CN117384096A - Preparation method of difluoro pyrazole acid - Google Patents
Preparation method of difluoro pyrazole acid Download PDFInfo
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- CN117384096A CN117384096A CN202311703876.8A CN202311703876A CN117384096A CN 117384096 A CN117384096 A CN 117384096A CN 202311703876 A CN202311703876 A CN 202311703876A CN 117384096 A CN117384096 A CN 117384096A
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- toluene
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- dimethylamino
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- CMYZHIHJNYIQLV-UHFFFAOYSA-N 3,5-difluoro-1h-pyrazole Chemical compound FC=1C=C(F)NN=1 CMYZHIHJNYIQLV-UHFFFAOYSA-N 0.000 title claims abstract description 36
- 239000002253 acid Substances 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 214
- 238000006243 chemical reaction Methods 0.000 claims abstract description 65
- 239000000243 solution Substances 0.000 claims abstract description 38
- 238000003756 stirring Methods 0.000 claims abstract description 22
- HDZGCSFEDULWCS-UHFFFAOYSA-N monomethylhydrazine Chemical compound CNN HDZGCSFEDULWCS-UHFFFAOYSA-N 0.000 claims abstract description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000005708 Sodium hypochlorite Substances 0.000 claims abstract description 17
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 claims abstract description 17
- 238000001816 cooling Methods 0.000 claims abstract description 14
- VFLGLCYPQBSTPI-UHFFFAOYSA-N CN(C)C=C(C(C(F)F)=O)C(C)=O Chemical compound CN(C)C=C(C(C(F)F)=O)C(C)=O VFLGLCYPQBSTPI-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000007864 aqueous solution Substances 0.000 claims abstract description 9
- 238000001914 filtration Methods 0.000 claims abstract description 7
- 238000010517 secondary reaction Methods 0.000 claims abstract description 6
- 238000002425 crystallisation Methods 0.000 claims abstract description 5
- 230000008025 crystallization Effects 0.000 claims abstract description 5
- 238000004321 preservation Methods 0.000 claims abstract description 5
- 238000001035 drying Methods 0.000 claims abstract description 4
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 40
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 30
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 21
- KURKJXZWCPWPFX-UHFFFAOYSA-N 2,2-difluoroacetyl chloride Chemical compound FC(F)C(Cl)=O KURKJXZWCPWPFX-UHFFFAOYSA-N 0.000 claims description 18
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 claims description 13
- XHFGWHUWQXTGAT-UHFFFAOYSA-N dimethylamine hydrochloride Natural products CNC(C)C XHFGWHUWQXTGAT-UHFFFAOYSA-N 0.000 claims description 12
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- QPWSKIGAQZAJKS-SNAWJCMRSA-N (e)-4-(dimethylamino)but-3-en-2-one Chemical compound CN(C)\C=C\C(C)=O QPWSKIGAQZAJKS-SNAWJCMRSA-N 0.000 claims description 10
- 239000007788 liquid Substances 0.000 claims description 10
- 239000011259 mixed solution Substances 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims description 8
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 8
- 238000000605 extraction Methods 0.000 claims description 7
- 238000011049 filling Methods 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- 239000008213 purified water Substances 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 3
- 239000007789 gas Substances 0.000 claims description 3
- QPWSKIGAQZAJKS-UHFFFAOYSA-N 4-(dimethylamino)but-3-en-2-one Chemical compound CN(C)C=CC(C)=O QPWSKIGAQZAJKS-UHFFFAOYSA-N 0.000 claims description 2
- 239000012153 distilled water Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 23
- 238000000034 method Methods 0.000 abstract description 13
- 238000003786 synthesis reaction Methods 0.000 abstract description 7
- 239000007810 chemical reaction solvent Substances 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 19
- 229940126062 Compound A Drugs 0.000 description 17
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 description 17
- 150000001875 compounds Chemical class 0.000 description 13
- 239000000203 mixture Substances 0.000 description 9
- 238000004811 liquid chromatography Methods 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 5
- RLOHOBNEYHBZID-UHFFFAOYSA-N 3-(difluoromethyl)-1-methylpyrazole-4-carboxylic acid Chemical class CN1C=C(C(O)=O)C(C(F)F)=N1 RLOHOBNEYHBZID-UHFFFAOYSA-N 0.000 description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N protonated dimethyl amine Natural products CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 4
- FBCCMZVIWNDFMO-UHFFFAOYSA-N dichloroacetyl chloride Chemical compound ClC(Cl)C(Cl)=O FBCCMZVIWNDFMO-UHFFFAOYSA-N 0.000 description 3
- -1 difluoro-methylpyrazole carboxamides Chemical class 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- XHILZHAQBOLGFD-UHFFFAOYSA-N 1,1-difluoropropan-2-one Chemical compound CC(=O)C(F)F XHILZHAQBOLGFD-UHFFFAOYSA-N 0.000 description 2
- DPBJAVGHACCNRL-UHFFFAOYSA-N 2-(dimethylamino)ethyl prop-2-enoate Chemical compound CN(C)CCOC(=O)C=C DPBJAVGHACCNRL-UHFFFAOYSA-N 0.000 description 2
- 102000019259 Succinate Dehydrogenase Human genes 0.000 description 2
- 108010012901 Succinate Dehydrogenase Proteins 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- PBWZKZYHONABLN-UHFFFAOYSA-N difluoroacetic acid Chemical compound OC(=O)C(F)F PBWZKZYHONABLN-UHFFFAOYSA-N 0.000 description 2
- 238000007599 discharging Methods 0.000 description 2
- GZKHDVAKKLTJPO-UHFFFAOYSA-N ethyl 2,2-difluoroacetate Chemical compound CCOC(=O)C(F)F GZKHDVAKKLTJPO-UHFFFAOYSA-N 0.000 description 2
- 238000010812 external standard method Methods 0.000 description 2
- 239000000417 fungicide Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- TVDSBUOJIPERQY-UHFFFAOYSA-N prop-2-yn-1-ol Chemical compound OCC#C TVDSBUOJIPERQY-UHFFFAOYSA-N 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
- KOPFEFZSAMLEHK-UHFFFAOYSA-N 1h-pyrazole-5-carboxylic acid Chemical class OC(=O)C=1C=CNN=1 KOPFEFZSAMLEHK-UHFFFAOYSA-N 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 229940124186 Dehydrogenase inhibitor Drugs 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 244000299507 Gossypium hirsutum Species 0.000 description 1
- 240000005979 Hordeum vulgare Species 0.000 description 1
- 235000007340 Hordeum vulgare Nutrition 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 244000098338 Triticum aestivum Species 0.000 description 1
- 244000042038 Tropaeolum tuberosum Species 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- FMVJYQGSRWVMQV-UHFFFAOYSA-N ethyl propiolate Chemical compound CCOC(=O)C#C FMVJYQGSRWVMQV-UHFFFAOYSA-N 0.000 description 1
- 239000012847 fine chemical Substances 0.000 description 1
- 238000004334 fluoridation Methods 0.000 description 1
- 244000000004 fungal plant pathogen Species 0.000 description 1
- 230000000855 fungicidal effect Effects 0.000 description 1
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 235000013311 vegetables Nutrition 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
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of 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
- Y02E—REDUCTION OF GREENHOUSE GAS [GHG] EMISSIONS, RELATED TO ENERGY GENERATION, TRANSMISSION OR DISTRIBUTION
- Y02E60/00—Enabling technologies; Technologies with a potential or indirect contribution to GHG emissions mitigation
- Y02E60/10—Energy storage using batteries
Abstract
The invention discloses a preparation method of difluoro pyrazole acid, which belongs to the technical field of organic synthesis, and comprises the following steps: primary reaction, secondary reaction and tertiary reaction; adding toluene and methyl hydrazine aqueous solution into a reaction kettle, stirring, cooling to the temperature of-10 ℃ to 10 ℃ for cyclization reaction, dropwise adding toluene solution of 3- (difluoroacetyl) -4- (dimethylamino) -3-butene-2-one, continuously carrying out heat preservation reaction for 30min after the dropwise addition is finished, taking a toluene layer, stirring, dropwise adding sodium hypochlorite solution into the toluene layer, reacting for 30min at the temperature of 25 ℃ after the dropwise addition is finished, taking a water layer, acidifying the water layer, cooling for crystallization, filtering, and drying to obtain difluoro pyrazole acid; the method has the advantages of mild reaction conditions, cheap and easily obtained reaction solvent and raw materials, few produced isomers, high raw material utilization rate, good reaction selectivity and high yield.
