反应详情

A mixture of (S)-2-{[2-(2-1H-Indazol-4-yl-acetylamino)-4-methyl-thiazole-5-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acid (50 mg, 0.0975 mmol), 4-morpholineethanol (1.06 mL, 8.751 mmol) and 1-propanephosphonic acid cyclic anhydride, 50 wt. % solution in ethyl acetate (0.4 mL, 0.672 mmol) in THF (2 mL) was heated at 600C for 25 h. The reaction mixture was cooled, diluted with 2/1 ethyl acetate/THF (100 mL), water (10 mL), brine (10 mL) and aqueous 1N KHSO4 (10 mL), mixed and separated the layers. The aqueous layer was extracted with 2/1 ethyl acetate/THF (2×50 mL). The organic layers were combined, washed with aqueous saturated sodium bicarbonate solution (30 mL), brine (30 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting crude compound was purified by flash chromatography (ethyl acetate to 10% methanol/ethyl acetate) followed by an ether trituration to give (S)-2-{[2-(2-1H-Indazol-4-yl-acetylamino)-4-methyl-thiazole-5-carbonyl]-amino}-3-[(thiophene-2-carbonyl)-amino]-propionic acid 2-morpholin-4-yl-ethyl ester (11.1 mg, 18.2%) as a white solid. MS m/e 626.7 (M+H+).

1. temperatureThe reaction mixture was cooled
2. additionmixed
3. customseparated the layers
4. extractionThe aqueous layer was extracted with 2/1 ethyl acetate/THF (2×50 mL)
5. washwashed with aqueous saturated sodium bicarbonate solution (30 mL), brine (30 mL)
6. dry with materialdried over MgSO4
7. filtrationfiltered
8. concentrationconcentrated under reduced pressure
9. customThe resulting crude compound was purified by flash chromatography (ethyl acetate to 10% methanol/ethyl acetate)