Brofoxine

Step 2: 6-Bromo-4, 4-dimethyl-1, 4-dihydro-2H-3, 1-benzoxazin-2-one; This compound was prepared as described in U.S. Pat. No. 6, 444, 668. To a solution of 2-(2-amino-5-bromo-phenyl)-propan-2-ol (18 g, 78 mmol), prepared in the previous step, in dry THF (150 mL) was added 1, 1'-carbonyldiimidazole (15.5 g, 94 mmol) under nitrogen. The reaction was heated at 50° C. overnight. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (100 mL). The solution was washed with 1 N HCl (2.x.40 mL), brine (20 mL), dried over anhydrous MgSOAdd 50g compound 16 to the 1L three-neck bottleThen add 500ml THF, Replace the air in the reaction flask with nitrogen, The reaction system is cooled to 0 ° C, Slowly add 160 ml of MeMgBr (3M in THF) under nitrogen protection.After maintaining the temperature for 1 h, the reaction was stirred for 6 h after warming to room temperature.38.8 g of N, N'-carbonyldiimidazole (CDI) was added to monitor the complete reaction of the starting materials.Continue to stir for 3h, The reaction was then quenched by the addition of saturated NH4Cl solution.The solution was separated and the aqueous phase was extracted twice with dichloromethane, 100 ml each time.The organic phase is combined and washed once with saturated brine.Dry anhydrous Na2SO4 for 1 h, remove the desiccant by filtration, After the filtrate was concentrated, the target product compound 17 was obtained as a white solid 40.5 g.The yield was 72.8percent.EXAMPLE 94 2-(4, 4-Dimethyl-2-oxo-1, 4-dihydro-2H-benzo[d] [1, 3]oxazin-6-yl)-pyrrole-1-carboxylic acid tert-butyl ester A solution of 6-bromo-4, 4-dimethyl-1, 4-dihydro-benzo[d] [1, 3]oxazin-2-one (0.87 g, 3.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (96 mg, 0.08 mmol) in toluene (40 mL) was stirred under a flow of nitrogen for 25 min. To the solution was added sequentially 1-t-butoxycarbonylpyrrole-2-boronic acid (1.4 g, 7.0 mmol) in absolute ethanol (10 mL) and potassium carbonate (0.94 g, 7.0 mmol) in water (10 mL). The mixture was heated at 80 C. for 16 h and allowed to cool to rt. The reaction mixture was poured into aqueous saturated sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (3*100 mL). The organic layers were combined, washed with water (100 mL) and brine (50 mL) and dried over magnesium sulfate. The solution was filtered, concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (30% ethyl acetate/hexane) to give the title compound as an off-white powder (0.7 g, 62%): mp 176 C. 1H NMR (CDCl3) delta1.40 (s, 9H), 1.73 (s, 6H), 6.17 (dd, 1H, J=1.8, 3.3 Hz), 6.22 (dd, 1H, J=3.3, 3.3 Hz), 6.77 (d, 1H, J=8.1 Hz), 7.13 (d, 1H, J=1.8 Hz), 7.23 (dd, 1H, J=1.8, 8.1 Hz), 7.33 (dd, 1H, J=1.8, 3.3 Hz), 7.69 (bs, 1H). MS ((-) ESI) m/z 341 [M-H]-. Anal. Calcd for C19H22N2O4: C, 66.65; H, 6.48; N, 8.18. Found: C, 65.46; H, 6.51; N, 7.74.A solution of 6-bromo-4, 4-dimethyl-1, 4-dihydro-benzo [d][1, 3]oxazin-2-one (5.0 g, 20 mmol) and tetrakis(triphenylphosphine)palladium(0) (580 mg, 0.5 mmol) in toluene (200 mL) was stirred under a flow of nitrogen for 25 min. To the solution was added sequentially 1-tert-butoxycarbonylpyrrole-2-boronic acid (8.24 g, 39 mmol) in absolute ethanol (50 mL) and potassium carbonate (5.39 g, 39 mmol) in water (50 mL). The mixture was heated to 80 C. for 16 h and allowed to cool. The reaction mixture was poured into aqueous saturated sodium bicarbonate solution (200 mL) and extracted with ethyl acetate (3*200 mL). The organic layers were combined, washed with water (200 mL) and brine (100 mL) and dried over magnesium sulfate. The solution was filtered, concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel (30% ethyl acetate/hexane) to give 2-(4, 4-dimethyl-2-oxo-1, 4-dihydro-2H-benzo [d] [1, 3] oxazin-6-yl)-pyrrole-1-carboxylic acid tert-butyl ester (4.0 g, 58%) as a tan solid, mp 172-173 C.EXAMPLE 17 tert-Butyl 2-cyano-5-(4, 4-dimethyl-2-thioxo-1, 4-dihydro-2H-3, 1-benzoxazin-6-yl)-1H-pyrrole-1-carboxylate A solution of To a tetrahydrofuran (5mL) solution of With a thermometer, Add 40g compound 17, to the 1L three-neck bottle of the condenser28.7 g carbazole, 32.3 g K2CO3, 0.62 g 1, 10-Phenanthroline, Then 450 ml of DMF was added.Replace the air in the reaction system with nitrogen, Add 0.45 g of CuBr under nitrogen protection.Heat to 120 C for 10 h, After the TLC was monitored, the starting material was completely reacted and the stirring was stopped and lowered to room temperature.The reaction system is added to 3 volumes of water, The product was precipitated by stirring and filtered.The filter cake was completely dissolved in 500 ml of dichloromethane (DCM) and washed 3 times with water.150ml each time. The organic phase is dried and concentrated.The crude product was passed through a silica gel column to give compound 18 as a white solid, 43.1 g, yield 80.6%.

Antipsychotic.

Molecular Weight:256.10
XLogP3:2.4
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Exact Mass:254.98949
Monoisotopic Mass:254.98949
Topological Polar Surface Area:38.3
Heavy Atom Count:14
Complexity:255
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes