2-METHOXY-N-(PROP-2-YNYL)ACETAMIDE synthesis

Yield: 50%

Reaction Conditions:

Stage #1:Methoxyacetyl chloride;Propargylamine in dichloromethane at -40 - -25; for 1 h;
Stage #2: with triethylamine at -25 - 20; for 3.75 h;

Steps:

2
A SOLUTION OF METHOXY ACETYL CHLORIDE (12.5 ML, 0.137 MOL, 1.2 EQUIV. ) IN DRY CH2CI2 (45 ml) kept under N2 was cooled TO-40°C. A solution of propargylamine (7.98 ML, 0.125 mol, 1.0 EQUIV. ) IN DRY CH2CI2 (40 ML) WAS ADDED OVER 45 MINUTES KEEPING THE TEMPERATURE LESS THAN-25°C. AFTER 15 MINUTES TRIETHYLAMINE (17.4 ML, 0.125 MOL, 1.0 EQUIV. ) WAS ADDED OVER 45 minutes keeping the temperature less THAN-25°C. The reaction mixture was warmed to room temperature. TLC after 3 hours showed conversion complete. The reaction mixture was quenched with H20 (50 ML) and the organic phase was washed with half-saturated NACI solution, filtered through cotton wool and concentrated at a temperature of 40°C and pressure of greater than 650 mbar. The crude compound was purified by short path distillation (boiling point of 49°C and p of 0.09 mbar). The title compound was obtained as a colorless liquid (7.84 g, 50 %) which crystallized upon standing. Rf = 0.36 (HEPTANE/ETOAC = 7/3). 'H NMR (CDCI3, 300 MHz): 8= 6.72 (br, s, 1H, N-H), 4.09 (dd, JE=5. 5 Hz, J2= 2.6 Hz, 2H, CH2-NH), 3.92 (s, 2H, CH2-OME), 3.43 (s, 3H, OCH3), 2.24 (t, J=2.6 Hz, 1 H, ALKYNE CH). 13C-NMR (CDCI3, 75 MHz): = 169.14 (C=O), 79.11 (C-2'), 71.63 (C-2), 71.41 (C-3'), 59.04 (OCH3), 28. 26 (_-1). Gas chromatography was used to determine the tR (min) of 6.42 under the conditions shown in the table below. Column DB-5 (30 m x 0.32 mm, 0.25 um film thickness) Injector Split, initial Temp. 250°C Split ratio 60. 243: 1 Split flow 108.3 ml/min, gas type: hydrogen Oven 60°C, 1 min, 10°C/min, 290°C, 10 min Inject-Temp 250°C Detector (FID) Detector Temp. 250°C Detector flow H2 : 40.0 ml/min, air: 450 ml/min Makeup flow N2 : 45.0 ml/min

References:

PFIZER PRODUCTS INC. WO2004/56802, 2004, A1 Location in patent:Page 14-15