Synthesis method of 1-[3, 5-bis (1-methyl ethyl) [1, 1 '-biphenyl]-4-yl]-2-bromo-1H-benzimidazole

Abstract

The invention discloses a synthetic method of a photoelectric material intermediate 1-[3, 5-bis (1-methyl ethyl) [1, 1 '-biphenyl]-4-yl]-2-bromo-1H-benzimidazole, which comprises the following steps: taking 2, 6-diisopropylaniline as an initial raw material, and sequentially carrying out free radical reaction, coupling reaction, Sandmeyer reaction, Wollman reaction and the like to obtain the 1-[3, 5-bis (1-methyl ethyl) [1, 1'-biphenyl]-4-yl]-2-bromo-1H-benzimidazole, namely the 1-[3, 5-bis (1-methyl ethyl) [1, 1 '-biphenyl]-4-yl]-2-bromo-1H-benzimidazole. The compound is 1, 1 '-biphenyl]-4-yl]-2-bromo-1H-benzimidazole. The synthesis method disclosed by the invention is relatively low in synthesis cost, simple in post-treatment method and high in yield, can be used for industrial production, conforms to the green chemical development trend, reduces the production cost of the whole process to the greatest extent, and has extremely high application value.

Description

Technical Field

[0001] This invention belongs to the field of chemical pharmaceuticals, specifically relating to a method for synthesizing 1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-2-bromo-1H-benzimidazole. Background Technology

[0002] OLEDs are self-emissive devices with advantages such as wide viewing angle, fast response, high brightness, and low driving voltage. Their structure consists of an anode, a cathode, and an organic layer containing an emission layer sandwiched between the two electrodes. During operation, holes in the anode and electrons in the cathode recombine in the emission layer via corresponding transport regions to form excitons, which then transition back to the ground state to emit light. 1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-1H-benzimidazole is an intermediate used in the preparation of such optoelectronic materials, with its core applications concentrated in the fabrication of organic optoelectronic functional components. The benzimidazole core in its molecule possesses excellent electron transport capabilities, while the 3,5-diisopropylbiphenyl group enhances the molecule's solubility, film-forming properties, and thermal stability. It is often used to prepare electron transport layer materials for OLEDs or as a host material for doping fluorescent / phosphorescent dyes to improve the device's luminous efficiency and lifetime. The steric hindrance of the isopropyl group inhibits intermolecular aggregation, reducing fluorescence quenching in the device.

[0003] Current research mainly focuses on derivatization modifications at three sites: the benzimidazole ring, the biphenyl skeleton, and the isopropyl substituent. For example, Samsung Electronics disclosed a patent in 2023 for coupling the bromine atom on the benzimidazole ring with 4-(4,4,5,5-tetramethyl-1,3,2-dioxabenloran-2-yl)dibenzofuran or phenylboronic acid to generate various types of organic light-emitting devices and electronic device materials, with product yields reaching up to 90%. Furthermore, introducing electron-withdrawing groups such as fluorine and cyano groups into the benzimidazole ring reduces the LUMO energy level of the molecule, optimizes the energy level matching with the light-emitting layer material, and improves the electron injection efficiency of the device.

[0004] However, there is currently no complete and publicly available synthetic route for 1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-1H-benzimidazole, and the price required for direct purchase is too high, which is not conducive to large-scale industrial production. Summary of the Invention

[0005] To address the gaps in existing synthetic routes, this invention provides a method for synthesizing 1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-2-bromo-1H-benzimidazole. Starting with 2,6-diisopropylaniline, the method proceeds sequentially through free radical reactions, coupling reactions, Sandmeier reactions, and Wolman reactions to obtain the 1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-2-bromo-1H-benzimidazole. This method features mild reaction conditions, high yield, low cost, readily available raw materials, and a synthetic process that meets the requirements of green chemistry. The innovative synthetic route improves the utilization rate of raw materials, reduces resource waste and pollution, and minimizes the overall production cost, demonstrating high application value.

[0006] The present invention provides a method for synthesizing 1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-2-bromo-1H-benzimidazole, comprising the following steps:

[0007] Step 1: Dissolve 2,6-diisopropylaniline in N,N-dimethylamide and place the solution in a reaction flask. Lower the temperature to 0°C, then mix the brominating reagent with a small amount of N,N-dimethylamide and slowly add the mixture dropwise to the reaction flask, controlling the temperature at approximately 5°C and below 10°C. After the addition is complete, stir the reaction for one hour. Take a sample and use LC-MS to confirm the complete reaction of 2,6-diisopropylaniline. Add ethyl acetate, extract with purified water, and then wash the organic phase three times with a saturated ammonium chloride aqueous solution. Finally, wash once with saturated brine, dry under anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the intermediate 1-4-bromo-2,6-bis(1-methylethyl)aniline.

