CN114315748A - Synthesis method of flurarana - Google Patents
Synthesis method of flurarana Download PDFInfo
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- CN114315748A CN114315748A CN202111644720.8A CN202111644720A CN114315748A CN 114315748 A CN114315748 A CN 114315748A CN 202111644720 A CN202111644720 A CN 202111644720A CN 114315748 A CN114315748 A CN 114315748A
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- benzoic acid
- dichlorophenyl
- trifluoro
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- 238000001308 synthesis method Methods 0.000 title abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- 238000006069 Suzuki reaction reaction Methods 0.000 claims abstract description 4
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 4
- -1 4- (3- (3, 5-dichlorophenyl) -4,4, 4-trifluoro-3-hydroxybutyl) -benzoic acid Chemical compound 0.000 claims description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 31
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 21
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- RVCJOGNLYVNRDN-UHFFFAOYSA-N 4-bromo-2-methylbenzoic acid Chemical compound CC1=CC(Br)=CC=C1C(O)=O RVCJOGNLYVNRDN-UHFFFAOYSA-N 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 229910001868 water Inorganic materials 0.000 claims description 17
- QNFBKOHHLAWWTC-UHFFFAOYSA-N Fraxidin Chemical compound C1=CC(=O)OC2=C1C=C(OC)C(OC)=C2O QNFBKOHHLAWWTC-UHFFFAOYSA-N 0.000 claims description 16
- 238000003756 stirring Methods 0.000 claims description 16
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- QGXDUDDPMXVLOO-UHFFFAOYSA-N 4-acetyl-2-methylbenzoic acid Chemical compound CC(=O)C1=CC=C(C(O)=O)C(C)=C1 QGXDUDDPMXVLOO-UHFFFAOYSA-N 0.000 claims description 13
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 12
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 claims description 10
- 239000005711 Benzoic acid Substances 0.000 claims description 10
- 230000002194 synthesizing effect Effects 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 8
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- 239000000203 mixture Substances 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- 230000035484 reaction time Effects 0.000 claims description 6
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 6
- ACUOJJBRHCFOKT-UHFFFAOYSA-N 2-amino-n-(2,2,2-trifluoroethyl)acetamide Chemical compound NCC(=O)NCC(F)(F)F ACUOJJBRHCFOKT-UHFFFAOYSA-N 0.000 claims description 4
- 239000004115 Sodium Silicate Substances 0.000 claims description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical group [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 4
- 235000019795 sodium metasilicate Nutrition 0.000 claims description 4
- NTHWMYGWWRZVTN-UHFFFAOYSA-N sodium silicate Chemical compound [Na+].[Na+].[O-][Si]([O-])=O NTHWMYGWWRZVTN-UHFFFAOYSA-N 0.000 claims description 4
- 229910052911 sodium silicate Inorganic materials 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 230000005494 condensation Effects 0.000 claims description 3
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 2
- 150000001263 acyl chlorides Chemical class 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 238000009833 condensation Methods 0.000 claims description 2
- 239000003960 organic solvent Substances 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 238000007363 ring formation reaction Methods 0.000 abstract description 6
- 238000006482 condensation reaction Methods 0.000 abstract description 3
- 230000018044 dehydration Effects 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- YWBVHLJPRPCRSD-UHFFFAOYSA-N Fluridone Chemical compound O=C1C(C=2C=C(C=CC=2)C(F)(F)F)=CN(C)C=C1C1=CC=CC=C1 YWBVHLJPRPCRSD-UHFFFAOYSA-N 0.000 abstract 2
- SEENCYZQHCUTSB-UHFFFAOYSA-N 5-bromo-2-methylbenzoic acid Chemical compound CC1=CC=C(Br)C=C1C(O)=O SEENCYZQHCUTSB-UHFFFAOYSA-N 0.000 abstract 1
- 150000001408 amides Chemical class 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 42
- 239000000543 intermediate Substances 0.000 description 25
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 11
- 238000001035 drying Methods 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 8
- 239000007787 solid Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000007795 chemical reaction product Substances 0.000 description 5
