反应详情

A mixture of 5-bromo-3-(methoxymethoxy)-1-(methoxymethyl)pyridin-2(1H)-one (Intermediate 15) (3.5 g, 12.6 mmol), Pd2(dba)3 (0.46 g, 0.50 mmol), Xantphos (0.58 g, 1.00 mmol) and DIPEA (4.40 ml, 25.2 mmol) in dioxane (60 ml) was degassed and then placed under an atmosphere of nitrogen. To this mixture was added methyl 3-mercaptopropanoate (1.66 g, 13.8 mmol) and the whole was heated under reflux for 3 hours. Upon cooling it was filtered through a pad of celite and ethyl acetate was washed through the pad of celite to recover any remaining compound. The organic filtrate was washed with water and then saturated aqueous sodium chloride solution and the organics were dried (MgSO4), filtered and concentrated under vacuum. The crude residue was purified by column chromatography (SiO2; 0-100% dichloromethane in petrol, then 0-10% methanol in dichloromethane). Product fractions were collected and concentrated in vacuo to give a yellow oil. This oil was purified further by reverse phase column chromatography (SiO2—C18; 5-95% methanol in water with 0.1% formic acid) to give methyl 3-{[5-(methoxymethoxy)-1-(methoxymethyl)-6-oxo-1,6-dihydropyridin-3-yl]sulfanyl}propanoate (3.4 g, 10.7 mmol, 85%).

1. customwas degassed
2. temperaturethe whole was heated
3. temperatureunder reflux for 3 hours
4. temperatureUpon cooling it
5. filtrationwas filtered through a pad of celite and ethyl acetate
6. washwas washed through the pad of celite
7. customto recover any remaining compound
8. washThe organic filtrate was washed with water
9. dry with materialsaturated aqueous sodium chloride solution and the organics were dried (MgSO4)
10. filtrationfiltered
11. concentrationconcentrated under vacuum
12. customThe crude residue was purified by column chromatography (SiO2
13. customProduct fractions were collected
14. concentrationconcentrated in vacuo
15. customto give a yellow oil
16. customThis oil was purified further by reverse phase column chromatography (SiO2—C18; 5-95% methanol in water with 0.1% formic acid)