Preparation method of 3, 4, 5-trifluoro-2 '-nitrobiphenyl

Abstract

The invention relates to the technical field of organic synthesis, in particular to a preparation method of 3, 4, 5-trimethyl-1, 3 The invention discloses a preparation method of 3, 4, 5-trifluoro-2 '-nitrobiphenyl, which comprises the following steps: taking 2-chloro (or bromo) nitrobenzene (III) and 3, 4, 5-trifluorophenylboronic acid or ester (II) thereof as raw materials, carrying out Suzuki coupling in the presence of alkali and under the synergistic catalysis of a trace amount of palladium catalyst and pyridine diamine ligand to obtain a corresponding target product TM, and replacing the raw material II with diaryl hypoboric acid (IV) or a mixture of the diaryl hypoboric acid (II) and the diaryl hypoboric acid (IV). According to the method, only a trace amount of palladium catalyst (less than or equal to 0.001 mol%) needs to be used, the raw materials are easy to obtain, separation and purification are easy, the comprehensive cost is low, and the industrial value is high.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to a method for preparing 3,4,5-trifluoro-2'-nitrobenzene. Background Technology

[0002] Fluopyram, developed by BASF, is a pesticide for controlling broad-spectrum fungal diseases. Its mechanism of action involves inhibiting succinate dehydrogenase in mitochondria, thereby suppressing the germination of spores, germ tubes, and mycelial growth of target fungi. Since its market launch, fluopyram sales have experienced rapid growth, and it is widely used in crops such as cereals, soybeans, cotton, fruits, and vegetables. Its classic compound formulations are available in many countries worldwide, and new products are continuously being developed, with the range of applicable crops expanding, indicating a promising market outlook.

[0003] The structure of fluopyram is shown in the following formula:

[0004]

[0005] The synthesis of fluopyram involves the docking of the following two fragments:

[0006]

[0007] The benzidine fragment is obtained by reduction of the corresponding nitro compound, and its synthesis can be achieved through the following methods:

[0008] The first method, as disclosed in BASF's original patents CN102076651A and CN105218378A, is a palladium-catalyzed Suzuki coupling method under the action of bisphosphine ligands, with the following reaction formula:

[0009]

[0010] This method can yield the target product in a relatively high yield, but its disadvantages are also obvious: the amount of precious metal palladium used is relatively high (0.2-0.5%), resulting in high costs.

[0011] The second method, disclosed in CN107344913A, involves the decarboxylation coupling of a salt of 2-nitrobenzoic acid with 3,4,5-trifluorobromobenzene under palladium, copper (I), and corresponding ligand catalysis. The reaction formula is as follows:

[0012]

[0013] This process has the same problem: the amount of precious metals used is still too high, which leads to a higher cost of palladium catalyst in the product.

[0014] In summary, reducing the amount of palladium used while ensuring the yield is the core issue of this coupling process. Summary of the Invention

[0015] To overcome the shortcomings of the prior art, this invention proposes a method for preparing 3,4,5-trifluoro-2'-nitrobenzene: by optimizing the ligands, the amount of precious metal palladium used is reduced, thereby achieving higher catalytic efficiency and better economic efficiency.

[0016] The technical solution of the present invention to solve the above-mentioned technical problems is as follows:

[0017] A method for preparing 3,4,5-trifluoro-2'-nitrobenzene includes the following steps: using compound III and compound II, or compound IV, or a mixture of compound II and compound IV as raw materials, under the conditions of a reaction solvent and base, and with the synergistic catalysis of trace amounts of palladium catalyst and pyridine diamine ligand, Suzuki coupling occurs to obtain the corresponding target product 3,4,5-trifluoro-2'-nitrobenzene, i.e., compound I; the structural formulas of compounds III, II, IV, and I are as follows:

[0018]

[0019] Where X = chlorine or bromine; R = hydrogen or a chemically acceptable alkyl group or two R groups forming a ring to form a pinacol ester.

