CN115974727B - Synthesis method of bifenazate - Google Patents
Synthesis method of bifenazate Download PDFInfo
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- CN115974727B CN115974727B CN202310059792.9A CN202310059792A CN115974727B CN 115974727 B CN115974727 B CN 115974727B CN 202310059792 A CN202310059792 A CN 202310059792A CN 115974727 B CN115974727 B CN 115974727B
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- bifenazate
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- hydroxybiphenyl
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- 239000005653 Bifenazate Substances 0.000 title claims abstract description 39
- VHLKTXFWDRXILV-UHFFFAOYSA-N bifenazate Chemical compound C1=C(NNC(=O)OC(C)C)C(OC)=CC=C1C1=CC=CC=C1 VHLKTXFWDRXILV-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 238000001308 synthesis method Methods 0.000 title claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 64
- YXVFYQXJAXKLAK-UHFFFAOYSA-N biphenyl-4-ol Chemical group C1=CC(O)=CC=C1C1=CC=CC=C1 YXVFYQXJAXKLAK-UHFFFAOYSA-N 0.000 claims abstract description 44
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 39
- DZGMMVYPLBTLRQ-UHFFFAOYSA-N 2-bromo-4-phenylphenol Chemical group C1=C(Br)C(O)=CC=C1C1=CC=CC=C1 DZGMMVYPLBTLRQ-UHFFFAOYSA-N 0.000 claims abstract description 38
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims abstract description 32
- 238000001914 filtration Methods 0.000 claims abstract description 30
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims abstract description 17
- 238000001816 cooling Methods 0.000 claims abstract description 17
- 239000003960 organic solvent Substances 0.000 claims abstract description 16
- 238000001035 drying Methods 0.000 claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 13
- 239000003446 ligand Substances 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 13
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 12
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229910052802 copper Inorganic materials 0.000 claims abstract description 11
- 239000010949 copper Substances 0.000 claims abstract description 11
- PHHLRHSOQWTNBH-UHFFFAOYSA-N propan-2-yl n-aminocarbamate Chemical compound CC(C)OC(=O)NN PHHLRHSOQWTNBH-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000005859 coupling reaction Methods 0.000 claims abstract description 9
- 239000012065 filter cake Substances 0.000 claims abstract description 9
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims abstract description 8
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims abstract description 8
- 238000005406 washing Methods 0.000 claims abstract description 8
- 239000000706 filtrate Substances 0.000 claims abstract description 7
- 239000012074 organic phase Substances 0.000 claims abstract description 7
- 239000012299 nitrogen atmosphere Substances 0.000 claims abstract description 5
- 239000012022 methylating agents Substances 0.000 claims abstract description 4
- 150000003839 salts Chemical class 0.000 claims abstract description 4
- 239000004289 sodium hydrogen sulphite Substances 0.000 claims abstract description 4
- 238000001953 recrystallisation Methods 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 6
- 239000012295 chemical reaction liquid Substances 0.000 claims description 6
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 5
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 5
- 229910017053 inorganic salt Inorganic materials 0.000 claims description 5
- 239000013557 residual solvent Substances 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 4
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 claims description 4
- 238000006266 etherification reaction Methods 0.000 claims description 4
- 230000011987 methylation Effects 0.000 claims description 4
- 238000007069 methylation reaction Methods 0.000 claims description 4
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 3
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- 238000005893 bromination reaction Methods 0.000 claims description 3
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 3
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 3
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 3
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 claims description 3
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 claims description 3
- 229940045803 cuprous chloride Drugs 0.000 claims description 3
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 claims description 3
- 229940112669 cuprous oxide Drugs 0.000 claims description 3
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 3
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 3
- 235000011009 potassium phosphates Nutrition 0.000 claims description 3
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- 238000011534 incubation Methods 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 24
- 230000015572 biosynthetic process Effects 0.000 abstract description 19
- 238000003786 synthesis reaction Methods 0.000 abstract description 19
- 238000010168 coupling process Methods 0.000 abstract description 7
- 230000008878 coupling Effects 0.000 abstract description 6
- 238000004537 pulping Methods 0.000 abstract description 5
- 239000000575 pesticide Substances 0.000 abstract description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 18
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 8
- 239000002994 raw material Substances 0.000 description 8
- 239000012535 impurity Substances 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 238000010189 synthetic method Methods 0.000 description 6