[0008] Step 2: Intermediate 1 and phenylboronic acid were dissolved together in toluene and placed in a reaction flask. Palladium acetate and triphenylphosphine were then added to the reaction flask. The air in the flask was evacuated and nitrogen gas was introduced. Potassium carbonate was then dissolved in water and mixed with a small amount of ethanol and added to the reaction flask. The mixture was stirred at room temperature for 20 hours. A sample was then spotted onto a TLC plate to confirm that the reaction of 4-bromo-2,6-bis(1-methylethyl)aniline was complete. The stirring was turned off, and the mixture was allowed to stand and separated. The solution was then concentrated under reduced pressure. The pH was adjusted to approximately 12 by adding a small amount of sodium hydroxide. The mixture was extracted with dichloromethane solution and concentrated under reduced pressure to obtain intermediate 2—3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-amine.

[0009] Step 3: Intermediate 2 was dissolved in acetonitrile and placed in a reaction flask. A brominating reagent and tert-butyl nitrite were then added. The flask was evacuated, and nitrogen gas was introduced. The mixture was heated to 65°C and stirred for 20 hours. TLC was then performed to confirm the complete reaction of 3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-amine. The mixture was extracted with purified water and ethyl acetate. The organic phase was removed, washed with saturated brine, and concentrated under reduced pressure with anhydrous sodium sulfate to obtain intermediate 3-4-bromo-3,5-bis(1-methylethyl)-1,1′-biphenyl.

[0010] Step 4: Intermediate 3 was dissolved in N,N-dimethylacetic acid and placed in a reaction flask. The catalyst, benzimidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene, and L-proline were added sequentially. The temperature was raised to 120℃ and the mixture was stirred for 20 hours. A sample was then sent to LCMS to confirm the complete reaction of 4-bromo-3,5-bis(1-methylethyl)-1,1′-biphenyl. The mixture was washed with purified water and dilute hydrochloric acid solution, then extracted with ethyl acetate. Finally, the organic phase was washed with saturated brine, and then concentrated under reduced pressure with anhydrous sodium sulfate to obtain intermediate 4—1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-1H-benzimidazole.

[0011] Step 5: Dissolve intermediate 4 in tetrahydrofuran and place it in a reaction flask. Add the brominating reagent, heat to 70°C, reflux for 1 hour, and then send a sample for LCMS detection to determine if 1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-1H-benzimidazole is completely removed. After the solution is evaporated under reduced pressure and stirred with silica gel, it is packed into a silica gel column and washed with a petroleum ether to ethyl acetate (volume ratio of 10:1) until all the product is carried out. Then, the eluent is concentrated under reduced pressure to obtain the target product.

[0012] In step 1, the molar ratio of 2,6-diisopropylaniline to the bromide reagent is 1:1.05, and the volume of N,N-dimethylamide is 20 times that of 2,6-diisopropylaniline.

[0013] In step 2, the molar ratio of intermediate 1 to phenylboronic acid is 1:1.5; the molar ratio of intermediate 1 to potassium carbonate is 1:5; the mass of palladium acetate is 1-2% of the mass of intermediate 1; the mass of triphenylphosphine is 2-4% of the mass of intermediate 1; the volume of toluene is 20 times that of intermediate 1; and the volume of ethanol is 7 times that of intermediate 1.

[0014] In step 3, the molar ratio of intermediate 2 to the brominizing agent is 1:1.2; the molar ratio of intermediate 2 to tert-butyl nitrite is 1:2.4; and the volume of acetonitrile is 6 times that of intermediate 2.

[0015] In step 4, the molar ratio of intermediate 3 to benzimidazole is 1:1-1.3; the molar ratio of intermediate 3 to catalyst is 1:0.2; the molar ratio of intermediate 3 to 1,8-diazabicyclo[5.4.0]undec-7-ene is 1:2; the volume of N,N-dimethylacetamide is 10 times that of intermediate 3, and the volume of L-proline is 7 times that of intermediate 3.

[0016] In step 5, the molar ratio of intermediate 4 to the brominizing agent is 1:3; the volume of tetrahydrofuran is 10 times that of intermediate 4.

[0017] The synthetic route of this invention is shown below:

[0018]

[0019] The present invention provides a synthetic method using 2,6-diisopropylaniline as the starting material, which proceeds sequentially through free radical reaction, coupling reaction, Sandmeier reaction, and Wollmann reaction to obtain 1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-2-bromo-1H-benzimidazole. This synthetic method features low synthesis cost, simple post-processing, high yield, and industrial-scale production capability, aligning with the trend of green chemistry development and minimizing overall process costs, thus possessing significant application value.

[0020] In a preferred embodiment of the present invention, the brominating reagent used in step 1 can be selected from liquid bromine, NBS, or copper bromide.

[0021] More preferably, to ensure that the bromination site is not affected, the brominating agent in step 1 is selected as the weak brominating agent NBS.

[0022] In the preferred embodiment of the present invention, the raw materials are preferably 2,6-diisopropylaniline, 2,6-diisopropylaniline hydrochloride, etc., and the reaction temperature in step 1 is 0-20℃.

[0023] More preferably, to ensure that the bromination site is not affected, the starting material for step 1 is preferably 2,6-diisopropylaniline, and the reaction environment is selected at 0°C. The regioselectivity of the electrophilic substitution reaction is affected by temperature, and the selectivity of the para-product is higher at low temperatures.

