Methanol → {1-[1-(Propylsulfonyl)-4-pyridin-2-ylpiperidin-4-yl]ethyl}amine

Temperature

0 °C

A solution of 1-(propylsulfonyl)-4-pyridin-2-ylpiperidine-4-carbonitrile (5.0 g, 17 mmol) in toluene (130 mL) at room temperature was treated with MeMgBr (48.9 mL of a 1.0 M solution in dibutyl ether, 28.9 mmol). After 18 h, the reaction was cooled to 0° C. and treated with MeOH (29 mL). After 10 min, the reaction was treated with NaBH4 (1.0 g, 26.4 mmol), warmed to room temperature, and stirred an additional 10 min after which the reaction mixture was cooled to 0° C. and quenched with the dropwise addition of saturated aqueous NH4Cl (15 mL). The reaction was diluted with H2O (300 mL) and extracted with EtOAc (3×200 mL). The combined organic extracts were dried (Na2SO4), concentrated under reduced pressure, and dissolved in pH 7 phosphate buffer (300 mL). The buffered solution was washed with EtOAc (200 mL) and the organic layer was extracted with fresh pH 7 buffer (2×150 mL). The combined buffer solutions were made basic with concentrated NH4OH and extracted with CH2Cl2 (3×200 mL), and these extracts were dried (Na2SO4) and concentrated under reduced pressure to afford {1-[1-(propylsulfonyl)-4-pyridin-2-ylpiperidin-4-yl]ethyl}amine. This material was fully resolved into 1R and 1S isomers (>99% ee) using a ChiralPak AD column. NOE analysis of Mosher's amides and single X-ray crystal analysis of a derivative confirmed the absolute stereochemistry of each isomer.

1. waitAfter 10 min
2. temperaturewarmed to room temperature
3. temperaturewas cooled to 0° C.
4. customquenched with the dropwise addition of saturated aqueous NH4Cl (15 mL)
5. additionThe reaction was diluted with H2O (300 mL)
6. extractionextracted with EtOAc (3×200 mL)
7. dry with materialThe combined organic extracts were dried (Na2SO4)
8. concentrationconcentrated under reduced pressure
9. dissolutiondissolved in pH 7 phosphate buffer (300 mL)
10. washThe buffered solution was washed with EtOAc (200 mL)
11. extractionthe organic layer was extracted with fresh pH 7 buffer (2×150 mL)
12. extractionextracted with CH2Cl2 (3×200 mL)
13. dry with materialthese extracts were dried (Na2SO4)
14. concentrationconcentrated under reduced pressure

ORD record

ord-963dc0cad1844504b2485dc3b8fb66ef

Source dataset

uspto-grants-2010_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07834031B2