Benzamide, 2-amino-4-fluoro- (9CI)

Step A: To solution of 2-amino-4-fluorobenzoic acid (4.0 g, 25.8 mmol) in degassed DMF (50 mL) were added HOBt (4.19 g, 31 mmol), DIEA (5.4 mL, 31 mmol), EDCI (5.94 g, 31 mmol) and 2N NHTo a stirred solution of 2-amino-4-fluoro-benzoic acid (300 mg, 1.93 mmol) in THF (6 mL), EDC.HCl (553 mg, 2.90 mmol), HOBt·NH3 (435 mg, 2.90 mmol), DIPEA (1.03 mL, 5.79mmol) were added at RT and stirred for 1 h (TLC indicated complete consumption of startingmaterial). The reaction mixture was diluted with water (25 mL) and extracted with EtOAc (3x 20 mL). The combined organic extracts were dried over Na2S04, concentrated underreduced pressure to get the crude residue which was purified by flash columnchromatography (100-200 mesh silica gel, 5g, 50percent EtOAc-Hexane) to furnish 2-amino-4-fluoro-benzamide (195 mg, 65percent) as a white solid.1H NMR [300 MHz, DMSO-d6]: J 7.71 (brs, 1H), 7.61-7.56 (m, 1H), 7.07 (brs, 1H), 6.89 (s, 2H), 6.42 (dd, J = 2.7, 12.0 Hz, 1H), 6.30-6.23 (m, 1H).59.23 g (0.387 mol) of benzotriazol-1-ol, 65.776 ml (0.387 mol) of N-ethyldiisopropylamine and 74.15 g (0.387 mol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride were added successively at room temperature to a solution of 50.0 g (0.322 mol) of 2-amino-4-fluorobenzoic acid in 600 ml of dimethylformamide. 64.46 ml (0.451 mol) of ammonia in methanol (7 mol/l) were added dropwise with stirring, and the mixture was stirred for 18 hours. Water (2 l) and concentrated sodium chloride solution (0.5 l) were added to the batch. The mixture was extracted three times with ethyl acetate (0.75 l each time). The organic phase was dried over sodium sulfate, filtered, and the solvent was subsequently stripped off in a Rotavapor. The residue was triturated with 2-methoxy-2-methylpropane (0.2 l) and ligroin (0.1 l). The crystalline precipitate was filtered off with suction and dried in a drying cabinet, giving 44.5 g of 2-amino-4-fluorobenzamide as solid. 35.85 g (0.520 mol) of sodium nitrite in 75 ml of water were added dropwise at room temperature to a suspension of 44.5 g (0.289 mol) of 2-amino-4-fluorobenzamide in 1.4 l of hydrochloric acid (25percent). The mixture was stirred for 2 hours with ice-cooling. The deposited precipitate was filtered off with suction, rinsed with water and dried at 60° C. in a vacuum drying cabinet, giving 32.58 g of 7-fluoro-3H-benzo[d]-1, 2, 3-triazin-4-one as solid; HPLC/MS (M+H)Stage 2: 2-amino-4-fluorobenzamide General procedure: A modified version of the reported procedure was employed.Step A:2-Amino-4-fluorobenzamide (77.1 mg, 0.5 mmol), ruthenium catalyst (4.4 mg, 0.01 mmol, 2 mol%), THF (0.5 mL), propylene alcohol (34.8 mg, 0.6 mmol) Go to the microwave reaction tube. The mixture was reacted at 130 C for 3 hours and then cooled to room temperature. The solvent was removed under reduced pressure in vacuo and then purified by column chromatography (eluent: ethyl acetate / petroleumEther) gave the pure title compound in a yield: 88%.

Molecular Weight:154.14
XLogP3:1.5
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:154.05424101
Monoisotopic Mass:154.05424101
Topological Polar Surface Area:69.1
Heavy Atom Count:11
Complexity:163
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes