Triethylamine → 3-(5-Bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione

A mechanically stirred mixture of 4-bromo-2-bromomethyl-benzoic acid methyl ester (121 g, 390 mmol) and 3-amino-piperidine-2,6-dione hydrochloride (64.2 g, 390 mmol) in DMF (400 mL) was treated dropwise with triethylamine (98.5 g, 980 mmol) over 75 minutes. After the addition was completed, the reaction mixture was stirred at room temperature overnight. The mixture was quenched sequentially with acetic acid (50 mL), water (2500 mL) and a 1:1 mixture of ethyl acetate and hexanes (600 mL). After stirring the mixture for 20 minutes, the solid was filtered, washed with water and air dried overnight. The solid was stirred in acetic acid (200 mL) and refluxed for 2 hours. The mixture was cooled to room temperature and filtered. The solid was washed with additional acetic acid, hexanes and air dried overnight to give 25.4 g of 3-(5-bromo-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione as a grey solid, in 20% yield; 1H NMR (DMSO-d6) δ 1.97-2.04 (m, 1H), 2.32-2.46 (m, 1H), 2.56-2.63 (m, 1H), 2.85-2.97 (m, 1H), 4.34 (d, J=17.7 Hz, 1H), 4.47 (d, J=17.7 Hz, 1H), 5.11 (dd, J=13.2 Hz, J=5.1 Hz, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.72 (dd, J=8.1 Hz, J=1.5 Hz, 1H), 7.89 (d, J=0.9 Hz, 1H), 11.00 (s, 1H).

1. additionAfter the addition
2. customThe mixture was quenched sequentially with acetic acid (50 mL), water (2500 mL)
3. additiona 1:1 mixture of ethyl acetate and hexanes (600 mL)
4. stirringAfter stirring the mixture for 20 minutes
5. filtrationthe solid was filtered
6. washwashed with water and air
7. customdried overnight
8. stirringThe solid was stirred in acetic acid (200 mL)
9. temperaturerefluxed for 2 hours
10. temperatureThe mixture was cooled to room temperature
11. filtrationfiltered
12. washThe solid was washed with additional acetic acid, hexanes and air
13. customdried overnight

ORDレコード

ord-d380ecd032244e47ba9f40b9e619aca5

出典データセット

uspto-grants-2016_09

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US09447070B2