Diisopropylethylamine → (S)-1-(1-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-3-(2-fluoro-4-((R)-3-hydroxypyrrolidine-1-carbonyl)phenoxy)pyrrolidin-2-one

To a solution of (S)-4-(1-(1-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-2-oxopyrrolidin-3-yloxy)-3-fluorobenzoic acid (Example 153, Step B; 0.10 g, 0.22 mmol) in DMF (2 mL) was added HATU (0.17 g, 0.44 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.12 mL, 0.66 mmol) and the reaction was stirred for 20 minutes at ambient temperature. (R)-pyrrolidin-3-ol hydrochloride (0.058 g, 0.66 mmol) was added and the reaction was stirred for 2 hours at ambient temperature. The reaction was diluted with EtOAc (30 mL), washed with HCl (1N, 10 mL), NaOH (1N, 10 mL), water (10 mL), and brine (10 mL), dried over MgSO4, filtered and concentrated under vacuum. The crude material was purified by reverse phase HPLC. The combined fractions were diluted with EtOAc (50 mL) and washed with 1 N NaOH (10 mL), water (10 mL), and brine (10 mL), dried over MgSO4, filtered and concentrated under vacuum to give (S)-1-(1-(5-chloro-3-fluoropyridin-2-yl)piperidin-4-yl)-3-(2-fluoro-4-((R)-3-hydroxypyrrolidine-1-carbonyl)phenoxy)pyrrolidin-2-one (0.038 g, 0.072 mmol, 33% yield). Mass spectrum (apci) m/z=521.0 (M+H).

1. stirringthe reaction was stirred for 2 hours at ambient temperature
2. washwashed with HCl (1N, 10 mL), NaOH (1N, 10 mL), water (10 mL), and brine (10 mL)
3. dry with materialdried over MgSO4
4. filtrationfiltered
5. concentrationconcentrated under vacuum
6. customThe crude material was purified by reverse phase HPLC
7. additionThe combined fractions were diluted with EtOAc (50 mL)
8. washwashed with 1 N NaOH (10 mL), water (10 mL), and brine (10 mL)
9. dry with materialdried over MgSO4
10. filtrationfiltered
11. concentrationconcentrated under vacuum

ORD record

ord-9063d53beaff4fb28371325f012e0535

Source dataset

uspto-grants-2014_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08754226B2