The general procedure for the synthesis of methylmalonamide from methyl 3-aminopropionate hydrochloride and diethyl chlorophosphate is as follows:
Example 10: Synthesis of 2-methoxycarbonyl ethylamides of monoacetic acid A
1. Monic acid A (1.72 g; 5 mM) was dissolved in THF (40 ml).
2. Triethylamine (0.7 ml; 5 mM) and diethyl chlorophosphate (0.85 g; 5 mM) were added and the reaction was stirred under argon protection for 3 hours.
3. The resulting triethylamine hydrochloride precipitate was removed by filtration.
4. To the filtrate, aqueous THF solution (50%; 40 ml) of β-alanine methyl ester hydrochloride (0.7 g; 5 mM) and triethylamine (0.7 ml) were added and the reaction was stirred at room temperature overnight.
5. After completion of the reaction, the reaction solution was evaporated to dryness.
6. The residue was dissolved in water (20 ml), washed with saturated brine and extracted with ethyl acetate (5 x 40 ml).
7. The ethyl acetate extracts were combined, dried with anhydrous MgSO4 and evaporated to dryness to give an oil.
8. Purification by silica gel column chromatography (Type 60, 30 g) gave the target product as an oil (0.335 g; 16% yield).
The characterization data of the product were as follows:
νmax (CDCl3) 3420, 3000, 1730, 1665, 1635 cm-1;
λmax (EtOH) 222 nm (εm 14,790).
δH (CDCl3) 6.47 (1H, t, NH), 5.65 (1H, s, C2-H), 3.67 (3H, s, -CO2CH3), 2.11 (3H, s, C15-CH3), 1.20 (3H, d, C14-CH3), 0.91 (3H, d, C17-CH3).
δC (CDCl3) 173.0 (C1'), 167.6 (C1), 151.3 (C3), 120.0 (C2), 75.1 (C5), 70.8 (C13), 70.5 (C7), 69.0 (C6), 65.4 (C16), 60.9 (C11), 55.7 (C10), 51.8 (OMe), 42.7 (C4, C12), 39.8 (C8), 34.9 (C3'), 34.0 (C2'), 31.8 (C9), 20.7 (C7), 18.8 (C15), 12.5 (C17).
