Hydrochloric Acid → Pioglitazone hydrochloride, (R)-

Participants

Reaction Steps

˜1.25 M HCl in MeOH (0.33 mL, 0.33 mmol) was added to a suspension of (5R)-5-{4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl}-1,3-thiazolidine-2,4-dione (from Example 1) (30 mg, 0.084 mmol) in MeOH (5 mL) and stirred at RT for 1 h. The solvent was removed in vacuo to afford the title compound (32.4 mg, 100%). LCMS (Method 4): Rt 5.95 min, m/z 357 [M-HCl+]. e.e (Method 3) 93.2%, Rt 12.10 min. Stereochemistry at C-5 was assigned (R) configuration by single crystal X-ray diffraction analysis. [α]D24+108° (c 1.0, MeOH). 1H NMR (400 MHz, DMSO-d6): δ 12.03-11.88 (1 H, bs), 8.68-8.62 (1 H, d, J 1.7), 8.34-8.25 (1 H, d, J 7.9), 7.91-7.83 (1 H, d, J 8.3), 7.14-7.05 (2 H, d, J 8.7), 6.86-6.77 (2 H, d, J 8.7), 4.85-4.77 (1 H, dd, J 4.3, 8.9), 4.38-4.28 (2 H, t, J 6.0), 3.42-3.36 (2 H, t, J 6.2), 3.28-3.20 (1 H, dd, J 9.0, 14.2), 3.06-2.96 (1 H, dd, J 9.0, 14.2), 2.77-2.67 (2 H, q, J 7.7), 1.23-1.15 (3H, t, J 7.7). Subsequent recrystallisations using MeOH-EtOAc or MeOH-Et2O gave the title compound with an e.e. >97%.

Provenance & Evidence