(R)-methyl 5-((5-((4-methylpiperazin-1-yl)methyl)-2-nitrophenyl)amino)-3-(1-(2-(trifluoromethyl)phenyl)ethoxy)thiophene-2-carboxylate synthesis

Yield:1094554-41-2 70%

Reaction Conditions:

with potassium carbonate;tris-(dibenzylideneacetone)dipalladium⁽⁰⁾;4,5-bis(diphenylphosphino)-9,9-dimethylxanthene in tert-butyl alcohol at 80; for 18 h;Product distribution / selectivity;

Steps:

A mixture of 1-[(3-chloro-4-nitrophenyl)methyl]-4-methylpiperazine (0.313 g, 1.16 mmol), methyl 5-amino-3-({(1 R)- 1 -[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate (0.401 g, 1.16 mmol), K₂CO₃ (0.401 g, 2.90 mmol), X-Phos (0.0587 g, 0.12 mmol), tris(benzylideneacetone)dipalladium(0) (0.0531 g, 0.06 mmol) and te/t-butanol (4.6 mL) in a sealed tube was heated at 80 ⁰C for 18 h. The crude reaction mixture was filtered through celite, washing with toluene and then purified by flash column chromatography (EtOAc:MeOH:NEt₃) to give the title compound (0.534 g, 70%) as a red amorphous solid.

References:

WO2009/2916,2008,A2 Location in patent:Page/Page column 30-31