1,2-Dichloroethane → Trifluoroacetic acid

Participants

Reaction Steps

To a solution of the title compound of Example 6 Step A (49.0 mg, 0.091 mmol) in 1,4-dioxane (0.5 mL) was added a solution of LiOH (22.0 mg, 0.91 mmol) in H2O (0.5 mL), and the resultant mixture was stirred at 45° C. for 4 h. The mixture was allowed to cool to room temperature whereupon it was quenched by the addition of 2 N aq. HCl. The aqueous phase was extracted with EtOAc, and the organic phase was dried over Na2SO4 and concentrated in vacuo. To the crude carboxylic acid obtained above were added EDC (52.0 mg, 0.27 mmol), HOBt (37.0 mg, 0.27 mmol), and 5-amino-1H-tetrazole (28.0 mg, 0.27 mmol). The resultant mixture was dissolved in DMF (1 mL), DIEA (0.158 mL, 0.91 mmol) was added, and the reaction mixture was stirred at 50° C. for 2 h. The reaction mixture was quenched by addition of sat. aq. NH4Cl, and the aqueous phase was extracted with EtOAc (2×). The combined organic phases were concentrated in vacuo. Purification by reverse phase HPLC (30 to 100% CH3CN in H2O, each with 0.1% v/v TFA) provided the title compound: LCMS A, tr=4.15 min, m/z 595.1 [M+H]+; 1H NMR (500 MHz, d6DMSO) δ 7.92 (d, J=8.0 Hz, 2H), 7.82 (d, J=2.0 Hz, 1H), 7.70 (m, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.55 (d, J=9.0 Hz, 2H), 7.36-7.34 (m, 3H), 6.98 (d, J=8.0 Hz, 2H), 5.90 (ABq, J=16.5 Hz, Δν=37.0 Hz), 3.93-3.89 (m, 1H), 2.98 (dd, J=14.0, 9.0 Hz, 1H), 2.81 (dd, J=14.0, 6.0 Hz, 1H), 1.56-1.51 (m, 1H), 1.44-1.37 (m, 1H), 1.09-1.01 (m, 2H), 0.71 (t, J=7.0 Hz, 3H).

Provenance & Evidence