- 238000005160 1H NMR spectroscopy Methods 0.000 description 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 230000000749 insecticidal effect Effects 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 241000607479 Yersinia pestis Species 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 239000002917 insecticide Substances 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000009987 spinning Methods 0.000 description 3
- 238000006467 substitution reaction Methods 0.000 description 3
- UZKWTJUDCOPSNM-UHFFFAOYSA-N 1-ethenoxybutane Chemical compound CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- 108010062745 Chloride Channels Proteins 0.000 description 2
- 102000011045 Chloride Channels Human genes 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 244000000054 animal parasite Species 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 229940125904 compound 1 Drugs 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 2
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 2
- 229960003088 loratadine Drugs 0.000 description 2
- JCCNYMKQOSZNPW-UHFFFAOYSA-N loratadine Chemical compound C1CN(C(=O)OCC)CCC1=C1C2=NC=CC=C2CCC2=CC(Cl)=CC=C21 JCCNYMKQOSZNPW-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000000575 pesticide Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- LYDRKKWPKKEMNZ-UHFFFAOYSA-N tert-butyl benzoate Chemical compound CC(C)(C)OC(=O)C1=CC=CC=C1 LYDRKKWPKKEMNZ-UHFFFAOYSA-N 0.000 description 2
- UYBQBUZXULIDMQ-UHFFFAOYSA-N 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene Chemical compound FC(F)(F)C(=C)C1=CC(Cl)=CC(Cl)=C1 UYBQBUZXULIDMQ-UHFFFAOYSA-N 0.000 description 1
- DZDSQRPDUCSOQV-UHFFFAOYSA-N 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone Chemical compound FC(F)(F)C(=O)C1=CC(Cl)=CC(Cl)=C1 DZDSQRPDUCSOQV-UHFFFAOYSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- DBNFKWRZLGVLSH-UHFFFAOYSA-N 2-amino-n-(2,2,2-trifluoroethyl)acetamide;hydrochloride Chemical compound Cl.NCC(=O)NCC(F)(F)F DBNFKWRZLGVLSH-UHFFFAOYSA-N 0.000 description 1
- CXKCZFDUOYMOOP-UHFFFAOYSA-N 3,5-dichlorobenzoic acid Chemical compound OC(=O)C1=CC(Cl)=CC(Cl)=C1 CXKCZFDUOYMOOP-UHFFFAOYSA-N 0.000 description 1
- CAUGMFYASUZURF-UHFFFAOYSA-N 3-(4-bromo-3-methylphenyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4h-1,2-oxazole Chemical compound C1=C(Br)C(C)=CC(C=2CC(ON=2)(C=2C=C(Cl)C=C(Cl)C=2)C(F)(F)F)=C1 CAUGMFYASUZURF-UHFFFAOYSA-N 0.000 description 1
- WEQPBCSPRXFQQS-UHFFFAOYSA-N 4,5-dihydro-1,2-oxazole Chemical compound C1CC=NO1 WEQPBCSPRXFQQS-UHFFFAOYSA-N 0.000 description 1
- GNSNJJYLCDTUHG-UHFFFAOYSA-N 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4h-1,2-oxazol-3-yl]-2-iodo-6-methylbenzoic acid Chemical compound IC1=C(C(O)=O)C(C)=CC(C=2CC(ON=2)(C=2C=C(Cl)C=C(Cl)C=2)C(F)(F)F)=C1 GNSNJJYLCDTUHG-UHFFFAOYSA-N 0.000 description 1
- BTJJGAWOGJAPDA-UHFFFAOYSA-N 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4h-1,2-oxazol-3-yl]-2-methylaniline Chemical compound C1=C(N)C(C)=CC(C=2CC(ON=2)(C=2C=C(Cl)C=C(Cl)C=2)C(F)(F)F)=C1 BTJJGAWOGJAPDA-UHFFFAOYSA-N 0.000 description 1
- DWEMIPZCGUHMSX-UHFFFAOYSA-N 4-acetyl-2-methylbenzoyl chloride Chemical compound CC(=O)C1=CC=C(C(Cl)=O)C(C)=C1 DWEMIPZCGUHMSX-UHFFFAOYSA-N 0.000 description 1
- OIWOOOJFKXTXKV-UHFFFAOYSA-N 4-formyl-2-methylbenzoic acid Chemical compound CC1=CC(C=O)=CC=C1C(O)=O OIWOOOJFKXTXKV-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- 241000255925 Diptera Species 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 241000258937 Hemiptera Species 0.000 description 1
- 241000255777 Lepidoptera Species 0.000 description 1
- 241001674048 Phthiraptera Species 0.000 description 1
- 235000006040 Prunus persica var persica Nutrition 0.000 description 1
- 240000006413 Prunus persica var. persica Species 0.000 description 1
- LYAQARPSMJIUQF-UHFFFAOYSA-N [1-(3,5-dichlorophenyl)-2,2,2-trifluoro-1-methoxyethoxy]-trimethylsilane Chemical compound C[Si](C)(C)OC(OC)(C(F)(F)F)C1=CC(Cl)=CC(Cl)=C1 LYAQARPSMJIUQF-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000005831 deiodination reaction Methods 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 238000012840 feeding operation Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 229940041033 macrolides Drugs 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- BTEVDFJXGLQUDS-UHFFFAOYSA-N methyl 3,5-dichlorobenzoate Chemical compound COC(=O)C1=CC(Cl)=CC(Cl)=C1 BTEVDFJXGLQUDS-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000006146 oximation reaction Methods 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000008048 phenylpyrazoles Chemical class 0.000 description 1
- 238000011403 purification operation Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- BTURAGWYSMTVOW-UHFFFAOYSA-M sodium dodecanoate Chemical compound [Na+].CCCCCCCCCCCC([O-])=O BTURAGWYSMTVOW-UHFFFAOYSA-M 0.000 description 1
- 229940082004 sodium laurate Drugs 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- HSVBBRKMHLTVSN-UHFFFAOYSA-N tert-butyl 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4h-1,2-oxazol-3-yl]-2-methylbenzoate Chemical compound C1=C(C(=O)OC(C)(C)C)C(C)=CC(C=2CC(ON=2)(C=2C=C(Cl)C=C(Cl)C=2)C(F)(F)F)=C1 HSVBBRKMHLTVSN-UHFFFAOYSA-N 0.000 description 1
- MWKJTNBSKNUMFN-UHFFFAOYSA-N trifluoromethyltrimethylsilane Chemical compound C[Si](C)(C)C(F)(F)F MWKJTNBSKNUMFN-UHFFFAOYSA-N 0.000 description 1
- 239000000273 veterinary drug Substances 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention discloses a synthesis method of fluridone, which takes 2-methyl-5-bromobenzoic acid as a raw material to finally obtain the fluridone through Suzuki coupling reaction, condensation reaction, dehydration cyclization reaction and amide condensation reaction. The synthesis method of the invention reduces the reaction cost, improves the yield and shortens the reaction period.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a synthetic method of flurandrine.
Background
Flurara is a broad spectrum insecticide of the isoxazoline type, which is currently registered on the market as a veterinary drug and is known under the trade name BRAVECTOTM[1]. The CAS number of the frailamide is 864731-61-3, the CAS name is 4- [5- (3, 5-two peaches phenyl) -4, 5-dihydro-5- (trifluoromethyl) -3-isoxazolyl]-2-methyl-2-oxo-2- [ (2,2, 2-trifluoroethyl) oxy]Ethyl radical]Benzamide, the common name in chinese is flurarana. The chemical structural formula is as follows:
the loratadine is mainly used for treating animal parasites, belongs to y-aminobutyric acid gated chloride ion channel interference agents similar to action targets of phenyl pyrazoles, cyclopentadiene, macrolides and other pesticides, and has an action mechanism of achieving +51 insecticidal effect by interfering y-aminobutyric acid gated chloride ion channels. According to the related literature, the fraxidin is reported to have better insecticidal activity on most agricultural pests as a broad-spectrum insecticide except for animal parasites. Compared with other insecticides in the market, the loratadine has equivalent or higher insecticidal activity, and particularly has good insecticidal effect on pests such as phthiraptera, egg order, hemiptera, diptera, lepidoptera and the like. Therefore, the fraxidin is expected to be developed as a pesticide and used for preventing and controlling agricultural pests.
At present, there are many methods for synthesizing fluralin, and the first one uses 4-acetyl-2-methylbenzoic acid as starting material to prepare 4-acetyl-2-methylbenzoyl chloride, and then reacts with 2-amino-; v- (2,2, 2-trifluoroethyl) acetamide is amidated to obtain 4-acetyl-2-methyl- # - [ 2-oxo-2- [ (2,2, 2-trifluoroethyl) amino ] ethyl ] benzamide, then the 4- [ (2 £ 3- (3, 5-dichlorophenyl) -4,4, 4-trifluoro-1-oxo-2-buten-1-yl ] -2-methyl- [ 2-oxo-2- [ (2,2, 2-trifluoroethyl) amino ] ethyl ] benzamide is prepared by reacting with 3', 5' -dichloro-2, 2, 2-trifluoroacetophenone, and finally the target product frabina fluoride is obtained by cyclization, the second one is that 4-bromo-2-methyl benzoic acid is used as a starting material, esterification and amidation reactions are carried out to obtain 2-methyl-4-formaldehyde oxime tert-butyl benzoate, then 1, 3-dipolar addition cyclization reaction is carried out on the tert-butyl benzoate and 1, 3-dichloro-5- (1-trifluoromethyl-vinyl) benzene to obtain 4- [5- (3, 5-dichlorophenyl) -4, 5-dihydro-5- (trifluoromethyl) -3-isoxazolyl ] -2-methyl benzoic acid tert-butyl ester, and an intermediate of 4- [5- (3, 5-dichlorophenyl) -4, 5-dihydro-5-trifluoromethyl-3-isoxazolyl ] -2-iodo-6-methyl benzoic acid is finally obtained through iodine substitution and hydrolysis reactions, the obtained intermediate is reacted with 2-amino-N (2,2, 2-trifluoroethyl) acetamide hydrochloride and subjected to deiodination reaction to finally obtain a target product of frabinan, the third route is that 3, 5-dichlorobenzoic acid is used as a starting material, the target product of frabinan is firstly esterified with methanol to obtain 3, 5-dichlorobenzoic acid methyl ester, then the target product of frabinan is reacted with trimethyl (trifluoromethyl) silane to obtain [1- (3, 5-dichlorophenyl) -2,2, 2-trifluoro-1-methoxyethoxy ] trimethylsilane, and then the intermediate is reacted with AK 4-acetyl-2-methylphenyl) acetamide to obtain 4- [5- (3, 5-dichlorophenyl) -5-trifluoromethyl-4, 5-dihydroisoxazol-3-yl ] -2-methylaniline, then 3- (4-bromo-3-methylphenyl) -5- (3, 5-dichlorophenyl) -5-trifluoromethyl-4, 5-dihydroisoxazole is obtained through diazotization reaction, then reacting with carbon monoxide to obtain 4- [5- (3, 5-dichlorophenyl) -5-trifluoromethyl-4, 5-dihydro-iso-claim oxazol-3-yl ] -2-methylbenzoic acid, and finally reacting with 2-amino-AK 2,2, 2-trifluoroethyl) acetamide to obtain the final product of the frailamide, wherein the first route has the problem of high preparation price, the second route has high preparation price and lower dipolar addition yield of key steps, the third route needs gas CO to participate, and the reaction conditions are harsh. The above routes are not suitable for industrial production.
CN109879826, CN111675667 and CN112457267 all refer to that 4-formyl-2-methylbenzoic acid is used as a raw material, and the flularnine is obtained through oximation, substitution, condensation and ring closure reaction, but in the key step and the ring closure reaction, the problem of low yield exists.
In addition, the existing synthesis process also comprises the steps of taking 4-bromo-2-methylbenzoic acid as a raw material, obtaining 4-acetyl-2-methylbenzoic acid through Suzuki coupling reaction, and preparing the flurarana through condensation, dehydration and cyclization, but the problems of high economic cost, long reaction time and the like exist.
Disclosure of Invention
The purpose of the invention is as follows: in order to solve the problems in the prior art, the invention provides a synthesis method of flurarana, which reduces the reaction cost, improves the yield and shortens the reaction period.
The technical scheme is as follows: the synthesis method of the fraxidin comprises the following steps:
(S1): 4-bromo-2-methyl-benzoic acid is subjected to Suzuki coupling reaction to obtain 4-acetyl-2-methyl benzoic acid, and the used catalyst is palladium acetate and 1, 3-bis (diphenylphosphino) propane in a molar ratio of 1: 2-4;
(S2): heating 4-acetyl-2-methylbenzoic acid (intermediate 1) and 3, 5-dichloro-trifluoro acetophenone (compound 2) to condense under alkaline condition to prepare 4- (3- (3, 5-dichlorophenyl) -4,4, 4-trifluoro-3-hydroxybutyl) -benzoic acid (intermediate 3);
(S3): 4- (3- (3, 5-dichlorophenyl) -4,4, 4-trifluoro-3-hydroxybutyl) -benzoic acid (intermediate 3) and triethylamine form triethylamine salt, and the triethylamine salt is dehydrated under the catalysis of DMAP to form 4- (3- (3, 5-dichlorophenyl) -4,4, 4-trifluoro-2-enol) -benzoic acid (intermediate 4);
(S4): preparation of 4- (5- (3, 5-dichlorophenyl) -5- (trifluoromethyl) -3- (4, 5-dihydroisothiazolyl)) -benzoic acid (intermediate 5) from 4- (3- (3, 5-dichlorophenyl) -4,4, 4-trifluoro-2-enol) -benzoic acid (intermediate 4) with tetrabutylammonium bromide, sodium hydroxide and hydroxylamine hydrochloride;
(S5): after 4- (5- (3, 5-dichlorophenyl) -5- (trifluoromethyl) -3-isoxazolyl) -benzoic acid (intermediate 5) forms acyl chloride with thionyl chloride, under the oxygen-free condition and the alkaline condition, the 4- (5- (3, 5-dichlorophenyl) -5- (trifluoromethyl) -3-isoxazolyl) -benzoic acid and 2-amino-N- (2,2, 2-trifluoroethyl) acetamide (compound 6) are synthesized into the flurarana (compound 7).
In a preferred embodiment of the present invention, the steps (S1) and (S2) are a continuous feeding step, and the steps (S3) and (S4) are continuous feeding, which shortens the reaction time of the whole process, reduces the time cost of the post-treatment and the intermediate loss of the target compound, improves the yield, and is suitable for industrial production.
As a preferred embodiment of the present invention, in the step (S1), the molar ratio of the 4-bromo-2-methyl-benzoic acid to the palladium catalyst is 1: 0.007-0.0085.