[0024] In a preferred embodiment of the present invention, the amount of palladium acetate added in the coupling reaction in step 2 can be 1%, 1.5%, 1.8%, 2.0%, etc. (mass ratio to intermediate 1), and the amount of triphenylphosphine added can be 2%, 2.5%, 3.0%, 3.5%, 4.0%, etc. (mass ratio to intermediate 1).

[0025] More preferably, in step 2, the amount of palladium acetate added is 2.0% (by mass of intermediate 1), and the amount of triphenylphosphine added is 4.0% (by mass of intermediate 1).

[0026] In a preferred embodiment of the present invention, the brominating reagent used in step 3 can be liquid bromine, NBS, or cuprous bromide.

[0027] More preferably, the brominating agent in step 3 is cuprous bromide.

[0028] In a preferred embodiment of the present invention, the brominating reagent used in step 3 can be selected as 1.0, 1.1, 1.2, 1.3, etc. (molar ratio with intermediate 2).

[0029] More preferably, in step 3, the feed ratio of cuprous bromide is selected as 1.2 (molar ratio with intermediate 2).

[0030] In a preferred embodiment of the present invention, the catalyst used in step 4 may be cuprous iodide, palladium acetate, triphenylphosphine, or tetratriphenylphosphine palladium.

[0031] More preferably, in step 4, the catalyst is selected as cuprous iodide.

[0032] In a preferred embodiment of the present invention, the brominating reagent used in step 5 may be copper bromide, dibromohydantoin, NBS, liquid bromine, N-bromosuccinimide, etc.

[0033] More preferably, the brominating agent in step 5 is N-bromosuccinimide.

[0034] The synthesis method of this invention has low synthesis cost, simple post-processing method, high yield, and can be industrialized. It conforms to the development trend of green chemistry, minimizes the overall production cost of the process, and has extremely high application value. Attached Figure Description

[0035] Figure 1 The proton NMR spectrum of the raw material.

[0036] Figure 2 This is the liquid phase diagram of intermediate 4.

[0037] Figure 3 This is the mass spectrum of intermediate 4. The relative molecular mass of this compound is known to be 354.2, and the peak with a mass-to-charge ratio (m / z) of 355.2 is [M+H]+.

[0038] Figure 4 The image shows the proton NMR spectrum of intermediate 4.

[0039] Figure 5 The liquid phase diagram is for the target product.

[0040] Figure 6 This is the mass spectrum of the target product. The relative molecular mass of this compound is known to be 432.2, and the peak with a mass-to-charge ratio (m / z) of 433.2 is [M+H]+.

[0041] Figure 7 The image shows the proton NMR spectrum of the target product. Detailed Implementation

[0042] The technical solution of the present invention is further illustrated below through specific embodiments. These embodiments are only for illustrative purposes and are not intended to limit the scope of the invention.

[0043] Example 1:

[0044] The synthesis method of 1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-2-bromo-1H-benzimidazole in this embodiment includes the following steps:

[0045] 1. Synthesis of 4-bromo-2,6-bis(1-methylethyl)aniline

[0046]

[0047] 2,6-Diisopropylaniline (169.34 mmol, 30.0 g) was dissolved in N,N-dimethylamide (375 ml) in a reaction flask. The temperature was lowered to 0 °C. Then, N-bromosuccinimide (177.82 mmol, 31.6 g) was mixed with a small amount of N,N-dimethylamide (185 ml) and slowly added dropwise to the reaction flask, maintaining the temperature at approximately 5 °C and below 10 °C. After the addition was complete, the mixture was stirred for one hour. LC-MS was used to confirm the complete reaction of 2,6-diisopropylaniline. After extraction, washing, and concentration under reduced pressure, 42.4 g of the product was obtained, with a yield of 98% and a purity of 98.6% as determined by LC-MS.

[0048] Synthesis of 2,5-bis(1-methylethyl)[1,1′-biphenyl]-4-amine

[0049]

[0050] 4-Bromo-2,6-bis(1-methylethyl)aniline (156.83 mmol, 40.0 g) and phenylboronic acid (235.24 mmol, 28.7 g) were dissolved together in toluene (800 ml) and placed in a reaction flask. Palladium acetate (2%, 0.8 g) and triphenylphosphine (4%, 1.6 g) were then added to the flask. The air in the flask was removed, and nitrogen gas was introduced. Potassium carbonate (784.13 mmol, 108 g) was dissolved in water (100 ml) and mixed with a small amount of ethanol (280 ml), then added to the reaction flask. The mixture was stirred at room temperature for 20 hours. A TLC sample was taken to confirm the complete reaction of 4-bromo-2,6-bis(1-methylethyl)aniline. After standing, separation, concentration, pH adjustment, extraction, and concentration, the product was obtained as a white solid (38.1 g), yield 96%, with a purity of 98.2% as determined by LCMS.

[0051] Synthesis of 3,4-bromo-3,5-bis(1-methylethyl)-1,1′-biphenyl

[0052]

[0053] 3,5-Bis(1-methylethyl)[1,1′-biphenyl]-4-amine (118.50 mmol, 30 g) was dissolved in acetonitrile (180 ml) and placed in a reaction flask. Cuprous bromide (142.20 mmol, 20.4 g) and tert-butyl nitrite (284.38 mmol, 29.3 g) were then added. The flask was evacuated and nitrogen gas was introduced. The mixture was heated to 65 °C and stirred for 20 hours. TLC was used to confirm the complete reaction of 3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-amine. After extraction and concentration, the product was obtained as a white solid (36.0 g), yield 96%, with a purity of 98.1% as determined by LCMS.