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a preparation method of difluoro pyrazole acid.
Background
Difluoro-pyrazole acids, also known as 1-methyl-3- (difluoromethyl) -1H-pyrazole-4-carboxylic acids, are useful in preparing difluoro-methylpyrazole carboxamides which are useful as fungicides for succinate dehydrogenase inhibitors. The succinate dehydrogenase inhibitor bactericide is a high-efficiency fungicide, has high activity on a wide range of plant pathogenic fungi, can be used for preventing and controlling fungi in various cultivated plants such as cotton, vegetables, barley, corn, rice, soybean, wheat and seeds, and has good prospect.
At present, raw materials for preparing 1-methyl-3- (difluoromethyl) -1H-pyrazole-4-carboxylic acid mainly comprise dichloroacetyl chloride, ethyl difluoroacetate, 1, 2-tetrafluoroethyl dimethylamine, propargyl alcohol, difluoroacetyl chloride and the like which are used as raw materials for preparing difluoroacetic acid and the like; the preparation method comprises the following steps:
chinese patent CN101687806 discloses a method for preparing pyrazole, which uses ethyl difluoroacetate, ethyl propiolate and methyl hydrazine as raw materials to synthesize, and the raw materials of dichloroacetyl chloride are cheap and easy to obtain, although having certain advantages in terms of cost, the reaction conditions are more severe, wherein the dichloroacetyl chloride and vinyl ether compound need to react at-40 ℃ to-20 ℃; the reaction of carboxyl in catalytic pressurization is too slow, the reaction temperature is up to 150 ℃, the pressure in the kettle is required to be continuously changed in the process, the operation is inconvenient, and isomers are not easy to separate, so that the method is not suitable for industrial production.
Chinese patent CN104945325B discloses a preparation method of pyrazole carboxylic acid derivative, which uses 1, 2-tetrafluoroethyl dimethylamine, 3-methoxy acrylate and methyl hydrazine as raw materials for synthesis, and the route has the problems that the raw materials are not easy to obtain, the used fluorinated reagent is dangerous, and the isomer is generated, so that the reaction yield is low.
Li Lifeng, xu Anyu, zhao Dongjiang, show that Wang Yu in the paper synthesis research [ J ] fine chemical intermediate of 3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carboxylic acid, 2013, 43 (6): 17-19, it is disclosed that propargyl alcohol, sodium hypochlorite, acyl chloride, dimethylamine, difluoroacetic acid and hydrazine hydrate are used as raw materials for reaction synthesis, the raw materials of the route are cheap and easy to obtain, the yield is higher, the reaction condition is mild, the existing problems are that the raw materials are extremely toxic, and the synthesis step is longer.
Chinese patent CN113912541A discloses a preparation method of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid, which is synthesized by taking difluoroacetyl chloride, dimethylaminoethyl acrylate and methyl hydrazine as raw materials, the raw materials difluoroacetyl chloride and dimethylaminoethyl acrylate are difficult to obtain, the reaction conditions are severe, the reaction temperature is between minus 30 ℃ and minus 50 ℃, the obtained mixture of 2 isomers has large proportion of the unwanted isomers, and the isomers are not easy to separate, thus being not suitable for industrial production.
Chinese patent CN106467492B discloses a preparation method, an intermediate and a preparation method of a polyfluoromethyl pyrazole compound, which are synthesized by three steps of reactions by taking 1, 1-difluoroacetone, methyl hydrazine and phosphorus oxychloride as raw materials, and the route has the problems that the raw material 1, 1-difluoroacetone is relatively expensive (50 ten thousand yuan/ton), and the generated isomer is not easy to separate.
