Methyl 4-fluoro-3-nitrobenzoate

light yellow solid powder

Preparation of 4-Fluoro-3-nitro-benzoic acid methyl ester; 4-Fluoro-3-nitrobenzoic acid (500 mg, 2.70 mmol) was dissolved in 20 mL of a 5:1 /toluene :MeOH mixture at 0°C under nitrogen. Trimethylsilyl diazomethane (2M in hexanes)(1.6 mL, 3.24 mmol) was added dropwise and the solution stirred at rt for 30 min. Thesolvent was concentrated. The product was purified by flash chromatography using 4:17hexanes:EtOAc as eluent on silica gel, to yield the desired title compound. Yield: 494 mg(92percent).Step-A Stage 1 Step A: Methyl 4-fluoro-3-nitrobenzoate; To a solution of 4-fluoro-3-nitrobenzoic acid (5.7 g, 30.8 mmol) in MeOH (50 ml_), cooled to 0 Synthesis of 4-Fluoro-3-nitro-benzoic acid methyl ester (25)Starting material 24 (10 g, 54 mmol) was placed in 60 ml methanol and 0.5 ml sulfuric acid was added dropwise. Now the reaction was stirred over night at 80 To a 100L flask was charged 12.7kg of 4-fluoro-3-nitrobenzoic acid was added 40kg of methanol and 2.82kg concentrated sulfuric acid. The mixture was stirred at reflux (65° C) for 36 hours. The reaction mixture was cooled to 0° C. Crystals formed at 38° C. The mixture was held at 0° C for 4 hrs then filtered under nitrogen. The 100L flask was washed and filter cake was washed with 10kg of methanol that had been cooled to 0° C. The solid filter cake was dried on the funnel for 1 hour, transferred to trays, and dried in a vacuum oven at room temperature to a constant weight of 13.695kg methyl 4-fluoro-3-nitrobenzoate (100percent yield; HPLC 99percent).To a 100 L flask was charged 12.7 kg of 4-fluoro-3-nitrobenzoic acid was added 40 kg of methanol and 2.82 kg concentrated sulfuric acid. To a 100 L flask was charged 12.7 kg of 4-fluoro-3-nitrobenzoic acid was added 40 kg of methanol and 2.82 kg concentrated sulfuric acid. The mixture was stirred at reflux (65 °C) for 36 hours. The reaction mixture was cooled to 0 °C. Crystals formed at 38 °C. The mixture was held at 0° C for 4 hrs then filtered under nitrogen. The 100 L flask was washed and filter cake was washed with 10 kg of methanol that had been cooled to 0 °C. The solid filter cake was dried on the funnel for 1 hour, transferred to trays, and dried in a vacuum oven at room temperature to a constant weight of 13.695 kg methyl 4-fluoro-3-nitrobenzoate (100percent yield; HPLC 99percent).To a 100 L flask was charged 12.7 kg of 4-fluoro-3-nitrobenzoic acid was added 40 kg of methanol and 2.82 kg concentrated sulfuric acid. The mixture was stirred at reflux (65° C) for 36 hours. The reaction mixture was cooled to 0 °C. Crystals formed at 38 °C. The mixture was held at 0 °C for 4 hrs then filtered under nitrogen. The 100 L flask was washed and filter cake was washed with 10 kg of methanol that had been cooled to 0 °C. The solidfilter cake was dried on the funnel for 1 hour, transferred to trays, and dried in a vacuum oven at room temperature to a constant weight of 13.695 kg methyl 4-fluoro-3-nitrobenzoate (100percent yield; HPLC 99percent).a) 4-Fluoro-3-nitrobenzoicacid (7, 0.85 g, 4.59 mmol) and acatalytic amount of sulfuric acid (0.40 mL) were dissolved in 18 mL of CHPreparation of (2-methyl-1-m-tolyl-1H-benzo[d]imidazol-5-yl)(piperidin-1-yl)methanone (Compound 98)[Step 1] [Step 1] Synthesis of intermediate J; To a solution of compound I (30.Og, 162mmol) in methanol (300ml) was added cone, sulfuric acid (5ml) and the mixture was stirred at reflux for 12 hours and then concentrated in vacuo. The concentrate was partitioned between ethyl acetate and saturated, aqueous bicarbonate. The organic layer was washed with water and brine, successively, and concentrated to afford J (31.5g, 97percent).4-fluoro-3-nitrobenzoic acid (1.110 g, 6 mmol) was dissolved in MeOH (30 mL). Then, cone. H4-Fluoro-3-nitrobenzoic acid (0.5 g, 2.7 mmol) was dissolvedin