2-FLUORO-3-METHOXYBENZOIC ACID

2-Fluoro-3-methoxy-benzoic acidTo a solution of 2-Fluoro-3-methoxy-benzaldehyde (5.0 g, 32.46 mmol) in acetonitrile(50 mL) was added sodium hydrogenphosphate (in 3 mL water) at room temperature. The j 5 mixture was cooled to 0 Step 1. [PENTAMETHYLENEDIETHYLENETETRAMINE] (31. [2ML)] was added to a solution of 2-fluoroanisole [(15.] 0g) in THF [(450ML).] The reaction mixture was cooled [TO-78C] and n-butyllithium (59. [6ML, ] 2. 5M solution in hexanes) was added dropwise. Stirring was maintained for 2h before the solution was added in a dropwise fashion to a flask containing solid carbon dioxide pellets. Upon complete addition (30min) the mixture was allowed to warm to room temperature before removal of the volatiles in vacuo. The residue was dissolved in 10% sodium hydroxide solution [(300ML)] and extracted with Et20 (3x). The aqueous was acidified to pH 1 with concentrated hydrochloric acid before extracting with DCM. The organics were washed with [H20, ] dried (MgS04) and concentrated in vacuo to afford the subtitle compound as a yellow solid. Yield: 7. [1G.] [LH NMR 6 (CDC13)] 7.50 [(1H, ] [M), ] 7.12 (2H, [M), ] 3.91 (3H, s).1.0 g, 1.0 equiv. of the compound of formula II is dissolved in 2 mL of THF solution;After adding 1.2 equiv. of diisopropylamino lithium in THF to the reactor, cooling, cooling to -78 C, the THF solution of the compound of formula II is added dropwise to the reaction system. After the dropwise addition, the temperature of the reaction solution is raised to -50 C.Insulation reaction for 1 h, During the heat preservation reaction, carbon dioxide is introduced into the reaction system until the TLC detection reaction is complete;After the reaction was completed, the reaction mixture was partitioned between ethyl acetate and 1N aqueous hydrochloric acid.The organic phase was separated and the organic phase was washed with brine and dried over sodium sulfate.Finally, the solvent is concentrated to dryness, and the residue is purified by column chromatography to give the compound of formula VI.The preparation of the compound of formula VII employs Method A, Method A is: 1.0 g, 1.0 equiv. of a compound of formula VI is added to the reactorDissolve in 2 mL of chloroform solution, and add 2 mL of thionyl chloride to the reaction system.The temperature was raised to reflux, and after refluxing for 4 hours, the solvent was concentrated to dryness under reduced pressure.The residue was dissolved in 10 mL of THF, based on the compound of formula VI.Add 1.2 equiv. of triethylamine, the reaction system is under ice bath conditions, Add 1.2equiv.TMSCH2N3 solution, stir for 48 hours in an ice bath.The reaction was completed; after the reaction was completed, the reaction solution was extracted with ethyl acetate.In the extraction process, the organic phase is washed successively with 1N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and the organic phase is dried over anhydrous sodium sulfate.Concentrating the solvent to give a residue;The residue was dissolved in the reactor in 20 mL of absolute ethanol.A solution of silver benzoate in triethylamine was added, and the reaction was stirred at room temperature for 18 h.Concentrated to dryness, and the residue was separated by column chromatography.Obtaining a compound of formula VII