(3Z)-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylidene]-2,3-dihydro-1H-indol-2-one → Rac-(z)-1,3-dihydro-5-fluoro-4-[(3-hydroxy-pyrrolidin-3-yl)ethynyl]-3-[(3-methoxy-1h-pyrrol-2-yl)methylene]-2h-indol-2-one hydrochloride salt

温度

0 °C

Using Method C above, rac-N-boc-3-hydroxy-3-ethynyl-pyrrolidine (70.7 mg, 0.33 mmol) (see Example 97B) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (0.10 g, 0.26 mmol) (Starting Material 6) using (Ph3P)4Pd (31 mg) and Cul (6.0 mg) as catalyst in DMF (5 mL) and Et3N (5 mL) as solvent at 85° C. for 1 day. To the resulting compound in CH2Cl2 (5 mL) was added a 1:1 mixture of trifluoroacetic acid/CH2Cl2 (5 mL) and 2 drops of water at 0° C. and the mixture was stirred at 0° C. for 1.5 h. The mixture was then quenched with conc. NH4OH (5 mL) and diluted with EtOAc. The organic layer was washed with brine and dried with MgSO4. The product was purified via flash column chromatography (10% MeOH in CH2Cl2). To free base in methanol (3 mL) was added 4N HCl in dioxane (0.03 mL).

1. customThe mixture was then quenched with conc. NH4OH (5 mL)
2. additiondiluted with EtOAc
3. washThe organic layer was washed with brine
4. dry with materialdried with MgSO4
5. customThe product was purified via flash column chromatography (10% MeOH in CH2Cl2)
6. additionTo free base in methanol (3 mL) was added 4N HCl in dioxane (0.03 mL)

ORD记录

ord-2265931a87504e91ac67ad6b9e8db5c1

来源数据集

uspto-grants-2001_06

DOI

10.6084/m9.figshare.5104873.v1

专利号

US06252086B1