[0020] Preferably, the chemically acceptable alkyl group is selected from C1-C6 alkyl groups, and more preferably, the chemically acceptable alkyl group is selected from C1-C3 alkyl groups.

[0021] Preferably, the base is a conventional inorganic or organic base, such as alkali metal carbonates, alkali metal bicarbonates, and alkali metal hydroxides; or organic bases such as triethylamine, dimethylcyclohexylamine, diisopropylethylamine, and 4-dimethylaminopyridine (DMAP). The pyridine diamine ligand is a compound having the following two structural features (V-VI):

[0022]

[0023] Where R1-R 13 It can be hydrogen or C1-C4 alkyl independently.

[0024] The palladium source used is divalent palladium or a palladium complex in the 0-valent oxidation state, such as palladium chloride, palladium acetate, palladium diacetonitrile chloride, bis(tricyclohexylphosphine)dichloride, palladium trifluoroacetate, and other chemically acceptable divalent palladium. The 0-valent palladium complex can be palladium diacetylacetonate, bis(dibenzylacetone)palladium, or tetra(triphenylphosphine)palladium. The amount of palladium used is trace (≤0.001 mol%, relative to substrate II or compound IV or a mixture of compounds II and IV).

[0025] The preferred reaction solvents are ether solvents, such as tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, and 2-methyltetrahydrofuran; hydrocarbon solvents, such as toluene, n-hexane, n-heptane, petroleum ether, and xylene; and alcohol solvents, such as methanol, ethanol, isopropanol, n-butanol, and tert-butanol. A mixture of water and the above-mentioned alcohols and ethers can also be used.

[0026] The molar ratio of compound III to compound II is 1:0.9 to 1, and the ratio remains unchanged when the borate ester is compound IV or a mixture of compound II and compound IV; the amount of base is 1 to 3 times (molar ratio) of compound II, the amount of pyridine diamine ligand is 0.005 to 0.02 mol% (molar ratio) of compound II, and the amount of solvent is usually 3 to 20 mL per 1 g of compound II.

[0027] The post-processing of this invention is a conventional method in the art. After the reaction is completed, the inorganic salt and solution are separated by filtration. The inorganic salt is washed 1 to 2 times with the reaction solvent. After the organic phase is concentrated, recrystallization is carried out with an appropriate solvent to obtain the high-purity target product (I).

[0028] In this invention, if there is a conflict between the Chinese name and the structural formula of a compound, the structural formula shall prevail, unless the structural formula is obviously incorrect.

[0029] The purpose of this invention is to provide an economical and feasible method for preparing 3,4,5-trifluoro-2'-nitrobenzene, which reduces the use of precious metal catalysts and only requires trace amounts of palladium catalyst (≤0.001 mol%). The raw materials are readily available, saving costs. Separation and purification are easy, and the overall cost is low, which has high industrial value. Technically, this method can be implemented on an industrial scale to prepare large quantities of compound (I). Detailed Implementation

[0030] The present invention is illustrated below with reference to examples, but is not intended to limit the invention. Any simple substitutions or modifications made to the present invention by those skilled in the art are within the scope of the technical solutions protected by this invention.

[0031] Example 1: Synthesis of pyridine diamine ligands

[0032] Formula V is synthesized according to the method described in J. Org. Chem. 1996, 61, 7240-7241, and will not be repeated here. For ease of description, the structures conforming to Formula V are numbered in this invention, as shown in the table below:

[0033]

[0034]

[0035]

[0036] Example 2: Synthesis of Symmetrical VI

[0037] Regarding the synthesis of VI, when the substituents on both sides of VI are the same (symmetric VI), the synthetic route used is as follows:

[0038]

[0039] 1. Synthesis of symmetrical IX (R3=-CH3, R1=R2=R4=R5=H, refer to the method in J.Org.Chem.1996,61,7240-7241; the synthesis method is the same for substrates with different substituents)