- QJGJVVIDRMVQMR-UHFFFAOYSA-N 2-bromo-1-methoxy-4-phenylbenzene Chemical group C1=C(Br)C(OC)=CC=C1C1=CC=CC=C1 QJGJVVIDRMVQMR-UHFFFAOYSA-N 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 230000000895 acaricidal effect Effects 0.000 description 3
- 239000000642 acaricide Substances 0.000 description 3
- -1 biphenyl hydrazine ester Chemical class 0.000 description 3
- 238000011033 desalting Methods 0.000 description 3
- 230000002147 killing effect Effects 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 description 3
- 238000004321 preservation Methods 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 241000238876 Acari Species 0.000 description 2
- 229910015900 BF3 Inorganic materials 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 241000488583 Panonychus ulmi Species 0.000 description 2
- 241001454295 Tetranychidae Species 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000006198 methoxylation reaction Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 240000009088 Fragaria x ananassa Species 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 230000002862 amidating effect Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- QYCSNMDOZNUZIT-UHFFFAOYSA-N benzhydrylidenehydrazine Chemical compound C=1C=CC=CC=1C(=NN)C1=CC=CC=C1 QYCSNMDOZNUZIT-UHFFFAOYSA-N 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 238000006193 diazotization reaction Methods 0.000 description 1
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 150000002429 hydrazines Chemical class 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 239000010805 inorganic waste Substances 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000003151 ovacidal effect Effects 0.000 description 1
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 229940067157 phenylhydrazine Drugs 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 235000021012 strawberries Nutrition 0.000 description 1
Abstract
The invention belongs to the technical field of pesticide synthesis, and relates to a method for synthesizing bifenazate, which comprises the following steps: adding 4-hydroxylbiphenyl into an organic solvent, adding hydrobromic acid and hydrogen peroxide for reaction, standing, adding sodium bisulphite solution into an organic phase for washing, concentrating, crystallizing, filtering and drying to obtain 3-bromo-4-hydroxylbiphenyl; reacting the prepared 3-bromo-4-hydroxybiphenyl with isopropyl hydrazinoformate, a copper catalyst, a ligand, a base and an organic solvent in a nitrogen atmosphere; and dropwise adding a methylating agent for reaction, cooling after the reaction is finished, filtering to remove salt, decompressing and desolventizing filtrate, adding water for pulping, filtering, adding toluene into a filter cake for recrystallization, and thus obtaining the bifenazate. The synthesis method of bifenazate provided by the invention uses a direct coupling route in a breakthrough manner, greatly reduces reaction steps, improves the product yield, greatly improves the productivity due to the reduction of reaction operation, and has remarkable advantages and practical values.
Description
Technical Field
The invention belongs to the technical field of pesticide synthesis, and particularly relates to a synthesis method of bifenazate.
Background
Bifenazate (bifenazate) is a selective foliar spray acaricide, is effective in killing mites in various life stages, has ovicidal activity and knockdown activity on adult mites, has long lasting period, is effective in killing spider mites, panonychus ulmi, and the like, and has contact killing effect; the acaricide has no cross resistance with the existing commercial acaricide, can be used for controlling spider mites and panonychus ulmi, strawberries and other crops, has low toxicity and is environment-friendly. At present, a plurality of synthesis methods of bifenazate are reported, and the synthesis methods mainly comprise the following synthesis routes:
in the scheme 1, 4-hydroxy biphenyl reacts with isopropyl azodicarboxylate, and biphenyl hydrazine ester is obtained through hydrolysis decarboxylation and methoxylation reaction. Although the steps of the route are shorter, the defects are obvious, isopropyl azodicarboxylate and boron trifluoride which are more expensive are needed, the boron trifluoride is difficult to recover, and the pollution is large; alkaline hydrolysis takes 4 days, and has poor selectivity and low yield.
Coupling 3-bromo-4-methoxybiphenyl and benzophenone hydrazone under the catalysis of palladium acetate, and then carrying out acid hydrolysis to obtain hydrazine salt, and amidating to obtain a target product. The coupling reaction and the hydrolysis reaction are difficult due to the large steric hindrance of the benzhydryl reaction, and the industrialization is difficult to realize due to the expensive palladium catalyst.
In the scheme 3, 4-hydroxy biphenyl is used as a starting material, and target product biphenyl hydrazine ester is obtained through nitration, methoxylation, nitroreduction, diazotization addition, azo reduction and amidation reaction. The method has the advantages of easily obtained raw materials, mild reaction conditions and high yield, and is a method for production and use in the existing factories. The greatest disadvantage of the route is that a large amount of inorganic waste salt can be generated, the productivity is low, and the method is not in accordance with the energy-saving and environment-friendly time requirements advocated at present.
Scheme 4, using 4-halophenol or 5-halo-2-methoxy aniline as starting material, synthesizing 2- (5-halo-2-methoxy phenyl) hydrazine-1-formic acid isopropyl ester, and then coupling by Suzuki to obtain the target product. This route, while inexpensive as a starting material for the previous step, requires expensive phenylboronic acid (ester) and palladium catalyst for the final step, which increases the cost significantly.
From the above routes, it can be seen that the key step in synthesizing the target product is the synthesis of amine and hydrazine on benzene ring, and the direct coupling is the best method from the aspects of atom economy and operation simplicity, but the direct coupling method of the above route 1 and route 2 has respective problems and defects. Therefore, there is a need to develop a new synthetic method of bifenazate.
Disclosure of Invention
The invention aims to solve the problems in the prior art, and provides a synthesis method of bifenazate, which comprises three reaction steps of bromination, coupling and etherification, has the advantages of less steps, high yield, low cost and the like, and is favorable for industrial production of the bifenazate.
The technical scheme of the invention is as follows:
a synthetic method of bifenazate comprises the following steps:
(1) Bromination reaction: adding 4-hydroxylbiphenyl into an organic solvent, wherein the molar ratio of the 4-hydroxylbiphenyl to hydrobromic acid to hydrogen peroxide is 1: (1-5): adding hydrobromic acid and hydrogen peroxide in the proportion of (1-3), setting the reaction temperature to be-10-50 ℃, preserving the heat for 2.5-3.5 h, standing after the reaction is finished, adding sodium bisulphite solution into an organic phase for washing, concentrating, crystallizing, filtering and drying to obtain 3-bromo-4-hydroxybiphenyl;
the molar ratio of the 4-hydroxybiphenyl to hydrobromic acid to hydrogen peroxide is 1: (1-5): any ratio within the range of (1-3), for example, may be 1:1:1, 1:1.5:1.3, 1:2:1, 1:3:2, 1:2:1.5, 1:1.5:1.5, 1:2:2, 1:3:3, 1:4:3, 1:5:3, etc., but is not limited to the recited values, as are other non-recited values within the range.
The reaction temperature is-10℃to 50℃and may be, for example, -10℃and-5℃and 0℃and 3℃and 5℃and 10℃and 15℃and 20℃and 25℃and 30℃and 40℃and 50℃respectively, but the reaction temperature is not limited to the values recited above, and other values not recited in the above range are similarly applicable.
The holding time is 2.5 to 3.5 hours, and may be, for example, 2.5 hours, 2.7 hours, 2.9 hours, 3 hours, 3.2 hours, 3.3 hours, 3.5 hours, etc., but not limited to the values recited, and other values not recited in the above range are equally applicable.
(2) Coupling reaction: the prepared 3-bromo-4-hydroxybiphenyl reacts with isopropyl hydrazinoformate, copper catalyst, ligand, alkali and organic solvent for 3.5 to 4.5 hours at 80 to 85 ℃ in nitrogen atmosphere;
the reaction temperature may be any value within the range of 80 to 85 ℃, for example, 80 ℃, 81 ℃, 82 ℃, 83 ℃, 84 ℃, 85 ℃, or the like, but is not limited to the values recited, and other values not recited in the range are equally applicable.
The reaction time may be any value within the range of 3.5 to 4.5 hours, for example, 3.5 hours, 3.6 hours, 3.7 hours, 3.8 hours, 3.9 hours, 4 hours, 4.1 hours, 4.2 hours, 4.3 hours, 4.4 hours, 4.5 hours, etc., but the reaction time is not limited to the recited value, and other values not recited in the range are equally applicable.
(3) Etherification reaction: cooling the reaction liquid in the step (2) to 60-65 ℃, maintaining nitrogen atmosphere, dropwise adding a methylation reagent, preserving heat for reaction for 1.5-2.5 h after dropwise adding, cooling, filtering to remove salt after the reaction is finished, decompressing and desolventizing filtrate until a large amount of solids are separated out, adding water to pulp and remove residual solvent and inorganic salt, filtering again, adding toluene into a filter cake for recrystallization, and obtaining the bifenazate.
The temperature may be any value within the range of 60 to 65 ℃, for example, 60 ℃, 61 ℃, 62 ℃, 63 ℃, 64 ℃, 65 ℃ and the like, but is not limited to the values recited, and other values not recited in the range are equally applicable.
