反应详情

A mixture of 2-(4-fluorophenyl)-4-[1-(thiazol-2-yl)-2-(1-methylimidazol-5-yl)ethoxymethyl]benzoic acid (0.44 g, 1.07 mmol) (from Example 65), DMAP (0.62 g, 5.03 mmol), L-methionine tert-butyl ester HCl (0.62 g, 5.03 mmol), EDC (0.39 g, 2.01 mmol) and HOBT (0.138 g, 1.01 mmol) in DMF (25 ml) was stirred at ambient temperature under a nitrogen atmosphere for 16 hours. The reaction was evaporated to dryness, the residue treated with aqueous citric acid (1M, 10 ml) and then extracted with dichloromethane (20 ml). The extracts were washed with saturated brine, dried and applied directly to a silica flash column eluting with dichloromethane/methanol (95:5, 9:1 and 85:15) to give a gum. This was dissolved in ethyl acetate and treated with ethereal 1M HCl (10 ml). The resulting solid was isolated by centrifuging, further washing with diethyl ether and drying under high vacuum to give tert-butyl (2S)-2-{2-(4-fluorophenyl)-4-[1-(thiazol-2-yl)-2-(1-methylimidazol-5-yl)ethoxymethyl]benzoylamino}-4-methylsulfanylbutyrate as a white solid, (0.373 g, 59%).

1. customThe reaction was evaporated to dryness
2. additionthe residue treated with aqueous citric acid (1M, 10 ml)
3. extractionextracted with dichloromethane (20 ml)
4. washThe extracts were washed with saturated brine
5. customdried
6. washeluting with dichloromethane/methanol (95:5, 9:1 and 85:15)
7. customto give a gum
8. customThe resulting solid was isolated by centrifuging
9. washfurther washing with diethyl ether
10. customdrying under high vacuum