4-Methylmorpholine → N-[(1,1-Dimethylethoxy)carbonyl]-L-alanyl-L-proline phenylmethyl ester

Temperature

-15 °C

Boc-L-alanine (19.5 g, 0.10 mol) was dissolved in dry tetrahydrofuran (90 ml) under an argon atmosphere in a flask fitted with an overhead stirrer and an internal thermometer. The solution was cooled to -15° C. and N-methylmorpholine (11.4 ml, 0.10 mol) was added followed by isobutylchloroformate (13.4 ml, 0.10 mol) at such a rate as to maintain the internal reaction temperature at -10° to -15° C. Five minutes after the addition was completed, a solution of L-proline benzyl ester hydrochloride (25.2 g, 0.10 mol) and N-methylmorpholine (11.4 ml, 0.10 mol) in chloroform (90 ml) was added dropwise at such a rate as to maintain the internal reaction temperature at -10° to -15° C. After the addition was completed, the reaction mixture was allowed to slowly warm to room temperature and then stirred at room temperature overnight. The reaction mixture was concentrated using a rotary evaporator, the residue diluted with ethyl acetate (500 ml)/ 0.2N hydrochloric acid (100 ml) and poured into a separatory funnel. The layers were separated and the aqueous phase extracted with a further 150 ml ethyl acetate. The combined organics were washed with 0.2N hydrochloric acid (2×100 ml), water (100 ml), saturated sodium bicarbonate (2×100 ml), again with water (100 ml) and finally brine (100 ml). The organic phase was dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. Chromatography using ethyl acetate-hexane as the eluent gave Boc-L-alanyl-L-proline benzyl ester, Rf: 0.15 (EtOAc/hexane--30:70).

1. customfitted with an overhead stirrer
2. temperatureto maintain the internal reaction temperature at -10° to -15° C
3. additionFive minutes after the addition
4. temperatureto maintain the internal reaction temperature at -10° to -15° C
5. additionAfter the addition
6. temperatureto slowly warm to room temperature
7. concentrationThe reaction mixture was concentrated
8. customa rotary evaporator
9. additionthe residue diluted with ethyl acetate (500 ml)/ 0.2N hydrochloric acid (100 ml)
10. additionpoured into a separatory funnel
11. customThe layers were separated
12. extractionthe aqueous phase extracted with a further 150 ml ethyl acetate
13. washThe combined organics were washed with 0.2N hydrochloric acid (2×100 ml), water (100 ml), saturated sodium bicarbonate (2×100 ml), again with water (100 ml) and finally brine (100 ml)
14. dry with materialThe organic phase was dried over magnesium sulfate
15. filtrationfiltered
16. concentrationconcentrated on a rotary evaporator

ORD record

ord-5ef733175df242c6b0269da13275ac41

Source dataset

uspto-grants-1996_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05496927