1,3-Dibromo-5,5-dimethylhydantoin → Methyl 2-(bromomethyl)-6-nitrobenzoate

Temperature

75 °C

A mixture of 2-methyl-6-nitro-benzoic acid methyl ester (99 g, 508 mmol), 1,3-dibromo-5,5-dimethylhydantoin (DBH) (80 g, 279 mmol), in methyl acetate (600 mL) was heated at 78° C. for 40 minutes, while stirred with a mechanical stirrer. Then a solution of 2,2′-azobisisobutyro-nitrile (AlBN) (4.2 g, 25 mmol) in methyl acetate (80 mL) was added and heated at 75° C. for 11 hours. The mixture was allowed to cool to 15° C. and stirred for 2 hours to age the precipitate. The suspension was filtered, washed with 10° C. methyl acetate (2×50 mL) to give a brown filtrate. To the filtrate, was added heptane (500 mL). The solution was washed with 2% brine (2×500 mL) and water (2×500 mL). The organic layer was concentrated to about 2 volumes, added t-butyl methyl ether (300 mL), heated at 70° C. for 15 minutes, cooled the solution to 53° C. over one hour, seeded with the product (about 250 mg) at 45° C., then at 20˜25° C., while blowing nitrogen with a glass pipette overnight. The resulting suspension was filtered via a medium pore-sized funnel, washed with a pre-cooled 10° C. mixed solvent of heptane/MTBE (1/2 vol/vol) and suction dried in hood overnight to give 2-bromomethyl-6-nitro-benzoic acid methyl ester as an off-white solid (49 g, 35% yield). The solid was used in the next step without further purification.

1. temperatureto cool to 15° C.
2. stirringstirred for 2 hours to age the precipitate
3. filtrationThe suspension was filtered
4. washwashed with 10° C. methyl acetate (2×50 mL)
5. customto give a brown filtrate
6. washThe solution was washed with 2% brine (2×500 mL) and water (2×500 mL)
7. concentrationThe organic layer was concentrated to about 2 volumes
8. additionadded t-butyl methyl ether (300 mL)
9. temperatureheated at 70° C. for 15 minutes
10. temperaturecooled the solution to 53° C. over one hour
11. customseeded with the product (about 250 mg) at 45° C.
12. customat 20˜25° C.
13. customwith a glass pipette overnight
14. filtrationThe resulting suspension was filtered via a medium pore-sized funnel
15. washwashed with a pre-cooled 10° C.
16. additionmixed solvent of heptane/MTBE (1/2 vol/vol) and suction
17. customdried in hood overnight

ORD record

ord-a7b39e28eb2e4b699a25265e6a27b6ff

Source dataset

uspto-grants-2014_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08921385B2