Chinese patent CN101959840B discloses a method for preparing alkyl 2-alkoxymethylene-4, 4-difluoro-3-oxobutyrate, which uses 1, 2-tetrafluoroethyldimethylamine, 3-methoxy acrylate and methyl hydrazine as raw materials for synthesis, and the route has the problems that the raw materials are not easy to obtain, the used fluoridation reagent is dangerous, and the isomer is generated, resulting in lower reaction yield.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention provides a preparation method of difluoro pyrazole acid, which has the advantages of mild reaction conditions, cheap and easily obtained reaction solvent and raw materials, few produced isomers, high raw material utilization rate, good reaction selectivity and high yield.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a preparation method of difluoro pyrazole acid comprises the following reaction routes:
the preparation method of difluoro pyrazole acid comprises the following steps: primary reaction, secondary reaction and tertiary reaction;
adding toluene and sodium methoxide into an autoclave, mixing the autoclave, using nitrogen to replace air in the autoclave, filling carbon monoxide gas, reacting for 30min at room temperature after the pressurization is finished, dropwise adding a mixed solution of toluene and acetone, reacting for 30min at 75 ℃ after the dropwise adding is finished, cooling to room temperature, opening the autoclave, continuously stirring, adding dimethylamine hydrochloride, reacting for 1h at 75 ℃, and then performing post-treatment to obtain a toluene solution of 4-dimethylamino-3-butene-2-one;
in the primary reaction, the mass ratio of toluene to acetone in the mixed solution of toluene and toluene to acetone is 50.14:100.01:10.13;
the molar ratio of the sodium methoxide to the carbon monoxide to the acetone to the dimethylamine hydrochloride in the mixed solution of the toluene and the acetone is 1-1.2:1:1:1-1.1;
preferably, the molar ratio of the sodium methoxide to the carbon monoxide to the acetone to the dimethylamine hydrochloride in the mixed solution of the toluene and the acetone is 1.05:1:1:1.05;
the nitrogen is used for replacing air in the kettle, the nitrogen is filled until the pressure in the kettle is 0.5MPa, then the pressure in the kettle is discharged to 0.1MPa, the nitrogen is filled again until the pressure in the kettle is 0.5MPa, then the pressure in the kettle is discharged to 0.1MPa, the nitrogen is continuously filled until the pressure in the kettle is 0.5MPa, and then the pressure in the kettle is discharged to 0.1MPa;
the dripping time of the mixed solution of toluene and acetone is 1h;
the post-treatment comprises the steps of concentrating distilled water and methanol, filtering to remove filter residues, rinsing with toluene, and combining filtrate;
the mass ratio of the sodium methoxide to the toluene used in the post-treatment is 9.53-11.35:19.97;
adding toluene and difluoroacetyl chloride into a reaction kettle, stirring, cooling to-15 ℃, dropwise adding tri-n-butylamine, dropwise adding a toluene solution of 4-dimethylamino-3-buten-2-one after 5min, continuously reacting for 30min after the dropwise adding of the toluene solution of 4-dimethylamino-3-buten-2-one is finished to obtain a reaction feed liquid, extracting the reaction feed liquid, wherein an extracted toluene layer is a toluene solution of 3- (difluoroacetyl) -4- (dimethylamino) -3-buten-2-one;
in the secondary reaction, the mass ratio of toluene to difluoroacetyl chloride is 100.16:19.61-21.57;
the molar ratio of the difluoroacetyl chloride to the tri-n-butylamine to the 4-dimethylamino-3-buten-2-one is 1-1.1:1.5-2.5:1;
preferably, the molar ratio of difluoroacetyl chloride, tri-n-butylamine, 4-dimethylamino-3-buten-2-one is 1:2:1;
the dripping time of the toluene solution of the tri-n-butylamine and the 4-dimethylamino-3-buten-2-one is 30min;
the extractant in the extraction is purified water, and the mass ratio of the purified water to the difluoroacetyl chloride is 350.02:19.61-21.57;
adding toluene and methyl hydrazine aqueous solution into a reaction kettle, stirring, cooling to the temperature of-10 ℃ to 10 ℃ for cyclization reaction, dropwise adding toluene solution of 3- (difluoroacetyl) -4- (dimethylamino) -3-butene-2-one, continuously carrying out heat preservation reaction for 30min after the dropwise addition is finished, taking a toluene layer, stirring, dropwise adding sodium hypochlorite solution into the toluene layer, reacting for 30min at the temperature of 25 ℃ after the dropwise addition is finished, taking a water layer, acidifying the water layer, cooling for crystallization, filtering, and drying to obtain difluoro pyrazole acid;
in the three reactions, the mass ratio of toluene to methyl hydrazine aqueous solution is 50:17.27-18.99;
methyl hydrazine and 3- (difluoroacetyl) -4- (dimethylamino) -3-buten-2-one and sodium hypochlorite in a molar ratio of 1-1.1:1:1-1.3;
preferably, the molar ratio of methyl hydrazine, 3- (difluoroacetyl) -4- (dimethylamino) -3-buten-2-one, sodium hypochlorite is 1:1:1.1;
preferably, the temperature of the cyclization reaction is-10 ℃;
the mass fraction of the methyl hydrazine aqueous solution is 40%;
the mass fraction of the sodium hypochlorite solution is 13%;
the dropwise adding time of the sodium hypochlorite solution is 20min;
acidifying the water layer, and adding hydrochloric acid with the mass fraction of 10% into the water layer to acidify to PH=1;
the temperature in the cooling crystallization is-5 ℃.
