CN106380447A - 3-difluoromethyl-1-methyl-1H-pyrazol-4-formic acid and preparation method of intermediate and intermediate - Google Patents
3-difluoromethyl-1-methyl-1H-pyrazol-4-formic acid and preparation method of intermediate and intermediate Download PDFInfo
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- CN106380447A CN106380447A CN201610781232.4A CN201610781232A CN106380447A CN 106380447 A CN106380447 A CN 106380447A CN 201610781232 A CN201610781232 A CN 201610781232A CN 106380447 A CN106380447 A CN 106380447A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- RLOHOBNEYHBZID-UHFFFAOYSA-N 3-(difluoromethyl)-1-methylpyrazole-4-carboxylic acid Chemical compound CN1C=C(C(O)=O)C(C(F)F)=N1 RLOHOBNEYHBZID-UHFFFAOYSA-N 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 31
- 239000002904 solvent Substances 0.000 claims abstract description 28
- 229940125904 compound 1 Drugs 0.000 claims abstract description 11
- 239000003054 catalyst Substances 0.000 claims abstract description 10
- 229940125782 compound 2 Drugs 0.000 claims abstract description 8
- 239000003513 alkali Substances 0.000 claims abstract description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 30
- RDGAINUSZOZWBJ-UHFFFAOYSA-N 1-(difluoromethyl)-3-methylcyclohex-4-ene-1,3-dicarboxylic acid Chemical compound FC(C1(CC(C(=O)O)(C=CC1)C)C(=O)O)F RDGAINUSZOZWBJ-UHFFFAOYSA-N 0.000 claims description 20
- 238000003682 fluorination reaction Methods 0.000 claims description 17
- 235000019253 formic acid Nutrition 0.000 claims description 15
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 15
- 239000000543 intermediate Substances 0.000 claims description 14
- -1 tetrafluoroborate Chemical compound 0.000 claims description 14
- 238000001514 detection method Methods 0.000 claims description 13
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 claims description 10
- 239000003444 phase transfer catalyst Substances 0.000 claims description 9
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 9
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical class [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 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 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 4
- 150000001408 amides Chemical group 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 4
- 239000002608 ionic liquid Substances 0.000 claims description 4
- 150000005846 sugar alcohols Polymers 0.000 claims description 4
- 150000003457 sulfones Chemical class 0.000 claims description 4
- OKIZCWYLBDKLSU-UHFFFAOYSA-M N,N,N-Trimethylmethanaminium chloride Chemical compound [Cl-].C[N+](C)(C)C OKIZCWYLBDKLSU-UHFFFAOYSA-M 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 125000001453 quaternary ammonium group Chemical class 0.000 claims description 3
- KAIPKTYOBMEXRR-UHFFFAOYSA-N 1-butyl-3-methyl-2h-imidazole Chemical compound CCCCN1CN(C)C=C1 KAIPKTYOBMEXRR-UHFFFAOYSA-N 0.000 claims description 2
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- 229940006460 bromide ion Drugs 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 2
- XKBGEWXEAPTVCK-UHFFFAOYSA-M methyltrioctylammonium chloride Chemical compound [Cl-].CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC XKBGEWXEAPTVCK-UHFFFAOYSA-M 0.000 claims description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- HWCKGOZZJDHMNC-UHFFFAOYSA-M tetraethylammonium bromide Chemical compound [Br-].CC[N+](CC)(CC)CC HWCKGOZZJDHMNC-UHFFFAOYSA-M 0.000 claims description 2
- ZUHZGEOKBKGPSW-UHFFFAOYSA-N tetraglyme Chemical compound COCCOCCOCCOCCOC ZUHZGEOKBKGPSW-UHFFFAOYSA-N 0.000 claims 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- 150000001768 cations Chemical class 0.000 claims 1
- 150000003983 crown ethers Chemical class 0.000 claims 1
- 150000002170 ethers Chemical class 0.000 claims 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims 1
- 230000035484 reaction time Effects 0.000 claims 1
- 150000003462 sulfoxides Chemical class 0.000 claims 1
- NRTLTGGGUQIRRT-UHFFFAOYSA-N triethylazanium;bromide Chemical compound [Br-].CC[NH+](CC)CC NRTLTGGGUQIRRT-UHFFFAOYSA-N 0.000 claims 1
- 235000021419 vinegar Nutrition 0.000 claims 1
- 239000000052 vinegar Substances 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 26
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 7
- 229940126214 compound 3 Drugs 0.000 abstract description 3
- 238000004334 fluoridation Methods 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- LELOWRISYMNNSU-UHFFFAOYSA-N hydrogen cyanide Chemical compound N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 29
- 238000010792 warming Methods 0.000 description 22
