CN111303035A - Preparation method of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid - Google Patents
Preparation method of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid Download PDFInfo
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- CN111303035A CN111303035A CN202010192683.0A CN202010192683A CN111303035A CN 111303035 A CN111303035 A CN 111303035A CN 202010192683 A CN202010192683 A CN 202010192683A CN 111303035 A CN111303035 A CN 111303035A
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- methyl
- pyrazole
- difluoromethyl
- carboxylic acid
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- 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 claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims abstract description 34
- 238000000034 method Methods 0.000 claims abstract description 23
- 239000001569 carbon dioxide Substances 0.000 claims abstract description 17
- 229910002092 carbon dioxide Inorganic materials 0.000 claims abstract description 17
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims abstract description 9
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 claims abstract description 9
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 9
- 239000011630 iodine Substances 0.000 claims abstract description 9
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 0.000 claims abstract description 9
- 229910052700 potassium Inorganic materials 0.000 claims abstract description 9
- 239000011591 potassium Substances 0.000 claims abstract description 9
- PBIMIGNDTBRRPI-UHFFFAOYSA-N trifluoro borate Chemical compound FOB(OF)OF PBIMIGNDTBRRPI-UHFFFAOYSA-N 0.000 claims abstract description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 8
- UFYFLBNWAMCOML-UHFFFAOYSA-N n-methyl-1h-pyrazol-5-amine Chemical compound CNC1=CC=NN1 UFYFLBNWAMCOML-UHFFFAOYSA-N 0.000 claims abstract description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 32
- 238000006243 chemical reaction Methods 0.000 claims description 24
- 239000007864 aqueous solution Substances 0.000 claims description 19
- 239000000243 solution Substances 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 14
- 238000010791 quenching Methods 0.000 claims description 13
- 230000000171 quenching effect Effects 0.000 claims description 13
- 238000001816 cooling Methods 0.000 claims description 11
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 235000010288 sodium nitrite Nutrition 0.000 claims description 7
- 239000007818 Grignard reagent Substances 0.000 claims description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 6
- 150000004795 grignard reagents Chemical class 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 claims description 5
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 claims description 5
- 229940112669 cuprous oxide Drugs 0.000 claims description 5
- 239000012954 diazonium Substances 0.000 claims description 5
- 150000001989 diazonium salts Chemical class 0.000 claims description 5
- 238000001953 recrystallisation Methods 0.000 claims description 5
- 238000002425 crystallisation Methods 0.000 claims description 4
- 230000008025 crystallization Effects 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- DBTNVRCCIDISMV-UHFFFAOYSA-L lithium;magnesium;propane;dichloride Chemical compound [Li+].[Mg+2].[Cl-].[Cl-].C[CH-]C DBTNVRCCIDISMV-UHFFFAOYSA-L 0.000 claims description 3
- OWIKHYCFFJSOEH-UHFFFAOYSA-N Isocyanic acid Chemical compound N=C=O OWIKHYCFFJSOEH-UHFFFAOYSA-N 0.000 claims description 2
- 230000003197 catalytic effect Effects 0.000 claims description 2
- 239000007789 gas Substances 0.000 claims description 2
- YMUBDNJWWYNAOA-UHFFFAOYSA-L lithium;magnesium;butane;dichloride Chemical compound [Li+].[Mg+2].[Cl-].[Cl-].CC[CH-]C YMUBDNJWWYNAOA-UHFFFAOYSA-L 0.000 claims description 2
- 239000012047 saturated solution Substances 0.000 claims description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 12
- VXYWCTANPTZYGM-UHFFFAOYSA-N 4-bromo-3-(difluoromethyl)-1-methylpyrazole Chemical compound CN1C=C(Br)C(C(F)F)=N1 VXYWCTANPTZYGM-UHFFFAOYSA-N 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 abstract description 2
- 230000003321 amplification Effects 0.000 abstract description 2
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 11
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 238000005070 sampling Methods 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- JWUJQDFVADABEY-UHFFFAOYSA-N 2-methyltetrahydrofuran Chemical compound CC1CCCO1 JWUJQDFVADABEY-UHFFFAOYSA-N 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- QGHYSXLQVPDKPQ-UHFFFAOYSA-N 3-(difluoromethyl)-4-iodo-1-methylpyrazole Chemical compound C1=C(C(=NN1C)C(F)F)I QGHYSXLQVPDKPQ-UHFFFAOYSA-N 0.000 description 3
- WYPUMGAZSVZUGJ-UHFFFAOYSA-N 4-bromo-1-methylpyrazol-3-amine Chemical compound CN1C=C(Br)C(N)=N1 WYPUMGAZSVZUGJ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 238000004537 pulping Methods 0.000 description 3
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- NODLZCJDRXTSJO-UHFFFAOYSA-N 1,3-dimethylpyrazole Chemical compound CC=1C=CN(C)N=1 NODLZCJDRXTSJO-UHFFFAOYSA-N 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000003899 bactericide agent Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 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 1
- 239000005738 Bixafen Substances 0.000 description 1
- 239000005783 Fluopyram Substances 0.000 description 1
- 239000005799 Isopyrazam Substances 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000006149 azo coupling reaction Methods 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
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- KVDJTXBXMWJJEF-UHFFFAOYSA-N fluopyram Chemical compound ClC1=CC(C(F)(F)F)=CN=C1CCNC(=O)C1=CC=CC=C1C(F)(F)F KVDJTXBXMWJJEF-UHFFFAOYSA-N 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Inorganic materials [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 1
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001308 synthesis method Methods 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/141—Feedstock
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a preparation method of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, belonging to the technical field of organic synthesis. N-methyl-3-aminopyrazole is used as a raw material, reacts with bromine/iodine to substitute pyrazole 4 position, is diazotized and coupled with potassium difluoromethyl trifluoroborate to obtain 4-bromo-3- (difluoromethyl) -1-methyl-1H-pyrazole, is subjected to Grignard exchange by isopropyl magnesium chloride and the like, and reacts with carbon dioxide to obtain the 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid. The method is simple and convenient to operate, the total yield of the three steps is up to 64%, the product purity can reach more than 99.5%, the condition that isomers exist in the traditional process is avoided, and the method has a potential process amplification prospect.
Description
Technical Field
The invention relates to a preparation method of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, belonging to the technical field of organic synthesis.
Background
3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, english name: 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, CAS: 176969-34-9. The 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid is an important medical and fine chemical intermediate, can be used for synthesizing various bactericides and pesticides, and particularly is a key intermediate for synthesizing novel amides bactericides such as fluopyram, bixafen and isopyrazam.
At present, the compound has more and more application values, the synthesis reports of the compound are more, and hydrazine or methylhydrazine is mostly used for cyclization, hydrolysis or oxidation and the like in the synthesis method. However, isomers are inevitably produced during the cyclization, and a great deal of effort is required for subsequent purification.
It is therefore necessary to develop more synthetic routes to avoid the isomers of the above products, with relative ease of operation, to meet the ever-increasing market demand.
Disclosure of Invention
In order to overcome the technical defects, the invention provides a preparation method of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid. N-methyl-3-aminopyrazole is used as a raw material, reacts with bromine/iodine to substitute pyrazole 4-position, is diazotized and coupled with potassium difluoromethyl trifluoroborate to obtain 4-bromo-3- (difluoromethyl) -1-methyl-1H-pyrazole, is subjected to Grignard exchange by isopropyl magnesium chloride, and reacts with carbon dioxide to obtain 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid. The method is simple and convenient to operate, the total yield of the three steps is up to 64%, the product purity can reach more than 99.5%, the condition that isomers exist in the traditional process is avoided, and the method has a potential process amplification prospect.
A method for preparing 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, comprising the steps of:
the first step is as follows: dissolving N-methyl-3-aminopyrazole in water, and reacting with halogen to obtain 4-halogen-1-methyl-1H-pyrazole-3-amine;
the second step is that: reacting 4-halo-1-methyl-1H-pyrazole-3-amine with a sodium nitrite aqueous solution to obtain diazonium salt, and then reacting with potassium difluoromethyl trifluoroborate in the presence of cuprous oxide to obtain 4-halo-3- (difluoromethyl) -1-methyl-1H-pyrazole;
the third step: exchanging 4-halogen-3- (difluoromethyl) -1-methyl-1H-pyrazole by adopting a Grignard reagent, then cooling, reacting with carbon dioxide, quenching and recrystallizing to obtain the 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid.
