Cesium carbonate → 4-[(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]-N-(1-ethyl-4-piperidyl)-2,5-difluoro-benzamide

Participants

Role	Name	HCID	Charge
Reactant	Cesium carbonate	HCID 10796	—
Reactant	1,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)	HCID 636044	—
Reactant	2-Chloro-9-cyclopentyl-7,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one	HCID 58154012	—
Reactant	4-amino-N-(1-ethyl-4-piperidyl)-2,5-difluoro-benzamide	HCID 68684847	—
Catalyst	tris(dibenzylideneacetone) palladium (II)	HCID 9897284	—
Solvent	1,4-Dioxane	HCID 31275	—
Product	4-[(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]-N-(1-ethyl-4-piperidyl)-2,5-difluoro-benzamide	HCID 68686107	54.6%

Reaction Conditions

Temperature	110 °C

Reaction Steps

10-chloro-2-cyclopentyl-4,4-dimethyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-8,10,12-trien-5-one (Intermediate 127; 100 mg, 0.32 mmol), 4-amino-N-(1-ethyl-4-piperidyl)-2,5-difluoro-benzamide (Intermediate 235; 101 mg, 0.36 mmol) and caesium carbonate (22 mg, 0.65 mmol) added to dioxane (5 mL) and the suspension bubbled with nitrogen for 10 minutes. tris(dibenzylideneacetone) palladium (II) (18 mg, 0.02 mmol) and XANTPHOS (17 mg, 0.03 mmol) were added and the mixture heated at 110° C. overnight. The mixture was filtered and the filtrate loaded onto an SCX (10 g) cartridge pre-wet with methanol, washed with methanol and eluted with methanolic ammonia. Product containing fractions were combined and evaporated and the resultant material purified by base modified reverse phase preparative HPLC to yield the title compound as a white crystalline solid (97 mg, 54%).

Provenance & Evidence

DOI	10.6084/m9.figshare.5104873.v1
Patent number	US07709471B2
Source dataset	uspto-grants-2010_05
ORD ID	ord-ef8721cc84e9428b9152816b27b78891
Source note	uspto-grants-2010_05