反应详情

To a stirred suspension of (2S)-5-[(benzyloxy)amino]-2-cyanopiperidine ethanedioate (1:1) (XI) (3.7 gm, 0.0115 mol, prepared according to the procedure described in step 8) in ethyl acetate:water (1:1, 37 ml:37 ml) was added solid sodium bicarbonate (1.9 gm, 0.022 mol) at 25° C. After 30 minutes of stirring the organic layer was separated. The aqueous layer was re-extracted with ethyl acetate (20 ml). The combined organic layer was washed with water (20 ml) and brine (20 ml), dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain 3 gm of ((2S)-5-[(benzyloxy)amino]-2-cyanopiperidine (XII) as an oil. The oily product, (2S)-5-[(benzyloxy)amino]-2-cyanopiperidine (XII) (1 gm, 0.00432 mol, prepared as mentioned above), was dissolved in acetonitrile (ACN) (15 ml), cooled to 10° C., stirred and triethyl amine (1.8 ml, 0.0129 mol) was added in one portion. To this mixture was added slowly a solution of triphosgene (0.564 gm, 0.0019 mol) in acetonitrile (6 ml). After 15 minutes of stirring, DMAP (0.0527 gm, 0.000432 mol) was added and the reaction mixture allowed to warm to 25° C. After 16 hours of stirring, the thin layer chromatography (ethyl acetate:hexane (1:1)) showed the two separable mixture of isomers. A solution of saturated sodium bicarbonate (10 ml) was added to the reaction mass and stirring continued for another 30 minutes. The volatiles were removed under reduced pressure. The residual mass was partitioned between ethyl acetate (10 ml) and water (10 ml). The organic layer was separated and the aqueous layer re-extracted with ethyl acetate (10 ml). The combined organic layer was washed with water (10 ml) and brine (10 ml), dried over anhydrous sodium sulphate and the solvent evaporated under reduced pressure. The resulting mixture was dissolved in dichloromethane (15 ml) and washed with 5% potassium hydrogen sulphate solution (3×10 ml), saturated sodium hydrogen carbonate (10 ml) and water (10 ml). The organic layer was concentrated under reduced pressure, to yield 0.610 gm of crude oily product.

1. customprepared
2. customwas separated
3. extractionThe aqueous layer was re-extracted with ethyl acetate (20 ml)
4. washThe combined organic layer was washed with water (20 ml) and brine (20 ml)
5. dry with materialdried over anhydrous sodium sulphate
6. concentrationconcentrated under reduced pressure