5-Fluoro-2-nitroanisole

In a 5L four-necked flask, DMF 2500 g, 4-fluoro-2-hydroxy nitrobenzene (500 g, 3.20 mol) and potassium carbonate (483 g, 3.50 mol) were added and heated to 60°C. 424 g (3.36 mol) of dimethyl sulfate was added dropwise for about 2-3 hours. After completion of dripping, heated to 90-100°C for 5-6 hours. Sampling GC analysis of 4-fluoro-2-hydroxy nitrobenzene was found to<0.5percent. The mixture was cooled to 50°C, generating monomethyl sulfate potassium salt. The filtrate was distilled under reduced pressure to recover DMF to give 515 g of 4-fluoro-2-methoxynitrobenzene as a yellow oily liquid. GC content of 99.5percent, yield 94.1percent.Example 127; Preparation of 3-(4-(4-(1, 1, 1, 3, 3, 3-hexafluoro-2-hydroxypropan-2-yl)-2-propylphenoxy)-2-methoxyphenethyl)-5-(1-(1-methylethoxy)phenyl-4-yl)-5-methylimidazolidine-2, 4-dione; 127-a-1) Preparation of 4-fluoro-2-methoxy-1-nitro-benzene; A solution of 4-fluoro-2-hydroxy-1-nitrobenzene (100 mg, 0.637 mmol) in N, N-dimethylformamide (3.2 mL) was added with potassium carbonate (132 mg, 0.955 mmol), then added with methyl iodide (48 μL, 0.764 mmol) under ice-cold conditions, and stirred at room temperature for 1 hour. The reaction solution was further added with potassium carbonate (132 mg, 0.955 mmol), then with methyl iodide (48 μL, 0.764 mmol) under ice-cold conditions, and stirred at 60° C. for 1 hour. The reaction solution was added with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. 4-fluoro-2-methoxy-1-nitro-benzene (118 mg, yield >100percent) was obtained as a yellow oil.To a stirred suspension of 4-fluoro-2-hydroxy- 1-nitrobenzene(35) (100 mg, 0.64 mmol) and K5-fluoro-2-nitrophenol (10 g, 63.65 mmol), potassium carbonate (8.8 g, 63.65 mmol) and acetone (100mL) wereadded in a 250 mL three-necked flask and stirred at room temperature for 30 minutes under the protection of nitrogengas. Iodomethane (9.03 g, 63.65 mmol) was then slowly added dropwise thereto, and the mixture was warmed up to60°C and reacted overnight. After the reaction was completed, the reaction solution was added with water (200 mL), extracted with ethyl acetate (100 mL 3 4), washed with 1M sodium hydroxide (100mL 3 3) and saturated brine (100mL 3 2) successively, dried over anhydrous sodium sulfate, filtered by suction and evaporated under reduced pressureto remove the solvent, to give 4-fluoro-2-methoxynitrobenzene (10.8 g, 99.1percent yield).4-fluoro-2-methoxy-1-nitro-benzene 20 g (126 mmol) 5-fluoro-2-nitro-phenol are dissolved in 300 ml acetone. 22.6 g (163 mmol) potassium carbonate are added and the mixture is stirred for 30 min at 20° C. Over a period of 10 min, 9.4 ml (150 mmol) methyl iodide, diluted in 50 ml acetone, is added and the mixture is stirred for a further 18 h at 20° C. Then it is left for another 12 h at 65° C. with stirring. The solvent is eliminated in vacuo, the residue is taken up in water and extracted three times with ethyl acetate. Then the combined organic phases are extracted three times with 10percent aqueous sodium carbonate solution. The organic phase is dried over magnesium sulphate. The solvent is eliminated in vacuo. Yield: 21.1 g (123 mmol; 98percent) UV max: 230/266/322 nm.(0540) 5-Fluoro-2-nitrophenol (7.85 g, 0.05 mol), iodomethane (8.52 g, 0.06 mol) and potassium carbonate (10.35 g, 0.075 mol) were added to acetonitrile (150 mL). The mixture was heated at 50° C. for 3 h, and the solvent was removed under reduced pressure. Water (200 mL) was added, and the mixture was extracted with ethyl acetate (200 mL). The organic phase was dried and concentrated to get the product (8.4 g, yield: 98percent).5.60.1 4-Fluoro-2-methoxy-1-nitrobenzene A mixture of 5-fluoro-2-nitrophenol (5.0 g, 31.8 mmol), iodomethane (13.5 g, 95.4 mmol), and potassium carbonate (16.7 g, 159 mmol) in acetone (80 mL) was heated to reflux for 4 hours. The mixture was cooled and evaporated under vacuum, and the residue was dissolved in ethyl acetate (200 mL) and washed with water (3.x.250 mL), dried (MgSOTo a stirred solution of 23 (0.60 g, 3.82 mmol) in acetone (20 mL) was added KStep 1 : KStep 1: K2C03 (131 g, 955 mmol) and Mel (66.7 mL) were added to a solution of 5-fluoro-2-nitrophenol (75.0 g, 478 mmol) in acetonitrile (750 mL) at rt and the resulting mixture was heated to 85 C for 5 h. The reaction mixture was chilled, filtered and washed with acetonitrile. The volatiles were removed under reduced pressure and the residue was diluted with water and was extracted with EtOAc. The combined organic layers were washed with water, brine, were dried and the volatiles were removed under reducedpressure to give the desired compound (75 g, 94percent).To 2-nitro-5-fluoro-phenol (56.0 g, 357 mmol) and iodomethane (24.5 mL, 393 mmol) in DMF (200 mL) was added KTo 2-nιtro-5-fluoro-phenol (56 0 g, 357 mmol) and iodomethane (24 5 mL, 393 mmol) in DMF (200 mL) was added KMethyl iodide (11.94 mL, 191 mmol) was added dropwise to a stirred suspension of 5-fluoro-2-nitrophenol (10 g, 63.7 mmol) and potassium carbonate (17.59 g, 127 mmol) in acetone (318 mL) at room