[0054] 4. Synthesis of 1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-1H-benzimidazole

[0055]

[0056] 4-Bromo-3,5-bis(1-methylethyl)-1,1′-biphenyl (110.73 mmol, 35 g) was dissolved in N,N-dimethylacetic acid (350 ml) and placed in a reaction flask. Cuprous iodide (22.15 mmol, 4.2 g), benzimidazole (132.88 mmol, 15.7 g), 1,8-diazacyclo[5,4,0]undecene-7 (221.47 mmol, 33.7 g), and L-proline (245 ml) were added sequentially. The mixture was heated to 120 °C and stirred for 20 hours. A sample was then sent to LCMS to confirm the complete reaction of 4-bromo-3,5-bis(1-methylethyl)-1,1′-biphenyl. After washing, pH adjustment, extraction, and drying, the product was obtained. 36.5 g of white solid was obtained, with a yield of 93% and a purity of 98.4% as determined by LCMS.

[0057] 5. Synthesis of 1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-2-bromo-1H-benzimidazole

[0058]

[0059] 1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-1H-benzimidazole (96.00 mmol, 34 g) was dissolved in tetrahydrofuran (340 mL) and placed in a reaction flask. N-bromosuccinimide (287.97 mmol, 51.25 g) was added, and the mixture was refluxed at 70 °C for 1 hour. A sample was then sent to LCMS for complete determination of 1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-1H-benzimidazole. The solution was concentrated under reduced pressure, and the concentrate was purified by column chromatography (PE:EA = 10:1). The final product, a white solid (38.1 g), was obtained after concentration with the developing solvent, with a yield of 92% and a purity of 98.4% as determined by LCMS.

[0060] 1H NMR (400 MHz, DMSO-d6) δ 7.85 – 7.78 (m, 2H), 7.74 (dd, J = 7.1,1.6 Hz, 1H), 7.70 (s, 2H), 7.52 (t, J = 7.6 Hz, 2H), 7.46 – 7.41 (m, 1H),7.29 (td, J = 7.5, 1.5 Hz, 2H), 7.02 (dd, J = 7.3, 1.8 Hz, 1H), 2.18 – 2.06(m, 2H), 1.24 – 1.18 (m, 7H), 1.01 (d, J = 6.9 Hz, 5H).

[0061] Example 2:

[0062] The synthesis method of 1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-2-bromo-1H-benzimidazole in this embodiment includes the following steps:

[0063] 1. Synthesis of 4-bromo-2,6-bis(1-methylethyl)aniline

[0064]

[0065] 2,6-Diisopropylaniline (169.34 mmol, 30.0 g) was dissolved in N,N-dimethylamide (375 ml) in a reaction flask. The temperature was lowered to 0 °C. Then, N-bromosuccinimide (177.82 mmol, 31.6 g) was mixed with a small amount of N,N-dimethylamide (185 ml) and slowly added dropwise to the reaction flask, maintaining the temperature at 10 °C and below 15 °C. After the addition was complete, the mixture was stirred for one hour. LC-MS was used to confirm the complete reaction of 2,6-diisopropylaniline. After extraction, washing, and concentration under reduced pressure, 41.9 g of the product was obtained, with a yield of 97% and a purity of 97.5% as determined by LC-MS.

[0066] Synthesis of 2,5-bis(1-methylethyl)[1,1′-biphenyl]-4-amine

[0067]

[0068] 4-Bromo-2,6-bis(1-methylethyl)aniline (156.83 mmol, 40.0 g) and phenylboronic acid (235.24 mmol, 28.7 g) were dissolved together in toluene (800 ml) and placed in a reaction flask. Palladium acetate (1.5%, 0.6 g) and triphenylphosphine (4%, 1.6 g) were then added to the reaction flask. The air in the flask was removed, and nitrogen gas was introduced. Potassium carbonate (784.13 mmol, 108 g) was dissolved in water (100 ml) and mixed with a small amount of ethanol (280 ml), and then added to the reaction flask. After stirring at room temperature for 20 hours, a sample was taken and plate-checked to confirm the complete reaction of 4-bromo-2,6-bis(1-methylethyl)aniline. After standing, separation, concentration, pH adjustment, extraction, and concentration, the product was obtained as a white solid (37.7 g), yield 95%, with a purity of 97.2% as determined by LC-MS.

[0069] Synthesis of 3,4-bromo-3,5-bis(1-methylethyl)-1,1′-biphenyl

[0070]

[0071] 3,5-Bis(1-methylethyl)[1,1′-biphenyl]-4-amine (118.50 mmol, 30 g) was dissolved in acetonitrile (180 ml) and placed in a reaction flask. Cuprous bromide (142.20 mmol, 20.4 g) and tert-butyl nitrite (237.00 mmol, 24.1 g) were then added. The flask was evacuated and nitrogen gas was introduced. The mixture was heated to 65 °C and stirred for 20 hours. TLC was used to confirm the complete reaction of 3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-amine. After extraction and concentration, the product was obtained as a white solid (35.2 g), yield 93%, with a purity of 96.6% as determined by LCMS.