Further, in the above technical solution, in the first step, the halogen is selected from bromine and iodine. When iodine is adopted, hydrogen peroxide is added for reaction.
Further, in the above technical solution, the molar ratio of N-methyl-3-aminopyrazole to halogen in the first step is 1: 0.5-1.05. Wherein, the iodine simple substance is needed to be approximately 0.5 equivalent, and the bromine is used for approximately equivalent reaction.
Further, in the above technical scheme, the molar ratio of the addition of the oxidized imino ketone and the addition of the 4-halogen-1-methyl-1H-pyrazol-3-amine in the second step is 0.05-0.10: 1.
furthermore, in the technical scheme, the molar ratio of the 4-halogen-1-methyl-1H-pyrazole-3-amine, the potassium difluoromethyl trifluoroborate and the sodium nitrite in the second step is 1:0.98-1.3: 2.0-2.5.
Further, in the above technical solution, in the third step, the grignard reagent is selected from isopropyl magnesium chloride, isopropyl magnesium chloride-lithium chloride or sec-butyl magnesium chloride-lithium chloride.
Further, in the above technical scheme, in the third step, the reaction with carbon dioxide is performed by introducing carbon dioxide gas or a saturated solution of carbon dioxide under the condition of a catalytic amount of DBU. The addition of DBU can reduce the consumption of carbon dioxide, accelerate the reaction speed and enhance the process stability.
Further, in the technical scheme, the molar ratio of the 4-halogen-3- (difluoromethyl) -1-methyl-1H-pyrazole, the Grignard reagent and the carbon dioxide in the third step is 1:1.01-1.15: 1-2.5.
Further, in the above technical solution, when the crystallization is performed in the third step, the solvent is selected from a mixture of an alcohol solvent and water used for the crystallization in the third step. The alcohol solvent is methanol, ethanol or isopropanol.
Further, in the above-mentioned embodiment, it is preferable that the crystallization in the third step is performed using 40% (v/v) ethanol aqueous solution.
Advantageous effects of the invention
The method takes N-methyl-3-aminopyrazole as a raw material, and comprises three steps of halogenation, diazo coupling, Grignard exchange/carbon dioxide and the like in sequence, and the product is finally purified after recrystallization. The method is simple and convenient to operate, the total reaction yield is up to 64%, the purity of the obtained product can reach more than 99.5%, and a new process approach is provided for the synthesis of the compounds.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The invention is further illustrated by the following specific examples. These examples are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. After reading the description of the invention, one skilled in the art can make various changes and modifications to the invention, and such equivalent changes and modifications also fall into the scope of the invention defined by the claims.
Example 1
97.1g (1mol,1.0eq) of N-methyl-3-aminopyrazole and 800mL of water and 500mL of ethanol are put into a three-port reaction bottle, 129.5g (0.51mol,0.51eq) of iodine is added in portions at the temperature of 15-25 ℃, and 72.9g (0.6mol,0.6eq) of 28% hydrogen peroxide is added dropwise at the temperature of 15-25 ℃. Heating to 30-35 ℃, reacting for 6 hours, taking a sample with GC raw material less than 1%, cooling to 10 ℃, adding 80mL of saturated sodium thiosulfate aqueous solution, stirring for 5-6 hours, distilling ethanol under reduced pressure, separating out a large amount of yellow-brown solid, filtering to obtain 207.6g of 4-iodine-1-methyl-1H-pyrazole-3-amine, wherein GC content is 95.6%, and yield is 93.1%.1HNMR(400MHz,CDCl3):7.40(s,1H),5.81(s,2H),3.80(s,3H).
4-iodine-1-methyl-1H-pyrazole-3-amine (100g,0.45mol) and 6mol/L hydrochloric acid aqueous solution are put into a reaction bottle, the pH value is regulated to be less than 1, the temperature is reduced to minus 5 ℃, 78.1g of 40 percent sodium nitrite aqueous solution is slowly dripped, the reaction is carried out for 1 hour at minus 5 to 5 ℃ after the dripping is finished, and the mixture is transferred into a dropping funnel under the protection of nitrogen.
Under the protection of nitrogen, adding 73.3g (470.8mmol,1.05eq) of potassium difluoromethyl trifluoroborate, 4.5g (31.4mmol,0.07eq) of cuprous oxide and 500mL of tetrahydrofuran into a reaction bottle, cooling to 0 ℃, starting to dropwise add the prepared diazonium salt solution, slowly heating to 35-50 ℃, sampling HPLC raw materials, cooling to 0-10 ℃, adding saturated sodium carbonate aqueous solution for quenching, extracting by ethyl acetate, washing an organic phase by water, concentrating, adding n-heptane for pulping, filtering to obtain 98.7g of 4-iodine-3- (difluoromethyl) -1-methyl-1H-pyrazole, and carrying out HPLC: 98.7% and yield 85.3%.1HNMR(400MHz,CDCl3):7.80(s,1H),6.02(s,1H),3.95(s,3H).
Under the protection of nitrogen, 95g (0.368mol,1eq) of 4-iodo-3-difluoromethyl-1-methylpyrazole and 500mL of tetrahydrofuran were put into a reaction flask, stirred uniformly, and then cooled to-5 ℃. 202mL of i-PrMgCl (2.0M,1.1eq) tetrahydrofuran solution was slowly added dropwise, and the mixture was stirred for 2 hours while maintaining the temperature after the addition of the solution, thereby obtaining a Grignard exchange solution. Sampling quenching GC detects that the raw material is less than 0.5 percent. 500mL of a tetrahydrofuran solution which is prepared in advance and contains 5.6g (0.037mol,0.1eq) of DBU and 21.6g (0.49mol,1.25eq) of carbon dioxide at-25 ℃ is added dropwise, the temperature is slowly increased to 0 ℃, the mixture is stirred for 5 hours at the temperature, the temperature is reduced to-10 ℃, 4mol/L hydrochloric acid is added for quenching, aqueous phase ethyl acetate is used for extraction, an organic phase is washed by water, an enriched organic phase is concentrated to a non-flowing liquid, the ethanol is replaced and then distilled to be dry again, and finally, 330mL of 40% (v/v) ethanol aqueous solution is added for recrystallization to obtain 53.9g of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, the GC purity is 99.5%, and the yield is 83.2%.1HNMR(400MHz,DMSO-d6):12.71(s,1H),8.33(s,1H),7.19(t,1H),3.89(s,3H)。
Example 2:
adding 97.1g (1mol,1eq) of 1, 3-dimethylpyrazole and 700mL of ethanol into a reaction bottle, slowly dropwise adding 158.4g (0.99mol,0.99eq) of bromine at 0-5 ℃ under stirring, dropwise adding for reaction at 0-15 ℃ for 1 hour, sampling GC raw materials, reducing the temperature to 10 ℃, adding 500mL of water, dropwise adding 30% sodium hydroxide aqueous solution for quenching reaction, adjusting the pH to 9-10, adding 80mL of saturated sodium thiosulfate aqueous solution, concentrating an organic phase under reduced pressure, removing ethanol, reducing the temperature to 15-20 ℃, pulping for 3 hours, and filtering to obtain 157.4g of 4-bromo-1-methyl-1H-pyrazol-3-amine, wherein the GC yield is 89.4%.1HNMR(400MHz,CDCl3):7.41(s,1H),5.90(s,2H),3.82(s,3H).
Under the protection of nitrogen, 4-bromine-1-methyl-1H-pyrazole-3 is put into a reaction bottle100g (568.1mmol) of amine and 6mol/L aqueous hydrochloric acid, pH adjusted<1, cooling to-5 ℃, slowly dropwise adding 87.8g of 45% sodium nitrite aqueous solution, and reacting for 1 hour at-5-5 ℃ after dropwise adding. Adding 89.7g (568.1mmol,1.0eq) of potassium difluoromethyl trifluoroborate, 4.1g (28.4mmol,0.05eq) of cuprous oxide and 500mL of acetonitrile into another reaction bottle under the protection of nitrogen, cooling to 0 ℃, dropwise adding the prepared diazonium salt solution, slowly heating to 35-50 ℃, sampling HPLC raw materials, cooling to 0-10 ℃, adding saturated sodium carbonate aqueous solution for quenching, extracting by ethyl acetate, washing an organic phase by water, concentrating, distilling under reduced pressure to obtain 105.7g of 4-bromo-3- (difluoromethyl) -1-methyl-1H-pyrazole, and carrying out HPLC: 98.5% and a yield of 88.2%.1HNMR(400MHz,CDCl3):7.93(s,1H),6.05(s,1H),3.95(s,3H).
Under the protection of nitrogen, 95g (0.368mol,1eq) of 4-iodo-3-difluoromethyl-1-methylpyrazole and 500mL of 2-methyltetrahydrofuran were put into a reaction flask, stirred uniformly, and then cooled to-5 ℃. 311mL of a 2-methyltetrahydrofuran solution of i-PrMgCl-LiCl (1.3M,1.1eq) was slowly added dropwise, and the mixture was stirred for 2 hours while maintaining the temperature, thereby obtaining a Grignard exchange solution. Sampling quenching GC detects that the raw material is less than 0.5 percent. 500mL of a pre-prepared 2-methyltetrahydrofuran solution containing 5.6g (0.037mol,0.1eq) of DBU5 and 21.6g (0.49mol,1.25eq) of carbon dioxide at-25 ℃ is added dropwise, the temperature is slowly raised to 0 ℃, the mixture is stirred for 5 hours at the temperature, the temperature is reduced to-10 ℃, 4mol/L hydrochloric acid is added for quenching, the water phase is extracted by ethyl acetate, the organic phase is washed by water, the organic phase is enriched and concentrated to a non-flowing liquid, the ethanol is replaced and distilled again to be dry, and finally, 340mL of 40% (v/v) ethanol aqueous solution is added for recrystallization to obtain 54.8g of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, the GC purity is 99.7%, and the yield is 84.6%.1HNMR(400MHz,DMSO-d6):12.71(s,1H),8.33(s,1H),7.19(t,1H),3.89(s,3H)。
Example 3:
adding 97.1g (1mol,1eq) of 1, 3-dimethylpyrazole and 700mL of ethanol into a reaction bottle, slowly dropwise adding 158.4g (0.99mol,0.99eq) of bromine at 0-5 ℃ under stirring, dropwise adding for reaction at 0-15 ℃ for 1 hour, sampling GC raw materials, reducing the temperature to 10 ℃, adding 500mL of water, dropwise adding 30% sodium hydroxide aqueous solution for quenching reaction, adjusting the pH to 9-10, adding 80mL of saturated sodium thiosulfate aqueous solution, concentrating an organic phase under reduced pressure, removing ethanol, reducing the temperature to 15-20 ℃, pulping for 3 hours, and filtering to obtain 157.4g of 4-bromo-1-methyl-1H-pyrazol-3-amine, wherein the GC yield is 89.4%.1HNMR(400MHz,CDCl3):7.41(s,1H),5.90(s,2H),3.82(s,3H).
Under the protection of nitrogen, 100g (568.1mmol) of 4-bromo-1-methyl-1H-pyrazol-3-amine and 6mol/L of hydrochloric acid aqueous solution are put into a reaction bottle, and the pH value is adjusted<1, cooling to-5 ℃, slowly dropwise adding 87.8g of 45% sodium nitrite aqueous solution, and reacting for 1 hour at-5-5 ℃ after dropwise adding. Adding 89.7g (568.1mmol,1.0eq) of potassium difluoromethyl trifluoroborate, 4.1g (28.4mmol,0.05eq) of cuprous oxide and 500mL of acetonitrile into another reaction bottle under the protection of nitrogen, cooling to 0 ℃, dropwise adding the prepared diazonium salt solution, slowly heating to 35-50 ℃, sampling HPLC raw materials, cooling to 0-10 ℃, adding saturated sodium carbonate aqueous solution for quenching, extracting by ethyl acetate, washing an organic phase by water, concentrating, distilling under reduced pressure to obtain 105.7g of 4-bromo-3- (difluoromethyl) -1-methyl-1H-pyrazole, and carrying out HPLC: 98.5% and a yield of 88.2%.1HNMR(400MHz,CDCl3):7.93(s,1H),6.05(s,1H),3.95(s,3H).
Under the protection of nitrogen, 95g (0.368mol,1eq) of 4-iodo-3-difluoromethyl-1-methylpyrazole and 500mL of tetrahydrofuran were put into a reaction flask, stirred uniformly, and then cooled to-5 ℃. S-BuMgCl-LiCl (1.2M,1.1eq) solution in tetrahydrofuran 337mL is slowly added dropwise, and stirring is carried out for 2 hours while maintaining the temperature after droppingAnd obtaining the Grignard exchange solution. Sampling quenching GC detects that the raw material is less than 0.5 percent. 500mL of a pre-prepared 2-methyltetrahydrofuran solution containing 5.6g (0.037mol,0.1eq) of DBU and 21.6g (0.49mol,1.25eq) of carbon dioxide at-25 ℃ is added dropwise, the temperature is slowly raised to 0 ℃, the mixture is stirred for 5 hours at the temperature, the temperature is reduced to-10 ℃, 4M/L hydrochloric acid is added for quenching, the water phase is extracted by ethyl acetate, the organic phase is washed by water, the organic phase is enriched and concentrated to a non-flowing liquid, the ethanol is replaced and distilled again to be dry, and finally, 320mL of 40% (v/v) ethanol aqueous solution is added for recrystallization to obtain 54.5g of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, the GC purity is 99.6%, and the yield is 84.1%.1HNMR(400MHz,DMSO-d6):12.71(s,1H),8.33(s,1H),7.19(t,1H),3.89(s,3H)。
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be able to cover the technical solutions and the inventive concepts of the present invention within the technical scope of the present invention.
Claims (10)
1. A method for preparing 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, which is characterized by comprising the following steps:
the first step is as follows: dissolving N-methyl-3-aminopyrazole in water, and reacting with halogen to obtain 4-halogen-1-methyl-1H-pyrazole-3-amine;
the second step is that: reacting 4-halo-1-methyl-1H-pyrazole-3-amine with a sodium nitrite aqueous solution to obtain diazonium salt, and then reacting with potassium difluoromethyl trifluoroborate in the presence of cuprous oxide to obtain 4-halo-3- (difluoromethyl) -1-methyl-1H-pyrazole;
the third step: exchanging 4-halogen-3- (difluoromethyl) -1-methyl-1H-pyrazole by adopting a Grignard reagent, then cooling, reacting with carbon dioxide, quenching and recrystallizing to obtain the 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid.
2. The process for the preparation of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid according to claim 1, characterized in that: in the first step, the halogen is selected from bromine and iodine elementary substance, wherein when the iodine elementary substance is adopted, hydrogen peroxide is added for reaction.
3. The process for the preparation of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid according to claim 1, characterized in that: in the first step, the molar ratio of the N-methyl-3-aminopyrazole to the halogen is 1: 0.5-1.05; wherein, the iodine simple substance adopts nearly 0.5 equivalent, and the bromine is adopted for nearly equivalent reaction.
4. The process for the preparation of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid according to claim 1, characterized in that: in the second step, the molar ratio of the addition of the oxidized imino ketone to the 4-halo-1-methyl-1H-pyrazol-3-amine is 0.05-0.10: 1.
5. the process for the preparation of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid according to claim 1, characterized in that: in the second step, the molar ratio of the 4-halogen-1-methyl-1H-pyrazole-3-amine, the potassium difluoromethyl trifluoroborate and the sodium nitrite is 1:0.98-1.3: 2.0-2.5.
6. The process for the preparation of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid according to claim 1, characterized in that: in the third step, the grignard reagent is selected from isopropyl magnesium chloride, isopropyl magnesium chloride-lithium chloride or sec-butyl magnesium chloride-lithium chloride.
7. The process for the preparation of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid according to claim 1, characterized in that: in the third step, the reaction with carbon dioxide is carried out by introducing carbon dioxide gas or carbon dioxide saturated solution and under the condition of catalytic amount of DBU.
8. The process for the preparation of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid according to claim 1, characterized in that: in the third step, the molar ratio of the 4-halo-3- (difluoromethyl) -1-methyl-1H-pyrazole, the Grignard reagent and the carbon dioxide is 1:1.01-1.15: 1-2.5.
9. The process for the preparation of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid according to any of claims 1 to 8, characterized in that: in the third step, a mixture of an alcohol solvent and water is used for crystallization.
10. The process for the preparation of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid according to claim 9, wherein: in the third step, 40% ethanol water solution is adopted for recrystallization.
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