Synthesis method of fluxapyroxad intermediate

Abstract

The invention relates to a synthesis method of a fluxapyroxad intermediate. The synthesis method comprises the step of reacting a compound Ia and a compound Ib in the presence of a catalyst and alkali. According to the method disclosed by the invention, the biphenyl compound shown in the formula I can be obtained with high yield. Moreover, the catalyst used in the invention is low in preparation cost and low in toxicity, the reaction does not need to be strictly controlled to be carried out in an anhydrous and oxygen-free environment, and the operation is simpler. Therefore, compared with the existing method, the preparation method disclosed by the invention is more efficient, simpler, safer and more friendly. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing a fluopyraclostrobin intermediate. Background Art

[0002] Fluopyrabamide belongs to the carboxamide class of chemicals. Its mode of action is to inhibit the succinate dehydrogenase in complex II of the mitochondrial respiratory chain, thereby inhibiting the spore germination, germ tube and mycelial growth of the target fungi. Fluopyrabamide can prevent and control at least 26 fungal diseases and can be used to prevent and control fungal diseases in nearly 100 crops, such as cereal crops, legumes, oil crops, pome and stone fruit trees, root and tuber vegetables, and fruiting vegetables. Fluopyrabamide is non-carcinogenic, non-teratogenic, has no side effects on reproduction, and is non-genotoxic, neurotoxic and immunotoxic.

[0003] The structure of fluopyrabactam is shown below:

[0004]

[0005] 3,4,5-trifluoro-2-aminobiphenyl and 3,4,5-trifluoro-2-nitrobiphenyl are the raw materials for the synthesis of the key intermediate biphenyl structure of the pesticide fluopyraclostrobin. The traditional method for synthesizing biphenyl structure mainly uses halogenated aromatic hydrocarbons and aromatic boronic acids as starting materials and is prepared by transition metal-catalyzed Suzuki coupling. However, since the reaction uses transition metals, it has high requirements for the absence of water and oxygen in the reaction system, and the toxicity of transition metals is high. At the same time, its preparation cost is high, the catalyst recovery is difficult, the yield is low, and the operation is cumbersome.

[0006] The traditional Suzuki coupling process for synthesizing the key intermediate biphenyl structure of the pesticide fluopyrabamide (such as 3,4,5-trifluoro-2-aminobiphenyl or 3,4,5-trifluoro-2-nitrobiphenyl) requires the use of a transition metal catalyst, such as a Pd or Ni catalyst, which is costly and has harsh reaction conditions, and has high requirements for anhydrous and oxygen-free conditions. Although it has been reported that its yield can reach 96%, it uses a commercially unavailable ligand 2,2-dimethyl-1,3-bis(diphenylphosphino)propane, which needs to be homemade and has harsh preparation process conditions. Therefore, the method disclosed in the prior art not only has a poor yield, but also has a high preparation cost, great difficulty, and low safety.

[0007] At present, regarding the Suzuki coupling reaction, the latest research reports that an amine catalyst can catalyze certain Suzuki coupling reactions. For example, patent document CN 112538052 A discloses an amine catalyst that can replace transition metal catalysts to catalyze Suzuki coupling reactions. When the inventors of the present application used the amine catalyst for the coupling reaction to prepare 3,4,5-trifluoro-2-aminobiphenyl or 3,4,5-trifluoro-2-nitrobiphenyl, they found that although the catalyst can catalyze the reaction, the yield is significantly reduced. The inventors have optimized a large number of reaction conditions, but failed to improve the yield. It can be seen that the amine catalyst has selectivity for raw materials. That is, the catalyst disclosed in patent document CN 112538052 A has a poor catalytic effect on the preparation of 3,4,5-trifluoro-2-aminobiphenyl or 3,4,5-trifluoro-2-nitrobiphenyl, and the amine catalyst used is relatively expensive and is not suitable for industrial production.

[0008] Therefore, there is an urgent need to find a more efficient, simple, safer and environmentally friendly method for synthesizing fluopyram intermediates. Summary of the invention

[0009] The purpose of the present invention is to overcome the problems of harsh process conditions and low product yield in the prior art, and to provide a method for synthesizing a fluopyraclostrobin intermediate.

