Dichlorobis(triphenylphosphine)palladium → Palladium

Participants

Reaction Conditions

Reaction Steps

Scheme 8 shows the synthesis of 4-(2-(1H-Indazol-4-yl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[2,3-d]pyrimidin-4-yl)morpholine II sulfate salt starting with Suzuki coupling of 4-(2-chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[2,3-d]pyrimidin-4-yl)morpholine 20 in 1,4-dioxane with 2-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole 10 (1.25 equiv.) and bis(triphenylphosphine)palladium (II) chloride (0.02 equiv.) in aqueous sodium carbonate. The mixture was heated to 88° C. and stirred for 14 hours. The reaction mixture was cooled, filtered, rinsed with water, and stirred with FLORISIL® (60-100 mesh, Sigma-Aldrich Chemical Company, Inc) in methylene chloride at ambient temperature for 5 hours. The mixture was filtered, rinsed with methylene chloride and ethyl acetate, and the filtrate and the rinse were combined and concentrated to give solid 21 with Pd content of 150 ppm. The solid was dissolved in methylene chloride and SILIABOND® Thiourea (Silicycle Inc) was added. The mixture was stirred for 5 hours, filtered, rinsed with methylene chloride and ethyl acetate. All the filtrate and the rinse were combined and concentrated to give 4-(6-((4-(methylsulfonyl)piperazin-1-yl)methyl)-2-(2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-yl)thieno[2,3-d]pyrimidin-4-yl)morpholine 21 as a solid in 70% yield with Pd content<10 ppm), along with a minor amount of THP regioisomer 21A.

Provenance & Evidence