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(E)-3-(2,2-dimethyl-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-N-methyl-N-((3-methylbenzofuran-2-yl)methyl)acrylamide[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
46%
With N-ethyl-N,N-diisopropylamine;palladium diacetate; tris-(o-tolyl)phosphine; In N,N-dimethyl-formamide; propiononitrile;Heating / reflux;
b) (E)-3 -(2,2-Dimethyl-3 -oxo-3 ,4-dihydro-2H-pyrido[3,2-&] [ 1 ,4]oxazin-7-yl)-iV-methyl-N- (3-methylbenzofuran-2-yhnethyl)acrylamide; A solution of N-methyl-N-(3-methylbenzofuran-2-yhnethyl)acrylamide (0.231 g,1.01 mmol) in propionitrile (4 mL) and DMF (0.8 mL) was deoxygenated with Ar for 20 min. The solution was treated with diisopropylethylamine (0.28 mL, 1.64 mmol) and 7- bromo-2,2-dimethyl-4H-rhoyrido[3,2-][l,4]oxazin-3-one (0.200 g, 0.775 mmol). The solution was deoxygenated with Ar for 20 min. Pd(OAc)2 (0.017 g, 0.078 mmol) and P(o- tol)3 (0.047 g, 0.15 mmol) were then added and the solution was deoxygenated again with Ar for 10 min. The mixture was heated to reflux for 18 h, then allowed to cool. The mixture was diluted with H2O (100 mL). The resulting solids were collected by filtration <n="132"/>and washed with Et2O (50 mL). Residual palladium was removed by silica gel plug (silica gel, 95:5, CH2Cl2/Me0H) the resulting solution concentrated to reveal a light orange solid. The solid was triturated with Et2O and dried to give the title compound (0.14 g, 46%) as a light pink solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-J
With potassium carbonate; In acetone; for 18h;Heating / reflux;
a) 7-Bromo-2,2-dimethyl-4H-pyrido[3,2-] [ 1 ,4]oxazin-3 -one; To a mixture of 2-amino-5-bromopyridin-3-ol (0.500 g, 2.64 mmol) and K2CO3 (1.09 g, 7.93 mmol) in acetone (11.0 niL) was added ethyl bromoisobutyrate (0.50 mL, 3.4 mmol). The solution was stirred under N2 for 18 h and then heated to reflux. After 18 h, the solution was cooled and concentrated. The light-pink, sweet-smelling solid was dissolved in CH2Cl2 (50 mL) and MeOH (5 mL). The solution was diluted with H2O (150 mL) and then washed with CH2Cl2 (3 x 75 mL). The combined organic layers were washed with brine (2 x 100 mL), dried (Na2SO4) and concentrated to yield the title compound (0.57 g, 84percent) as an off-white solid: 1H NMR (300 MHz, DMSO-J,*) delta 11.39 (s, IH), 8.03 (d, J=1.2 Hz, IH), 7.66 (d, 0.9 Hz, IH), 1.43 (s, 6H).
a) 7-Bromo-2,2-dimethyl-3,4-dihydro-2H-pyrido[3,2-][l,4]oxazine; To a solution of 7-bromo-2,2-dimethyl-4H-pyrido[3,2-][l,4]oxazin-3-one (0.360 g, 1.39 mmol) in TetaF (8.9 mL) at 0 0C was added BH3 (8.43 mL of a 1.0 M solution in THF, 8.43 mmol). The solution was heated to reflux. After 18 h, the solution was cooled to 0 0C and the reaction quenched with MeOH (15 mL). The mixture was concentrated and the resulting off-white solid was dissolved in MeOH (15 mL) and NaOH (10 mL of a 1 N solution). The mixture was heated at reflux to 4 h. The MeOH was removed under reduced pressure. The resulting precipitate was collected by filtration and washed with H2O (10 mL). The white solid was dried to give the title compound (0.260 g, 76%) as white needles: 1H NMR (300 MHz, DMSO-^) delta 7.62 (d, J= 2.1 Hz, IH), 7.10 (d, J = 1.5 Hz, IH), 7.03(br s, IH), 3.14 (d, J= 2.4 Hz, 2H), 1.25 (s, 6H); MS (ESI) m/e 243 (M + H)+.
A dichloroethane (10 mL) solution of 7-bromo-2,2-dimethyl-2H-pyrido[3,2-b][l,4]oxazin-3(4H)-one(930 rag, 3.6 mmol) and phosphorus pentachloride (1518 mg, 7.8 mmol) was irradiated in a microwave oven for 10 min at 160 0C. The solution was cooled to -78 0C and NH3 gas was condensed over it. The mixture was slowly let to warm to 21 0C, diluted with CH2Cl2, washed with dilute solution of NaOH, dried and evaporated. Crystallization from CH2Cl2/hexane afforded 602 mg (65%) of the title compound. 1HNMR (300 MHz, CDCl3, delta) 8.06 (d, J=2.0 Hz, IH), 7.24 (d, J=2.0 Hz, IH), 3.73 (s, IH), 1.53 (s, 6H). MS (ESI) m/e 256 (M + H)+.
To a suspension of sodium hydride (60% dispersion in mineral oil, 0.68 g) in N,N-dimethylformamide (15 mL) was added dropwise a solution of 2-amino- 5- bromopyridin-3-ol (3.22 g) in N,N-dimethylformamide (25 mL) at room temperature over a period of 10 minutes, and the mixture was stirred at room temperature for 20 minutes. To the mixture was added dropwise ethyl alpha-bromoisobutyrate (3.32 g) over a period of 20 minutes, and the reaction mixture was stirred at room temperature for 1 hour and at 80 C for 2 hours. After cooling, to the reaction mixture was added cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively water and brine, dried over magnesium sulfate and concentrated in vacuo by a half volume. The precipitates were collected by filtration to give 7-bromo-2,2- dimethyl-2H-pyrido[3,2-b][l,4]oxazin- 3(4H)-one (0.90 g) was obtained as a powder. MS(APCI) m/z: 257/279 [M+H]+
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