4-BROMO-2,5-DIFLUORONITROBENZENE

Reference Example-50 Concentrated sulfuric acid (57 mL) was cooled inan ice bath, and 69percent nitric acid (25.5 g, 279 mmol) was added dropwise over 25minutes to prepare a mixed acid. To this mixed acid, under ice-cooling, dichloroethane(125mL) solution of 2-bromo-1, 4-difluoro-benzene (50g, 254mmol) was droppedslowly over a period of 1.5 hours. After completion of the dropwise addition, the reaction solution was further stirred for 2 hours at room temperature.After completion of the reaction, the reaction solution was added in portionsto ice-water (500 g), then extracted with ether (300mL × 2). The organic layerwas washed successively with water (300mL), saturated aqueous sodium hydrogencarbonate solution (300mL), saturated brine (300mL), and then dried overanhydrous magnesium sulfate, and the solvent was evaporated under reducedpressure. The resulting crude product was purified by silica gel chromatography(hexane: chloroform = 4/1) to give a pale yellow solid of 1-bromo-2, 5-difluoro-4-nitrobenzene(56 g, yield: 93percent ).Concentrated sulfuric acid (57 mL) was cooled in an ice bath, 69percent nitric acid (25.5 g, 279 mmol) was added dropwise over 25 minutes to prepare a mixed acid. In this mixed acid under ice-cooling 2-bromo-1, 4-difluorobenzene (50g, 254mmol) was dropped slowly over a period of 1.5 hours of dichloroethane (125mL) solution . After completion of the dropwise addition, the reaction solution was further stirred for 2 hours at room temperature. After completion of the reaction, added little by little the reaction solution into ice water (500g), then ether (300mL ×And extracted with 2). The organic layer was washed with water (300mL), saturated aqueous sodium hydrogen carbonate solution (300mL), was washed successively with saturated brine (300mL), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by silica gel chromatography - (hexane: chloroform = 4/1) to give 1-bromo-2, 5-difluoro-4-nitrobenzene as a pale yellow solid (56 g, yield: 93percent ) was obtained.Nitric acid (d 1.42) (26.2 g, 286.81 mmol) was slowly added dropwise to conc. sulfuric acid (102 g, 1042.96 mmol) over 1 hr under ice water, while the mixture was maintained at 10°C or below. Then, 2-bromo-1, 4-difluorobenzene (50.32 g, 260.74 mmol) was slowly added thereto over 3 hr while the mixture was maintained at 10°C or below. The reaction mixture was stirred at 5°C for 30 min, and then at room temperature for 1 hr. The reaction mixture was poured into ice (about 600 g), and the mixture was extracted three times with a mixed solvent of Et2O/THF (3:1). The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent; 20percent ethyl acetate/hexane) to give 1-bromo-2, 5-difluoro-4-nitrobenzene (49.64 g, 209 mmol, 80percent) as a pale yellow solid.INTERMEDIATE 6 1-((3S, 5S)-1 -Oxaspiror2.5loctan-5-ylmethyl)-5-fluoro-1 H-benzo[d]imidazole-6- carbonitrile1-Bromo-2, 5-difluoro-4-nitrobenzene To a stirred solution of 2-bromo-1 , 4-difluoro-benzene (98.6 g, 510.88 mmol) in 1.2 L of concentrated H1-Bromo-2, 5-difluoro-4-nitrobenzeneTo a stirred solution of 2-bromo-1 , 4-difluoro-benzene (98.6 g, 510.88 mmol) in 1.2 L of concentrated H1-Bromo-2, 5-difluoro-4-nitrobenzene:

Molecular Weight:237.99
XLogP3:2.6
Hydrogen Bond Acceptor Count:4
Exact Mass:236.92370
Monoisotopic Mass:236.92370
Topological Polar Surface Area:45.8
Heavy Atom Count:12
Complexity:187
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes