Pyridine → 2-(2'-tert-Butylsulfamoyl-3-fluoro-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester

Temperature

0 °C

Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.6 g, 7.4 mmol) was dissolved in 40 mL dry diethyl ether under Ar, cooled in an ice water bath, added dry pyridine (3 mL, 37.2 mmol) followed by the dropwise addition of oxalyl chloride (1.6 mL, 18.6 mmol). A precipitate forms immediately. The reaction was stirred vigorously at 0° C. for one hour, then at ambient temperature for one hour. Added 50 mL diethyl ether, filtered off solids washing with diethyl ether. Concentrated the filtrates to an off-white oil. Redissolved oil in 40 mL dry DCM under Ar, cooled to 0° C., added 3 mL pyridine followed by 4′-amino-3′-fluoro-biphenyl-2-sulfonic acid tert-butylamide (2 g, 6.2 mmol). The reaction was allowed to warm to ambient temperature, stirred for 3 hours then concentrated. Redissolved in 250 mL EtOAc, washed with 10% citric acid (2×100 mL), water (3×100 mL), brine (100 mL), dried with MgSO4, filtered and concentrated. Purified on a silica gel column eluted with 30% moving to 50% EtOAc in hexanes. Combined and concentrated pure fractions to yield title compound as a white solid. (1.4 g, 42%) APCI (AP−): 518.2 (M−H)−.

1. temperaturecooled in an ice water bath
2. waitat ambient temperature for one hour
3. filtrationfiltered off solids
4. washwashing with diethyl ether
5. concentrationConcentrated the filtrates to an off-white oil
6. dissolutionRedissolved oil in 40 mL dry DCM under Ar
7. temperaturecooled to 0° C.
8. additionadded 3 mL pyridine
9. temperatureto warm to ambient temperature
10. stirringstirred for 3 hours
11. concentrationthen concentrated
12. dissolutionRedissolved in 250 mL EtOAc
13. washwashed with 10% citric acid (2×100 mL), water (3×100 mL), brine (100 mL)
14. dry with materialdried with MgSO4
15. filtrationfiltered
16. concentrationconcentrated
17. customPurified on a silica gel column
18. washeluted with 30%
19. concentrationconcentrated pure fractions

ORD record

ord-1e6f178f1d764be7812afce653e102d4

Source dataset

uspto-grants-2006_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07030141B2