Acetic Acid → Ard-353

Participants

Reaction Steps

Glacial acetic acid (0.635 mL, 11.1 mmol) was added to a solution of 4-[(R)-((2S,5R)-2,5-dimethyl-1-piperazinyl)-(3-hydroxyphenyl)methyl]-N,N-diethylbenzamide (1.98 g, 5 mmol) and 4-carboxybenzaldehyde (1.50 g, 10 mmol) in anhydrous tetrahydrofuran (35 mL. While stirring briskly, sodium triacetoxyborohydride (2.12 g, 10 mmol) was added in 50-100 mg portions, allowing effervescence to subside after each addition. The reaction was monitored for absence of starting material by HPLC. After stirring at room temperature for 16 hours, more 4-carboxybenzaldehyde (0.75 g, 5 mmol), acetic acid (0.318 mL, 5 mmol), and sodium triacetoxyborohydride (1.06 g, 5 mmol) was added. After stirring an additional 4 hours, the reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (50 mL) and 3 M hydrochloric acid (10 mL). The layers were separated and the organic layer was extracted again with 3 M hydrochloric acid (5×10 mL). The aqueous solution was adjusted to pH 4.5-5 with saturated aqueous sodium carbonate solution and extracted with methylene chloride (3×50 mL). The combined organic extracts were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to yield 4-{(2R, 5S)-4-[(R)-(4-diethylcarbamoylphenyl)(3-hydroxyphenyl)methyl]-2,5-dimethyl-1-piperazinyl-methyl}benzoic acid as a brittle white foam (2.34 g). The product showed a single peak on HPLC (Zorbax RX-C8, 4.6 mm×25 cm, isocratic 40% 0.01 M NH4OAc in MeOH, 3 min; linear gradient to 100% MeOH, 45 min; isocratic MeOH, 5 min; 1.0 mL/min; λobs=210 nm, Rt=13.75 min).

Provenance & Evidence