Chlorotrimethylsilane → 1,3-Piperidinedicarboxylic acid, 3-(2-propen-1-yl)-, 1-(1,1-dimethylethyl) ester

Temperature

0 °C

To a solution of piperidine-1,3-dicarboxylic acid 3-allyl ester 1-tert-butyl ester (62.5 g) in tetrahydrofuran (625 ml) cooled to −72° C. was added lithium hexamethyl disilazide (1.6M tetrahydrofuran solution, 160 ml). The mixture was stirred at the same temperature for 30 minutes, and then the reaction mixture was warmed to 0° C. over 12 minutes and cooled to −67° C. again. To the mixture was added trimethylsilyl chloride (35.2 ml). The reaction mixture was warmed to 2.5° C. over 1 hour, and stirred at the same temperature for additional 2 hours. To the mixture were sequentially added methanol (250 ml) and 1M aqueous sodium hydroxide solution (250 ml), and the mixture was washed with n-hexane (940 ml). The separated aqueous layer was washed with n-hexane (250 ml) again. The separated aqueous layer was acidified by 1M hydrochloric acid water, and then extracted with ethyl acetate (800 ml). The organic layer was sequentially washed with water (800 ml) and saturated aqueous sodium chloride solution (400 ml), and the separated aqueous layer was extracted with ethyl acetate (500 ml) again. The combined organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was slurry-washed with n-hexane/ethyl acetate (10/1, 660 ml) to give the titled compound (53.4 g).

1. temperaturecooled to −67° C. again
2. temperatureThe reaction mixture was warmed to 2.5° C. over 1 hour
3. stirringstirred at the same temperature for additional 2 hours
4. washthe mixture was washed with n-hexane (940 ml)
5. washThe separated aqueous layer was washed with n-hexane (250 ml) again
6. extractionextracted with ethyl acetate (800 ml)
7. washThe organic layer was sequentially washed with water (800 ml) and saturated aqueous sodium chloride solution (400 ml)
8. extractionthe separated aqueous layer was extracted with ethyl acetate (500 ml) again
9. dry with materialThe combined organic layer was dried over anhydrous sodium sulfate
10. concentrationconcentrated under reduced pressure
11. washThe resulting residue was slurry-washed with n-hexane/ethyl acetate (10/1, 660 ml)

ORD record

ord-db2737bb939a4b52a1baefb22c258ae5

Source dataset

uspto-grants-2013_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08609647B2