5,8-Dichloropyrido[2,3-d]pyridazine → (R)-(4-(5-chloropyrido[2,3-d]pyridazin-8-yl)-3-methylpiperazin-1-yl)(phenyl)methanone

Participants

Reaction Conditions

Reaction Steps

To a reaction vial was added 5,8-dichloropyrido[2,3-d]pyridazine 78 (165 mg, 825 μmol) and (R)-(3-methylpiperazin-1-yl)(phenyl)methanone (337 mg, 1.65 mmol). The mixture was heated to 100° C. for 2 h. After cooling to room temperature, the resultant glassy product was dissolved in dichloromethane (40 mL) and washed with 1×5 mL NaHCO3 and 1×5 mL of brine. The organic layer was dried over MgSO4, filtered and concentrated. Purification by silica gel column chromatography using a gradient of 70% ethyl acetate in hexanes to 90% EtOAc in hexanes afforded the regioisomeric products. The first eluting product (R)-(4-(5-chloropyrido[2,3-d]pyridazin-8-yl)-3-methylpiperazin-1-yl)(phenyl)methanone 79 (132 mg, 44% yield) was the major product, the second eluting product (R)-(4-(8-chloropyrido[3,2-d]pyridazin-5-yl)-3-methylpiperazin-1-yl)(phenyl)methanone 80 (74 mg, 24% yield) was the minor product. Data for 79: 1H-NMR (400 MHz, CDCl3): δ 9.10 (brs, 1H), 8.47 (dd, J=8.2, 1.6 Hz, 1H), 7.83 (dd, J=8.2, 4.3 Hz, 1H), 5.46 (br m, 1H), 4.97-4.40 (series of m, 2H), 3.99-3.20 (series of m, 4H), 1.40 (br m, 3H). MS 367.1 (calc'd) 368.0 (M+H, found). Data for (R)-(4-(8-chloropyrido[3,2-d]pyridazin-5-yl)-3-methylpiperazin-1-yl)(phenyl)methanone: 1H-NMR (400 MHz, CDCl3): δ 9.27 (dd, J=4.3, 1.6, 1H), 8.39 (J=8.6, 1.6 Hz, 1H), 7.83 (dd, J=8.2, 4.3 Hz, 1H), 7.45 (s, 5H), 4.31 (br s, 1H), 4.11 (br s, 1H), 2.68 (m, 5H), 1.27 (br s, 3H). MS 367.1 (calc'd) 368.0 (M+H, found).

Provenance & Evidence