As a preferred embodiment of the present invention, the molar ratio of 4-bromo-2-methyl-benzoic acid to palladium catalyst is 1: 0.0075-0.008.
As a preferred embodiment of the present invention, the molar ratio of 4-bromo-2-methyl-benzoic acid to palladium catalyst is 1: 0.0076-0.0078.
In a preferred embodiment of the present invention, the molar ratio of the palladium acid to 1, 3-bis (diphenylphosphino) propane is 1:4.
In a preferred embodiment of the present invention, in the step (S1), the molar ratio of 1:4.8 to 5:0.03 to 0.032: 0.0075-0.008: 1.65-1.7 of 4-bromo-2-methyl-benzoic acid, n-butyl vinyl ether, 1, 3-bis (diphenylphosphino) propane, palladium acetate and potassium carbonate, adding n-butyl alcohol, replacing with nitrogen for 2-3 times, heating to 85-95 ℃, refluxing for 8-10 h, stopping heating, cooling to room temperature, and purifying a reaction product.
In the step (S1), the method for purifying the reaction product comprises: adding water and concentrated hydrochloric acid into the reaction product to adjust the pH value to 1-2, extracting with ethyl acetate, washing the organic phase with water, washing with saturated sodium chloride aqueous solution, filtering with kieselguhr, drying with anhydrous sodium sulfate, and spin-drying.
In a preferred embodiment of the present invention, in the step (S2), the 4-acetyl-2-methylbenzoic acid, the 3, 5-dichloro-trifluoroacetophenone, the sodium laurate, the potassium carbonate and the mixture are uniformly mixed, and stirred and reacted at a temperature of 55 to 65 ℃ for 20 to 24 hours, wherein a molar ratio of the 4-acetyl-2-methylbenzoic acid to water is 1:0.2 to 0.5.
As a preferred embodiment of the present invention, in the step (S2), 4-acetyl-2-methylbenzoic acid, 3, 5-dichloro-trifluoroacetophenone, sodium metasilicate, potassium carbonate, and water are mixed in a molar ratio of 1: 0.06-0.07: 1.5-1.6: 0.2-0.5, stirring and reacting at the temperature of 55-65 ℃ for 20-24 hours to obtain a reactant in a slightly white mud shape, and purifying the obtained product to obtain a slightly yellow solid.
As a preferred embodiment of the present invention, in the step (S2), the molar ratio of 4-acetyl-2-methylbenzoic acid, 3, 5-dichloro-trifluoroacetophenone, sodium metasilicate, potassium carbonate, and water is 1: 0.06-0.07: 1.5-1.6: 0.2 to 0.3.
As a preferred embodiment of the present invention, in the step (S2), the purification method is: adding water into the slightly white mud-shaped reactant, adjusting the pH value to 1-2 by concentrated hydrochloric acid, extracting by ethyl acetate, drying by anhydrous sodium sulfate, and purifying by column chromatography.
In a preferred embodiment of the present invention, in the step (S3), the molar ratio of 4- (3- (3, 5-dichlorophenyl) -4,4, 4-trifluoro-3-hydroxybutyl) -benzoic acid to triethylamine is 1:5 to 6.
In a preferred embodiment of the present invention, in the step (S3), the reaction condition of the dehydration is that triethylamine salt is dissolved in an organic solvent, 4-dimethylaminopyridine is added, the temperature is raised to 55 to 65 ℃, acetic anhydride is added dropwise, after the dropwise addition, the temperature is raised to 75 to 85 ℃, and the stirring reaction is performed for 5.5 to 6.5 hours.
In a preferred embodiment of the present invention, in the step (S3), the molar ratio of the 4- (3- (3, 5-dichlorophenyl) -4,4, 4-trifluoro-3-hydroxybutyl) -benzoic acid, the 4-dimethylaminopyridine and the acetic anhydride is 1 to 1.2:0.2 to 0.3:4 to 4.5.
In a preferred embodiment of the present invention, in step (S3), 4- (3- (3, 5-dichlorophenyl) -4,4, 4-trifluoro-3-hydroxybutyl) -benzoic acid is dissolved in dichloromethane, triethylamine is added with stirring to react at room temperature for 0.5 to 1 hour, then the reaction solution is dried by spinning to obtain triethylamine salt, toluene and 4-dimethylaminopyridine are added to the triethylamine salt and heated to 55 to 65 ℃, acetic anhydride is added dropwise, after the dropwise addition, the temperature is raised to 75 to 85 ℃, the stirring is carried out for 5.5 to 6.5 hours, and the completion of the reaction is monitored.
In a preferred embodiment of the present invention, in the step (S4), the molar ratio of 4- (3- (3, 5-dichlorophenyl) -4,4, 4-trifluoro-2-enol) -benzoic acid, tetrabutylammonium bromide, sodium hydroxide and hydroxylamine hydrochloride is 1:0.3 to 0.4:4.5 to 5.5:2 to 3.
In a preferred embodiment of the present invention, in the step (S4), the reaction is performed under stirring at room temperature for 12 to 24 hours.
In a preferred embodiment of the present invention, the reaction time in step (S5) is 5 to 6 hours.
In a preferred embodiment of the present invention, in step (S5), 4- (5- (3, 5-dichlorophenyl) -5- (trifluoromethyl) -3-isoxazolyl) -benzoic acid is dissolved in benzene, thionyl chloride is added, the mixture is refluxed for 4 to 6 hours, and after the reaction is completed, the reaction product is dried by spinning to obtain a reaction product intermediate 0; under the protection of nitrogen, dissolving 2-amino-N- (2,2, 2-trifluoroethyl) acetamide in dichloromethane, adding triethylamine at 0 ℃, stirring for 5-10 min, dropwise adding the intermediate 0 dissolved in dichloromethane, keeping for 5-10 min after dropwise adding is finished, removing an ice bath, reacting at room temperature for 5-6 h, monitoring the reaction, drying by spinning, and carrying out column chromatography.
Has the advantages that: (1) the invention adjusts the dosage of the catalyst, and reduces the production cost while ensuring the yield and the production efficiency; (2) the present invention increases the heating temperature in step S3 to shorten the reaction time; (3) the steps S1 and S2 can be continuously fed, and the steps S3 and S4 can be continuously fed, so that the reaction time of the whole process is shortened, the time cost of post-treatment and the intermediate loss of a target compound are reduced, the yield is improved, and the method is suitable for industrial production; (4) the synthesis method of the invention improves economic benefits, reduces reagent dosage and increases reaction safety.
Detailed Description
The benefits of the present invention will now be illustrated by the following detailed description, and variations and modifications as would be apparent to a person of ordinary skill in the art, given the benefit of this disclosure, are also within the scope of the present invention.
Example 1: preparation of 4-acetyl-2-methylbenzoic acid (intermediate 1)
4-bromo-2-methyl-benzoic acid (Compound 0) (0.2)77g, 1.29mmol), n-butyl vinyl ether (0.83 mL, 6.42mmol), 1, 3-bis (diphenylphosphino) propane (0.17g, 0.04mmol), palladium acetate (0.0023g, 0.01mmol), potassium carbonate (0.3g, 2.17mmol) were added to a bottle, 10mL of n-butanol was added, 3 times with nitrogen substitution, heating was controlled at 90 ℃ and refluxing was carried out for 9 to 10 hours, the reaction of the starting materials was completed, heating was stopped, cooling was carried out to room temperature, water and concentrated hydrochloric acid were added to adjust pH to 1-2, ethyl acetate was extracted, the organic phase was washed with water, a saturated aqueous sodium chloride solution, filtered with celite, dried over anhydrous sodium sulfate, and spin-dried. 0.263g of compound 1 are obtained in the form of a yellow solid with a yield of 95%.1HNMR(300MHz,CDCl3)δ8.17(d,J=7.9Hz,1H),7.88(d,J=8.4Hz,2H),2.72(d, J=19.4Hz,6H).
Example 2: preparation of 4- (3- (3, 5-dichlorophenyl) -4,4, 4-trifluoro-3-hydroxybutyl) -benzoic acid (intermediate 3)
Compound 1(0.5g, 2.8mmol), compound 2(0.68g, 2.8mmol), sodium metasilicate (0.04g, 0.18 mmol), potassium carbonate (0.6g, 4.34mmol), water (12mL, 0.66mol) were mixed well and stirred at 60 ℃ for 24h, at which time the reaction became a slightly white paste, water was added to the reaction solution, pH was adjusted to 1-2 with concentrated hydrochloric acid, extraction was performed with ethyl acetate, drying was performed with anhydrous sodium sulfate, purification was performed by column chromatography with mobile phases of Petroleum Ether (PE) and Ethyl Acetate (EA), (PE: ethyl acetate EA ═ 2:1, v: v), yielding 0.915g of a slightly yellow solid at a yield of 77.42%.
1HNMR(300MHz,CDCl3)δ8.21(d,J=8.3Hz,1H),7.87(d,J=7.5Hz,2H),7.55(d,J=1.8Hz,2H),7.41(d,J=1.8Hz,1H),5.64(s,1H),3.92(d,J=17.6Hz,1H),3.76(d,J=17.6 Hz,1H),2.78(s,3H).