methanol (5 mL) and conc. H2SO4 (0.5 mL) atroom temperature. The reaction mixture was heated withstirring in a 10 mL microwave process vial for 10 min at80 °C. After completion of the reaction (as evident fromthin layer chromatography (TLC)), the solvent was evaporatedunder reduced pressure, the reaction mixture basifiedby sodium bicarbonate and the aqueous layer extracted intoethyl acetate (3 × 5 mL). The organic layer was dried overanhydrous Na2SO4 and concentrated under reduced pressureto yield 2 as a cream-colored powder (95percent).1H NMR (CDCl3, 400 MHz) δ 8.73 (1H, dd, J = 7.2, 2.2Hz, H-2), 8.31 (1H, m, H-6), 7.38 (1H, dd, J = 10.2, 8.8 Hz, H-5), 3.95 (3H, s, H-8); 13C NMR (CDCl3, 100 MHz) δ164.1 (C-7), 158.1 (d, JCF = 270.0 Hz, C-4), 137.3 (C-3), 136.5 (d, J = 9.7 Hz, C-6), 127.8 (C-2), 127.2 (d, J = 4.2 Hz, C-1), 118.8 (d, J = 21.2 Hz, C-5), 52.9 (C-8); 19F NMR(CDCl3, 376.5MHz) δ −110.55.[00220] To a solution of 4-fluoro-3-nitrobenzoic acid 1 (5.0 g, 27.0 mmol) in dry MeOH (30 mL), H2SO4 (5 mL, 0.3 M) was added and the reaction mixture was heated to reflux for 12 h. The solvent was removed under reduced pressure, crude reaction mixture was dissolved in EtOAc (150 mL), washed with saturated NaHCO3 (20 mL _ 2), water (10 mL _ 2) and brine (10 mL). The EtOAc layer was dried over anhydrous MgSO4 and evaporated to get methyl 4-fluoro-3-nitrobenzoate 2 (95percent) as a white solid.Thionyl chloride (191.4 g, 1.61 mol) was added to a solution of 4-fluoro-3-nitrobenzoic acid (150.0 g, 810.81 mmol) in methanol (500 ml) at 0°C. The resulting solution was heated to reflux overnight, concentrated in vacuo, the product was precipitated by the addition of petroleum ether (200 ml), and the solids were collected by filtration to afford methyl 4-fluoro-3-nitrobenzoate as a light yellow solid (150 g, 93percent).'H-NMR (300 MHz, CDC1To a solution of 4-fluoro-3-nitrobenzoic acid (2 g, 11 mmol) in MeOH (20 mL) was slowly added SOCl5.55 g of 4-Fluoro-3-nitro-benzoic acid were dissolved in 50 ml of methanol, 6.4 ml of concentrated sulfuric acid were added and the reaction was heated to reflux for 3 h. The reaction was cooled, poured unto ice and the precipitated product was collected by suction and dried in vacuo. 5.40 g (90percent) of 4-fluoro-3-nitro-benzoic acid methyl ester were obtained. Ca) 4-Fluoro-3-nitro-benzoic acid methyl ester [1938] 4-Fluoro-3-nitro-benzoic acid were dissolved in 50 ml of methanol, 6.4 ml of concentrated sulfuric acid were added and the reaction was heated to reflux for 3 h. The reaction was cooled, poured unto ice and the precipitated product was collected by suction and dried in vacuo. 5.40 g (90percent) of 4-fluoro-3-nitro-benzoic acid methyl ester were obtained. [1940] CA mixture of acid 5 (1.85 g, 1 mol), methanol (15 mL) and 96percent H[Example 49] EXAMPLE 49 TRIFLUOROMETHANESULFONIC acid (600 UL, 6.8 MMOL) was added to a solution of 4-fluoro-3-nitro-benzoic acid (25.00 g, 135 MMOL) and trimethyl orthoformate (29.5 mL, 270 MMOL) in MEOH (250 mL), which was refluxed and monitored to completion over 4 days with 1 H-NMR. The resulting solution was concentrated to remove most of the methanol, and then was diluted with 2 volumes of water to precipitate the product. The filter cake was washed with additional water and vacuum dried to afford 25.45 g (95percent) desired product as a slightly off-white solid. 1H NMR (300 MHz, CDCl3 6 8.68 (dd, J=2.2 Hz, J=7.25 Hz, 1 H), 8.35 (ddd, J=2.2 Hz, 1 H), 7.55 (dd, J=10.8 Hz, J=8.8 Hz, 1 H), 3.96 (s, 3 H). F NMR (300 MHz, CDCI3) # - 114. 33 (symmetric 7 line multiplet).

Molecular Weight:199.14
XLogP3:1.7
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:2
Exact Mass:199.02808583
Monoisotopic Mass:199.02808583
Topological Polar Surface Area:72.1
Heavy Atom Count:14
Complexity:240
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes