Process for the preparation of substituted biphenyls
By using palladium catalyst and ferrocene compound ligands in the presence of mixed solvent and base for the synthesis of substituted biphenyls, the problems of excessive palladium catalyst dosage and complex reaction were solved, and efficient and low-cost industrial production was achieved.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- NUTRICHEM LAB CO LTD
- Filing Date
- 2024-12-24
- Publication Date
- 2026-06-26
Smart Images
Figure CN122277408A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of biphenyl synthesis technology, and more specifically to a method for preparing substituted biphenyls. Background Technology
[0002] Substituted biphenyl compounds can serve as important intermediates for pharmaceutical or pesticide compounds, especially in the synthesis of succinate dehydrogenase inhibitors (SDHI) fungicides, such as fluopyram, chlorofluorobifenpyroxime, and bifenpyrazinamide.
[0003] The synthesis of Suzuki coupling reactions often utilizes metal catalysts, particularly palladium-catalyzed coupling reactions. WO2009156359A1 discloses a method for preparing nitro or aminobiphenyls via Suzuki coupling in the presence of a base and a palladium catalyst containing a bidentate phosphorus ligand derived from dppp, but with substituents in the alkylene bridge. In this embodiment, the coupling reaction is carried out in a mixed solvent of water and tetrahydrofuran in the presence of NaOH as a base.
[0004] WO2015011032A1 discloses a method for preparing diphenylaniline chloride or aniline by Suzuki coupling using a palladium catalyst containing optionally substituted di-tert-butylphenylphosphine or its salt as a ligand. This catalyst avoids the formation of undesirable triphenyl compounds. In examples, the coupling reaction is carried out in a mixed solvent of water and 1-butanol in the presence of potassium carbonate as a base.
[0005] However, currently, such reactions either require excessive amounts of palladium catalyst, use complex and unstable catalysts, lack commercially available or expensive ligands, or have overly complex reaction conditions (such as high temperature, high pressure, microwave assistance, etc.), and are not suitable for industrial production. Summary of the Invention
[0006] The purpose of this invention is to overcome the problems of excessive palladium catalyst usage in existing technologies and to provide a method for preparing biphenyl substituted products. This method uses less catalyst, is simple to operate, produces less waste, and significantly improves the yield.
[0007] To achieve the above objectives, the present invention provides a method for preparing substituted biphenyls, wherein the method comprises: in the presence of a mixed solvent and a base, and in the presence of a catalyst and a ligand, a coupling reaction is carried out between a compound with the structure shown in formula (1) and a compound with the structure shown in formula (2) to obtain a coupling reaction product.
[0008] The catalyst is selected from palladium catalysts, and the ligand is selected from ferrocene compounds with the structure shown in formula (4).
[0009] The mixed solvent is water and an organic solvent that is immiscible with water, or water and an alcohol solvent.
[0010]
[0011] In equations (1)-(2),
[0012] R1 is nitro;
[0013] R2 is hydrogen, cyano, or halogen;
[0014] R3 is a cyano, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 haloalkoxy, n is an integer from 0 to 4, and when n is 2 to 4, the group R3 can have the same or different definitions;
[0015] X is a halogen.
[0016] In equation (4),
[0017] R3, R4, R5 and R6 are each independently a phenyl or a phenyl substituted with an alkyl group having 1-3 carbon atoms;
[0018] R7 and R8 are each independently hydrogen or alkyl groups having 1-3 carbon atoms.
[0019] Preferably, the molar ratio of the compound with the structure shown in formula (1) to the catalyst is 1:0.00001-0.005, more preferably 1:0.00005-0.001.
[0020] Preferably, the molar ratio of the compound with the structure shown in formula (1) to the ligand is 1:0.00001-0.005, more preferably 1:0.0001-0.002.
[0021] Preferably, the molar ratio of the compound with the structure shown in formula (1) to the compound with the structure shown in formula (2) is 1:0.9-1.5, and more preferably 1:1-1.2.
[0022] Preferably, the molar ratio of the compound with the structure shown in formula (1) to the base is 1:2-3, more preferably 1:2.01-2.5;
[0023] Preferably, when the mixed solvent is water and an organic solvent that is immiscible with water, the ratio of the amount of water to the total mass of the compounds of formula (1) and formula (2) is 1-5:1, and the ratio of the amount of organic solvent to the total mass of the compounds of formula (1) and formula (2) is 1-5:1.
[0024] Alternatively, when the mixed solvent is water and an alcohol solvent, the ratio of the amount of water to the total mass of the compounds of formula (1) and formula (2) is 1-5:1, and the ratio of the amount of alcohol solvent to the total mass of the compounds of formula (1) and formula (2) is 1-5:1.
[0025] Preferably, the palladium catalyst is one or more of palladium dichloride, palladium acetate, and tetratriphenylphosphine palladium.
[0026] Preferably, the ligand is selected from one or more of compounds with the structure shown in formula (4-1), 1,1'-bis(diphenylphosphine)-ferrocene, and 1,1'-bis(dicyclohexylphosphine)-ferrocene; more preferably, it is a compound with the structure shown in formula (4-1).
[0027]
[0028] Preferably, the compound with the structure shown in formula (1) is selected from one or more of o-chloronitrobenzene, o-bromonitrobenzene and 4-fluoro-2-bromonitrobenzene.
