Reference of 425379-16-4, A common heterocyclic compound, 425379-16-4, name is 2-Bromo-3-fluorobenzonitrile, molecular formula is C7H3BrFN, its traditional synthetic route has been very mature, but the traditional synthetic route has various shortcomings, such as complicated route, low yield, poor purity, etc, below Introduce a new synthetic route.
Step 3. 2′,6-Difluoro-5 ‘-(5 -(2-hydroxy- 1.1.1,3.3.3 – c -propan-2- ylV 1 H- benzo 1imidazol-l-yl biphenyl-2-carbonitrile (108): A mixture of lOu (1.7 g, 4.78 mmol), bis(pinacolato)diboron (1.47 g, 5.8 mmol) and KOAc (1.18 g, 12.0 mmol) in dioxane (30 mL) was purged with nitrogen for 5 minutes. Bis(triphenylphosphine)palladium(II)- dichloride (270 mg, 0.38 mmol) was added and the mixture was heated at 120 C overnight. The mixture was diluted with EtOAc (200 mL) and the solution was washed with water (2 x 30 mL) and brine, then dried (Na S04). After concentrating to dryness the material was dissolved in MeOH (30 mL) and concentrated to dryness again. The concentration step from MeOH was repeated a total of five times until about 2.1 g of a tan colored solid was obtained. This intermediate (2.1 g) was stirred in THF (20 mL) and water (10 mL) and was treated with 3-fluoro-2-bromo-l-cyanobenzene (1.2 g, 6 mmol) and K2C03 (1.5 g, 10.8 mmol). The mixture was purged with nitrogen for five minutes, then bis(di-t-butylphosphine) ferrocene palladium(II)dichloride (130 mg, 0.2 mmol) was added. The solution was heated at 60 C overnight. The cooled mixture was diluted with EtOAc (120 mL) and washed with water (30 mL). The organic phase was dried (Na2S04) and concentrated. The crude product was purified on an Analogix automated chromatography system eluting with 0-3% MeOH/CH2Cl2. The partially purified mixture was further purified on a reverse-phase CI 8 column eluting with 0-50% acetonitrile/water. The purest fractions were collected and concentrated to remove acetonitrile and the solid was isolated by filtration. This solid was passed through a short silica gel column eluting with 3% MeOH/CH2Cl2 to give 320 mg (17%) of 108 with 99.8% purity. 1H-NMR (300 MHz, CDC13): delta 1.89 (s, 1H), 7.42-7.44 (m, 0.19H), 7.45-7.47 (m, 0.65H), 7.47-7.50 (m, 0.76H), 7.51 (app d, J= 1.46, 0.33H), 7.53-7.67 (m, 6H), 7.99 (dd, J= 0.7, 1.7, 1H), 8.12 (s, 1H). 13C-NMR (75 MHz, CDC13): delta 109.95, 116.31, 117.79, 118.11, 120.75, 121.05, 121.32, 127.03, 127.15, 127.38, 129.32, 129.37, 131.15, 131.27, 132.53, 142.47, 143.92, 144.65, 158.05, 161.41. HPLC (method: Waters Atlantis T3 2.1 column 2.1 x 50 mm 3mu?iota – gradient method 5-95% ACN + 0.1% formic acid in 14 min with 4 min hold at 95% ACN+0.1% formic acid; wavelength: 305 nm):retention time: 5.85 min; 99.8% purity. MS (M+H): 396.3. Elemental Analysis(C^HnDgFa^O): Calculated: C=69.87, H=4.33, F=9.61, N=10.63. Found: C=79.27, H=4.05, F=9.63, N=10.53.
The basis of chemical reaction formula synthesis, the synthesis route is composed of some specific reactions and combined according to certain logical thinking. We look forward to the emergence of more reaction modes in the future.
Reference:
Patent; CONCERT PHARMACEUTICALS, INC.; LIU, Julie, F.; HARBESON, Scott, L.; WO2011/47315; (2011); A1;,
Nitrile – Wikipedia,
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