Hydrochloric Acid → Methyl 4-(2-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)phenyl)acetyl)-5-methyl-1H-pyrrole-3-carboxylate

Participants

Reaction Conditions

Reaction Steps

A solution of methyl 5-methyl-1H-pyrrole-3-carboxylate (61) (0.104 g, 0.74 mmol) in anhydrous DCM (5 mL) was added dropwise to a stirred suspension of aluminum trichloride (0.226 g, 1.69 mmol) in anhydrous DCM (10 mL) at 0° C., under nitrogen. The resulting suspension was stirred at 0° C. for 10 minutes. A solution of the requisite acid chloride [prepared earlier; 1-chloro-N,N,2-trimethylprop-1-en-1-amine (0.090 mL, 0.68 mmol) was added to a solution of 2-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)phenyl)acetic acid (0.200 g, 0.68 mmol) in anhydrous DCM (5 mL) at 0° C. and stirred for 2 hours] was added dropwise to the stirred suspension at 0° C. The resulting suspension was allowed to warm to room temperature and then stirred at room temperature for a further 18 hours. The reaction was incomplete and further aluminum trichloride (0.226 g, 1.69 mmol) was added and the solution was stirred at room temperature for a further 1 hour. The reaction mixture was poured onto ice (50 mL) and conc HCl (2 mL). The layers were separated and the aqueous layer extracted with DCM (2×50 mL). The combined organics were washed sequentially with 2M HCl (2×75 mL), water (50 mL), and saturated NaHCO3 (50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% ethyl acetate in isohexane. Pure fractions were evaporated to dryness to afford the desired material as a colourless gum (0.117 g, 41.5% yield); 1H NMR (400.132 MHz, CDCl3) δ 1.44-1.77 (3H, m), 1.85 (1H, m), 2.10 (3H, s), 3.08 (1H, m), 3.29 (3H, s), 3.36-3.55 (3H, m), 3.75 (3H, s), 3.92 (1H, m), 4.16 (2H, m), 6.93 (1H, t), 7.07-7.12 (2H, m), 7.21 (1H, m), 8.82 (1H, s); m/z (LC-MS, ESI+), RT=1.72 min (M+H=417.20).

Provenance & Evidence