Hydrochloric Acid → Edaglitazone

Participants

Reaction Conditions

Reaction Steps

A 1500-ml 4-necked flask was equipped with a mechanical stirrer, a thermometer, a dropping funnel and an argon inlet. To a solution of 11.71 g of 2,4-thiazolidinedione (0.100 mol) in 600 ml of tetrahydrofurane 100 ml of lithium diisopropylamide 2.0 M in THF/heptane/ethylbenzene (0.200 mol) were added dropwise within 30 min at a temperature between −2° and 0° C. The light brown suspension was stirred at −2° C. for 10 min and then a solution of 17.14 g of 4-[2-(7-Bromomethyl-benzo[b]thiophen-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole in 250 ml of tetrahydrofuran was added dropwise at −20° C. within 1 h 15 min. After stirring for 30 min, 160 ml of deionized water were added to the yellow suspension within 12 min at −20°-−4° C. The resulting yellow emulsion was stirred for 70 min at 2° C., transferred to a rotary evaporator with aid of a total of 75 ml of tetrahydrofurane and of a total of 75 ml of deionized water. The largest part of organic solvents was removed (45° C., 250 mbar) and the residue (237 g of turbid aqueous phase) was treated with 200 ml of t-butyl methylether. The resulting yellow thick suspension was stirred in an ice bath for 1 h, then 22 ml of hydrochloric acid 25% (170 mmol) were added dropwise and the resulting beige suspension was stirred for 15 min in an ice bath and filtered with suction. The filter cake was washed three times with 10 ml, a total of 30 ml of cold (2° C.) deionized water, three times with 10 ml, a total of 30 ml of t-butyl methylether and dried to constant weight (80° C., 0.15 mbar, 17 h), affording 15.97 g (85.9%) of 5-{4-[2-(5-Methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-ylmethyl}2,4-thiazolidinedione as off-white crystals with a m.p. of 195.5-197° C.

Provenance & Evidence