反应详情

温度

0 °C

420 mg 1-Dimethylamino-4-{hydroxy-[2-(2,4,6-trimethyl-phenyl)-acetyl]-amino}-piperidine-4-carboxylic acid methyl ester (from Step 4) is dissolved in 15 ml dimethylformamide, cooled to 0° C., then 43 mg sodium hydride is added. It is warmed to room temperature, and stirred for 30 minutes. Then, 186 mg 1-Bromo-2-methoxy-ethane is added slowly at ambient temperature. The mixture is stirred for an additional hour, cooled to 0° C., and 180 mg sodium methoxide is added. Stirring is continued for 2 hours at room temperature. Then the mixture is poured into 200 ml aqueous ammonium chloride and the pH is adjusted to 4.3 by the addition of hydrochloric acid. It is extracted three times with ethyl acetate, the organic layer is separated, dried over sodium sulfate, and the solvent is evaporated. The residue is purified by chromatography on silica gel with cyclohexane/acetone as a solvent, from 1:2 to pure acetone. Thus, 160 mg 8-Dimethylamino-1-(2-methoxy-ethoxy)-3-(2,4,6-trimethylphenyl)-1,8-diaza-spiro[4.5]decane-2,4-dione is obtained as a solid, mp 108° C. 1H-NMR (d4-methanol): 6.84 ppm (s, 2H), 4.28 ppm (m, 2H), 3.68 ppm (m, 2H), 3.37 ppm (s, 3H), 2.70 ppm (s, 6H), 2.22 ppm (m, 5H), 2.10 ppm (m, 8H).

1. temperatureIt is warmed to room temperature
2. stirringThe mixture is stirred for an additional hour
3. temperaturecooled to 0° C.
4. stirringStirring
5. waitis continued for 2 hours at room temperature
6. extractionIt is extracted three times with ethyl acetate
7. customthe organic layer is separated
8. dry with materialdried over sodium sulfate
9. customthe solvent is evaporated
10. customThe residue is purified by chromatography on silica gel with cyclohexane/acetone as a solvent, from 1:2 to pure acetone