反应详情

To a solution of (4-fluoro-phenyl)-acetic acid (22.33 g, 144.9 mmol) in 100 mL of methyl tert-butyl ether and 250 μL of DMF was added 13.02 mL (146.3 mmol) of oxalyl chloride at room temperature dropwise over 30 minutes. The resulting mixture was stirred at room temperature for an additional 20 minutes (HPLC indicated completed reaction), and then the entire solution was added dropwise over 1 hour to a solution of N,N-diisopropylethylamine (50.48 mL, 289.8 mmol) and ethyl 2-(triphenylphosphoranylidene)propionate (50.0 g, 138.0 mmol) in 100 mL of methyl tert-butyl ether, while maintaining the internal temperature between 0-15° C. After the addition was complete, the reaction mixture was stirred for an additional 10 minutes at 0-10° C., when HPLC indicated a completed reaction. The reaction mixture was then diluted with 100 mL of heptane, and stirred for 30 minutes at 0-10° C. The resulting solid was filtered and washed with 2×100 mL of 1:1 methyl tert-butyl ether:heptane. The filtrate and the washings were combined and washed with 100 mL of water, 100 mL of 1M citric acid, 2×100 mL of water, then concentrated azeotropically at 25° C./60 mmHg to a total volume of ˜40 mL. The residue was diluted with 60 mL of methyl tert-butyl ether. This solution was then directly used for the next step.

1. custom(HPLC indicated completed reaction)
2. temperaturewhile maintaining the internal temperature between 0-15° C
3. additionAfter the addition
4. stirringthe reaction mixture was stirred for an additional 10 minutes at 0-10° C.
5. customa completed reaction
6. stirringstirred for 30 minutes at 0-10° C
7. filtrationThe resulting solid was filtered
8. washwashed with 2×100 mL of 1:1 methyl tert-butyl ether
9. washwashed with 100 mL of water, 100 mL of 1M citric acid, 2×100 mL of water
10. concentrationconcentrated azeotropically at 25° C./60 mmHg to a total volume of ˜40 mL
11. additionThe residue was diluted with 60 mL of methyl tert-butyl ether