Water → HCID 68981265, compound

Temperature

0 °C

A 5 L three-neck round bottom flask was charged with (5-methyl-6-oxo-1,6-dihydro-pyridazin-3-3-yl)-acetic acid tert-butyl ester (10; 223 g, 0.996 mol) and THF (700 mL). The resulting solution was cooled to 0° C. and potassium tert-butoxide (1.2 L, 1.66 M in THF, 1.99 mol) was added dropwise over approximately 30 min. After cooling the reaction mixture to −55° C., a solution of 5-(2,3-difluoro-6-nitro-phenoxy)-isophthalonitrile (22; 150 g; 0.498 mol) in THF (1.0 L) was added dropwise over approximately 1 h. Following a THF rinse (500 mL), the cooling bath was removed, and the reaction mixture was stirred for 19 h with warming to ambient temperature. The reaction mixture was then quenched by the addition of 1N HCl (1.75 L). Following removal of the aqueous layer (2 L, pH of 3-4) the organic phase was washed with water (1.0 L) and brine (750 mL). The resulting THF solution was filtered through CELITE® and the filter aid washed with THF (500 mL). The solution was then concentrated in vacuo to afford a dark oil which was dissolved in NMP (850 mL) and warmed to approximately 50° C. Water (425 mL) was added dropwise. The cloudy solution was stirred slowly, seeded with a crystal and cooled to 0° C. After stirring at 0° C. for 30 min, the product was filtered. The filter cake was then washed with MeOH (100 mL, 200 mL) and dried in a vacuum oven (50° C., 25 Torr) to afford [3-(3,5-dicyano-phenoxy)-2-fluoro-4-nitro-phenyl]-(5-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl)-acetic acid tert-butyl ester (23; 157 g, 62% theory).

1. temperatureAfter cooling the reaction mixture to −55° C.
2. washrinse (500 mL)
3. customthe cooling bath was removed
4. temperaturewith warming to ambient temperature
5. customThe reaction mixture was then quenched by the addition of 1N HCl (1.75 L)
6. customremoval of the aqueous layer (2 L, pH of 3-4) the organic phase
7. washwas washed with water (1.0 L) and brine (750 mL)
8. filtrationThe resulting THF solution was filtered through CELITE®
9. washthe filter aid washed with THF (500 mL)
10. concentrationThe solution was then concentrated in vacuo
11. customto afford a dark oil which
12. temperaturewarmed to approximately 50° C
13. stirringThe cloudy solution was stirred slowly
14. temperaturecooled to 0° C
15. stirringAfter stirring at 0° C. for 30 min
16. filtrationthe product was filtered
17. washThe filter cake was then washed with MeOH (100 mL, 200 mL)
18. customdried in a vacuum oven (50° C., 25 Torr)

ORD record

ord-d55fa1b64bcb4cab8e7674523b17e05c

Source dataset

uspto-grants-2009_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07608731B2