Dicyclohexylcarbodiimide → HCID 67005247, compound

Temperature

30 °C

A solution of 1,3-dicyclohexylcarbodiimide (2.9011 g, 13.9 mmol) in toluene (3 ml) is added to a stirred mixture of (R)-2-(tert-butoxycarbonyl-methyl-amino)-3-(3,4-dichloro-phenyl)-propionic acid (1, 4.179 g, 12 mmol), 2,2-dimethyl-[1,3]dioxane-4,6-dione (2, 1.7815 g, 12.36 mmol) and dimethyl-pyridin-4-yl-amine (2.0943 g, 16.8 mmol) in toluene (32 ml) at 29-31° C. over a period of approx. 1 hour. Toluene (1 ml) is used for rinsing. Stirring at 29-31° C. is continued for approx. 3 hours. After cooling to ca. 0° C., a 25% w/w solution of potassium hydrogen sulfate (approx. 9 ml) is added to the suspension at −2° C./2° C., until pH 2-3 is reached. Stirring is stopped and the layers are allowed to separate. The mixture is slowly stirred and filtrated cold (0-5° C.) and the filter cake is rinsed with toluene (12 ml, 0-5° C.). The layers of the filtrate are allowed to separate at approx. 0-5° C. The lower, aqueous layer is separated. The upper, organic layer, containing the intermediate [(R)-1-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-yl)-2-oxo-ethyl]-methyl-carbamic acid tert-butyl ester (3) is passed through a filter charged with anhydrous sodium sulfate (5 g) at 0-5° C. and the filtrate is added to a reactor, containing methanol (18 ml, 20-25° C.). The filter cake is rinsed with toluene (5 ml) and the filtrate is also added to the reactor. The resulting solution is heated (mantle temperature ca. 68° C.) and stirred at approx. 63° C. for approx. 4 hours, then concentrated at a mantle temperature of approx. 50° C. under reduced pressure to obtain an oily residue, which is dissolved in tert-butyl methyl ether (24 ml) at normal pressure and a mantle temperature of ca. 50° C., then concentrated again under reduced pressure to obtain (R)-4-(tert-butoxycarbonyl-methyl-amino)-5-(3,4-dichloro-phenyl)-1-oxo-pentanoic acid methyl ester (4) as an oily residue. The residue is dissolved again in tert butyl methyl ether (24 ml) at normal pressure and a mantle temperature of 50° C., then cooled to 18-22° C. and used as such in the next step.

1. washfor rinsing
2. temperatureAfter cooling to ca. 0° C.
3. additiona 25% w/w solution of potassium hydrogen sulfate (approx. 9 ml) is added to the suspension at −2° C./2° C.
4. stirringStirring
5. customto separate
6. stirringThe mixture is slowly stirred
7. filtrationfiltrated cold (0-5° C.)
8. washthe filter cake is rinsed with toluene (12 ml, 0-5° C.)
9. customto separate at approx. 0-5° C
10. customThe lower, aqueous layer is separated
11. additionThe upper, organic layer, containing the intermediate [(R)-1-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-yl)-2-oxo-ethyl]-methyl-carbamic acid tert-butyl ester (3)
12. additioncharged with anhydrous sodium sulfate (5 g) at 0-5° C.
13. additionthe filtrate is added to a reactor
14. additioncontaining methanol (18 ml, 20-25° C.)
15. washThe filter cake is rinsed with toluene (5 ml)
16. additionthe filtrate is also added to the reactor
17. temperatureThe resulting solution is heated (mantle temperature ca. 68° C.)
18. stirringstirred at approx. 63° C. for approx. 4 hours
19. concentrationconcentrated at a mantle temperature of approx. 50° C. under reduced pressure
20. customto obtain an oily residue, which
21. concentrationa mantle temperature of ca. 50° C., then concentrated again under reduced pressure

ORD record

ord-ad26b25426724dd28175dd62f4667b8a

Source dataset

uspto-grants-2011_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08008479B2