Toluene → [(1S)-5-({1-[2-(4-ethylphenyl)-5-methyl-4-pyrimidinyl]-4-piperidinyl}methyl)-2,3-dihydro-1H-inden-1-yl]acetic acid

Participants

Reaction Conditions

Reaction Steps

To a mixture of toluene (5.8 mL) and 1,4-dioxane (1.16 mL) were added ethyl ((1S)-5-{[1-(2-chloro-5-methyl-4-pyrimidinyl)-4-piperidinyl]oxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 459, 100 mg, 0.23 mmol), 4-ethylphenyl boronic acid (139.5 mg, 0.93 mmol), and PdCl2(dppf).CH2Cl2 (17 mg, 0.02 mmol). A flow of argon was passed through the mixture for 30 min, then Na2CO3 (1.16 mL, 2.33 mmol, 2 M aqueous solution) was added, and the reaction was stirred at 75° C. for 4 h. The reaction mixture was cooled to rt and filtered through a plug of silica gel. Then the desired fractions were concentrated under reduced pressure. The crude ester was dissolved in a mixture of THF (3 mL), water (3 mL), and EtOH (1.5 mL) was added LiOH (55.8 mg, 2.33 mmol). The reaction mixture was vigorously stirred for 24 h and then concentrated under reduced pressure. The residue was purified by preparative HPLC and the fractions containing the desired product were concentrated under reduced pressure. The residue was dissolved in CH2Cl2, treated with to Dowex 66® resin, filtered, and then concentrated under reduced pressure to give the product (50 mg, 43%). 1H NMR (400 MHz, CDCl3) δ 1.27 (t, 3H), 1.73-1.78 (m, 1H), 1.90-1.96 (m, 2H), 2.18-2.22 (m, 2H), 2.40 (s, 3H), 2.35-2.44 (m, 2H), 2.69-2.91 (m, 4H), 3.46-3.49 (m, 1H), 3.67-3.72 (m, 2H), 4.00-4.06 (m, 2H), 4.70-4.72 (m, 1H), 6.81 (d, 1H), 6.90 (d, 1H), 7.16 (s, 1H), 7.34 (d, 2H), 8.29 (s, 1H), 8.35 (d, 2H); LC-MS: RT=2.66 min, (M+H)+ 472.4.

Provenance & Evidence