The reaction time may be any one of the values within the range of 1.5 to 2.5 hours, for example, 1.5 hours, 1.6 hours, 1.7 hours, 1.8 hours, 1.9 hours, 2 hours, 2.1 hours, 2.2 hours, 2.3 hours, 2.4 hours, 2.5 hours, etc., but the present invention is not limited to the above-mentioned values, and other values not mentioned within the range are equally applicable.
Further, the organic solvent in the step (1) is dichloromethane or dichloroethane, and the weight ratio of the organic solvent to the 4-hydroxydiphenyl is (2-8): 1.
the weight ratio of the organic solvent to the 4-hydroxydiphenyl is (2-8): any ratio within the range of 1, for example, may be 2:1, 2.5:1, 3:1, 3.7:1, 4:1, 4.2:1, 5:1, 5.5:1, 6:1, 6.3:1, 7:1, 7.5:1, 8:1, etc., but is not limited to the recited values, as other non-recited values within the range are equally applicable.
Further, in the step (1), the molar ratio of the 4-hydroxybiphenyl, hydrobromic acid and hydrogen peroxide is 1:3:2, the hydrobromic acid added is 40 percent hydrobromic acid, and the concentration of hydrogen peroxide is 20 to 50 percent.
The concentration of the hydrogen peroxide can be 20%, 30%, 40%, 50%, etc., and other values not listed in the range of 20% -50% are applicable.
Further, the reaction temperature in the step (1) is 0-5 ℃, and the heat preservation time is 3 hours.
Further, the molar ratio of isopropyl carbazate to 3-bromo-4-hydroxybiphenyl in the step (2) is (1-3): 1, a step of; for example, it may be 1:1, 1.5:1, 2:1, 2.5:1, 3:1, etc., but is not limited to the recited values, and other values not recited in this range are equally applicable.
Further, the molar ratio of the copper catalyst to the 3-bromo-4-hydroxybiphenyl in the step (2) is (0.001 to 0.1): 1, the copper catalyst is one or more of cuprous chloride, cuprous bromide, cuprous iodide or cuprous oxide.
The molar ratio of the copper catalyst to the 3-bromo-4-hydroxybiphenyl is (0.001 to 0.1): any ratio within the range of 1 may be, for example, 0.001:1, 0.003:1, 0.005:1, 0.01:1, 0.015:1, 0.02:1, 0.03:1, 0.05:1, 0.08:1, 0.1:1, etc., but is not limited to the recited values, as are other non-recited values within the range.
Further, the molar ratio of the base to the 3-bromo-4-hydroxybiphenyl in the step (2) is (2 to 5): 1, wherein the alkali is one or more of sodium carbonate, potassium phosphate and cesium carbonate.
The molar ratio of the alkali to the 3-bromo-4-hydroxybiphenyl is (2-5): any ratio within the range of 1, for example, may be 2:1, 2.3:1, 2.5:1, 2.7:1, 3:1, 3.5:1, 4:1, 4.5:1, 5:1, etc., but is not limited to the recited values, as other non-recited values within the range are equally applicable.
Further, the molar ratio of the ligand to the copper catalyst in the step (2) is (1-2): 1, wherein the ligand is one or more of L1-L10;
the molar ratio of the ligand to the copper catalyst is (1-2): any ratio within the range of 1, for example, may be 1:1, 1.1:1, 1.2:1, 1.3:1, 1.5:1, 1.7:1, 1.8:1, 2:1, etc., but is not limited to the recited values, as other non-recited values within the range are equally applicable.
Further, the weight ratio of the organic solvent to the 3-bromo-4-hydroxydiphenyl in the step (2) is (3-10): 1, the organic solvent is one or more of dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile and dioxane.
The weight ratio of the organic solvent to the 3-bromo-4-hydroxydiphenyl is (3-10): any ratio within the 1 range may be, for example, 3:1, 3.5:1, 4:1, 4.5:1, 5:1, 6:1, 6.5:1, 7:1, 8:1, 9:1, 10:1, etc., but is not limited to the recited values, as other non-recited values within the range are equally applicable.
Further, the molar ratio of the methylating agent to 3-bromo-4-hydroxybiphenyl in step (3) (0.8 to 2): 1, the methylation reagent comprises one or more of dimethyl sulfate, methyl iodide and dimethyl carbonate.
