Triethylamine → [(N-benzyloxycarbonyl-L-alanyl)amino]-methylphosphonic acid

온도

-5 °C

24.2 g (0.24 mol) of triethylamine were added to 53.5 g (0.24 mol) of N-benzyloxycarbonyl-L-alanine in 2 liters of dry toluene and the mixture was cooled to -5° C. 32.8 g (0.24 mol) of isobutyl chloroformate were added dropwise while stirring and the mixture was maintained at -5° C for a further 25 minutes. While stirring this mixture at -5° C, there was added dropwise a solution of 6.66 g (0.060 mol) of aminomethylphosphonic acid in 60 ml of 2-N sodium hydroxide and the stirring continued for a further 3 hours at -5° C. The mixture was then allowed to warm to room temperature and stirred overnight. The aqueous layer was separated, back-extracted with toluene and adjusted to pH 9.5 with 45 ml of 2-N sodium hydroxide. The solution was evaporated at room temperature to remove triethylamine. The residue was dissolved in 200 ml of water three times and re-evaporated each time. The final residue was dissolved in 500 ml of water and the resulting solution extracted three times with 350 ml portions of chloroform. The aqueous layer was adjusted to pH 2.5 with 50 ml of 2-N hydrochloric acid and then extracted successively with three 350 ml portions of ether and three 350 ml portions of chloroform. The aqueous layer was evaporated at room temperature and the resulting white solid dissolved in 50 ml of water and 20 ml of 2-N ammonium hydroxide and then passed down a column of cation exchange resin (B.D.H., Zerolit 225, SRC 13, RSO3H; 250 g; freshly regenerated in the acid cycle). The column was eluted with water and the acid eluate evaporated. The residue was evaporated at room temperature three times with 100 ml of water each time to remove hydrogen chloride. There was obtained a final residue of [(N-benzyloxycarbonyl-L-alanyl)amino]-methylphosphonic acid, which was converted to its benzylamine salt as follows:

1. temperaturethe mixture was maintained at -5° C for a further 25 minutes
2. stirringWhile stirring this mixture at -5° C
3. temperatureto warm to room temperature
4. stirringstirred overnight
5. customThe aqueous layer was separated
6. extractionback-extracted with toluene
7. customThe solution was evaporated at room temperature
8. customto remove triethylamine
9. dissolutionThe residue was dissolved in 200 ml of water three times
10. customre-evaporated each time
11. dissolutionThe final residue was dissolved in 500 ml of water
12. extractionthe resulting solution extracted three times with 350 ml portions of chloroform
13. extractionextracted successively with three 350 ml portions of ether and three 350 ml portions of chloroform
14. customThe aqueous layer was evaporated at room temperature
15. dissolutionthe resulting white solid dissolved in 50 ml of water
16. washThe column was eluted with water
17. customthe acid eluate evaporated
18. customThe residue was evaporated at room temperature three times with 100 ml of water each time
19. customto remove hydrogen chloride

ORD 기록

ord-a47a7844c9894a0cac7434ecb0817bfd

출처 데이터셋

uspto-grants-1977_04

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US04016148