| 51% |
Stage #1: methyl 5-[N-(tert-butoxycarbonyl)amino]-pyridine-2-carboxylate With sodium hydride In N,N-dimethyl-formamide; paraffin oil at 20℃; Inert atmosphere;
Stage #2: methyl iodide In N,N-dimethyl-formamide; paraffin oil at 20℃; |
A10.1 A10.1 : 5-(tert-Butoxycarbonyl-methyl-amino)-pyridine-2-carboxylic acid methyl ester
5-tert-Butoxycarbonylamino-pyridine-2-carboxylic acid methyl ester (282.0 mg; 1.118 mmol) and sodium hydride suspension (60% suspension in paraffin oil; 29.5 mg; 1.230 mmol) were stirred in DMF (3.0 mL) under nitrogen (0346) atmosphere at room temperature for 10 min. lodomethane (174.5 mg; 1.230 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. Further sodium hydride suspension (60% suspension in paraffin oil; 16.1 mg; 0.671 mmol) and iodomethane (95.2 mg; 0.671 mmol) were added and the reaction mixture stirred at room temperature overnight. The mixture was diluted with water and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated. The residue was dried under high vacuum. Yield: 152.0 mg (51 %) pale-orange solid; (0347) LC/MS (A): Rt: 1.98 min; (M+H) 267.1. |
| 48% |
Stage #1: methyl 5-[N-(tert-butoxycarbonyl)amino]-pyridine-2-carboxylate With sodium hydride In N,N-dimethyl-formamide at 0℃; for 0.5h;
Stage #2: methyl iodide In N,N-dimethyl-formamide at 20℃; |
77.2 Step 2: methyl 5-((tert-butoxycarbonyl)(methyl)amino)picolinate
To a solution of methyl 5-((tert-butoxycarbonyl)(methyl)amino)picolinate (700 mg, 0.78 mmol) in DMF (15 mL) was added NaH (200 mg, 60%, 3.33 mmol) at 0 °C, and the mixture was stirred at 0 °C for 30 minutes. Mel was added and the mixture was stirred at rt overnight. The mixture was quenched with water (30 mL) and extracted with EA (30 mL*3). The combined organic layers were washed with water (30 mL*2) and brine (30 mL), dried over Na2S04, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (petroleum ether/EtOAc = 2/1) to afford product (150 mg, 48%) as a white solid. [M+H] MS Calcd.: Ci3Hi8N204, 267.1, Found: 267.1. |
| 180 mg |
Stage #1: methyl 5-[N-(tert-butoxycarbonyl)amino]-pyridine-2-carboxylate With sodium hydride In N,N-dimethyl-formamide; mineral oil at 0℃; for 0.25h;
Stage #2: methyl iodide In N,N-dimethyl-formamide; mineral oil at 20℃; for 18h; |
49.3 Step 3, Method 49: Methyl 5-[(tert-butoxy)carbonylj(methyl)amino}pyridine-2- carboxylate
103471 Methyl 5- { [(tert-butoxy)carbonyl] amino}pyridine-2-carboxylate (406 mg, 1.34 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL) and cooled to 0 °C. Sodium hydride (60% in mineral oil, 136 mg, 3.34 mmol) was added and the mixture stirred for 15 minutes. lodomethane (100 jiL, 1.60 mrnol) was added and the mixture stirred at room temperature for 18 hours. The reaction mixture was quenched by the addition of water (5 mL) and extracted with ethyl aceate (2 x 15 mL). The combined organic extracts were washed with brine (3 x 10 mL), dried over magnesium sulfate, filtered and concentrated. Purification by FCC (silica, eluent: 50-75% ethyl acetate in heptane) gave the title compound 180 mg (51% yield) as a yellow oil. On NMR (500 MHz, DMSO) 8.70 (d, I = 2.5 Hz, 1H),8.03 (d, I = 8.5 Hz, 1H), 7.91 (dd, .1 = 8.5, 2.6 Hz, 1H), 3.87 (s, 3H), 3.27 (s, 311), 1.43 (s, 9H). Tr(METCR1278) = 1.68 mi (ESj (M+H) 267. |
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