| 65% |
With acetic acid; In methanol; toluene; at 90℃; for 2h; |
A 62% aqueous sulfuric acid solution (306 mg, 1.9 mmol) was added to a toluene (2.7 mL)-formic acid (6.7 mL) solution of compound 13C (666 mg, 1.3 mmol) at room temperature, and the mixture was stirred at the same temperature for 3 hours. After the completion of reaction, the solution was cooled to 5C and neutralized by the addition of a saturated aqueous solution of sodium bicarbonate (37.0 g), followed by extraction with ethyl acetate (10 mL x 2). The solvent was distilled off under reduced pressure. Then, toluene (6.7 mL) was added to the obtained residue, and methanol (124 mg, 3.9 mmol), <strong>[61477-40-5](R)-3-amino-butan-1-ol</strong> (138 mg, 1.6 mmol), and acetic acid (85 mg, 1.4 mmol) were further added dropwise thereto in this order at room temperature. The mixture was heated to 90C, stirred for 2 hours, and then allowed to cool to room temperature. Then, water (7 mL) was added thereto, followed by extraction with ethyl acetate (10 mL x 2). The solvent was distilled off under reduced pressure, and toluene was added to the residue. Then, the solvent was distilled off under reduced pressure to bring the contents to approximately 4.0 g. The residue was concentrated and crystalized. The obtained yellow slurry solution was filtered to obtain 429 mg (yield: 65%) of compound 12D as pale yellow crystals. |
| 0.2 g |
With acetic acid; In methanol; toluene; at 120℃; for 4h; |
Example 18: Preparation of (4R J2aS)-7-(benzyloxy)-N-(2,4-difluorobenzvO-4-methyI- 6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-[l,31oxazino[3<2-dlpyrido[l<2-alpyrazine-9- carboxamide Methyl 3-(benzyloxy)-5-(2,4-difluorobenzylcarbamoyl)-4-oxo- 1 -(2-oxoethyl)- 1 ,4- dihydropyridine-2-carboxylate (0.5 gm) was dissolved in toluene (5 ml) and methanol (0.5 ml). (R)-3-Aminobutane-l-ol (0.17 gm) and acetic acid (0.5 ml) were added to the solution at room temperature. The contents were heated to 120 C and stirred for 4 hours. The reaction mass was cooled to 0C, and then quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. Combined organic layers were dried with anhydrous sodium sulfate and concentrated to obtain a residual solid. The residual solid was purified by silica gel column chromatography with a mixture of ethyl acetate and -hexane (1 :3) to obtain 0.2 gm of (4R,12aS)-7-(benzyloxy)-N-(2,4-difluorobenzyl)-4-methyl-6,8-dioxo-3,4,6,8, 12,12a- hexahydro-2H-[ 1 ,3]oxazino[3,2-d]pyrido[ 1 ,2-a]pyrazine-9-carboxamide. 1H NMR (300 MHz, CDC13): delta 10.41 (bs, IH), 8.35 (s, IH), 7.63-7.61 (m, 2H), 7.38-7.33 (m, 5H), 6.86-6.78 (m, 2H), 5.33-5.25 (m, 2H), 5.17 (t, J = 5.7 Hz, IH), 5.03-4.99 (m, IH), 4.64 (d, J = 5.7 Hz, 2H), 4.25-4.19 (m, IH), 4.16-4.07 (m, IH), 3.97-3.95 (m, 2H), 2.29-2.12 (m, IH), 1.54-1.49 (m, IH), 1.34 (d, J = 7.2 Hz, 3H). |
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