Compared with the prior art, the invention has the beneficial effects that:
(1) The preparation method of the difluoro pyrazole acid is innovative in finding a new process method for synthesizing the side chain, using acetone and carbon monoxide which are raw materials with lower cost, preparing the side chain with higher yield at milder reaction temperature, then synthesizing the difluoro pyrazole acid, generating fewer isomers in the process, and having simpler post-treatment process without excessive substances influencing the environment, wherein the process has industrialized popularization value;
(2) Compared with the prior art, the preparation method of the difluoro pyrazole acid has high utilization rate of raw materials, the purity of the difluoro pyrazole acid prepared by the method can reach 98.67-99.41%, the isomer content is less than 0.01%, and the total yield of three-step reaction can reach 86.70% at most.
Drawings
FIG. 1 is a liquid chromatogram of the toluene layer prepared in example 7;
FIG. 2 is a liquid chromatogram of the difluoro pyrazole acid product prepared in example 11.
Detailed Description
Specific embodiments of the present invention will now be described in order to provide a clearer understanding of the technical features, objects and effects of the present invention.
The yields of compound A in examples 1-6 were calculated based on the amount of acetone added;
the yields of Compound B in examples 7 to 10 were calculated based on the amount of Compound A added;
the yields of difluoropyrazole acids in examples 11 to 15 were calculated based on the amount of compound B added.
The reaction schemes for examples 1-6 are:
the reaction schemes for examples 7-10 are:
the reaction schemes for examples 11-15 are:
example 1
(1) Adding 50.14g of toluene into a 500mL autoclave, adding 9.53g of sodium methoxide solid (AR, 98%), placing a stirring magnet into the autoclave, closing the autoclave, filling nitrogen until the pressure in the autoclave is 0.5MPa, discharging the mixture to the autoclave at 0.1MPa, continuously filling nitrogen until the pressure is 0.5MPa, discharging the mixture to the autoclave at 0.1MPa, filling the mixture after being connected with a carbon monoxide steel cylinder, filling 4.84g of carbon monoxide gas into the mixture, stirring the mixture at room temperature for 30min after the filling, and controlling the stirring rotation speed to 200rpm;
(2) Continuously stirring the autoclave at a stirring speed of 200rpm, simultaneously dropwise adding 100.01g of a mixed solution of toluene and 10.13g of acetone into the autoclave by using a high-pressure pump for 1h, keeping the temperature at 75 ℃ after dropwise adding, reacting for 30min, cooling the autoclave to room temperature after the reaction is finished, and opening the autoclave;
(3) While continuing to stir the autoclave at a stirring speed of 200rpm, 14.24g of dimethylamine hydrochloride (AR, 99%) was added and reacted at 75℃for 1 hour, then water and methanol were concentrated and distilled off therefrom, the solids were removed by filtration, and rinsed with 19.97g of toluene, and the filtrates were combined to give 182.91g of a toluene solution of 4-dimethylamino-3-buten-2-one (Compound A), the content of Compound A was 9.67% and the yield was 89.78% was calculated.
Example 2
The difference between this example and example 1 is that the addition amount of sodium methoxide was 9.97g, 177.13g of toluene solution of Compound A was finally obtained, the content of Compound A was 10.26% by calibration, and the yield was 92.28% (based on acetone).
