CN113402464A - Synthetic method of fluxapyroxad based on Suzuki reaction - Google Patents
Synthetic method of fluxapyroxad based on Suzuki reaction Download PDFInfo
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- CN113402464A CN113402464A CN202110278296.3A CN202110278296A CN113402464A CN 113402464 A CN113402464 A CN 113402464A CN 202110278296 A CN202110278296 A CN 202110278296A CN 113402464 A CN113402464 A CN 113402464A
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- organic solvent
- palladium
- difluoromethyl
- prazole
- fluxapyroxad
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- 239000005788 Fluxapyroxad Substances 0.000 title claims abstract description 21
- 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 title claims abstract description 21
- 238000006069 Suzuki reaction reaction Methods 0.000 title claims abstract description 8
- 238000010189 synthetic method Methods 0.000 title claims abstract description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000003054 catalyst Substances 0.000 claims abstract description 18
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229910052751 metal Inorganic materials 0.000 claims abstract description 14
- 239000002184 metal Substances 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 14
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 33
- 239000003153 chemical reaction reagent Substances 0.000 claims description 20
- 239000003960 organic solvent Substances 0.000 claims description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 230000008878 coupling Effects 0.000 claims description 12
- 238000010168 coupling process Methods 0.000 claims description 12
- 238000005859 coupling reaction Methods 0.000 claims description 12
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 9
- 125000006304 2-iodophenyl group Chemical group [H]C1=C([H])C(I)=C(*)C([H])=C1[H] 0.000 claims description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 8
- 239000002994 raw material Substances 0.000 claims description 8
- 238000003786 synthesis reaction Methods 0.000 claims description 8
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical group Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 claims description 7
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 238000001308 synthesis method Methods 0.000 claims description 6
- UBPDKIDWEADHPP-UHFFFAOYSA-N 2-iodoaniline Chemical compound NC1=CC=CC=C1I UBPDKIDWEADHPP-UHFFFAOYSA-N 0.000 claims description 5
- 238000006482 condensation reaction Methods 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 235000010290 biphenyl Nutrition 0.000 claims description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical group C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 4
- UHDDEIOYXFXNNJ-UHFFFAOYSA-N (3,4,5-trifluorophenyl)boronic acid Chemical compound OB(O)C1=CC(F)=C(F)C(F)=C1 UHDDEIOYXFXNNJ-UHFFFAOYSA-N 0.000 claims description 3
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims description 2
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 claims description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 claims description 2
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 claims description 2
- XGZVUEUWXADBQD-UHFFFAOYSA-L lithium carbonate Chemical compound [Li+].[Li+].[O-]C([O-])=O XGZVUEUWXADBQD-UHFFFAOYSA-L 0.000 claims description 2
- 229910052808 lithium carbonate Inorganic materials 0.000 claims description 2
- PBDBXAQKXCXZCJ-UHFFFAOYSA-L palladium(2+);2,2,2-trifluoroacetate Chemical compound [Pd+2].[O-]C(=O)C(F)(F)F.[O-]C(=O)C(F)(F)F PBDBXAQKXCXZCJ-UHFFFAOYSA-L 0.000 claims description 2
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 abstract description 3
- 229910002091 carbon monoxide Inorganic materials 0.000 abstract description 3
- 239000002360 explosive Substances 0.000 abstract description 2
- 231100000331 toxic Toxicity 0.000 abstract description 2
- 230000002588 toxic effect Effects 0.000 abstract description 2
- 230000007613 environmental effect Effects 0.000 abstract 1
- 239000000047 product Substances 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 9
- 239000007789 gas Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- FTIKVBVUYPQUBF-UHFFFAOYSA-N 2-(3,4,5-trifluorophenyl)aniline Chemical compound NC1=CC=CC=C1C1=CC(F)=C(F)C(F)=C1 FTIKVBVUYPQUBF-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000031888 Mycoses Diseases 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229910000510 noble metal Inorganic materials 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000000575 pesticide Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- ZMYFCFLJBGAQRS-IRXDYDNUSA-N (2R,3S)-epoxiconazole Chemical compound C1=CC(F)=CC=C1[C@@]1(CN2N=CN=C2)[C@H](C=2C(=CC=CC=2)Cl)O1 ZMYFCFLJBGAQRS-IRXDYDNUSA-N 0.000 description 1
- VXYWCTANPTZYGM-UHFFFAOYSA-N 4-bromo-3-(difluoromethyl)-1-methylpyrazole Chemical compound CN1C=C(Br)C(C(F)F)=N1 VXYWCTANPTZYGM-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 244000105624 Arachis hypogaea Species 0.000 description 1
- 235000016068 Berberis vulgaris Nutrition 0.000 description 1
- 241000335053 Beta vulgaris Species 0.000 description 1
- 241000123650 Botrytis cinerea Species 0.000 description 1
- 208000003643 Callosities Diseases 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- 229940124186 Dehydrogenase inhibitor Drugs 0.000 description 1
- 239000005760 Difenoconazole Substances 0.000 description 1
- 239000005767 Epoxiconazole Substances 0.000 description 1
- 241000221785 Erysiphales Species 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 241000219146 Gossypium Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010020649 Hyperkeratosis Diseases 0.000 description 1
- 239000005869 Pyraclostrobin Substances 0.000 description 1
- 241001361634 Rhizoctonia Species 0.000 description 1
- 241001533598 Septoria Species 0.000 description 1
- 102000019259 Succinate Dehydrogenase Human genes 0.000 description 1
- 108010012901 Succinate Dehydrogenase Proteins 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
- 238000004458 analytical method Methods 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 238000005810 carbonylation reaction Methods 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- BQYJATMQXGBDHF-UHFFFAOYSA-N difenoconazole Chemical compound O1C(C)COC1(C=1C(=CC(OC=2C=CC(Cl)=CC=2)=CC=1)Cl)CN1N=CN=C1 BQYJATMQXGBDHF-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000000855 fungicidal effect Effects 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 235000020232 peanut Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- HZRSNVGNWUDEFX-UHFFFAOYSA-N pyraclostrobin Chemical compound COC(=O)N(OC)C1=CC=CC=C1COC1=NN(C=2C=CC(Cl)=CC=2)C=C1 HZRSNVGNWUDEFX-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
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Classifications
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- 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
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- 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 a synthetic method of fluxapyroxad based on Suzuki reaction. Compared with the prior art, the method avoids highly toxic, flammable and explosive carbon monoxide gas and the complex palladium metal catalyst, uses the relatively cheap and easily available tetrakis (triphenylphosphine) palladium catalyst, and prepares the fluxapyroxad product through mild and high-universality Suzuki reaction. The method disclosed by the invention has the characteristics of simplicity, economy, environmental protection, safety and high efficiency, and has strong industrial application potential.
Description
Technical Field
The invention belongs to the field of organic chemical synthesis of pesticide molecules, and particularly relates to a method for preparing and industrializing fluxapyroxad which is a pesticide molecule by using an independently related and innovative synthesis method.
Background
Fluxapyroxad is a succinate dehydrogenase inhibitor based fungicide developed by BASF corporation. It was first registered and marketed in the uk market in 2011 and its global sales reached $ 3.90 billion in 2015, and the product is currently registered and marketed in australia, argentina, the united states, canada, the european union, brazil and china.
The fluxapyroxad has good residual activity on various fungal diseases, and can effectively prevent main diseases of crops such as grains, soybeans, corns, rapes, beet, peanuts, cotton and the like. The product can be used for preventing a series of fungal diseases such as septoria, botrytis cinerea, powdery mildew and rhizoctonia and the like by a method of controlling leaf surfaces and seeds, and is particularly suitable for leguminous crops. At various doses, it proved to be very safe for crops. And the fluxapyroxad has strong adaptability, and can be compounded with products such as pyraclostrobin, epoxiconazole and difenoconazole for use, so as to obtain better control effect.
Molecular structure of fluxapyroxad
Currently, the synthesis of fluxapyroxad is mainly carried out in the following two ways:
in the first method, 3-difluoromethyl-1-methyl-1-prazole-4-acyl chloride is used as a raw material and is subjected to condensation reaction with 2- (3, 4, 5-trifluorophenyl) aniline to obtain a product.
The method has simple and convenient steps, but the price of the used raw materials is higher, and the acyl chloride compound has unstable property and is easy to degrade to generate impurities, so that the purity of the product obtained by the reaction is not high, and the method is not favorable for purification production.
In the second method, 3-difluoromethyl-4-bromo-1-methylpyrazole is used as a raw material, and the raw material and 2- (3, 4, 5-trifluorophenyl) aniline are subjected to carbonylation reaction in the atmosphere of palladium metal catalyst and carbon monoxide to obtain a product.
The product obtained by the method has high purity, but the noble metal catalyst used in the process is difficult to prepare, the reaction relates to carbon monoxide gas, the toxicity is high, special gas reaction equipment is required, and the production difficulty is high.
In summary, there is a need for improved processes for the synthesis of fluxapyroxad.
Disclosure of Invention
Aiming at the defects of the prior art and solving the problems of high safety risk and the like in the synthesis of fluxapyroxad, the invention provides an independently designed and innovative synthesis method. The method has the innovation point that a reverse synthesis analysis mode is adopted, and cheap 3-difluoromethyl-1-methyl-1-prazole-4-carboxylic acid is used as a raw material to carry out two-step reaction to obtain a product.
The synthesis method of fluxapyroxad provided by the invention comprises the following steps: the method comprises the steps of taking 3-difluoromethyl-1-methyl-1-prazole-4-carboxylic acid as a raw material, carrying out condensation reaction with 2-iodoaniline (formula II) under the action of a coupling reagent, and carrying out Suzuki reaction with 3,4, 5-trifluorophenylboronic acid (formula IV) under the action of a palladium metal catalyst to generate a fluxapyroxad product. The reaction process is as follows:
according to one embodiment of the invention, the synthesis method comprises the steps of:
s1.3-difluoromethyl-1-methyl-1-prazole-4-carboxylic acid and 2-iodoaniline are subjected to condensation reaction in an organic solvent under the action of a coupling reagent and 4-dimethylaminopyridine to generate 3-difluoromethyl-N- (2-iodophenyl) -1-methyl-1-prazole-4-amide;
S2.3-difluoromethyl-N- (2-iodophenyl) -1-methyl-1-prazole-4-amide is subjected to Suzuki reaction in an organic solvent in the presence of a palladium metal catalyst and an alkaline reagent to generate 3-difluoromethyl-1-methyl-N- [3 '-4' -5 '-trifluoro- (1, 1' -biphenyl) -2-yl ] -1-prazole-4-amide, namely fluxapyroxad product.
Preferably, in step S1, the coupling reagent is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and the organic solvent is dichloromethane; in step S2, the palladium metal catalyst is tetrakis (triphenylphosphine) palladium, the alkaline reagent is potassium carbonate, and the organic solvent is tetrahydrofuran.
Step S1 uses a coupling reagent and an organic solvent: the coupling reagent is N, N' -carbonyldiimidazole, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and hydroxybenzotriazole; the organic solvent is at least one of dichloromethane, tetrahydrofuran, N-dimethylformamide, methanol, ethanol and isopropanol or a combination thereof; preferably, the coupling reagent is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and the organic solvent is dichloromethane. In step S2, a palladium metal catalyst, an alkaline reagent, and an organic solvent are used: the palladium metal catalyst is at least one of tetrakis (triphenylphosphine) palladium, palladium dichloride/triphenylphosphine, palladium acetate/triphenylphosphine and palladium trifluoroacetate/triphenylphosphine or a combination thereof; the alkaline reagent is at least one or the combination of lithium hydroxide, lithium carbonate, sodium hydroxide, sodium carbonate, potassium hydroxide and potassium carbonate; the organic solvent is at least one of dichloromethane, tetrahydrofuran, N-dimethylformamide, methanol, ethanol and isopropanol or the combination thereof; preferably, the metal catalyst is tetrakis (triphenylphosphine) palladium, the basic agent is potassium carbonate, and the organic solvent is tetrahydrofuran.
Compared with the existing synthesis mode, the synthesis route provided by the invention has the following characteristics:
1. the synthetic route provided by the invention does not relate to high-activity raw materials or compounds, does not generate degradation, and the purity of the obtained product is higher;
2. the synthetic route provided by the invention does not relate to toxic, flammable and explosive gases, does not need special gas reaction equipment, and has simple preparation process and high safety;
3. the noble metal catalyst provided by the invention is simple and easy to obtain, and the preparation cost of the catalyst is low.
The synthetic route provided by the invention has relatively mild reaction conditions, solves a plurality of defects of the existing route, and has great commercial value and potential.
Drawings
FIG. 1 is a NMR spectrum of 3-difluoromethyl-N- (2-iodophenyl) -1-methyl-1-prazole-4-amide;
FIG. 2 is a NMR spectrum of the compound 3-difluoromethyl-1-methyl-N- [3 '-4' -5 '-trifluoro- (1, 1' -biphenyl) -2-yl ] -1-prazole-4-amide, fluxapyroxad.
Example one
A round bottom flask is provided with a stirrer. To this was added 3-difluoromethyl-1-methyl-1-prazole-4-carboxylic acid (1.00 g, 5.70 mmol), 2-iodoaniline (1.50 g, 6.84 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.20 g, 6.27 mmol), 4-dimethylaminopyridine (0.84 g, 6.84 mmol) and dichloromethane (20 ml). The resulting mixture was stirred at room temperature overnight, and after completion of the reaction was monitored by thin layer chromatography, distilled water (20 ml) was added to the reaction system. The organic phase was separated and the aqueous phase was washed 3 times with dichloromethane (20 ml). The organic phases were combined and evaporated to dryness and the crude product was purified by column chromatography to give pure 3-difluoromethyl-N- (2-iodophenyl) -1-methyl-1-prazole-4-amide as a white solid in 81% yield and 91% purity by NMR.
