Hydrochloric Acid → ((1S)-5-{3-[[2-(4-ethylphenyl)-5-methyl-4-pyrimidinyl](propyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetic acid

Participants

Reaction Conditions

Reaction Steps

To a mixture of toluene (2.8 mL) and 1,4-dioxane (0.56 mL) were added ethyl ((1S)-5-{3-[(2-chloro-5-methyl-4-pyrimidinyl)(propyl)amino]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 409, 50 mg, 0.11 mmol), 4-ethylphenyl boronic acid (67.3 mg, 0.45 mmol), and PdCl2(dppf).CH2Cl2 (8.2 mg, 0.01 mmol). A flow of argon was passed through the reaction mixture for 30 min, then Na2CO3 (0.56 mL, 1.12 mmol, 2 M aqueous solution) was added, and the reaction was stirred at 75° C. for 18 h. The reaction mixture was cooled to rt, and then concentrated under reduced pressure. The residue was partly purified by preparative HPLC. The resulting crude ester was dissolved in a mixture of THF (2 mL), water (2 mL), and EtOH (1.0 mL), and then LiOH (24.2 mg, 1.01 mmol) was added. The reaction mixture was vigorously stirred for 18 h, acidified to pH ˜5 using HCl (1N aqueous solution), and the aqueous phase was extracted with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered, and concentrated under reduced pressure to give the product (11.5 mg, 21%). 1H NMR (400 MHz, CDCl3) δ 0.93 (t, 3H), 1.27 (t, 3H), 1.69 (q, 2H), 1.76-1.81 (m, 1H), 2.13-2.16 (m, 2H) 2.30 (s, 3H), 2.40-2.51 (m, 2H), 2.68-2.85 (m, 5H), 3.47-3.55 (m, 3H), 3.80 (t, 2H), 3.98 (t, 2H), 6.66 (d, 1H), 6.71 (s, 1H), 7.07 (d, 1H), 7.267 (d, 2H), 8.05 (s, 1H), 8.22 (d, 2H); LC-MS: RT=3.38 min, (M+H)+ 488.4.

Provenance & Evidence