A method for synthesizing 3-(4-amino-1-isoindolinone-2-yl)piperidine-2,6-dione
A technology of isoindolinone and piperidine, applied in the fields of medicine and drug synthesis, can solve problems such as unfavorable labor protection for employees, unfavorable industrialized production, and difficulties in industrialized production, avoid the use of highly toxic reaction auxiliaries, and eliminate the need for post-treatment. Simple steps and methods
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Embodiment 1
[0072] 3-(4-Amino-1-isoindolin-2-yl)piperidine-2,6,-dione
[0073]
[0074] 1) Under nitrogen protection, add 14.8g of compound III, 50ml of N-methylpyrrolidone, 14g of potassium carbonate, and 20g of bromoglutaric anhydride into the reaction flask, and react overnight at 25°C under stirring. The solid was filtered off, and the reaction solution was concentrated under reduced pressure to obtain 25 g. Yield: 96%.
[0075] 2) Under the protection of nitrogen, add 13g of compound II and 4g of urea into the reaction bottle, and react at 180°C for 3 hours under stirring. Add 80ml of acetonitrile and 30ml of dimethyl sulfoxide to the system, stir at 70-80°C for 1 hour, cool down to room temperature, filter with suction, and dry the solid at 100°C to obtain 9g of off-white solid, yield: 69%.
Embodiment 2
[0077] 3-(4-Amino-1-isoindolin-2-yl)piperidine-2,6,-dione
[0078]
[0079] 1) Under nitrogen protection, add 14.8g of compound III, 50ml of N,N-dimethylformamide, 14g of potassium carbonate, 30g of 1-benzyl-3-bromopiperidine-2,6-dione into the reaction flask, React overnight at 80°C with stirring. Add 75ml of water and 150ml of dichloromethane, discard the aqueous phase, and extract the organic phase with 2mol / L hydrochloric acid. Add 150ml of dichloromethane to the aqueous hydrochloric acid solution, add sodium carbonate until the pH of the aqueous phase is 7, take the organic phase, dry it with anhydrous sodium sulfate, and concentrate the mother liquor to dryness under reduced pressure to obtain 30 g of compound VIII with a yield of 86%.
[0080] 2) Add 5g of compound VIII (where R is benzyl), 100mL of methanol and stir in the reaction flask, add 0.25g of 10% palladium carbon, the solution is gray and turbid, vacuumize, replace N2 three times, H2 three times, hydrogena...
Embodiment 3
[0082] 3-(4-Amino-1-isoindolin-2-yl)piperidine-2,6,-dione
[0083]
[0084] 1) Under nitrogen protection, add 14.8g of compound III, 50ml of N,N-dimethylformamide, 14g of potassium carbonate, and 35g of 1-benzyloxycarbonyl-3-bromopiperidine-2,6-dione into the reaction flask , react overnight at 80°C with stirring. Add 75ml of water and 150ml of dichloromethane, discard the aqueous phase, and extract the organic phase with 2mol / L hydrochloric acid. Add 150ml of dichloromethane to the aqueous hydrochloric acid solution, add sodium carbonate until the pH of the aqueous phase is 7, take the organic phase, dry it with anhydrous sodium sulfate, and concentrate the mother liquor to dryness under reduced pressure to obtain 30 g of compound VIII with a yield of 86%.
[0085] 2) Add 5.6g of compound VIII (where R is benzyloxycarbonyl), 100mL of methanol and stir in the reaction flask, add 0.25g of 10% palladium carbon, the solution is gray and turbid, vacuumize, replace N2 three tim...
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