Succinic anhydride → (R)-4-(1-(3'-chlorobiphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoic acid

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Reaction Steps

A solution of (R)-ethyl 3-amino-4-(3′-chlorobiphenyl-4-yl)butanoate hydrochloride (400 mg, 1.13 mmol), succinic anhydride (136 mg, 1.36 mmol) and DIPEA (0.237 mL, 1.36 mmol) in dichloromethane (5 mL) is allowed to stir for 2.5 hours. The reaction is quenched with 1 M aqueous HCl and extracted with dichloromethane. The organic layer is separated and concentrated under reduced pressure. The resulting residue is purified by preparative HPLC using a gradient of 20% MeCN/water (0.1% TFA) to 100% MeCN to give (R)-4-(1-(3′-chlorobiphenyl-4-yl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoic acid (255 mg). HPLC retention time=1.15 minutes (condition B); MS (m+1)=418.0; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (t, J=7.08 Hz, 3H) 2.46-2.58 (m, 4H) 2.64-2.67 (m, 2H) 2.87 (A of ABX, Jab=13.6 Hz, Jax=7.8 Hz, 1H) 2.99 (B of ABX, Jab=13.6 Hz, Jbx=6.6 Hz, 1H) 4.12-4.24 (m, 2H) 4.47-4.55 (m, 1H) 6.50 (br d, J=8.8 Hz, 1H) 7.24-7.37 (m, 4H) 7.43-7.46 (m, 1H) 7.48-7.52 (m, 2H) 7.55-7.56 (m, 1H). Chiral HPLC retention time=3.59 min. Column: Daicel CHIRALPAK AD-H (4.6×100 mm); flow rate=1 ml/min.; eluent: EtOH (containing 0.1% TFA)/heptane=4/6.

Provenance & Evidence