[0029] Preferably, the compound with the structure shown in formula (2) is selected from one or more of 3,4,5-trifluorophenylboronic acid, 3,4-dichlorophenylboronic acid and 3,4-difluorophenylboronic acid.
[0030] Preferably, the alkali is selected from one or more of sodium hydroxide, potassium hydroxide, potassium tert-butoxide, and potassium trimethylsilanolate.
[0031] Preferably, the organic solvent is selected from one or more of toluene, chlorobenzene, ethanol, and tetrahydrofuran.
[0032] Preferably, the conditions for the coupling reaction include: a reaction temperature of 80-120℃ and a reaction time of 2-15h.
[0033] Preferably, when the mixed solvent is water and an organic solvent that is immiscible with water, the method further includes the step of: performing solid-liquid separation on the obtained coupling reaction product and separating the organic phase, and then performing a hydrogenation reaction on the organic phase with a hydrogenation catalyst and hydrogen to obtain a compound with the structure shown in formula (3);
[0034] Alternatively, when the mixed solvent is water and an alcohol solvent, the method further includes the steps of: performing solid-liquid separation on the obtained coupling reaction product, and performing hydrogenation reaction on the obtained solid phase with a hydrogenation catalyst and hydrogen in the presence of a solvent to obtain a compound with the structure shown in formula (3);
[0035]
[0036] In formula (3)
[0037] R 1` It is an amino group;
[0038] R2 is hydrogen, cyano, or halogen;
[0039] R3 is a cyano, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 haloalkoxy group, where n is an integer from 0 to 4, and when n is 2 to 4, the group R3 may have the same or different definitions.
[0040] Preferably, the molar ratio of the compound with the structure shown in formula (1) to the hydrogenation catalyst is 1:0.00001-0.005, more preferably 1:0.00005-0.001.
[0041] Preferably, the hydrogenation catalyst is palladium-carbon or platinum-carbon, and more preferably platinum-carbon.
[0042] Preferably, the conditions for the hydrogenation reaction include: a reaction temperature of 25-120°C, a reaction time of 0.5-12 h, and a hydrogen pressure of 0.2-2.0 MPa.
[0043] Preferably, when the solvent is water or an organic solvent that is immiscible with water, the method further includes: using the solid phase obtained by solid-liquid separation of the resulting coupling reaction product as the catalyst.
[0044] Preferably, the method further includes a step of recrystallizing the hydrogenation reaction product.
[0045] Through the above technical solution, the present invention can provide a method for preparing substituted biphenyls. This method uses significantly less catalyst and base, is simple to operate, produces less waste, and has a significantly improved yield, making it particularly suitable for large-scale industrial production.
[0046] When the mixed solvent is water and an organic solvent that is immiscible with water, the resulting coupling reaction product is subjected to solid-liquid separation to separate the organic phase. Then, the organic phase is subjected to hydrogenation reaction with a hydrogenation catalyst and hydrogen. Thus, the hydrogenation reaction can be carried out without purifying the Suzuki coupling product or replacing the solvent, which can further reduce the difficulty of operation, reduce waste, and improve the yield.
[0047] Furthermore, when the mixed solvent is water and an organic solvent that is immiscible with water, the solid phase obtained from solid-liquid separation can be reused as a coupling catalyst. Even after repeated use, the purity and yield of the target product can be maintained at an extremely high level. Attached Figure Description
[0048] Figure 1 The 3',4',5'-trifluoro-2-aminobiphenyl prepared in Example 1 1 H-NMR spectrum. Detailed Implementation
[0049] The endpoints and any values of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values should be understood to include values close to these ranges or values. For numerical ranges, the endpoint values of the various ranges, the endpoint values of the various ranges and individual point values, and individual point values can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.
[0050] This invention provides a method for preparing substituted biphenyls, wherein the method includes: a coupling reaction of a compound with the structure shown in formula (1) and a compound with the structure shown in formula (2) in the presence of a mixed solvent and a base, and in the presence of a catalyst and a ligand, to obtain a coupling reaction product.
[0051] The catalyst is selected from palladium catalysts, and the ligand is selected from ferrocene compounds with the structure shown in formula (4).
[0052] The mixed solvent is water and an organic solvent that is immiscible with water, or water and an alcohol solvent.
[0053]
[0054] In equations (1)-(2),
[0055] R1 is nitro;
[0056] R2 is hydrogen, cyano, or halogen;
[0057] R3 is a cyano, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 haloalkoxy, n is an integer from 0 to 4, and when n is 2 to 4, the group R3 can have the same or different definitions;
[0058] X is a halogen.
[0059] In equation (4),
[0060] R3, R4, R5 and R6 are each independently a phenyl or a phenyl substituted with an alkyl group having 1-3 carbon atoms;
[0061] R7 and R8 are each independently hydrogen or alkyl groups having 1-3 carbon atoms.
[0062] In this invention, halogen refers to F, Cl, Br, I, preferably F, Cl, Br, more preferably Cl, Br, and especially preferably Cl.
[0063] In this invention, C1-C6 alkyl refers to saturated straight-chain, branched or cyclic, primary, secondary or tertiary hydrocarbons, for example: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.
[0064] In this invention, C1-C6 haloalkyl refers to a group in which the hydrogen atoms of the aforementioned C1-C6 alkyl group are partially or completely replaced by halogens.