[0010] The technical solution of the present invention is as follows:

[0011] A method for synthesizing a compound represented by formula I, comprising:

[0012] Reacting compound Ia and compound Ib in the presence of a catalyst and a base;

[0013]

[0014] wherein R1, R2, R3, R4 and R5 are the same or different and are independently selected from H, halogen, nitro, amino, cyano, C 1-12 Alkyl, C 1-12 Alkoxy, 3-20 membered heterocyclic group, C 3-20 Cycloalkyl, C 6-20 Aryl, 5-20 membered heteroaryl;

[0015] R6, R7, R8, R9 and R 10 are the same or different and are independently selected from H, nitro, amino, cyano, C 1-12 Alkyl, C 1-12 Alkoxy, 3-20 membered heterocyclic group, C 3-20 Cycloalkyl, C 6-20 Aryl, 5-20 membered heteroaryl;

[0016] X is a halogen;

[0017] The catalyst is an oxalate and / or a copper salt catalyst and / or

[0018] According to an embodiment of the present invention, the oxalate is selected from at least one of ammonium oxalate, sodium oxalate and potassium oxalate.

[0019] According to an embodiment of the present invention, the copper salt catalyst is at least one of cupric chloride, cuprous iodide and cupric iodide.

[0020] According to an embodiment of the present invention, the base is a carbonate or a bicarbonate, such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, cesium carbonate, rubidium carbonate, lithium carbonate or sodium carbonate.

[0021] According to an embodiment of the present invention, R1, R2, R3, R4 and R5 are the same or different and are independently selected from H, F, nitro, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, 3-14 membered heterocyclic group, C 3-14 Cycloalkyl, C 6-14 Aryl, 5-14 membered heteroaryl;

[0022] R6, R7, R8, R9 and R 10 are the same or different and are independently selected from H, nitro, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, 3-14 membered heterocyclic group, C 3-14 Cycloalkyl, C 6-14 Aryl, 5-14 membered heteroaryl;

[0023] X is chlorine or bromine.

[0024] In some embodiments of the present invention, R1 and R5 are H; R2, R3 and R4 are selected from F;

[0025] R6 is selected from amino or nitro; R7, R8, R9 and R 10 For H.

[0026] According to an embodiment of the present invention, the reaction is carried out in an organic solvent, and the organic solvent is selected from aromatic hydrocarbon solvents, such as toluene or xylene.

[0027] According to an embodiment of the present invention, the catalyst is a mixed catalyst consisting of one of ammonium oxalate, sodium oxalate and potassium oxalate and one of cupric chloride, cuprous iodide and cupric iodide.

[0028] According to an embodiment of the present invention, the molar ratio of oxalate to copper salt in the mixed catalyst is (0.1-1):(0.1-1), for example (0.2-0.8):(0.2-0.8), such as (0.3-0.7):(0.3-0.7).

[0029] According to an embodiment of the present invention, the reaction temperature is 60-130°C, such as 90-110°C.

[0030] According to an embodiment of the present invention, the copper salt catalyst is used in an amount of 1 to 100% of the molar amount of compound Ia, such as 5 to 50%, such as 10 to 30%.

[0031] According to an embodiment of the present invention, the molar ratio of compound Ia to oxalate is 1:0.05-10, for example 1:0.1-5, such as 1:0.5-1.

[0032] According to an embodiment of the present invention, the molar ratio of compound Ia to the base is 1:0.1-5, for example 1:0.5-3, such as 1:0.8-8.

[0033] According to an embodiment of the present invention, the molar ratio of compound Ia to compound Ib is 1:0.1-10, for example 1:0.5-5, such as 1:0.8-2.

[0034] According to an embodiment of the present invention, the reaction time is 0.5 to 12 hours, such as 1 to 6 hours.

[0035] Beneficial Effects

[0036] The method of the present invention can obtain the biphenyl compound shown in formula I with high yield. In addition, the catalyst used in the present application has low preparation cost and low toxicity, and there is no need to strictly control the reaction to be carried out in an anhydrous and oxygen-free environment, which makes the operation simpler. Therefore, the preparation method of the present application is more efficient, simpler, safer and more friendly than the existing method.

[0037] Terms and Definitions

[0038] Unless otherwise defined, all technical and scientific terms herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs.

[0039] "Halogen" means fluorine, chlorine, bromine or iodine.

[0040] The term "C 1-12 "Alkyl" is understood to mean a straight-chain or branched saturated monovalent hydrocarbon group having 1 to 12 carbon atoms, preferably "C 1-6 Alkyl". "C 1-6The term "alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, 1,2-dimethylbutyl, or the like or isomers thereof.

[0041] The term "C 1-12 "Alkoxy" is understood to mean -OC 1-12 Alkyl, where C 1-12 Alkyl has the above definition.