[0040] Add 40 mL of NMP to a 250 mL flask, and add compound VIII (R5 = H, 10 mmol) while stirring until dissolved. Slowly add 4-methylaniline (VII, R3 = -CH3, R1 = R2 = R4 = H, 20 mmol), and the system will exothermically react. After stirring for 10 min, add 3 mL of N-ethylpiperidine dropwise, heat to 120 °C and maintain the temperature for 2 h. After cooling to room temperature, pour the solution into 200 mL of water, precipitate a solid, filter, wash with water, slurry with 50% ethanol, filter again, and dry the filter cake under vacuum at 100 °C to constant weight to obtain compound IX.

[0041] 2. Synthesis of symmetrical X (R3=-CH3, R1=R2=R4=R5=H, substrates with different substituents are synthesized using the same method)

[0042] Add 30 g of polyphosphoric acid and 1.5 g of compound IX to a 100 mL flask, heat to 200 °C, maintain the temperature for 90 min, then cool to approximately 80 °C, pour into 150 g of ice and stir. A solid precipitates out; stir again to obtain intermediate X. ESI-MS: 342 [M+H] + ]; 1 ¹H NMR (400 MHz, 99% D₂SO₄, DHSO₄ shift 12.00 pprn): δ = 10.71 (s, 1H), 8.74 (s, 2H), 8.65 (d, J = 8 Hz, 2H), 8.36 (d, J = 8 Hz, 2H), 3.18 (s, 6H).

[0043] 3. Synthesis of symmetrical VI (substrates with different substituents such as R3=-CH3, R1=R2=R4=R5=H, the synthesis method is the same)

[0044] Add 30 mL of trifluoroacetic acid to a 100 mL flask, add 2.0 g of intermediate X and stir to dissolve. Slowly add 6 mL of triethylsilane. The system is exothermic. After stirring at room temperature overnight, concentrate to recover trifluoroacetic acid. Add 20 mL of water to the residue and stir. A solid precipitates. Filter. Stir the filter cake with 10 mL of n-hexane for 1 h. Filter. Recrystallize the filter cake with 95% ethanol to give 1.6 g of compound VI.

[0045] The present invention numbers the symmetrical VI structures, as shown in the table below:

[0046]

[0047]

[0048]

[0049] Example 3: Synthesis of Asymmetric VI

[0050] If the substituents on the left and right sides of the benzene ring are different (asymmetric VI), then the following route is used:

[0051]

[0052] By controlling the molar ratio of VII and VIII and optimizing the operation, the product is mainly monosubstituted. After separation, pure XI is obtained, which is then reacted with XII to obtain XIII. Subsequently, it undergoes PPA cyclization and triethylsilane reduction. The steps are the same as those of the symmetrical VI route, and will not be described in detail.

[0053] 1. Synthesis of compound XI (R3=-CH3, R1=R2=R4=R5=R6=R7=R8=H, substrates with different substituents are synthesized using the same method)

[0054]

[0055] Add 40 mL of NMP to a 250 mL flask, and add compound VIII (10 mmol, R5 = H) while stirring to dissolve it. Slowly add VII (9.5 mmol, R3 = -CH3, R1 = R2 = R4 = H), and the system will exothermically react. After stirring for 10 min, add 3 mL of N-ethylpiperidine dropwise, heat to 110 °C and hold for 2 h. After cooling to room temperature, pour into 200 mL of water, and the solid will precipitate. Filter, wash with water, recrystallize from a mixture of ethyl acetate and petroleum ether or by rapid column chromatography to obtain a pale yellow solid. Dry under vacuum at 60 °C to obtain compound XI. ESI-MS: 269, 271 [M + H] + ]; 1 H NMR (400MHz, DMSO-d) 6):8.95(brs,1H),8.62(s,1H),7.31(d,2H,J=8Hz),7.02(d,2H,J=8Hz),2.30(s,3H).

[0056] 4. Synthesis of compound XIII (R3=-CH3, R1=R2=R4=R5=R6=R7=R8=R9=H, substrates with different substituents are synthesized using the same method)

[0057]

[0058] Add 40 mL of NMP to a 250 mL flask, and add compounds XI (10 mmol, R3 = -CH3, R1 = R2 = R4 = R5 = H) and XII (10 mmol, R6 = R7 = R8 = R9 = H) while stirring. After stirring for 10 min, add 3 mL of N-ethylpiperidine dropwise, heat to 125 °C and maintain the temperature for 2 h. After cooling to room temperature, pour the solution into 200 mL of water to precipitate the solid. Filter, wash with water, and dry under vacuum at 60 °C to obtain XIII (3.03 g), yield 93.2%. ESI-MS: 326 [M+H] + ], 1 H NMR: 8.50 (s, 1H), 7.31-7.26 (m, 4H), 7.13 (t, 1H, J = 8Hz), 7.02-6.95 (m, 4H), 2.30 (s, 3H).

[0059] 5. Synthesis of asymmetric VI (R3=-CH3, R1=R2=R4=R5=R6=R7=R8=R9=H, substrates with different substituents, the synthesis method is the same)

[0060] The preparation of asymmetric VI from compound XIII is exactly the same as the method from compound IX to symmetric VI, and will not be repeated here. Compound XIV (R3=-CH3, R1=R2=R4=R5=R6=R7=R8=R9=H), ESI-MS: 328 [M+H + ]; 1 ¹H NMR (400MHz, 99% D₂SO₄, DHSO₄ shift 12.00pprn): δ = 10.70 (s, 1H), 8.74 (s, 1H), 8.70 (d, J = 8Hz, 1H), 8.65–8.60 (m, 2H), 8.38–8.34 (m, 3H), 3.15 (s, 3H).

[0061] The asymmetric VI structures are also numbered in this invention, as shown in the table below:

[0062]

[0063]

[0064]

[0065] Example 4: Synthesis of TM

[0066]

[0067] o-Nitrochlorobenzene (0.205 mol, 1.0 eq), 3,4,5-trifluorophenylboronic acid (0.2 mol, 1.0 eq), ligand E (0.02 mmol), palladium acetate (0.002 mmol), and K₂CO₃ (83 g, 0.6 mol, 3.0 eq) were added to a 2 L four-necked flask. The mixture was replaced with N₂, and xylene (600 mL) was added as solvent. The reaction was carried out at 110 °C for 2 h, then cooled to room temperature. The mixture was filtered, and the filter cake was washed twice with xylene (100 mL × 2). The filtrates were combined, concentrated, and the product was recrystallized from 75% ethanol to obtain 45.62 g of the target product TM, with a yield of 90.1% and an HPLC purity of 99.3% (normalization method). 1 H NMR (400MHz, CDCl3): δ7.90 (d, J = 8.0 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 6.92 (t, J = 8.0 Hz, 2H). 19 F NMR (376MHz, CDCl3): δ-137.8(s),-164.7(s). 13 C NMR (100MHz, CDCl3): δ 151.8 (s, Ar), 150.1 (s, Ar), 148.5 (s, Ar), 133.3 (s, Ar), 132.8 (s, Ar), 131.5 (s, Ar), 129.3 (s, Ar), 124.4 (s, Ar), 112.5 (s, Ar), 112.4 (s, Ar). The retention time and melting point of the product were consistent with those of the commercially available standard on HPLC, and the melting point of the mixture did not decrease.

[0068] Using the above process conditions, only X and R are changed, while other conditions remain unchanged. The effect of substituents is then investigated:

[0069]

[0070] Note: Substrate R in number 3 is pinacol, which refers to the cyclic borate pinacol ester formed by 3,4,5-trifluorophenylboronic acid and one molecule of pinacol.