[0065] In this invention, C1-C6 haloalkoxy refers to a group in which the hydrogen atom of a C1-C6 alkoxy group is partially or completely replaced by a halogen. Examples of C1-C6 alkoxy groups include methoxy, ethoxy, n-propoxy, sec-butoxy, tert-butoxy, pentoxy, and n-hexoxy.
[0066] According to the method of the present invention, preferably, in formula (1), R1 is nitro; R2 is hydrogen or halogen; X is F, Cl or Br; more preferably, in formula (1), R1 is nitro; R2 is hydrogen; X is Cl or Br.
[0067] In a preferred embodiment of the present invention, the compound with the structure shown in formula (1) is selected from one or more of o-chloronitrobenzene, o-bromonitrobenzene and 4-fluoro-2-bromonitrobenzene; preferably o-chloronitrobenzene and / or o-bromonitrobenzene, and particularly preferably o-chloronitrobenzene.
[0068] According to the method of the present invention, preferably, in formula (2), R3 is a halogen, C1-C3 alkyl, C1-C3 haloalkyl or C1-C3 haloalkoxy, n is an integer from 0 to 3, and when n is 2 to 3, the group R3 may have the same or different definitions; more preferably, in formula (2), R3 is F, Cl, Br, n is an integer from 0 to 3, and when n is 2 to 3, the group R3 may have the same or different definitions; particularly preferably, in formula (2), R3 is F, and n is 3.
[0069] In a preferred embodiment of the present invention, the compound with the structure shown in formula (2) is one or more of 3,4,5-trifluorophenylboronic acid, 3,4-dichlorophenylboronic acid and 3,4-difluorophenylboronic acid; preferably 3,4,5-trifluorophenylboronic acid.
[0070] In this invention, the ligand is selected from ferrocene compounds with the structure shown in formula (4). Preferably, in formula (4), R3, R4, R5 and R6 are each independently phenyl, methyl-substituted phenyl, ethyl-substituted phenyl or propyl-substituted phenyl; R7 and R8 are each independently hydrogen, methyl, ethyl or propyl.
[0071] In a preferred embodiment of the present invention, the ligand is selected from one or more of compounds with the structure shown in formula (4-1), 1,1'-bis(diphenylphosphine)-ferrocene, and 1,1'-bis(dicyclohexylphosphine)-ferrocene; preferably, it is a compound with the structure shown in formula (4-1).
[0072]
[0073] According to the method of the present invention, the amount of catalyst can be selected according to the amount of compound with the structure shown in formula (1). Preferably, the molar ratio of compound with the structure shown in formula (1) to catalyst is 1:0.00001-0.005; more preferably, the molar ratio of compound with the structure shown in formula (1) to catalyst is 1:0.00005-0.001.
[0074] In this invention, specific examples of the molar ratio of the compound with the structure shown in formula (1) to the catalyst include, for example: 1:0.00001, 1:0.00002, 1:0.00003, 1:0.00004, 1:0.00005, 1:0.00006, 1:0.00007, 1:0.00008, 1:0.00009, 1:0.0001, 1:0.0002, 1 :0.0003, 1:0.0004, 1:0.0005, 1:0.0006, 1:0.0007, 1:0.0008, 1:0.0009, 1:0.001, 1:0.0015, 1:0.002, 1:0.0025, 1:0.003, 1:0.0035, 1:0.004, 0.0045, 1:0.005, etc., and any two of the above ranges.
[0075] According to the method of the present invention, the amount of the ligand can be selected according to the amount of the compound with the structure shown in formula (1). Preferably, the molar ratio of the compound with the structure shown in formula (1) to the ligand is 1:0.00001-0.005; more preferably, the molar ratio of the compound with the structure shown in formula (1) to the ligand is 1:0.0001-0.002.
[0076] In this invention, specific examples of the molar ratio of the compound with the structure shown in formula (1) to the ligand can be given, for example: 1:0.00001, 1:0.00002, 1:0.00003, 1:0.00004, 1:0.00005, 1:0.00006, 1:0.00007, 1:0.00008, 1:0.00009, 1:0.0001, 1:0.0002, 1:0.0003, 1:0.000 4. 1:0.0005, 1:0.0006, 1:0.0007, 1:0.0008, 1:0.0009, 1:0.001, 1:0.0012, 1:0.0014, 1:0.0016, 1:0.0018, 1:0.002, 1:0.0025, 1:0.003, 1:0.0035, 1:0.004, 1:0.0045, 1:0.005, etc., and any two of the above that constitute a range.
[0077] According to the method of the present invention, the amount of the compound with the structure shown in formula (2) can be selected according to the amount of the compound with the structure shown in formula (1). Preferably, the molar ratio of the compound with the structure shown in formula (1) to the compound with the structure shown in formula (2) is 1:0.9-1.5; more preferably, the molar ratio of the compound with the structure shown in formula (1) to the compound with the structure shown in formula (2) is 1:1-1.2.
[0078] In this invention, specific examples of the molar ratio of the compound with the structure shown in formula (1) to the compound with the structure shown in formula (2) can be given, for example: 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, etc., as well as any two of the above ranges.
[0079] According to the method of the present invention, the amount of the base can be selected according to the amount of the compound with the structure shown in formula (1). Preferably, the molar ratio of the compound with the structure shown in formula (1) to the base is 1:2-3; more preferably, the molar ratio of the compound with the structure shown in formula (1) to the base is 1:2.01-2.5.
[0080] In this invention, specific examples of the molar ratio of the compound with the structure shown in formula (1) to the base can be, for example, 1:2, 1:2.01, 1:2.05, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3, etc., as well as any two of the above ranges.
