Imidazole → 1-(Ethoxymethyl)-1H-imidazole

Temperature

80 °C

To a solution of imidazole (10.0 g, 146.9 mmole) in 100 ml dimethyl sulfoxide at room temperature under nitrogen is added sodium hydride (6.46 g, 161.6 mmole). The solution is stirred at 80° C. for 2 hours. Chloromethyl ethyl ether (16.35 ml, 176.3 mmole) is added dropwise. The reaction mixture is stirred for another 2 hour at 80° C., cooled to room temperature, poured into 5% aqueous solution and extracted with dichloromethane (4×200 ml). The combined organic extracts are dried over sodium sulfate, filtered, concentrated in vacuo. The residue is fresh chromatographed in hexane/ethyl acetate from 5:1 to 2:1 to give 1-ethoxymethyl-1H-imidazole as a brown oil 1.68 g (90%) MS(ES+): (M+H)=127.0 To the solution of 1-ethoxymethyl-1H-imidazole (1.24 g, 0.98 mmole) in 3.92 ml anhydrous tetrahydrofuran at −78° C. is added n-butyllithium (1.6 M in hexane) over 5 minutes. Reaction mixture is stirred at −78° C. for 1.5 hour, then (1S,2E)-1-isopropyl-4-[methoxy(methyl)amino]-3-methyl-4-oxobut-2-enyl(methyl)carbamate (427 mg, 1.36 mmole) in 2 ml anhydrous tetrahydrofuran is added over 10 minutes. The reaction mixture is stirred at −78° C. for 1 hour. Then, it is warmed to room temperature, stirred for 1 hour at room temperature. The reaction mixture is diluted with dichloromethane/water. The organic layer is washed with 5% sodium bicarbonate, dried over sodium sulfate, filtered, concentrated in vacuo. The residue is fresh chromatographed in hexane/ethyl acetate from 3:1 to 1:1 to give light yellow oil: [4-(1-Ethoxymethyl-1H-imidazol-2-yl)-1-isopropyl-3-methyl-4-oxo-but-2-enyl]-methyl-carbamic acid tert-butyl ester (120 mg, 23%) MS(ES+): (M+H)=380.2

1. stirringThe reaction mixture is stirred for another 2 hour at 80° C.
2. temperaturecooled to room temperature
3. extractionextracted with dichloromethane (4×200 ml)
4. dry with materialThe combined organic extracts are dried over sodium sulfate
5. filtrationfiltered
6. concentrationconcentrated in vacuo
7. customThe residue is fresh chromatographed in hexane/ethyl acetate from 5:1 to 2:1

ORD record

ord-a9ef6415547e4ea08c19692f467d9f90

Source dataset

uspto-grants-2008_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07390910B2