[0071] The effects of these two factors were investigated by replacing II with different bases, borate esters IV, or mixtures of IV and II:

[0072] The effect of different palladium sources on the yield was investigated using different palladium sources (with the molar ratio of each material remaining constant):

[0073]

[0074] Example 5: Ligand Screening

[0075] Following the approach of Example 4, only the type of ligand was changed to examine the catalytic efficiency of different ligands for the reaction.

[0076]

[0077] Example 6: Screening of ligand dosage

[0078] Referring to Example 4, H was used as the ligand, and only the amount of the ligand was changed to investigate the catalytic efficiency of the ligand.

[0079]

[0080] The results in the table above show that when the amount of ligand fluctuates around 0.01 mol% (numbers 2-5), it has little effect on the product yield and purity.

[0081] Example 7: Screening of Reaction Solvents

[0082] Referring to Example 4, with H as the ligand, only the reaction solvent was changed (a sealed reactor was used when the solvent boiling point was below 120°C) to investigate the effect of different solvents on the catalytic efficiency of the reaction.

[0083]

[0084] The above description is only a preferred embodiment of the present invention. It should be noted that those skilled in the art can make several modifications and improvements without departing from the inventive concept of the present invention, and these all fall within the protection scope of the present invention.

Claims

1. A process for the preparation of 3,4,5-trifluoro-2'-nitro-biphenyl, characterized in that, The method comprises the following steps: taking compound III and compound II or compound IV or a mixture of compound II and compound IV as raw materials, and under the catalysis of trace palladium catalyst and pyridine diamine ligand, a Suzuki coupling reaction is carried out in the presence of a reaction solvent and a base to obtain the corresponding target product 3,4,5-trifluoro-2'-nitro-biphenyl, i.e. compound TM; the structural formulas of compound III, compound II, compound IV and compound TM are as follows: wherein, X = chlorine, bromine; R = hydrogen or a chemically acceptable alkyl group or two R groups form a ring into pinacol ester.

2. The production method according to claim 1, wherein The base is an inorganic or organic base.

3. The production method according to claim 2, wherein The inorganic base is one or more of alkali metal carbonate, alkali metal bicarbonate and alkali metal hydroxide.

4. The production method according to claim 2, wherein The organic base is one or more of triethylamine, dimethylcyclohexylamine, diisopropyl ethylamine and 4-dimethylamino pyridine.

5. The production method according to claim 1, wherein The palladium catalyst is divalent palladium or a palladium complex in 0-valence oxidation state.

6. The production method according to claim 5, wherein The divalent palladium is one or more of palladium chloride, palladium acetate, diacetonitrile palladium chloride, bis(tricyclohexylphosphine) palladium dichloride and palladium trifluoroacetate; the palladium complex in 0-valence oxidation state is one or more of bis(acetylacetone) palladium, bis(bidentate acetylacetone) palladium and tetraphenylphosphine palladium.

7. The production method according to claim 1, wherein The trace palladium catalyst is ≤0.001 mol%, relative to compound II or compound IV or a mixture of compound II and compound IV.

8. The production method according to claim 1, wherein The pyridine diamine ligand is a compound having the following two structural characteristics V and VI: wherein R1-R 13 independently hydrogen or C1-C4alkyl.

9. The production method according to claim 1, wherein The reaction solvent is an ether solvent, a hydrocarbon solvent, an alcohol solvent or a mixed solvent of water and the above-mentioned alcohol solvent, ether solvent.

10. The production method according to claim 1, wherein When compound II is used as the raw material, the molar ratio of compound III to compound II is 1:0.9-1; when compound IV or a mixture of compound II and compound IV is used as the raw material, the molar ratio of compound III to compound IV or a mixture of compound II and compound IV is 1:0.9-1; the amount of the base is 1-3 times the molar amount of compound II or compound IV or a mixture of compound II and compound IV, the amount of the pyridine diamine ligand is 0.005-0.02 mol% (molar ratio) of compound II or compound IV or a mixture of compound II and compound IV, and the amount of the solvent is 3-20 mL of solvent per 1 g of compound II or compound IV or a mixture of compound II and compound IV.

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