Methyl methoxyacetate → 3-Hydroxy-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic Acid Methyl Ester

Participants

Reaction Steps

To a solution of 3.17 ml methoxyacetic acid methyl ester (31.4 mmol) in 30 ml of THF, 3.5 ml of titanium tetrachloride (31.4 mmol) was added dropwise within 15 min at 0° C. After stirring the yellow solution for additional 15 min at the same temperature, 6.0 ml of N-ethyldiisopropylamine (34.1 mmol) were added within 5 min and the yellow/orange solution stirred for additional 15 min. A solution of 5.00 g of 4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-carbaldehyde (13.66 mmol) in 70 ml of dichloromethane was added dropwise within 20 min and the the reaction mixture was stirred for additional 60 min. The reaction solution was allowed to warm up to r.t. and stirred the same temperature for 90 min, cooled to 0° C. and treated with 50 ml of ice water. The organic layer was separated, washed with 25 ml water, dried over sodium sulfate and evaporated to dryness to yield 8.15 g of crude 3-Hydroxy-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid methyl ester ((syn/anti=6:4) as an orange oil. After this intermediate was dissolved at r.t. in 50 ml of DMF, 1.20 ml of conc. sulfuric acid (10.5 mmol) were added and the resulting dark brown solution was stirred at 100° C. for 17 h. The reaction solution was cooled to r.t., whereas the product crystallized. 50 ml of ethanol were added and the suspension stirred for 1 h at 0° C. The white crystals were filtered off, washed with 75 ml of cold (−15° C.) methanol in two portions and dried to constant weight (20° C./5 mbar/16 h) to afford 3.82 g (61%) of the title compound with a purity of 98.6% (GC area).

Provenance & Evidence