[0081] According to the method of the present invention, when the mixed solvent is water and an organic solvent that is immiscible with water, the ratio of the amount of water to the total mass of the compounds of formula (1) and formula (2) is 1-5:1, and the ratio of the amount of the organic solvent to the total mass of the compounds of formula (1) and formula (2) is 1-5:1.
[0082] Alternatively, when the mixed solvent is water and an alcohol solvent, the ratio of the amount of water to the total mass of the compounds of formula (1) and formula (2) is 1-5:1, and the ratio of the amount of alcohol solvent to the total mass of the compounds of formula (1) and formula (2) is 1-5:1.
[0083] As an organic solvent that is immiscible with water, it is acceptable as long as it is inert to the raw material and immiscible with water. Preferably, the organic solvent is selected from one or more of toluene, chlorobenzene and 1,2-dichloroethane; more preferably, the organic solvent is selected from toluene and / or chlorobenzene.
[0084] As an alcohol solvent, alcohols with 1-4 carbon atoms are preferred, and more preferably one or more of methanol, ethanol and isopropanol.
[0085] According to the method of the present invention, the catalyst is selected from palladium catalysts, preferably, the palladium catalyst is one or more of palladium dichloride, palladium acetate and tetraphenylphosphine palladium; more preferably, the palladium catalyst is palladium dichloride.
[0086] According to the method of the present invention, the alkali can be an inorganic alkali or an organic alkali, preferably an inorganic alkali.
[0087] In a preferred embodiment of the present invention, the alkali is selected from one or more of sodium hydroxide, potassium hydroxide, potassium tert-butoxide and potassium trimethylsilanolate; more preferably, the alkali is selected from sodium hydroxide and / or potassium hydroxide.
[0088] According to the method of the present invention, preferably, the conditions for the coupling reaction include: a reaction temperature of 80-120°C and a reaction time of 2-15 h; more preferably, the conditions for the coupling reaction include: a reaction temperature of 90-100°C and a reaction time of 4-6 h.
[0089] According to the method of the present invention, preferably, when the mixed solvent is water and an organic solvent that is immiscible with water, the method further includes: performing solid-liquid separation on the obtained coupling reaction product and separating the organic phase, and then performing a hydrogenation reaction on the organic phase with a hydrogenation catalyst and hydrogen to obtain a compound with the structure shown in formula (3);
[0090] Alternatively, when the mixed solvent is water and an alcohol solvent, the method further includes the steps of: performing solid-liquid separation on the obtained coupling reaction product, and performing hydrogenation reaction on the obtained solid phase with a hydrogenation catalyst and hydrogen in the presence of a solvent to obtain a compound with the structure shown in formula (3);
[0091]
[0092] In formula (3)
[0093] R 1` It is an amino group;
[0094] The definitions of R2 and R3 are the same as those of R2 in equation (1) and R3 in equation (2), respectively.
[0095] According to the method of the present invention, the amount of the hydrogenation catalyst can also be selected according to the amount of the compound with the structure shown in formula (1). Preferably, the molar ratio of the compound with the structure shown in formula (1) to the hydrogenation catalyst is 1:0.00001-0.005; more preferably, the molar ratio of the compound with the structure shown in formula (1) to the hydrogenation catalyst is 1:0.00005-0.001.
[0096] In this invention, the molar ratio of the compound with the structure shown in formula (1) to the hydrogenation catalyst can be, for example, 1:0.00001, 1:0.00002, 1:0.00003, 1:0.00004, 1:0.00005, 1:0.00006, 1:0.00007, 1:0.00008, 1:0.00009, 1:0.0001, 1:0.0002, 1: 0.0003, 1:0.0004, 1:0.0005, 1:0.0006, 1:0.0007, 1:0.0008, 1:0.0009, 1:0.001, 1:0.0015, 1:0.002, 1:0.0025, 1:0.003, 1:0.0035, 1:0.004, 0.0045, 1:0.005, etc., and any two of the above ranges.
[0097] According to the method of the present invention, preferably, the hydrogenation catalyst is palladium-carbon or platinum-carbon, more preferably platinum-carbon.
[0098] According to the method of the present invention, preferably, the conditions for the hydrogenation reaction include: a reaction temperature of 25-120°C, a reaction time of 0.5-12 h, and a hydrogen pressure of 0.2-2.0 MPa; more preferably, the conditions for the hydrogenation reaction include: a reaction temperature of 60-80°C, a reaction time of 1-3 h, and a hydrogen pressure of 0.4-0.6 MPa.
[0099] According to the method of the present invention, preferably, when the solvent is water and an organic solvent that is immiscible with water, the method further includes: using the solid phase obtained by solid-liquid separation of the obtained coupling reaction product as the catalyst.
[0100] In this invention, the solid phase obtained from solid-liquid separation is reused as a coupling catalyst. Even after repeated use, the purity and yield of the target product can be maintained at an extremely high level.
[0101] According to the method of the present invention, after the hydrogenation reaction is completed, purification can be carried out using conventional purification methods in the art. However, since the present invention can significantly improve the yield even when the amount of catalyst used is significantly reduced, the post-processing can be very simple. For example, the hydrogenation reaction product can be recrystallized to obtain the target product. There are no particular limitations on the recrystallization method. For example, concentration and / or cooling crystallization can be used.
