* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Stage #1: With sodium hydroxide In water for 5 h; Reflux Stage #2: at 0℃;
Step 2: 3-Amino-5-bromo-pyridine-2-carboxylic acid To a 100 mL round bottom flask, 3-amino-5-bromo-pyridine-2-carboxylic acid amide (1.05 g, 0.0049 mol) and aqueous sodium hydroxide solution (0.98 g in 10 mL water, 0.0245 mol) was added. The reaction mixture was stirred at reflux temperature for 5 h. The volatiles were evaporated under reduced pressure to get the residue. The residue was neutralized to pH = 7.0, using 2N HC1 at 0°C to obtain the precipitate. The precipitate was filtered and dried to get the title compound as light yellow solid [1 g, 95percent]. 1H NMR (300 MHz, DMSO-d6): δ 7.65 (d, J = 2.1 Hz, 1H), 7.20 (d, J = 2.1 Hz, 1H), 7.01-7.16 (brs, 2H); LC-MS (ESI): Calculated mass: 215.9; Observed mass: 217.0 [M+H]+ (RT: 0.43 min).
95%
for 5 h; Reflux
To a 100 mL round bottom flask, 3-amino-5-bromo-pyridine-2-carboxylic acid amide (1.05 g, 0.0049 mol) and aqueous sodium hydroxide solution (0.98 g in 10 mL water, 0.0245 mol) were added. The reaction mixture was stirred at reflux temperature for 5 hours. The volatiles were evaporated under reduced pressure to provide the residue. The residue was neutralized to pH 7.0, using 2N HCl at 0° C. to obtain the precipitate. The precipitate was filtered and dried to provide the title compound as light yellow solid (1 g, 95percent). 1H NMR (300 MHz, DMSO-d6): δ 7.65 (d, J=2.1 Hz, 1H), 7.20 (d, J=2.1 Hz, 1H), 7.01-7.16 (br s, 2H); LC-MS (ESI): Calculated mass: 216.0; Observed mass [M+H]+: 217.0. (RT: 0.43 min).
55%
Stage #1: at 100℃; for 20 h; Stage #2: at 0℃;
(5) Production of 3-amino-5-bromopyridine-2-carboxylic acid: 3-Amino-5-bromopyridine-2-carboxamide (216 mg, 1.0 mmol) was dissolved in concentrated hydrochloric acid (3 mL), and stirred at 100°C for 20 hours. After cooled to 0°C, water (10 mL) was added to it and controlled to have a pH of 7 with sodium hydrogencarbonate solution added thereto. The resulting gray solid was taken out through filtration and dried to obtain the intended compound (119 mg, 55 percent).
Step 2: 3-Amino-5-bromo-pyridine-2-carboxylic acid To a 100 mL round bottom flask, 3-amino-5-bromo-pyridine-2-carboxylic acid amide (1.05 g, 0.0049 mol) and aqueous sodium hydroxide solution (0.98 g in 10 mL water, 0.0245 mol) was added. The reaction mixture was stirred at reflux temperature for 5 h. The volatiles were evaporated under reduced pressure to get the residue. The residue was neutralized to pH = 7.0, using 2N HC1 at 0C to obtain the precipitate. The precipitate was filtered and dried to get the title compound as light yellow solid [1 g, 95%]. 1H NMR (300 MHz, DMSO-d6): delta 7.65 (d, J = 2.1 Hz, 1H), 7.20 (d, J = 2.1 Hz, 1H), 7.01-7.16 (brs, 2H); LC-MS (ESI): Calculated mass: 215.9; Observed mass: 217.0 [M+H]+ (RT: 0.43 min).
95%
With water; sodium hydroxide; for 5.0h;Reflux;
To a 100 mL round bottom flask, 3-amino-5-bromo-pyridine-2-carboxylic acid amide (1.05 g, 0.0049 mol) and aqueous sodium hydroxide solution (0.98 g in 10 mL water, 0.0245 mol) were added. The reaction mixture was stirred at reflux temperature for 5 hours. The volatiles were evaporated under reduced pressure to provide the residue. The residue was neutralized to pH 7.0, using 2N HCl at 0 C. to obtain the precipitate. The precipitate was filtered and dried to provide the title compound as light yellow solid (1 g, 95%). 1H NMR (300 MHz, DMSO-d6): delta 7.65 (d, J=2.1 Hz, 1H), 7.20 (d, J=2.1 Hz, 1H), 7.01-7.16 (br s, 2H); LC-MS (ESI): Calculated mass: 216.0; Observed mass [M+H]+: 217.0. (RT: 0.43 min).
55%
(5) Production of 3-amino-5-bromopyridine-2-carboxylic acid: 3-Amino-5-bromopyridine-2-carboxamide (216 mg, 1.0 mmol) was dissolved in concentrated hydrochloric acid (3 mL), and stirred at 100C for 20 hours. After cooled to 0C, water (10 mL) was added to it and controlled to have a pH of 7 with sodium hydrogencarbonate solution added thereto. The resulting gray solid was taken out through filtration and dried to obtain the intended compound (119 mg, 55 %).
(b) 3-Amino-5-bromopicolinic acid. A mixture of 3-amino-5- bromopicolinamide (28.2 g, 0.13 mol) and concentrated HCl (361 inL) was heated at reflux for 12 hours. The reaction mixture was allowed to reach room temperature, and the solid which precipitated was filtered. The filter cake was dissolved in water, and the pH of the aqueous solution was adjusted to pH = 4 with saturated NaOAc, and extracted with EtOAc (3 x). The combined organic extracts were dried over anhydrous MgSO4, and filtered. The filtrate was evaporated under reduced pressure, and the residue dried in vacuo to afford the title compound as a solid.
(b) 3-Amino-5-bromopicolinic acid. A mixture of 3-amino-5- bromopicolinamide (28.2 g, 0.13 mol) and concentrated HCl (361 mL) was heated at reflux for 12 hours. The reaction mixture was left to reach room temperature, and the solid which precipitated was filtered. The filter cake was dissolved in water, and the pH of the aqueous solution was adjusted to pH = 4 with saturated NaOAc, and extracted with EtOAc (3 x). The combined organic layers were dried over anhydrous MgSO4, and filtered. The filtrate was evaporated under reduced pressure, and the residue was dried in vacuo to afford the title compound as a solid.
In 1,4-dioxane; toluene; at 20℃; for 3.0h;Heating / reflux;
(c) 7-Bromo-1H-pyrido[3,2-rf][l,3]oxazine-2,4-dione. To a solution of <strong>[870997-85-6]3-amino-5-bromopicolinic acid</strong> (18.5 g, 85.3 mmol) in dioxane (185 inL) was added 20% solution of phosgene in toluene (53.4 mL, 108 mmol) dropwise with stirring at room temperature. The reaction mixture was stirred at reflux for 3 hours, left to reach room temperature, and the solid precipitate was filtered, and dried in vacuo to give the title compound.
Step 3: 7-Bromo-pyrido [3,2-d]pyrimidine-2,4-diolTo a 100 mL round bottom flask, <strong>[870997-85-6]3-amino-5-bromo-pyridine-2-carboxylic acid</strong> (1 g, 0.0046 mol) and urea (2.768 g, 0.4629 mol) were added. The reaction mixture was stirred at 200C for 2.5 h. The reaction mixture was cooled, water was added and stirred to provide a precipitate. The precipitate was filtered and dried to provide the title compound [1 g, 91%]. This material was taken to the next step without any further purification.
Example B5, Step 2. A solution of the starting material (e.g., 7-methoxy-2-oxa-6- azaspiro[3.4]oct-6-ene, 1 equiv) and <strong>[870997-85-6]3-amino-5-bromopicolinic acid</strong> (1.5 equiv) in toluene (0.02 M) was refluxed under nitrogen atmosphere until the reaction was complete. After concentration, the residue was purified by silica gel chromatography to give the desired product (e.g., 6'-bromo-l'H-spiro[oxetane-3,2'-pyrrolo[2,l- 6]quinazolin]-9'(3'H)-one).
To a 100 mL round bottom flask, <strong>[870997-85-6]3-amino-5-bromo-pyridine-2-carboxylic acid</strong> (1 g, 0.0046 mol) and urea (27.8 g, 0.4629 mol) were added. The reaction mixture was stirred at 200 C. for 2.5 hours. The reaction mixture was cooled, water was added and the mixture was stirred to provide a precipitate. The precipitate was filtered and dried to provide the title compound (1 g, 91%). This material was taken to the next step without further purification.
With ammonium hydroxide; N-ethyl-N,N-diisopropylamine; N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate; In N,N-dimethyl-formamide;
To a solution of <strong>[870997-85-6]3-amino-5-bromopicolinic acid</strong> 18A (300 mg, 1.38 mmol, 1 equiv.) in DMF (11 ml, 0.1 M) was added HATU (598 mg, 1.57 mmol, 1.1 equiv.) followed by DIPEA (0.48 mL, 2.76 mmol, 2 equiv.) and ammonium hydroxide (0.8 mL, 5.55 mmol, 4 equiv.). The mixture was allowed to stir overnight. Water (50 mL) was added and the mixture then extracted with EtOAc (3 times). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The product ( 18B) was obtained after flash chromatography. MS (m/z): 216.8 [M+H]+