反应详情

温度

-78 °C

A solution of oxalyl chloride (3.16 ml, 36.17 mmol) in dichloromethane (50 ml) was coooled to -78° C. A solution of dimethylsulfoxide (3.42 ml, 48.22 mmol) in dichloromethane (50 ml) was added dropwise. The reaction mixture was stirred for 5 min at -78° C. A solution of N-((1R)-1-(hydroxymethyl)-2-phenylethyl)-N-methylcarbamic acid tert-butylester (6.40 g, 24.11 mmol) in dichloromethane (100 ml) was added dropwise over a period of 10 min. The solution was stirred for 25 min at -78° C. Ethyldiisopropylamine (16.68 ml, 96.44 mmol) was added dropwise at -78° C. The solution was warmed to -35° C., and immediately cooled to -78° C. Glacial acetic acid (6.07 ml, 106.08 mmol) was added. The reaction mixture was warmed to room temperature and diluted with dichloromethane (150 ml). It was washed with saturated sodium chloride solution (2×200 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was dissolved in methanol (200 ml). Benzylamine (2.6 ml, 24.1 mmol) was added. Glacial acetic acid (6.0 ml, 106 mmol) and 3 Å mol sieves (32 g) were added. Sodium cyanoborohydride (1.00 g, 15.9 mmol) was added as a solid. The reaction mixture was stirred for 1h, before another portion of sodium cyanoborohydride (0.97 g, 15.4 mmol) was added. The mixture was first stirred for 16 h at room temperature and successively left 3 days without stirring. The mol sieves was filtered off through a plug of celite. The celite was washed with methanol (200 ml). The solvent was removed in vacuo. The residue was dissolved in 1N sodium hydroxide solution/diethyl ether (250 ml/250 ml). The phases were separated. The aqueous phase was extracted with diethyl ether (2×100 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (230 g), using dichloromethane/methanol/25% aqueous ammonia (first 100:10:1, then 50:10:1) as eluent, to give 4.54 g of N-((1R)-1-benzyl-2-(benzylamino)ethyl)-N-methylcarbamic acid tert-butylester.

1. customwas coooled to -78° C
2. stirringThe solution was stirred for 25 min at -78° C
3. temperatureThe solution was warmed to -35° C.
4. temperatureimmediately cooled to -78° C
5. temperatureThe reaction mixture was warmed to room temperature
6. washIt was washed with saturated sodium chloride solution (2×200 ml)
7. dry with materialdried over magnesium sulfate
8. customThe solvent was removed in vacuo
9. dissolutionThe crude product was dissolved in methanol (200 ml)
10. additionwas added
11. stirringThe mixture was first stirred for 16 h at room temperature and successively left 3 days
12. stirringwithout stirring
13. filtrationThe mol sieves was filtered off through a plug of celite
14. washThe celite was washed with methanol (200 ml)
15. customThe solvent was removed in vacuo
16. dissolutionThe residue was dissolved in 1N sodium hydroxide solution/diethyl ether (250 ml/250 ml)
17. customThe phases were separated
18. extractionThe aqueous phase was extracted with diethyl ether (2×100 ml)
19. dry with materialThe combined organic layers were dried over magnesium sulfate
20. customThe solvent was removed in vacuo
21. customThe crude product was purified by flash chromatography on silica (230 g)