Hydrochloric Acid → Aleglitazar

Participants

Reaction Conditions

Reaction Steps

In a glove box (O2 content≦2 ppm), a 185-ml stainless steel autoclave was charged with 2.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (4.59 mmol), 2.70 mg of [Ir((Sa,R)-DBT-Bn-SIPHOX)(COD)]BF4 (0.0023 mmol, S/C 2,000), 24 ml of methanol, 16 ml of tetrahydrofuran and 0.12 ml of (S)-1-phenylethylamine (0.92 mmol). The autoclave was sealed and the hydrogenation was run under 30 bar of hydrogen at 60° C. for 20 h and subsequently at 80° C. for 2 h. Then the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford crude (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 89.9% (>99.9% conversion) and an enantiomeric purity of 99.8%. The crude product was dissolved in 50 ml of ethyl acetate. 10 ml of water and 3 ml of 2M aqueous HCl were added and the biphasic mixture was stirred at 55° C. for 15 min. The organic layer was separated, the aqueous layer extracted with 20 ml of ethyl acetate and the combined organic layers stirred over 0.5 g of carcoal (Darko KB) at r.t. for 2 h. After filtration over celite, the colorless solution was dried over 3 g of sodium sulfate and evaporated to dryness (40° C./10 mbar). The crude product was dissolved in 50 ml of isopropyl acetate at reflux (oil bath temp. 100° C.) and allowed to cool to room temperature whereby crystallization started spontaneously. The formed crystals were filtered off, washed with 10 ml of isopropyl acetate and dried at 75° C./500 mbar for 4 h to yield 1.60 g (79%) of pure (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white crystals with a chemical purity of 99.6% and an enantiomeric purity of 99.8% ee.

Provenance & Evidence