The test results of example 1 and example 2 demonstrate that increasing the amount of sodium methoxide added effectively increases the yield.
Example 3
The difference between this example and example 2 is that the addition amount of sodium methoxide was 10.42g, the addition amount of dimethylamine hydrochloride was 14.86g, 178.36g of toluene solution of compound A was finally obtained, the content of compound A was calibrated to 10.34%, and the yield was calculated to 93.64%.
Example 4
This example and example 3 were different in that the addition amount of sodium methoxide was 11.35g, 177.56g of toluene solution of Compound A was finally obtained, the content of Compound A was 9.83% in the obtained solution, and the yield was 88.58%.
The results of examples 1-4 demonstrate that an increase in the amount of sodium methoxide added facilitates the reaction, and can greatly increase the reaction yield, with a molar ratio of acetone to sodium methoxide of 1:1.05 being the preferred condition, and continued increase in the amount of sodium methoxide added adversely affecting the reaction.
Example 5
This example and example 2 were different in that the addition amount of dimethylamine hydrochloride was 15.66g, 181.32g of toluene solution of Compound A was finally obtained, the content of Compound A was 9.98% in the obtained solution, and the yield was 91.89%.
Example 6
This example and example 5 differ in that the amount of dimethylamine hydrochloride added was 15.05g, 178.11g of a toluene solution of compound a was finally obtained, the content of compound a was 10.56% in the toluene solution, and the yield was calculated to be 95.48%.
The results of examples 1-3 and 5-6 demonstrate that increasing the amount of dimethylamine hydrochloride added facilitates the reaction, can greatly increase the reaction yield, and is a preferred condition when the molar ratio of acetone to dimethylamine hydrochloride is 1:1.05, and can adversely affect the continued increase in the amount of dimethylamine hydrochloride added.
Example 7
100.16g of toluene is added into a 500mL four-port bottle, 19.61g of difluoroacetyl chloride (AR, 97%) is added, stirring is carried out at a stirring speed of 200rpm, then the temperature is reduced to minus 15 ℃, 47.15g of tri-n-butylamine (AR, 98%) is started to be added dropwise after 5min, 178.11g of toluene solution of the compound A prepared in example 6 is started to be added dropwise, the dropwise adding time of the tri-n-butylamine and the toluene solution of the compound A is controlled to be 30min, the reaction is continued for 30min after the dropwise adding of the toluene solution of the compound A is finished to ensure complete conversion of raw materials, then 350.02g of purified water is added into the obtained feed liquid for extraction, the quality of the toluene layer after extraction is 308.17g, the liquid chromatography analysis is carried out on the toluene layer, the obtained liquid chromatography is shown in figure 1, the content of 3- (difluoroacetyl) -4- (dimethylamino) -3-butene-2-one (compound B) in the toluene layer is calculated according to an external standard method, and the product yield is 86.89%.
Example 8
This example and example 7 were different in that the amount of tri-n-butylamine added was 62.87g, the amount of difluoroacetyl chloride added was 21.57g, and the mass of the toluene layer after extraction was 325.71g, wherein the content of the product compound B was 8.93%, and the product yield was 91.55%.
Example 9
This example and example 7 were different in that the amount of tri-n-butylamine added was 78.58g, the mass of toluene layer after extraction was 339.52g, the content of the product compound B was 8.44%, and the product yield was 90.19%.
Example 10
The difference between this example and example 8 is that the amount of difluoroacetyl chloride added was 19.61g and the mass of toluene layer after extraction was 323.71g, wherein the content of product compound B was 8.95% and the product yield was 91.23%.
The results of examples 7 to 10 show that when the molar ratio of the compound A to tri-n-butylamine is 1:2, the effect of the excessive tri-n-butylamine on the improvement of the reaction is not obvious, the compound A and the difluoroacetyl chloride are added according to the molar ratio of 1:1, and the yield of the compound B is improved by adding excessive difluoroacetyl chloride compared with the price of difluoroacetyl chloride.
