L-Methionine → Benzyloxycarbonyl-L-methionine

Temperature

0 °C

In a 2L flask equipped with a mechanical stirrer and internal thermometer, sodium hydroxide (61.65 g, 1.541 mol) was dissolved in distilled water (1000 ml). To this solution, L-methionine (100.0 g, 0.670 mol) was added at room temperature. The solution was cooled in an ice bath (internal temperature 3° C.) and benzyl chloroformate (110 ml, 0.737 mol) was added over 10 minutes. After a 15 minute induction period, the internal temperature rose from 3° C. to 12° C. over 30 minutes and then dropped to 0° C. over 15 minutes. The reaction was stirred at 0° C. for 2 hours, during which time the initially cloudy reaction mixture became homogeneous. The ice bath was removed, and the reaction was allowed to warm to room temperature over 1 hour. The reaction mixture was transferred into a separatory funnel and washed with hexane (2×300 ml). The aqueous layer was acidified with 6N hydrochloric acid to pH 5 and diluted with ethyl acetate (600 ml). The mixture was further acidified to pH 2. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×600 ml). The organic extracts were combined and washed with brine (750 ml), dried (magnesium sulfate), filtered and concentrated in vacuo to produce a light yellow oil. The crude product (oil) was dissolved in toluene (1500 ml), and the solution was concentrated to half of its volume. A second portion of toluene (750 ml) was added, and concentrated again such that 630 ml of toluene remained. This solution was stored at 5° C. overnight, during which time some of the product crystallized from solution. The solid was redissolved by warming to room temperature. Toluene (134 ml) was then added (a few seed crystals remained). With mechanical stirring, heptane (500 ml) was added in 30 ml portions at 10 minute intervals (approximately 3 hours total addition time). At this point, the product started to crystallize from solution. An additional portion of heptane (1020 ml) was added over 1.5 hours, and the resulting slurry was stirred for 2 hours. The product was collected by vacuum filtration, washed with 1:2 toluene:heptane (3×150 ml) and heptane (3×500 ml) and air-dried to give 158.6 g of title product as a white solid; m.p. 66° C.; [α]D =-1.5° (c=1, 95% ethanol). TLC (ethanol:water, 3:1) Rf =0.78.

1. additionwas added over 10 minutes
2. waitthe internal temperature rose from 3° C. to 12° C. over 30 minutes
3. additiondropped to 0° C. over 15 minutes
4. customthe initially cloudy reaction mixture
5. customThe ice bath was removed
6. temperatureto warm to room temperature over 1 hour
7. customThe reaction mixture was transferred into a separatory funnel
8. washwashed with hexane (2×300 ml)
9. additiondiluted with ethyl acetate (600 ml)
10. customThe organic layer was separated
11. extractionthe aqueous layer was extracted with ethyl acetate (3×600 ml)
12. washwashed with brine (750 ml)
13. dry with materialdried (magnesium sulfate)
14. filtrationfiltered
15. concentrationconcentrated in vacuo
16. customto produce a light yellow oil
17. concentrationthe solution was concentrated to half of its volume
18. additionA second portion of toluene (750 ml) was added
19. concentrationconcentrated again such that 630 ml of toluene
20. waitThis solution was stored at 5° C. overnight, during which time
21. customsome of the product crystallized from solution
22. dissolutionThe solid was redissolved
23. temperatureby warming to room temperature
24. additionToluene (134 ml) was then added (a few seed crystals
25. additionWith mechanical stirring, heptane (500 ml) was added in 30 ml portions at 10 minute intervals (approximately 3 hours total addition time)
26. customto crystallize from solution
27. additionAn additional portion of heptane (1020 ml) was added over 1.5 hours
28. stirringthe resulting slurry was stirred for 2 hours
29. filtrationThe product was collected by vacuum filtration
30. washwashed with 1:2 toluene
31. dry with materialheptane (3×150 ml) and heptane (3×500 ml) and air-dried

ORD record

ord-f26c30e0f9a246609a07dcf39146516f

Source dataset

uspto-grants-1996_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05508272