Tris(hydroxymethyl)aminomethane → (4R,9aR)-6-Isopropylcarbamoyloxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester

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A solution of (4R,9aR)-6-hydroxymethyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (Example 15, intermediate b) (0.01 g, 0.03 mmol) and DCM (1 mL) was added to PS-BEMP (2.2 mmol/g, 0.03 g, 0.06 mmol). The mixture was shaken at room temperature for 5 min, isopropyl isocyanate (17 μL, 0.15 mmol) was added, the mixture was heated at 40° C. and left to shake for 24 h. PS-Trisamine (4.7 mmol/g, 0.06 g, 0.3 mmol) and DCM (1 mL) were added and the reaction mixture was left to shake at room temperature for 4 h. The reaction mixture was filtered and the solid washed with DCM (3 mL). The filtrate was evaporated and the crude product purified by reverse phase preparative HPLC (Prep Nova-Pak HR C18 6 μm 60 Å 30 mm×300 mm column, UV detection at 254 nm, mobile phase 95:5 methanol:water and 10 mmol ammonium acetate, gradient 50 methanol to 100% 0 to 10 min then 100% methanol to 13 min, 20 mL/min) to afford the title compound (0.053 g, 44% yield) as a pale yellow oil: m/z 405.29 (MH+); NMR δH (400 MHz, CDCl3) 1.15 (6H, d, J 6.5 Hz), 1.24 (3H, d, J 6.5 Hz), 1.47 (9H, s) 2.50–2.60 (2H, m), 3.0–3.1 (2H, m), 3.8–3.9 (1H, m), 3.9–4.1 (2H, m), 4.5–4.6 (2H, m), 4.7–4.8 (1H, br s), 5.04 (2H, s), 6.50 (1H, d, J 7.0 Hz) and 7.18 (1H, d, J 7.0 Hz).

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