2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl → 1,1,1-trifluoro-2-(4-((S)-2-(((S)-3-methylmorpholino)methyl)-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)propan-2-ol

Participants

Reaction Conditions

Reaction Steps

A 1-L pressure vessel was charged with (3S)-3-methyl-4-(((2S)-4-(2-thiophenylsulfonyl)-2-piperazinyl)methyl)morpholine (10.50 g, 30.4 mmol), 100 mL of toluene, (2R)-(4-bromophenyl)-1,1,1-trifluoropropan-2-ol (9.81 g, 36.5 mmol, Example 243, Step 1), and sodium tert-butoxide (7.30 g, 76 mmol). Nitrogen gas through the solution for 3 min then RuPhos Palladacycle (1.107 g, 1.520 mmol) and dicyclohexyl(2′,6′-diisopropoxy-[1,1′-biphenyl]-2-yl)phosphine, RuPhos (0.709 g, 1.520 mmol) were added. The vessel was sealed and heated at 60° C. for 12 h. The mixture diluted with water and extracted with EtOAc. The combined organics were dried with MgSO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (0-70% EA/Hex) to give a tan foam. To this foam was added 200 mL of IPA and stirred at rt for 1 h. The white solid that had formed was collected by filtration, dissolved in MeOH, then dried under high vac at 70° C. for 1 h to give pure 1,1,1-trifluoro-2-(4-((S)-2-(((S)-3-methylmorpholino)methyl)-4-(thiophen-2-ylsulfonyl)piperazin-1-yl)phenyl)propan-2-ol (8.15 g). This material was identical to peak 2 in example 45.

Provenance & Evidence