Hydrochloric Acid → (S)-2-ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid

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Reaction Steps

In a glove box (O2 content≦2 ppm), a 185 ml stainless steel autoclave was charged with 11.5 g of (Z)-2-ethoxy-3-{4-[2-(2-fluoro-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-acrylic acid (28.0 mmol), 35 ml of dichloromethane, 35 ml of methanol, 2.5 ml of a 30% aqueous NaOH solution (14.0 mmol) and 22.6 mg (0.028 mmol) of [Ru(OAc)2((+)-TMBTP)]. TMBTP is 4,4′-Bis(diphenylphosphino)-2,2′,5,5′-tetramethyl-3,3′-dithiophene, its synthesis as (R) or (S) enantiomer is described in WO 96/01831 appl to Italfarmaco Sud and in T. Benincori et al, J. Org. Chem. 2000, 65, 2043. The complex [Ru(OAc)2((+)-TMBTP)] has been synthesized in analogy to a general procedure reported in N. Feiken et al, Organometallics 1997, 16, 537, 31P-NMR (CDCl3): 61.4 ppm (s). The autoclave was sealed and the hydrogenation was run under stirring at 40° C. under 60 bar of hydrogen. After 16 h the autoclave was opened and the yellow-brown solution was rotary evaporated to dryness (50° C./5 mbar). The residue was dissolved in 60 ml of ethyl acetate, 60 ml of water and 3 ml of aqueous hydrochloric acid (25%). The organic layer was separated and evaporated to dryness (50° C./5 mbar) to afford 12 g of crude product as a solid with an enantiomeric purity of 92% and a chemical purity of >99% according to HPLC. The crude product was dissolved in dichloromethane, (S)-phenylethylamine (4.12 ml, 31.1 mmol) was added and the solvent removed under reduced pressure. The brown residue was crystallized from ethyl acetate to obtain colorless crystals which were suspended in ice water/ethyl acetate 1/1. The pH of the suspension was adjusted to 1 with 1 M aqueous hydrochloric acid, the layers were separated and the aqueous layer extracted two more times with ethyl acetate. The combined extracts were washed with ice water/brine 1/1, dried over sodium sulfate and the solvent removed in vacuo to obtain colorless crystals which were recrystallized from ethyl acetate to afford 8.45 g (20.4 mmol, 73%) of the title compound as colorless crystals. According to chiral HPLC (Chiralcel-ODH column, 25 cm×4.6 mm, 97% heptane/3% iso-propanol with 0.15% trifluoroacetic acid, flow at 0.7 ml/min, 25° C., 274 nm. Retention times: R-acid 30.2 min, S-acid 32.8 min, α,β-unsaturated Z-acid 39.1 min), the enantiomeric excess amounts to 100%.

Provenance & Evidence