[0042] The term "C 3-20 "Cycloalkyl" should be understood to mean a saturated monovalent monocyclic, bicyclic hydrocarbon ring or polycyclic hydrocarbon ring (also called condensed hydrocarbon ring) having 3-20 carbon atoms. Bicyclic or polycyclic cycloalkyl groups include paracyclic cycloalkyl, bridged cycloalkyl and spirocyclic cycloalkyl; the paracyclic refers to a condensed ring structure formed by two or more cyclic structures sharing two adjacent ring atoms (i.e., sharing one bond). The bridged ring refers to a condensed ring structure formed by two or more cyclic structures sharing two non-adjacent ring atoms. The spirocyclic refers to a condensed ring structure formed by two or more cyclic structures sharing one ring atom. For example, the C 3-20 The cycloalkyl group may be C 3-8 Monocyclic cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, or C 7-12 Cycloalkyl, such as decahydronaphthalene; it can also be C 7-12 Bridged ring cycloalkyl, such as norbornane, adamantane, bicyclo[2,2,2]octane.

[0043] The term "3-20 membered heterocyclyl" means a saturated or unsaturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5 heteroatoms independently selected from N, O and S, preferably a "3-14 membered heterocyclyl". The term "3-14 membered heterocyclyl" means a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 1-5, preferably 1-3 heteroatoms selected from N, O and S. The heterocyclyl may be connected to the rest of the molecule through any one of the carbon atoms or the nitrogen atom (if present). In particular, the heterocyclyl may include, but is not limited to: a 4-membered ring, such as azetidinyl, oxetanyl; a 5-membered ring, such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl; or a 7-membered ring, such as diazepanyl. Optionally, the heterocyclic group may be benzo-fused. The heterocyclic group may be bicyclic, such as, but not limited to, a 5,5-membered ring, such as a hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring, or a 5,6-membered bicyclic ring, such as a hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl ring. The ring containing nitrogen atoms may be partially unsaturated, i.e., it may contain one, two or more double bonds, such as, but not limited to, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl or 4H-[1,4]thiazinyl, or it may be benzo-fused, such as, but not limited to, dihydroisoquinolyl, 1,3-benzoxazolyl, 1,3-benzodioxolyl. According to the present invention, the heterocyclic group is non-aromatic.

[0044] The term "C 6-20 "Aryl" is understood to mean a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, preferably "C 6-14 The term "C 6-14 The term "aryl" is understood to mean preferably a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring ("C 6-14 or a ring having 9 carbon atoms ("C9 aryl"), for example indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 aryl), such as fluorenyl, or a ring having 14 carbon atoms ("C 14 aryl”), such as anthracenyl. When the C 6-20When the aryl group is substituted, it may be monosubstituted or polysubstituted. Also, there is no limitation on the substitution position, for example, it may be substituted at the ortho position, para position or meta position.

[0045] The term "5-20 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S, for example "5-14 membered heteroaryl". The term "5-14 membered heteroaryl" is understood to include monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and containing 1 to 5, preferably 1 to 3 heteroatoms each independently selected from N, O and S and, in addition, in each case may be benzo-fused. In particular, the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl and the like; or azinyl, indolizinyl, purinyl and the like and benzo derivatives thereof; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and the like. DETAILED DESCRIPTION

[0046] The technical solution of the present invention is described in detail below. It should be understood that the specific implementation methods described herein are only used to illustrate and explain the present invention, and are not used to limit the present invention.

[0047] The experimental methods in the following examples, unless otherwise specified, are all conventional methods in the art. The experimental materials used in the following examples, unless otherwise specified, are all commercially available.

[0048] The purity of the products in the following examples and comparative examples was obtained by HPLC detection.

[0049] Example 1

[0050] Add 0.1 mol 3,4,5-trifluorophenylboric acid and 0.11 mol o-chloroaniline to the reaction vessel, then add 0.01 mol cuprous iodide, 0.01 mol ammonium oxalate and 0.11 mol potassium carbonate, add 500 g of solvent toluene under nitrogen protection, heat to 110°C, keep stirring at this temperature for 5 hours, stop the reaction, wash with 200 g of water, repeat the water washing operation three times, dry with anhydrous sodium sulfate, filter and desolventize to obtain a crude product, and purify by column chromatography to obtain 0.095 mol of the product 3,4,5-trifluoro-2-aminobiphenyl, with a yield of 95% (purity of 98%).

[0051] Example 2

[0052] 0.1 mol 3,4,5-trifluorophenylboric acid and 0.11 mol o-chloronitrobenzene were added to the reaction vessel, and then 0.01 mol cuprous chloride, 0.01 mol ammonium oxalate and 0.11 mol potassium carbonate were added as catalysts. Under nitrogen protection, 500 g of toluene solvent was added, the temperature was raised to 110°C, and the mixture was kept stirred at this temperature for 5 hours, the reaction was stopped, and the mixture was washed with 200 g of water, and the washing operation was repeated three times. The mixture was dried with anhydrous sodium sulfate, and the crude product was filtered off by suction to remove the solvent. The product 3,4,5-trifluoro-2-nitrobenzene biphenyl 0.093 mol was obtained by column chromatography purification, and the yield was 93% (purity was 95%).

