O-(2,4,6-Trimethylbenzenesulfonyl)hydroxylamine → HCID 86662453, compound

Participants

Reaction Conditions

Reaction Steps

Methyl 5-(3-(tert-butoxycarbonyl(methyl)carbamoyl)-2-(4-fluorophenyl)pyrazolo[1,5-h]pyridazin-5-yl)-2-methoxy-4-methylbenzoate and methyl 5-(3-(tert-butoxycarbonyl(methyl)carbamoyl)-2-(4-fluorophenyl)pyrazolo[1,5-h]pyridazin-4-yl)-2-methoxy-4-methylbenzoate. Part A: To a cooled solution (0° C., ice bath) containing methyl 2-methoxy-4-methyl-5-(pyridazin-4-yl)benzoate (0.16 g, 0.66 mmol) and dichloromethane (3 mL) was added O-(mesitylsulfonyl)hydroxylamine (0.32 g, 0.90 mmol) in dichloromethane (3 mL) quickly, dropwise. The solution was maintained at 0° C. for 5 min, removed from the cooling bath and maintained at ambient temperature for 5 h. The solution was concentrated to afford 1-amino-4-(4-methoxy-5-(methoxycarbonyl)-2-methylphenyl)pyridazin-1-ium 2,4,6-trimethylbenzenesulfonate as a foam (274 MH+). Part B: The product thus obtained in part A was suspended in THF (2.0 mL). tert-butyl 3-(4-fluorophenyl)propioloyl(methyl)carbamate (0.17 g, 0.60 mmol) was added and the suspension cooled to −78° C. (dry Ice/acetone bath). DBU (0.27 g, 1.8 mmol) in THF (1.0 mL) was added dropwise over 2 min. The mixture was left in the cooling bath for 20 min, then removed from cooling and allowed to proceed for 20 h at ambient temperature. The mixture was filtered and concentrated. Purification on silica gel (20-80% ethyl acetate/hexanes, 60 min gradient) afforded methyl 5-(3-(tert-butoxycarbonyl(methyl)carbamoyl)-2-(4-fluorophenyl)pyrazolo[1,5-b]pyridazin-5-yl)-2-methoxy-4-methylbenzoate and methyl 5-(3-(tert-butoxycarbonyl(methyl)carbamoyl)-2-(4-fluorophenyl)pyrazolo[1,5-b]pyridazin-4-yl)-2-methoxy-4-methylbenzoate as separate regioisomers.

Provenance & Evidence