Potassium Carbonate → 1,1-Dimethylethyl N-[1-(6-chloro-2-pyrazinyl)-4-piperidinyl]carbamate

Participants

Reaction Conditions

Reaction Steps

A suspension of 2,6-dichloropyrazine (223.5 g, 1.5 mol, 1.0 eq), 4-N-boc-aminopiperidine (300 g, 1.5 mol, 1.0 eq) and K2CO3 (228 g, 1.65 mol, 1.1 eq) in DMF (900 mL) was heated to 85° C. for 20 h. LC-MS analysis showed that tert-butyl 1-(6-(trimethylstannyl)pyrazin-2-yl)piperidin-4-ylcarbamate was formed as the major product. The reaction mixture was cooled to RT and poured into ice-water (3 L). The resulting precipitate was collected by filtration, washed with water (1 L×2) and hexane (1 L×2), and dried at 50° C. under vacuum affording tert-butyl 1-(6-chloropyrazin-2-yl)piperidin-4-ylcarbamate (252 g, >98% purity) in 54% yield. MS (ESI, pos. ion) m/z: 393.0 (M+1). A suspension of tert-butyl 1-(6-chloropyrazin-2-yl)piperidin-4-ylcarbamate (245 g, 0.75 mol, 1.0 eq), hexamethylditin (492 g, 1.5 mol, 2.0 eq) and Pd(PPh3)4 (87 g, 0.075 mol, 0.1 eq) in anhydrous toluene (2 L) was degassed with N2 for 30 min and heated to 110° C. for 24 h. LC-MS analysis showed around 50% conversion and no more further reaction. The reaction mixture was cooled to RT, quenched with water (2 L), and stirred well. After filtration through a celite pad and phase separation, the aqueous layer was extracted with EtOAc (1 L×2). The combined organics were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography eluting with DCM/EtOAc (20/1), affording title compound 1d (150 g, >96% purity) in 45% yield. MS (ESI, pos. ion) m/z: 443.2 (M+1)

Provenance & Evidence