CN116082163A - Preparation method of 3',4' -difluoro-2 ' -aminobiphenyl - Google Patents
Preparation method of 3',4' -difluoro-2 ' -aminobiphenyl Download PDFInfo
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- CN116082163A CN116082163A CN202310016409.1A CN202310016409A CN116082163A CN 116082163 A CN116082163 A CN 116082163A CN 202310016409 A CN202310016409 A CN 202310016409A CN 116082163 A CN116082163 A CN 116082163A
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- difluoro
- aminobiphenyl
- chloroaniline
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
- B01J31/2409—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring with more than one complexing phosphine-P atom
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/40—Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
- B01J2231/42—Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
- B01J2231/4205—C-C cross-coupling, e.g. metal catalyzed or Friedel-Crafts type
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
- B01J2531/824—Palladium
Abstract
The invention provides a preparation method of 3',4' -difluoro-2 ' -aminobiphenyl, which belongs to the technical field of compound synthesis, and the preparation method is characterized in that 3, 4-difluorophenylboronic acid and o-chloroaniline are taken to perform a coupling reaction under the combined action of catalyst bis (tricyclohexylphosphine) palladium dichloride and catalyst ligand 2-dicyclohexylphosphine-2 ' - (N, N-dimethylamino) biphenyl, so as to obtain the 3',4' -difluoro-2 ' -aminobiphenyl. The invention improves the reaction activity of chlorine on o-chloroaniline by selecting proper catalyst, catalyst ligand and auxiliary catalyst, reduces the difficulty of coupling reaction, and enables the reaction to be carried out smoothly, thereby effectively improving the reaction yield.
Description
Technical Field
The invention relates to preparation of a pesticide intermediate, in particular to a preparation method of 3',4' -difluoro-2 ' -aminobiphenyl.
Background
The 3',4' -difluoro-2 ' -aminobiphenyl is an important pesticide intermediate and is mainly used for preparing pyrazinamide bactericides.
At present, relatively few researches are conducted on 3',4' -difluoro-2 ' -aminobiphenyl, and the preparation method is mainly divided into a direct method and an indirect method. The direct method is characterized in that 3, 4-difluorophenylboronic acid or phenylboronic anhydride and o-chloroaniline are used as raw materials, and Suzuki coupling reaction is carried out under the action of a palladium catalyst to synthesize 3',4' -difluoro-2 ' -aminobiphenyl, but the steric hindrance is increased due to the existence of amino beside chlorine on the o-chloroaniline, the reactivity of chlorine on the o-chloroaniline is very low, the coupling reaction cannot be smoothly carried out, and the yield is very low, so that the method is not suitable for industrial production. The indirect method is to prepare 3, 4-difluoro-2 ' -nitrobiphenyl first and then reduce the 3',4' -difluoro-2 ' -aminobiphenyl to obtain the 3',4' -difluoro-2 ' -aminobiphenyl, but the method has a complex synthetic route and the overall yield needs to be improved. Meanwhile, the existing production method, whether the direct method or the indirect method, is synthesized by three steps of Grignard reagent, borate and hydrolysis of halogenated benzene, has complex synthetic route and high cost, and the Grignard reaction has severe requirements on equipment conditions and high industrialization difficulty, and is not suitable for industrial production.
Disclosure of Invention
The present invention provides a method for preparing 3',4' -difluoro-2 ' -aminobiphenyl.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
the preparation method is characterized in that 3,4 '-difluoro-2' -aminobiphenyl is taken to take 3, 4-difluorophenylboronic acid and o-chloroaniline to perform a coupling reaction under the combined action of catalyst bis (tricyclohexylphosphine) palladium dichloride and catalyst ligand 2-dicyclohexylphosphine-2 '- (N, N-dimethylamino) biphenyl, so that the 3',4 '-difluoro-2' -aminobiphenyl is obtained, wherein the specific chemical reaction formula is as follows:
furthermore, auxiliary catalysts lithium bromide, tetrabutylammonium bromide and potassium carbonate are also required to be added in the coupling reaction process.
Further, the molar ratio between o-chloroaniline and lithium bromide, tetrabutylammonium bromide and potassium carbonate is 1:0.1 to 0.12:0.5 to 0.6:2.2 to 2.4.
Further, the solvent for the coupling reaction is water.
Further, the molar ratio of the 3, 4-difluorophenylboronic acid to the o-chloroaniline is 1.05-1.2: 1.
further, the molar ratio of o-chloroaniline to bis (tricyclohexylphosphine) palladium dichloride is 1:0.0004 to 0.0006.
