1,2-Dichloroethane → N-{(1S)-1-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-2,2-dimethylpropyl}-1H-indole-2-carboxamide

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Reaction Steps

To a 500 ml flask was added 1,1-dimethylethyl (1S,4S)-5-(3-methyl-L-valyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (17.1 g, 54.9 mmol), 1H-indole-2-carboxylic acid (10.62 g, 65.9 mmol), HOBt (10.09 g, 65.9 mmol) and EDC (25.3 g, 132 mmol) followed by CH2Cl2 (366 ml) and NMM (24.15 ml, 220 mmol). The mixture was stirred for 18 h. The reaction was diluted with water (150 ml) and sat. Na2CO3 (150 ml). Stirring was continued for an additional 0.5 h then the two layers were separated. The organic solution was washed with sat. NaHCO3, 1N HCl, sat. NaHCO3, and brine. The organic layer was passed over a phase separator and concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (100 ml). To the solution was added TFA (25 ml, 324 mmol). Stirring continued for 2 h then the solution was concentrated under reduced pressure. The resulting residue was dissolved in CH2Cl2 then washed twice with 2N HCl. The acidic solution was made basic and extracted with CH2Cl2. The organics were dried and concentrated to afford a brown residue. The residue was purified by reverse phase chromatography on a Biotage SP4 with a 65i column at a flow rate of 65 ml/min, 0.1% TFA eluting with 3 CV water, the 0-50% ACN/Water over 10 CV. The fractions containing the product were combined and diluted with CH2Cl2 and sat. NaHCO3. The layers were separated and the resulting aqueous layer was saturated with NaCl and extracted three times with CH2Cl2. The combined CH2Cl2 extracts were combined, dried and concentrated to afford the desired product (10 g, 28.2 mmol) as an off white solid. LCMS (m/z): 355.2 (M+H).

Provenance & Evidence