4-Methylmorpholine → N-(cyanomethyl)-3-(hydroxymethyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide

Temperature

-78 °C

(1S,2R,3R,4R)-3-{[(Cyanomethyl)amino]carbonyl}bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (840 mg, 3.81 mmol) was placed in a 25 mL round bottom flask and the flask was fitted with a rubber septum. After flushing the flask with nitrogen, tetrahydrofuran (8.0 mL) was added and the solution was cooled to −78° C. 4-Methylmorpholine (0.46 mL, 4.0 mmol) and isobutyl chloroformate (0.52 mL, 4.0 mmol) were added and the reaction mixture was stirred at −78° C. for 10 min., and then warmed to ambient temperature over 1 h. After stirring for an additional 1 h, the reaction mixture was recooled to −78° C. and sodium borohydride (0.25 g, 6.5 mmol) and methanol (6.0 mL) were added. After stirring for 1 h, the reaction mixture was allowed to warm to ambient temperature over 1 hour and then quenched with saturated aqueous ammonium chloride. The reaction mixture was diluted with saturated aqueous sodium chloride solution (100 mL) and the product was extracted with ethyl acetate. The combined organics were dried over anhydrous sodium sulfate and then concentrated on a rotary evaporator. Chromatography of the residue on a silica gel using a mixture ethyl acetate:hexanes (gradient elution 5:2 to 3:1) provided (1R/S,2R/S,3R/S,4S/R)-N-(cyanomethyl)-3-(hydroxymethyl)bicyclo[2.2.1]hept-5-ene-2-carboxamide as a colorless solid.

1. customthe flask was fitted with a rubber septum
2. customAfter flushing the flask with nitrogen, tetrahydrofuran (8.0 mL)
3. additionwas added
4. temperaturewarmed to ambient temperature over 1 h
5. stirringAfter stirring for an additional 1 h
6. customwas recooled to −78° C.
7. stirringAfter stirring for 1 h
8. temperatureto warm to ambient temperature over 1 hour
9. customquenched with saturated aqueous ammonium chloride
10. additionThe reaction mixture was diluted with saturated aqueous sodium chloride solution (100 mL)
11. extractionthe product was extracted with ethyl acetate
12. dry with materialThe combined organics were dried over anhydrous sodium sulfate
13. concentrationconcentrated on a rotary evaporator

ORD record

ord-b3c2d7ab2ed74453ad23637ce37732d5

Source dataset

uspto-grants-2008_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07371747B2