4-Methylmorpholine → (R)-N-(2,5-difluoro-4-((2-(2-methoxypropanamido)pyridin-4-yl)oxy)phenyl)-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution of (R)-2-methoxy-propionic acid (300 mg, 2.88 mmol) and N-methylmorpholine (432 mg, 4.32 mmol) in anhydrous CH2Cl2 was added drop wise isobutyl chloroformate (588 mg, 4.32 mmol). The resultant mixture was stirred at RT for 1 h. N-(4-(2-Chloropyridin-4-yloxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (200 mg, 0.452 mmol) was added and the resulting mixture was stirred at RT for 12 h. The reaction mixture was concentrated under vacuo and purified by HPLC separation to give (R)—N-(2,5-difluoro-4-((2-(2-methoxypropanamido)pyridin-4-yl)oxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (50 mg, 21%). 1H NMR (400 MHz, CDCl3): δ 9.79 (s, 1H), 9.07 (s, 1H), 8.51 (s, 1H), 8.32-8.27 (m, 1H), 8.16 (d, J=5.6 Hz, 1H), 7.83 (d, J=2 Hz, 1H), 7.48-7.44 (m, 2H), 7.06-6.98 (m, 3H), 6.66-6.64 (m, 1H), 3.82 (q, J=6.8 Hz, 1H), 3.50 (s, 3H), 1.75-1.67 (m. 4H), 1.42 (d, J=6.8 Hz, 3H); MS (ESI): m/z 529.1[M+H]+.

1. concentrationThe reaction mixture was concentrated under vacuo
2. custompurified by HPLC separation

ORD-Eintrag

ord-831e51de4da24aacb62bb9a185099e40

Quelldatensatz

uspto-grants-2014_01

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08637672B2