[0072] 4. Synthesis of 1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-1H-benzimidazole

[0073]

[0074] 4-Bromo-3,5-bis(1-methylethyl)-1,1′-biphenyl (110.73 mmol, 35 g) was dissolved in N,N-dimethylacetic acid (350 ml) and placed in a reaction flask. Cuprous iodide (16.61 mmol, 3.16 g), benzimidazole (132.88 mmol, 15.7 g), 1,8-diazacyclo[5,4,0]undecene-7 (221.47 mmol, 33.7 g), and L-proline (245 ml) were added sequentially. The mixture was heated to 120 °C and stirred for 20 hours. A sample was then sent to LCMS to confirm the complete reaction of 4-bromo-3,5-bis(1-methylethyl)-1,1′-biphenyl. After washing, pH adjustment, extraction, and drying, the product was obtained. 35.3 g of white solid was obtained, with a yield of 90% and a purity of 97.4% as determined by LCMS.

[0075] 5. Synthesis of 1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-2-bromo-1H-benzimidazole

[0076]

[0077] 1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-1H-benzimidazole (96.00 mmol, 34 g) was dissolved in tetrahydrofuran (340 ml) and placed in a reaction flask. N-bromosuccinimide (240 mmol, 43 g) was added, and the mixture was refluxed at 70 °C for 1 hour. A sample was then sent to LCMS to determine the completeness of 1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-1H-benzimidazole. The solution was concentrated under reduced pressure, and the concentrate was purified by column chromatography (PE:EA = 10:1). The final product, a white solid (37.7 g), was obtained after concentration with the developing solvent, with a yield of 91% and a purity of 98.2% as determined by LCMS.

[0078] 1H NMR (400 MHz, DMSO-d6) δ 7.85 – 7.78 (m, 2H), 7.74 (dd, J = 7.1,1.6 Hz, 1H), 7.70 (s, 2H), 7.52 (t, J = 7.6 Hz, 2H), 7.46 – 7.41 (m, 1H),7.29 (td, J = 7.5, 1.5 Hz, 2H), 7.02 (dd, J = 7.3, 1.8 Hz, 1H), 2.18 – 2.06(m, 2H), 1.24 – 1.18 (m, 7H), 1.01 (d, J = 6.9 Hz, 5H).

[0079] Example 3:

[0080] The synthesis method of 1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-2-bromo-1H-benzimidazole in this embodiment includes the following steps:

[0081] 1. Synthesis of 4-bromo-2,6-bis(1-methylethyl)aniline

[0082]

[0083] 2,6-Diisopropylaniline (169.34 mmol, 30.0 g) was dissolved in N,N-dimethylamide (375 ml) in a reaction flask. The temperature was lowered to 0 °C. Then, N-bromosuccinimide (177.82 mmol, 31.6 g) was mixed with a small amount of N,N-dimethylamide (185 ml) and slowly added dropwise to the reaction flask, maintaining the temperature at approximately 5 °C and below 10 °C. After the addition was complete, the mixture was stirred for one hour. LC-MS was used to confirm the complete reaction of 2,6-diisopropylaniline. After extraction, washing, and concentration under reduced pressure, 41.5 g of the product was obtained, with a yield of 96% and a purity of 98.2% as determined by LC-MS.

[0084] Synthesis of 2,5-bis(1-methylethyl)[1,1′-biphenyl]-4-amine

[0085]

[0086] 4-Bromo-2,6-bis(1-methylethyl)aniline (156.83 mmol, 40.0 g) and phenylboronic acid (235.24 mmol, 28.7 g) were dissolved together in toluene (800 ml) and placed in a reaction flask. Palladium acetate (1.5%, 0.6 g) and triphenylphosphine (3%, 1.2 g) were then added to the reaction flask. The air in the flask was removed, and nitrogen gas was introduced. Potassium carbonate (784.13 mmol, 108 g) was dissolved in water (100 ml) and mixed with a small amount of ethanol (280 ml), then added to the reaction flask. The mixture was stirred at room temperature for 20 hours. A TLC sample was taken to confirm the complete reaction of 4-bromo-2,6-bis(1-methylethyl)aniline. After standing, separation, concentration, pH adjustment, extraction, and concentration, the product was obtained as a white solid (36.9 g), yield 93%, with a purity of 96.8% as determined by LCMS.

[0087] Synthesis of 3,4-bromo-3,5-bis(1-methylethyl)-1,1′-biphenyl

[0088]

[0089] 3,5-Bis(1-methylethyl)[1,1′-biphenyl]-4-amine (118.50 mmol, 30 g) was dissolved in acetonitrile (180 ml) and placed in a reaction flask. Cuprous bromide (118.50 mmol, 17 g) and tert-butyl nitrite (284.38 mmol, 29.3 g) were then added. The flask was evacuated and nitrogen gas was introduced. The mixture was heated to 65 °C and stirred for 20 hours. TLC was used to confirm the complete reaction of 3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-amine. After extraction and concentration, the product was obtained as a white solid (35.2 g), yield 94%, with a purity of 96.1% as determined by LCMS.