The molar ratio of the methylating agent to 3-bromo-4-hydroxybiphenyl is (0.8-2): any ratio within the range of 1, for example, may be 0.8:1, 0.9:1, 1:1, 1.2:1, 1.3:1, 1.5:1, 1.7:1, 1.8:1, 2:1, etc., but is not limited to the recited values, as other non-recited values within the range are equally applicable.
Further, after the etherification reaction in the step (3) is finished, the temperature is reduced to 20-40 ℃ and then the filtration is carried out.
The above temperature is preferably from 20 to 40℃and room temperature is preferably 25℃and may be from 20℃to 22℃to 24℃to 27℃to 28℃to 30℃to 35℃to 40℃and other values not shown in the range of from 20 to 40℃are similarly applicable.
Further, the amount of toluene added in the step (3) is 2-5 times of the dry weight of the filter cake.
The weight ratio is in the range of 2 to 5 times, and may be, for example, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 5 times, etc., but is not limited to the values recited, and other values not recited in the range are equally applicable.
The invention has the beneficial effects that:
the synthesis method of bifenazate provided by the invention uses a direct coupling route in a breakthrough manner, greatly reduces reaction steps, improves the product yield, greatly improves the productivity due to the reduction of reaction operation, and has remarkable advantages and practical values.
Detailed Description
For a further understanding of the present invention, the technical aspects of the present invention will be clearly and fully described in connection with the following embodiments, and it is apparent that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
A synthetic method of bifenazate comprises the following steps:
step (1): synthesis of 3-bromo-4-hydroxybiphenyl
Adding 50g of 4-hydroxybiphenyl, 250g of methylene dichloride and 89.1g of 40% hydrobromic acid into a 500mL three-port bottle, stirring, then cooling to 0-5 ℃, dropwise adding 43.3g of 30% hydrogen peroxide at the temperature of 0-5 ℃, after the dropwise adding is completed, carrying out heat preservation reaction for 3 hours, detecting the contents of a product, the raw material and impurities 1a to judge the reaction completion condition, standing and separating liquid after the reaction is completed, adding 50mL of 5% sodium bisulphite into a lower organic phase, washing, concentrating and crystallizing, filtering and drying to obtain a product 1, namely 3-bromo-4-hydroxybiphenyl;
64.4g of 3-bromo-4-hydroxybiphenyl is synthesized, the yield is 86.9%, and the purity is 98.8%.
Step (2): synthesis of isopropyl 2- [3- (4-hydroxybiphenyl) ] -hydrazino-1-carboxylate
50g of 3-bromo-4-hydroxybiphenyl, 300g of N, N-dimethylformamide, 69.4g of potassium carbonate, 28.5g of isopropyl hydrazinoformate, 0.38g of cuprous iodide and 10.41g of ligand L are added into a 500mL three-necked flask, nitrogen is added for protection, the temperature is raised to 80-85 ℃ for reaction for 4 hours, and the product 2, namely the 2- [3- (4-hydroxybiphenyl) ] -hydrazino-1-isopropyl formate is obtained, and the purity of the reaction liquid is 91.3%.
Step (3): synthesis of biphenylhydrazine esters
Cooling the reaction solution in the step (2) to 60-65 ℃, keeping nitrogen protection, dropwise adding 25.3g of dimethyl sulfate, keeping the temperature for reaction for 2 hours, and detecting the contents of a product 3, a raw material 2, impurities 3a+3b+3c, impurities 4a and impurities 4b to judge the completion condition of the reaction;
cooling the reaction solution after the reaction to room temperature, filtering, decompressing and desolventizing the filtrate, cooling to room temperature, adding water, pulping for 1 hour, filtering, adding 110g of toluene to 80 ℃ for drying about 55g of filter cake, standing to separate out the lower water after the reaction solution is completely dissolved, cooling and crystallizing the toluene phase, filtering and drying to obtain a yellowish product, namely the bifenazate;
43.1g of bifenazate is synthesized, the purity is 99.2%, the external standard content is 98.7%, and the yield of two steps of the step (2) and the step (3) is 75.0%.
Comparative example 1
Step (1): synthesis of 3-bromo-4-hydroxybiphenyl
Adding 50g of 4-hydroxybiphenyl, 250g of dichloroethane and 118.8g of 40% hydrobromic acid into a 500mL three-port bottle, stirring, cooling to 0-5 ℃, dropwise adding 50g of 30% hydrogen peroxide at the temperature of 0-5 ℃, after the dropwise adding is completed, dropwise adding, carrying out heat preservation reaction for 3 hours, detecting the contents of a product, the raw material and impurities 1a to judge the reaction completion condition, standing for separating liquid after the reaction is completed, adding 50mL of 5% sodium bisulfite into a lower organic layer, washing, concentrating and crystallizing, filtering and drying to obtain a product 1, namely 3-bromo-4-hydroxybiphenyl;
59.6g of 3-bromo-4-hydroxybiphenyl is synthesized, the yield is 81.4%, and the purity is 97.5%.
Step (2): synthesis of 3-bromo-4-methoxybiphenyl
50g of 3-bromo-4-hydroxybiphenyl and 250g of N, N-dimethylformamide are added into a 500mL three-necked flask, 55.5g of potassium carbonate is added in batches, then the temperature is slowly raised to 80 ℃, 50.6g of dimethyl sulfate is added dropwise, the thermal insulation reaction is completed for 2 hours, the solvent is distilled under reduced pressure, 300g of water is added, the temperature is kept at 80 ℃ for 1 hour, the pH value is regulated to be more than 11 by potassium hydroxide solution, and the product 4, namely 3-bromo-4-methoxybiphenyl, is obtained after cooling, filtering and drying;
51.7g of 3-bromo-4-methoxybiphenyl is detected, the yield is 98%, and the purity is 98.6%.
Step (3): synthesis of biphenylhydrazine esters
50g of 3-bromo-4-methoxybiphenyl, 300g of N, N-dimethylformamide, 65.7g of potassium carbonate, 26.9g of isopropyl hydrazinoformate, 0.36g of cuprous iodide and 10.39g of ligand L are added into a 500mL three-necked flask, nitrogen is added for protection, the temperature is raised to 80-85 ℃ for reaction for 4 hours, the content of a detected product 3 (namely phenylhydrazine ester) is 0.2%, the content of raw material 4 is 63.0%, the content of impurity 4a is 35.5%, and the content of impurity 4b is 0%;
from this, it was found that the synthetic route of comparative example 1 was not capable of producing bifenazate.
Example 2
A synthetic method of bifenazate comprises the following steps:
step (1): synthesis of 3-bromo-4-hydroxybiphenyl
Adding 50g of 4-hydroxybiphenyl, 250g of methylene dichloride and 178.3g of 40% hydrobromic acid into a three-port bottle, stirring, setting the reaction temperature to 20 ℃, keeping the temperature at 20 ℃, dropwise adding 66.6g of 30% hydrogen peroxide, keeping the temperature for 3 hours after the raw materials are dissolved after the dropwise adding is finished, standing for liquid separation after the reaction is finished, adding 50mL of 5% sodium bisulfite into a lower organic phase for washing, concentrating, crystallizing, filtering and drying to obtain a product 1, namely 3-bromo-4-hydroxybiphenyl;
step (2): synthesis of isopropyl 2- [3- (4-hydroxybiphenyl) ] -hydrazino-1-carboxylate
50g of 3-bromo-4-hydroxybiphenyl, 300g of dimethyl sulfoxide, 63.8g of sodium carbonate, 35.6g of isopropyl hydrazinoformate, 0.99g of cuprous chloride and 21.73g of ligand L are added into a three-port bottle, nitrogen protection is added, the temperature is raised to 83 ℃ for reaction for 4 hours, and the product 2, namely the isopropyl 2- [3- (4-hydroxybiphenyl) ] -hydrazino-1-carboxylate, is obtained, and the purity of the reaction liquid is 90.6%;
step (3): synthesis of biphenylhydrazine esters
Cooling the reaction solution in the step (2) to 63 ℃, keeping nitrogen protection, dropwise adding 28.5g of methyl iodide, and keeping the temperature for reaction for 2 hours after dropwise adding; filtering the reaction solution after the reaction is completed to 30 ℃ for desalting, decompressing and desolventizing the filtrate until a large amount of solids are separated out, adding water and pulping for about 1 hour to remove residual solvent and inorganic salt, filtering again, adding 159g of toluene to the dry weight of a filter cake to raise the temperature to 80 ℃, standing after the reaction solution is completely dissolved, separating out the lower water layer, cooling and crystallizing a toluene phase, filtering and drying to obtain a yellowish product, namely the bifenazate;
44.3g of bifenazate is synthesized, the purity is 98.9%, the external standard content is 98.5%, and the yield of two steps of the step (2) and the step (3) is 73.5%.
