p-Toluenesulfonic acid monohydrate → 4-(9'-cyclohexyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-1,7'-pyrimido[5,4-b][1,4]diazepine]-2'-ylamino)-2-fluoro-5-methoxy-N-[(3R)-1-methylpyrrolidin-3-yl]benzamide

Participants

Reaction Steps

2′-chloro-9′-cyclohexyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 270; 103 mg, 0.32 mmol), 4-amino-2-fluoro-5-methoxy-N-[(3R)-1-methylpyrrolidin-3-yl]benzamide (Intermediate 182; 87 mg, 0.32 mmol) and p-toluenesulphonic acid monohydrate (154 mg, 0.81 mmol) were heated in 4-methyl-2-pentanol (3 mL) at 140° C. for 3 hours. The mixture was cooled and absorbed on to an SCX column, which was then washed with methanol and eluted with ammonia in methanol. Product containing fractions were combined and evaporated and purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (70 mg, 40%).

Provenance & Evidence