Chlorotrimethylsilane → N-[(2E)-3-Cyclohexyl-2-propenoyl]-3,5-difluorophenylalanine

Temperature

0 °C

6.3 ml (49.7 mmol) of chlorotrimethylsilane are added to a solution of 5.0 g (24.9 mmol) of 3,5-difluoro-DL-phenylalanine in dichloromethane (150 ml) and the reaction mixture is heated to reflux for 1 h. After cooling to 0° C., 9.7 ml (55.9 mmol) of ethyldiisopropylamine are slowly added and then, dropwise, 4.29 g (24.9 mmol) of trans-3-cyclohexyl-2-propenoyl chloride. The reaction mixture is stirred overnight with slow warming to RT and remains standing at RT for two days. For working up, the mixture is evaporated to dryness in vacuo, the residue is taken up using diethyl ether and extracted with 2.5 pc. aq. sodium hydrogencarbonate solution (250 ml). The aqueous phase is extracted twice with diethyl ether. The combined organic phases are extracted a further three times with sodium hydrogencarbonate solution. The combined aqueous phases are brought to pH=2 using 1N aqueous hydrochloric acid and extracted three times with ethyl acetate. The combined ethyl acetate phases are dried over sodium sulfate, filtered, and the solvent is concentrated in vacuo. The residue (4.63 g) is washed by stirring with diethyl ether and filtered. 3.64 g (43% of th.) of colorless solid are obtained. The residue from the concentrated mother liquor and the residue from the concentrated diethyl ether phase of the alkaline extraction (see above), are taken up together in ethyl acetate and extracted with 1N hydrochloric acid. The organic phase is dried over sodium sulfate, filtered and concentrated. The residue is washed by stirring with diethyl ether and filtered off with suction. A further 2.18 g (26%) of product are isolated.

1. temperaturethe reaction mixture is heated
2. temperatureto reflux for 1 h
3. temperaturewith slow warming to RT
4. waitremains standing at RT for two days
5. customthe mixture is evaporated to dryness in vacuo
6. extractionextracted with 2.5 pc
7. extractionThe aqueous phase is extracted twice with diethyl ether
8. extractionThe combined organic phases are extracted a further three times with sodium hydrogencarbonate solution
9. extractionextracted three times with ethyl acetate
10. dry with materialThe combined ethyl acetate phases are dried over sodium sulfate
11. filtrationfiltered
12. concentrationthe solvent is concentrated in vacuo
13. washThe residue (4.63 g) is washed
14. stirringby stirring with diethyl ether
15. filtrationfiltered
16. custom3.64 g (43% of th.) of colorless solid are obtained
17. extractionThe residue from the concentrated mother liquor and the residue from the concentrated diethyl ether phase of the alkaline extraction (see above)
18. extractionextracted with 1N hydrochloric acid
19. dry with materialThe organic phase is dried over sodium sulfate
20. filtrationfiltered
21. concentrationconcentrated
22. washThe residue is washed
23. stirringby stirring with diethyl ether
24. filtrationfiltered off with suction

ORD record

ord-05e8083a32364374af83a7d30d6d2d16

Source dataset

uspto-grants-2008_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07405201B2