methyl 2-amino-5-methyl-4-(trifluoromethyl)benzoate synthesis

Yield: 92%

Reaction Conditions:

with cesium fluoride;(1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride in 1,4-dioxane at 20 - 80; for 3 h;

Steps:

3.4
Step 4; Preparation of Methyl 2-amino-5-methyl-4-trifluoromethylbenzoate; Add cesium fluoride (184.3 g, 1.21 mol), methyl boronic acid (63.7 g, 1.05 mol, 3 molequiv.) andbis(diphenylphosphinoferrocene)palladium(II) chloride (27.83 g, 35.1 mmol)to a solution of methyl 2-amino-5-iodo-4-trifluoromethylbenzoate (121 g, 351 mmol) inanhydrous 1,4-dioxane (2.5 L) at room temperature under an atmosphere of nitrogen andheat the mixture at 80 °C for 3 h. Allow the mixture to cool to room temperature thenpartition between ethyl acetate (2.5 L) and water (2.5 L) and filter through a pad ofCelite to remove the fine black suspension. Extract the aqueous phase with ethylacetate (2 x 100 mL) and wash the combined organic extracts with brine (1 L). Dry overanhydrous magnesium sulfate, filter and remove the solvent under reduced pressure at 45°C to give a red oil. Purify the residue by column chromatography on silica gel, elutingwith isohexane/ethyl acetate (9:1), to give the title compound as a pale yellow crystallinesolid (75.25 g, 92%).

References:

ELI LILLY AND COMPANY WO2006/2342, 2006, A1 Location in patent:Page/Page column 56-57