Tri-o-tolylphosphine → (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-cyano-2,6-dimethylphenyl)propanoate

Temperature

35 °C

A 5 L three-necked round-bottomed flask equipped with a nitrogen inlet, a mechanical stirred, an addition funnel and a thermocouple was charged with 4-bromo-3,5-dimethyl-benzonitrile (210 g, 1.0 mol) and DMAc (750 ml). The resulting suspension was stirred and heated to 35° C. to dissolve the solids. To the resulting mixture was then added P(o-tol)3 (6.0 g, 0.02 mol), Pd2(dba)3 (9.2 g, 0.01 mol) and the resulting mixture heated to about 75-80° C. The cooled mixture prepared in STEP A above was added by cannula to the reaction mixture at a rate which maintained the temperature at about 75-80° C. (about 2 hours). The resulting suspension was cooled to ambient temperature, then aged overnight with moderate agitation. The resulting suspension was then heated to about 35-40° C., filtered with silica (540 g). The silica bed was washed with DMAc (400 mL×2), the combined DMAc solutions cooled to about 0-5° C. and then added slowly to a mixture of ice and deionized water. The resulting mixture was maintained cold for 2 hours, over which time a white solid was observed to precipitate. The resulting mixture was then warmed to ambient temperature and aged overnight. The solid precipitate was cooled by vacuum filtration using a Buchner funnel. The filter cake was rinsed with deionized water (1 L×3), air dried overnight, then dried in a vacuum oven overnight. MeOH (1 L) was added to the solid and the resulting slurry was cooled to about 0-5° C., then aged at this temperature for 1 hour, with stirring. The solid was collected by filtration, washed with cold methanol (400 mL) and dried in a vacuum oven at 45° C. to yield the title compound as an off-white solid.

1. customA 5 L three-necked round-bottomed flask equipped with a nitrogen inlet
2. dissolutionto dissolve the solids
3. temperaturemaintained the temperature at about 75-80° C. (about 2 hours)
4. temperatureThe resulting suspension was cooled to ambient temperature
5. temperatureThe resulting suspension was then heated to about 35-40° C.
6. filtrationfiltered with silica (540 g)
7. washThe silica bed was washed with DMAc (400 mL×2)
8. temperaturethe combined DMAc solutions cooled to about 0-5° C.
9. additionadded slowly to a mixture of ice
10. temperatureThe resulting mixture was maintained cold for 2 hours, over which time a white solid
11. customto precipitate
12. temperatureThe resulting mixture was then warmed to ambient temperature and aged overnight
13. temperatureThe solid precipitate was cooled by vacuum filtration
14. washThe filter cake was rinsed with deionized water (1 L×3), air
15. customdried overnight
16. customdried in a vacuum oven overnight
17. additionMeOH (1 L) was added to the solid
18. temperaturethe resulting slurry was cooled to about 0-5° C.
19. waitaged at this temperature for 1 hour
20. stirringwith stirring
21. filtrationThe solid was collected by filtration
22. washwashed with cold methanol (400 mL)
23. customdried in a vacuum oven at 45° C.

ORD record

ord-3c9d9364f32b46318f1c12912a6780ce

Source dataset

uspto-grants-2014_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08710256B2