temperature. The reaction mixture was allowed to stir at room temperature for 4 days, whereupon the acetone was evaporated under reduced pressure and the residue was partitioned between water and ethyl acetate. The aqueous layer was neutralised with concentrated hydrochloric acid. The organic layer was separated, washed with water and brine, dried (MgSO.)), filtered and evaporated to give an off-white solid that was recrystallised from isopropanol/dichloromethane to give 4-fiuoro-2-methoxy-l- nitrobenzene as an off-white solid (9.6 g, 88percent).A mixture of commercially available 5-fluoro-2-nitrophenol (1.00 g, 6.37 mmol), MeI (1.36 g, 9.58 mmol), and potassium carbonate (1.32 g, 9.55 mmol) in DMF (10 mL) was heated at 140° C. for 23 hours. The reaction was diluted with aq. 0.5 N NaOH (50 mL) and extracted with EtOAc (2.x.50 mL). The EtOAc-extracts were washed once more with aq. 0.5 N NaOH (50 mL). The combined organic layers were dried (Na4-Fluoro-2-methoxy-l-nitro-benzene was synthesized by suspending 5-fluoro-2-nitrophenol (5.0 g, 31.8 mmol, 1.0 equiv.), potassium carbonate (6.59 g, 47.7 mmol, 1.5 equiv.), and Iodomethane (2.98 mL, 47.7 mmol, 1.5 equiv.) in DMF (50 mL) and allowing the resulting reaction mixture to stir overnight at 14OPotassium carbonate(14.5 g, 105.1 mol) and iodomethane(7.1 ml, 114.6 mmol) were added to a solution of 2-nitro-5-fluorophenol(15 g, 95.5 mmol) in ethanol (100 ml), which was then refluxed for 12 hours. The resulting solid was filtered, washed with ethanol, and concentrated. The resulting oily residue was diluted with ethyl acetate and washed with water. The separated organic layer was concentrated and the residual oil was purified by column chromatography(ethylacetate/hexane=1/3) to give 1.65 g of the titled compound. (Yield 9.7percent). To a solution of 4-fluoro-2-hydroxy-l -nitrobenzene (5.0 g, 31.8 mmol) in DMF (10 mL) was added KToluene (500 ml) was added into clean and dry round bottom flask, then 2, 4- difluoro-1 -nitrobenzene (500 gms) was added. The reaction mass was cooled to 0°C then methanol (100 ml) was slowly added to reaction mass at 0°C. To the reaction mass potassium tert-butoxide (PTB) (353 gms) was added in lots (10 lots) at 0°C. The reaction mass was stirred at 0°C for 15-30 minutes, then temperature raised to 20°C and the reaction mass was stirred at 20°C for 4 hrs. The reaction mass was decomposed in water (1500 ml). The contents were stirred for 10-15 minutes followed by toluene was added to the reaction mass. The layers were separated, and the aqueous layer was extracted with toluene followed by separated the organic layer. Total organic layer was washed with water (1000 ml). The organic layer was then washed with brine solution (NaCl (50 gms) + water (500 ml)) and dried over sodium sulphate. The solvent was distilled out under vacuum. Petroleum ether (1000 ml) was added to the residue and the contents were cooled to below 10°C then stirred for 30 minutes. The solid was filtered off and washed with petroleum ether (200 ml). The solid was dried at 50-60°C for 3-5 hrs (Yield - 470 gms; 87.38percent).A mixture of 5-fluoro-2-nitrophenol (3.0 g, 19.1 mmol), potassium carbonate (2.50 g, 21.0 mmol) and dimethyl sulfate (2.65 g, 21.0 mmol) in acetone was stirred at ambient temperature for 24 hours. The solvents were removed under reduced pressure and then water (30 mL) and dichloromethane (30 mL) was added to the residue. The combined organics solutions were dried over magnesium sulfate then filtered and the filtrate concentrated under reduced pressure to provide an oil. This was purified by flash chromatography on silica gel using dichloromethane/heptane (7:3) as an eluent to provide the title compound as a crystalline solid (3.24 g, 100percent): 1H NMR (CDCl3, 400 MHz) δ7.96 (M, 1H), 6.80 (m, 1H), 6.73 (m, 1H), 3.96 (s, 3H); RP-HPLC (Hypersil HS C18, 5 μm, 100A, 250.x.4.6 mm; 5percent-100percent acetonitrile-0.05 M ammonium acetate over 25 min, 1 mL/min) tr 17.82 min; MS:MH+ 172.22-methoxy-4-fluoro-nitrobenzene (10g, 58.44mmol) was dissolved in methanol, was added 1g of palladium / carbon, substituted with hydrogen, the reaction under a hydrogen atmosphere for three days. Filtered and the filtrate was collected, methanol was distilled off to give an oily crude product. Was added at 0 crude product concentrated sulfuric acid was dissolved solid mixture, in batches added potassium nitrate (5.91g). The reaction solution was slowly warmed to room temperature and stirred overnight. The reaction solution was poured into ice water and NaHC03, adjustment pH6.0-8.0. The aqueous phase was thrice extracted with dichloromethane, the organic phase was collected, dried. The organic solvent was distilled off, the residue was purified by column chromatography to give 4-fluoro-2-methoxy-5-nitroaniline (4.0g).

Molecular Weight:171.13
XLogP3:1.7
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:1
Exact Mass:171.03317122
Monoisotopic Mass:171.03317122
Topological Polar Surface Area:55
Heavy Atom Count:12
Complexity:171
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes