-04-27 | 2018-08-14 | 深圳市众康动保科技有限公司 | A kind of synthetic method of multi-substituted pyrazol class compound |
| CN109354572A (en) * | 2018-11-29 | 2019-02-19 | 成都海杰亚医药科技有限公司 | A kind of preparation method of malonic acid monoester sylvite |
| CN109485609A (en) * | 2018-12-10 | 2019-03-19 | 常州大学 | A kind of preparation method of urea groups pyrimidone precursor |
| CN111116364A (en) * | 2019-12-30 | 2020-05-08 | 浙江本立科技股份有限公司 | Process for preparing 2-polyhaloacetyl-3-alkoxy acrylate |
| CN114195715A (en) * | 2021-12-31 | 2022-03-18 | 福建永晶科技股份有限公司 | Process for preparing 1-methyl-3-difluoromethyl-4-pyrazolic acid and 1-methyl-3-trifluoromethyl-4-pyrazolic acid |
| CN117384096A (en) * | 2023-12-13 | 2024-01-12 | 山东国邦药业有限公司 | Preparation method of difluoro pyrazole acid |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101970412A (en) * | 2008-03-10 | 2011-02-09 | 拜耳作物科学公司 | Method for regioselective synthesis of 1-alkyl-3-haloalkyl-1-pyrazol-4-carbonic acid derivatives |
| CN102026981A (en) * | 2008-02-25 | 2011-04-20 | 拜耳作物科学股份公司 | Method for the regioselective synthesis of 1-alkyl-3-haloalkyl-pyroazole-4-carboxylic acid derivatives |
| WO2012025469A1 (en) * | 2010-08-24 | 2012-03-01 | Solvay Sa | Improved process for the preparation of esters of 1-h-pyrazole-4-carboxylic acids |
| CN102731402A (en) * | 2012-06-29 | 2012-10-17 | 上海康鹏化学有限公司 | Preparation method of 3-trifluoromethylpyrazole-4-carboxylic acid and 3-difluoromethylpyrazole-4-carboxylic acid |
| EP2644598A1 (en) * | 2012-03-30 | 2013-10-02 | Solvay Sa | Method for the manufacture of heterocycles |
| EP2671874A1 (en) * | 2012-06-06 | 2013-12-11 | Solvay Sa | Preparation of esters of 1-substituted-3-fluoroalkyl-pyrazole-4-carboxylic acids |
| CN104016920A (en) * | 2014-06-16 | 2014-09-03 | 联化科技(上海)有限公司 | Co-production method of fluorine-containing methylpyrazole compounds |
-
2015
- 2015-08-14 CN CN201510502466.6A patent/CN106467492B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102026981A (en) * | 2008-02-25 | 2011-04-20 | 拜耳作物科学股份公司 | Method for the regioselective synthesis of 1-alkyl-3-haloalkyl-pyroazole-4-carboxylic acid derivatives |
| CN101970412A (en) * | 2008-03-10 | 2011-02-09 | 拜耳作物科学公司 | Method for regioselective synthesis of 1-alkyl-3-haloalkyl-1-pyrazol-4-carbonic acid derivatives |
| WO2012025469A1 (en) * | 2010-08-24 | 2012-03-01 | Solvay Sa | Improved process for the preparation of esters of 1-h-pyrazole-4-carboxylic acids |
| EP2644598A1 (en) * | 2012-03-30 | 2013-10-02 | Solvay Sa | Method for the manufacture of heterocycles |
| EP2671874A1 (en) * | 2012-06-06 | 2013-12-11 | Solvay Sa | Preparation of esters of 1-substituted-3-fluoroalkyl-pyrazole-4-carboxylic acids |
| CN102731402A (en) * | 2012-06-29 | 2012-10-17 | 上海康鹏化学有限公司 | Preparation method of 3-trifluoromethylpyrazole-4-carboxylic acid and 3-difluoromethylpyrazole-4-carboxylic acid |
| CN104016920A (en) * | 2014-06-16 | 2014-09-03 | 联化科技(上海)有限公司 | Co-production method of fluorine-containing methylpyrazole compounds |
Non-Patent Citations (1)
| Title |
|---|
| JANIS JAUNZEMS，等: "An Atom-Efficient Route to Ethyl 3‑(difluoromethyl)-1-methyl‑1H‑pyrazole-4-carboxylate (DFMMP)A Key Building Block for a Novel Fungicide Family", 《ORG. PROCESS RES. DEV.》 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108395404A (en) * | 2018-04-27 | 2018-08-14 | 深圳市众康动保科技有限公司 | A kind of synthetic method of multi-substituted pyrazol class compound |
| CN108395404B (en) * | 2018-04-27 | 2021-12-28 | 深圳市众康动保科技有限公司 | Synthesis method of polysubstituted pyrazole compound |
| CN109354572A (en) * | 2018-11-29 | 2019-02-19 | 成都海杰亚医药科技有限公司 | A kind of preparation method of malonic acid monoester sylvite |
| CN109485609A (en) * | 2018-12-10 | 2019-03-19 | 常州大学 | A kind of preparation method of urea groups pyrimidone precursor |
| CN111116364A (en) * | 2019-12-30 | 2020-05-08 | 浙江本立科技股份有限公司 | Process for preparing 2-polyhaloacetyl-3-alkoxy acrylate |
| CN111116364B (en) * | 2019-12-30 | 2022-11-11 | 浙江本立科技股份有限公司 | Process for preparing 2-polyhaloacetyl-3-alkoxy acrylate |
| CN114195715A (en) * | 2021-12-31 | 2022-03-18 | 福建永晶科技股份有限公司 | Process for preparing 1-methyl-3-difluoromethyl-4-pyrazolic acid and 1-methyl-3-trifluoromethyl-4-pyrazolic acid |
| CN114195715B (en) * | 2021-12-31 | 2024-05-10 | 福建永晶科技股份有限公司 | Process for preparing 1-methyl-3-difluoromethyl-4-pyrazole acid and 1-methyl-3-trifluoromethyl-4-pyrazole acid |
| CN117384096A (en) * | 2023-12-13 | 2024-01-12 | 山东国邦药业有限公司 | Preparation method of difluoro pyrazole acid |
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