Cesium carbonate → 4-(9'-cyclopentyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-1,7'-pyrimido[5,4-b][1,4]diazepine]-2'-ylamino)-2,5-difluoro-N-[(3R)-1-methylpyrrolidin-3-yl]benzamide

Participants

Reaction Conditions

Reaction Steps

2′-chloro-9′-cyclopentyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 130; 109 mg, 0.36 mmol), aniline (Intermediate 229; 83 mg, 0.324 mmol), and caesium carbonate (211 mg, 0.648 mmol) added to dioxane (3 mL) and the suspension bubbled with nitrogen for 10 minutes. Tris-dibenzylideneacetone dipalladium (II) (11 mg, 0.02 mmol) and XANTPHOS (17 mg, 0.03 mmol) were added and the mixture heated to 100° C. for 16 hours. The reaction mixture was cooled to room temperature filtered, and the filter cake washed with DCM and the filtrate evaporated. The residue was dissolved in DCM and purified on a silica column eluting with a gradient of 0-5% 2M ammonia in MeOH/DCM over 30 column volumes. Product containing fractions were combined and evaporated and the residue purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (95 mg, 56%).

Provenance & Evidence