[0090] 4. Synthesis of 1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-1H-benzimidazole

[0091]

[0092] 4-Bromo-3,5-bis(1-methylethyl)-1,1′-biphenyl (110.73 mmol, 35 g) was dissolved in N,N-dimethylacetic acid (350 ml) and placed in a reaction flask. Cuprous iodide (11.07 mmol, 2.1 g), benzimidazole (132.88 mmol, 15.7 g), 1,8-diazacyclo[5,4,0]undecene-7 (221.47 mmol, 33.7 g), and L-proline (245 ml) were added sequentially. The mixture was heated to 120 °C and stirred for 20 hours. A sample was then sent to LCMS to confirm the complete reaction of 4-bromo-3,5-bis(1-methylethyl)-1,1′-biphenyl. After washing, pH adjustment, extraction, and drying, the product was obtained. 34.9 g of white solid was obtained, with a yield of 89% and a purity of 96.2% as determined by LCMS.

[0093] 5. Synthesis of 1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-2-bromo-1H-benzimidazole

[0094]

[0095] 1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-1H-benzimidazole (96.00 mmol, 34 g) was dissolved in tetrahydrofuran (340 ml) and placed in a reaction flask. N-bromosuccinimide (192.53 mmol, 34.3 g) was added, and the mixture was refluxed at 70 °C for 1 hour. A sample was then sent to LCMS for complete determination of 1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-1H-benzimidazole. The solution was concentrated under reduced pressure, and the concentrate was purified by column chromatography (PE:EA = 10:1). The final product, a white solid (37.3 g), was obtained after concentration with the developing solvent, with a yield of 90% and a purity of 97.5% as determined by LCMS.

[0096] 1H NMR (400 MHz, DMSO-d6) δ 7.85 – 7.78 (m, 2H), 7.74 (dd, J = 7.1,1.6 Hz, 1H), 7.70 (s, 2H), 7.52 (t, J = 7.6 Hz, 2H), 7.46 – 7.41 (m, 1H),7.29 (td, J = 7.5, 1.5 Hz, 2H), 7.02 (dd, J = 7.3, 1.8 Hz, 1H), 2.18 – 2.06(m, 2H), 1.24 – 1.18 (m, 7H), 1.01 (d, J = 6.9 Hz, 5H).

[0097] Example 4:

[0098] The synthesis method of 1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-2-bromo-1H-benzimidazole in this embodiment includes the following steps:

[0099] 1. Synthesis of 4-bromo-2,6-bis(1-methylethyl)aniline

[0100]

[0101] 2,6-Diisopropylaniline (169.34 mmol, 30.0 g) was dissolved in N,N-dimethylamide (375 ml) in a reaction flask. The temperature was lowered to 0 °C. Then, cuprous bromide (177.82 mmol, 38.35 g) was mixed with a small amount of N,N-dimethylamide (185 ml) and slowly added dropwise to the reaction flask, maintaining the temperature at approximately 5 °C and below 10 °C. After the addition was complete, the mixture was stirred for one hour. LC-MS was performed to confirm the complete reaction of 2,6-diisopropylaniline. After extraction, washing, and concentration under reduced pressure, 39.74 g of the product was obtained, with a yield of 92% and a purity of 97.7% as determined by LC-MS.

[0102] Synthesis of 2,5-bis(1-methylethyl)[1,1′-biphenyl]-4-amine

[0103]

[0104] 4-Bromo-2,6-bis(1-methylethyl)aniline (156.83 mmol, 40.0 g) and phenylboronic acid (235.24 mmol, 28.7 g) were dissolved together in toluene (800 ml) and placed in a reaction flask. Palladium acetate (2.5%, 0.6 g) and triphenylphosphine (4.5%, 1.2 g) were then added to the reaction flask. The air in the flask was removed, and nitrogen gas was introduced. Potassium carbonate (784.13 mmol, 108 g) was dissolved in water (100 ml) and mixed with a small amount of ethanol (280 ml), and then added to the reaction flask. The mixture was stirred at room temperature for 20 hours. A TLC sample was taken to confirm the complete reaction of 4-bromo-2,6-bis(1-methylethyl)aniline. After standing, separation, concentration, pH adjustment, extraction, and concentration, the product was obtained as a white solid (36.13 g), yield 91%, with a purity of 95.6% as determined by LCMS.

[0105] Synthesis of 3,4-bromo-3,5-bis(1-methylethyl)-1,1′-biphenyl

[0106]

[0107] 3,5-Bis(1-methylethyl)[1,1′-biphenyl]-4-amine (118.50 mmol, 30 g) was dissolved in acetonitrile (180 ml) and placed in a reaction flask. Liquid bromine (118.50 mmol, 18.9 g) and tert-butyl nitrite (284.38 mmol, 29.3 g) were then added. The flask was evacuated and nitrogen gas was introduced. The mixture was heated to 65 °C and stirred for 20 hours. TLC was used to confirm the complete reaction of 3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-amine. After extraction and concentration, the product was obtained as a white solid (35.6 g), yield 95%, with a purity of 96.8% as determined by LCMS.

