Bromoacetate → Ethyl 3-amino-4-(3'-chloro-3-fluorobiphenyl-4-yl)butanoate

Beteiligte Stoffe

Reaktionsbedingungen

Reaktionsschritte

A suspension of zinc (479 mg, 7.33 mmol) and 1,2-dibromoethane (0.032 ml, 0.366 mmol) in THF (8 ml) is heated at 70° C. under nitrogen then a few drops of ethyl bromoacetate is added. After stirring for 20 min, a solution of 2-(3′-chloro-3-fluorobiphenyl-4-yl)acetonitrile (300 mg, 1.221 mmol) in THF (2 ml) is added in one portion. The remaining bromoacetate is added dropwise over 50 min (total amount of ethyl bromoacetate: 4.88 mmol). After stirring for 15 min at the same temperature, the reaction mixture is cooled to ambient temperature. To the reaction mixture, sodium triacetoxyborohydride (2588 mg, 12.22 mmol) and AcOH (8 ml) are added. The reaction mixture is allowed to stir for 13 hours, and concentrated to give crude. The crude is diluted with EtOAc, and 2M aqueous Na2CO3 is added to be pH of 10. The products are extracted with EtOAc. The organic layer is dried over K2CO3, filtered, and concentrated to give crude. The resulting residue is purified by preparative HPLC using a gradient of 20% MeCN/water (0.1% NH4OH) to 100% MeCN to give ethyl 3-amino-4-(3′-chloro-3-fluorobiphenyl-4-yl)butanoate (148 mg) as orange oil; HPLC retention time=0.85 minutes (condition B); MS (m+1)=336.13; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.27 (t, J=7.1 Hz, 3H) 2.36 (A of ABX, Jab=15.9 Hz, Jax=8.8 Hz, 1H) 2.52 (B of ABX, Jab=15.9 Hz, Jbx=4.0 Hz, 1H) 2.71-2.76 (m, 1H) 2.82-2.87 (m, 1H) 3.51-3.57 (m, 1H) 4.15 (d, J=7.1 Hz, 2H) 7.24-7.39 (m, 5H) 7.42-7.44 (m, 1H) 7.54-7.55 (m, 1H).

Herkunft & Nachweise