Dimethylformamide → HCID 70945388, compound

A solution of (R)-3-((cyclopropylmethyl)sulfonyl)-2-(((S)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-amino)propanoic acid [56.7 g; 148 mmol] in dichloromethane (1800 mL) was treated with HATU (67.5 g; 178 mmol; 120 mol %) and stirred at ambient temperature for 10 minutes. N-cyclopropyl 3S-amino-2-hydroxypentanamide hydrochloride (30.9 g; 148 mmol) was then added and the mixture stirred at ambient temperature for 10 minutes, then cooled in an ice water bath. N,N-Diisopropylamine (DIPEA; 77 mL; 57 g; 441 mmol; 298 mole %) was added slowly, along with DMF (25 mL). The resulting mixture was stirred in the ice bath for 30 minute then overnight at ambient temperature. The dichloromethane was removed by distillation and the residue partitioned between ethyl acetate and a 10% aqueous solution of potassium hydrogensulfate. The layers were separated and the organic phase was washed with water, aqueous sodium bicarbonate, water and finally aqueous sodium chloride. The organic phase was dried (MgSO4) and concentrated to a wet solid. The solid was slurried in diethyl ether with stirring for a few hours. The gelatinous solid was filtered, washing with hexane to facilitate drying. The wet solid was dried on the filter providing a solid, which was ground to a powder. The solid was suspended in a solution of 5% MTBE in hexane and stirred overnight to provide a finely-powdered solid. The slurry was cooled in an ice-water bath and filtered and dried in a vacuum oven at 40° C. to give 63.3 g (79.6%) of (3S)—N-cyclopropyl-3-((R)-3-((cyclopropylmethyl)sulfonyl)-2-(((S)-2,2,2-trifluoro-1-(4-fluorophenyl)-ethyl)amino)propanamido)-2-hydroxypentanamide. LC-MS, positive ion mode: m/z=538 [M+H]+ (100%); negative ion mode: m/z=536 [M−H]− (100%). Methods for the preparation of starting materials are disclosed in U.S. Pat. No. 7,488,848, which is incorporated herein by reference in its entirety with respect to such methods.

1. stirringthe mixture stirred at ambient temperature for 10 minutes
2. temperaturecooled in an ice water bath
3. customovernight
4. customat ambient temperature
5. customThe dichloromethane was removed by distillation
6. customthe residue partitioned between ethyl acetate
7. customThe layers were separated
8. washthe organic phase was washed with water, aqueous sodium bicarbonate, water and finally aqueous sodium chloride
9. dry with materialThe organic phase was dried (MgSO4)
10. concentrationconcentrated to a wet solid
11. stirringwith stirring for a few hours
12. filtrationThe gelatinous solid was filtered
13. washwashing with hexane
14. customto facilitate drying
15. customThe wet solid was dried on the filter
16. customproviding a solid, which
17. stirringstirred overnight
18. customto provide a finely-powdered solid
19. temperatureThe slurry was cooled in an ice-water bath
20. filtrationfiltered
21. customdried in a vacuum oven at 40° C.

ORD record

ord-db38eda78be245c1b40bdb56a940a34f

Source dataset

uspto-grants-2014_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08680152B2