Sodium Hydroxide → 2-bromo-4-[[[(1H-indol-4-yl)methyl]amino]carbonyl]benzoic acid

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Reaction Steps

Sodium hydroxide (21.5 mg, 0.54 mmol) was added to a solution of 2-bromo-4-[[[(1H-indol-4-yl)methyl]amino]carbonyl]benzoic acid methyl ester (Example 83; 208 mg, 0.54 mmol) in tetrahydrofuran/methanol (2:1; 1.8 mL). The solution was allowed to stir at room temperature for 4 h and then more sodium hydroxide (21.5 mg, 0.54 mmol) was added. The solution was allowed to stir at room temperature overnight, then it was diluted with ethyl acetate and the solution was washed with 1N hydrochloric acid solution (10 mL), washed with brine, dried (MgSO4), filtered and concentrated to give crude 2-bromo-4-[[[(1H-indol-4-yl)methyl]amino]carbonyl]benzoic acid. This was mixed with a solution of rac.-2-(dimethoxyphosphinyl)glycine methyl ester (Example 125) freshly prepared from rac.-N-(benzyloxycarbonyl)-2-(dimethoxyphosphinyl)glycine methyl ester (213.5 mg, 0.64 mmol), O-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (203.5 mg, 0.54 mmol), 1-hydroxybenzotriazole (72.6 mg, 0.54 mmol) and diisopropylethylamine (281 μL, 1.61 mmol) in N,N-dimethylformamide (1.5 mL). The solution was allowed to stir for 3 h, then ethyl acetate (20 mL) was added. The solution was washed with 1N hydrochloric acid solution (10 mL), saturated sodium bicarbonate solution (15 mL) and each aqueous layer was back-extracted with ethyl acetate. The combined organic layers were washed with brine (10 mL), dried (MgSO4), filtered, evaporated and chromatographed over silica gel (3-5% methanol/dichloromethane) to give rac.-N-[2-bromo-4-[[[(1H-indol-4-yl)methyl]amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (206.8 mg, 69% yield) as a pale yellow solid.

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