Lithium Hydroxide → ((1S)-5-{3-[[5-(4-ethylphenyl)-2-pyrimidinyl](methyl)amino]propoxy}-2,3-dihydro-1h-inden-1-yl)acetic acid

Participants

Reaction Conditions

Reaction Steps

To a round-bottom flask charged with ethyl ((1S)-5-{3-[(5-bromo-2-pyrimidinyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 282, 100 mg, 0.220 mmol), 4-ethylphenyl boronic acid (134 mg, 0.090 mmol) and PdCl2(dppf).CH2Cl2 (16.4 mg, 0.020 mmol) were added toluene (6 mL) and 1,4-dioxane (1.12 mL). A flow of argon was passed through the mixture for 30 min. Then a 2 N aqueous solution of Na2CO3 (1.12 mL, 2.24 mmol, 2 N aqueous solution) was added, and the reaction was heated to 75° C. for 18 h. The reaction mixture was cooled to rt. Filtration through a short plug of silica gel gave the crude ester, which was dissolved in a mixture of THF (3 mL), water (3 mL), and EtOH (1.5 mL). Subsequently, LiOH (57 mg, 2.39 mmol) was added, and the reaction was stirred at rt for 18 h. The reaction mixture was concentrated under reduced pressure, and then purified by preparative HPLC. The desired fractions were concentrated under reduced pressure. The residue was dissolved in CH2Cl2, and treated for 15 min with Dowex® 66 weakly basic resin. The mixture was then filtered and the filtrate concentrated under reduced pressure to give the product (65 mg, 61%). 1H NMR (400 MHz, CDCl3) δ 1.29 (t, 3H), 1.73-1.84 (m, 1H), 2.16 (qt, 2H), 2.33-2.51 (m, 2H), 2.70 (q, 2H), 2.77-2.96 (m, 3H), 3.24 (s, 3H), 3.49-3.56 (m, 1H), 3.87 (t, 2H), 4.03 (t, 2H), 6.72 (dd, 1H), 6.78 (d, 1H), 7.08 (d, 1H), 7.27 (d, 2H), 7.39 (d, 2H), 8.24 (s, 2H); LC-MS: RT=3.39 min, (M+H)+ 446.3.

Provenance & Evidence