Lithium Hydroxide → [(1S)-5-(2-{6-[methyl(phenyl)amino]-2-pyridinyl}ethoxy)-2,3-dihydro-1H-inden-1-yl]acetic acid

Participants

Reaction Conditions

Reaction Steps

An oven-dried flask charged with ethyl{(1S)-5-[2-6-chloro-2-pyridinyl)ethoxy]-2,3-dihydro-1H-inden-1-yl}acetate (Example 471, 100 mg, 0.277 mmol), Pd(OAc)2 (1.3 mg, 0.01 mmol), 2-di-t-butylphosphino)biphenyl (3.3 mg, 0.02 mmol), and sodium tert-butoxide (37.4 mg, 0.39 mmol) was purged with argon. Toluene (1 mL) and N-methyl aniline (59.6 mg, 0.56 mmol) were added, and the mixture was stirred at 100° C. for 18 h. The reaction mixture was then cooled to rt, loaded on an ion-exchange resin column (SCX sorbent, Varian, strong cation exchange), and eluted with MeOH followed with NH3 (1N solution in MeOH). The fractions containing the desired product were combined and then concentrated under reduced pressure. The crude ester was then dissolved in a mixture of THF (2 mL), H2O (2 mL), and EtOH (1 mL), to which LiOH (26.8 mg, 1.12 mmol) was added. The reaction mixture was stirred at rt for 18 h, concentrated under reduced pressure, and then purified by preparative HPLC. The fractions containing the desired fractions were concentrated under reduced pressure, and then dissolved in a mixture of CH2Cl2 and a saturated aqueous solution of NaHCO3. The aqueous phase was brought to pH 4 using HCl (1N aqueous solution), the organic layer separated, dried, and then concentrated to give the product (51.4 mg, 46%). 1H NMR (400 MHz, CDCl3) δ 1.70-1.75 (m, 1H), 2.34-2.43 (m, 2H), 2.70-2.87 (m, 3H), 3.43-3.50 (m, 3H), 3.71 (s, 3H), 4.32 (t, 2H), 6.41 (d, 1H), 6.66 (d, 1H) 6.75 (s, 1H), 6.79 (d, 1H), 7.03 (d, 1H), 7.25 (d, 1H), 7.27 (d, 1H), 7.43 (t, 1H), 7.49-7.53 (m, 3H); LC-MS: RT=2.32 min, (M+H)+ 403.3.

Provenance & Evidence