[0053] Comparative Example 1

[0054] Add 0.1 mol 3,4,5-trifluorophenylboric acid and 0.1 mol o-bromoaniline to a reaction vessel, then add a catalyst of tetrakistriphenylphosphine palladium (0.01 mol) and 0.1 mol potassium carbonate, add 500 g of solvent tetrahydrofuran under nitrogen protection, heat to 70° C. and stir for 5 hours. When using the catalyst of tetrakistriphenylphosphine palladium for catalytic reaction, ensure that the reaction system is free of water and oxygen. After stopping the reaction, wash with 200 g of water, repeat the water washing operation three times, dry with anhydrous sodium sulfate, filter and desolventize to obtain a crude product, and purify by column chromatography to obtain 0.075 mol of the product 3,4,5-trifluoro-2-aminobiphenyl with a yield of 75% (purity of 98%).

[0055] Comparative Example 2

[0056] Add 0.1 mol 3,4,5-trifluorophenylboric acid and 0.11 mol o-chloroaniline to the reaction vessel, then add the catalyst tetrakistriphenylphosphine palladium (0.01 mol) and 0.11 mol potassium carbonate, add 500 g of solvent toluene under nitrogen protection, heat to 110°C, keep stirring at this temperature for 5 hours, stop the reaction, wash with 200 g of water, repeat the water washing operation three times, dry with anhydrous sodium sulfate, filter and desolventize to obtain a crude product, and purify by column chromatography to obtain 0.060 mol of the product 3,4,5-trifluoro-2-aminobiphenyl, with a yield of 60% (purity of 55%).

[0057] The above is an explanation of the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for synthesizing a compound of formula I, characterized in that: include: Reacting compound Ia and compound Ib in the presence of a catalyst and a base; wherein R1, R2, R3, R4 and R5 are the same or different and are independently selected from H, halogen, nitro, amino, cyano, C 1-12 Alkyl, C 1-12 Alkoxy, 3-20 membered heterocyclic group, C 3-20 Cycloalkyl, C 6-20 Aryl, 5-20 membered heteroaryl; R6, R7, R8, R9 and R 10 are the same or different and are independently selected from H, nitro, amino, cyano, C 1-12 Alkyl, C 1-12 Alkoxy, 3-20 membered heterocyclic group, C 3-20 Cycloalkyl, C 6-20 Aryl, 5-20 membered heteroaryl; X is a halogen; The catalyst is an oxalate and / or a copper salt catalyst and / or 2. The synthesis method according to claim 1, characterized in that The oxalate is selected from at least one of ammonium oxalate, sodium oxalate and potassium oxalate; Preferably, the copper salt catalyst is at least one of cupric chloride, cuprous iodide and cupric iodide; Preferably, the base is a carbonate or a bicarbonate, such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, cesium carbonate, rubidium carbonate, lithium carbonate or sodium carbonate.

3. The synthesis method according to claim 1 or 2, characterized in that R1, R2, R3, R4 and R5 are the same or different and are independently selected from H, F, nitro, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, 3-14 membered heterocyclic group, C 3-14 Cycloalkyl, C 6-14 Aryl, 5-14 membered heteroaryl; R6, R7, R8, R9 and R 10 are the same or different and are independently selected from H, nitro, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, 3-14 membered heterocyclic group, C 3-14 Cycloalkyl, C 6-14 Aryl, 5-14 membered heteroaryl; X is chlorine or bromine.

4. The synthesis method according to any one of claims 1 to 3, characterized in that R1 and R5 are H; R2, R3 and R4 are selected from F; R6 is selected from amino or nitro; R7, R8, R9 and R 10 For H.

5. The synthesis method according to any one of claims 1 to 4, characterized in that The reaction is carried out in an organic solvent, and the organic solvent is selected from aromatic hydrocarbon solvents.

6. The synthesis method according to any one of claims 1 to 5, characterized in that The catalyst is a mixed catalyst consisting of one of ammonium oxalate, sodium oxalate and potassium oxalate and one of cupric chloride, cuprous iodide and cupric iodide.

7. The synthesis method according to any one of claims 1 to 6, characterized in that The reaction temperature is 60-130°C.

8. The synthesis method according to any one of claims 1 to 7, characterized in that The amount of the copper salt catalyst used is 1 to 100% of the molar amount of compound Ia.

9. The synthesis method according to any one of claims 1 to 8, characterized in that The molar ratio of compound Ia to oxalate is 1:0.05-10.

10. The synthesis method according to any one of claims 1 to 9, characterized in that: The molar ratio of compound Ia to the base is 1:0.1-5.

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