Example 11
(1) 50g of toluene is added into a 500mL four-mouth bottle, 17.27g of methyl hydrazine aqueous solution (AR, 40%) is added, the mixture is stirred at a stirring speed of 200rpm, then the temperature is reduced to 0 ℃, 320.22g of toluene solution of the compound B prepared in example 10 is added dropwise into the mixture for 20min, the mixture is subjected to heat preservation reaction for 30min after the dropwise addition is finished, so that the raw material conversion is ensured to be complete, and the material liquid is layered after the heat preservation reaction is finished;
(2) Taking a toluene layer, stirring at a stirring speed of 200rpm, dropwise adding 85.84g of 13% sodium hypochlorite solution for oxidation for 20min, reacting at 25 ℃ for 30min after the completion of dropwise adding, layering the material liquid again after the reaction, acidifying the water layer to PH=1 by using 10% hydrochloric acid, cooling to-5 ℃, crystallizing to separate out solid, filtering, drying to obtain 26.31g of difluoro pyrazole acid product, performing liquid chromatography analysis on the difluoro pyrazole acid product, obtaining a liquid chromatogram shown in figure 2, and calculating according to an external standard method to obtain the difluoro pyrazole acid with the purity of 98.75%, the isomer content of less than 0.01% and the product yield of 98.75%.
Example 12
The difference between this example and example 11 is that the amount of methyl hydrazine aqueous solution added is 18.99g, the amount of sodium hypochlorite solution added is 94.43g, the reaction temperature in step (1) is 10 ℃, 25.82g of difluoropyrazole acid product is obtained, the purity of difluoropyrazole acid obtained by liquid chromatography analysis is 98.18%, the isomer content is less than 0.01%, and the product yield is 96.01%.
Example 13
The difference between this example and example 12 is that the sodium hypochlorite solution is 103.01g, the reaction temperature in step (1) is-10 ℃, 26.35g of difluoropyrazole acid product is obtained, the purity of difluoropyrazole acid is 98.89% by liquid chromatography analysis, the isomer content is less than 0.01%, and the product yield is 98.69%.
Example 14
The difference between the method and example 11 is that the sodium hypochlorite solution is 111.59g, 25.89g of difluoro pyrazole acid product is obtained, the purity of difluoro pyrazole acid is 99.41% by liquid chromatography analysis, the isomer content is less than 0.01%, and the product yield is 97.48%.
Example 15
The difference between the method and example 12 is that the reaction temperature of step (1) is 0 ℃, 26.54g of difluoro pyrazole acid product is obtained, the purity of difluoro pyrazole acid is 98.67% by liquid chromatography analysis, the isomer content is less than 0.01%, and the product yield is 99.18%.
The results of examples 11-15 demonstrate that a molar ratio of compound B to methyl hydrazine of 1:1.1 is suitable if the molar ratio of compound B to methyl hydrazine is fed in 1:1 with incomplete conversion of part of the starting material; the molar ratio of the compound B to the sodium hypochlorite is 1:1.1, and the excessive sodium hypochlorite is added to cause the solution to be too alkaline, so that the reaction is unfavorable; the reaction temperature in step (1) is to be carried out at a relatively low temperature, and a relatively high temperature is disadvantageous for the reaction, so that a relatively low temperature should be selected as much as possible under the condition of energy saving.
The percentages used in the present invention are mass percentages unless otherwise indicated.
