反应详情

A solution of 0.66 g (3.0 mmol) of (S)-1-chloro-3-methyl-4-pivaloyloxybutan-2-one in 4 mL of THF was cooled to 0° C., and 3.9 mL (3.3 mmol) of a 0.86 M solution of 2,5-difluorophenylmagnesium bromide prepared by the same method as that in Example 3 was added dropwise thereto over a period of 5 minutes. After the completion of the dropwise addition, stirring was continued for another 1 hour, 10 mL of a saturated aqueous solution of ammonium chloride was added to stop the reaction. Furthermore, 10 mL of water was added, and extraction was performed with ethyl acetate (20 mL×2). After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure to obtain a crude product. The resulting product was purified by column on silica gel to obtain 0.50 g of 1-chloro-2-(2,5-difluorophenyl)-3-methyl-4-pivaloyloxybutan-2-ol as a diastereomeric mixture (yield: 50%) ((2S,3S):(2R,3S)=72:28) (HPLC, column: YMC-A302 manufactured by YMC Co. Ltd., mobile phase: acetonitrile/20 mM (potassium) phosphate buffer solution (pH=2.5)=6/4, flow rate: 1.0 mL/min, column temperature: 30° C., detector: UV 210 nm, retention time: 18 minutes (2S,3S), 20 minutes (2R,3S)). The resulting compound was dissolved in 10 mL of THF, and 1.02 g (5.25 mmol) of a 28% solution of NaOMe in methanol was added thereto under ice cooling. The reaction was performed for 5 hours. A reaction product was extracted with ethyl acetate (10 mL×2). After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure to obtain a crude product. The resulting product was purified by column on silica gel to obtain 0.28 g of the title compound (yield: 88%) (HPLC, column: YMC-A302 manufactured by YMC Co. Ltd., mobile phase: acetonitrile/20 mM (potassium) phosphate buffer solution (pH=2.5)=3/7, flow rate: 1.0 mL/min, column temperature: 30° C., detector: UV 210 nm, retention time: 17 minutes (2R,3S), 18 minutes (2S,3S)). 1H-NMR (400 MHz, CDCl3) (2R,3S) δ: 0.97 (d, 3H, J=6.6 Hz), 2.25 (q, 1H, J=6.6 Hz), 2.88 (d, 1H, J=4.4 Hz), 3.21 (d, 1H, J=4.4 Hz), 3.51 (d, 2H, J=6.1 Hz), 6.99-7.01 (m, 2H), 7.13-7.17 (m, 1H); (2S,3S) δ: 1.27 (d, 3H, J=6.6 Hz), 2.14 (q, 1H, J=6.6 Hz), 2.83 (d, 2H, J=4.4 Hz), 3.17 (d, 1H, J=4.4 Hz), 3.60 (d, 2H, J=5.9 Hz), 6.99-7.01 (m, 2H), 7.13-7.17 (m, 1H).

1. additionwas added dropwise
2. additionAfter the completion of the dropwise addition
3. waitwas continued for another 1 hour
4. customthe reaction
5. extractionextraction
6. dry with materialAfter drying over anhydrous sodium sulfate, concentration
7. customto obtain a crude product
8. customThe resulting product was purified by column on silica gel