Example two
A round bottom flask is provided with a stirrer. To this was added pure 3-difluoromethyl-N- (2-iodophenyl) -1-methyl-1-prazole-4-amide (0.31 g, 0.82 mmol), 3,4, 5-trifluorophenylboronic acid (0.17 g, 0.98 mmol), tetrakis (triphenylphosphine) palladium (300 mg), potassium carbonate (0.57 g, 4.10 mmol) and tetrahydrofuran (9 ml). The resulting mixture was placed under nitrogen and heated to reflux and reacted overnight. After completion of the reaction, water (20 ml) and methylene chloride (50 ml) were added thereto and stirred for 30 minutes. The organic phase was separated, washed with saturated ammonium chloride solution (10 ml) and dried, and concentrated to dryness. And purifying the obtained crude product by column chromatography to obtain a pure fluxapyroxad product which is a light yellow solid with the yield of 92 percent and the purity of 95 percent calculated by nuclear magnetic resonance hydrogen spectrum.
Claims (4)
1. A synthetic method of fluxapyroxad is characterized in that: taking 3-difluoromethyl-1-methyl-1-prazole-4-carboxylic acid as a raw material, carrying out condensation reaction with 2-iodoaniline (formula II) under the action of a coupling reagent, and carrying out Suzuki reaction with 3,4, 5-trifluorophenylboronic acid (formula IV) under the action of a palladium metal catalyst to generate a fluxapyroxad product;
the key intermediate is 3-difluoromethyl-N- (2-iodophenyl) -1-methyl-1-prazole-4-amide (formula III).
2. The synthesis according to claim 1, which gives a product of 3-difluoromethyl-1-methyl-N- [3 '-4' -5 '-trifluoro- (1, 1' -biphenyl) -2-yl ] -1-prazole-4-amide, fluxapyroxad; the synthesis method is characterized by comprising the following steps:
s1.3-difluoromethyl-1-methyl-1-prazole-4-carboxylic acid and 2-iodoaniline are subjected to condensation reaction in an organic solvent under the action of a coupling reagent and 4-dimethylaminopyridine to generate 3-difluoromethyl-N- (2-iodophenyl) -1-methyl-1-prazole-4-amide;
S2.3-difluoromethyl-N- (2-iodophenyl) -1-methyl-1-prazole-4-amide is subjected to Suzuki reaction in an organic solvent in the presence of a palladium metal catalyst and an alkaline reagent to generate 3-difluoromethyl-1-methyl-N- [3 '-4' -5 '-trifluoro- (1, 1' -biphenyl) -2-yl ] -1-prazole-4-amide, namely a fluxapyroxad product, preferably, in the step S1, the coupling reagent is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, and the organic solvent is dichloromethane; in step S2, the palladium metal catalyst is tetrakis (triphenylphosphine) palladium, the alkaline reagent is potassium carbonate, and the organic solvent is tetrahydrofuran.
3. The method of claim 2, wherein step S1 is performed using a coupling reagent and an organic solvent: the coupling reagent is N, N' -carbonyldiimidazole, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and hydroxybenzotriazole; the organic solvent is at least one of dichloromethane, tetrahydrofuran, N-dimethylformamide, methanol, ethanol and isopropanol or a combination thereof; preferably, the coupling reagent is 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and the organic solvent is dichloromethane.
4. The synthesis method according to claim 2, wherein in step S2, palladium metal catalyst, alkaline reagent and organic solvent are used: the palladium metal catalyst is at least one of tetrakis (triphenylphosphine) palladium, palladium dichloride/triphenylphosphine, palladium acetate/triphenylphosphine and palladium trifluoroacetate/triphenylphosphine or a combination thereof; the alkaline reagent is at least one or the combination of lithium hydroxide, lithium carbonate, sodium hydroxide, sodium carbonate, potassium hydroxide and potassium carbonate; the organic solvent is at least one of dichloromethane, tetrahydrofuran, N-dimethylformamide, methanol, ethanol and isopropanol or the combination thereof; preferably, the metal catalyst is tetrakis (triphenylphosphine) palladium, the basic agent is potassium carbonate, and the organic solvent is tetrahydrofuran.
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| CN101374829A (en) * | 2005-12-19 | 2009-02-25 | 健泰科生物技术公司 | Inhibitors of IAP |
| CN110891940A (en) * | 2017-08-28 | 2020-03-17 | 日本凡凯姆股份有限公司 | Process for preparing pyrazole-4-carboxamide derivatives |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101374829A (en) * | 2005-12-19 | 2009-02-25 | 健泰科生物技术公司 | Inhibitors of IAP |
| CN110891940A (en) * | 2017-08-28 | 2020-03-17 | 日本凡凯姆股份有限公司 | Process for preparing pyrazole-4-carboxamide derivatives |
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| AIGUI ZHANG ET AL.: "Design, Synthesis, and Antifungal Activities of Novel Aromatic Carboxamides Containing a Diphenylamine Scaffold", 《JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY》 * |
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