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

温度

140 °C

Ethyl isocyanate (22 mL, 0.31 mmol) was added to a mixture of DMAP (0.008 g, 0.063 mmol) (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) (0.02 g, 0.063 mmol), 4 Å molecular sieves (0.02 g, crushed) and DCM (2 mL). The reaction vessel was sealed and heated at 140° C. in a CEM Discoverer™ microwave for 15 min. The reaction mixture was cooled to room temperature, DCM (2 mL) and AP-trisamine (2.49 mmol/g, 0.25 g, 0.63 mmol) were added, the reaction vessel was sealed and heated at 130° C. in a CEM Discoverer™ microwave for 5 min. The reaction mixture was filtered and the solid washed with DCM (4 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 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, 22% yield) as a pale yellow oil: m/z 391.28 (MH+); HPLC (50% to 80% gradient [95:5 MeOH:water, 10 mmol ammonium acetate] 255 nm XTERRA 2.0 ml/min) 2.98 min, 99%.

1. customThe reaction vessel was sealed
2. temperatureThe reaction mixture was cooled to room temperature
3. customthe reaction vessel was sealed
4. temperatureheated at 130° C. in a CEM Discoverer™ microwave for 5 min
5. filtrationThe reaction mixture was filtered
6. washthe solid washed with DCM (4 mL) the filtrate
7. customwas evaporated
8. customthe crude product purified by reverse phase preparative HPLC (Prep Nova-Pak HR

ORDレコード

ord-89a1ffbd0a1940589eb615ed420e2337

出典データセット

uspto-grants-2006_08

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US07098337B2