- 239000011698 potassium fluoride Substances 0.000 description 18
- 239000007921 spray Substances 0.000 description 16
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 15
- 238000000034 method Methods 0.000 description 15
- 239000007788 liquid Substances 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 11
- DDGQGGLJXLMWTC-UHFFFAOYSA-N ClC(C1(CC(C(=O)O)(C=CC1)C)C(=O)O)Cl Chemical compound ClC(C1(CC(C(=O)O)(C=CC1)C)C(=O)O)Cl DDGQGGLJXLMWTC-UHFFFAOYSA-N 0.000 description 9
- 238000012805 post-processing Methods 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 230000007062 hydrolysis Effects 0.000 description 6
- 238000001914 filtration Methods 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 4
- 235000011121 sodium hydroxide Nutrition 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- AYDQIZKZTQHYIY-UHFFFAOYSA-N OC(=O)C1(C)CC(C(O)=O)=CC=C1 Chemical compound OC(=O)C1(C)CC(C(O)=O)=CC=C1 AYDQIZKZTQHYIY-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 239000007791 liquid phase Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 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 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 239000005788 Fluxapyroxad Substances 0.000 description 2
- 239000005799 Isopyrazam Substances 0.000 description 2
- 229930013930 alkaloid Natural products 0.000 description 2
- 150000003851 azoles Chemical class 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- SXSGXWCSHSVPGB-UHFFFAOYSA-N fluxapyroxad Chemical compound FC(F)C1=NN(C)C=C1C(=O)NC1=CC=CC=C1C1=CC(F)=C(F)C(F)=C1 SXSGXWCSHSVPGB-UHFFFAOYSA-N 0.000 description 2
- 235000003270 potassium fluoride Nutrition 0.000 description 2
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 2
- 229910001948 sodium oxide Inorganic materials 0.000 description 2
- 238000013517 stratification Methods 0.000 description 2
- 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 1
- OXHNLMTVIGZXSG-UHFFFAOYSA-N 1-Methylpyrrole Chemical compound CN1C=CC=C1 OXHNLMTVIGZXSG-UHFFFAOYSA-N 0.000 description 1
- QCXFMQGOKGZSDS-UHFFFAOYSA-N 2,2-dichloro-n-(3-imidazol-1-ylpropyl)acetamide Chemical compound ClC(Cl)C(=O)NCCCN1C=CN=C1 QCXFMQGOKGZSDS-UHFFFAOYSA-N 0.000 description 1
- ARJXZMAQFNINHE-UHFFFAOYSA-N 3-(dichloromethyl)-N,N,1-trimethylpyrazole-4-carboxamide Chemical compound CN1C=C(C(=N1)C(Cl)Cl)C(=O)N(C)C ARJXZMAQFNINHE-UHFFFAOYSA-N 0.000 description 1
- JQDCYDWZWBUECX-UHFFFAOYSA-N 3-(difluoromethyl)-1-methylpyrazole Chemical class CN1C=CC(C(F)F)=N1 JQDCYDWZWBUECX-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 239000005738 Bixafen Substances 0.000 description 1
- OKUSWAGOKUGEDX-UHFFFAOYSA-N C(CCC)Br(CCCC)(CCCC)CCCC Chemical compound C(CCC)Br(CCCC)(CCCC)CCCC OKUSWAGOKUGEDX-UHFFFAOYSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- 208000035126 Facies Diseases 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- LUZMLJILUGSLNT-UHFFFAOYSA-M P.[Br-].C(CCC)[P+](CCCC)(CCCC)CCCC Chemical compound P.[Br-].C(CCC)[P+](CCCC)(CCCC)CCCC LUZMLJILUGSLNT-UHFFFAOYSA-M 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical class C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- CHQVQXZFZHACQQ-UHFFFAOYSA-M benzyl(triethyl)azanium;bromide Chemical compound [Br-].CC[N+](CC)(CC)CC1=CC=CC=C1 CHQVQXZFZHACQQ-UHFFFAOYSA-M 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
- 230000003197 catalytic effect Effects 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 150000002221 fluorine Chemical class 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000001465 metallisation Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 1
- 238000003408 phase transfer catalysis Methods 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- RKHXQBLJXBGEKF-UHFFFAOYSA-M tetrabutylphosphanium;bromide Chemical compound [Br-].CCCC[P+](CCCC)(CCCC)CCCC RKHXQBLJXBGEKF-UHFFFAOYSA-M 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses 3-difluoromethyl-1-methyl-1H-pyrazol-4-formic acid and a preparation method of an intermediate thereof and the intermediate. The preparation method of the intermediate comprises the following step: in the absence of a solvent or in the presence of a solvent, a compound 1 and KF undergo a fluoridation reaction under the action of a catalyst so as to obtain a compound 2. The preparation method also comprises the following step: the compound 2 is subjected to a hydrolysis reaction under the action of alkali so as to obtain a compound 3. The preparation method has the following advantages: raw materials are cheap and easily available; operation is simple; and security risk is low. The preparation method is suitable for industrial production.
Description
Technical field
The present invention relates to the preparation method of a kind of 3- difluoromethyl -1- methyl isophthalic acid H- pyrazoles -4- formic acid and its intermediate and
Intermediate.
Background technology
3- difluoromethyl -1- methyl isophthalic acid H- pyrazoles -4- carboxylic acid, is synthesizing new high-efficiency low-toxicity sterilised products isopyrazam
(Bixafen) a, important intermediate of fluxapyroxad (Fluxapyroxad), biphenyl pyrrole bacterium amine (Isopyrazam) etc.,
In future, there is quite wide market prospect, its synthetic method has also obtained the great interest of chemist and widely studied.
What report was more at present is with 3- dichloromethyl -1- methyl isophthalic acid H- pyrazoles -4- formic acid esters as raw material, through fluorination again
Hydrolysis is obtained 3- difluoromethyl -1- methyl isophthalic acid H- pyrazoles -4- carboxylic acid, as implied above.Chinese patent literature CN101558044A,
CN105218448A, CN1875006A, US2006276656A1, CN200480032248, CN102718712A,
CN102731402A etc. reports with 3- dichloromethyl -1- methyl isophthalic acid H- pyrazoles -4- formic acid esters as raw material, with fluohydric acid gas or fluorine
Change hydrogen and catalytic amount or equivalent amine blends are fluorinated as fluorination reagent, then through peracidity or hydrolyzed under basic conditions, from
And the method preparing 3- dichloromethyl -1- methyl isophthalic acid H- pyrazoles -4- formic acid；Chinese patent literature CN1875006A,
CN105218448A there was reported the method being fluorinated with potassium fluoride as fluorination reagent, but the former does not refer to yield, after
Person's yield is low；Chinese patent literature CN103582631A reports with 3- dichloromethyl -1- methyl isophthalic acid H- pyrazoles -4- formic acid esters
Or the reaction that 3- dichloromethyl -1- methyl isophthalic acid H- pyrazoles -4- formic acid is carried out in potassium fluoride aqueous solution is although operate and reaction bar
Part is more gentle, but because dichloromethyl is very active, is easy to hydrolysis in the presence of water it is more difficult to obtain very high yield.On
The method with 3- dichloromethyl -1- methyl isophthalic acid H- pyrazoles -4- formic acid esters as raw material of stating has one common to be unfavorable for commercially producing
Method be exactly this raw material be usually through methyl hydrazine cyclization, the bad control of isomer, lead to yield losses and raw material one-tenth
This is higher.
Also having a kind of is exactly Chinese patent literature CN102718712B report with 3- dichloromethyl -1- methyl isophthalic acid H- pyrrole
Azoles -4- formonitrile HCN is raw material, hydrolyzes, through fluorination, the method preparing 3- difluoromethyl -1- methyl isophthalic acid H- pyrazoles -4- carboxylic acid again.This fluorine
Metallization processes are carried out using fluohydric acid gas or under conditions of amines catalyst, and yield is very high.The method raw materials used 3- dichloromethyl-
In 1- methyl isophthalic acid H- pyrazoles -4- formonitrile HCN building-up process, isomer produces seldom, improves yield, decreases unnecessary isomer
Purification step, reduces the cost of this raw material.But this technique uses anhydrous hydrogen fluoride as fluorination reagent, and fluohydric acid gas has height
Poison and severe corrosive, very big to harm, consersion unit requires also more harsh, therefore produces when implementing security risk relatively
Height, operation is also more difficult.
Therefore searching raw material is cheap and easily-available, simple to operate, and what security risk was low is suitable for the 3- difluoro first of industrialized production
The preparation method of base -1- methyl isophthalic acid H- pyrazoles -4- formic acid is the current technical problem be badly in need of and solving.
Content of the invention
The technical problem to be solved is, in order to overcome existing 3- difluoromethyl -1- methyl isophthalic acid H- pyrazoles -
In the preparation method of 4- carboxylic acid and its intermediate, the harm of reaction raw materials cost fluohydric acid gas costly and in course of reaction is relatively
Greatly, be unfavorable for the defect of industrialized production, thus provide a kind of 3- difluoromethyl -1- methyl isophthalic acid H- pyrazoles -4- carboxylic acid and its
The preparation method of intermediate and intermediate, the method had both avoided expensive raw material 3- dichloromethyl -1- methyl isophthalic acid H- pyrazoles -4- first
The use of acid esters, it also avoid the use of high risk fluohydric acid gas, and simple to operate, is 3- difluoromethyl -1- methyl isophthalic acid H- pyrrole
The synthesis of azoles -4- formic acid and its intermediate provides a kind of method of new suitable industrialized great production.