Example 3: (1) preparation of 4- (3- (3, 5-dichlorophenyl) -4,4, 4-trifluoro-2-enol) -benzoic acid (intermediate 4)
Dissolving the compound 3(0.5g, 1.19mmol) in 20mL dichloromethane, adding triethylamine (0.62g, 6.12mmol) under stirring to react at room temperature for 1h, then spin-drying the reaction liquid to obtain triethylamine salt, adding toluene 20mL and 4-dimethylaminopyridine (0.03g, 0.24mmol) into the triethylamine salt, heating to 60 ℃, dropwise adding acetic anhydride (0.4mL, 4.2mmol), after dropwise adding, heating to 80 ℃, stirring for 6h, monitoring the reaction completion, cooling to room temperature, adding water, adjusting the pH to 1-2 with concentrated hydrochloric acid, extracting with EA, washing with water, washing with salt, drying with anhydrous sodium sulfate to obtain 0.405g yellow solid. The yield was 84.6%, and the next preparation was carried out.
Example 4: preparation of 4- (5- (3, 5-dichlorophenyl) -5- (trifluoromethyl) -3- (4, 5-dihydroisothiazolyl)) -benzoic acid (intermediate 5)
Step (1): 0.2g of sodium hydroxide and 0.17g of hydroxylamine hydrochloride are respectively prepared into solutions with mass concentration of 50%, and the solutions are cooled, mixed and cooled to room temperature for later use.
Step (2): adding compound 4(0.405g and 1mmol), tetrabutylammonium bromide (0.12g and 0.37mmol) into a two-neck flask, under the protection of nitrogen, injecting 20mL of toluene, stirring at 0 ℃ for 10min, dropwise adding the solution prepared in the step (1), stirring at room temperature overnight after dropwise adding, after the reaction is finished, adding water, adjusting the pH to 1-2 by using concentrated hydrochloric acid, extracting by EA, washing with water, drying, and performing column chromatography (PE: EA is 2:1) to obtain 0.42g of yellow solid with the yield of 84.6%.
1HNMR(300MHz,CDCl3)δ7.97(d,J=8.1Hz,1H),7.59(d,J=18.9Hz,2H),7.45(d,J= 18.7Hz,1H),7.37(s,1H),7.18~7.12(m,1H),4.14(dd,J=15.6,7.1Hz,1H),3.76(d,J=17.4 Hz,1H),2.72(s,1H),2.63(s,2H).
In order to shorten the reaction period, the intermediate 4 of the present invention is not subjected to a purification operation, and the reaction of the intermediates 3 to 5 is subjected to a continuous feeding operation: the method comprises the following specific steps:
step (1): 0.2g of sodium hydroxide and 0.17g of hydroxylamine hydrochloride are respectively prepared into solutions with mass concentration of 50%, and the solutions are cooled, mixed and cooled to room temperature for later use.
Step (2): dissolving a compound 3(0.5g, 1.19mmol) in 20mL of dichloromethane, adding triethylamine (0.62g, 6.12mmol) under stirring to react at room temperature for 1h, then evaporating the reaction liquid to dryness to obtain triethylamine salt, adding 20mL of toluene and 4-dimethylaminopyridine (0.03g, 0.24mmol) into the triethylamine salt under nitrogen protection, heating to 60 ℃, dropwise adding acetic anhydride (0.4mL, 4.2mmol), after dropwise adding, heating to 80 ℃, stirring for 6h, monitoring the reaction completion, cooling to room temperature, adding tetrabutylammonium bromide (0.12g, 0.37mmol) at 0 ℃, stirring for 10min, dropwise adding the solution prepared in the step (1), after dropwise adding, stirring at room temperature overnight, after the reaction is completed, adding water, adjusting the pH to 1-2 with concentrated hydrochloric acid, EA extracting, washing with water, drying, carrying out column chromatography (PE: EA: 2:1, v: v) to obtain a yellow solid, and verifying the product to be an intermediate 5 by a nuclear magnetic spectrum, the yields were comparable to those obtained in example 4, indicating that intermediate 3 to intermediate 5 of the present invention can be administered directly in succession.
Example 5: preparation of flurarana (Compound 7)
Dissolving the compound 5(0.42g, 1mmol) in 20mL of benzene, adding thionyl chloride (0.33g, 2.8mmol), heating and refluxing at 85 ℃ for reaction for 5h, and after the reaction is completed, spin-drying to obtain an intermediate 0.
Under nitrogen protection, compound 6(0.18g, 1.2mmol) was dissolved in 10mL of dichloromethane, triethylamine (0.13g, 1.3mmol) was added at 0 ℃, the mixture was stirred for 10min, intermediate 0(0.47g) obtained in step (1) dissolved in 5mL of dichloromethane was added dropwise, after completion of the dropwise addition, the mixture was kept for 10min, the ice bath was removed, the reaction was carried out at room temperature for 5h, and after completion of the reaction was monitored, the mixture was spin-dried and subjected to column chromatography (PE: EA ═ 2.5:1) to obtain 0.465g of a yellowish solid. The yield was 85.73%.
