(1R,2R)-(-)-1,2-Cyclohexanedicarboxylic acid → trans-Cyclohexane-1,2-dicarboxylic anhydride

Participants

Reaction Conditions

Reaction Steps

(1R,2R)-Cyclohexane-1,2-dicarboxylic acid (150 mg, 0.87 mmol) was suspended in acetic anhydride (2 mL) and stirred at 80° C. for 1 hour. The mixture was cooled, concentrated in vacuo, azeotroped once with toluene and dried under vacuum to give (3aR,7aR)-hexahydro-2-benzofuran-1,3-dione as a white solid. It was taken up in DMF (5 mL), 8-fluoro-2,3,4,5-tetrahydropyrido[4,3-B]indole (166 mg, 0.87 mmol) was added and the solution stirred at room temperature for 3 hours. 1-Aminocyclopropanecarbonitrile hydrochloride (114 mg, 0.96 mmol) was added followed by triethylamine (0.36 mL, 2.61 mmol) and benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP, 499 mg, 0.96 mmol) and the mixture stirred overnight. DMF was removed in vacuo and the residue partitioned between DCM (2×30 mL) and 50% brine (10 mL). The combined organics were treated with saturated aqueous sodium bicarbonate (10 mL) and brine (10 mL), dried (magnesium sulphate), concentrated in vacuo and adsorbed onto silica for purification by flash chromatography (0-80% ethyl acetate/isohexane). To purify further, the sample was triturated twice with anhydrous diethyl ether (2×5 mL), filtered and dried under vacuum. This gave (1R,2R)-N-(1-cyanocyclopropyl)-2-[(8-fluoro-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)carbonyl]cyclohexanecarboxamide as a white solid (24.0 mg, 7%).

Provenance & Evidence