Further, the weight ratio of the o-chloroaniline to the 2-dicyclohexylphosphine-2' - (N, N-dimethylamino) biphenyl is 1: 0.002-0.003.
Further, the temperature of the coupling reaction is 40-90 ℃ and the time is 1-4 h.
Further, before the coupling reaction starts, the air in the container used for the reaction needs to be replaced with an inert gas.
Further, after the coupling reaction is completed, directly separating liquid, washing the obtained organic phase to be neutral by water, drying and fractionating to obtain the 3',4' -difluoro-2 ' -aminobiphenyl.
The preparation method of the 3',4' -difluoro-2 ' -aminobiphenyl has the beneficial effects that:
the invention improves the reaction activity of chlorine on o-chloroaniline by selecting a proper catalyst, a catalyst ligand and an auxiliary catalyst, reduces the difficulty of coupling reaction, and enables the reaction to be carried out smoothly, thereby effectively improving the reaction yield;
the preparation method has the advantages of simple process, easy operation, higher product yield and purity, the yield can reach more than 97.61 percent, the purity can reach more than 99.50 percent, the reaction condition is mild, the harsh production condition is not needed, and the preparation method is suitable for industrial production.
Drawings
FIG. 1 is a nuclear magnetic resonance diagram of 3',4' -difluoro-2 ' -aminobiphenyl prepared in example 1 of the present invention;
FIG. 2 is a high performance liquid chromatogram of 3',4' -difluoro-2 ' -aminobiphenyl prepared in example 1 of the present invention.
Detailed Description
The following description of the technical solution in the embodiments of the present invention is clear and complete. In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways other than those described herein, and persons skilled in the art will readily appreciate that the present invention is not limited to the specific embodiments disclosed below.
Example 1 preparation method of 3',4' -difluoro-2 ' -aminobiphenyl
The embodiment is a preparation method of 3',4' -difluoro-2 ' -aminobiphenyl, and the specific preparation process comprises the following steps in sequence:
to a 250ml three-necked flask, 17.4g (0.11 mol) of 3, 4-difluorophenylboronic acid, 32g (0.23 mol) of potassium carbonate, 100g of distilled water, 0.96g (0.011 mol) of lithium bromide, 16.1g (0.05 mol) of tetrabutylammonium bromide, 12.57g (0.1 mol) of o-chloroaniline, 0.04g (0.000054 mol) of catalyst bis (tricyclohexylphosphine) palladium dichloride, 0.032g of catalyst ligand 2-dicyclohexylphosphine-2 '- (N, N-dimethylamino) biphenyl were added, the air in the three-necked flask was replaced by nitrogen, the temperature was raised to 86℃for coupling reaction for 4 hours, after the reaction was completed, the resultant organic phase was separated, washed with water to neutrality, the spin-dried solvent and distilled under reduced pressure to obtain 20.14g of 3',4 '-difluoro-2' -aminobiphenyl labeled LB1, the yield was 98.15%, the purity was 99.78%, and the specific chemical reaction formula was as follows:
examples 2 to 63 ', preparation method of 4' -difluoro-2 ' -aminobiphenyl
Examples 2 to 6 are a preparation method of 3',4' -difluoro-2 ' -aminobiphenyl, respectively, and the steps are basically the same as those of example 1, except that the raw material amounts and the process parameters are different, and the details are shown in table 1:
table 1 list of process parameters in examples 2 to 6
The procedure and process parameters of the other parts of examples 2 to 6 are the same as in example 1.
Experimental example
Comparative examples 1 to 5 are comparative experiments for preparing 3',4' -difluoro-2 ' -aminobiphenyl in example 1, differing only in that:
comparative example 1 was not added with 2-dicyclohexylphosphine-2 '- (N, N-dimethylamino) biphenyl to give 2.12g of 3',4 '-difluoro-2' -aminobiphenyl in a yield of 10.33% and purity of 94.62%;
in comparative example 2, bis (triphenylphosphine) palladium dichloride was used as a catalyst instead of bis (tricyclohexylphosphine) palladium dichloride to obtain 12.68g of 3',4' -difluoro-2 ' -aminobiphenyl, the yield was 61.79% and the purity was 99.53%;
no lithium bromide is added in the comparative example 3, 7.96g of 3',4' -difluoro-2 ' -aminobiphenyl is obtained, the yield is 38.79 percent, and the purity is 99.37 percent;
no tetrabutylammonium bromide was added in comparative example 4 to obtain 9.23g of 3',4' -difluoro-2 ' -aminobiphenyl with a yield of 44.98% and a purity of 99.63%;
in comparative example 5, no potassium carbonate was added, and the reaction was hardly performed, so that 3',4' -difluoro-2 ' -aminobiphenyl could not be obtained.
