4-Methylmorpholine → HCID 59465467, compound

Participants

Reaction Conditions

Reaction Steps

A solution of Boc-d-alanine, A1 (10.0 g, 52.9 mmol) in CH2Cl2 (140 mL) was cooled to −25° C. (measured internally). N-Methylmorpholine (NMM) (13.8 mL, 125 mmol) followed by iso-butylchloroformate (IBCF) (13.5 mL, 104 mmol) were added at such a rate to maintain the internal temperature below −25° C. After 1.5 h the mixture was transferred via cannula to a 250 mL, three-neck flask equipped with a thermometer and containing dry 2-aminonicotinic acid (7.28 g, 52.7 mmol). After the addition was complete (ca. 10 min.) the internal temperature of the mixture was adjusted to −10° C. The reaction mixture was allowed to warm with vigorous stirring over 17 h reaching a final temperature of 15° C. The mixture was cooled to 0° C. and washed with ice-cold 1N HCl (2×100 mL), brine (100 mL) and dried over Na2SO4. The resulting solution of A2 was charged into a 250 mL three neck, cooled to −25° C. and treated with solid 4-iodoaniline (11.61 g, 53 mmol). The resulting dark mixture was allowed to warm to 15° C. with stirring over 12 h. The solution was washed with 1N HCl (2×100 mL), saturated NaHCO3 (2×100 mL), brine (100 mL) and dried over Na2SO4. The mixture was cooled to −25° C. and treated with NMM (6.8 mL, 61.8 mmol) followed by IBCF (6.7 mL, 56.1) maintaining the internal temperature below −25° C. After stirring for 12 h the reaction mixture was washed with 1N HCl (2×100 mL), saturated NaHCO3 (2×100 mL), brine (100 mL) and dried over Na2SO4 and concentrated. Purification of the concentrate by silica gel chromatography (50×400 mm column; 5% acetone/CH2Cl2 to 25% acetone/CH2Cl2) gave A3 (3.41 g, 13%; purity 96% AUC). Rf=0.37 (15% acetone/CH2Cl2).

Provenance & Evidence