Sodium sulfate decahydrate → [2-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-oxazol-5-yl]-methanol

Participants

Reaction Conditions

Reaction Steps

A mixture of 1-cyclohexylmethyl-7-methoxy-1H-indole-3-carboxylic acid amide (563 mg, 1.97 mmol), 2-chloro-3-oxo-propionic acid methyl ester (Gangjee et al., J. Med. Chem. 44, 1993-2003, 2001; 1.48 g, 9.85 mmol) and dimethylacetamide (10 ml) was subjected to microwave irradiation at 90° C. for 2×5 minutes using an Emrys™ Optimizer EXP. The reaction mixture was diluted with dichloromethane (150 ml), then washed with 5% aqueous magnesium sulfate (2×100 ml) and brine (150 ml). The organic extracts were dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by flash column chromatography eluting with 25% (v/v) ethyl acetate in heptane to afford an inseparable mixture of 2-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-oxazole-5-carboxylic acid methyl ester and 1-cyclohexylmethyl-7-methoxy-3-oxazol-2-yl-1H-indole (87:13 ratio by HPLC; 0.613 g). Lithium aluminum hydride solution (1M solution in diethyl ether; 2.88 ml, 2.88 mmol) was added dropwise to a mixture of 2-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-oxazole-5-carboxylic acid methyl ester and 1-cyclohexylmethyl-7-methoxy-3-oxazol-2-yl-1H-indole (557 mg) dissolved in tetrahydrofuran (10 ml) under ice-methanol cooling. The resulting mixture was stirred for 30 minutes at 0° C., then diluted with diethyl ether (40 ml). Excess sodium sulfate decahydrate was then added and the resulting mixture stirred at room temperature for 18 h. The mixture was filtered through a pad of dicalite and washed with diethyl ether (100 ml); the filtrate was then concentrated in vacuo. The resulting residue was purified by column chromatography eluting with 50% ethyl acetate in n-heptane to afford [2-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-oxazol-5-yl]-methanol as a yellow solid (242 mg, 0.71 mmol). Methanesulfonyl chloride (98 mg, 0.85 mmol) was added dropwise to a solution of [2-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)-oxazol-5-yl]-methanol (242 mg, 0.71 mmol) dissolved in dichloromethane (15 ml) under ice-methanol cooling, then triethylamine (93 mg, 0.92 mmol) was added dropwise, cooling was then removed and the mixture stirred for 16 h. The mixture was then diluted with dichloromethane (30 ml), washed with saturated sodium carbonate solution (30 ml) in a hydrophobic frit tube. The organic extracts were dried over magnesium sulfate, then concentrated in vacuo. A mixture of the resulting residue (110 mg, 0.26 mmol), pyrrolidine (185 mg, 2.60 mmol) and tetrahydrofuran (2.5 ml) was subjected to microwave irradiation at 150° C. for 15 minutes. The resulting mixture was concentrated in vacuo and purified by flash column chromatography (2% (v/v) ammonia in methanol/dichloromethane in 1:49 ratio as eluant) to give a brown gum. The gum was further purified by semi-prep. HPLC [Method (i)] to furnish 1-cyclohexylmethyl-7-methoxy-3-(5-pyrrolidin-1-ylmethyl-oxazol-2-yl)-1H-indole as a trifluoroacetic acid salt (14 mg). 1H NMR (400 MHz, CD3OD) δ 0.99-1.27 (5H, m), 1.54-1.78 (5H, m), 1.86 (1H, m), 2.00-2.24 (4H, m), 3.25-3.44 (2H, m), 3.53-3.74 (2H, m), 3.97 (3H, s), 4.29 (2H, d, J 7.0), 4.64 (2H, s), 6.81 (1H, s, J 7.0), 7.15 (1H, t, J 8.0), 7.41 (1H, s), 7.79 (1H, d, J 7.5), 7.82 (1H, s). EsIMS: m/z 394.1 [M+H]+, 323.1.

Provenance & Evidence