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

Temperature

0 °C

Boc-Ala-OH (56.76 g, 0.3 mole) dissolved in acetonitrile (500 mL) and cooled to 0° C. before adding NMM (32.97 mL). The solution was cooled to -15°±1° C. and isobutyl chloroformate (41.01 mL) was added slowly under stirring while maintaining the temperature at -15° C. After stirring the reaction mixture for 10 rain at this temperature, HOBt (40.56 g, 0.3 mole) was added. The reaction mixture was stirred for an additional 10 rain and a precooled solution of HCl·H-Pro-OBzL (72.5 g, 0.3 mole) and NMM (32.97 mL) in DMF (600 mL) were added slowly. After 20 min, the pH of the solution was adjusted to 8 by the addition of NMM and the reaction was continued overnight. The solvent was removed under reduced pressure and the residual DMF solution was poured into about 2000 mL of ice-cold 90% saturated KHCO3 solution and stirred for 30 mm. Since the peptide did not precipitate out, it was extracted into CHCl3, which was washed with water, 20% citric acid, and water, and dried over Na2SO4, and the solvent was washed with water, 20% citric acid, and water, before drying over Na2SO4, and removing solvent under reduced pressure. The resulting oil was recrystallized from ether/petroleum ether. The crystals were faltered, washed with petroleum ether, and dried to obtain 79.9 g (yield, 70.75%) of I. Rf1, 0.5; Rf2, 0.61.

1. temperatureThe solution was cooled to -15°±1° C.
2. temperaturewhile maintaining the temperature at -15° C
3. additionwas added
4. stirringThe reaction mixture was stirred for an additional 10 rain
5. waitthe reaction was continued overnight
6. customThe solvent was removed under reduced pressure
7. additionthe residual DMF solution was poured into about 2000 mL of ice-cold 90% saturated KHCO3 solution
8. stirringstirred for 30 mm
9. customSince the peptide did not precipitate out
10. extractionit was extracted into CHCl3, which
11. washwas washed with water, 20% citric acid, and water
12. dry with materialdried over Na2SO4
13. washthe solvent was washed with water, 20% citric acid, and water
14. dry with materialbefore drying over Na2SO4
15. customremoving solvent under reduced pressure
16. customThe resulting oil was recrystallized from ether/petroleum ether
17. washwashed with petroleum ether
18. customdried
19. customto obtain
20. custom79.9 g (yield, 70.75%) of I

ORD record

ord-617b3f92d8594beaa939dc0b4053db2d

Source dataset

uspto-grants-1996_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05519004