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温度

0 °C

2,8-Dimethyl-1-oxa-3,8-diaza-spiro[4.5]decane (1.52 g, 8.95 mmol) was dissolved in dry dichloromethane (5 ml) under an argon atmosphere. Distilled triethylamine (1.87 ml, 13.42 mmol) was added and the resulting solution was cooled to 0° C. Valproyl chloride (1.46 g, 8.95 mmol) was added dropwise with a syringe. The reaction flask was allowed to warm to room temperature with stirring, and a white solid started to precipitate. After 4 h of stirring, dichloromethane (100 ml) was added and the resulting solution was washed with water (10 ml). The two phases were separated and the aqueous phase was extracted with dichloromethane (2×50 ml). The combined organic phase was dried with anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (silica, CH2Cl2/EtOH/NH4OH 130/10/1) to give AF712 (389 mg, 98.7% chemical purity) as a yellow powder. 1H NMR (CDCl3, 300 MHz) δ 5.43 (q, J=5.2 Hz, 1H, CHCH3), 4.13, 3.63 (2d, J=11.35 and J=9.6 Hz, 1H, CHHNCO), 3.22, 3.00 (2d, J=9.6 and J=11.35 Hz, 1H, CHHNCO), 2.56-2.38 (m, 5H), 2.30, 2.29 (2s, 3H, NCH3), 1.84-1.53 (3m, 6H), 1.44, 1.43 (2d, J=5.2 Hz, 3H, CH3CH), 1.4-1.19 (m, 6H), 0.90 (app t, J=7.11 Hz, 6H, CH3CH2) ppm; 13C NMR (CDCl3, 300 MHz) δ 173.92, 173.68 (C), 84.75, 84.20 (CH), 78.32, 78.09 (C), 54.24 (CH2), 52.34 (CH2), 52.02 (CH2), 46.03 (CH3), 44.34, 43.64 (CH), 35.63 (CH2), 35.05 (CH2), 34.92 (CH2), 32.83 (CH2), 23.52, 20.91 (CH3), 20.59 (CH2), 20.43 (CH2), 14.30 (CH3), 14.16 (CH3) ppm.

1. temperatureto warm to room temperature
2. customto precipitate
3. stirringAfter 4 h of stirring
4. additiondichloromethane (100 ml) was added
5. washthe resulting solution was washed with water (10 ml)
6. customThe two phases were separated
7. extractionthe aqueous phase was extracted with dichloromethane (2×50 ml)
8. dry with materialThe combined organic phase was dried with anhydrous sodium sulfate
9. filtrationfiltered
10. customevaporated under reduced pressure
11. customThe residue was purified by flash chromatography (silica, CH2Cl2/EtOH/NH4OH 130/10/1)
12. customto give AF712 (389 mg, 98.7% chemical purity) as a yellow powder