It will be apparent that the described embodiments are only some, but not all, embodiments of the invention. 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.
Claims (10)
1. The preparation method is characterized in that 3,4 '-difluoro-2' -aminobiphenyl is prepared by taking 3, 4-difluorophenylboronic acid and o-chloroaniline to perform a coupling reaction under the combined action of catalyst bis (tricyclohexylphosphine) palladium dichloride and catalyst ligand 2-dicyclohexylphosphine-2 '- (N, N-dimethylamino) biphenyl, and the 3',4 '-difluoro-2' -aminobiphenyl is obtained, wherein the specific chemical reaction formula is as follows:
2. the method for preparing 3',4' -difluoro-2 ' -aminobiphenyl according to claim 1, wherein auxiliary catalysts of lithium bromide, tetrabutylammonium bromide and potassium carbonate are added in the coupling reaction process.
3. The method for preparing 3',4' -difluoro-2 ' -aminobiphenyl according to claim 2, wherein the molar ratio between o-chloroaniline and lithium bromide, tetrabutylammonium bromide and potassium carbonate is 1:0.1 to 0.12:0.5 to 0.6:2.2 to 2.4.
4. A process for the preparation of 3',4' -difluoro-2 ' -aminobiphenyl according to any of claims 1-3 wherein the solvent for the coupling reaction is water.
5. The method for producing 3',4' -difluoro-2 ' -aminobiphenyl according to any of claims 1-3, wherein the molar ratio of 3, 4-difluorophenylboronic acid to o-chloroaniline is 1.05-1.2: 1.
6. a process for the preparation of 3',4' -difluoro-2 ' -aminobiphenyl according to any of claims 1-3, characterized in that the molar ratio of o-chloroaniline to bis (tricyclohexylphosphine) palladium dichloride is 1:0.0004 to 0.0006.
7. A process for the preparation of 3',4' -difluoro-2 '-aminobiphenyl according to any of claims 1-3, characterized in that the weight ratio of o-chloroaniline to 2-dicyclohexylphosphine-2' - (N, N-dimethylamino) biphenyl is 1: 0.002-0.003.
8. The process for producing 3',4' -difluoro-2 ' -aminobiphenyl according to any of claims 1-3, wherein the coupling reaction is carried out at a temperature of 40-90 ℃ for a period of 1-4 hours.
9. The process for preparing 3',4' -difluoro-2 ' -aminobiphenyl according to claim 8, wherein,
before the coupling reaction starts, the air in the container used in the reaction is replaced by an inert gas.
10. The method for preparing 3',4' -difluoro-2 '-aminobiphenyl according to any of claims 1-3 and 9, wherein after the coupling reaction, the liquid is directly separated, the obtained organic phase is washed to be neutral by water, dried and fractionated, and the 3',4 '-difluoro-2' -aminobiphenyl is obtained.
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Citations (6)
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| CN101006076A (en) * | 2004-06-24 | 2007-07-25 | 沃泰克斯药物股份有限公司 | Modulators of ATP-binding cassette transporters |
| US20110105766A1 (en) * | 2008-06-25 | 2011-05-05 | Basf Se | Method for Producing Substituted Biphenyls |
| CN102652128A (en) * | 2009-12-11 | 2012-08-29 | 沃泰克斯药物股份有限公司 | 4 -oxo- iH -quinoline- 3 - carboxamides as modulators of ATP -binding cassette transporters |
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| US20180237459A1 (en) * | 2015-08-18 | 2018-08-23 | Dow Global Technologies Llc | Method for coupling an aromatic or vinylic compound to a boron-containing compound |
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Patent Citations (7)
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| CN101006076A (en) * | 2004-06-24 | 2007-07-25 | 沃泰克斯药物股份有限公司 | Modulators of ATP-binding cassette transporters |
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| JP2013023466A (en) * | 2011-07-20 | 2013-02-04 | Nippon Nohyaku Co Ltd | Method for producing substituted biphenyl amine |
| US20180237459A1 (en) * | 2015-08-18 | 2018-08-23 | Dow Global Technologies Llc | Method for coupling an aromatic or vinylic compound to a boron-containing compound |
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