The present invention mainly solves above-mentioned technical problem by the following technical programs.
The invention provides a kind of preparation of the intermediate of the methyl isophthalic acid H- pyrazoles -4- formic acid of 3- difluoromethyl -1- shown in formula 2
Method, it comprises the following steps：Solvent-free or under conditions of having solvent, compound 1 is entered in the presence of catalyst with KF
Row fluorination reaction, you can；
In described compound 1, R is CN or CONR1R2, R1And R2It is independently each C1-C4Alkyl；Or NR1R2For C2-C5
3-6 unit C-N heterocycle, only comprise 1 N atom in wherein said C-N heterocycle；
Described catalyst is tetraphenylphosphonibromide bromide, quaternary ammonium salt-type phase transfer catalyst, ionic liquid class phase transfer catalysis
One or more of agent and crown ether-like phase transfer catalysts.
Wherein, described R1And R2Preferably it is each independently methyl or ethyl, be further preferably each independently first
Base.
Wherein, the preferred tetramethyl ammonium chloride of described quaternary ammonium salt-type phase transfer catalyst, tetrabutylammonium chloride, tetrabutyl bromine
Change ammonium, benzyltriethylammoinium chloride, tri-n-octyl methyl ammonium chloride, tetraethylammonium bromide, benzyl triethyl ammonium bromide, tetramethyl bromide
Change one or more of ammonium and tetrabutyl ammonium fluoride, more preferably tetramethyl ammonium chloride, tetrabutylammonium chloride, tetrabutyl phosphonium bromide
One or more of ammonium, 4 bromide and tetrabutyl ammonium fluoride；
Wherein, described ionic liquid class phase transfer catalyst preferred cationic is N- alkyl pyridine or N- alkyl imidazole,
And anion is one of chloride ion, bromide ion, fluorion, trifluoracetic acid root, tetrafluoroborate and hexafluoro-phosphate radical or many
Kind；More preferably 1- butyl -3- methyl imidazolium tetrafluoroborate and/or 1- butyl -3- Methylimidazole. hexafluorophosphate；Described N- alkane
Alkyl in base is C1-C6Alkyl, preferably butyl.
Wherein, described crown ether-like phase transfer catalysts preferred 18- crown- 6；
Described have solvent under conditions of, described solvent is in amide solvent, sulfone class solvent and polyalcohols solvent
One or more；
Wherein, the preferred DMF of described amide solvent, N,N-dimethylacetamide and N- methylpyrrole
One or more of alkanone；And/or, the preferred dimethyl sulfoxide of described sulfone class solvent and/or sulfolane, more preferably sulfolane；With/
Or, described polyalcohols compound preferred polyethylene glycols solvent, the preferably poly- TEG two of described polyethylene glycols solvent
Methyl ether.
Heretofore described fluorination reaction, the mol ratio of described KF and compound 1 is referred to this area, and such is anti-
Should conventional ratio, specifically preferred according to the invention 2:1-6:1, more preferably 3:1-5:1.
Heretofore described fluorination reaction, the consumption of described catalyst is referred to the routine use of such reaction of this area
Amount, the 0.1%-5%, more preferably 1%-2% of compound 1 mass specifically preferred according to the invention.
Heretofore described fluorination reaction temperature is referred to this area, and such reacts ordinary temperature, and the present invention is especially excellent
Select 100-200 DEG C, further preferred 130-180 DEG C, more preferably 150 DEG C.
Using this area conventional sense mode, the time of heretofore described fluorination reaction can be to monitor whether reaction ties
Bundle, whether HPLC detection reaction specifically preferred according to the invention terminates.
Heretofore described fluorination reaction is preferably carried out under having solvent condition.
Wherein, the consumption of described solvent be referred to this area such react conventional amount used, specifically preferred according to the invention for change
1-5 times of compound 1 mass, more preferably 1.6-2 times.
Heretofore described fluorination reaction, described reaction typically also includes post-processing stages, and described post processing is permissible
With reference to this area routine post processing mode, following post processing mode specifically preferred according to the invention：Filter, rectification obtains described compound
2, you can.
Wherein, in the post processing of described fluorination reaction, filter, distillation operation all refers to this area routine operation.
