| 95% |
With sodium methylate; In methanol; at 25℃; for 20h;Inert atmosphere; |
General procedure: To a solution of sodium methoxide (25 wt-% in methanol) (67.6 mL, 296 mmol) and methanol (70 mL) at 25 C was added formamidine acetate (11.00 g, 106 mmol) and then ethyl N-benzyl-3-oxo-4-piperidine carboxylate hydrochloride (25.16 g, 84 mmol). The resulting mixture was stirred at 25 C for 20 h. The mixture was cooled to 0 C. Water (90mL) was added, followed by the dropwise addition of acetic acid (6.05 mL, 106 mmol), and the reaction mixture was stirred at 25 C for another 3 h. The mixture was reduced in volume under vacuum until most of the methanol had been removed. The suspension was filtered. The solids were washed with water and thendried under vacuum to afford 7-benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (16.10 g, 79 %) as an off-white solid; LC/MS:m/z 242.06 (M + H)+, 0.598 min (method 12). 1H-NMR (500 MHz, CDCl3) delta12.61 (br s, 1 H), 7.99 (s, 1 H), 7.38-7.26 (m, 5 H),3.73 (m, 2 H), 3.50 (m, 2 H), 2.74 (m, 2 H), 2.66 (m, 2 H). |
| 77% |
With sodium ethanolate; In ethanol; for 16h;Heating / reflux;Product distribution / selectivity; |
Example 51Preparation of Compounds 211, 215, 216, 225, 226 and 231Compounds 211, 215, 216, 225, 226 and 231 were prepared using the method set forth below. <n="193"/>Step A - Synthesis of7-benzyl-2-methyl-5,6, 7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-oneTo a solution of l-benzyl-3-oxo-piperidine-4-carboxylic acid ethyl ester hydrochloride (5.0 g, 16.8 mmol) in 80 mL ethanol was added acetamidine hydrochloride (2.4 g, 25.2 mmol) followed by sodium ethoxide (21% in ethanol, 10.6 mL, 33.6 mmol). The resulting reaction was heated to reflux and allowed to stir at this temperature for 16 hours. The reaction was then cooled to room temperature, diluted with dichloromethane, and the organic phase was washed with water and brine, dried and concentrated in vacuo, the resulting residue was purified using flash column chromatography (5% methanol in dichloromethane) to provide 7-benzyl-2- methyl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-one in 77% yield. |
| 17.1 g (95%) |
With sodium ethanolate; In ethanol; water; acetic acid; |
Step A: 7-Benzyl-2-methyl-5,6,7,8-tetrahydro-3H-pyrido[3,4-d]pyrimidin-4-one A solution of sodium ethoxide in ethanol was prepared by addition of sodium metal (5.7 g, 247 mmol) to absolute ethanol (141 mL). After the sodium metal had all dissolved, ethyl 1-benzyl-3-oxo-4-piperidine carboxylate hydrochloride (21 g, 70.5 mmol) was added followed by acetamidine hydrochloride (13.3 g, 141 mmol). This mixture was stirred at reflux for 1 h, cooled to room temperature, and concentrated. The residue was dissolved in a minimum amount of water and the pH was adjusted to about 7 with glacial acetic acid. The resulting yellow precipitate was filtered, washed with water (3*), air-dried for 2 h, then vacuum-dried overnight to provide 17.1 g (95%) of the title compound of Example 86, Step A as a yellow solid. 1H NMR (CDCl3, 250 MHz) delta7.35-7.25 (c, 5H), 3.70 (s, 2H), 3.42 (s, 2H), 2.73-2.64 (c, 2H), 64-2.60 (c, 2H), 2.41 (s, 3H); MS (APCI) 256 (MH+). |
Chemistry
Pharmaceutical Intermediates
Inhibitors/Agonists
Material Science
For Research Only
110K+ Compounds
Competitive Price
1-2 Day Shipping
