4-Methylmorpholine → HCID 59465467, compound

Temperature

0 °C

A solution of Boc-d-alanine, N1 (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 2 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), sat'd 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), sat'd 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 15 (3.41 g, 13%; purity 96% AUC). Rf=0.37 (15% acetone/CH2Cl2).

1. additionwere added at such a rate
2. temperatureto maintain the internal temperature below −25° C
3. customequipped with a thermometer
4. additionAfter the addition
5. custom(ca. 10 min.)
6. customwas adjusted to −10° C
7. temperatureto warm
8. customtemperature of 15° C
9. washwashed with ice-cold 1N HCl (2×100 mL), brine (100 mL)
10. dry with materialdried over Na2SO4
11. additionThe resulting solution of 2 was charged into a 250 mL three neck
12. temperaturecooled to −25° C.
13. temperatureto warm to 15° C.
14. stirringwith stirring over 12 h
15. washThe solution was washed with 1N HCl (2×100 mL), sat'd NaHCO3 (2×100 mL), brine (100 mL)
16. dry with materialdried over Na2SO4
17. temperatureThe mixture was cooled to −25° C.
18. temperaturemaintaining the internal temperature below −25° C
19. stirringAfter stirring for 12 h the reaction mixture
20. washwas washed with 1N HCl (2×100 mL), sat'd NaHCO3 (2×100 mL), brine (100 mL)
21. dry with materialdried over Na2SO4
22. concentrationconcentrated
23. customPurification of the
24. concentrationconcentrate by silica gel chromatography (50×400 mm column; 5% acetone/CH2Cl2 to 25% acetone/CH2Cl2)

ORD record

ord-193e6a78a3fa438ea3fbe6f3a73eeebf

Source dataset

uspto-grants-2011_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07939538B2