[0102] The present invention will be described in detail below through embodiments, but the present invention is not limited to the following embodiments.
[0103] Unless otherwise specified, the raw materials used in the following examples and comparative examples are all disclosed in the prior art, such as those that can be directly purchased or prepared according to the preparation methods disclosed in the prior art.
[0104] In the following examples, the synthesized compounds... 1 H nuclear magnetic resonance (H nuclear magnetic resonance) 1 H-NMR was performed on a Bruker AVANCE III-500MHz spectrometer using CDCl3 as solvent at 25°C.
[0105] Example 1
[0106] 1) Under nitrogen protection, in an apparatus equipped with a reflux condenser, thermometer, and stirrer, add o-chloronitrobenzene (159 g, 99 wt%, 1 mol), 3,4,5-trifluorophenylboronic acid (183 g, 98 wt%, 1.02 mol), sodium hydroxide aqueous solution (250 g, 32 wt%, 2 mol), palladium dichloride (1.8 mg, 99 wt%, 0.01 mmol), ligand (using the compound with the structure shown in formula (4-1) above, 13.0 mg, 98 wt%, 0.02 mmol), and 1000 mL of toluene. After stirring evenly, the mixture is heated to reflux for 3 h. HPLC analysis shows that the o-chloronitrobenzene content is less than 0.2% and the 3',4',5'-trifluoro-2-nitrobenzene content is 98.6%, at which point the reaction is complete.
[0107] 2) The reaction solution obtained in step 1) was filtered, and the filter cake was used as a catalyst for recovery. The filtrate was separated, and the organic phase was added to a high-pressure reactor. Platinum / carbon catalyst (5 wt%, 2 g) was added, and hydrogen gas was introduced to carry out the reduction reaction at a pressure of 0.6 MPa for 1 h. HPLC analysis showed that the content of 3',4',5'-trifluoro-2-nitrobiphenyl was less than 0.5%. The reaction was completed, and the reaction solution was filtered. The filter cake was used as a catalyst and could be reused for the next batch of reduction reaction. After removing some solvent from the filtrate, it was cooled to 0-5℃ for crystallization. After filtration and drying, 3',4',5'-trifluoro-2-aminobiphenyl was obtained with a content of 98.5 wt% and a yield of 96.6% (based on o-chloronitrobenzene). Its NMR data ( 1 H-NMR) such as Figure 1 As shown.
[0108] 3) Using the catalyst recovered in step 2), continue the coupling and hydrogenation reactions for 9 rounds according to steps 1) and 2) above. The purity and yield of 3',4',5'-trifluoro-2-aminobiphenyl obtained in each round are shown in Table 1.
[0109] Purity (wt%) Yield (%) Round 1 98.5 96.4 Round 2 98.5 96.5 Round 3 98.8 96.2 Round 4 98.6 96.9 Round 5 98.3 97.2 Round 6 98.4 96.5 Round 7 98.6 96.1 Round 8 98.2 96.7 Ninth round 98.2 96.6
[0110] Example 2
[0111] 1) Under nitrogen protection, in an apparatus equipped with a reflux condenser, thermometer, and stirrer, add o-chloronitrobenzene (159 g, 99 wt%, 1 mol), 3,4,5-trifluorophenylboronic acid (188.5 g, 98 wt%, 1.05 mol), sodium hydroxide aqueous solution (262.5 g, 32 wt%, 2.1 mol), palladium dichloride (1.8 mg, 99 wt%, 0.01 mmol), ligand (using the compound with the structure shown in formula (4-1) above, 13.0 mg, 98 wt%, 0.02 mmol), and 1000 mL of toluene. After stirring evenly, the mixture is heated to reflux for 3 h. HPLC analysis shows that the o-chloronitrobenzene content is less than 0.2% and the 3',4',5'-trifluoro-2-nitrobenzene content is 99.1%, at which point the reaction is complete.
[0112] 2) Filter the reaction solution obtained in step 1), and recover the filter cake as catalyst. Separate the filtrate, add the organic phase to the high-pressure reactor, add the catalyst platinum / carbon (5 wt%, 2 g), and purge with hydrogen to carry out the reduction reaction at a pressure of 0.6 MPa for 1 h. HPLC analysis showed that the content of 3',4',5'-trifluoro-2-nitrobiphenyl was less than 0.5%. The reaction was completed, and the reaction solution was filtered. The filter cake was used as catalyst and could be reused for the next batch of reduction reaction. After removing some solvent from the filtrate, it was cooled to 0-5℃ to crystallize, filtered, and dried to obtain 3',4',5'-trifluoro-2-aminobiphenyl (the compound structure is the same as in Example 1, and was confirmed by NMR), with a content of 98.6 wt% and a yield of 97.1% (based on o-chloronitrobenzene).
[0113] Example 3
[0114] 1) Under nitrogen protection, in an apparatus equipped with a reflux condenser, thermometer, and stirrer, add o-chloronitrobenzene (159 g, 99 wt%, 1 mol), 3,4,5-trifluorophenylboronic acid (183 g, 98 wt%, 1.02 mol), sodium hydroxide aqueous solution (250 g, 32 wt%, 2 mol), palladium dichloride (1.8 mg, 99 wt%, 0.01 mmol), ligand (using the compound with the structure shown in formula (4-1) above, 13.0 mg, 98 wt%, 0.02 mmol), and 1000 mL of toluene. After stirring evenly, the mixture is heated to reflux for 3 h. HPLC analysis shows that the o-chloronitrobenzene content is less than 0.2% and the 3',4',5'-trifluoro-2-nitrobenzene content is 98.5%, at which point the reaction is complete.
