2-(4-Fluorophenyl)thiophene

white solid

A solution of 4.98 g (36 mmol) of 4-fluorobenzeneboronic acid, 4.1 g (30 mmol) of 2-bromothiophene and 10.98 g (60 mmol) of anhydrous potassium carbonate was dissolved in 20 mL of DMF and 24 mg (0.5% (Diphenylphosphino) ferrocene] palladium dichloride, heated to 120 C under nitrogen protection, quenched by constant temperature for 15 h, quenched by adding 30 mL of distilled water, treated with 30 mL CH2Cl2Extracted twice, the combined organic phase, anhydrous Na2SO4Dried and evaporated to dryness. The residue was diluted with petroleum ether and the filtrate was filtered to obtain a pale green filtrate. The filtrate was evaporated to dryness. The residue was purified by silica gel column chromatography using petroleum ether as eluent to give 2- (4-fluorophenyl) Thiophene 4.50 g, the yield was 85%.Sodium carbonate (130 g) was added to a solution of 2-bromothiophene (100 g) and 4-flourophenylboronic acid (85.8 g) in dimethoxyethane (400 mL) and de-ionized water (400 mL) at 25C to 30C. The reaction mixture was heated at 70C to 75C for 30 minutes. Tetrakis(triphenylphosphine)palladium (1 g) was added to the reaction mixture at 70C to 75C under nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 1 to 2 hours. After completion of the reaction, the reaction mixture was allowed to cool to 25C to 30C. Hexane (1000 mL) was added to the reaction mixture at 25 C to 30C, and then the reaction mixture was stirred for 30 minutes. The reaction mixture was filtered through a Hyflo bed and silica gel (60-120 mesh). De-ionized water (100 mL) was added to the filtrate and the mixture was stirred for 10 to 15 minutes. The reaction mixture was allowed to settle for 15 minutes, and then the layers were separated. The organic layer was washed with de-ionized water (100 mL). The organic layer was concentrated under reduced pressure at 45C to obtain a residue. Hexanes (100 mL) were added to the residue and the mixture was stirred for 1 to 2 hours at 0C to 5C to obtain a solid. The solid was filtered, then washed with pre-cooled hexane, and then dried under reduced pressure to obtain 2-(4-fluorophenyl)thiophene. Yield: 82.5%2-(4-Fluorophenyl)thiophene A solution of 2-bromothiophene (233.0 g, 1.43 mol), 4-fluorophenyl boronic acid (200.0 g, 1.43 mol), bis(triphenylphosphine)palladium(II) dichloride (10.0 g, 14.2 mmol) and aqueous Na2CO3 (454.5 g, 4.3 mol in 1.5 L of H2O) in 1, 2-dimethoxyethane (2 L) was stirred at 75-80 C. (internal temperature) for 2 hours. The resulting mixture was cooled to room temperature and then stirred overnight. The solid was separated and discarded. The liquid was washed with water (2× 500 mL). The combined aqueous layer was extracted with diethylether (2× 500 mL). The combined organic layers were then dried over NaCl, concentrated and purified by flask distillation to yield the title compound as a white solid.[000763] To a stirred solution of Compound 174A (2.0 g, 15.4 mmol) in dioxane (60 mL) and water (20 mL) was added Pd(PPh3)2Cl2 (1.08 g, 1.54 mmol), Compound 174B (3.0 g, 18.5 mmol) and Na2C03 (6.53 g, 61.6 mmol) under nitrogen. The mixture was stirred at 80 0 C overnight. After the reaction was completed, it was evaporated to remove the solvent. The residue was diluted with EA (200 mL), washed with water (5 mL) and brine (5 mL), and dried over anhydrous sodium sulfate. The crude product was purified with flash column chromatography on silica gel (petroleum in ethyl acetate, 3% v/v) to furnish Compound 174C.(5) Weighed 28.00 g (molecular weight 140, 0.2 mol, 0.5 mol / L) of 4-fluorobenzeneboronic acid obtained in the step (4)39.16 g (molecular weight 163, 0.24 mol, 0.6 mol / L) of bromothiophene, (Molecular weight: 1156, 0.001 mol, 0.0025 mol / L) was added to 400 ml of anhydrous ethanol to dissolve it as material 3; 55.32 g of potassium carbonate was weighed and dissolved in 400 ml of water, The material 3 and the material 4 are respectively introduced into the first pre-heat preservation module 11 and the second pre-heat preservation module 12 shown in Fig. 2, pre-insulated and pre-insulated to 80; (6) Both the material 3 and the material 4 are pre-incubated into the first reaction module, and as shown in Fig. 2, the material 3 and the material 4 are mixed and reacted in the first reaction module 21 and then reacted in the seven second reaction modules 22 , The reaction temperature in both the first reaction module and the seven second reaction modules was 80 C, The total residence time of the reaction liquid in the first reaction module and the seven second reaction modules is 4 minutes, and then the last second reaction module flows out; since the concentrations of the materials 3 and 4 are constant and the influx of the two materials in the first reaction module The flow rate of the material 3 and the material 4 in the first reaction module can be controlled to control the number of moles of the material introduced into the first reaction module per unit time, The molar ratio of 4-fluorobenzeneboronic acid to 2-bromothiophene is 1: 1.2 moles of the mixture of 4, 4-fluorophenylboronic acid and tetrakistriphenylphosphine palladium; the molar ratio of 4-fluorophenylboronic acid to 2-bromothiophene is 1: The ratio of 1: 0.005, the introduction of potassium carbonate for the reaction to provide an alkaline environment; (7) When each reactor in the steady state of the material, the collection from the last one out of the second reaction moduleFluorobenzene boronic acid obtained in the step (4) as an example, the reaction solution was filtered to remove insoluble solids, and the filtrate was evaporated under reduced pressure to remove the solvent, The crude 2- (4-fluorophenyl) thiophene was recrystallized from a 1: 3 by volume mixture of ethanol and water, 7 ml of a mixture of ethanol and water was used per 1 g of crude 2- (4-fluorophenyl) thiophene to obtain 27.23 g of a white solid powdery 2- (4-fluorophenyl) thiophene in a yield of 85.5%The purity of the product was 99.2% by HPLC and the total yield of the two-step reaction was 78.66%.Preparation 43 A solution of sodium carbonate (1.63 g) in H2O (7.65 ml), 4-fluorobenzeneboronic acid (1.03 g) and tetrakis(triphenylphosphine) palladium(0) (70.9 mg) were added successively to a solution of 2-bromothiophene (1.00 g) in dimethoxyethane (12.3 ml). The mixture was refluxed for 4 hours. The mixture was cooled to ambient temperature and partitioned between AcOEt and H2O. The organic layer was washed with 0.5N aqueous NaOH solution and saturated aqueous NaCl solution, dried over MgSO4 and concentrated in vacuo. The residue was purified by SiO2 column chromatography (eluent: n-hexane and then AcOEt in n-hexane 10%). The solvent was evaporated in vacuo to give 1.05 g of 2-(4-fluorophenyl)thiophene as a white solid. m.p.: 51-52 C. 1H-NMR (300 MHz, CDCl3, delta): 7.01-7.14(3H, m), 7.21-7.29(2H, m), 7.52-7.62(2H, m)Next, a solution of 2-methylbenzoic acid chloride (0.86 g, 5.6 mmol) in methylene chloride (6 mL) was cooled to 2 C. Aluminum chloride (0.9 g, 6.6 mmol) was added to the resulting reaction solution such that the temperature of the reaction solution was 10 C. or less. Aluminum chlorideAnd after stirring for 15 minutes, methylene chloride of 2- (4-fluorophenyl) thiophene (1 g, 5.6 mmol) obtained in the first step such that the temperature of the reaction solution becomes 10 C. or less The solution (3 mL) was added dropwise to the reaction solution, and the mixture was stirred for 1 hour at the same temperature, heated to 23 C., and stirred for 3 hours.Ice (30 g) is added to the obtained reaction liquid to dilute, and then separated. The aqueous layer is extracted with methylene chloride, combined with the previously obtained methylene chloride layer, washed with water, and concentrated under reduced pressure.Crude crystals of 2- (4-fluorophenyl) -5- (2-methylbenzoyl) thiopheneObtained (1.61 g, 97%). The crude crystals were recrystallized from ethyl acetate / hexane (0.65 g, yield 40 mol%) to obtain the desired product as yellow crystals. The purity of the yellow crystals was determined by high performance liquid chromatography (HPLC) to be 99.89%.

Molecular Weight:178.23
XLogP3:3.8
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:178.02524956
Monoisotopic Mass:178.02524956
Topological Polar Surface Area:28.2
Heavy Atom Count:12
Complexity:141
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes