2,4-DICHLOROPYRIDO[2,3-D]PYRIMIDINE

To a 500 mL two-neck round bottom flask equipped with a thermometer and a reflux condenser, Intermediate 12 (10.0g, 0.061 mol) and phosphorous oxychloride (200 mL) were added, mixed uniformly, heated to reflux at 105 °C and stirred for 24 hours. Thereafter, the reaction product was subjected to vacuum distillation for removal of phosphorus oxychloride. The remaining syrupy substance was poured onto 200 g of crushed ice, and immediately extracted 3 times with chloroform, 150 mL each time. The extracts were combined, washed 3 times with saturated brine, concentrated, and separated through a silica gel column (eluent: petroleum ether/ethyl acetate), to give 10.36 g of a white solid product, yield 84.9percent. [0085] To a 500 mL two-neck round bottom flask equipped with a thermometer and a reflux condenser, Intermediate 12 (10.0 g, 0.061 mol) and phosphorous oxychloride (200 mL) were added, mixed uniformly, heated to reflux at 105° C. and stirred for 24 hours. Thereafter, the reaction product was subjected to vacuum distillation for removal of phosphorus oxychloride. The remaining syrupy substance was poured onto 200 g of crushed ice, and immediately extracted 3 times with chloroform, 150 mL each time. The extracts were combined, washed 3 times with saturated brine, concentrated, and separated through a silica gel column (eluent: petroleum ether/ethyl acetate), to give 10.36 g of a white solid product, yield 84.9percent.(2) 1 g of intermediate B was addedTo a 500 mL two-neck round bottom flask equipped with a thermometer and a reflux condenser, Intermediate 12 (10.0g, 0.061 mol) and phosphorous oxychloride (200 mL) were added, mixed uniformly, heated to reflux at 105 C and stirred for 24 hours. Thereafter, the reaction product was subjected to vacuum distillation for removal of phosphorus oxychloride. The remaining syrupy substance was poured onto 200 g of crushed ice, and immediately extracted 3 times with chloroform, 150 mL each time. The extracts were combined, washed 3 times with saturated brine, concentrated, and separated through a silica gel column (eluent: petroleum ether/ethyl acetate), to give 10.36 g of a white solid product, yield 84.9%. [0085] 1H-NMR (400 MHz, CDCl3) delta ppm: 9.34 (1H, m), 8.66 (1H, m), 7.76 (1H, m); EI-MS (m/z): 199.0[M]+To a 500 mL two-neck round bottom flask equipped with a thermometer and a reflux condenser, Intermediate 12 (10.0 g, 0.061 mol) and phosphorous oxychloride (200 mL) were added, mixed uniformly, heated to reflux at 105 C. and stirred for 24 hours. Thereafter, the reaction product was subjected to vacuum distillation for removal of phosphorus oxychloride. The remaining syrupy substance was poured onto 200 g of crushed ice, and immediately extracted 3 times with chloroform, 150 mL each time. The extracts were combined, washed 3 times with saturated brine, concentrated, and separated through a silica gel column (eluent: petroleum ether/ethyl acetate), to give 10.36 g of a white solid product, yield 84.9%.1H-NMR (400 MHz, CDCl3) delta ppm: 9.34 (1H, m), 8.66 (1H, m), 7.76 (1H, m); EI-MS (m/z): 199.0[M]+.Compound 356; 2, 4-Dichloro-pyrido[2, 3-d]pyrimidine; To a 100 mL flask was added Compound 355 (500 mg, 3.06 mmol), N, N-diethylaniline (1 mL), and POCl3 (10 mL). The reaction mixture was heated to reflux for 5.5 h. After cooled to room temp, the reaction was concentrated in vacuo. The residue was quenched with ice-water (50 mL) and was immediately extracted with CHCl3 (50 mL×3). The combined organic extracts was washed with water (50 mL), dried (MgSO4), filtered and concentrated to give crude the title Compound 356. The material was used for next step without purification.(2) 1 g of intermediate B was added4With POCl3, PCl5The reaction was refluxed at 135 C to give the intermediate C4, Yield 54%; reaction equation is as follows:To a solution of 1H-Pyrido[2, 3-d]pyrimidine-2, 4-dione (5.0 g, 30.65 mmol) in toluene (50 ml), under an inert atmosphere, was added N, N-diiospropylethylamine (19.81 g, 153.2 mmol). Phosporous oxychloride (23.50 g, 153.2 mmol) was then added to the mixture dropwise before the reaction was heated to 100 C. for 3 hours. The mixture was then concentrated in vacuo and then diluted in CH2Cl2 (200 ml) before being poured carefully into ice water (300 ml). The biphasic mixture was then filtered through a thin pad of Celite, neutralized and separated. The aqueous phase was extracted further with CH2Cl2 (2×100 ml) and the combined organic extract dried (sodium sulfate), filtered and concentrated in vacuo to give a thick syrup which was used in it crude form for the next step.A mixture of 1 H-pyrido[2, 3-d]pyrimidine-2, 4-dione (1.4 g, 8.5 mmol) and Lambda/, /V-diethylaniline (1 .4 ml_, 8.5 mmol) in phosphorus oxychloride (8 ml) was refluxed for 3 hours. It was then concentrated in vacuo and the residue was carefully poured on an ice-cold saturated aqueous solution of sodium bicarbonate. The suspension was diluted with ethyl acetate and the organic layer was decanted, dried over magnesium sulphate and concentrated in vacuo. The crude oil was purified by flash chromatography on silica gel (eluent gradient: 0% to 60% ethyl acetate in cyclohexane). The title compound was obtained as a white solid. 1H NMR (CDCI3): 7.72 (dd, 1 H), 8.64 (dd, 1 H), 9.43 (dd, 1 H).General procedure: A mixture of commercially available 2, 4-(1H, 3H)-quinazolinedione (6.0 mmol), POCl3 (5 mL) and N, N-DMF (catalytic amount) was stirred and heated under reflux for 48 h. The solvents were removed under vacuum and cold water (0 C, 25 mL) and chloroform (25 mL) were added. The organic layer was washed with water (3 × 20 mL) and dried over anhydrous sodium sulfate. The solvent was removed under vacuum and the product was used immediately without further purification.g) Preparation of 2, 4-dichloro-pyrido[2, 3-d]pyrimidine: A mixture of 1H-pyrido[2, 3-d]pyrimidine-2, 4-dione (1.4 g, 8.5 mmol) and N, N-diethylaniline (1.4 mL, 8.5 mmol) in phosphorus oxychloride (8 ml) was refluxed for 3 hours. It was then concentrated in vacuo and the residue was carefully poured on an ice-cold saturated aqueous solution of sodium bicarbonate. The suspension was diluted with ethyl acetate and the organic layer was decanted, dried over magnesium sulphate and concentrated in vacuo. The crude oil was purified by flash chromatography on silica gel (eluent gradient: 0% to 60% ethyl acetate in cyclohexane). The title compound was obtained as a white solid. 1H NMR (CDCl3): 7.72 (dd, 1H), 8.64 (dd, 1H), 9.43 (dd, 1H).(ii) 2, 4-Dichloro-pyridopyrimidines (3) The appropriate 1H-pyridopyrimidine-2, 4-dione (2)(1 equivalent) was dissolved in POCl3 (44 equivalents). To this mixture was added N, N-diisopropylamine (2.8 equivalents) in a dropwise fashion. The reaction was stirred at room temperature under an inert atmosphere for 5 hours. After this time the mixture was concentrated in vacuo while taking care to keep the temperature below 30 C. The resulting black residue was poured onto crushed ice. The mixture was extracted with CH2Cl2 (×2) and the organic extracts then washed with water, dried (MgSO4), filtered and concentrated in vacuo to provide a tar like material that corresponded to the desired product in suitably clean form to be used without any further purification. 3a: 2, 4-Dichloropyrido[2, 3-d]pyrimidine (170.0 mg, 0.85 mmol) and 2-(4-nitrophenyl)ethan-1-amine hydrochloride (172.0 mg, 0.85 mmol) were dissolved in iPrOH (8.5 mL), and Et3N (250.0 muL, 1.80 mmol) was added thereto at room temperature. The reaction mixture was stirred at 21C for 5 hours and distilled under reduced pressure. After addition of CH2Cl2and water, the residue was stirred. The obtained solid was filtered and dried to obtain the white solid compound, 2-chloro-N-(4-nitrophenethyl)pyrido[2, 3-d]pyrimidin-4-amine (250.0 mg, 89%).[735][736]1H NMR (300 MHz, DMSO-d6) delta = 9.15 (t, J= 5.3 Hz, 1H), 8.97 (d, J= 2.7 Hz, 1H), 8.71 - 8.61 (m, 1H), 8.20 - 8.12 (m, 2H), 7.62 - 7.52 (m, 3H), 3.86 - 3.74 (m, 2H), 3.17 - 3.06 (m, 2H)[737]LC/MS ESI (+): 330 (M+1)