2-Amino-5-fluorobenzamide

Intermediate 32; 2-Amino-5-fluorobenzamide A round-bottomed flask was charged with 5-fluororanthranilic acid (3 g, 19.34 mmol) in tetrahydrofuran (64.5 mL) and a 20percent solution of phosgene (11.2 mL, 21.3 mmol) in toluene was added dropwise at room temperature. The mixture was stirred for 18 hr at room temperature, then cooled to 0° C., at which time concentrated ammonium hydroxide (27.9 mL, 193 mmol) was added cautiously. The mixture was then allowed to warm to room temperature and then stirred for 1 hr. The organic phase was diluted with EtOAc, washed with aqueous dipotassium hydrogen phosphate and brine, then dried over sodium sulfate and concentrated to give a white solid (2.46 g, 82percent yield). MS: M(CA suspension of 2-amino-5-fluorobenzoic acid (1) (1.0 g, 6.3 mmol) in benzene (30 mL) underreflux was mixed with thionyl chloride (1.5 g, 12.6 mmol). The resulting mixture was stirred underreflux for 4 h, and then evaporated. The residue was dissolved in 200 mL of benzene and treated with anhydrous ammonia gas at room temperature. After removing the solvent, compound 2 wascrystalized from ethanol and obtained as brown powder [25]. Yield 75percent; m.p.: 144–146°C; 1H-NMR(DMSO-d6, 300 MHz) δ: 5.72(s, 2H, NH2, ), 6.54(s, CONH2, 2H) 7.63 (d, 1H, J = 8.6 Hz, Ar-H), 7.92 (d, 1H, J = 7.4 Hz, Ar-H), 8.14 (s, 1H, Ar-H). C7H7FN2O (154.05): MS (ESI) m/z 155.05 [M + 1].To a stirred solution of 2-amino-5-fluoro-benzoic acid (15 g, 96.69 mmol) in THF (300 mL), EDC.HCl (27.70 g, 145.03 mmol), HOBt·NH3 (21.75 g, 145.03 mmol) and DIPEA (51.0 mL, 290.07 mmol) were added at RT and stirred for 6 h (TLC indicated complete consumption ofstarting material). The reaction mixture was concentrated under reduced pressure to give thecrude residue which was diluted with water (150 mL) and extracted with EtOAc (3 x 150mL). The combined organic extracts were washed with water (2 x 100 mL), brine (1 x 100mL), dried over Na2S04, and concentrated under reduced pressure to give the crude residue.The crude material was purified by column chromatography (100-200 silica gel, 300 g, 40percentEtOAc-Hexane) to provide 2-amino-5-fluoro-benzamide (10.0 g, 67percent) as a pale yellow solid.LCMS: mlz: 155.38 [M+Ht.To a dry flask purged with NInto a 500-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a mixture of 5-fluoro-2-nitrobenzamide (17.5 g, 95.04 mmol, 1.00 equiv) and palladium carbon (10percent) (1.75 g, 0.10 equiv) in methanol (150 mL). To the above HGeneral procedure: (a) Thionyl chloride (1.5 g, 12.6 mmol) was added dropwise to a suspension of a 5-substituted-2-nitrobenzoic acid (1a: 1.1 g, 6.3 mmol; 1b: 1.2 g, 6.3 mmol) in dichloroethane (30 mL) under reflux. The resulting mixture was stirred under reflux for 4 h and dried under vacuum. (b) The residue was dissolved in 200 mL of dichloroethane and treated with anhydrous ammonia gas at room temperature. (c) After removing solvent, the intermediate 5-substituted-2-nitrobenzamide (2a, b) was dissolved in MeOH and hydrogenated over 10percent Pd/C for 1-2 h. The catalyst was removed by filtration, and the solution was dried under vacuum to afford the 5-substituted-2-aminobenzamides as pale yellow powders (3a: 0.7 g, 85percent; 3b: 0.8 g, 85percent).General procedure: Adapted from a literature procedure, 1 the appropriate organonitrile (1.0 eq.) and K2CO3(0.2eq.)wereaddedtoamicrowavetubewithastir-barwithdeionizedwater(8.5mLpermmolsubstrate).Afterirradiationundermicrowaveat150°Cfor30minutes, thereactionmixturewascooled, extractedwithEtOAc(320mL), thecombinedphasesdriedoverMgSO4andexcesssolventremovedinvacuo.TheresiduewaspurifiedbyFCC, ifrequired, togivethetitlecompound.

Molecular Weight:154.14
XLogP3:0.4
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