反应详情

3-[4-(Azetidin-1-ylcarbonyl)-2-chlorophenoxy]-5-[(1R)-2-hydroxy-1-methylethoxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (0.23 g, 0.48 mmol (60% pure)) and triethylamine (0.2 mL, 1.44 mmol) were dissolved in ethanol (8 mL) and the flask evacuated and purged with argon (3 times). 10% Palladium on carbon (23 mg) was added and the flask further evacuated and finally purged with hydrogen gas. The reaction mixture was stirred at ambient temperature for 6 days until completion. The reaction mixture was evacuated and purged with nitrogen (3 times). The catalyst was filtered off through celite and the filtrate concentrated in vacuo to a residue which was chromatographed on silica, eluting with a gradient of 0-10% methanol in ethyl acetate. An impurity remained at a level of 40%. This mixture (0.27 g, 0.6 mmol) was dissolved in DMF (5 mL) and imidazole (0.29 g, 4.2 mmol) and tert-butyldimethylsilylchloride (180 mg, 1.2 mmol) were added. After stirring at RT for 20 hours water (30 mL) was added and the mixture extracted into diethyl ether (2×50 mL). The combined extracts were washed with brine (50 mL) dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with a gradient of 0-10% methanol in ethyl acetate, and then chromatographed by preparative HPLC on C18 reversed phase using 5-95% acetonitrile (+0.2% TFA) in water (+0.2% TFA) as eluant. The chromatography fractions were allowed to stand overnight and the acetonitrile removed in vacuo. The aqueous residue was basified with saturated aqueous sodium bicarbonate solution and extracted into ethyl acetate (2×50 mL) and the combined extracts reduced in vacuo to give the desired compound. (28 mg)

1. customthe flask evacuated
2. custompurged with argon (3 times)
3. addition10% Palladium on carbon (23 mg) was added
4. customthe flask further evacuated
5. customfinally purged with hydrogen gas
6. customThe reaction mixture was evacuated
7. custompurged with nitrogen (3 times)
8. filtrationThe catalyst was filtered off through celite
9. concentrationthe filtrate concentrated in vacuo to a residue which
10. customwas chromatographed on silica
11. washeluting with a gradient of 0-10% methanol in ethyl acetate
12. additionwas added
13. extractionthe mixture extracted into diethyl ether (2×50 mL)
14. washThe combined extracts were washed with brine (50 mL)
15. dry with materialdried (MgSO4)
16. customevaporated to a residue which
17. customwas chromatographed on silica
18. washeluting with a gradient of 0-10% methanol in ethyl acetate
19. customchromatographed by preparative HPLC on C18 reversed phase
20. waitto stand overnight
21. customthe acetonitrile removed in vacuo
22. extractionextracted into ethyl acetate (2×50 mL)