Present invention also offers a kind of preparation method of the methyl isophthalic acid H- pyrazoles -4- formic acid of 3- difluoromethyl -1- shown in formula 3,
Comprise the steps of：
(1) according to the preparation method of described compound 2, prepare described compound 2；
(2) have solvent or solvent-free under the conditions of, gained compound 2 in step (1) is carried out water in the presence of alkali
Solution reaction, obtains described compound 3, you can,
In preparation method of the present invention, the method for hydrolysis described in step (2) and condition can be all ability
The conventional method of the such hydrolysis in domain and condition, following methods specifically preferred according to the invention and condition：
In preparation method of the present invention, the aqueous solution of the alkali preferred inorganic base compound described in step (2), enters
One or more of aqueous solution of the preferred sodium hydroxide of one step, potassium hydroxide and Lithium hydrate, more preferably sodium hydroxide is water-soluble
Liquid.
Wherein, the concentration of the aqueous solution of described alkaloid compound is preferred 10-50%, more preferably 10-30%, described dense
Degree refers to mass fraction in its aqueous solution for the alkaloid compound.
In preparation method of the present invention, preferably, described hydrolysis are carried out under condition of no solvent.
In preparation method of the present invention, after described reaction terminates, post processing can also be included, described post processing can
For this area routine post processing mode, preferably stratification, acidifying, cooling, filtering and washing, drying obtain described compound 3, that is,
Can.
Wherein, in described hydrolysis post processing, during described acidifying, hydrochloric acid, the preferred 3%- of concentration of hydrochloric acid are preferably used
8%, further preferred 5%；The consumption of hydrochloric acid is defined when preferably adjusting pH value to 1-5, further preferably adjusts pH value to 3
It is defined；The preferred Deca of described hydrochloric acid adds aqueous phase；And/or, described cooling is preferably dropped to room temperature (20-25 DEG C)；And/or, institute
The filtering and washing stated preferably employs water washing；And/or, described drying preferable temperature is 80-100 DEG C, and vacuum is preferably greater than
10-100mbar.
The present invention also provides a kind of 3- difluoromethyl -1- methyl isophthalic acid H- pyrazoles -4- carboxylic acid intermediates as follows, its structure
For：
Wherein, R is CONR1R2, R1And R2It is independently C1-C4Alkyl；Or NR1R2For C2-C53-6 unit C-N heterocycle,
1 N atom is only comprised in wherein said C-N heterocycle；Described R1And R2All preferred methyl or ethyl, further preferred methyl.
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.
The positive effect of the present invention is：
1st, in the present invention, it is to avoid the use of expensive raw material 3- dichloromethyl -1- methyl isophthalic acid H- pyrazoles -4- formic acid esters, and
The consumption of KF is less, so that the synthesis cost of 3- difluoromethyl -1- methyl isophthalic acid H- pyrazoles -4- formic acid is substantially reduced.
2nd, in the present invention, it is to avoid the use of high risk fluohydric acid gas and simple to operate, be 3- difluoromethyl -1- methyl -
The synthesis of 1H- pyrazoles -4- formic acid and its intermediate provides a kind of method of new suitable industrialized great production.
Specific embodiment
Further illustrate the present invention below by the mode of embodiment, but therefore do not limit the present invention to described reality
Apply among a scope.The experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or according to business
Product description selects.
Embodiment 1
95.0g (0.5mol) 1- methyl isophthalic acid H- pyrazoles -4- formonitrile HCN, 88.0g (1.5mol) is added in four round flask
The KF being spray-dried, 0.95g tetrabutylammonium chloride, it is warming up to 150 DEG C, after raw material reaction to be detected finishes, filter, filtrate rectification
Obtain 3- difluoromethyl -1- methyl isophthalic acid H- pyrazoles -4- formonitrile HCN 67.5g, purity 99.0%, yield 85%, can be directly used for next step
Reaction.
Embodiment 2
95.0g3- dichloromethyl -1- methyl isophthalic acid H- pyrazoles -4- formonitrile HCN, 88.0g spray dried is added in four round flask
Dry KF, 0.95g tetrabutyl ammonium bromide, 190.0g sulfolane, it is warming up to 150 DEG C, after raw material reaction to be detected finishes, filter,
Filtrate rectification obtains 3- difluoromethyl -1- methyl isophthalic acid H- pyrazoles -4- formonitrile HCN 72.1g, purity 99.2%, yield 91%, can directly use
In next step reaction.
Embodiment 3
95.0g3- dichloromethyl -1- methyl isophthalic acid H- pyrazoles -4- formonitrile HCN, 88.0g spray dried is added in four round flask
Dry KF, 1.9g tetrabutyl ammonium bromide, 190.0g sulfolane, it is warming up to 150 DEG C, after raw material reaction to be detected finishes, filter, filter
Liquid rectification obtains 3- difluoromethyl -1- methyl isophthalic acid H- pyrazoles -4- formonitrile HCN 74.4g, purity 99.3%, yield 94%, can be directly used for
Next step is reacted.
Embodiment 4
Add 95.0g3- dichloromethyl -1- methyl isophthalic acid H- pyrazoles -4- formonitrile HCN in four round flask, 146.7g sprays
The KF being dried, 0.95g tetrabutyl ammonium fluoride, 190.0g sulfolane, it is warming up to 150 DEG C, after raw material reaction to be detected finishes, mistake
Filter, filtrate rectification obtains 3- difluoromethyl -1- methyl isophthalic acid H- pyrazoles -4- formonitrile HCN 75.3g, purity 99.1%, and yield 95% can be direct
For next step reaction.
Embodiment 5
Add 95.0g3- dichloromethyl -1- methyl isophthalic acid H- pyrazoles -4- formonitrile HCN in four round flask, 146.7g sprays
The KF being dried, 0.95g 4 bromide, 190.0g sulfolane, it is warming up to 130 DEG C, after raw material reaction to be detected finishes, mistake
Filter, filtrate rectification obtains 3- difluoromethyl -1- methyl isophthalic acid H- pyrazoles -4- formonitrile HCN 57.0g, purity 98.6%, and yield 72% can be direct
For next step reaction.
Embodiment 6
95.0g3- dichloromethyl -1- methyl isophthalic acid H- pyrazoles -4- formonitrile HCN, 88.0g spray dried is added in four round flask
Dry KF, 0.95g1- butyl -3- methyl imidazolium tetrafluoroborate, 190.0g sulfolane, it is warming up to 150 DEG C, raw material to be detected is anti-
After should finishing, filter, filtrate rectification obtains 3- difluoromethyl -1- methyl isophthalic acid H- pyrazoles -4- formonitrile HCN 62.2g, purity 98.5%, yield
78%, can be directly used for next step reaction.
Embodiment 7
119.2g (0.5mol) N, N- dimethyl -3- dichloromethyl -1- methyl isophthalic acid H- pyrrole is added in four round flask
Azoles -4- Methanamide, the KF that 88.0g is spray-dried, 0.95g tetrabutyl ammonium bromide, 190.0g sulfolane, it is warming up to 150 DEG C, to be checked
After survey raw material reaction finishes, filter, filtrate rectification obtains N, N- dimethyl -3- difluoromethyl -1- methyl isophthalic acid H- pyrazole-4-carboxamide
75.8g, purity 97.6%, yield 73%, can be directly used for next step reaction.
Embodiment 8
Add 95.0g3- dichloromethyl -1- methyl isophthalic acid H- pyrazoles -4- formonitrile HCN in four round flask, 146.7g sprays
The KF being dried, 0.95g tetraphenylphosphonibromide bromide, 190.0g sulfolane, it is warming up to 150 DEG C, react 20h, Liquid Detection is calculated theoretical
Yield 12%.
Embodiment 9
95.0g3- dichloromethyl -1- methyl isophthalic acid H- pyrazoles -4- formonitrile HCN, 88.0g spray dried is added in four round flask
Dry KF, 0.95g1- butyl -3- Methylimidazole. hexafluorophosphate, 190.0g sulfolane, it is warming up to 150 DEG C, react 20h, liquid phase
Theoretical yield 6% is calculated to obtain in detection.
Embodiment 10
Add 95.0g3- dichloromethyl -1- methyl isophthalic acid H- pyrazoles -4- formonitrile HCN in four round flask, 146.7g sprays
The KF being dried, 0.95g tetrabutyl ammonium bromide, 190.0gN, dinethylformamide, it is warming up to 150 DEG C, reacts 20h, liquid phase is examined
Calculate to obtain theoretical yield 43%.
Embodiment 11
Add 95.0g3- dichloromethyl -1- methyl isophthalic acid H- pyrazoles -4- formonitrile HCN in four round flask, 146.7g sprays
The KF being dried, 0.95g tetrabutyl ammonium bromide, 190.0gDMSO, it is warming up to 150 DEG C, reacts 20h, Liquid Detection calculates to obtain theoretical receipts
Rate 15%.
Embodiment 12
Add 95.0g3- dichloromethyl -1- methyl isophthalic acid H- pyrazoles -4- formonitrile HCN in four round flask, 146.7g sprays
The KF being dried, 0.95gN- butyl-pyridinium tetrafluoroborate, 190.0g sulfolane, it is warming up to 150 DEG C, react 20h, Liquid Detection
Calculate to obtain theoretical yield 67%.
Embodiment 13
Add 95.0g3- dichloromethyl -1- methyl isophthalic acid H- pyrazoles -4- formonitrile HCN in four round flask, 146.7g sprays
The KF being dried, 0.95g tetrabutyl ammonium bromide, 190.0gPEG400, it is warming up to 150 DEG C, react 22h, Liquid Detection is calculated theoretical
Yield 26%.
Embodiment 14
Add 95.0g3- dichloromethyl -1- methyl isophthalic acid H- pyrazoles -4- formonitrile HCN in four round flask, 146.7g sprays
The KF being dried, 0.95g tetrabutyl ammonium bromide, 190.0g sulfolane, 5.0g18- crown- 6, it is warming up to 150 DEG C, react 22h, liquid phase
Theoretical yield 62% is calculated to obtain in detection.
Embodiment 15
31.4g3- difluoromethyl -1- methyl isophthalic acid H- pyrazoles -4- formonitrile HCN, 80.0g15% hydrogen is added in four round flask
Aqueous solution of sodium oxide, is warming up to 90-100 DEG C, after raw material reaction to be detected finishes, slowly Deca 233.6g5% at 90-100 DEG C
Hydrochloric acid, is less than 3 to pH, after slowly muddy liquid temp is down to room temperature, filtering and washing, drying 3- difluoromethyl -1- methyl -
1H- pyrazoles -4- formic acid finished product 33.8g, purity 99.0%, yield 95%.
Embodiment 16
31.4g3- difluoromethyl -1- methyl isophthalic acid H- pyrazoles -4- formonitrile HCN, 80.0g15% hydrogen is added in four round flask
Aqueous solution of sodium oxide, 62.8g toluene, it is warming up to 90-100 DEG C, after raw material reaction to be detected finishes, stratification, aqueous phase 90-
Slowly Deca 233.6g5% hydrochloric acid at 100 DEG C, is less than 3 to pH, after slowly muddy liquid temp is down to room temperature, filtering and washing, dry
Dry obtain final product 3- difluoromethyl -1- methyl isophthalic acid H- pyrazoles -4- formic acid finished product 33.0g, purity 99.2%, yield 93%.
Embodiment 17
20.5gN, N- dimethyl -3- difluoromethyl -1- methyl isophthalic acid H- pyrazoles -4- formyl is added in four round flask
Amine, 80.0g15% sodium hydrate aqueous solution, 62.8g toluene, it is warming up to 90-100 DEG C, after raw material reaction to be detected finishes, standing
Layering, slowly Deca 233.6g5% hydrochloric acid at 90-100 DEG C of aqueous phase, be less than 3 to pH, after slowly muddy liquid temp is down to room
Temperature, filtering and washing, drying 3- difluoromethyl -1- methyl isophthalic acid H- pyrazoles -4- formic acid finished product 16.8g, purity 99.6%, yield
95%.
Embodiment 18
Add 95.0g3- dichloromethyl -1- methyl isophthalic acid H- pyrazoles -4- formonitrile HCN in four round flask, 146.7g sprays
The KF being dried, 1.9g18- crown- 6,285.0g NHD, it is warming up to 150 DEG C, after raw material reaction to be detected finishes, mistake
Filter, filtrate rectification obtains 3- difluoromethyl -1- methyl isophthalic acid H- pyrazoles -4- formonitrile HCN 53.2g, purity 99.3%, and yield 67.2% can be straight
Connect for next step reaction.
Comparative example 1
95.0g (0.5mol) 1- methyl isophthalic acid H- pyrazoles -4- formonitrile HCN, 88.0g (1.5mol) is added in four round flask
The KF being spray-dried, is warming up to 150 DEG C, reacts 20h, and Liquid Detection no product generates.
Comparative example 2
Add 95.0g3- dichloromethyl -1- methyl isophthalic acid H- pyrazoles -4- formonitrile HCN in four round flask, 146.7g sprays
The KF being dried, 0.95g tetrabutylammonium chloride, 190.0g o-dichlorohenzene, it is warming up to 150 DEG C, react 20h, Liquid Detection no product
Generate.
Comparative example 3
Add 95.0g3- dichloromethyl -1- methyl isophthalic acid H- pyrazoles -4- formonitrile HCN in four round flask, 146.7g sprays
The KF being dried, 0.95g tetrabutyl phosphonium bromide phosphine, 190.0g sulfolane, it is warming up to 150 DEG C, react 20h, Liquid Detection no product life
Become.
Comparative example 4
Add 95.0g3- dichloromethyl -1- methyl isophthalic acid H- pyrazoles -4- formonitrile HCN in four round flask, 106.1g sprays
The NaF being dried, 0.95g tetrabutyl ammonium bromide, 190.0g sulfolane, it is warming up to 150 DEG C, react 20h, Liquid Detection no product life
Become.
Reference implementation example
To 22.5g3- (dichloromethyl) -1- methyl isophthalic acid H- pyrazoles -4- phosgene (being prepared according to document CN103396363A)
In, add the dissolving of 110.0g dichloromethane, be cooled to 0-5 DEG C, slowly instill the dimethylamine agueous solution of 32.4g40%, drip
Bi Hou, allows reactant liquor naturally be back to room temperature and continues stirring, after Liquid Detection raw material reaction finishes, adds frozen water to be quenched, layering,
Organic faciess are washed twice with 5% dilute hydrochloric acid (pH is less than 3) respectively, then with 5% NaOH solution washing twice, be layered afterwards,
Precipitation obtains final product 3- (dichloromethyl)-N, N, 1- trimethyl -1H- pyrazole-4-carboxamide, yield 89%, purity 98.5%.3- (two
Chloromethyl)-N, N, 1- trimethyl -1H- pyrazole-4-carboxamide：LC-MS(ESI)calcd for C8H11Cl2N3O[M+H+]:
236.0357, found：236.0319.
Claims (10)
1. the preparation method of the intermediate of the methyl isophthalic acid of 3- difluoromethyl -1- shown in a kind of formula 2 H- pyrazoles -4- formic acid, its feature exists
In comprising the following steps：Solvent-free or under conditions of having solvent, compound 1 is carried out fluorine with KF in the presence of catalyst
Change reaction, you can；
In described compound 1, R is CN or CONR1R2, R1And R2It is independently each C1-C4Alkyl；Or NR1R2For C2-C53-6
First C-N heterocycle, only comprises 1 N atom, R in wherein said C-N heterocycle1And R2It is independently each preferably all methyl or ethyl；
Described catalyst is tetraphenylphosphonibromide bromide, quaternary ammonium salt-type phase transfer catalyst, ionic liquid class phase transfer catalyst and crown ether
One or more of class phase transfer catalyst；Described have solvent under conditions of, described solvent is amide solvent, sulfone class is molten
One or more of agent and polyalcohols solvent.
2. preparation method as claimed in claim 1 it is characterised in that described quaternary ammonium salt catalyst be tetramethyl ammonium chloride,
Tetrabutylammonium chloride, tetrabutyl ammonium bromide, benzyltriethylammoinium chloride, tri-n-octyl methyl ammonium chloride, tetraethylammonium bromide, benzyl
One or more of triethylammonium bromide, 4 bromide and tetrabutyl ammonium fluoride；And/or, described ionic liquid class
Catalyst is N- alkyl pyridine or N- alkyl imidazole for cation, and anion is chloride ion, bromide ion, fluorion, trifluoro vinegar
One or more of acid group, tetrafluoroborate and hexafluoro-phosphate radical, preferably 1- butyl -3- methyl imidazolium tetrafluoroborate and/
Or 1- butyl -3- Methylimidazole. hexafluorophosphate；Alkyl in described N- alkyl is C1-C6Alkyl, preferably butyl；Described hat
Ethers phase transfer catalyst preferred 18- crown- 6.
3. preparation method as claimed in claim 1 is it is characterised in that described amide solvent is N, N- dimethyl formyl
Amine, one or more of N,N-dimethylacetamide and N-Methyl pyrrolidone；And/or, described sulfone class solvent is diformazan
Sulfoxide and/or sulfolane；And/or, described polyalcohols solvent is polyethylene glycols solvent, preferably poly- tetraethyleneglycol dimethyl ether.
4. preparation method as claimed in claim 1 is it is characterised in that described KF is 2 with the mol ratio of compound 1:1-6:
1, preferably 3:1-5:1.
5. preparation method as claimed in claim 1 is it is characterised in that the consumption of described catalyst is compound 1 mass
0.1%-5%, preferably 1%-2%.
6. preparation method as claimed in claim 1 is it is characterised in that the temperature of described fluorination reaction is 100-200 DEG C, preferably
130-180 DEG C, further preferred 150 DEG C.
7. preparation method as claimed in claim 1 it is characterised in that described fluorination reaction time with HPLC detection reaction be
No end.
8. preparation method as claimed in claim 1 is it is characterised in that when carrying out fluorination reaction under conditions of having solvent, institute
The consumption stating solvent in fluorination reaction is 1-5 times of quality of compound 1, preferably 1.6-2 times.
9. a kind of preparation method of the methyl isophthalic acid of 3- difluoromethyl -1- shown in formula 3 H- pyrazoles -4- formic acid, comprises the steps of：
(1) according to the preparation method any one of claim 1-8, prepare compound 2；
(2) have solvent or solvent-free under the conditions of, gained compound 2 in step (1) is hydrolyzed instead in the presence of alkali
Should, you can,
10. a kind of 3- difluoromethyl -1- methyl isophthalic acid H- pyrazoles -4- carboxylic acid intermediates as follows, its structure is：
Wherein, R is CONR1R2, R1And R2It is independently each C1-C4Alkyl；Or NR1R2For C2-C53-6 unit C-N heterocycle, its
Described in only comprise 1 N atom in C-N heterocycle；R1And R2It is independently each preferably all methyl or ethyl.
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