Example 3
A synthetic method of bifenazate comprises the following steps:
step (1): synthesis of 3-bromo-4-hydroxybiphenyl
Adding 50g of 4-hydroxybiphenyl, 100g of dichloroethane and 59.4g of 40% hydrobromic acid into a three-port bottle, stirring, setting the reaction temperature to-10 ℃, keeping the temperature at-10 ℃, dropwise adding 50g of 20% hydrogen peroxide, keeping the temperature for 2.5h after the raw materials are completely added, standing for liquid separation after the reaction is completed, adding 50mL of 5% sodium bisulfite into a lower organic phase for washing, concentrating, crystallizing, filtering and drying to obtain a product 1, namely 3-bromo-4-hydroxybiphenyl;
58.2g of 3-bromo-4-hydroxybiphenyl is synthesized, the yield is 79.5%, and the purity is 96.2%;
step (2): synthesis of isopropyl 2- [3- (4-hydroxybiphenyl) ] -hydrazino-1-carboxylate
50g of 3-bromo-4-hydroxybiphenyl, 150g of N, N-dimethylacetamide, 85.2g of potassium phosphate, 30.8g of isopropyl hydrazinoformate, 0.029g of cuprous bromide and 30.025g of ligand L are added into a three-port bottle, nitrogen is added for protection, the temperature is raised to 80 ℃ for reaction for 3.5 hours, and a product 2, namely 2- [3- (4-hydroxybiphenyl) ] -hydrazino-1-isopropyl formate is obtained, and the purity of a reaction liquid is 90.3%;
step (3): synthesis of biphenylhydrazine esters
The reaction solution in the step (2) is cooled to 60 ℃, nitrogen protection is kept, 36.2g of dimethyl carbonate is added dropwise, and the reaction is carried out for 1.5 hours after the dropwise addition; filtering the reaction solution after the reaction is completed to 20 ℃, desalting the reaction solution by filtration, decompressing and desolventizing the filtrate until a large amount of solids are separated out, adding water and pulping for about 1 hour to remove residual solvent and inorganic salt, filtering again, adding 130g of toluene to about 52g of dry weight of a filter cake, heating to 80 ℃, standing after the reaction solution is completely dissolved, separating out the lower water layer, cooling and crystallizing a toluene phase, filtering and drying to obtain a yellowish product, namely the bifenazate;
43.4g of bifenazate is synthesized, the purity is 98.7%, the external standard content is 98.2%, and the yield of two steps of the step (2) and the step (3) is 72%.
Example 4
A synthetic method of bifenazate comprises the following steps:
step (1): synthesis of 3-bromo-4-hydroxybiphenyl
Adding 50g of 4-hydroxybiphenyl, 400g of dichloromethane and 118.8g of 40% hydrobromic acid into a three-port bottle, stirring, setting the reaction temperature to 50 ℃, keeping the temperature at 50 ℃, dropwise adding 40g of 50% hydrogen peroxide, keeping the temperature for 3.5 hours after the raw materials are dissolved after the dropwise adding is finished, standing for liquid separation after the reaction is finished, adding 50mL of 5% sodium bisulfite into a lower organic phase for washing, concentrating and crystallizing, and filtering and drying to obtain a product 1, namely 3-bromo-4-hydroxybiphenyl;
step (2): synthesis of isopropyl 2- [3- (4-hydroxybiphenyl) ] -hydrazino-1-carboxylate
50g of 3-bromo-4-hydroxybiphenyl, 500g of N-methylpyrrolidone, 327g of cesium carbonate, 47.4g of isopropyl hydrazinoformate, 2.87g of cuprous oxide and 45.83g of ligand L are added into a three-mouth bottle, nitrogen is added for protection, the temperature is raised to 85 ℃ for reaction for 4.5 hours, and the product 2, namely 2- [3- (4-hydroxybiphenyl) ] -hydrazino-1-isopropyl formate is obtained, and the purity of the reaction liquid is 93.2%;
step (3): synthesis of biphenylhydrazine esters
Cooling the reaction solution in the step (2) to 65 ℃, keeping nitrogen protection, dropwise adding 38g of dimethyl sulfate, and keeping the temperature for reaction for 2.5 hours after dropwise adding; filtering the reaction solution after the reaction is completed to 40 ℃, desalting the reaction solution by filtration, decompressing and desolventizing the filtrate until a large amount of solids are separated out, adding water and pulping for about 1 hour to remove residual solvent and inorganic salt, filtering again, adding 203g of toluene to about 58g of dry weight of a filter cake, heating to 80 ℃, standing after the reaction solution is completely dissolved, separating out the lower water layer, cooling and crystallizing a toluene phase, filtering and drying to obtain a yellowish product, namely the bifenazate;
46g of bifenazate is synthesized, the purity is 99.5%, the external standard content is 99.0%, and the yield of the two steps of the step (2) and the step (3) is 76.3%.
The foregoing description is only a preferred embodiment of the present invention and is not intended to limit the present invention, but although the present invention has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that modifications may be made to the technical solutions described in the foregoing embodiments, or that equivalents may be substituted for part of the technical features thereof. Any modification, equivalent replacement, variation, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. The synthesis method of the bifenazate is characterized by comprising the following steps of:
(1) Bromination reaction: adding 4-hydroxylbiphenyl into an organic solvent, wherein the molar ratio of the 4-hydroxylbiphenyl to hydrobromic acid to hydrogen peroxide is 1: (1-5): adding hydrobromic acid and hydrogen peroxide in the proportion of (1-3), setting the reaction temperature to be-10-50 ℃, preserving the heat for 2.5-3.5 h, standing after the reaction is finished, adding sodium bisulphite solution into an organic phase for washing, concentrating, crystallizing, filtering and drying to obtain 3-bromo-4-hydroxybiphenyl;
(2) Coupling reaction: the prepared 3-bromo-4-hydroxybiphenyl reacts with isopropyl hydrazinoformate, copper catalyst, ligand, alkali and organic solvent for 3.5 to 4.5 hours at 80 to 85 ℃ in nitrogen atmosphere;
the copper catalyst is one or more of cuprous chloride, cuprous bromide, cuprous iodide or cuprous oxide; the alkali is one or more of sodium carbonate, potassium phosphate and cesium carbonate; the ligand is one or more of L1-L4;
(3) Etherification reaction: cooling the reaction liquid in the step (2) to 60-65 ℃, maintaining nitrogen atmosphere, dropwise adding a methylation reagent, preserving heat for reaction for 1.5-2.5 h after dropwise adding, cooling, filtering to remove salt after the reaction is finished, decompressing and desolventizing filtrate until a large amount of solids are separated out, adding water to pulp and remove residual solvent and inorganic salt, filtering again, adding toluene into a filter cake for recrystallization, and obtaining the bifenazate.
2. The method for synthesizing bifenazate according to claim 1, wherein the organic solvent in the step (1) is dichloromethane or dichloroethane, and the weight ratio of the organic solvent to 4-hydroxydiphenyl is (2-8): 1.
3. the method for synthesizing bifenazate according to claim 1, wherein the molar ratio of 4-hydroxybiphenyl, hydrobromic acid and hydrogen peroxide in the step (1) is 1:3:2, the hydrobromic acid added is 40 percent hydrobromic acid, and the concentration of hydrogen peroxide is 20 to 50 percent.
4. The method for synthesizing bifenazate according to claim 1, wherein the reaction temperature in the step (1) is 0-5 ℃ and the incubation time is 3 hours.
5. The method for synthesizing bifenazate according to claim 1, wherein the molar ratio of isopropyl carbazate to 3-bromo-4-hydroxybiphenyl in the step (2) is (1-3): 1.
6. the method for synthesizing bifenazate according to claim 1, wherein the molar ratio of the copper catalyst to 3-bromo-4-hydroxydiphenyl in the step (2) is (0.001-0.1): 1.
7. the method for synthesizing bifenazate according to claim 1, wherein the molar ratio of the base to 3-bromo-4-hydroxydiphenyl in the step (2) is (2-5): 1.
8. the method for synthesizing bifenazate according to claim 1, wherein the molar ratio of the ligand to the copper catalyst in the step (2) is (1-2): 1.
9. the method for synthesizing bifenazate according to claim 1, wherein the weight ratio of the organic solvent to 3-bromo-4-hydroxydiphenyl in the step (2) is (3-10): 1, the organic solvent is one or more of dimethyl sulfoxide, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, acetonitrile and dioxane.
10. The method for synthesizing bifenazate according to claim 1, wherein the molar ratio of the methylating agent to 3-bromo-4-hydroxydiphenyl in the step (3) (0.8 to 2): 1, the methylation reagent comprises one or more of dimethyl sulfate, methyl iodide and dimethyl carbonate; the amount of toluene added in the step (3) is 2-5 times of the dry weight of the filter cake.
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