An industrial method for synthesizing a flumizole amide biphenylamine intermediate by one-pot method
A one-pot synthesis of fluopyram-methyl benzidine intermediate was achieved using a Pd/C catalyst and ligand, overcoming the problems of difficult catalyst recovery and high cost in existing technologies. This enabled the efficient industrial production of 3',4',5'-trifluoro-2-aminobiphenyl.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- JIANGSU FLAG CHEM IND CO LTD
- Filing Date
- 2023-10-16
- Publication Date
- 2026-06-09
Smart Images
Figure BDA0004494330660000011 
Figure BDA0004494330660000012 
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of pesticide fungicide technology, and particularly relates to an industrial method for one-pot synthesis of fluopyram benzidine intermediate. Background Technology
[0002] This invention relates to a one-pot method for synthesizing fluopyram-benzidine intermediate (Formula I):
[0003]
[0004] Succinate dehydrogenase inhibitors (SDHIs) are fungicides that work by covering the coenzyme Q site in mitochondrial complex II, blocking electron transfer from the iron-sulfur center to coenzyme Q, thereby interfering with fungal respiration, hindering their energy metabolism, inhibiting pathogen growth, and ultimately leading to their death. In recent years, the SDHI fungicide market has grown rapidly, attracting significant global attention. In 2019, global sales of this class of fungicides reached US$2.311 billion, accounting for 12.7% of the fungicide market that year, with a compound annual growth rate of 8.5% from 2014 to 2019, far exceeding the growth rate of other fungicide classes. Among the fastest-growing SDHI fungicides globally, BASF has several products listed, especially fluopyram, launched in 2012, which successfully surpassed its own developed cyazofamid in 2015 to become the number one SDHI fungicide product. Currently, fluopyram's global sales are close to US$500 million, making it BASF's second-largest fungicide (after pyraclostrobin) and ranking eighth in the global fungicide market.
[0005]
[0006] Orthoaminobiphenyl compounds have a wide range of applications in pharmaceuticals, pesticides and other fields. Among them, compound (I) 3',4',5'-trifluoro-2-aminobiphenyl is a key intermediate of the SDHI fungicide fluopyram. Researching its industrial synthesis method is of great significance and has always been a problem that needs to be solved in this field.
[0007] Regarding the synthesis of the compound of formula (I):
[0008] BASF patent CN102325747A uses a protected o-aminochlorobenzene and trifluorophenyl zinc reagent to perform a coupling reaction to obtain o-aniline intermediates. This strategy uses a protecting group, has a long procedure, and is also more complicated to treat waste due to the use of zinc reagent, making it unsuitable for industrial production.
[0009] BASF patent CN104220417A uses 3,4,5-trifluorophenylhydrazine and aniline as raw materials to obtain benzidine intermediates via oxidative coupling reaction. In this strategy, the raw material 3,4,5-trifluorophenylhydrazine is difficult to obtain industrially, and the reaction yield is low, only 59%, making it unsuitable for industrial production.
[0010] Chinese patent CN107488113A discloses a method for obtaining 3',4',5'-trifluoro-2-aminobiphenyl via decarboxylation coupling using o-nitrobenzoic acid and 3,4,5-trifluorobromobenzene as raw materials. This route utilizes complex noble metal catalysts Pd(acac)2 and cuprous iodide as raw materials, requires a large amount of catalyst, and uses a homogeneous catalyst, making recovery difficult and unsuitable for industrial production.
[0011] WO2010102980A1 discloses a method for synthesizing 3',4',5'-trifluoro-2-nitrobiphenyl from 1,2,3-trifluoro-5-(2-nitrovinyl)benzene and 1,3-butadiene, followed by reduction of the nitrated compound to yield 3',4',5'-trifluoro-2-aminobiphenyl. This strategy suffers from low yields (only 50%), complex reaction procedures, and demanding reaction conditions, making it unsuitable for industrial production.
[0012] European patents WO2018035685A1 and WO2009156359A2 describe a process using trifluorophenylboronic acid and o-chloronitrobenzene as raw materials, via a Suzuki coupling reaction to obtain 3',4',5'-trifluoro-2-nitrobenzene. The target product, 3',4',5'-trifluoro-2-aminobiphenyl, can then be obtained through catalytic hydrogenation. This Suzuki coupling uses a combination of divalent palladium and a ligand, employing a homogeneous catalyst, which is difficult to recover, costly, and challenging for industrial production. Furthermore, the complex post-coupling process increases equipment investment for industrial production, further hindering its feasibility.
[0013] Patent WO2021 / 01447 uses 3,4,5-trifluorophenylboronic acid and o-chloroaminobenzene as raw materials to obtain 3',4',5'-trifluoro-2-aminobiphenyl via a coupling reaction. This strategy also uses PdCl2, which has good solubility, as a catalyst, and suffers from difficulties in catalyst recovery and high production costs, making it difficult to industrialize.
[0014] Given the current situation, developing an industrial synthesis method for 3',4',5'-trifluoro-2-aminobiphenyl and addressing the shortcomings of existing technologies has always been a challenging problem in this field.
[0015] Suzuki coupling reactions primarily utilize homogeneous catalysts, such as PdCl2(PPh3)2 and Pd(OAc)2dppf. Supported catalysts, due to their poor solubility and low catalytic activity, are generally difficult to efficiently catalyze Suzuki coupling. Hydrogenation reduction reactions typically employ supported heavy metal catalysts, such as Pd / C and Pt / C, and generally avoid using homogeneous catalysts like PdCl2(PPh3)2.
[0016] This invention discloses a one-pot synthesis method for the intermediate of fluopyram-methylbenzidine, using Pd / C as a catalyst. Through the addition of a ligand, the Suzuki coupling and hydrogenation reduction reactions are completed in a one-pot process, efficiently achieving the industrial synthesis of 3',4',5'-trifluoro-2-aminobiphenyl. The Pd / C catalyst requires a low dosage, resulting in lower catalyst cost. Furthermore, the catalyst can be efficiently recovered through simple filtration after the reaction, successfully solving the problem of the industrial synthesis of 3',4',5'-trifluoro-2-aminobiphenyl. Summary of the Invention
[0017] The purpose of this invention is to address the problems existing in the prior art by providing an industrial-scale method for the one-pot synthesis of fluopyram-benzidine intermediates.
[0018] To achieve the above objectives, the technical solution of this invention is: an industrial method for the one-pot synthesis of fluopyram-2-aminobiphenyl intermediate, wherein the method uses 3,4,5-trifluorophenylboronic acid and o-chloronitrobenzene as raw materials, uses Pd / C as a catalyst, adds ligands and solvents, and obtains the key intermediate 3',4',5'-trifluoro-2-aminobiphenyl in a one-pot process under the action of an acid-binding agent.
[0019] The specific reaction formula is as follows:
[0020]
[0021] Preferably, the molar equivalent ratio of 3,4,5-trifluorophenylboronic acid and the substituted o-chloronitrobenzene is 1:0.5-3.0;
[0022] Preferably, the solvent is an aqueous solution of isopropanol, an aqueous solution of tert-butanol, an aqueous solution of N,N-dimethylformamide, an aqueous solution of N,N-dimethylacetamide, an aqueous solution of acetonitrile, or an aqueous solution of 1,4-dioxane.
[0023] Preferably, the weight ratio of 3,4,5-trifluorophenylboronic acid to solvent is 1:2-20; more preferably, 1:2-10.
[0024] Preferably, the Pd catalyst used is commercially available palladium on carbon, containing 5-10% palladium by mass.
[0025] Preferably, the molar equivalent of the Pd catalyst used is 0.1%-0.3% of the molar equivalent of the substituted phenylboronic acid;
[0026] Preferably, the ligand used is one or more of the following: 2-dicyclohexylphosphine-2′-(N,N-dimethylamine)-biphenyl, 2-bicyclohexylphosphine-2',6'-diisopropoxybiphenyl, 1,1'-bis(diphenylphosphine)-ferrocene, 1,1'-binaphthyl-2,2'-bisdiphenylphosphine, 2-bicyclohexylphosphine-2',6'-dimethoxybiphenyl, dicyclohexyl[3,6-dimethoxy-2',4',6'-triisopropyl[1,1'-biphenyl]-2-yl]phosphine, tricyclohexylphosphine, triphenylphosphine, and dba.
[0027] Preferably, the molar equivalent of the ligand used is 0.1%-1% of the molar equivalent of the substituted phenylboronic acid;
[0028] Preferably, the acid-binding agent used is a commonly used organic or inorganic base such as triethylamine, potassium phosphate, potassium carbonate, or sodium carbonate;
[0029] Preferably, the amount of acid-binding agent used is 1-3 times the molar equivalent of replacing phenylboronic acid.
[0030] The beneficial effects of this invention are: 1) It completes the Suzuki coupling and catalytic hydrogenation reaction in one pot with high catalytic efficiency; 2) It uses palladium supported on activated carbon as a catalyst, which is easy to recover and reuse; 3) It has low process cost and simple waste treatment, which greatly reduces the process cost and the difficulty of waste treatment, and has good prospects for industrial application. Detailed Implementation
[0031] Example 1
[0032] Under nitrogen protection, 37.5 g of 50% acetonitrile aqueous solution, 5.0 g of 3,4,5-trifluorophenylboronic acid, and 4.48 g of o-chloronitrobenzene were added sequentially to a four-necked flask. Stirring was started, and then 5.9 g of potassium carbonate, 0.2% palladium on carbon (containing 6 mg palladium), and 16 mg of the ligand 2-dicyclohexylphosphino-2′-(N,N-dimethylamine)-biphenyl (DavePhos) were added to the system. After the addition was complete, the mixture was heated to reflux and reacted for 2 hours. Then, hydrogen gas was introduced into a cylinder and the pressure was maintained at 2.0 MPa, and the reaction was stirred for 20 hours. After the reaction was complete, the reaction solution was filtered to recover the palladium on carbon catalyst, and then concentrated to remove the organic solvent. The residue was extracted with dichloromethane, and the dichloromethane phase was concentrated to obtain 11.85 g of the target product 3',4',5'-trifluoro-2-aminobiphenyl, with a quantitative yield of 96.9% and an HPLC purity of 99.72%.
[0033] 1H NMR (400MHz, DMSO) δ7.25-7.38 (m, 2H), 7.03-7.10 (t, 1H), 6.95-7.00 (d, 1H), 6.71-6.76 (d, 1H), 6.56-6.66 (t, 1H), 4.88-5.10 (s, 2H).
[0034] Example 2
[0035] Under nitrogen protection, 37.5 g of 50% acetonitrile aqueous solution, 5.0 g of 3,4,5-trifluorophenylboronic acid, and 4.48 g of o-chloronitrobenzene were added sequentially to a four-necked flask. Stirring was started, and then 5.9 g of potassium carbonate, 0.2% palladium on carbon (containing 6 mg palladium), and 19 mg of the ligand 2-bicyclohexylphosphine-2',6'-diisopropoxybiphenyl (RuPhos) were added to the system. After the addition was complete, the mixture was heated to reflux for 2 hours, then hydrogen gas was introduced and the pressure was maintained at 2.0 MPa, and the reaction was stirred for 20 hours. After the reaction was complete, the reaction solution was filtered to recover the palladium on carbon catalyst, and then concentrated to remove the organic solvent. The residue was extracted with dichloromethane, and the dichloromethane phase was concentrated to obtain 11.85 g of the target product 3',4',5'-trifluoro-2-aminobiphenyl, with a quantitative yield of 93.9% and an HPLC purity of 97.94%.
[0036] 1 H NMR (400MHz, DMSO) δ7.25-7.38 (m, 2H), 7.03-7.10 (t, 1H), 6.95-7.00 (d, 1H), 6.71-6.76 (d, 1H), 6.56-6.66 (t, 1H), 4.88-5.10 (s, 2H).
[0037] Example 3
[0038] Under nitrogen protection, 37.5 g of 50% acetonitrile aqueous solution, 5.0 g of 3,4,5-trifluorophenylboronic acid, and 4.48 g of o-chloronitrobenzene were added sequentially to a four-necked flask. Stirring was started, and then 5.9 g of potassium carbonate, 0.2% palladium on carbon (containing 6 mg palladium), and 25 mg of ligand 1,1'-bis(diphenylphosphino)-ferrocene (dppf) were added to the system. After the addition was complete, the mixture was heated to reflux and reacted for 2 hours. Then, hydrogen gas was introduced into a cylinder and the pressure was maintained at 2.0 MPa, and the reaction was stirred for 20 hours. After the reaction was complete, the reaction solution was filtered to recover the palladium on carbon catalyst, and then concentrated to remove the organic solvent. The residue was extracted with dichloromethane, and the dichloromethane phase was concentrated to obtain 11.85 g of the target product 3',4',5'-trifluoro-2-aminobiphenyl, with a quantitative yield of 90.2% and an HPLC purity of 97.89%.
[0039] 1H NMR (400MHz, DMSO) δ7.25-7.38 (m, 2H), 7.03-7.10 (t, 1H), 6.95-7.00 (d, 1H), 6.71-6.76 (d, 1H), 6.56-6.66 (t, 1H), 4.88-5.10 (s, 2H).
[0040] Example 4
[0041] Under nitrogen protection, 37.5 g of 50% acetonitrile aqueous solution, 5.0 g of 3,4,5-trifluorophenylboronic acid, and 4.48 g of o-chloronitrobenzene were added sequentially to a four-necked flask. Stirring was started, and then 5.9 g of potassium carbonate, 0.2% palladium on carbon (containing 6 mg palladium), and 34 mg of ligand Sphos were added to the system. After the addition was complete, the mixture was heated to reflux and reacted for 2 hours. Then, hydrogen gas was introduced into a cylinder and the pressure was maintained at 2.0 MPa, and the reaction was stirred for 20 hours. After the reaction was complete, the reaction solution was filtered to recover the palladium on carbon catalyst, and then concentrated to remove the organic solvent. The residue was extracted with dichloromethane, and the dichloromethane phase was concentrated to obtain 11.85 g of the target product 3',4',5'-trifluoro-2-aminobiphenyl, with a quantitative yield of 92.9% and an HPLC purity of 98.20%.
[0042] 1 H NMR (400MHz, DMSO) δ7.25-7.38 (m, 2H), 7.03-7.10 (t, 1H), 6.95-7.00 (d, 1H), 6.71-6.76 (d, 1H), 6.56-6.66 (t, 1H), 4.88-5.10 (s, 2H).
[0043] Example 5
[0044] Under nitrogen protection, 37.5 g of 50% acetonitrile aqueous solution, 5.0 g of 3,4,5-trifluorophenylboronic acid, and 4.48 g of o-chloronitrobenzene were added sequentially to a four-necked flask. Stirring was started, and then 5.9 g of potassium carbonate, 0.2% palladium on carbon (containing 6 mg of palladium), and 20 mg of the ligand dicyclohexyl[3,6-dimethoxy-2',4',6'-triisopropyl[1,1'-biphenyl]-2-yl]phosphine (BrettPhos) were added to the system. After the addition was complete, the mixture was heated to reflux and reacted for 2 hours. Then, hydrogen gas was introduced into a steel cylinder and the pressure was maintained at 2.0 MPa, and the reaction was stirred for 20 hours. After the reaction was complete, the reaction solution was filtered to recover the palladium on carbon catalyst, and then concentrated to remove the organic solvent. The residue was extracted with dichloromethane and the liquid was separated. The dichloromethane phase was concentrated to obtain 11.85 g of the target product 3',4',5'-trifluoro-2-aminobiphenyl, with a quantitative yield of 88.3% and an HPLC purity of 98.15%.
[0045] 1H NMR (400MHz, DMSO) δ7.25-7.38 (m, 2H), 7.03-7.10 (t, 1H), 6.95-7.00 (d, 1H), 6.71-6.76 (d, 1H), 6.56-6.66 (t, 1H), 4.88-5.10 (s, 2H).
[0046] Example 6
[0047] Under nitrogen protection, 37.5 g of 50% tert-butanol aqueous solution, 5.0 g of 3,4,5-trifluorophenylboronic acid, and 4.48 g of o-chloronitrobenzene were added sequentially to a four-necked flask. Stirring was started, and then 5.9 g of potassium carbonate, 0.2% palladium on carbon (containing 6 mg palladium), and 16 mg of the ligand 2-dicyclohexylphosphino-2′-(N,N-dimethylamine)-biphenyl (DavePhos) were added to the system. After the addition was complete, the mixture was heated to reflux for 2 hours, then hydrogen was introduced into a steel cylinder and the pressure was maintained at 2.0 MPa. The mixture was stirred for 20 hours. After the reaction was complete, the reaction solution was filtered to recover the palladium on carbon catalyst, and then concentrated to remove the organic solvent. The residue was extracted with dichloromethane, and the dichloromethane phase was concentrated to obtain 11.85 g of the target product 3',4',5'-trifluoro-2-aminobiphenyl, with a quantitative yield of 93.6% and an HPLC purity of 98.58%.
[0048] 1 H NMR (400MHz, DMSO) δ7.25-7.38 (m, 2H), 7.03-7.10 (t, 1H), 6.95-7.00 (d, 1H), 6.71-6.76 (d, 1H), 6.56-6.66 (t, 1H), 4.88-5.10 (s, 2H).
[0049] Example 7
[0050] Under nitrogen protection, 37.5 g of 50% isopropanol aqueous solution, 5.0 g of 3,4,5-trifluorophenylboronic acid, and 4.48 g of o-chloronitrobenzene were added sequentially to a four-necked flask. Stirring was started, and then 5.9 g of potassium carbonate, 0.2% palladium on carbon (containing 6 mg palladium), and 16 mg of the ligand 2-dicyclohexylphosphino-2′-(N,N-dimethylamine)-biphenyl (DavePhos) were added to the system. After the addition was complete, the mixture was heated to reflux and reacted for 2 hours. Then, hydrogen gas was introduced into a cylinder and the pressure was maintained at 2.0 MPa, and the reaction was stirred for 20 hours. After the reaction was complete, the reaction solution was filtered to recover the palladium on carbon catalyst, and then concentrated to remove the organic solvent. The residue was extracted with dichloromethane, and the dichloromethane phase was concentrated to obtain 11.85 g of the target product 3',4',5'-trifluoro-2-aminobiphenyl, with a quantitative yield of 95.6% and an HPLC purity of 99.51%.
