2-AMINO-5-BROMOBENZAMIDE

Off-white to light yellow solid

A stirred solution of 2-aminobenzamide (1.00 g, 7.34 mmol) in acetonitrile (20 mL) at room temperature was treated with N-bromosuccinimide (1.36 g, 7.70 mmol). Compound 26 (9.1 g, 42.1 mmol), HOBT (13.6 g, 101.1 mmol) and EDC.HC1 (19.4 g, 101.1 mmol) were dissolved in DMF (60 mL) and NH12464] To a suspension of compound 69-4 (9.1 g, 42.1 mmol), HOST (13.6 g, 101.1 mmol) and EDC.HC1 (19.4 g, 101.1 mmol) in DMF (60.0 mE) was added NH3.H20 (30.0 mE) dropwise. At the end of addition, the mixture was stirred at rt for 15 irs. After the reaction was completed, the solvent was removed. The residue was dissolved in EtOAc (100 mE). The resulting mixture was washed with NaOH aqueous solution (20 mE, 1 M) and brine, dried over anhydrous Na2504 and concentrated in vacuo to give the title compound 69-5 (7.6 g, 84percent). The compound was characterized by the following spectroscopic data:12465] MS (ESI, pos.ion) mlz: 216.5 [M+H]12466] ‘H NMR (400 MHz, CDC13) ö (ppm): 7.57 (d, 1H), 7.22, 7.19 (d, d, 1H), 6.58, 6.56 (d, d, 1H), 6.40 (s, 2H), 5.98 (brs, 2H).To a stirred solution of 2-amino-5-bromobenzoic acid (14.0 g, 0.065 mol) dissolved in THF (230 mL) was added CDI (12.6 g, 0.077 mol). The reaction mixture was stirred for 2 h at rt. To this mixture ammonia (321 mL, 25percent solution in water) wasadded and the mixture was stirred at room temperature for 14 h. The volatiles were evaporated to dryness; water (100 mL) was added and the mixture was extracted with ethyl acetate (2 x 150 mL). The combined organic extracts were concentrated under reduced pressure to afford a residue. The product was purified by silica gel colunm chromatography using 70percent ethyl acetate in hexanes. The required fractions werecollected and concentrated under reduced pressure to afford 2-amino-5- bromobenzamide (14.0 g, 0.065 mol, 82percent yield) as a brown solid. LCMS (ESI) m/e 215.0 (bromo pattern) [(M+H), calcd for C7H8BrN2O, 214.97]; LC/MS retention time (method B): ti = 0.93 mm.To a suspension of compound 28-7 (1.52 g, 7.00 mmol) in dry THF (5.0 mL) was added CDI (0.83 g, 5.12 mmol) dropwise. At the end of the addition, the mixture was stirred at rt for 2.0 hrs, and then NHTo a mixture of compound 1-18 (1.51 g.7.00 mmol) in dry THF (5.0 mL) was added CD1 (0.83 g.5.12 mmol). At the end of the addition, the mixture was stirred at rt for 2.0 hrs. And then NHTo a solution of compound 24-2 (1.51 g, 7.00 mmol) in anhydrous THF (5 mL) was added CDI (0.83 g, 5.12 mmol). After the mixture was stirred at rt for 2 hours, the mixure was cooled to 0 °C and ammonium hydroxide (20 mL) was added dropwise. At the end of the addition, the mixture was stirred at rt overnight. After the reaction was completed, the THF was removed in vacuo and the rediue was dissolved in EtOAc (100 mL). The solution was washed with a saturated aqueous solution of NaCl, dried over anhydrous Na2S04 and concentrated in vacuo to afford a pale yellow solid (1.2 g, 80 percent). The compound was characterized by the following spectroscopic data: MS (ESI, pos.ion) mlz: 217 [M+H]+; and lU NMR (400 MHz, CDC13): δ 7.78 (s, 1H), 7.45 (d, 1H, J = 8.0 Hz), 7.15 (s, 1H), 6.89 (d, 1H, J = 2.0 Hz), 6.79 (s, 1H), 6.61 (dd, 1H, J = 8.0 Hz, 2.0 Hz) ppm.General procedure: To a 25 mL round-bottom flask equipped with magnetic stirrer were added nitrile (2.5 mmol), acetaldoxime (3.75 mmol), copper oxide (0.25 mmol) and HTo a solution of 2-amino-5-bromobenzonitrile (2 g, 10.2 mmol) in methanol(20 mL) and DMSO (1.5 g, 20 mmol) was added hydrogen peroxide (30 percent solutionin water, 1.4 g, 40 mmol) dropwise followed by the addition of sodium hydroxide(0.2 g, 5 mmol) in water (5 mL). The resultant mixture was heated at 60 °C for 1 h.Upon reaction completion the volatiles were removed under reduced pressure and theresidue was diluted with water (5 mL). The solid obtained was filtered, washed withwater and dried under vacuum to afford 2-amino-5-bromobenzamide (1.3 g, 60percentyield): ‘H NMR (400 MHz, DMSO-d6) ö 7.84 (bs, 1 H), 7.71 (s, 1 H), 7.25 (dd, J2.4 Hz, J= 8.8 Hz, 1 H), 7.17 (bs, 1 H), 6.71 (bs, 2 H), 6.66 (d, J 8.8 Hz, 1 H).Methyl 2-amino-5-bromobenzoate (1 equiv) was added to a solution of NH6-BROMO-LH-BENZO [d] [1, 3] oxazine-2, 4-dione (5g, 20mmol) was suspended in 30ML of tetrahydrofuran and to it was bubbled NH3 gas for 1. 5hr. The solvent was removed in a rotary evaporator and residue partitioned between methylene chloride and water. The solid was filtered and dried to yield title compound (3. 8G, 85percent).Synthesis of 2:To a stirred solution of 6-bromoisatoic anhydride 1 (10 g, 41.3 mmol) in THF to (500 mL) was added slowly NH6-Bromo-lNo.-benzo[d][l, 3]oxazine-2, 4-dione (56.0 g, 230 mmol) was suspendedin 1 N aq. NH4OH (600 mL, 2.6 equivalents), and the suspension was stirred 3 d at room temperature. After filtration, the collected solid was washed with water and subsequently dissolved in tetrahydrofuran. This solution was filtered, evaporated to dryness, and dried by repeated azeotropic distillation with toluene. The solid was suspended in CH2CI2, filtered, and washed once CH2CI2 with yielding 35.4 g (71.2percent) 2-amino-5-bromo-benzamide.

Molecular Weight:215.05
XLogP3:1
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:1
Exact Mass:213.97418
Monoisotopic Mass:213.97418
Topological Polar Surface Area:69.1
Heavy Atom Count:11
Complexity:163
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes