3-Fluoro-4-nitrobenzoic acid,C7H4FNO4,403-21-4

2-Fluoro-4-methyl-l-nitro-benzene (1.0 g, 12.9 mmol) was added portion- wise to a suspension of potassium dichromate (5.04 g, 17.16 mmol) in glacial acetic acid (8 mL) follow by concentrated sulfuric acid (3.6 mL). The reaction mixture was heated to 120Reference Example 39 (a) Stage 1: EXAMPLE A1; N, N-bis(3-methylbutyl)-11-oxo-5-(3-piperidin-1-ylpropyl)-5, 11-dihydrothieno[3', 2':4, 5]pyrimido[1, 2-a]benzimidazole-7-carboxamide hydrochloride; Stage 1: 3-fluoro-4-nitrobenzoic acid; A mixture of 3-fluoro-4-nitrotoluene (10 g, 1 eq) and potassium permanganate (25.5 g, 2.5 eq) in water (1 L) is heated under reflux for 6 hours then cooled down to ambient temperature. The mixture is filtered on celite and the aqueous phase is washed twice with diethyl ether (2.x.300 ml). The aqueous phase is acidified, at 0° C., with a solution of concentrated hydrochloric acid then concentrated under reduced pressure at 40° C. to a volume of approximately 300 ml. The precipitate formed is filtered then washed with petroleum ether and dried in order to produce the expected compound in the form of a white solid (6.9 g; 58percent yield).NMR (Stage 1: Concentrated H2SO4 (190 mL) was added dropwise to a cooled solution of 3-fluoro-4- nitrotoluene (161.2 mmol, 25 g) and sodium dichromate dihydrate (225.6 mmol, 67.2 g) in water (200 mL). The addition was carried out while maintaining the temperature of the reaction mixture below 10 [C.] Once the addition was complete, the solution was refluxed at 100 [C] for approximately 2 h. The reaction mixture was cooled to room temperature, diluted with H20 (200 mL) and the product extracted with ethyl acetate. The organic extracts were combined and extracted with a solution of 2N sodium hydroxide. The basic phase was acidified with concentrated [HC1] to afford (65.9 mmol, 12.2 g) as an off-white solid precipitate (yield: 40.8percent). The precipitate was further purified by recrystallization from an ethanol/water mixture to afford 3-fluoro-4- nitrobenzoic acid as white crystals.To a solution [OF 3-FLUORO-4-NITROTOLUENE] (22.45 g, 144.7 mmol) and sodium dichromate dihydrate (60.38 g, 202.6 mmol) in water at [0 C] was added concentrated sulfuric acid (140 mL) dropwise over 3 h. When the addition was complete, the solution was allowed to warm to room temperature over [1] h, and then brought to 90 C for 1 h. The mixture was allowed to cool to room temperature, diluted with 300 mL water and extracted with ethyl acetate (3 x 250 mL). The combined organic extracts were concentrated down to 300 mL and extracted with [1] N NaOH (3 x 250 mL). The aqueous extracts were acidified with 6 N [HC1] and extracted with ethyl acetate (3 x 300 mL). The combined organic extracts were dried over [MGS04] and concentrated to give a gummy solid. Trituration with hexane gave the [3-FLUORO-4-NITROBENZOIC] acid as a solid that was collected by filtration (6.51 g, 24percent).Example 8 In the step D-3, to a solution of 3-fluoro-4-nitrobenzyl alcohol (2. 97 g) in acetone (60 ml) was added Jones reagent (13 ml), prepared from CHROMIC acid (26.7 g) and sulfuric acid (23 ml) in water (100 ml), dropwise at 0C. The mixture was stirred on a ice-bath for 0.5 hours and quenched with isopropanol (20 ml) to be concentrated in vacuo. The residue was dissolved in ethyl acetate (30 ml) and washed with water (30 ml X 3), and brine (30 ml X 1), successively. The organic layer was dried over sodium sulfate and concen- trated in vacuo to obtain a yellow solid, that was triturated with hexane to give 3-FLUORO-4-NITROBENZOIC acid as a pale yellow solid (2.94 g, 92percent).