[0115] 2) The reaction solution obtained in step 1) was filtered, and the filter cake was used as a catalyst for recovery. The filtrate was separated, and the organic phase was added to a high-pressure reactor. Platinum / carbon catalyst (5% by weight, 1g) was added, and hydrogen gas was introduced to carry out the reduction reaction. The reaction was carried out at a pressure of 0.6 MPa for 2 hours. HPLC analysis showed that the content of 3',4',5'-trifluoro-2-nitrobiphenyl was less than 0.5%. The reaction was completed, and the reaction solution was filtered. The filter cake was used as a catalyst and could be reused for the next batch of reduction reaction. After removing part of the solvent from the filtrate, it was cooled to 0-5℃ for crystallization. After filtration and drying, 3',4',5'-trifluoro-2-aminobiphenyl (the compound structure is the same as in Example 1 and was confirmed by NMR) was obtained with a content of 98.3% by weight and a yield of 96.5% (based on o-chloronitrobenzene).
[0116] Example 4
[0117] 1) Under nitrogen protection, in an apparatus equipped with a reflux condenser, thermometer, and stirrer, add o-chloronitrobenzene (159 g, 99 wt%, 1 mol), 3,4,5-trifluorophenylboronic acid (183 g, 98 wt%, 1.02 mol), sodium hydroxide aqueous solution (250 g, 32 wt%, 2 mol), palladium dichloride (3.6 mg, 99 wt%, 0.02 mmol), ligand (using the compound with the structure shown in formula (4-1) above, 26.1 mg, 98 wt%, 0.04 mmol), and 1000 mL of toluene. After stirring evenly, the mixture is heated to reflux for 3 h. HPLC analysis shows that the o-chloronitrobenzene content is less than 0.2% and the 3',4',5'-trifluoro-2-nitrobenzene content is 99.5%, at which point the reaction is complete.
[0118] 2) Filter the reaction solution obtained in step 1), and recover the filter cake as catalyst. Separate the filtrate, add the organic phase to the high-pressure reactor, add the catalyst platinum / carbon (5 wt%, 2 g), and purge with hydrogen to carry out the reduction reaction at a pressure of 0.6 MPa for 1 h. HPLC analysis showed that the content of 3',4',5'-trifluoro-2-nitrobiphenyl was less than 0.5%. The reaction was completed, and the reaction solution was filtered. The filter cake was used as catalyst and could be reused for the next batch of reduction reaction. After removing some solvent from the filtrate, it was cooled to 0-5℃ to crystallize, filtered, and dried to obtain 3',4',5'-trifluoro-2-aminobiphenyl (the compound structure is the same as in Example 1, and was confirmed by NMR), with a content of 98.9 wt% and a yield of 97.6% (based on o-chloronitrobenzene).
[0119] Example 5
[0120] The procedure was carried out according to Example 1, except that palladium dichloride was replaced with the same molar amount of palladium acetate catalyst to obtain 3',4',5'-trifluoro-2-aminobiphenyl (the compound structure is the same as in Example 1 and was confirmed by NMR), with a content of 98.8% by weight and a yield of 97.0% (based on o-chloronitrobenzene).
[0121] Example 6
[0122] The procedure was carried out according to Example 1, except that palladium dichloride was replaced with the same molar amount of tetratriphenylphosphine palladium catalyst, yielding 3',4',5'-trifluoro-2-aminobiphenyl (the compound structure is the same as in Example 1, and was confirmed by NMR), with a content of 98.1% by weight and a yield of 92.% (based on o-chloronitrobenzene).
[0123] Example 7
[0124] The procedure was carried out according to Example 1, except that compound (4-1) was replaced with the same molar amount of 1,1'-bis(diphenylphosphine)-ferrocene compound to obtain 3',4',5'-trifluoro-2-aminobiphenyl (the structure of which was the same as in Example 1 and confirmed by NMR), with a content of 98.0 wt% and a yield of 86.6% (based on o-chloronitrobenzene).
[0125] Example 8
[0126] The procedure was carried out according to Example 1, except that compound (4-1) was replaced with the same molar amount of 1,1'-bis(dicyclohexylphosphine)-ferrocene compound to obtain 3',4',5'-trifluoro-2-aminobiphenyl (the structure of which was the same as in Example 1 and confirmed by NMR), with a content of 98.1% by weight and a yield of 82.2% (based on o-chloronitrobenzene).
[0127] Example 9
[0128] 1) Under nitrogen protection, in an apparatus equipped with a reflux condenser, thermometer, and stirrer, add o-chloronitrobenzene (159 g, 99 wt%, 1 mol), 3,4,5-trifluorophenylboronic acid (188 g, 98 wt%, 1.05 mol), sodium hydroxide aqueous solution (263 g, 32 wt%, 2.1 mol), palladium dichloride (3.6 mg, 99 wt%, 0.02 mmol), ligand (using the compound with the structure shown in formula (4-1) above, 26.1 mg, 98 wt%, 0.04 mmol), and 1000 mL of ethanol. After stirring evenly, the mixture is heated to reflux for 3 h. HPLC analysis shows that the o-chloronitrobenzene content is less than 0.1% and the 3',4',5'-trifluoro-2-nitrobenzene content is 99.0%, at which point the reaction is complete.
[0129] 2) Filter the reaction solution obtained in step 1). The filter cake consists of 3',4',5'-trifluoro-2-nitrobiphenyl and catalyst. Add 1000 ml of toluene to the filter cake to dissolve it, and then filter it again. The filter cake is used as catalyst for recovery. Add the toluene phase of the filtrate to a high-pressure reactor, add the catalyst palladium / carbon (5 wt%, 1 g), and purge with hydrogen to carry out the reduction reaction. The reaction is carried out at a pressure of 0.6 MPa for 1 h. HPLC analysis shows that 3',4',5'-trifluoro-2-nitrobiphenyl is less than 0.5%. The reaction is then completed. Filter the reaction solution. The filter cake is used as catalyst and can be reused for the next batch of reduction reaction. After removing some solvent from the filtrate, cool it to 0-5℃ to crystallize. Filter and dry to obtain 3',4',5'-trifluoro-2-aminobiphenyl (the compound structure is the same as in Example 1 and was confirmed by NMR), with a content of 98.5 wt% and a yield of 92.7% (based on o-chloronitrobenzene).
[0130] Example 10
[0131] 1) Under nitrogen protection, in an apparatus equipped with a reflux condenser, thermometer, and stirrer, add o-chloronitrobenzene (159 g, 99 wt%, 1 mol), 3,4-difluorophenylboronic acid (164.4 g, 98 wt%, 1.02 mol), sodium hydroxide aqueous solution (250 g, 32 wt%, 2 mol), palladium dichloride (3.6 mg, 99 wt%, 0.02 mmol), ligand (using the compound with the structure shown in formula (4-1) above, 26.1 mg, 98 wt%, 0.04 mmol), and 1000 mL of toluene. After stirring evenly, the mixture is heated to reflux for 3 h. HPLC analysis shows that the content of 4-fluoro-2-bromonitrobenzene is less than 0.2%, and the content of 3',4'-dichloro-4-fluoro-2-nitrobenzene is 99.5%. The reaction is then complete.
[0132] 2) The reaction solution obtained in step 1) was filtered, and the filter cake was used as a catalyst for recovery. The filtrate was separated, and the organic phase was added to a high-pressure reactor. Platinum / carbon catalyst (5 wt%, 2 g) was added, and hydrogen gas was introduced to carry out the reduction reaction at a pressure of 0.6 MPa for 1 h. HPLC analysis showed that the content of 3',4'-dichloro-4-fluoro-2-nitrobiphenyl was less than 0.5%. The reaction was completed, and the reaction solution was filtered. The filter cake was used as a catalyst and could be reused for the next batch of reduction reaction. After removing some solvent from the filtrate, it was cooled to 0-5℃ for crystallization, filtered, and dried to obtain 3',4'-dichloro-4-fluoro-2-aminobiphenyl (the compound structure is the same as in Example 1 and was confirmed by NMR), with a content of 98.8 wt% and a yield of 97.3% (based on 4-fluoro-2-bromonitrobenzene).
[0133] Example 11
[0134] 1) Under nitrogen protection, in an apparatus equipped with a reflux condenser, thermometer, and stirrer, add 222.2 g of 4-fluoro-2-bromonitrobenzene (99 wt%, 1 mol), 198.6 g of 3,4-dichlorophenylboronic acid (98 wt%, 1.02 mol), 250 g of sodium hydroxide aqueous solution (32 wt%, 2 mol), 3.6 mg of palladium dichloride (99 wt%, 0.02 mmol), 26.1 mg of a ligand (using the compound with the structure shown in formula (4-1) above, 98 wt%, 0.04 mmol), and 1000 mL of toluene. After stirring evenly, the mixture is heated to reflux for 3 h. HPLC analysis shows that the content of 4-fluoro-2-bromonitrobenzene is less than 0.2%, and the content of 3',4'-difluoro-2-nitrobenzene is 99.0%. The reaction is then complete.
[0135] 2) Filter the reaction solution obtained in step 1), and recover the filter cake as catalyst. Separate the filtrate, add the organic phase to the high-pressure reactor, add the catalyst platinum / carbon (5 wt%, 2 g), and pass hydrogen gas to carry out the reduction reaction. The reaction is carried out at a pressure of 0.6 MPa for 1 h. HPLC analysis shows that the content of 3',4'-difluoro-2-nitrobiphenyl is less than 0.5%. The reaction is completed, filter the reaction solution, and use the filter cake as catalyst for the next batch of reduction reaction. After removing part of the solvent from the filtrate, cool it to 0-5℃ to crystallize, filter and dry to obtain 3',4'-difluoro-2-aminobiphenyl (the compound structure is the same as in Example 1, and was confirmed by NMR), with a content of 98.5 wt% and a yield of 96.3% (based on 4-fluoro-2-bromonitrobenzene).
[0136] Comparative Example 1
[0137] The procedure was carried out according to Example 1, except that the ligand was triphenylphosphine, yielding 3',4',5'-trifluoro-2-aminobiphenyl in a content of 77% by weight and a yield of 25% (based on o-chloronitrobenzene).
[0138] Comparative Example 2
[0139] The procedure was carried out according to Example 1, except that the ligand was 1,3-bis(diphenylphosphine)propane, yielding 3',4',5'-trifluoro-2-aminobiphenyl in a content of 51% by weight and a yield of 17% (based on o-chloronitrobenzene).
