p-Toluenesulfonic acid monohydrate → 4-(9'-cyclopentyl-5'-methyl-6'-oxo-5',6',8',9'-tetrahydrospiro[cyclopropane-1,7'-pyrimido[5,4-b][1,4]diazepine]-2'-ylamino)-N-(1-ethyl-4-piperidyl)-2-fluoro-5-methoxy-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; 121 mg, 0.39 mmol) and 4-amino-N-(1-ethyl-4-piperidyl)-2-fluoro-5-methoxy-benzamide (Intermediate 205; 116 mg, 0.39 mmol) were taken up in 4-methyl-2-pentanol (4 mL) and p-toluenesulphonic acid monohydrate (150 mg, 0.79 mmol) added. The reaction mixture was heated at 160° C. by microwave irradiation for 1 hour. The cooled reaction mixture was poured into a mixture of methanol & water (5:2 v/v, 7 mL) and the resultant solution loaded onto an SCX-3 cartridge (5 g), which had been pre-wet with methanol. The cartridge was washed through with methanol (40 mL) and eluted with 2M ammonia in methanol (30 mL). The ammoniacal solution was evaporated to give an amber gum afforded which was purified by base modified reverse phase preparative HPLC which was re-purified by flash chromatography on a silica column eluting with 2.5-10% ammonia/methanol in DCM. Product containing fractions were combined and evaporated and the residue triturated with diethyl ether and resultant solid dried under vacuum, at 60° C., for 3 hours to yield the title compound as a flocculent white solid (86 mg, 39%)

Provenance & Evidence