1HNMR(300MHz,DMSO~d6)δ8.65(dt,J=6.5,3.6Hz,2H),7.84(d,J=1.9Hz,1H), 7.70~7.56(m,4H),7.53(d,J=8.4Hz,1H),4.43(d,J=18.4Hz,1H),4.33(d,J=18.5Hz,1H), 4.11–3.87(m,4H),2.43(s,3H) 。
Claims (10)
1. A synthetic method of flurarana is characterized by comprising the following steps:
(S1): 4-bromo-2-methyl-benzoic acid is subjected to Suzuki coupling reaction to obtain 4-acetyl-2-methyl benzoic acid, and the used catalyst is palladium acetate and 1, 3-bis (diphenylphosphino) propane in a molar ratio of 1: 2-4;
(S2): heating 4-acetyl-2-methylbenzoic acid and 3, 5-dichloro-trifluoro acetophenone for condensation under alkaline condition to prepare 4- (3- (3, 5-dichlorophenyl) -4,4, 4-trifluoro-3-hydroxybutyl) -benzoic acid;
(S3): 4- (3- (3, 5-dichlorophenyl) -4,4, 4-trifluoro-3-hydroxybutyl) -benzoic acid and triethylamine form triethylamine salt, and the triethylamine salt is dehydrated under the catalysis of DMAP to form 4- (3- (3, 5-dichlorophenyl) -4,4, 4-trifluoro-2-enol) -benzoic acid;
(S4): preparing 4- (5- (3, 5-dichlorophenyl) -5- (trifluoromethyl) -3- (4, 5-dihydroisothiazolyl)) -benzoic acid from 4- (3- (3, 5-dichlorophenyl) -4,4, 4-trifluoro-2-enol) -benzoic acid with tetrabutylammonium bromide, sodium hydroxide and hydroxylamine hydrochloride;
(S5): after 4- (5- (3, 5-dichlorophenyl) -5- (trifluoromethyl) -3-isoxazolyl) -benzoic acid and thionyl chloride form acyl chloride, the acyl chloride and 2-amino-N- (2,2, 2-trifluoroethyl) acetamide are synthesized into the flurara sodium under the anaerobic condition and the alkaline condition.
2. The method for synthesizing fraxidin according to claim 1, wherein in step (S1), the molar ratio of 4-bromo-2-methyl-benzoic acid to palladium catalyst is 1: 0.007-0.0085.
3. The method of synthesizing fraxidin according to claim 2, wherein the molar ratio of 4-bromo-2-methyl-benzoic acid to palladium catalyst is 1: 0.0075-0.008.
4. The method for synthesizing flurarana as claimed in claim 1, wherein in the step (S2), the 4-acetyl-2-methylbenzoic acid, 3, 5-dichloro-trifluoro acetophenone, sodium metasilicate, potassium carbonate and the mixture are uniformly mixed and stirred to react for 20-24 h at 55-65 ℃, and the molar ratio of the 4-acetyl-2-methylbenzoic acid to water is 1: 0.2-0.5.
5. The method for synthesizing fraxidin according to claim 1, wherein in step (S3), the molar ratio of 4- (3- (3, 5-dichlorophenyl) -4,4, 4-trifluoro-3-hydroxybutyl) -benzoic acid to triethylamine is 1: 5-6.
6. The method for synthesizing fraxidin according to claim 1, wherein in the step (S3), the dehydration reaction is performed under the conditions that triethylamine salt is dissolved in an organic solvent, 4-dimethylaminopyridine is added, the temperature is raised to 55-65 ℃, acetic anhydride is added dropwise, the temperature is raised to 75-85 ℃ after the dropwise addition, and the stirring reaction is performed for 5.5-6.5 hours.
7. The method for synthesizing frasnarinin according to claim 6, wherein the molar ratio of 4- (3- (3, 5-dichlorophenyl) -4,4, 4-trifluoro-3-hydroxybutyl) -benzoic acid, 4-dimethylaminopyridine and acetic anhydride is 1-1.2: 0.2-0.3: 4-4.5.
8. The method for synthesizing fraxidin according to claim 1, wherein in step (S4), the molar ratio of 4- (3- (3, 5-dichlorophenyl) -4,4, 4-trifluoro-2-enol) -benzoic acid, tetrabutylammonium bromide, sodium hydroxide and hydroxylamine hydrochloride is 1: 0.3-0.4: 4.5-5.5: 2-3.
9. The method for synthesizing frainer as claimed in claim 8, wherein in the step (S4), the reaction is carried out under stirring at room temperature for 12-24 h.
10. The method for synthesizing frainer as claimed in claim 1, wherein the reaction time in step (S5) is 5-6 hours.
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