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

Temperature

0 °C

A solution of 5-iodopyridazin-3(2H)-one (52 g, 234 mmol) in tetrahydrofuran (1000 mL) was treated with sodium hydride (11.2 g, 280 mmol) at 0° C. The mixture was stirred at 0° C. for 5˜10 min and then stirred at 25° C. for an additional 40˜50 min. At this time, the reaction mixture was treated with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10, 72.6 g, 281 mmol). The resulting reaction mixture was heated at 50° C. for 18 h and allowed to cool down to 25° C. The reaction mixture was then partitioned between water (500 mL) and methylene chloride (500 mL). The aqueous layer was back extracted with methylene chloride (1×300 mL). The combined organics were washed with a saturated aqueous sodium chloride solution (1×300 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (8/1 ethyl acetate/petroleum ether) afforded 3-cyclopentyl-2-(4-iodo-6-oxo-6H-pyridazin-1-yl)-propionic acid methyl ester (60.1 g, 68.3%).

1. stirringstirred at 25° C. for an additional 40˜50 min
2. customThe resulting reaction mixture
3. temperaturewas heated at 50° C. for 18 h
4. temperatureto cool down to 25° C
5. customThe reaction mixture was then partitioned between water (500 mL) and methylene chloride (500 mL)
6. extractionThe aqueous layer was back extracted with methylene chloride (1×300 mL)
7. washThe combined organics were washed with a saturated aqueous sodium chloride solution (1×300 mL)
8. dry with materialdried over magnesium sulfate
9. filtrationfiltered
10. concentrationconcentrated in vacuo

ORD record

ord-82cd48cbb4d444068410317c5df139e1

Source dataset

uspto-grants-2012_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08258134B2