[0140] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.
Claims
1. A method for preparing substituted biphenyls, characterized in that, The method includes the step of coupling a compound with the structure shown in formula (1) to a compound with the structure shown in formula (2) in the presence of a mixed solvent and a base, and in the presence of a catalyst and a ligand, to obtain the coupling reaction product. The catalyst is selected from palladium catalysts, and the ligand is selected from ferrocene compounds with the structure shown in formula (4). The mixed solvent is water and an organic solvent that is immiscible with water, or water and an alcohol solvent. In equations (1)-(2), R1 is nitro; R2 is hydrogen, cyano, or halogen; R3 is a cyano, halogen, C1-C6 alkyl, C1-C6 haloalkyl or C1-C6 haloalkoxy, n is an integer from 0 to 4, and when n is 2 to 4, the group R3 can have the same or different definitions; X is a halogen. In equation (4), R3, R4, R5 and R6 are each independently a phenyl or a phenyl substituted with an alkyl group having 1-3 carbon atoms; R7 and R8 are each independently hydrogen or alkyl groups having 1-3 carbon atoms.
2. The method according to claim 1, wherein, The molar ratio of the compound with the structure shown in formula (1) to the catalyst is 1:0.00001-0.005, preferably 1:0.00005-0.001; Preferably, the molar ratio of the compound with the structure shown in formula (1) to the ligand is 1:0.00001-0.005, more preferably 1:0.0001-0.
002.
3. The method according to claim 1, wherein, The molar ratio of the compound with the structure shown in formula (1) to the compound with the structure shown in formula (2) is 1:0.9-1.5, preferably 1:1-1.2; Preferably, the molar ratio of the compound with the structure shown in formula (1) to the base is 1:2-3, more preferably 1:2.01-2.
5.
4. The method according to any one of claims 1-3, wherein, When the mixed solvent is water and an organic solvent that is immiscible with water, the ratio of the amount of water to the total mass of the compounds of formula (1) and formula (2) is 1-5:1, and the ratio of the amount of organic solvent to the total mass of the compounds of formula (1) and formula (2) is 1-5:
1. Alternatively, when the mixed solvent is water and an alcohol solvent, the ratio of the amount of water to the total mass of the compounds of formula (1) and formula (2) is 1-5:1, and the ratio of the amount of alcohol solvent to the total mass of the compounds of formula (1) and formula (2) is 1-5:
1.
5. The method according to any one of claims 1-3, wherein, The palladium catalyst is one or more of palladium dichloride, palladium acetate, and tetratriphenylphosphine palladium; Preferably, the ligand is selected from one or more of compounds with the structure shown in formula (4-1), 1,1'-bis(diphenylphosphine)-ferrocene, and 1,1'-bis(dicyclohexylphosphine)-ferrocene; more preferably, it is a compound with the structure shown in formula (4-1). Preferably, the compound with the structure shown in formula (1) is selected from one or more of o-chloronitrobenzene, o-bromonitrobenzene, and 4-fluoro-2-bromonitrobenzene; Preferably, the compound with the structure shown in formula (2) is selected from one or more of 3,4,5-trifluorophenylboronic acid, 3,4-dichlorophenylboronic acid and 3,4-difluorophenylboronic acid; Preferably, the alkali is selected from one or more of sodium hydroxide, potassium hydroxide, potassium tert-butoxide, and potassium trimethylsilanolate; Preferably, the organic solvent is selected from one or more of toluene, chlorobenzene, ethanol, and tetrahydrofuran.
6. The method according to any one of claims 1-3, wherein, The conditions for the coupling reaction include: a reaction temperature of 80-120℃ and a reaction time of 2-15h.
7. The method according to any one of claims 1-3, wherein, When the mixed solvent is water and an organic solvent that is immiscible with water, the method further includes the following steps: performing solid-liquid separation on the obtained coupling reaction product and separating the organic phase, and then subjecting the organic phase to a hydrogenation reaction with a hydrogenation catalyst and hydrogen to obtain a compound with the structure shown in formula (3); Alternatively, when the mixed solvent is water and an alcohol solvent, the method further includes the steps of: performing solid-liquid separation on the obtained coupling reaction product, and performing hydrogenation reaction on the obtained solid phase with a hydrogenation catalyst and hydrogen in the presence of a solvent to obtain a compound with the structure shown in formula (3); In formula (3) R 1` It is an amino group; R2 is hydrogen, cyano, or halogen; R3 is a cyano, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 haloalkoxy group, where n is an integer from 0 to 4, and when n is 2 to 4, the group R3 may have the same or different definitions.
8. The method according to claim 7, wherein, The molar ratio of the compound with the structure shown in formula (1) to the hydrogenation catalyst is 1:0.00001-0.005, preferably 1:0.00005-0.001; Preferably, the hydrogenation catalyst is palladium-carbon or platinum-carbon, and more preferably platinum-carbon.
9. The method according to claim 7, wherein, The conditions for the hydrogenation reaction include: a reaction temperature of 25-120℃, a reaction time of 0.5-12h, and a hydrogen pressure of 0.2-2.0Mpa.
10. The method according to claim 7, wherein, When the solvent is water or an organic solvent that is immiscible with water, the method further includes: using the solid phase obtained by solid-liquid separation of the resulting coupling reaction product as the catalyst.
11. The method according to claim 7, wherein, The method also includes a step of recrystallizing the hydrogenation reaction product.