1,2-Diaminocyclohexane, trans- → Gsk-2798745

Participants

Reaction Conditions

Reaction Steps

To a light yellow solution of 1-(((5S,7S)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (0.050 g, 0.154 mmol) in 1,4-dioxane (2.052 mL) was added copper(I) iodide (2.94 mg, 0.015 mmol), potassium phosphate tribasic (0.065 g, 0.308 mmol), trans-1,2-diaminocyclohexane (3.71 μL, 0.031 mmol), and 2-(5-bromopyrazin-2-yl)propan-2-ol (0.040 g, 0.185 mmol). The reaction mixture was heated at 100° C. for 15 h. Then, additional copper(I) iodide (2.94 mg, 0.015 mmol) and trans-1,2-diaminocyclohexane (3.71 μL, 0.031 mmol) were added and stirred for an additional hour at 100° C. Additional copper(I) iodide (2.94 mg, 0.015 mmol) and trans-1,2-diaminocyclohexane (3.71 μL, 0.031 mmol) were then added and stirred for an additional 3 h at 100° C. The reaction was then cooled to RT and CH3CN (5 mL) was added and the mixture vacuum filtered using a Hirsch funnel. The solid was rinsed with CH3CN (3×2 mL) and the filtrate was loaded onto florisil and purified using silica gel chromatography CISCO): 0.5-2% MeOH/DCM (30 min), 12 g silica gel column. The product eluted at 19 minutes to obtain 1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile as an orange foam (43 mg, 38% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.59 (s, 1H), 8.47 (s, 1H), 8.37 (s, 1H), 7.82 (d, J=8.28 Hz, 1H), 7.58 (d, J=8.28 Hz, 1H), 5.41 (s, 1H), 4.16 (br. s., 2H), 3.77-3.96 (m, 2H), 1.98 (d, J=7.03 Hz, 1H), 1.82-1.93 (m, 1H), 1.72 (d, J=14.56 Hz, 2H), 1.58-1.67 (m, 2H), 1.28-1.57 (m, 8H), 1.06 (s, 3H). MS (m/z) 461.0 (M+H+).

Provenance & Evidence