Sodium hydride → 2-[4-(2-cyano-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-propionic acid methyl ester

Participants

Reaction Conditions

Reaction Steps

A solution of 2-(6-oxo-1,6-dihydro-pyridazin-4-yloxy)-benzonitrile (13.4 g, 62.9 mmol) in tetrahydrofuran (300 mL) cooled to −10° C. under nitrogen was treated with a 60% suspension of sodium hydride in mineral oil (3.5 g, 88.1 mmol). The reaction was stirred at −10° C. for 10 min and then warmed to 25° C. where it stirred for an additional 40 min. After this time, the reaction was treated with 2-bromo-3-cyclopentylpropionic acid methyl ester (Intermediate 10, 17.7 g, 75.5 mmol). The reaction was warmed to 50° C. for 18 h. After this time, the reaction was partitioned between water and methylene chloride. The aqueous layer was back extracted with methylene chloride. The combined organics were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, rinsed and concentrated in vacuo. Silica gel column chromatography afforded 2-[4-(2-cyano-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-propionic acid methyl ester (14.7 g, 63%) as a pale yellow solid; ESI-MS 368 [M+H+]; HPLC: >92% (purity). 1H-NMR (300 MHz, CDCl3) δ 7.91 (s, 1H), 7.69-7.79 (m, 2H), 7.41-7.46 (m, 1H), 7.28-7.31 (m, 1H), 5.97 (s, 1H), 5.52-5.57 (m, 1H), 3.73 (s, 3H), 2.28-2.37 (m, 1H), 2.04-2.15 (m, 1H), 1.48-1.81 (m, 7H), 1.11-1.28 (m, 2H).

Provenance & Evidence