[0051] 1 H NMR (400MHz, DMSO) δ7.25-7.38 (m, 2H), 7.03-7.10 (t, 1H), 6.95-7.00 (d, 1H), 6.71-6.76 (d, 1H), 6.56-6.66 (t, 1H), 4.88-5.10 (s, 2H).
[0052] Example 8
[0053] Under nitrogen protection, 37.5 g of 50% 1,4-dioxane aqueous solution, 5.0 g of 3,4,5-trifluorophenylboronic acid, and 4.48 g of o-chloronitrobenzene were added sequentially to a four-necked flask. Stirring was started, and then 5.9 g of potassium carbonate, 0.2% palladium on carbon (containing 6 mg palladium), and 16 mg of the ligand 2-dicyclohexylphosphino-2′-(N,N-dimethylamine)-biphenyl (DavePhos) were added to the system. After the addition was complete, the mixture was heated to reflux and reacted for 2 hours. Then, hydrogen gas was introduced into a steel cylinder and the pressure was maintained at 2.0 MPa, and the reaction was stirred for 20 hours. After the reaction was complete, the reaction solution was filtered to recover the palladium on carbon catalyst, and then concentrated to remove the organic solvent. The residue was extracted with dichloromethane and the liquid was separated. The dichloromethane phase was concentrated to obtain 11.85 g of the target product 3',4',5'-trifluoro-2-aminobiphenyl, with a quantitative yield of 94.4% and an HPLC purity of 98.97%.
[0054] 1 H NMR (400MHz, DMSO) δ7.25-7.38 (m, 2H), 7.03-7.10 (t, 1H), 6.95-7.00 (d, 1H), 6.71-6.76 (d, 1H), 6.56-6.66 (t, 1H), 4.88-5.10 (s, 2H).
[0055] The above description is merely a specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any variations or substitutions that can be easily conceived by those skilled in the art within the technical scope disclosed in the present invention should be included within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the scope of the claims.
Claims
1. An industrial method for one-pot synthesis of fluopyram-methyl benzidine intermediate, characterized in that, The method uses 3,4,5-trifluorophenylboronic acid and o-chloronitrobenzene as raw materials, employs Pd / C as a catalyst, adds ligands and solvents, and completes the Suzuki coupling and catalytic hydrogenation reaction in a one-pot process under the action of an acid-binding agent to obtain the fluopyram intermediate 3',4',5'-trifluoro-2-aminobiphenyl. The catalytic hydrogenation reaction is carried out under the action of hydrogen gas. The acid-binding agent is potassium carbonate or sodium carbonate, and the molar equivalent of the Pd / C catalyst used is 3,4,5-trifluoro The molar equivalent of phenylboronic acid is 0.1%-0.3%; the ligand is one or more of 2-dicyclohexylphosphine-2′-(N,N-dimethylamine)-biphenyl, 2-bicyclohexylphosphine-2',6'-diisopropoxybiphenyl, 1,1'-bis(diphenylphosphine)-ferrocene, 2-bicyclohexylphosphine-2',6'-dimethoxybiphenyl, and dicyclohexyl[3,6-dimethoxy-2',4',6'-triisopropyl[1,1'-biphenyl]-2-yl]phosphine; The specific reaction formula is as follows: 。 2. The method according to claim 1, characterized in that, The molar equivalent ratio of 3,4,5-trifluorophenylboronic acid and o-chloronitrobenzene is 1:0.5-3.
0.
3. The method according to claim 1, characterized in that, The solvent is an aqueous solution of isopropanol, an aqueous solution of tert-butanol, an aqueous solution of N,N-dimethylformamide, an aqueous solution of N,N-dimethylacetamide, an aqueous solution of acetonitrile, or an aqueous solution of 1,4-dioxane.
4. The method according to claim 1, characterized in that, The weight ratio of 3,4,5-trifluorophenylboronic acid to solvent is 1:2-20.
5. The method according to claim 1, characterized in that, The Pd / C catalyst contains 5-10% palladium.
6. The method according to claim 1, characterized in that, The molar equivalent of the ligand used is 0.1%-1% of the molar equivalent of 3,4,5-trifluorophenylboronic acid.
7. The method according to claim 1, characterized in that, The amount of the acid-binding agent used is 1-3 times the molar equivalent of 3,4,5-trifluorophenylboronic acid.