Ethyl Acetate → 5-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-6-(hydroxymethyl)-2-(4-(methylsulfonyl)phenyl)pyridazin-3(2H)-one

Temperature

100 °C

To a stirring solution of 6-(hydroxymethyl)-2-(4-(methylsulfonyl)phenyl)-5-(piperidin-4-yloxy)pyridazin-3(2H)-one HCl (18.97 mg, 0.05 mmol) in NMP (2 mL) at room temperature under argon was added DIPEA (19.4 mg, 0.150 mmol) and 5-chloro-2-iodopyrimidine (24 mg, 0.1.0 mmol). The resulting reaction mixture was heated at 100° C. under argon overnight. 15 mL of EtOAc was added to the reaction mixture. The reaction mixture was washed with water (15 mL), and brine (15 mL). Organic phase was dried (MgSO4), filtered and concentrated. The crude product was dissolved in a small amount of DCM (˜2 ml) and loaded onto a 24 g ISCO silica gel column which was eluted with a 20 min gradient from 20% to 100% EtOAc/Hexanes. 16 mg (62%) of 5-(1-(5-chloropyrimidin-2-yl)piperidin-4-yloxy)-6-(hydroxymethyl)-2-(4-(methylsulfonyl)phenyl)pyridazin-3(2H)-one was obtained as a tan solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.73-1.95 (m, 2H) 1.98-2.22 (m, 2H) 2.58 (s, 1H) 2.96-3.16 (m, 3H) 3.61-3.83 (m, 2H) 3.96-4.17 (m, 2H) 4.48-4.82 (m, 3H) 6.30 (s, 1H) 7.88 (d, J=8.79 Hz, 2H) 8.04 (d, J=8.35 Hz, 2H) 8.24 (s, 2H). MS (ESI) 492 (M+H).

1. customThe resulting reaction mixture
2. washThe reaction mixture was washed with water (15 mL), and brine (15 mL)
3. dry with materialOrganic phase was dried (MgSO4)
4. filtrationfiltered
5. concentrationconcentrated
6. dissolutionThe crude product was dissolved in a small amount of DCM (˜2 ml)
7. washwas eluted with a 20 min gradient from 20% to 100% EtOAc/Hexanes

ORD record

ord-abd147b2cdfe4cbcaeb51b05b959dcf0

Source dataset

uspto-grants-2013_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08372837B2