[0108] 4. Synthesis of 1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-1H-benzimidazole

[0109]

[0110] 4-Bromo-3,5-bis(1-methylethyl)-1,1′-biphenyl (110.73 mmol, 35 g) was dissolved in N,N-dimethylacetic acid (350 ml) and placed in a reaction flask. Palladium acetate (2.0%, 0.7 g), triphenylphosphine (4.0%, 1.4 g), benzimidazole (132.88 mmol, 15.7 g), 1,8-diazacyclo[5,4,0]undecene-7 (221.47 mmol, 33.7 g), and L-proline (245 ml) were added sequentially. The mixture was stirred at 120 °C for 20 hours. A sample was then sent to LCMS to confirm the complete reaction of 4-bromo-3,5-bis(1-methylethyl)-1,1′-biphenyl. After washing, pH adjustment, extraction, and drying, the product was obtained. 32.2 g of white solid was obtained, with a yield of 82% and a purity of 96.2% as determined by LCMS.

[0111] 5. Synthesis of 1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-2-bromo-1H-benzimidazole

[0112]

[0113] 1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-1H-benzimidazole (96.00 mmol, 34 g) was dissolved in tetrahydrofuran (340 ml) and placed in a reaction flask. Dibromohydantoin (287.97 mmol, 51.25 g) was added, and the mixture was refluxed at 70 °C for 1 hour. A sample was then sent to LCMS for complete determination of 1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-1H-benzimidazole. The solution was concentrated under reduced pressure, and the concentrate was purified by column chromatography (PE:EA = 10:1). The final product, a white solid (33.6 g), was obtained after concentration with the developing solvent, with a yield of 81% and a purity of 95.4% as determined by LCMS.

[0114] 1H NMR (400 MHz, DMSO-d6) δ 7.85 – 7.78 (m, 2H), 7.74 (dd, J = 7.1,1.6 Hz, 1H), 7.70 (s, 2H), 7.52 (t, J = 7.6 Hz, 2H), 7.46 – 7.41 (m, 1H),7.29 (td, J = 7.5, 1.5 Hz, 2H), 7.02 (dd, J = 7.3, 1.8 Hz, 1H), 2.18 – 2.06(m, 2H), 1.24 – 1.18 (m, 7H), 1.01 (d, J = 6.9 Hz, 5H).

[0115] The following conclusions can be drawn from the above examples 1-4:

[0116] 1. In the synthesis of 4-bromo-2,6-bis(1-methylethyl)aniline, after comparative experiments, N-bromosuccinimide was preferred as the brominating agent. At the same time, the temperature when adding N-bromosuccinimide dropwise must be strictly controlled between 0-10℃. This ensures that 2,6-bis(1-methylethyl)aniline reacts fully and guarantees the purity and yield of 4-bromo-2,6-bis(1-methylethyl)aniline.

[0117] 2. When synthesizing 3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-amine, excess triphenylphosphine and palladium acetate should be added to ensure that 4-bromo-2,6-bis(1-methylethyl)aniline reacts fully, thereby increasing the yield of 3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-amine.

[0118] 3. In the synthesis of 4-bromo-3,5-bis(1-methylethyl)-1,1′-biphenyl, after comparative experiments, cuprous bromide is preferred as the brominating agent. At the same time, excess tert-butyl nitrite and excess cuprous bromide should be added to ensure that 3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-amine reacts fully, thereby increasing the yield of 4-bromo-3,5-bis(1-methylethyl)-1,1′-biphenyl.

[0119] 4. In the synthesis of 1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-1H-benzimidazole, after comparative experiments, cuprous iodide was preferred as the brominating agent. Excess cuprous iodide should be added to ensure that 4-bromo-3,5-bis(1-methylethyl)-1,1′-biphenyl reacts fully, thereby increasing the yield of 1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-1H-benzimidazole.

[0120] 5. In the synthesis of 1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-2-bromo-1H-benzimidazole, after comparative experiments, N-bromosuccinimide is more preferably chosen as the brominating agent. An excess of N-bromosuccinimide should be added to ensure that 1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-1H-benzimidazole reacts fully, thereby increasing the yield of 1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-2-bromo-1H-benzimidazole.

[0121] This invention provides a method for synthesizing 1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-2-bromo-1H-benzimidazole. Starting with 2,6-diisopropylaniline, the method involves a series of reactions including free radical reaction, coupling reaction, Sandmeier reaction, and Wolman reaction to obtain the 1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-2-bromo-1H-benzimidazole. This method features mild reaction conditions, high yield, low cost, readily available raw materials, and a synthesis process that meets the requirements of green chemistry. The innovative synthetic route improves the utilization rate of raw materials, reduces resource waste and pollution, and minimizes the overall production cost, thus possessing high application value.

[0122] 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 improvements without departing from the principle of the present invention, and these improvements are also considered to be within the scope of protection of the present invention.

Claims

1. A method for synthesizing 1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-2-bromo-1H-benzimidazole, characterized in that... Includes the following steps: Step 1: 2,6-Diisopropylaniline reacts with N,N-dimethylformamide and a brominating agent at low temperature via a free radical reaction to generate intermediate 1-4-bromo-2,6-bis(1-methylethyl)aniline; Step 2: Intermediate 1 undergoes a coupling reaction with phenylboronic acid, triphenylphosphine, palladium acetate, and potassium carbonate in toluene-ethanol solution to generate intermediate 2—3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-amine; Step 3: Intermediate 2 is reacted with the brominizing agent and tert-butyl nitrite in acetonitrile solvent at high temperature to generate intermediate 3-4-bromo-3,5-bis(1-methylethyl)-1,1′-biphenyl; Step 4: Intermediate 3 and benzimidazole undergo a Wolman reaction at high temperature in the presence of a catalyst and N,N-dimethylacetamide to generate intermediate 4—1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-1H-benzimidazole; Step 5: React intermediate 4 with a brominating agent to generate the target product—1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-2-bromo-1H-benzimidazole; The reaction route is shown below: 。 2. The synthesis method according to claim 1, characterized in that: In step 1, 2,6-diisopropylaniline was dissolved in N,N-dimethylamide and placed in a reaction flask. When the temperature was lowered to 0°C, the brominating reagent was mixed with N,N-dimethylamide and added dropwise to the reaction flask. The temperature was controlled at 5°C. After the addition was complete, the reaction was stirred until the 2,6-diisopropylaniline was completely reacted. Ethyl acetate was added, and the mixture was extracted with purified water. The organic phase was then washed successively with saturated ammonium chloride aqueous solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the intermediate 1-4-bromo-2,6-bis(1-methylethyl)aniline.

3. The synthesis method according to claim 2, characterized in that: In step 1, the molar ratio of 2,6-diisopropylaniline to the brominizing agent is 1:1.

05.

4. The synthesis method according to claim 2, characterized in that: In step 2, intermediate 1 and phenylboronic acid are dissolved together in toluene solvent and placed in a reaction flask. Then, palladium acetate and triphenylphosphine are added to the reaction flask. The air in the flask is removed and nitrogen gas is introduced. Then, potassium carbonate is dissolved in water and mixed with ethanol and added to the reaction flask. The reaction is stirred at room temperature until intermediate 1 is completely reacted. After standing and separation, the mixture is concentrated under reduced pressure. The pH of the system is then adjusted to 12 with sodium hydroxide solution. The mixture is extracted with dichloromethane solution and concentrated under reduced pressure to obtain intermediate 2—3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-amine.

5. The synthesis method according to claim 4, characterized in that: In step 2, the molar ratio of intermediate 1 to phenylboronic acid is 1:1.5; the molar ratio of intermediate 1 to potassium carbonate is 1:5; the mass of palladium acetate is 1-2% of the mass of intermediate 1; and the mass of triphenylphosphine is 2-4% of the mass of intermediate 1.

6. The synthesis method according to claim 2, characterized in that: In step 3, intermediate 2 is dissolved in acetonitrile and placed in a reaction flask. Then, a brominizing agent and tert-butyl nitrite are added. After evacuating the flask, nitrogen gas is introduced and the temperature is raised to 65°C. The mixture is stirred until intermediate 2 is completely reacted. Pure water and ethyl acetate are added for extraction. The organic phase is collected, washed with saturated brine, and concentrated under reduced pressure with anhydrous sodium sulfate to obtain intermediate 3-4-bromo-3,5-bis(1-methylethyl)-1,1′-biphenyl.

7. The synthesis method according to claim 6, characterized in that: In step 3, the molar ratio of intermediate 2 to the brominizing agent is 1:1.2; the molar ratio of intermediate 2 to tert-butyl nitrite is 1:2.

4.

8. The synthesis method according to claim 2, characterized in that: In step 4, intermediate 3 and N,N-dimethylacetic acid ammonium were placed in a reaction flask, and catalyst, benzimidazole, 1,8-diazabicyclo[5.4.0]undec-7-ene and L-proline were added in sequence. The temperature was raised to 120°C and the mixture was stirred until intermediate 3 was completely reacted. Pure water was added, followed by washing with dilute hydrochloric acid solution, and then extraction with ethyl acetate. Finally, the organic phase was washed with saturated brine, and then concentrated under reduced pressure with anhydrous sodium sulfate to obtain intermediate 4—1-[3,5-bis(1-methylethyl)[1,1′-biphenyl]-4-yl]-1H-benzimidazole.

9. The synthesis method according to claim 8, characterized in that: In step 4, the molar ratio of intermediate 3 to benzimidazole is 1:1-1.3; the molar ratio of intermediate 3 to catalyst is 1:0.2; and the molar ratio of intermediate 3 to 1,8-diazabicyclo[5.4.0]undec-7-ene is 1:

2.

10. The synthesis method according to claim 2, characterized in that: In step 5, intermediate 4 is dissolved in tetrahydrofuran and placed in a reaction flask. A brominating reagent is added, and the mixture is heated to 70°C and refluxed until intermediate 4 is completely dissolved. The solution is then dried under reduced pressure and stirred with silica gel. The solution is then packed into a silica gel column and washed with a petroleum ether to ethyl acetate volume ratio of 10:1 until all the product is carried out. The eluent is then concentrated under reduced pressure to obtain the target product.

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