反应详情

A mixture of (1R*,2R*,5S*,6S*)-8-benzyl-2-(tert-butyldimethylsilyloxy)-6-cyano-1-phenyl-8-azabicyclo[3.2.1]octane (Description 42; 43 g), sodium azide (27 g), triethylamine hydrochloride (55 g) and N,N-dimethylformamide (150 ml) was stirred at +130° C. for 7 hours. The reaction mixture was cooled to room temperature, treated with water (500 ml) and extracted into ethyl acetate (4×200 ml). The combined organic extracts were washed with water (3×200 ml) and brine. The combined water layers were extracted again with ethyl acetate (2×200 ml). The organic phase was washed with small amount of water (50 ml). The combined organic extracts were dried (Na2SO4) and concentrated to give crude (1R*,2R*,5S*,6S*)-8-benzyl-2-(tert-butyldimethylsilyloxy)-1-phenyl-6-(tetrazol-5-yl]-8-azabicyclo[3.2.1]octane (47 g), which was mixed with potassium carbonate (25 g) and acetonitrile (220 ml), warmed up to +70° C. and finally treated with 2-methoxyethoxymethyl chloride (20 ml). The reaction mixture was stirred for 15 minutes, cooled to room temperature, then treated with water (500 ml) and extracted into ethyl acetate (3×200 ml). The combined organic extracts were dried (Na2SO4) and concentrated to give a 1:1.5 mixture of isomers A and B, respectively. Regioisomers were separated by chromatography on silica gel (iso-hexane:diethyl ether).

1. extractionextracted into ethyl acetate (4×200 ml)
2. washThe combined organic extracts were washed with water (3×200 ml) and brine
3. extractionThe combined water layers were extracted again with ethyl acetate (2×200 ml)
4. washThe organic phase was washed with small amount of water (50 ml)
5. dry with materialThe combined organic extracts were dried (Na2SO4)
6. concentrationconcentrated