Diethyl (cyanomethyl)phosphonate → HCID 24812116, compound

Participants

Reaction Steps

1-(6-Chloro-pyrazin-2-yl)-4-methyl-[1,4] diazepane (360 mg, 1.59 mmol), (intermediate C prepared in example 3), 3-formylphenylboronic acid (235 mg, 1.58 mmol) and bistriphenylphosphinepalladium(II)chloride (21 mg, 0.03 mmol) were dispersed in 10 mL DMF in a reaction tube. Subsequently 1.5 mL of 2M Na2CO3 was added. The tube was sealed and the reaction mixture was heated at 90° C. for 3 hours. The reaction mixture was then filtered through a plug of celite, diluted with ethyl acetate and water (25 mL), and the organic phase was separated. The aqueous phase was extracted with 2×10 mL ethyl acetate. The organic extracts were combined, washed with brine, dried and concentrated. The residue was purified by flash chromatography. Intermediate L (337 mg, 72%; MS analysis electrospray, 297, M+H) was isolated by concentration of the solvents and used directly. Sodium hexamethyldisilazane (0.22 mL, 1M in THF, 0.22 mmol) was added to a solution of cyanomethyl-phosphonic acid diethyl ester (0.034 mL, 0.21 mmol) in 1 mL THF under an atmosphere of N2. The mixture was stirred for 2 h after which time a solution of 3-[6-(4-methyl-[1,4] diazepan-1-yl)-pyrazin-2-yl]-benzaldehyde in 2 mL THF was added. After 15 min. the solvents were evaporated and the residue was diluted with 5 mL water and extracted with ethyl acetate (2×5 mL). The organic extracts were combined, washed with brine, dried and concentrated. The residue was purified by flash chromatography to provide the title compound (40 mg, 62%); MS analysis electrospray, 320 (M+H).

Provenance & Evidence