Finally, it should be noted that: the foregoing description is only a preferred embodiment of the present invention, and the present invention is not limited thereto, but it is to be understood that modifications and equivalents of some of the technical features described in the foregoing embodiments may be made by those skilled in the art, although the present invention has been described in detail with reference to the foregoing embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (8)
1. The preparation method of difluoro pyrazole acid is characterized by comprising the following steps: primary reaction, secondary reaction and tertiary reaction;
adding toluene and sodium methoxide into an autoclave, mixing the autoclave, using nitrogen to replace air in the autoclave, filling carbon monoxide gas, reacting for 30min at room temperature after the pressurization is finished, dropwise adding a mixed solution of toluene and acetone, reacting for 30min at 75 ℃ after the dropwise adding is finished, cooling to room temperature, opening the autoclave, continuously stirring, adding dimethylamine hydrochloride, reacting for 1h at 75 ℃, and then performing post-treatment to obtain a toluene solution of 4-dimethylamino-3-butene-2-one;
adding toluene and difluoroacetyl chloride into a reaction kettle, stirring, cooling to-15 ℃, dropwise adding tri-n-butylamine, dropwise adding a toluene solution of 4-dimethylamino-3-buten-2-one after 5min, continuously reacting for 30min after the dropwise adding of the toluene solution of 4-dimethylamino-3-buten-2-one is finished to obtain a reaction feed liquid, extracting the reaction feed liquid, wherein an extracted toluene layer is a toluene solution of 3- (difluoroacetyl) -4- (dimethylamino) -3-buten-2-one;
adding toluene and methyl hydrazine aqueous solution into a reaction kettle, stirring, cooling to the temperature of-10 ℃ to 10 ℃ for cyclization reaction, dropwise adding toluene solution of 3- (difluoroacetyl) -4- (dimethylamino) -3-butene-2-one, continuously carrying out heat preservation reaction for 30min after the dropwise addition is finished, taking a toluene layer, stirring, dropwise adding sodium hypochlorite solution into the toluene layer, reacting for 30min at the temperature of 25 ℃ after the dropwise addition is finished, taking a water layer, acidifying the water layer, cooling for crystallization, filtering, and drying to obtain difluoro pyrazole acid.
2. The method for producing difluoropyrazole acid according to claim 1, wherein a mass ratio of toluene to acetone in the mixed solution of toluene and acetone in the one-time reaction is 50.14:100.01:10.13;
the molar ratio of the sodium methoxide to the carbon monoxide to the acetone to the dimethylamine hydrochloride in the mixed solution of the toluene and the acetone is 1-1.2:1:1:1-1.1.
3. The method for producing difluoropyrazole acid according to claim 1, wherein in the one-time reaction, the air in the reactor is replaced with nitrogen, nitrogen is charged to 0.5MPa in the reactor, then discharged to 0.1MPa in the reactor, nitrogen is continuously charged to 0.5MPa in the reactor, and then discharged to 0.1MPa in the reactor;
the dripping time of the mixed solution of toluene and acetone is 1h.
4. The method for producing difluoropyrazole acid according to claim 1, wherein in the one-time reaction, the post-treatment is performed by concentrating distilled water and methanol, filtering to remove filter residues, and then rinsing with toluene and combining the filtrates;
the mass ratio of the sodium methoxide to the toluene used in the post-treatment is 9.53-11.35:19.97.
5. The method for producing difluoropyrazole acid according to claim 1, wherein in the secondary reaction, a mass ratio of toluene to difluoroacetyl chloride is 100.16:19.61-21.57;
the molar ratio of the difluoroacetyl chloride to the tri-n-butylamine to the 4-dimethylamino-3-buten-2-one is 1-1.1:1.5-2.5:1.
6. The method for producing difluoropyrazole acid according to claim 1, wherein in the secondary reaction, the dropwise addition time of the toluene solutions of tri-n-butylamine and 4-dimethylamino-3-buten-2-one is 30 minutes;
the extractant in the extraction is purified water, and the mass ratio of the purified water to the difluoroacetyl chloride is 350.02:19.61-21.57.
7. The method for producing difluoropyrazole acid according to claim 1, wherein in the three reactions, a mass ratio of toluene to methyl hydrazine aqueous solution is 50:17.27-18.99;
the molar ratio of methyl hydrazine to 3- (difluoroacetyl) -4- (dimethylamino) -3-buten-2-one to sodium hypochlorite is 1-1.1:1:1-1.3.
8. The method for producing difluoropyrazole acid according to claim 1, wherein the mass fraction of the aqueous solution of methylhydrazine in the three reactions is 40%;
the mass fraction of the sodium hypochlorite solution is 13%;
the dropwise adding time of the sodium hypochlorite solution is 20min;
acidifying the water layer, and adding hydrochloric acid with the mass fraction of 10% into the water layer to acidify to PH=1;
the temperature in the cooling crystallization is-5 ℃.
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| CN117447401A (en) * | 2023-12-26 | 2024-01-26 | 山东国邦药业有限公司 | Synthesis method of difluoro pyrazole acid |
| CN117447401B (en) * | 2023-12-26 | 2024-04-19 | 山东国邦药业有限公司 | Synthesis method of difluoro pyrazole acid |
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